Tesi Dottorato
ALMA MATER STUDIORUM
UNIVERSITÀ DI BOLOGNA
DOTTORATO DI RICERCA IN SCIENZE CHIMICHE (XIX° ciclo)
Area 03 Scienze Chimiche-CHIM/06 Chimica Organica
Dipartimento di Chimica Organica “A. Mangini”
Coordinatore: Chiar.mo Prof. Vincenzo Balzani
Advanced Studies on the Synthesis
of Organophosphorus Compounds
Dissertazione Finale
Presentata da:
Dott. ssa Marzia Mazzacurati
Relatore:
Prof. Graziano Baccolini
Co-relatore:
Dott.ssa Carla Boga
INDEX
Index:
Keywords…………………………………………………………….………….VII
Chapter 1…………………………………………………………………………..3
GENERAL INTRODUCTION ON PHOSPHORUS CHEMISTRY
1.1 Organophosphorus Chemistry………………………………………………….4
1.1.1 Phosphines………………………………………………………………..5
1.1.2 Phosphonates……………………………………………………………..6
1.1.3 Phosphites………………………………………………………………...7
1.2 Uses of Organophosphorus Compounds………………………………………..7
1.2.1 Agricultural Application………………………………………………….8
1.2.2 Catalysis……………………………………………………………..…....9
1.2.3 Organophosphorus Conpounds in Medicine…………………………….11
1.2.4 Phosphorus in Biological Compounds…………………………………..12
1.3 References……………………………………………………………………..15
Chapter 2…………………………………………………………………………17
THE HYPERCOORDINATE STATES OF PHOSPHORUS
2.1 The 5-Coordinate State of Phosphorus……………………………………….17
2.2 Pentacoordinated structures and their non rigid character…………………….18
2.3 Permutational isomerization…………………………………………………..19
2.3.1 Berry pseudorotation……………………………………………………20
2.3.2 Turnstile rotation………………………………………………………..21
2.4 The 6-Coordinate State of Phosphorus……………………………………….22
2.5 References…………………………………………………………………......24
I
Chapter 3…………………………………………………………………………27
PHOSPHORUS-31 NMR SPECTROSCOPY
3.1 Chemical Shifts………………………………………………………………..27
3.2 Spin-Spin Coupling Constants………………………………………………...29
3.2.1 31P-11B coupling…………………………………………………………30
3.3 References……………………………………………………………………..32
Chapter 4…………………………………………………………………………33
THE PHOSPHORUS DONOR REAGENT
4.1 References……………………………………………………………………..43
Ain of the thesis…………………………………………………………………..49
Chapter 5…………………………………………………………………………53
SYNTHESIS OF HALOALKYL PHOSPHOLANE AND
PHOSPHINANE DERIVATIVES AND THEIR APPLICATION
5.1 Introduction……………………………………………………………………53
5.2 Results and discussion………………………………………………………...54
5.3 Conclusion…………………………………………………………………….57
5.4 Experimental section…………………………………………………………..57
5.5 References……………………………………………………………………..62
Chapter 6…………………………………………………………………………65
GENERAL SYNTHESIS OF ACYCLIC TERTIARY PHOSPHINE SULFIDES
6.1 Introduction……………………………………………………………………65
6.2 Results and discussion………………………………………………………...66
6.3 Conclusion…………………………………………………………………….70
6.4 Experimental section………………………………………………………….70
6.5 References…………………………………………………………………….77
II
INDEX
Chapter 7…………………………………………………………………………81
ONE-POT SYNTHESIS OF SECONDARY PHOSPHINES AND THEIR
BORANE COMPLEXES
7.1 Introduction……………………………………………………………………81
7.2 Results and discussion………………………………………………………...82
7.2.1 Developing of synthetic procedure……………………………………...82
7.2.2 Study of intermediates…………………………………………………..85
7.2.3 Synthesis of secondary phosphines containing bulky group……………92
7.3 Conclusion…………………………………………………………………….94
7.4 Experimental section…………………………………………………………..95
7.5 References……………………………………………………………………108
Chapter 8……………………………………………………………………….111
SYNTHESIS OF TERTIARY PHOSPHINE-BORANE COMPLEXES
8.1 Introduction………………………………………………………………….111
8.2 Results and discussion……………………………………………………….112
8.3 Conclusion…………………………………………………………………...117
8.4 Exsperimental section………………………………………………………..118
8.5 References……………………………………………………………………123
Chapter 9………………………………………………………………………..127
CATALYTIC TRANSPORT SYSTEM OF ELEMENTS: SYNTHESIS OF
ARSINE AND STIBINE DERIVATIVES
9.1 Introduction…………………………………………………………………..127
9.2 Results and discussion…………………………………………………...…..127
9.2.1 Penta and hexacoordinated phosphorus intermediate: a possible
explanation of ribozyme and enzyme phosphoryl transfer reactions…………….133
9.3 Conclusion……………………………………………………...……………137
9.4 Experimental section…………………………………………………...….…138
9.5 References……………………………………………………………………143
III
Charter 10……………………………………………………………………….145
GENERAL ONE-POT SYNTHESIS OF 1,2,5-DITHIAPHOSPHEPINES AND
THEIR PRECURSOR PHOSPHINETHIOLS
10.1 Introduction…………………………………………………………………145
10.2 Results and discussion……………………………………………………...145
10.3 Conclusion………………………………………………………………….150
10.4 Experimental section………………………………………………………..151
10.5 References…………………………………………………………………..155
Chapter 11………………………………………………………………………158
SYNTHESIS AND EVALUATION OF A NEW SERIES OF LIGANDS
DERIVING FROM MEOXUPHOS IN THE ASYMMETRIC
HYDROGENATION OF KETONES
11.1 Introduction…………………………………………………………………158
11.1.1 Monodentate Phosphorus Ligands in Catalytic for Asymmetric
Hydrogenation……………………………………………………………………160
11.1.2 A New family of Monodentate Phosphorus Ligand: XuPHOS………162
11.2 Results and discussion……………………………………………………...164
11.2.1 Synthesis of ligands and corresponding Ru-DPEN complexes………165
11.2.2 Asymmetric hydrogenation of ketones……………………………….172
11.3 Conclusion………………………………………………………………….174
11.4 Experimental Section……………………………………………………….176
11.5 References…………………………………………………………………..183
Chapter 12………………………………………………………………………185
RUTHENIUM-CATALYZED HYDROGENATION OF KETONES AND
AROMATIC RINGS
12.1 Introduction…………………………………………………………………186
12.2 Results and discussion……………………………………………………...187
12.2.1 Hydrogenation reaction catalyzed by RuCl3,
1,1,1-Tris(hydroxymethyl)ethane and bases……………………………………..188
12.2.2 Synthesis of phosphorus ligands…………………………………...…194
IV
INDEX
12.3 Conclusion………………………………………………………………….197
12.4 Experimental Section……………………………………………………….198
12.4 References…………………………………………………………………..202
Appendix 1………….……………..……………………..……….……………..205
Appendix 2……….……………………………………..……….…..…………..207
Appendix 3..……….……………………………………..……….……………..209
V
VI
Keywords
Keywords
Phosphines
Grignard reagents
Organophosphorus compounds
Hypercoordinate phosphorus intermediates
Phosphorus ligands
VII
VIII
Introduction
INTRODUCTION : Chapter 1
Chapter 1
GENERAL INTRODUCTION ON PHOSPHORUS
CHEMISTRY
In what is perhaps the most disgusting method of discovering an element,
phosphorus was first isolated in 1669 by Hennig Brand, a German physician and
alchemist, by boiling, filtering and otherwise processing as many as 60 buckets of
urine. Now, phosphorus is primarily obtained from phosphate rock (Ca3(PO4)2).
Phosphorus has three main allotropes: white, red and black. White phosphorus is
poisonous and can spontaneously ignite when it comes in contact with air. For this
reason, white phosphorus must be stored under water and is usually used to
produce phosphorus compounds. Red phosphorus is formed by heating white
phosphorus to 250°C (482°F) or by exposing white phosphorus to sunlight. Red
phosphorus is not poisonous and is not as dangerous as white phosphorus,
although frictional heating is enough to change it back to white phosphorus. Red
phosphorus is used in safety matches, fireworks, smoke bombs and pesticides.
Black phosphorus is also formed by heating white phosphorus, but a mercury
catalyst and a seed crystal of black phosphorus are required. Black phosphorus is
the least reactive form of phosphorus and has no significant commercial uses.
The number of known phosphorus compounds probably now exceeds 106 and a
large number of them are included in organophosphorus chemistry.
1.1
Organophosphorus Chemistry
Phosphorus can form bonds with many other elements. It can also form bonds
with varying number of atoms (Coordination Number), which can vary from 1 to
3
General Introduction on Phosphorus Chemistry
6 and more. Also it can have different valencies, either 3 or 5. Also it has empty
d-orbitals which readily accept electrons from any good donors.
Organophosphorus compounds are chemical compounds containing carbonphosphorus bonds. Organophosphorus chemistry is the corresponding science
exploring the properties and reactivity of organophosphorus compounds.1
Common examples of those compound are reported in Figure 1.1.
R
OR
P
P
R
R
R
Phosphine
P
R
Phosphinite
RO
R
Phosphonite
OR
NR2
NR2
P
P
P
RO
R
OR
Phosphite
R
Phosphinous amide
NR2
R2N
R
Phosphnous diamide
O
R
R
P
P
P
Phosphonium salt
R
R
Phosphine oxide
O
O
O
P
P
P
R2N
NR2
Phosphinous triamide
R
OR
R
R
OR
Phosphinate
R
R
OR
OR
Phosphonate
R
RO
OR
OR
Phosphate
Figure 1.1 Examples of organophosphorus compounds.
The thermal stability of the P-C bond is quite high. The heat of dissociation of the
4-coordinated C-P bond is generally accepted to be about 65 Kcal/mol, and there
is never any difficulty in handling most aryl and alkyl phosphorus compounds
even at moderate temperatures.2a
4
INTRODUCTION : Chapter 1
1.1.1 Phosphines
Phosphanes or phosphines have oxidation state −3 and can be primary (RPH2),
secondary (R2PH) or tertiary (R3P). An often used organic phosphine is
triphenylphosphine. Like amines, phosphines have a trigonal pyramidal molecular
geometry although with larger angles. The C-P-C bond angle is 98.6° for
trimethylphosphine increasing to 109.7° when the methyl groups are replaced by
tert-butyl groups. The barrier to inversion is high for a process like inversion to
occur and therefore phosphines with three different substituents can display
optical isomerism. 2b
Synthetic procedures for phosphines are:3
•
Nucleophilic displacement of phosphorous halides with organometallic
reagents such as Grignard reagents.
•
Nucleophilic displacement of metal phosphides, generated by reaction of
potassium metal with phosphine, as in sodium amide with alkyl halides.
•
Nucleophilic addition of phosphine with alkenes in presence of a strong
base (often KOH in DMSO), Markovnikov's rules apply. Phosphine can be
prepared in situ from red phosphorus and potassium hydroxide. Primary
(RPH2) and secondary phospines (R2PH) do not require a base with
electron-deficient alkenes.
•
Nucleophilic addition of phosphine or phosphines to alkynes in presence
of base. Secondary phosphines react with electron-deficient alkynes
without base.
•
Radical addition of phosphines to alkenes with AIBN or organic peroxides
to give anti-Markovnikov adducts.
Oxidation has been a major obstacle when working with trivalent phosphorus as
phosphines. Especially alkyl-substituted phosphines oxidise readily in air making
elaborating and handling of such compounds tedious. For this reason, usually
phosphines are oxidized into stable compounds after their preparation, obtaining
phosphine oxide, sulfide, selenide (less common) or borane complexes
derivatives.4
5
General Introduction on Phosphorus Chemistry
•
Phosphine oxides are obtained by simple treatment of free phosphine with
an oxidizing agent such as H2O2,5 O2,4b t-BuOOH,6 m-CPBA7 (Reduction
by PhSiCl3,8 HSiCl39 with retention of configuration or LiAlH4 that causes
racemization).
•
Phosphine sulfides and selenides are obtained from phosphine oxidized by
elementar sulfur or selenium (Reduction by Si2Cl6 with retention of
configuration or LiAlH4 that causes racemization). 10
•
Phosphine borane complexes are obtained by mixing phosphines with
BH3.THF or BH3.Me2S (decomplexation by amines, such as Et2NH or
morpholine with retention of configuration).11
The main reaction types of phosphines are: 3
•
as nucleophiles for instance with alkyl halides to phosphonium salts.
•
as reducing agents:
Phosphines are reducing agents in the Staudinger reduction converting azides
to amines and in the Mitsunobu reaction converting alcohols into esters. In
these processes the phosphine is oxidized to phosphine oxide.
1.1.2 Phosphonates
Phosphonates have the general structure R−P(=O)(OR)2. They have many
technical applications and bisphosphonates are a class of drugs.
All bisphosphonate drugs share a common P-C-P "backbone":
-
O
O
R1
O
P
C
P
O-
R2
O-
O-
Figure 1.2 typical backbones of bisphosphonate drugs
The two PO3 (phosphate) groups covalently linked to carbon determine both the
name "bisphosphonate" and the function of the drugs. The long side chain (R2 in
the diagram) determines the chemical properties, the mode of action and the
6
INTRODUCTION : Chapter 1
strength of bisphosphonate drugs. The short side chain (R1), often called the
'hook,' mainly influences chemical properties and pharmacokinetics.12
1.1.3 Phosphites and Phosphates
Phosphite esters or phosphites have the general structure P(OR)3 with oxidation
state +3. Phosphites are employed in the Perkow reaction and the Arbusov
reaction. Phosphate esters with the general structure P(=O)(OR)3 and oxidation
state +5 are of great technological importance as flame retardant agents and
plasticizers. Lacking a P−C bond, these compounds are technically not
organophosphorus compounds.3
1.2
Uses of Organophosphorus Compounds
Organophosphorus compounds, have widespread use throughout the world,
mainly in agriculture as insecticides, herbicides, and plant growth regulators.13
They have also been used as nerve agents in chemical warfare and as therapeutic
agents, such as ecothiopate used in the treatment of glaucoma.14 In academic
research organophosphorus compounds find important application in organic
synthesis (Wittig, Mitsunobu, Staudinger, organocatalysis etc.).15 The use of
organophosphorus compounds as achiral or chiral ligands for transition metalcatalyzed transformations is also rapidly growing in both laboratory synthesis and
industrial production.16 Furthermore, organophosphorus compound, can be used
as flame retardants for fabrics and plastic plasticising and stabilising agents in the
plastics industry, selective extractants for metal salts from ores, additives for
petroleum products, and corrosion inhibitors.
7
General Introduction on Phosphorus Chemistry
1.2.1 Agricultural Applications
Over the years, many organophosphorus compounds have been made and used in
very large quantities in agriculture, not only as insecticides but also later as
herbicides and in other applications.
Phosphorus compounds have distinct advantages in the pesticides market; they are
relatively easy to make, and they biodegrade readily by hydrolysis, so that the
problems of residual activity, so serious with the chlorinated hydrocarbon
pesticides, are avoided.
The active compounds are normally esters, amides, or thiol derivatives of
phosphoric or phosphonic acid:
O
(or S)
P
X
R1
R2
X = OR, SR
Figure 1.3 Structure of derivatives of phosphoric or phosphonic acid
Where R1 and R2 are usually simple alkyl or aryl groups, both of which may be
bonded directly to phosphorus (in phosphinates), or linked via -O-, or -S- (in
phosphates), or R1 may be bonded directly and R2 , bonded via one of the above
groups (phosphonates).
Parathion (1) was one of the first commercially produced insecticides; its toxicity
(LD50) is 55 mg/Kg, which is rather low but still requires careful handling and
application in the field. It was very popular in 1960s, but after this period the
interest in Parathion has greatly declined with the introduction of safer agents.
Definitely, many compounds are now produced that are relatively harmless to
humans yet with excellent toxicity to insects for example the well-known garden
insecticide Malathion (2) and Phosmet (3) with LD50 up 4000 mg/Kg (Figure
1.4).
8
INTRODUCTION : Chapter 1
O
O2N
O
O P (OEt)2
(OMe)2
S
O
H
P S C C OEt
H2C C OEt
O
1
S
(O2Me) PSHCH2 N
O
3
2
(OH)2
O
P CH2NHCH2CO2H
4
(Oi-Pr)2
S
P SCH2CH2NHSO2Ph
5
Figure 1.4 Examples of some insecticides and herbicides based on organophosphorus compounds.
On the other hand, the phosphorus compounds were late entries in the fields of
organic herbicides, and to this date only a few compounds have attained major
commercial importance. Glyphosphate (4) was the first discovered and is still
used (Figure 1.4). Its is known to act by the inhibition of the plant enzyme 5enolpyruvoyl-shikimate-3-phosphate synthetase, which is involved in the
biosynthesis of aromatic aminoacids and other aromatic compounds in plants.
Many other phosphorus compounds show herbicidal activity, and much current
research effort is going on in this area. In addition to the phosphorus-containing
amino acid derivatives, other structural types are of interest, such as is seen in
Betasan (5) (Figure 1.4).
1.2.2 Catalysis
Between various types of enantiomerically pure ligands used for catalytic
asymmetric reactions, chiral tertiary phosphines have established their position as
the most effective ligands for most homogeneous transition-metal catalyses.
Homogeneous asymmetric hydrogenation started with modest results (ee 15%) in
1968 using chiral monophosphine 6 (MPPP) (Figure 1.5) as ligand.17
Neomenthyldiphenylphosphine 7 (NMDPP) and menthyldiphenylphosphine 8
(MDPP) were prepared in 1971 by Morrison et al,18 giving up to 61% ee in some
cases. Knowles et al also published some interesting results in 1972 (ee 90%) with
chiral phosphines 9 (PAMP) and 10 (CAMP).19 At the same time
9
General Introduction on Phosphorus Chemistry
alkyldimenthylphosphines 11 were used by Wilke, Bogdanovic et al. as ligands of
nickel complexes in the catalysis of alkene codimerization and alkene-1,3-dienes
codimerization.20 In 1971-1972 we demonstrated that a chelating chiral C2symmetric diphosphine 12 (DIOP) without asymmetric phosphorus atoms was an
excellent enantioselective catalyst (ee 88%).21 A multitude of chelating
diphosphines are presently known (of C1 or C2-symmetry), some of them are
patented because of industrial applications.22 One of the most effective chiral
biphosphine
ligands
is
BINAP
13,23
which
has
exhibited
its
high
enantioselectivity in several asymmetric reactions including rhodium- or
ruthenium-catalyzed hydrogenation. Another important class of chelating
biphosphine ligand is ferrocenylbiphosphines BPPF-X 14,24 which had been
demonstrated to be effective for palladium-catalyzed allylic substitution reactions,
gold- or silver-catalyzed aldol reactions, and so on.
P
Ph
nPr
PPh2
Me
MPPP 6
NMDPP 7
MeO
MeO
P
Me
P
Me
PAMP 9
PPh2
MDPP 8
PR
2
CAMP 10
H
O
PPh2
PPh2
O
H
(S,S)-DIOP 12
PPh2
PPh2
(S)-BINAP 13
Figure 1.5 Examples of ligands for homogeneous catalysis.
10
11 R= Me
R= i-Pr
H Me
Fe
X
PPh2
PPh2
(S)-(R)-BPPF-X 14
INTRODUCTION : Chapter 1
1.2.3 Organophosphorus Conpounds in Medicine
A source of C-P compounds of natural origin was first recognised in 1969.25 From
the products in a fermentation broth of the bacterium Streptomyces fradiae a new
phosphoric acid that had the properties of an antibacterial antibiotic was isolated.
The compound was named Fosfomycin 15 (figure 1.6) and its discovery was an
extremely important event in phosphorus chemistry. Phosphorus compounds had
been largely ignored by medicinal chemists seeking new agents against infectious
disease. Fosfomycin is active against both Gram-positive Gram-negative bacteria,
and its effectiveness is comparable to that of the well-known antibiotics
Tetracycline.2c
High-level anticancer activity has been found in a large number of phosphorus
compounds of quite different structural types, and there is much current research
in this field. Probably the first organophosphorus compound to receive acclaim as
a valuable chemotherapeutic agent is the anticancer drug cyclophosphamide 16
(figure 1.6). Its activity was discovered in 1958,26 and remains in clinical use to
this day.2c
H3C
P(O)(OH)2
C C
H O H
O O
P
NH N(CH2CH2Cl)2
15
16
O
O
H
HO P CH2C N CHCOOH
OH
CH2
COOH
17
c-C6H11
O
P
N
O
O
(H3C)2HC CH
O CCH2CH3
O
18
COONa
O O
NaO P C ONa
ONa
19
Figure 1.6 Organophosphorus compounds in medicine.
In the design of anticancer drugs, rationales were done. An obvious one is that an
exact phosphonate replica of a known biologically active phosphate could inhibit
the process in which the phosphate is involved. The CH2 group attached to P has a
11
General Introduction on Phosphorus Chemistry
very similar size and bond angle with an O atom of a phosphate. The high stability
of P-C bond would block any important natural processes involving hydrolysis of
a phosphate ester group. A second rationale is that a phosphonic acid designed to
be similar to a naturally occurring carboxylic acid might inhibit the biochemical
work of acid.12c Using those concepts a large amount of phosphonic acids has
been synthesized and thus had useful chemotherapeutic properties. Some
examples of the above rationalization are, the PALA (N-phosphonoacetyl-Laspartic acid (17) which is a potent anticancer drug and the Fosinopril (18) which
has an antihypertensive activity.2c
Phosphorus compounds can also have antiviral activity, the first active compound
to be discovered had the very simple structure of trisodium phosphonoformiate.
Its activity was discovered27 in 1978, and is still in clinical use under the name
Foscarnet 19. It inhibits viral DNA polymerase, and it is a useful agent in the
treatment of Herpes and is also active against HIV.
1.2.4 Phosphorus in Biological Compounds
Phosphorus is present in plants and animals. There is over 454 grams of
phosphorus in the human body. It is a component of fundamental living
compounds. It is found in complex organic compounds in the blood, muscles, and
nerves, and in calcium phosphate, the principal material in bones and teeth.
Phosphorus compounds are essential in the diet. Organic phosphates, ferric
phosphate, and tricalcium phosphate are added to foods. Especially, phosphoric
acid is essential in many biological derivatives such as nucleotides, nucleic acids,
phospholipids and sugar phosphates.
Nucleotides are monomers consisting of a phosphate group, a five carbon sugar
(either ribose or deoxyribose) and a one or two ring nitrogen containing base.
Nucleotides are the monomers of nucleic acids, with three or more bonding
together in order to form a nucleic acid. The genetic material (DNA) is a polymer
of four different nucleotides. The genetic information is coded in the sequence of
nucleotides in a DNA molecule. Nucleotides and related compounds are also
12
INTRODUCTION : Chapter 1
important “energy carrying” compounds. Among the ones commonly encountered
are ATP (20), and NADH (21) (Figure 1.7).28a
OH
H2N
N
N
O
N
N
OH
CH2 O
N
HO P O N
N
HO
O
NH2
O
HO
OH
O
O P
O
O
HO P
P
OH
O
O
HO
N
OH
OH
HO P O
O
CH2 O
N
H2NOC
adenosine triphosphate ATP 20
Nicotinamide adenine dinucleotide
dehydrogenase NADH 21
Figure 1.7 Structures of ATP and NADH.
Certain phosphoric acid derivatives play a major role in driving some processes
by “energy release” that accompanies the cleavage of a phosphate group and
transfer to a nucleophilic substrate. The best known of the “energy-rich”
phosphates is adenosine triphosphates ATP (20, Figure 1.7), which can transfer
the terminal phosphate group to a substrate with the release of significant
energy.2c
Actually the phosphoryl group transfer mechanism, in “energy-rich” phosphate
substrates, is explained by intervention of pentacoordinated phosphorus in the
transition state species. In particular the formation of cyclic pentacoordinated
phosphorus species on the reactive phosphate group facilitate the attainment of the
required transition state or intermediate allowing to obtain a fast and selective
reaction.29
A phospholipid molecule consists of a hydrophilic polar head group and a
hydrophobic tail (22 figure 1.8). The polar head group contains one or more
phosphate groups. The hydrophobic tail is made up of two fatty acyl chains. When
many phospholipid molecules are placed in water, their hydrophilic heads tend to
13
General Introduction on Phosphorus Chemistry
face water and the hydrophobic tails are forced to stick together, forming a
bilayer. Phospholipids are a major component of all biological membranes, along
with glycolipids and cholesterol.28b
Glycerol
O
C O CH2
Choline
C O CH
O
O H C O P O
2
OFatty acid
CH3
CH2 CH2 N+ CH3
CH3
Phosphate
22
Figure 1.8 Typical structure of phospholipids.
Sugar phosphates are present in the human body as intermediates in the many
important processes like glucose metabolism. One example is the glucose 6phosphate 23 (figure 1.9).
It is glucose sugar phosphorylated on carbon 6. This compound is very common
in cells as the vast majority of glucose entering a cell will become phosphorylated
in this way. Because of its prominent position in cellular chemistry, glucose 6phosphate has many possible fates within the cell. It lies at the start of two major
metabolic pathways: the Glycolysis and Pentose phosphate pathway
In addition to these metabolic pathways, glucose 6-phosphate may also be
converted to glycogen or starch for storage. This storage, in the form of glycogen,
is in the liver and muscles for most multicellular animals, and in intracellular
starch or glycogen granules for most other organisms.28c
O
P OO
OH
H O
HO
HO
H
H
H
OH
OH
glucose-6-phosphate 23
Figure 1.9 Structure of glucose 6-phosphate.
14
INTRODUCTION : Chapter 1
1.3
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(1)
Vereshchagina, Y. A.; Ishmaeva, E. A.; Zverev, V.V. Russ. Chem. Rev.,
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Quin, L. D. A Guide to Otganophosphorus Chemistry, John Wiley & Sons,
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(3)
Engel, R. Synthesis of Carbon-Phosphorus Bonds, CRC Press, Inc. Boca
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(4)
Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev., 1994, 94, 1375, 1404.
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(a) Fleisch, H. Breast. Cancer. Res., 2002, 4, 30. (b) Krise, J. P.; Stella, V.
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Kovacie, P. Curr. Med. Chem., 2003, 10, 2705.
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(a) Lu, X.-Y, Zhang, C.-M.; Xu, Z.-R. Acc. Chem. Rev. 2001, 34, 535; (b)
Du, Y.S.; Feng, J.-Q.; Yu, Y.-H. J. Org. Chem. 2002, 67, 8901. (c) Lu, C.;
Lu, X.Y. Org. Lett., 2002, 4, 4677; (d) Du, Y.-S.; Lu, X.-Y.; Zhang, C.-M.
Angew. Chem., Int. Ed. 2003, 42, 1035; (e) Du, Y.S.; Lu, X.-Y. J. Org.
Chem., 2003, 68, 6463; (f) Lu, C.; Lu, X.-Y. Tetrahedron 2004, 60, 6575;
(g) Du, Y.S.; Feng, J.-Q.; Lu, X.-Y. Org. Lett., 2005, 7, 1987; (h) Koehn,
M.; Breinbauer, R. Angew. Chem. Int. Ed., 2004, 43, 3106; (i) Vedejs, E.
15
General Introduction on Phosphorus Chemistry
J. Org.Chem., 2004, 69, 5159; (j) Methot, J. L.; Roush, W. R. Adv. Synth.
Catal., 2004, 346, 1035.
(16)
(a) Tang, W.; Zhang, X. Chem. Rev., 2003, 103, 3029; (b) Grushin, V. V.
Chem. Rev., 2004, 104, 1629.
(17)
(a) Horner, L.; Siegel, H.; Büthe, H. Angew. Chem. Int. Ed. Engl., 1968, 7,
942. (b) Horner, L.; Siegel, H. Phosphorus, 1972, 1, 209. (c) Knowles, W.
S. M.; Sabacky, J. J. Chem. Soc. Chem. Commun., 1968, 1445.
(18)
Morrison, J. D.; Burnett, R. E.; Aguiar, A. M.; Morrow, C. J.; Philipps, C.
J. Am. Chem. Soc., 1971, 93, 1301.
(19)
Morrison, J. D.; Masler, W. F. J. Org. Chem., 1974, 39, 270.
(20)
(a) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D. J. Chem. Soc. Chem.
Commun., 1972, 10. (b) Bogdanovic, B.; Henc, B.; Meister, B.; Pauling,
H.; Wilke, G. Angew. Chem. Int. Ed. Engl., 1972, 11, 1023.
(21)
(a) Bogdanovic, B. Angew. Chem. Int. Ed. Engl., 1973, 12, 954. (b) Dang,
T. P.; Kagan, H. B. J. Chem. Soc. Chem. Commun., 1971, 481.
(22)
Lagasse, F.; Kagan, H. B. Chem. Pharm. Bull., 2000, 48, 315.
(23)
Noyori, R.; Takaya, H. Acc. Chem. Rev., 1990, 23, 345.
(24)
Hayashi, T. Acc. Chem. Rev., 2000, 33, 354.
(25)
Hendlin, D. Science, 1969, 166, 122.
(26)
Arnold, H.; Bourseaux, F. Angew. Chem., 1958, 70, 539.
(27)
Helgstand, F. Science, 1978, 201, 819.
(28)
Voet, D.; Voet, J. G. Biochemistry, 2nd Edition, John Wiley & Sons. Inc.,
Printed in United States of America, 1995. (a) pag. 848. (b) pag. 277 (c)
pag. 865.
(29)
Holmes, R. R. Pentacoordinated Phosphorus, Vol. II, Edn ACS,
Washington, D.C. 1980, Chapter 2.
16
INTRODUCTION : Chapter 2
Chapter 2
THE HYPERCOORDINATE STATES OF
PHOSPHORUS
One of the special properties of phosphorus that is of importance is its ability to
accept more than the usual complement of 8 bonding electrons, thus acquiring 5coordinate character with 10 electrons, or 6-coordinate with 12 electrons. This
property of phosphorus was not firmly established until 1948, when the compound
Ph5P was synthesized and characterized by Wittig and Rieber.1 Now there are
many compounds known with this structural feature, which is also known to
appear frequently in reactions mechanism as a transient intermediate or transition
state. 2
2.1
The 5-Coordinate State of Phosphorus
Phosphorus can undergo rapid and reversible changes between a four-coordinate
and a five-coordinate state (Scheme 2.1). The preferred skeletal geometries of this
states correspond to the tetrahedron and the trigonal bipyramid (TBP),
respectively.2
L
L
L
L
P
L
+
L
L
P
L
L
L
TBP
Scheme 2.1 convertion between a four-coordinate and a five-coordinate state.
17
The Hypercoordinate State of Phosphorus
Molecules with five-coordinate phosphorus are essential to life3 and the
recognition of the role played by the five-coordinate state of the element in
biochemistry has spurred interest in this field. On this basis, a consistent
interpretation has been made of a number of significant problems of
biochemistry,4 for example: the transfer of the terminal phosphoryl group from
adenosine triphosphate to nucleophiles under basic conditions; the enzymatic
transformation of mevalonic acid into isopentyl diphosphate by ATP and metal
ions or the role of ATP in the biological reduction of nitrogen to ammonia
(nitrogen-fixation).
Pentacoordinated phosphorus compounds are not only present as reaction
intermediates in biological reactions or chemical reactions as Arbusov, Perkov
and Wittig,4b but they can be isolated as stable compounds.5
2.2
Pentacoordinated structures and their non rigid
character
The development of structural principles for pentacoordinated species, was
centered on the trigonal bipyramid geometry. These principles have been applied
with considerable success in the construction of reaction intermediates. The
systematic application of mechanistic criteria for postulating the most likely
pentacoordinated intermediates has led to a consistent rationalization of a large
number of information on phosphorus reactions. Certain principles emerged that
govern conformational preferences regarding the positioning of ligands in a TBP
structure. They are listed as follows in order of importance:6
1. Four- or five- membered cyclic systems preferentially span axialequatorial positions;
2. The most electronegative ligands preferentially occupy axial sites;
3. P-bonding donor ligands, in general, are positioned at equatorial sites.
4. Steric effects are minimized by locating bulky groups in equatorial
positions.
18
INTRODUCTION : Chapter 2
The stability of phosphoranes (pentavalent phosphorus) is markedly increased by
the presence of four- anf five-membered rings, and to a lesser extent, by sixmembered rings, since cyclization decreases intramolecular crowding relative to
the comparable acyclic situation.7 This assistance from intramolecular growding
can outweigh any strain resulting from the deformation of bond angles within the
ring. Nevertheless, ring-strain rather than intramolecular crowding is the main
factor in determining the stability of tetracoordinate phosphorus. Consequently, a
five membered cycle loses in stability while the corresponding cyclic phosphorane
gains in stability relative to the corresponding compounds in which the
phosphorus is not incorporated in rings.8 These is thermodynamic and kinetic
advantage in adding a nucleophile such as alkoxide or water to four-coordinate
phosphorus to form a phosphorane intermediate when a five-membered ring is
present in the phosphate, or when such a ring is easily formed during a reaction.
This is in accord with Westheimer and co-workers7,9 found studying the acid
hydrolysis of cyclic esters, in fact their experimental results reported that a fivemembered cyclic phosphate esters hydrolyze much more rapidly (105-108 times)
than their open chain analogous in either acid or base.
2.3
Permutational isomerization
The permutational isomerization of the phosphoranes can occur by bond
deformations (regular process) and by bond breaking and recombinations
(irregular process). The regular permutational isomerizations of acyclic
phosphanes can take place by either Berry pseudorotation10, 11 (BPR) or turnstile
rotation10b, 11, 12 (TR) or by both of these mechanism.
19
The Hypercoordinate State of Phosphorus
2.3.1 Berry pseudorotation
In 1960, R. S. Berry10 suggested that the position exchange of the fluorine atoms
of PF5 occurs by a regular bond-deformation mechanism which he called
pseudorotation (scheme 2.2).
F
F'
F'
F
*
F
*F
P
P
F'
F
F
F'
Scheme 2.2 Exchange of the fluorine atoms of PF5, consequence of BPR.
In general, this Berry pseudorotation (BPR) can be described as shown in Scheme
2.3. A pair of equatorial ligands, for istance 4 and 5, move in a plane and the two
apical ligands move in another plane, perpendicular to the first. The fifth ligand,
the pivot (3), does not move at all. The synchronous expansion of the original
120° diequatorial angle 4-P-5 leads to an angle of 150° in the idealized barrier
situation; this angle reaches 180° in the new TBP. Similarly, the synchronous
contraction of the original 180° diapical angle 1-P-2, leads to 150° in the idealized
barrier situation and 120° in the new TBP. During this bending motions, the bond
distances adjust to the new TBP skeletal arrangement. After the BPR, the new
TBP is oriented as if the entire molecule had rotated by 90° about the pivotal
bond, even though, in fact, neither a rotation of the whole molecule, and not a
rotation of a ligand subsisted, for this reason the name rotation.11
Therefore in other words, the BPR mechanism realizes of two apical and two
equatorial ligands, and the retention of the equatorial position of the pivot.
1
1
4
3
P
3
2
3
P
5
2
Scheme 2.3 Berry pseudo rotation with ligand 3 as pivot.11
20
1
4
P
5
4
4
1
3
P
2
2
5
5
INTRODUCTION : Chapter 2
2.3.2 Turnstile rotation
About 10 years later than the Berry pseudo rotation was formulated, another
theory was proposed, the turnstile rotation12 (TR). The turnstile rotation consist in
a permutation of the ligands among skeletal positions of the TBP which, in
general takes the form shown in scheme 2.4.
The first TR process of scheme 2.4 corresponds to the ligand permutation (1 4) (2
3 5), which means ligand 1 replaces ligand 4 and ligand 4 replaces ligand 1, while
ligand 2 replaces ligand 3, 3 replaces 5 and 5 replaces 2. The second, third and
fourth equivalent TR processes correspond, respectively, to the ligand
permutations (1 5) (2 3 4), (2 4) (1 3 5), (2 5) (1 3 4). It should be noted that the
five ligands have been partitioned into a pair, which always contains one apical
and one equatorial ligand and a trio.11
Obviously, the TR and the BPR processes correspond to different types of
permutations of the ligands among the skeletal positions of the TBP, but the same
isomerization of it can be achieved by one BPR process or by four TR process.
The differences between the two processes in the case of certain acyclic
phosphoranes are not so evident, this means that the potential surface for
permutational isomerization does not contain high barriers between the BPR
barrier model and the TR barrier model.10b When two or more ligands participate
in cyclic structures, the situation changes. In fact, for regular isomerizations of
acyclic phosphoranes existed two mechanistic possibilities, BRP and TR, but for
the case of regular isonerizations of cyclic phosphanes the only mechanistic
possibility is the TR process, with the four- and the five- membered ring always
as the pair of the TR pair-trio combination.
21
The Hypercoordinate State of Phosphorus
4
1
5
4
Pair (1 4)
Trio (2 3 5)
3
1
P
P
2
3
5
2
5
1
3
5
Pair (1 5)
Trio (2 3 4)
2
1
P
P
3
4
4
2
4
2
3
4
Pair (2 4)
Trio (1 3 5)
1
2
P
P
3
5
5
1
5
2
4
5
Pair (2 5)
Trio (1 3 4)
3
2
P
P
1
3
1
4
Scheme 2.4 Four equivalent turnstile processes showing the pairs and trios of ligands which
effects the same isomerization as Berry pseudorotation with ligand 3 as pivot.11
2.4
The 6-Coordinate State of Phosphorus
The chemistry of hexacoordinated phosphorus compounds has received much less
attention than that of the pentacoordinated state. In recent years many stable
compounds have been made in which phosphorus has six attached groups.13,14 In
general the octahedral structure, with two apical and four equatorial bonds, is
adopted. In this coordination state, phosphorus is known in neutral, anionic and
cationic forms. Many of the known compounds can be considered as Lewis salts
22
INTRODUCTION : Chapter 2
obtaining from the interaction between a donor group (neutral or ionic) with fivecoordinated phosphorus.
Some of the concepts of the five-coordinate state are useful also in six-coordinate
state. As Muetterties and Mahler15 showed highly electronegative elements, in
particular fluorine, stabilize the hexacoordinated state and their prefer the apical
position. Fluxional character can be present,16 and 31P NMR shift are usual found
at high field.
Six-coordinate compounds are receiving attention at present because they are
recognised as transient intermediates in certain reactions of five-coordinate
structures, adding a new dimension to considerations of reaction mechanisms.
Generally, it is considered that pentacoordination to hexacoordination occurs
through a square pyramidal (SP) geometry from a trigonal bipyramidal (TBP)
geometry. A careful analysis of the equilibrium reported17 in Scheme 2.5 reveals
that the coordination at these sulfonyl phosphoranes 2 having a square pyramidal
distortion on the pathway toward an octahedron, it is also accompanied by a
change in the ring orientation. When no coordination is present, the eight-member
ring occupies a diequatorial orientation, as seen in phosphorane 1, 2 (Scheme
2.5).18 However, it changes to an axial-equatorial orientation before distorting
toward the SP geometry.
O S
O
OR
O
O
O
P
S O
OR
OR
R
R
P
R
R
1
OR
OR
O
O
OR
2
Scheme 2.5 Equilibrium from pentacoordination to hexacoordination.17
Other studies carried out by Ramirez19 and others, suggested that hexacoordinated
phosphorus compounds are formed during nucleophilic displacement reactions on
pentacoordinated phosphorus compounds. Most of these studies have centered on
oxyphosphoranes. In addition, there are studies of reactions of tetracoordinate
phosphorus which have been considered to involve hexacoordinate states.14,20 For
23
The Hypercoordinate State of Phosphorus
example, nucleophilic catalysis of the phosphorylation of alcohols by the cyclic
phosphate 3 in the presence of imidazole was proposed by Ramirez et al.20 to
proceed with ring opening via the hexacoordinate intermediate A to give 4
(Scheme 2.6). The imidazole catalyst acts in a nucleophilic assisted attack at
phosphorus by the alcohol. Ramirez and co-workers20 infer that analogous
mechanisms may be important to the behavior of some enzymes that are involved
with phosphoryl group transfer whereby amino acid residues enter into the
catalytic activity. The intervention of both five- and six-coordinate species is
suggested.14b,21
O
O
N
R''OH
+
R'O
O
P
R'O
NH
+
R''O
O
P
OH
H
N
O
N
3
A
OR''
H
O
R'O P O C C
O
CH3 CH3
N
NH
+
4
Scheme 2.6 Nucleophilic catalysis of the phosphorylation of alcohols by the cyclic phosphate 3 in
the presence of imidazole.
24
INTRODUCTION : Chapter 2
2.5
References
(1)
Wittig, G.; Rieber, M. Liebigs Ann. Chem., 1948, 562, 187.
(2)
Holmes, R. R. Pentacoordinated Phosphorus, Vol. I and II, Edn ACS,
Washington, D.C. 1980.
(3)
(a) Westheimer, F. H. Chem. Soc., (London), Spec. Publn no.8, 1957; (b)
Cramer, F. Angew. Chem. Int. Edn., 1966, 5, 173; (c) Mahler, H. R.;
Cordes, E. H. Biological chemistry, 2nd edn. London, Harper and Row,
1971; (d) Bunton, C. A. Acc. Chem. Res., 1970, 3, 257.
(4)
(a) Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D. Angew. Chem. Int.
Edn., 1972, 11; (b) Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D.
Angew. Chem. Int. Edn., 1973, 2, 91.
(5)
Holmes, R. R. Pentacoordinated Phosphorus, Vol. I Chapter 2 , Edn ACS,
Washington, D.C. 1980.
(6)
Holmes, R. R. Pentacoordinated Phosphorus, Vol. II Chapter 2 , Edn
ACS, Washington, D.C. 1980.
(7)
Westheimer, F. Acc. Chem Res., 1968, 1, 70.
(8)
(a) Ramirez, F. Acc. Chem Res., 1968, 1, 168; (b) Denney, D. B.; Denney,
D. J.; Chang, B. C.; Marsi, K. L. J. Am, Chem. Soc., 1970, 91,5243.
(9)
(a) Tennis, E. A.; Westheimer, F. J. Am, Chem. Soc., 1966, 88, 3432; (b)
Haake, P. C.; Westheimer, F. J. Am, Chem. Soc., 1961, 83, 1102; (c)
Kluger R.; Covitz, F.; Tennis, E.; Williams, L. D.; Westheimer, F. J. Am,
Chem. Soc., 1969, 91, 6066.
(10)
(a) Berry, R. S. J. Chem. Phys., 1960, 32, 933; (b) Holmes R. R.,
Pentacoordinated Phosphorus, Vol. I Chapter 4 , Edn ACS, Washington,
D.C. 1980.
(11)
Ugi, I.; Ramirez, F.; Chemistry in Britain, 1972, 8, 189.
(12)
(a) Gillespie, P.; Hoffmann, P.; Ramirez, F.; Ugi, I.; Marquarding, D.;
Klusacek, H.; Pfohl, S.; Tsolis, E. A. Angew. Chem. Int. Edn., 1971, 10,
687; (b) Gillespie, P.; Ramirez, F.; Ugi, I.; Marquarding, D.; Klusacek, H.
Acc. Chem Res., 1971, 4, 288.
25
The Hypercoordinate State of Phosphorus
(13)
Wong, C. Y.; Kennepohl, D. K.; Cavell, R. G. Chem. Rev., 1996, 96, 1917.
(14)
(a) Holms, R. R. Acc. Chem. Res., 1996, 96, 927. (b) Holms, R. R. Acc.
Chem. Res., 1998, 31, 535.
(15)
Muetterties, E. L.; Mahler, W. Inorg. Chem., 1965, 4, 119.
(16)
Cavell, R. C.; Vande Griend, L. Inorg. Chem., 1983, 22, 2066.
(17)
Chandrasekaran, A.; Timosheva, N. V.; Holmes, R. R. Phoshorus and
Sulfor 2006, 181, 1493.
(18)
(a) Chandrasekaran, A.; Day, R. O.; Holmes, R. R.; J. Am. Chem. Soc.
1997, 119, 11434. (b) Chandrasekaran, A.; Day, R. O.; Holmes, R. R.
Inorg. Chem., 1997, 36, 2578.
(19)
(a) Ramirez, F.; Tasaka, K.; Desac, N. B.; Smith, C. P. J. Am. Chem. Soc.
1968, 90, 751. (b) Ramirez, F.; Loewengart, G. V.; Tsalis, E. A.; Tasaka,
K. J. Am. Chem. Soc. 1972, 94, 3531. (c) Ramirez, F.; Lee, S.; Stern, P.;
Ugi, I.; Gillespie, P.; Phosphorus 1974, 4, 21. (d) Aksnes, G. Phosphorus
and Sulfur 1977, 3, 227.
(20)
(a) Ramirez, F.; Marecek, J. F.; Okazaki, H. J. Am. Chem. Soc. 1976, 98,
5310. (b) Ramirez, F.; Marecek, J. F. J. Org. Chem. 1975, 40, 2849.
(21)
26
Holms, R. R. Acc. Chem. Res., 2004, 37, 746.
INTRODUCTIO : Chapter 3
Chapter 3
PHOSPHORUS-31 NMR SPECTROSCOPY
The phosphorus atom frequently plays a central role in the chemistry of most
compounds in which it is incorporated. Without 31P NMR spectroscopy, the task
of sorting out the incredible changes in coordination number, and the additional
stereochemical changes associated with the three-, four, five- and six- coordinate
compounds world have been much slower.1, 2
Chemical shifts in the nuclear magnetic resonance of
31
P were discovered by
Knight.3 Subsequent measurements, particularly those by Gutowsky and his coworkers4 indicate that NMR spectroscopy can became a valuable tool for chemical
studies involving phosphorus compounds. Today this technique can also be used
to determine the complexity of a reaction mixture or the purity of products,
because different signals are almost always seen for each phosphorus compound.
Many other applications of phosphorus NMR have been made, such as performing
conformational analysis and studying reaction mechanisms by means of signals
for intermediates.
The large use of 31P NMR is due to the presence of only one natural isotope with
mass 31, so strong signals can be obtained with a small quantity of compound,
that render the taking of phosphorus NMR spectra easy.2
3.1
Chemical Shifts
Phosphorus-31 chemical shifts have been observed over a range exceeding 1000
ppm. However, many classes of phosphorus compounds give signals within quite
small parts of this range. The relationship between structure and phosphorus
chemical shift is often well enough established to permit quite detailed structural
27
Phosphorus-31 NMR Spectroscopy
inferences, even to the extent of identifying the stereochemistry in some instances.
The presence of a lone pair of electrons on phosphorus tends to widen the
chemical shift range, and additional information is usually required to obtain
structural information. For organophosphorus compounds 1H and
can often be linked directly to the
31
13
C NMR data
P information. Together they form a very
powerful structural tool for the chemist. Phosphorus-31 chemical shifts are
reported relative to the signal for 85% phosphoric acid.5 The acid is invariably
used as an external reference due to its reactivity. Care must be taken when
collecting data from the literature to establish whether the phosphorus isotope
signal appears upfield or downfield of the standard, 85% phosphoric acid. There
was a change in sign convention in the mid-1970s, and now positive chemical
shifts are downfield of the standard.2a
Even if the 31P NMR shifts extent in a large range, the vast majority are included
in the region of about δ -200 to +300 ppm. Each type of functional group ha sits
own range of shifts within this region. It should be noted that there is overlap of
this functional group subregions, and it is not often possible to use only the
31
P
shift, without other characterization for identify unambiguously a compound.
Many factors have been considered to be important in effecting the shift for a
particular structure. A few of this factor are reported to follow:2b,6
•
Electron withdrawal by electronegative groups, generally considered to act
by contracting the p-orbitals at P and causing deshielding.
•
Resonance interactions at phosphorus with unsaturated groups that change
electron density on phosphorus in either direction causing shielding.
•
Chain lengthening and branching effects, which cause deshielding as the
number of β-carbons to P increases or shielding as the number of γcarbons increases.
•
Changes in bond angles at phosphorus, increases in which are said to
cause deshielding of 3-coordinate phosphorus and shielding in phosphates.
•
Steric interaction in acyclic compounds manifested by shielding.
•
Five cyclic-member compounds showed to be more deshield than the
analogous six cyclic-member. This phenomena is caused by major
28
INTRODUCTIO : Chapter 3
overlapping between dπ-pπ orbital in the five cyclic-member compounds
in which the bong angle is closer to 90°.
Besides structural properties can be achieved by analysis of 31P NMR spectra. In
fact each P-coordinations has its range of chemical shift that covered all the
ordinary range (Figure 3.1). It could be important to note that 6-coordinate
compounds are also found outside their usual range; in fact they can have a
positive chemical shift, as reported in the literature.7
300
200
100
0
-100
-200
-300 ppm
H3PO4
(85%)
P
PX3
P
P
X3P=O
P
PX 5
P
PX 6
Figure 3.1 Chemical shift range for the different P-coordination.
3.2
The
Spin-Spin Coupling Constants
31
P nucleus coupled with 1H, and both types of spectra show the effect.
Couplings constants can be as small as a few Hertz or as a many as several
hundred Hertz for the direct P-H bond. Because the coupling effect is commonly
seen on 1H spectra, but usually avoided by decoupling in
31
P NMR, coupling
constants are usually determined from the previous spectra. Therefore couplings
to neighboring protons are very useful for determining the nature and the number
29
Phosphorus-31 NMR Spectroscopy
of aliphatic groups bound to the phosphorus atom. The protons of aryl groups
rarely produce resolvable couplings in the 31P spectrum.2c
The lone pair effect is clearly seen in the decrease of the positive 1J(31P,1H) values
from PH4+ (546-548 Hz) to PH3 (182-195 Hz) to PH2- (138-140 Hz).8 Although
there is a general increase in 1J(31P,1H) with increasing oxidation states of
phosphorus, the ranges for the various oxidation states overlap considerably,
perhaps owing in large measure to the reduction of s character in the P-H bond as
the coordination numbers increase. As expected, the loss of a P lone pair upon
coordination of a phosphine to a boron Lewis acid or a transition metal results in a
marked increment in coupling. The effect of electronegativity is evident in the rise
of 1J(31P,1H) especially when electron electronegative halogens are bound to
phosphorus.9
A different situation prevails for the coupling of
31
P with
couplings to phosphorus are manifest in proton decoupled
13
13
C where useful
C NMR spectra. In
this case the effect is seen only on the 13C NMR spectra, because the low natural
abundance of
coupled
31
13
C (1.1%) in insufficient to lead to an observable number of
P nuclei. Such couplings greatly aid the identification of the carbon
resonances adjacent to phosphorus as well as providing important stereochemical
information in many instances.2c
3.2.1
31
P-11B coupling
The one-bond coupling of 31P and 11B has been recorded mainly for tricovalent P
ligands bonded to a BZ3 moiety for which the range of couplings is 13-174 Hz.
Most of these 11B signals appear as a quartet due to the 31P-11B coupling. 1N NMR
spectra usually display a quartet (1H-11B coupling) which is further split into a
doublet by 1H-31P coupling.2c,10
The difference between the chemical shift of the free tricoodinated phosphorus
compound and the chemical shift of its borane adduct is called the coordination
chemical shift (CCS), which varies depending on the nature of the groups bonded
to phosphorus. Several compounds have been compared, and it appear that
30
INTRODUCTIO : Chapter 3
trialkyl- or triarylphosphines complexation with borane results in a rather strong
deshielding (CCS = 95 to 133 ppm).11
3.3
(1)
References
Koraghiosoff, K. in D. M. Grant and R. K. Harris, eds., Encyclopedia
of Nuclear Magnetic Resonance, vol 12, John Wiley & sons, Inc., New
York, 1997.
(2)
Quin, L. D.; Verkade, J. G. eds., Phosphorus-31 NMR Spectral
Properties in Compound Characterization and Structural Analysis,
VCH Publishers, Inc., New York, 1987; (a) Chapter 1; (b) Chapter 2;
(c) Chapter 13.
(3)
Knight, W. D. Phys. Rev. 1949, 76, 1259.
(4)
Gutowsky, H. S.; McCall, D. W.; Slichter, C. P. J. Chem. Phys 1953,
21, 279; Gutowsky, H. S.; McCall, D. W. J. Chem. Phys 1954, 22,
162.
(5)
Tebby, J. C.; Trippett, S. eds.; Organophosphorus Chemistry, Vol. 4,
Specialist periodical Reports; The Chemical Society: London, 1973,
Chapter 1.
(6)
Quin, L. D. A Guide to Otganophosphorus Chemistry, John Wiley &
sons, Inc., New York, 2000, Chapter 6.
(7)
Prakasha, T. K.; Day, R. O.; Holmes, R. R. Inorg. Chem., 1992, 31,
3391.
(8)
Moser, E.; Fisher, E. O. J. Organomet. Chem., 1968, 15, 157.
(9)
(a) Vande Griend, L. J.; Verkade, J. G. J. Am. Chem. Soc., 1975, 97,
5958; (b) Kretschmer, M.; Pregosin, P. S.; Garralda, M. J. Organomet.
Chem., 1983, 244, 175.
(10)
Brunel, J. M.; Faure, B.; Maffei, M. Coord. Chem. Rev., 1998, 178180, 665.
(11)
Cowely, A. H.; Damasco, M. C. J. Am. Chem. Soc., 1971, 93, 6815.
31
Phosphorus-31 NMR Spectroscopy
32
INTRODUCTION : Chapter 4
Chapter 4
THE PHOSPHORUS DONOR REAGENT
During studies on the reactivity and use of PCl3 in organic synthesis, Baccolini
and his co-workers found1 the surprising result that fused benzo-l,2,3thiadiphospholes (1) was formed by reaction of p-methylthioanisole with PCl3 and
AlCl3. This synthetic procedure has been improved during recent years and now it
is possible to obtain compound 1 with good yields (45%), using a one-pot threestep procedure.2 The prevalent product isolated from the reaction was the
compound cis-1, and only in trace the isomeric compound cis-2 (scheme 4.1). No
appreciable amount of the corresponding trans isomers were observed.
S
S
PCl3 \ AlCl3
80°C
S
P
P S
P
P
+
cis-1
S
cis-2
Scheme 4.1 Synthesis of compound 1 (containing traces of 2).
The X-ray crystal structure determination of cis-11 and cis-23 compounds showed
that both of the molecules exhibit a 'butterfly' arrangement with the phosphorus
electron lone pairs in an eclipsed conformation (Figure 4.1). As this conformation
is unusual for a molecule containing a P(III)-P(III) single bond, a solid state 31PNMR study was performed. The changes in 1J(P,P) and δ31P observed from
solution to solid state indicated that crystal packing effects force of two “wings”
of the butterfly molecule to open slightly in the solid state.4
33
The Phosphorus Donor Reagent
Figure 4.1 X-ray crystal structure of cis-11, where yellow indicates sulfur atoms and red indicates
phosphorus atoms.
This method has also been generalized employing several alkyl aryl sulphides,
providing in this way the corresponding fused benzo-l,2,3-thiadiphospholes, such
as cis-1, but with a decrement of the obtained product.5 In particular the
tioanisoles (3) and PCl3 and AlCl3 were allowed to reflux in the absence of
solvent for ca. 2h. and the products were purified by filtration on Florisil column.
In the scheme 4.2 reports the products (4) are obtained by reaction of different
alkyl- substituted tioanisoles (3) with PCl3 and AlCl3. The best results were
obtained using a ratio (3)- PCl3- AlCl3 of 1:3:0.75. The yields of products (3) were
also dependent on the starting sulphide. The substrate 3b provided the higher
yield. Compounds 4 were stable to air and moisture and for this reason easy to
purify. The reaction appeared to be favoured when the methyl group occupied the
para-position, presumably reducing the by-products arising from the electrophilic
substitution of PCl3 in that position. In addition the ortho-substituent does not
allow the formation of 4 probably because of the steric hindrance of the methyl
group.5
34
INTRODUCTION : Chapter 4
X
S
X
PCl3 \ AlCl3
X
Y
80°C
S
P1
P2 S
Y
3
4
X
Y
a:
b:
c:
d:
e:
f:
Y
H H
Me H
H Me
Me Me
Et
H
t
Bu H
Yield%
22
38
20
35
30
11
Scheme 4.2 Generalization of the method.
Exploiting the reactivity of the heterocycle 1 in order to synthesize other
phosphorus and sulphur heterocycles, different reactions were carried out.6, 7
This new system showed to be highly unstable in the conditions under which
phosphines normally react, i.e. formation of phosphonium salts with alkyl halides,
oxidation with H2O2 reaction with diethyl azodicarboxylate (DEAD)8/catechol or
with phenyl azide. In such cases, rather than the corresponding salts, oxides, spiro
derivatives or phosphazenes9 of 1, decomposition products were obtained,
presumably deriving from P-S and P-P bond cleavage.
Studying this instability of 1, a Friedel-Crafts acylation with acetyl chloride and
AlCl36 was carried out and surprisingly, a highly stereospecific replacement of the
phosphorus P2 with the carbonyl carbon atom of acetyl chloride was obtained.
This phosphorus-carbon exchange occurred under mild conditions in a one-pot
reaction,
and
gave
the
cis-6-R-[1,3]benzothiaphospholo[2,3-b][l
,3]benzothiaphosphole derivative 5 in very good yields (scheme 4.3).
1
S
P
P2 S
1) MeCOCl \ AlCl3,
CH2Cl2 5-10°C
2) room temp.
20 min
cis-1
P
C S
S
Me
cis-5
Scheme 4.3 Exchange of P2 by the carbonyl carbon atom of acetyl chloride.
35
The Phosphorus Donor Reagent
A possible generalization of the reaction with other acyl chlorides was tried in
order to obtain information about the mechanism involved in this phosphoruscarbon exchange.6b In all the reactions performed, the corresponding compound
5-like were isolated in very good yields. In contrast, when acyl chlorides with R
= tBu, Ph, p-ClC6H4, CCl3 were used, the starting material 1 disappeared to give
formation of unidentified products. Only traces of the corresponding fused l,3benzothiaphospholes were detected by GC-MS analysis. From these simple results
it was possible to deduce that this exchange reaction was dependent on the steric
factors associated with the acyl chloride. In fact, with a more forced R group, it
was very likely that the cleavage of P-S and/or P-P bonds did occur, but the ring
closure is disfavoured presumably because of steric congestion.
In scheme 4.4 a mechanism6b for the reactions is illustrated; it is based on the
lability of the P-S bond, the affinity of the phosphorus for the oxygen atom, and
the observed stereospecificity with inversion of configuration in the initial
reaction. As depicted, it was supposed that initially a concerted breaking of the PS bonds occurs with formation of C-S and P-O bonds; in the final step there is a
ring closure, which is favoured when the R group is relatively small; this is in
accord with the above experimental data.
AlCl3
S
R
C
δ+
P1
P2 S
O
Cl-
P
P
+
O
S C
S
AlCl4-
R
P
C S
S
R
cis-5
Scheme 4.4 Proposed mechanism of the phosphorus-carbon exchange.
With the intention of continuing to explore the peculiar reactivity of compound 1,
the reaction with conjugated azoalkenes was investigated.7 They are known to
react with phosphorus halides10 and phosphates,11 but not with trisubstituted
phosphines. Unexpectedly, all the isomers of phenylazostilbene 6a reacted with 1
to afford the previously unknown diazaphosphole 7a, and this procedure
represents a new route for obtaining diazaphosphole derivatives (scheme 4.5).
36
INTRODUCTION : Chapter 4
Unfortunately, all attempts to obtain or to characterize an intermediate adduct
were unsuccesful. However, it is possible to hypothesise a spirocyclic adduct 8
with pentacoordinate P2 atom, in probable equilibrium with different ionic forms.
Its decomposition gave 7a-c, presumably by a reductive elimination12 mechanism.
Unfortunately, it was not possible to identify other by-products in order to
confirm the above hypothesis.
R1-N=N-CR3=CHR2
6a-b
1
S
P
P2
S
R3
2
Toluene reflux
R
P
N
N
R1
7a-b
cis-1
S
R1 N
N
P1
P2 S
R3
H
R3
a: R1=R2=R3= Ph
b: R1= Me, R2=R3= Ph
c: R1= Ph, R2=R3= Me
8a-b
Scheme 4.5 Reaction with conjugated azoalkenes.7
Since the formation of this heterocycle, the fused benzo-l,2,3-thiadiphosphole (1)
from the reaction of p-methyl tioanisole, PCl3 and AlCl3 resulted unusual, its
formation mechanism has been studied.13 The principal problem was the
complexity of the cyclization reaction, but fortunately the separation and the
characterization of the prevalent product (cis-1) was very easy.
The breaking of two S-Me bonds, the formation of two C-P bonds, two P-S bonds,
and one P-P bond are involved in this cyclization, and several pathways could be
hypothesised, but due to a lack of data it had not been possible to determine an
unequivocal reaction pathway. In order to determine the most probable pathway,
it was necessary to uncover some information regarding the demethylation
process, the ortho- and S-phosphorylation, the P-P linkage formation and, if it was
possible, to have some explanation for the facile regioselective and stereoselective
formation of cis-1.
37
The Phosphorus Donor Reagent
It is well documented in the literature14 that when a diphenyl sulfide is caused to
react with AlCl3, a sulfonium salt or complex is formed in a reversible manner,
and evidence for methyl phenyl sulfide-AlCl3 complex formation has also been
reported.15 In addition, when this complex is treated with other reagents, a
cleavage of the C-S bond occurs presumably via a tetracovalent sulfur
compound.14-16 Furthermore, benzyl phenyl sulfide is known16 to form a complex
with AlCl3, which undergoes reaction with water to give thiophenol and benzyl
chloride.
In consideration of the above-mentioned observations reported in the literature, a
multi-step mechanism was proposed as depicted in Scheme 4.6.
In order to obtain supporting evidence for the above-proposed multistep
mechanism, a series of reactions using various conditions were conducted
(different reagent ratios and various temperatures). Aliquots of the reaction
mixtures were analyzed by
determinations .13 The
31
31
P- and 1H-NMR spectroscopy and by GC-MS
P chemical shifts and P-P and P-H coupling constants
found,13 were in good agreement with the formulation of intermediates reported in
the Scheme 4.6.
38
INTRODUCTION : Chapter 4
SMe
PCl3
Me S AlCl3
+
Me
S AlCl3
PCl3
AlCl3
Me
Me
Me A1
B
- MeCl
S
Me
SPCl2
S
P
Cl
A1
+
AlCl3
+
AlCl3
Me
D
Me C
AlCl4
AlCl4
S
P
Cl
Me
PCl3
S
Me
Cl
Cl P Cl
P
S
Me
D'
Me
S
E
- HCl
AlCl4
AlCl4
Cl
P
Me
S
P
Me
- HCl
Cl
P Cl
Me
S
S
P
S
E'
F
Me
Me
AlCl4
Me
Me
H2O
P
P
S
S
Cl
-Cl
F'
Me
S
P
P
S
cis-1
Scheme 4.6 Proposed mechanism of formation of fused benzo-l,2,3-thiadiphospholes (cis-1).
13
39
The Phosphorus Donor Reagent
After the mechanism study, an improved synthetic procedure was formulated, and
now, as reported above, it is possible to obtain the compound cis-1 in moderate
yields.
The increment in the yield has permitted the development of the studies on the
reactivity of this new heterocycle. As reported above, in both reactions6,7 carried
out on the compound 1, the molecule reacted losing a phosphorus atom P2.
Its reactivity was also studied using Grignard reagents, demonstrating that
compound 1 could react with those reagents in an unusual manner. In particular
the simultaneous addition of an equimolar mixture of a bis-Grignard (n = 1, 2) and
a mono-Grignard RMgBr to an equimolar amount of 1 at room temperature,
which gave the cyclic tertiary phosphines 9 as the prevalent product after
quenching with water.17
P
P2
XMg(CH2)3(CH2)nMgX
S P
S
P1
S
S
1
n
MgX
MgX
n = 1,2
A
RMgX
n
P2
H2O
P
S
S
R
9
P1
R
MgX
n
MgX
MgX
B
Scheme 4.7 Reaction between reagent 1 and bis- and mono-Grignard reagents.
These results were explained by the presumed intervention of hypervalent
phosphorus intermediates penta- and hexacoordinates such as A and B, in which
the dibenzo-butterfly moiety of reagent 1 might favour their formation. This
observed favored cyclization might be in accord with a hypervalent intermediate
40
INTRODUCTION : Chapter 4
in which the formation of a cyclic form is favored by a larger factor (105–108)
with respect to an acyclic form (as reported in the Chapter 2). With the aim of
obtaining information about the stability of the hypothetical intermediate A, the
reaction was carried out in a three-step procedure between bis-Grignard reagents
and 1 monitoring the progress of the reaction by 31P NMR spectroscopy. 18 A few
minutes after mixing the reagents the disappearance of the two doublets of 1 was
noted [ δ = 88.3 (d, P1), 65.4 (dt, P2, 3JPH = 7.8 Hz), 1JPP = 211.5 Hz] and the
concomitant appearance of two new doublets [ δ = -43.3 (dm, P1, JPP = 188 Hz);
δ = -47.0 (dt, P2 JPH = 7 Hz), JPP = 188 Hz)], tentatively assigned to the
intermediate A (Scheme 4.7). The large P-P coupling constant indicates that
intermediate A has a P-P bond again; the doublet of triplets observed for P2
indicates that this P atom is bonded to two phenyl groups, while the doublet of
multiplets suggests that P1 is bonded to alkyl groups. This intermediate A is very
stable. Only after the addition of a mono-Grignard reagent and quenching with
water, the disappearance of these signals and the appearance of new signals
corresponding to the phosphine 9 were observed.18 After the study on the reaction
mechanism, the reaction was carried out in a one-pot, two-step procedure, where
the addition in two steps of equimolar amounts of a bis-Grignard reagent and a
mono-Grignard reagent RMgBr to one equivalent of 1 at room temperature, gave
the cyclic phosphine 9, after quenching with water. In this manner the yield was
improved, with a better control of the final products (Scheme 4.7).
With similar methods different classes of tertiary cyclic phosphines were obtained
(see Scheme 4.8). In order to easily characterize the compounds, the final reaction
mixture was treated in situ with elementar sulfur to obtain the corresponding
cyclic phosphines sulfides 10, 11.17, 18 If the reaction mixture is treated with water
instead of S8 the corresponding cyclic phosphines 9 are obtained. Consequently, it
was discovered in the second step that a large variety of Grignard reagents and
other nucleophilic reagents, such as sodium alcoholate or thiolate and lithium
derivatives could be used, obtaining various 1-substitued cyclophosphine
derivatives 12, 13 and 14 respectively (Scheme 4.8).19
41
The Phosphorus Donor Reagent
12
n
P
13
R'S
S
P n
R'O S
n
P
n
1) 2,
2) RONa,
3) S8
1) 2,
2) RSNa,
11
1) 2,
2) CH2=CH(CH2)nMgBr,
3) S8
P
S
P
S 1
3) S8
S
1) 2,
2) RMgBr,
3) S8
n
P
R
S
10
1) 2,
2) R''Li,
3) S8
n
P
14 R''
2 = BrMg(CH2)3(CH2)nMgBr, n = 1, 2
n = 0, 1, 2
R, R', R" = alkyl, alkenyl, phenyl
S
Scheme 4.8 Reaction of compound 1 with bis-Grignard reagents and mono-Grignard reagents
(containing alkyl, phenyl and alkenyl groups), R’ONa, R’SNa and lithium derivatives.
The above reaction was further studied when intermediate A, formed by reaction
of 1 with one equivalent of bis-Grignard reagent, was treated with water.
Unexpectedly, in this case, secondary cyclic phosphanes 1520 were obtained in
70–80% yields (Scheme 4.9).21 Moreover, if the reaction mixture was treated with
acidic water instead of only water, the new compound 16, which is the end
product derived from 1, was isolated, in very good yields (before it could only be
observed by a GC-MS in the reaction mixture). These can be easily separated by
treating the solution with aqueous basic solution; in this way the sodium salt of 16
dissolves in the aqueous soluton, whereas the organic phase contains almost pure
cyclic secondary phosphines, which can be purified by distillation. Compound 16
can be recovered from the basic aqueous layer by acidification and extraction, and
purified by distillation. Simply treating a dry solution of 16 with an equimolar
amount of PCl3 regenerates 1 in sufficiently pure form that it can be reused
without further purification.20
42
INTRODUCTION : Chapter 4
PCl3
P
P XMg(CH2)3(CH2)nMgX
S P
S
S
S
n
MgX
1
H3O+
P
PH
P
H
A
n
15
Y= 70-80%
MgX
+
SH
SH
Y= 90%
1. RMgX
2. H3O+
PCl3
PH
+
SH
n = 1,2
SH
9
Y= 90%
P
R
n
16
Y= 60-70%
Scheme 4.9 Synthesis of secondary and tertiary cyclic phosphines, with recycling of starting
reagent 1.
Following on from the results obtained with secondary phosphines 15, the
reaction to obtain tertiary cyclic phosphines 9 was carried out using the same
treatment of the crude reaction mixture used to obtain secondary cyclic
phosphines, and also in this case the by-product 16 was isolated.
Due to the simple isolation of 16 and its easy recycling into 1, these syntheses can
be considered atom-economic.
43
16
The Phosphorus Donor Reagent
4.2 References
(1)
Baccolini, G.; Mezzina, E.; Todesco, P. E.; Foresti, E.; J. Chem. Soc.
Chem. Commun., 1988, 304.
(2)
The unpublished improved procedure is reported in the Appendix 1
(3)
Baccolini, G.; Mosticchio, C.; Mezzana, E.; Rizzoli, C.; Sgarabotto, P.;
Heteroatom Chemistry, 1993, 4, 319.
(4)
Gang Wu, R.; Wasylishen, E.; Power, W. P.; Baccolini, G.; Can. J. Chem.,
1992, 72, 1229.
(5)
Baccolini, G.; Mezzina, E.; Todesco, P. E.; J. Chem. Soc. Perkin Trans. 1,
1988, 3281.
(6)
(a) Baccolini, G.; Mezzina. E.; Todesco, P. E.; Foresti, E.; J. Chem. Soc.,
Chem. Comm., 1989, 122; (b) Baccolini, G.; Mezzina. E.; J. Chem. Soc.
Perkin Trans. 1, 1990, 19.
(7)
Baccolini, G.; Orsolan, G.; Mezzina, E.; Tetrahedron Lett., 1995, 36, 447.
(8)
(a) von ltzstein, M.; Jenkins, J. D.; J. Chem. Soc., Perkin Trans. 1., 1986,
437. (b) Majoral, J. P.; Kraemer, R.; N'gando M'pondo, T.; Navech. J.;
Tetrahedron Lett., 1980, 21,1307. (c) Goncalves, H.; Dormoy, J. R.;
Chapleur, Y.; Castro, B.; Fauduet, H.; Burgada, R.; Phosphorus Sulfur,
1980, 8, 147.
(9)
(a) Staudinger, H.; Meyer, J.; Helv. Chim. Acta, 1919, 2, 635; (b) Singh,
G.; Zimmer, H.; Organometal. Chem. Rev. Sect. A, 1967, 2, 279.
(10)
(a) Baccolini, G.; Todesco, P. E.; J. Org. Chem, 1974, 39, 2650; (b)
Baccolini, G.; Dalpozzo, R.; Todesco, P. E.; Heteroatom Chem., 1990, 1,
333.
(11)
Baccolini, G.; Todesco, P. E; Tetrahedron Lett., 1978, 2313.
(12)
Schmidpeter, A.; Luber, J.; Tautz, H.; Angew. Chem. Int. Ed., 1977, 16,
546.
(13)
Baccolini, G.; Beghelli, M.; Boga, C.; Heteroatom Chem., 1997, 8, 551.
(14)
Han, C. H.; McEwen, W. E.; Tetrahedron Lett. 1970, 30, 2629.
(15)
Pines, S. H.; Czaja, R. F.; Abramson, N. L.; J. Org. Chem., 1975, 40,
1920.
44
INTRODUCTION : Chapter 4
(16)
Harnish, D. P.; Tarbell, D. S.; J. Am. Chem. Soc., 1948, 70, 4123.
(17)
Baccolini, G.; Boga, C.; Negri, U.; Synlett 2000, 11, 1685.
(18)
Baccolini, G.; Boga, C.; Buscaroli, R. A.; Eur. J. Org. Chem. 2001, 3421.
(19)
Baccolini, G.; Boga, C.; Buscaroli, R. A.; Synthesis. 2001, 13, 1938.
(20)
Baccolini, G.; Boga, C.; Galeotti, M.; Angew. Chem. Int. Ed. 2004, 43,
3058.
(21)
It should be noted that the methods reported in the literature to obtain
phospholanes and phosphinanes multi-steps and with very low yields 35%. For literature on the synthesis of phospholanes and phosphinanes see:
a)
Dimroth,
K.
Heterocyclic
Rings
Containing
Phosphorus
in
Comprehensive Heterocyclic Chemistry, Vol. I (Eds.: A. R. Katritzky,
C.W. Rees), Pergamon, New York, 1984, pp. 500, 513; b) Quin, D.
Phospholes in Comprehensive Heterocyclic Chemistry II, Vol. 2 (Eds.: A.
Katritzky, R.; Rees, C.W.; Scriven, E. F. V.; Bird, C. W.), Pergamon, New
York, 1996, pp. 826; c) Hewitt, D. G.; Six-membered Rings with One
Phosphorus Atom in Comprehensive Heterocyclic Chemistry II, Vol. 5
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven, A. McKillop),
Pergamon, New York, 1996, p. 639. d) Burg, A. B.; Slota, P. J.; J. Am.
Chem. Soc. 1960, 82, 2148. e) Aitken, R. A.; Masamba, W.; Wilson, N. J.;
Tetrahedron Lett. 1997, 38, 8417. f) Lambert, J. B.; Oliver, W. L.;
Tetrahedron 1971, 27, 4245.
45
The Phosphorus Donor Reagent
46
Aim of the Thesis
Aim of the Thesis
AIM OF THE THESIS
As previously reported in the introduction, organophosphorus compounds are
important in many fields. In particular their use as ligands in homogeneous
catalysis has increased enormously in the past 50 years. From here, it is important
to find new synthetic procedures that produce phosphines and organophosphorus
derivatives with an easy and inexpensive approach.
The aim of the first part of this thesis (Chapter 5-10) has been to develop new
synthetic procedures for the synthesis of organophosphorus compounds and in
particular of phosphines. The initial intention was to find innovative methods in
which it was possible to use inexpensive and not air-sensitive starting reagents, as
usually happens in the reported syntheses where halogen phosphorus derivatives
are employed.
For these reasons, the fused benzo-l,2,3-thiadiphosphole was chosen as the
starting reagent. This was possible because previous studies on fused benzo-l,2,3thiadiphosphole demonstrated its ability to release a phosphorus atom when it
reacted with Grignard reagents and was easily recycled at the end of reaction. In
addition, the fused benzo-l,2,3-thiadiphospholes is easily obtained and it is not airsensitive and as such can be conserved for long time.
Moreover, the study of the mechanism of the reaction between fused benzo-l,2,3thiadiphosphole and Grignard reagents was attempted in order to understand
which were the hypervalent phosphorus species involved in the reaction.
The aim of the second part of this thesis (Chapter 11-12) has been to apply the
knowledge, acquired during the making of the first part of this thesis, for the
development of new phosphorus ligands for homogeneous catalysis.
This second part was carried out developing two different projects at the
University of Warwick under the supervision of Professor Martin Wills.
49
50
Results and Discussion
RESULTS and DISCUSSION : Chapter 5
Chapter 5
SYNTHESIS OF HALOALKYL PHOSPHOLANE AND
PHOSPHINANE DERIVATIVES AND THEIR
APPLICATION
5.1 Introduction
The synthesis of cyclic phosphine derivatives is of considerable current interest
principally because these compounds are the most commonly studied ligands for
application in homogeneous catalysis.1 In fact, the development of bisphosphine
and phospho-amino compounds and their application to the homogeneous
catalysis and coordination chemistry have increased enormously in the past
decade.1,2
Generally, the reported syntheses of 1-substituted cyclic phosphines are related to
the interaction of several reagents with halophosphines3,4 or with primary and
secondary phosphines.4-7 However, we have noted that haloalkyl derivatives of tricoordinate phospholane and phosphinane are still unknown. In spite of this,
compounds can be used in the synthesis of bidentate ligands. A possible reason
for their absence in the literature could be that primary or secondary phosphanes
(RPH2 or R2PH) cannot be used to obtain haloalkyl derivatives of cyclic
phosphanes with halogen group derivatives because of the possible reactivity of
the PH group with the halogen group.8 For this reason, it is either very difficult to
obtain haloalkyl cyclic phosphine derivatives with current procedures.
53
Synthesis of Haloalkyl Phospholane and Phosphinane Derivatives
5.2 Results and discussion
Recently a new synthesis9 of tertiary cyclic phosphines, and their sulfides, was
developed using the benzothiadiphosphole 1 as a starting reagent. In fact, as
reported in Chapter 4, the simultaneous or the sequential addition of equimolar
amounts of a bis- and a mono-Grignard reagent RMgBr (R = alkyl, phenyl,
alkenyl) to one equivalent amount of 1 gave tertiary cyclic phosphines and, after
the addition of elemental sulfur, their sulfides in good yields at room temperature
(Chapter 4, Scheme 4.8). In particular a new class of 1-alkenyl derivatives of
cyclic phosphines was obtained that was not possible or very difficult to obtain
with the known procedures.
These results encouraged us to develop a synthetic method to obtain haloalkyl
phospholanes and haloalkyl phosphinanes using our phosphorus-donating reagent
1 by the addition of bis- and a mono- Grignard reagents at room temperature.
Consequently, we obtained the haloalkyl cyclophosphane derivatives 3 (70-80%
yield) by addition to 1, in the first step, of equimolar amounts of a bis-Grignard
reagent 2 (n = 1 or 2), and in the second step, addition of a mono-Grignard reagent
RMgBr (R = haloalkyl group). As reported in Chapter 4, this reaction mechanism
had already been studied and explained by the intervention of hypervalent
phosphorus species such as the intermediate A (scheme 5.1).
In addition we found that the treatment of the resulting reaction mixture with
acidic (HCl) water gave the cyclic tertiary phosphines 3 and the by-product 4 in
90% yield (Scheme 5.1). These two reaction products can be separated easily by
treating the organic solution with aqueous NaOH; in this way the sodium salt of
compound 4 dissolves in the aqueous solution, whereas the organic phase contains
almost pure phosphine 3. Compound 4 can be recovered, as reported previously,11
from the basic aqueous layer by acidification and extraction, and then transformed
to 1 for re-use. It should be noted that phosphines 3 were analyzed only by GCMS analysis, and were not isolated. Rather they were immediately treated with
sulfur to obtain the corresponding sulfides 5 (Scheme 5.1), which are stable and
thus were separated by column chromatography and fully characterized.
54
RESULTS and DISCUSSION : Chapter 5
PCl3
P
S
S
P
1
1) RMgBr;
2) H3O+
P
2
S
S
MgBr
MgBr
P
P
R
n
A
3
n
P
R
SH
SH
4 (90%)
S8
2 = BrMg(CH2)3(CH2)nMgBr
n = 1, 2
R = CH2(CH2)2(CH2)nCl
PH
n +
S
5 (70-80%)
Scheme 5.1 Synthesis of haloalkyl cyclophosphane derivatives 3, and their sulfides 5.
As we hypothesized the presence of an halogen group in the moiety permit the use
of these haloalkyl cyclophosphane derivatives 3 in the synthesis of bidentate
ligands. In fact, the high reactivity of the chlorine group as a living group easily
permits substitution by secondary phosphines and amines.
For the synthesis of the bisphosphine 6, the compound 5b was treated with a
solution of sodium diphenyl phosphine. After treatment of the reaction mixture
with elemental sulfur, compound 6 was obtained in moderate yields (65%)
(scheme 5.2) and purified by column chromatography and fully characterized.
Also phospho-amino compound 7 can be synthesized using 5a which was treated
with piperidine in toluene at reflux. Compound 7 was obtained in high yield
(90%) (scheme 5.2) and purified by column chromatography and fully
characterized.
55
Synthesis of Haloalkyl Phospholane and Phosphinane Derivatives
n
P
R
S
5
N
H
1) NaPPh2
2) S8
S
P
S
N
7 (90%)
P
S
PPh2
6 (65%)
n = 1, 2
R = CH2(CH2)2(CH2)nCl
Scheme 5.2 Synthetic application of haloalkyl cyclophosphines.
Alternatively we optimized a one-pot three-step procedure for the synthesis of a
C2-symmetric bisphospholane compound. We obtained bisphospholane 8 by
addition, in the first step, of two equimolar amounts of bis-Grignard reagent 2 to
one of reagent 1; in the second step another equimolar amount of bis-Grignard
reagent 2 was added to the reaction mixture, finally in the third step, a dropwise
addition of one equimolar amount of 1 was performed (scheme 5.3). After
quenching the reaction mixture with acidic water we obtained the bisphospholane
8 and the end product 4 (90% yield, respect to 1). The two compounds were easily
separated as previously described. After separation, the bisphospholane 8 was
immediately treated with elemental sulfur, giving the sulphide 9 in moderate yield
(45%), which was purified by column chromatography and fully characterized.
56
RESULTS and DISCUSSION : Chapter 5
PCl3
P
S
1) 2 eq 2
2) 1 eq 2
PH
P
P
S
1
3) 1 eq 1
4) H3O+
P
SH
+
8
SH
4 (90%)
S8
S
P
2 = BrMg(CH2)4MgBr
S
P
9 (45%)
Scheme 5.3 Synthesis of bisphospholane 8 and sulfide derivative 9.
5.3 Conclusion
In conclusion, the one-pot synthesis of tertiary acyclic phosphines reported
permits the production of a new class of compounds, as haloalkyl phospholanes
and phoaphinanes in high yields. In this procedure, by-product 4 was recovered
and transformed into the starting reagent 1, making the process very atomeconomic and environmentally friendly.
Importantly, these products could be useful in the synthesis of diphosphine and
phospho-amine derivatives that have a large use in asymmetric catalysis.
5.4 Experimental section
General: 1H,
13
C, and
31
P NMR spectra were recorded at 300 (400), at 76.46
(100.56) and 120.76 (161.89) MHz, respectively. Chemical shifts are referenced
to internal standard TMS (1H NMR), to solvent (77.0 ppm for
13
C NMR) and to
external standard 85% H3PO4 (31P NMR). J values are given in Hz. MS spectra
were recorded at an ionisation voltage of 70 eV. Flash chromatography (FC) was
57
Synthesis of Haloalkyl Phospholane and Phosphinane Derivatives
performed on silica gel (0.040-0.063 mm). Melting points are uncorrected. THF
was distilled from sodium benzophenone ketyl and all solvents were purified
appropriately before use and degassed immediately prior to use. All Grignard
reagents used, both commercially available and prepared from the corresponding
alkyl halide or alkyl dihalide12 and magnesium turnings, were titrated immediately
prior to use by standard methods.13 Air and moisture sensitive solutions and
reagents were handled in a dried apparatus under a dry argon atmosphere using
standard Schlenk-type techniques.
General one-step procedure for the synthesis of cyclic tertiary haloalkyl
phosphine sulfides
The bis-Grignard reagent (1.1 mmol) was added to a solution of 1 (1 mmol) in
THF (10 mL), at room temperature. The mixture was stirred for 15 min, then the
mono-Grignard reagent (1.1 mmol) was added. The reaction mixture was stirred
for 1 h after that the solvent was partially evaporated and the reaction mixture was
treated with aqueous acid solution (HCl). Extraction with CH2Cl2 gave a mixture
of phosphines and the residue 3. The phosphines were easily separated from 3 by
treating the organic solution with aqueous NaOH; after this treatment, the sodium
salt of 4 was dissolved in the aqueous solution, whereas the phosphines were in
the organic phase. Treatment of this layer with a slight excess of elemental sulfur
gave the corresponding sulfides, which were purified by flash chromatography
(dichloromethane: petroleum ether 3:2) and fully characterized. Compound 410
was recovered (90%) from the basic aqueous layer by acidification and extraction
with dichloromethane, and was then purified by distillation and stored under
argon. Simple treatment of a dry solution of compound 4 with an equimolar
amount of PCl3 led to the regeneration of the starting reagent 1 in almost pure
form, allowing it to be reused without further purification.
1-(4-chlorobutyl) phospholane sulfide (5a): y = 80%, colourless oil, RF = 0.44
(dichlromethane);
1
H NMR (300 MHz, CDCl3, 25 °C): δ = 3.58 (t, 2 H, J=5.6
Hz, CH2Cl), 2.20-1.74 (m, 14 H, CH2 ) ppm;
13
C NMR (76.46 MHz, CDCl3, 25
°C): δ = 44.1 (s), 33.2 (d, J=52 Hz), 33.1 (d, J= 15 Hz), 32.8 (d, J=47 Hz), 26.0
58
RESULTS and DISCUSSION : Chapter 5
(d, J=6 Hz), 20.5 (d, J=3 Hz ) ppm; 31P NMR (120.76 MHz, CDCl3, 25 °C): δ =
64.5 (m) ppm; MS (70 eV, EI): m/z : 212 (M+,9), 210 (26), 175 (100), 120 (99);
IR: 598 (CCl), 725 (PS), 1111 (PC) cm-1.
1-(4-chlorobutyl) phosphinane sulfide (5b): y = 82%, grease solid, RF = 0.38
(dichlromethane);
1
H NMR (300 MHz, CDCl3, 25 °C): δ = 3.58 (t, 2 H, J=6.1
Hz, CH2Cl ), 2.20- 1.50 (m, 16 H, CH2) ppm; 13C NMR (76.46 MHz, CDCl3, 25
°C): δ = 44.2 (s), 33.3 (d, J=15 Hz) , 30.9 (d, J=48 Hz), 30.0 (d, J=50 Hz ), 26.4
(d, J=6Hz), 21.9 (d, J=6 Hz), 19.3 (d, J=3 Hz) ppm;
31
P NMR (120.76 MHz,
CDCl3, 25 °C): δ = 37.8 (m) ppm; MS (70 eV, EI): m/z : 226 (M+, 6) 224 (18),
189 (100), 134 (53); IR: 595 (CCl), 728 (PS), 1110 (PC) cm-1.
1-(5-chloropentanyl) phospholane sulfide (5c): y = 73%, grease solid, RF = 0.43
(dichlromethane);
1
H NMR (300 MHz, CDCl3, 25 °C): δ = 3.56 (t, 2 H, J=6.6
Hz, CH2Cl ), 2.20-1.40 (m, 16 H, CH2 ) ppm; 13C NMR (76.46 MHz, CDCl3, 25
°C): δ = 44.7 (s), 33.4 (d, J=47 Hz), 33.2 (d, J=52 Hz) , 32.0 (d, J=15Hz), 26.0
(d, J=6Hz), 22.4 (d, J=3 Hz) ppm;
31
P NMR (120.76 MHz, CDCl3, 25 °C): δ =
64.6 (m) ppm; MS (70 eV, EI): m/z : 226 (M+ , 8), 224 (24), 189 (81), 120 (100);
IR: 598 (CCl), 724 (PS), 1109 (PC) cm-1.
1-(5-chloropentanyl) phosphinane sulfide (5d): y = 75%, grease solid, RF = 0.40
(dichlromethane);
1
H NMR (300 MHz, CDCl3, 25 °C): δ = 3.56 (t, 2 H, J=6.4
Hz, CH2Cl), 2.20-1.40 (m, 18 H, CH2) ppm;
13
C NMR (76.46 MHz, CDCl3, 25
°C): δ = 44.7 (s), 32.1(s), 30.9 (d, J=49 Hz), 30.6 (d, J=51 Hz), 28.0 (d, J=15
Hz), 26.4 (d, J=6 Hz), 21.9 (d, J=6 Hz), 21.1 (d, J=3 Hz) ppm; 31P NMR (120.76
MHz, CDCl3, 25 °C): δ = 38.7 (m) ppm; MS (70 eV, EI): m/z : 240 (M+ , 5), 238
(15), 203 (91), 134 (100).; IR: 595 (CCl), 725 (PS), 1111 (PC) cm-1.
Synthesis of 1-[4-(diphenylphosphorathioyl)butyl]-phosphinane 1-sulfide (6):
To a solution of diphenyl phosphine (0.689 mmol) in THF (4 ml) was added
metallic sodium (0.013 mol) at 0°C, than the mixture was stirred for 5 h at room
temperature. After that the resulting orange-red solution was dropwise added
59
Synthesis of Haloalkyl Phospholane and Phosphinane Derivatives
under argon to a solution of 1-(4-chlorobutyl) phosphinane sulfide (5b) (0.53
mmol) in THF (4 ml). The reaction mixture was stirred for 1 h than was treated
with a slight excess of elemental sulfur to give the corresponding sulfides, which
were purified by flash chromatography (dichloromethane: petroleum ether 3:2)
and fully characterized.
1-[4-(diphenylphosphorathioyl)butyl]-phosphinane 1-sulfide (6): y = 65 %,
yellow solid, pf = 134-136 °C, RF = 0.14 (dichlromethane); 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.86-7.78 (m, 4 H), 7.54-7.42 (m, 6 H), 2.55-2.44 (m, 2 H),
2.12-1.40 (m, 16 H) ppm;
2
13
C NMR (100.56 MHz, CDCl3, 25 °C): δ = 21.8 (d,
JPC=6.48 Hz,), 22.6 (dd, JPC=17.8 Hz, JPP=3.3 Hz), 23.3 (dd, JPC=16.2 Hz,
JPP=2.4 Hz), 26.2 (d, 2JPC= 6.5 Hz), 30.2 (d, 1JPC= 50.2 Hz), 30.8 (d, 1JPC= 48.6
Hz), 32.1 (d, 1JPC= 57.0 Hz), 128.6 (d, JPC =12.1 Hz), 130.9 (d, JPC = 9.7 Hz),
131.5 (d, JPC =3.2 Hz), 132.5 (d, JPC = 80.14 Hz) ppm; 31P NMR (161.89 MHz,
CDCl3, 25 °C): δ = 38.5, 43.0 ppm; IR: 716 (PS), 1439 (P-Ph), 2863 (Ph) cm-1.
Synthesis of 1-[4-(1-sulfidophospholan-1-yl)butyl] piperidine (7):
A solution of 1-(4-chlorobutyl) phospholane sulphide (5a) (1 mmol) and
piperidine (3 mmol) in toluene (10 ml) was refluxed for 20 h. After that the
solvent was partially evaporated and the reaction mixture was treated with water
and extracted with CH2Cl2. The organic layer, containing the product, was
purified by flash chromatography (dichloromethane) and the product fully
characterized.
1-[4-(1-sulfidophospholan-1-yl)butyl] piperidine (7): y = 90%, grease solid, RF
= 0.0 (dichlromethane); 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.50-1.40 (m, 26
H, CH2) ppm; 13C NMR (76.46 MHz, CDCl3, 25 °C): δ = 57.9, 54.1, 33.4 (d, J =
52 Hz), 33.1 (d, J = 47 Hz), 29.7, 26.0 (d, J = 6 Hz), 24.5, 23.4, 21.0 (d, J = 3
Hz) ppm; 31P NMR (120.76 MHz, CDCl3, 25 °C): δ = 64.7 (m) ppm; MS (70 eV,
EI): m/z : 259 (M+, 2), 226 (13), 175 (3), 143 (13), 98 (100).
60
RESULTS and DISCUSSION : Chapter 5
One-step procedure for the synthesis of cyclic tertiary bis-phosphine :
A solution of 1 (1 mmol) in THF (10 mL) was added drop wise to a solution of
bis-Grignard reagent (2 mmol) in THF (5 ml), at room temperature. The mixture
was stirred for 2 h, then again the bis-Grignard reagent (1 mmol) was added to the
resulting solution. After that to the reaction mixture was added drop wise a
solution of 1 (1 mmol) in THF (10 mL), and stirred for 4h. During the 4 h, the
reaction was monitored by GC-MS. After that the solvent was partially evaporated
and the reaction mixture was treated with aqueous acid solution (HCl). Extraction
with CH2Cl2 gave a mixture of diphosphine and the residue 4. The diphosphine
was easily separated from 4 by treating the organic solution with aqueous NaOH;
after this treatment, the sodium salt of 4 was dissolved in the aqueous solution,
whereas the diphosphine was in the organic phase. Treatment of this layer with a
slight excess of elemental sulfur gave the corresponding sulfides (9), which were
purified by flash chromatography (dichloromethane: petroleum ether 3:2) and
fully characterized. Compound 4 was recovered (90%) from the basic aqueous
layer by acidification and extraction with dichloromethane, and was then purified
by distillation and stored under argon. Simple treatment of a dry solution of
compound 4 with an equimolar amount of PCl3 led to the regeneration of the
starting reagent 1 in almost pure form, allowing it to be reused without further
purification.
1,1’-butane-1,4-diylbis(phospholane) 1,1’-disulfide (9)14: y = 45%, brown solid,
pf = 29°C; p.eb. = 115-120°C (0.1 mmHg); 1H NMR (300 MHz, CDCl3, 25 °C): δ
= 1.7-2.1 (m, 24 H) ppm ppm;
13
C NMR (75.46 MHz, CDCl3, 25 °C): δ = 24.0
(2C, dd, 2JPC = 3 Hz, 1JPC = 15 Hz), 26.0 (4C, d, 2JPC = 6 Hz), 33.2 (2C, d, 1JPC =
45 Hz), 33.5 (4C, d, 1JPC = 52 Hz) ppm; 31P NMR (120.76 MHz, CDCl3, 25 °C):
δ = 63.2 ppm; MS (70 eV, EI): m/z : 294 (M+,14), 175 (66), 119 (58), 85 (27), 63
(100), 55 (59), 41 (46); IR: 715.78 (PS), 1113 (PC) cm-1.
61
Synthesis of Haloalkyl Phospholane and Phosphinane Derivatives
5.5 References
(1)
(a) Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New
York, 1994; (b) Burk, M. J.; Gross, M. F.; Martinez, J. P. J. Am. Chem.
Soc., 1995, 117, 9375-9376; (c) Jiang, Q.; Xiao, D.; Zhang, Z.; Cao, P.;
Zang, X. Angew. Chem. Int. Ed., 1999, 38, 516-518.
(2)
(a) Guiry, P. J.; Saunders, C. P. Adv. Synth. Catal., 2004, 346, 497; (b)
Cipot, J.; Weshsler, D.; McDonald, R.; Ferguson, M. J.; Stradiotto, M.
Organometallics, 2005, 24, 1737; (c) Jiang, B.; Huang, Z.G.; Cheng, K.J.
Tetrahedron: Asymmetry, 2006, 17, 942.
(3)
For a review on phospholanes and phosphinanes see: K. Dimroth,
Heterocyclic
Rings
containing
Phosphorus,
in
Comprehensive
Heterocyclic Chemistry, Vol.1 (Eds.: A. R. Katritzky, C. W. Rees),
Pergamon: New York, 1984, pp.494-523.
(4)
Featherman, S. F.; Lee, S. O.; Quin, L. D. J. Org. Chem. 1974, 39, 2899.
(5)
Issleib, K.; Krech, K.; Gruber, K. Chem. Ber. 1963, 96, 2186.
(6)
Davies, H.; Downer, J. D.; Kirby, P. J. Chem. Soc. C. 1966, 245.
(7)
For recent examples of P-H addition to olefins to form phospholanes and
phosphinanes see: (a) Douglass, M. R.; Marks, T. J. J. Am. Chem. Soc.
2000, 122, 1824; (b) Hackney, M. L. J.; Schubert, D. M.; Brandt, P. F.;
Haltiwanger, R.C.; Norman, A. D. Inorg. Chem. 1997, 36, 1867.
(8)
Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev., 1994, 94, 1375, 1404.
(9)
(a) Baccolini, G.; Boga, C.; Negri, U. Synlett, 2000, 1685; (b) Baccolini,
G.; Boga, C.; Buscaroli, R. A. Eur. J. Org. Chem., 2001, 3421.
(10)
(a) Baccolini, G.; Mezzina, E.; Todesco, P. E.; Foresti, E. J. Chem. Soc.
Chem. Commun., 1988, 304; (b) Baccolini, G.; Beghelli, M.; Boga, C.
Heteroatom Chem., 1997, 8, 551; (c) Gang Wu, R.; Wasylishen, E.;
Power, W. P.; Baccolini, G. Can. J. Chem., 1992, 72, 1229.
(11)
Baccolini; G.; Boga, C.; Galeotti, M. Angew. Chem. Int. Ed., 2004, 43,
3058.
(12)
Azuma, Y.; Newcomb, M. Organometallics, 1984, 3, 9.
(13)
Bergbreiter, D. E.; Pendergrass, E. J. Org. Chem., 1981, 46, 219.
62
RESULTS and DISCUSSION : Chapter 5
(14)
Alder, R.W. J. Chem. Soc., Perkin.Trans 1, 1998, 1643.
63
Synthesis of Haloalkyl Phospholane and Phosphinane Derivatives
64
RESULTS and DISCUSSION : Chapter 6
Chapter 6
GENERAL SYNTHESIS OF ACYCLIC TERTIARY
PHOSPHINE SULFIDES
6.1 Introduction
Tertiary phosphines (R3P) are attracting considerable current interest due to their
central role in coordination chemistry1 and homogeneous catalysis.2 However, the
methods available for synthesizing acyclic tertiary phosphines containing different
groups are long and tedious, sometimes difficult and dangerous, and in the case of
tertiary asymmetric phosphines, give poor yields.3-11 In addition, all of these
procedures are made up of sequences of several reactions, some of which require
forcing conditions. Although the publications on the synthesis of triaryl- or
trialkylphosphines and their organic derivatives and their complexes are very
numerous, the literature on the synthesis of trialkenylphosphines or alkenylcontaining phosphines is very limited. For example, trivinylphosphine was
originally prepared via the Grignard method using vinylmagnesium bromide12,13
and PCl3 and subsequently has been synthesized via vinylsodium14 and by a direct
route from elemental phosphorus via potassium phosphide and acetylene.15 All of
these methods require controlled conditions (low temperature) but even under
optimal conditions produce only low to moderate yields.12b,13a The tendency to
produce only low to moderate yields has been attributed to the P-P coupling
reactions of intermediates that form during the preparation of most tertiary
phosphines with Grignard reagents.16,17
65
General Synthesis of Acyclic Tertiary Phosphine Sulfides
6.2 Results and discussion
From the beginning of our research, we found that the reaction between 1 and
mono-Grignard reagents (Scheme 6.1) is more complex than the corresponding
reaction in which a bis-Grignard reagent is used in the first step18,19 (Chapter 4).
In fact, if we added equimolar amounts of three different mono-Grignard reagents
in three successive steps, we obtained a very complex reaction mixture without
appreciable formation of the corresponding tertiary phosphines PR1R2R3. The
absence of the tertiary phosphines PR1R2R3 suggested that the reaction proceeds
via an intermediate such as A' (Scheme 6.1), which can be formed when monoGrignard reagents are used. The intermediate A' is expected to have a shorter
lifetime than A because the latter molecule is stabilized by the presence of the
additional ring formed by the reaction of 1 with the bis(Grignard) reagent. With
this in mind, we tried various procedures in which only a very short time elapsed
between the addition of the three Grignard reagents. The simplest procedure tested
was the simultaneous addition of 3 mol of RMgBr. When R1 = R2 = R3, the yields
are very high, as in the synthesis of phosphines 2 (85-90% yield), which are
obtained by simple addition of three moles of RMgBr to a THF solution of one
mole of 1. It should be noted that using this procedure it is possible to obtain vinyl
and allyl phosphines (2d,e) in better yields and in a more facile manner than using
previously reported methods.12-15 After quenching the reaction mixture with acid
(HCl) water we obtained 2 and the end product 3 in 90% yield (Scheme 6.1).
These two compounds can be easily separated by treating the organic solution
with aqueous NaOH; in this way, the sodium salt of compound 3 dissolves in the
aqueous solution, whereas the organic phase contains almost pure phosphine 2,
which can be further purified by bulb-to-bulb distillation. Compound 2 can be
recovered, as reported previously,20 from the basic aqueous layer by acidification
and extraction, and then transformed to 1 for reuse.
66
RESULTS and DISCUSSION : Chapter 6
Me
P
S P
S
Me
R1MgBr,
R2MgBr
Me
1
3 RMgBr
P
Me
MgBr
S P R2
S
R1
MgBr
R3MgBr
PR1R2R3
PCl3
A'
Me
+
Me
PH
SH
SH
Me
4a-g
5a-b
3 (90%)
S8
Me
PH
SH
SH
+
PR3
2a-f
S8
3 (90%)
S=PR3
1 2 3
S=PR R R
6a-f (85-90%)
7a-g (75-80%)
8a-b (45%)
4, 7 a-g
a: R1=R2= n-Bu, R3= Ph;
b: R1=R2= n-Bu, R3= Me;
c: R1=R2= Ph, R3= vinyl;
d: R1=R2= allyl, R3= Et;
e: R1=R2= 3-butenyl, R3= Et;
f: R1=R2= 3-butenyl, R3= Ph;
g: R1=R2= 3-butenyl, R3= p-ClC6H4
2, 6 a-f
a: R = Ph;
b: R = Et;
c: R = n-C5H11;
d: R = vinyl;
e: R = allyl;
f: R = 3-butenyl
5, 8 a-b
a: R1= Ph; R2= Et ; R3= Me
b: R1= Ph; R2= n-Bu; R3= Me
Scheme 6.1: the reaction between 1 and mono-Grignard reagents.
When R1=R2≠R3, a mixture of tertiary phosphines is obtained in which P(R1)2R3
(4) is the most prevalent (about 45% of the mixture, from GC-MS analysis).
67
General Synthesis of Acyclic Tertiary Phosphine Sulfides
When R1≠R2≠R3, PR1R2R3 (5) is the most prevalent product, although it is only
obtained in about 23% yield; the other nine possible symmetric tertiary phoshines
such as P(R1)3 or P(R1)2R2 are obtained in smaller yields (about 3% and 11%,
respectively), indicating that the reaction is driven by statistical factors and
implies a contemporaneous and equiprobable attack of the three different
Grignard reagents on the phosphorus atom, independent of their steric hindrance.
This can be explained by considering the structure of 1, which possesses a folded
geometry that is very suitable for this kind of attack. This behavior, which might
be named the "butterfly effect", was recently observed in the facile formation of
transition metal complexes containing a "dibenzo butterfly" moiety.25
To increase the yield of the desired product beyond the statistical limit, we tried a
second procedure in which the different RMgBr reagents were added in two steps
with very short reaction times (4-5 min) between the first and second steps. In this
manner, it could be predicted, on a statistical basis, that the addition in the first
step of equimolar amounts of two different Grignard reagents (R1MgBr and
R2MgBr), followed by the addition in the second step of the third Grignard
reagent (R3MgBr) would give a final mixture containing PR1R2R3 (50%),
P(R1)2R3 (25%), and P(R2)2R3 (25%) (Scheme 6.2).
68
RESULTS and DISCUSSION : Chapter 6
Me
P
S
P
S
1
Me
R1MgX +
R2MgX
Me
Me
MgX
Me
P2
S P1 R1
S R1
A2'
Me
P2
S P1 R2
S R1
A1'
Me
MgX
MgX
Me
MgX
P2
S P1 R2
S R2
A3'
MgX
MgX
R3MgX
R1, R2, R3= alkyl, aryl
Me
PR1R2R3
+
5
P(R1)2R3 + P(R2)2R3
Me
PH
SH
SH
3 ( 90%)
S8
S=PR1R2R3
8 (45%)
S=P(R1)2R3 + S=P(R2)2R3
(40-45%)
Scheme 6.2: The reaction of 1 and three different mono-Grignard reagent using the two-step
procedure. In the scheme are reported the possible statistical intermediates.
In fact, when we used this two-step procedure we obtained asymmetric
phosphines (5a,b) or their sulfides 8a,b in 45% yield together with about 20-25%
of the other symmetric phosphine sulfides, which were separated by column
chromatography (Scheme 6.2). In this procedure, the end product 3 can be
69
General Synthesis of Acyclic Tertiary Phosphine Sulfides
recovered and recycled as described above. Using this one-pot two-step
procedure, symmetric disubstituted phosphines 4a-g (and their sulfides 7a-g) were
obtained in 75-80% yield. It should be noted that phosphines 2, 4, and 5 were
analyzed only by GC-MS analysis, and were not isolated. Rather, they were
immediately treated with sulfur to obtain the corresponding sulfides 6, 7, and 8
(Scheme 6.1), which are stable and thus were isolated and fully characterized.
It is worth noting that the synthesis reported herein makes it possible to obtain, in
a simple one-pot procedure, sulfide derivatives of symmetric and asymmetric
acyclic tertiary phosphines, also containing alkenyl groups (6d-f and 7c-g); the
synthesis of such compounds, which are of great interest in organic chemistry, has
been previously studied only to a very limited extent.
6.3 Conclusion
In conclusion, the one-pot synthesis of symmetric and asymmetric tertiary acyclic
phosphines reported can be achieved through a very simple, efficient, low-cost
method and gives higher yields than previously reported methods. In these
procedures, the byproduct 3 was recovered and transformed into the starting
reagent 1, making the process very atom-economic and environmentally friendly.
It should be noted that this method can also be used to easily obtain trivinyl- or
triallyl phosphines or alkenyl-containing phosphines, making this procedure a new
general protocol and a very convenient, quite unique, method for the simultaneous
construction of three different C-P bonds.
6.4 Experimental section
General: 1H, 13C, and 31P NMR spectra were recorded at 300 (or 400) MHz, 75.46
(or 100.56, or 150.80) MHz, and at 121.47 (or 161.9) MHz, respectively.
Chemical shifts are referenced to internal standard TMS (1H NMR), to solvent
(77.0 ppm for
13
C NMR), and to external standard 85% H3PO4 (31P NMR). J
values are given in Hz. MS spectra were recorded at an ionisation voltage of 70
70
RESULTS and DISCUSSION : Chapter 6
eV. Flash chromatography (FC) was performed on silica gel (0.040-0.063 mm).
Melting points are uncorrected. THF was distilled from sodium benzophenone
ketyl. Air and moisture sensitive solutions and reagents were handled in a dried
apparatus under an atmosphere of dry argon.
One-Step Procedure: Synthesis of Phosphine Sulfides with Simultaneous
Addition of Grignard Reagents. The three Grignard reagents (R1MgBr,
R2MgBr, R3MgBr, 1.2 mmol of each) were simultaneously added to a solution of
benzothiadiphosphole (1) (1.0 mmol) in anhydrous THF under a dry nitrogen
atmosphere. After 30-40 min, the solvent was partially evaporated and the
reaction mixture was treated with aqueous acid solution (HCl). Extraction with
CH2Cl2 gave a mixture of phosphines and the residue 3. The phosphines were
easily separated from 3 by treating the organic solution with aqueous NaOH; after
this treatment, the sodium salt of 3 was dissolved in the aqueous solution, whereas
the phosphines were in the organic phase. Treatment of this layer with a slight
excess of elemental sulfur gave the corresponding sulfides, which were purified
by flash chromatography and fully characterized. Compound 320 was recovered
(90%) from the basic aqueous layer by acidification and extraction with
dichloromethane, and was then purified by distillation and stored under argon.
Simple treatment of a dry solution of compound 3 with an equimolar amount of
PCl3 led to the regeneration of the starting reagent 1 in almost pure form, allowing
it to be reused without further purification.
The yields of the phosphines obtained by the one-step procedure are as follows:
When R1 = R2 = R3, phosphine sulfides (6a-f) were obtained in 85-90% yields.
Triphenylphosphine (2a) and triethylphosphine (2b) and their sulfides 6a and 6b
were characterized by comparison with physicochemical data of commercially
available authentic samples. When R1 = R2 ≠ R3, the reaction mixture contains a
mixture of phosphines P(R1)2R3, P(R1)3, PR1(R3)2, and P(R3)3 in relative
proportions (calculated by GC-MS analysis) of about 45%, 29%, 23%, and 3%,
respectively. When R1 ≠ R2 ≠ R3, the reaction mixture contains a mixture of
phosphines, in which PR1R2R3 is the most prevalent (23% yield; calculated by
GC-MS analysis). The other nine possible symmetric tertiary phosphines such as
71
General Synthesis of Acyclic Tertiary Phosphine Sulfides
P(R1)3 or P(R1)2R2 were present in smaller proportions (about 3% and 11%,
respectively).
In these last two cases, phosphines 4 and 5 and the corresponding sulfides 7 and 8
were obtained in higher yields using the two-step procedure described below.
Two-Step procedure: Preparation of Phosphine Sulfides 7a-g and 8a,b. The
first Grignard reagent (R1MgBr, 2.4 mmol) was added to a solution of
benzothiadiphosphole (1) (1.0 mmol) in anhydrous THF under a dry nitrogen
atmosphere. After 4-5 min, the second Grignard reagent (R2MgBr, 1.2 mmol) was
added. After about 30-40 min, the reaction mixture was treated as described above
for the one-step procedure. Phosphine sulfides 7a-g were purified by FC and
isolated in 75-80% yield. Phosphine sulfides 8a and 8b were obtained in 45%
yield (they were easily separated from the other phosphine sulfides by FC) as
described above for the preparation of compounds 7; in this case, two different
Grignard reagents, R1MgBr (1.2 mmol) and R2MgBr (1.2 mmol), instead of 2.4
mmol of the same organometallic, were added to 1 in the first step and the
Grignard reagent R3MgBr (1.2 mmol) was added in the second step.
Triphenylphosphine sulfide (6a): yield = 85 %; solid, m.p.: 161-163°C (from
ethanol) Lit.26: 162-163 °C; 1H NMR (300 MHz, CDCl3) δ = 7.25-7.50 (m., 9H),
7.50-7.80 (m, 6H); 13C NMR (75.46 MHz, CDCl3) δ = 128.5 (d, J = 13 Hz), 131.5
(d, J = 3 Hz), 132.2 (d, J = 11 Hz), 133.0 (d, J = 85 Hz); 31P NMR (121.47 MHz,
CDCl3) δ = 43.4 (m); MS (70 eV, EI): m/z : 294 [M+, 90], 262 (15), 217 (15), 183
(100); HRMS calcd for C18H15PS, 294.0632; found: 294.0635. Anal Calcd for
C18H15PS, C, 73.45; H, 5.14. found: C, 73.37; H, 5.15; IR (KBr)( ν, cm-1): 640,
690, 710, 1105, 1440.
Triethylphosphine sulfide (6b): yield = 90 %; solid, m.p.: 96-98°C (from
ethanol) Lit.27: 96-97 °C; RF = 0.16 (petroleum ether : diethyl ether 4 : 1); 1H
NMR (300 MHz, CDCl3) δ = 1.20 (dt, 9H, JP-H = 18.2 Hz, JH-H = 7.7 Hz), 1.84
(dq, 6H, JP-H = 11.4 Hz, JH-H = 7.7 Hz); 13C NMR (75.46 MHz, CDCl3) δ = 6.5 (d,
J = 5 Hz), 23.0 (d, J = 52 Hz); 31P NMR (121.47 MHz, CDCl3) δ = 53.7 (m); MS
72
RESULTS and DISCUSSION : Chapter 6
(70 eV, EI): m/z : 150 [M+, 20], 122 (27), 117 (3), 94 (100), 65 (52); HRMS calcd
for C6H15PS, 150.0632; found: 150.0634. Anal Calcd for C6H15PS, C, 47.97; H,
10.06. found: C, 47.90; H, 10.09; IR (CHCl3)( ν, cm-1): 667, 688, 759, 1043,
1453.
Tripentylphosphine sulfide28 (6c): yield = 85 %; oil; 1H NMR (400 MHz,
CDCl3) δ = 0.91 (t, 9H, J = 6.6 Hz), 1.20-1.90 (m.s, 24H);
13
C NMR (150.80
MHz, CDCl3) δ = 13.9, 22.1 (d, J = 4 Hz), 22.2, 30.8 (d, J = 50 Hz), 33.0 (d, J =
15 Hz); 31P NMR (161.9 MHz, CDCl3) δ = 49.3 (m); MS (70 eV, EI): m/z : 276
[M+, 31], 206 (41), 136 (100); HRMS calcd for C15H33PS, 276.2041; found:
276.2045. Anal Calcd for C15H33PS, C, 65.17; H, 12.03. found: C, 65.26; H,
12.06; IR (CHCl3)(ν, cm-1):726, 1067, 1457.
Trivinylphosphine sulfide29 (6d): yield = 90 %; colorless oil; 1H NMR (400
MHz, CDCl3) δ = 6.18 (ddd, 1H, J = 46.1 Hz, J = 10.6 Hz, J = 2.4 Hz,), 6.28-6.45
(m, 2H); 13C NMR (100.56 MHz, CDCl3) δ = 130.4 (d, J = 81 Hz), 133.5 (d, J = 2
Hz);
31
P NMR (161.9 MHz, CDCl3) δ = 29.9; MS (70 eV, EI): m/z : 144 [M+,
100], 118 (33), 111 (12), 85 (35), 63 (37); HRMS calcd for C9H9PS, 144.0163;
found: 144.0160. Anal Calcd for C9H9PS, C, 49.98; H, 6.29. found: C, 49.93; H,
6.31; IR (neat)(ν, cm-1):651, 705, 737, 909, 1265.
Triallylphosphine sulfide (6e): yield = 90 %; colorless oil; 1H NMR (300 MHz,
CDCl3) δ = 2.58-2.75 (m, 6H), 5.10-5.30 (m, 6H), 5.70-5.92 (m, 3H, CH=);
13
C
NMR (75.46 MHz, CDCl3) δ = 36.1 (d, J = 49 Hz), 121.0 (d, J = 12 Hz), 127.7 (d,
J = 9 Hz); 31P NMR (121.47 MHz, CDCl3) δ = 41.4 (m); MS (70 eV, EI): m/z :
186 [M+, 4], 145 (19), 103 (46), 63 (100); HRMS calcd for C9H15PS, 186.0632;
found: 186.0630. Anal Calcd for C9H15PS, C, 58.04; H, 8.12. found: C, 58.08; H,
8.14; IR(neat)(ν, cm-1): 641, 729, 925, 991, 1417, 1634.
Tri(3-butenyl)phosphine sulfide (6f): yield = 85 %; colorless oil;1H NMR (300
MHz, CDCl3) δ = 2.43-2.62 (m, 6H), 2.85-3.08 (m, 6H), 5.55-5.80 (m, 6H), 6.356.55 (m, 3H); 13C NMR (75.46 MHz, CDCl3) δ = 26.5 (d, J = 3 Hz), 30.2 (d, J =
50 Hz), 115.7, 136.9 (d, J = 15 Hz); 31P NMR (121.47 MHz, CDCl3) δ = 47.6 (m);
73
General Synthesis of Acyclic Tertiary Phosphine Sulfides
MS (70 eV, EI): m/z : 228 [M+, 1], 174 (4), 120 (79), 63 (60), 55 (100); HRMS
calcd for C12H21PS, 228.1102; found: 228.1100. Anal Calcd for C12H21PS, C,
63.12; H, 9.27. found: C, 63.03; H, 9.30; IR (neat)(ν, cm-1): 791, 909, 989, 1440,
1637.
Dibutyl(phenyl)phosphine sulfide28,30 (7a): yield = 77 %; solid; m.p.: 47-48°C
(from ethanol) Lit.3: 47 °C; 1H NMR (300 MHz, CDCl3) δ = 0.87 (t, 6H, J = 7.2
Hz), 1.20-2.50 (m.s, 12H), 7.40-7.56 (m, 3H), 7.78-7.95 (m, 2H);
13
C NMR
(75.46 MHz, CDCl3) δ = 13.6, 23.8 (d, J = 16 Hz), 24.3 (d, J = 3 Hz), 32.9 (d, J =
54 Hz), 128.5 (d, J = 12 Hz), 130.9 (d, J = 10 Hz), 131.3 (d, J = 3 Hz), 133.1 (d, J
= 80 Hz); 31P NMR (121.47 MHz, CDCl3) δ = 47.4 (m); MS (70 eV, EI): m/z (%):
254 [M+, 33], 198 (55), 142 (100), 79 (25), 63 (15); HRMS calcd for C14H23PS,
254.1258, found: 254.1255; Anal Calcd for C14H23PS, C, 66.10; H, 9.11. found:
C, 66.01; H, 9.14; IR (CHCl3)(ν, cm-1): 691, 739, 1104, 1435, 1458.
Dibutyl(methyl)phosphine sulfide31 (7b): yield = 75 %; greasy solid, m.p.: 2426°C (from ethanol) Lit.30b: 25-26 °C; 1H NMR (300 MHz, CDCl3) δ = 0.89 (t,
6H, J = 7.2 Hz), 1.35-1.50 (m, 4H), 1.58 (d, 3H, J = 12.4 Hz), 1.50-1.75 (m, 4H),
1.75-1.95 (m, 4H); 13C NMR (75.46 MHz, CDCl3) δ = 13.6, 18.4 (d, J = 53 Hz),
23.9 (d, J = 16 Hz), 24.5 (d, J = 4 Hz), 32.7 (d, J = 52 Hz);
31
P NMR (121.47
MHz, CDCl3) δ = 41.9 (m); MS (70 eV, EI): m/z (%): 192 [M+, 92], 136 (95), 94
(62), 80 (100), 63 (8), 55 (10); HRMS calcd for C9H21PS, 192.1102, found:
192.1100; Anal Calcd for C9H21PS, C, 56.21; H, 11.01. found: C, 56.30; H, 10.99;
IR (CHCl3) (ν, cm-1): 728, 1094, 1450.
Diphenyl(vinyl)phosphine sulfide (7c): yield = 76%; colorless oil; 1H NMR (400
MHz, CDCl3) δ = 6.15-6.50 (m, 3H), 7.42-7.56 (m, 6H), 7.72-7.84 (m, 4H);
13
C
NMR (150.80 MHz, CDCl3) δ = 128.6 (d, J = 12 Hz), 131.4 (d, J = 80 Hz), 131.5
(d, J = 10 Hz), 131.6 (d, J = 3 Hz), 132.6 (d, J = 86 Hz), 134.3; 31P NMR (161.9
MHz, CDCl3) δ = 37.7 (m); MS (70 eV, EI): m/z (%): 244 [M+, 100], 218 (19),
183 (55), 133 (26); HRMS calcd for C14H13PS, 244.0476, found: 244.0480; Anal
Calcd for C14H13PS, C, 68.83; H, 5.36. found: C, 68.90; H, 5.38; IR (neat) (ν, cm1
): 605, 636, 689, 712, 727, 1103, 1377, 1438.
74
RESULTS and DISCUSSION : Chapter 6
Diallyl(ethyl)phosphine sulfide (7d): yield = 80 %; colorless oil; 1H NMR (300
MHz, CDCl3) δ = 1.15-1.35 (m, 3H), 1.75-2.00 (m, 2H), 2.65-2.80 (m, 4H), 5.205.45 (m, 4H), 5.80-6.00 (m, 2H); 13C NMR (75.46 MHz, CDCl3) δ = 6.1 (d, J = 5
Hz), 22.8 (d, J = 52 Hz), 36.4 (d, J = 49 Hz), 120.6 (d, J = 12 Hz), 128.0 (d, J = 9
Hz); 31P NMR (121.47 MHz, CDCl3) δ = 45.9 (m); MS (70 eV, EI): m/z (%): 174
[M+, 5], 133 (19), 105 (13), 92 (7), 63 (100); HRMS calcd for C8H15PS, 174.0632,
found: 174.0630; Anal Calcd for C8H15PS, C, 55.14; H, 8.68. found: C, 55.06; H,
8.71; IR (neat) (ν, cm-1): 806, 922, 989, 1456, 1633.
Di(3-butenyl)ethylphosphine sulfide (7e): yield = 78 %; colorless oil; 1H NMR
(300 MHz, CDCl3) δ = 1.10-1.30 (m, 3H), 1.70-2.00 (m, 6H), 2.30-2.50 (m, 4H),
5.00-5.20 (m, 4H), 5.75-5.95 (m, 2H); 13C NMR (75.46 MHz, CDCl3) δ = 6.5 (d,
J = 5 Hz), 24.4 (d, J = 51 Hz), 26.4 (d, J = 3 Hz), 29.5 (d, J = 50 Hz), 115.6, 137.0
(d, J = 15 Hz); 31P NMR (121.47 MHz, CDCl3) δ = 49.7 (m); MS (70 eV, EI): m/z
(%): 202 [M+, 6], 174 (2), 147 (7), 120 (100), 92 (39), 63 (70); HRMS calcd for
C10H19PS, 202.0945, found: 202.0948; Anal Calcd for C10H19PS, C, 59.37; H,
9.47. found: C, 59.33; H, 9.50; IR (neat) (ν, cm-1): 792, 913, 997, 1441, 1639.
Di(3-butenyl)phenylphosphine sulfide (7f): yield = 80 %; colorless oil; 1H NMR
(300 MHz, CDCl3) δ = 1.98-2.20 (m, 4H), 2.30-2.50 (m, 4H), 4.85-5.02 (m, 4H),
5.62-5.80 (m, 2H), 7.37-7.50 (m, 3H), 7.74-7.85 (m, 2H); 13C NMR (75.46 MHz,
CDCl3) δ = 26.2 (d, J = 2 Hz), 32.2 (d, J = 53 Hz), 115.4, 128.6 (d, J = 11 Hz),
130.9 (d, J = 10 Hz), 131.5 (d, J = 80 Hz), 131.6 (d, J = 3 Hz), 137.0 (d, J = 17
Hz); 31P NMR (121.47 MHz, CDCl3) δ = 45.3 (m); MS (70 eV, EI): m/z (%): 250
[M+, 2], 196 (6), 168 (6), 91 (29), 63 (100); HRMS calcd for C14H19PS, 250.0945,
found: 250.0949; Anal Calcd for C14H19PS, C, 67.17; H, 7.65. found: C, 67.11; H,
7.67; IR (neat) (ν, cm-1): 793, 910, 994, 1438, 1481, 1576, 1636.
Di(3-butenyl)4-chlorophenylphosphine sulfide (7g): yield = 78 % colorless oil;
1
H NMR (300 MHz, CDCl3) δ = 1.95-2.25 (m, 4H), 2.30-2.60 (m, 4H), 4.90-5.17
(m, 4H), 5.70-5.90 (m, 2H), 7.49 (dd, 2H, J = 8.7 Hz, J = 2.1 Hz), 7.82 (dd, 2H, J
= 11.8 Hz, J = 8.7 Hz); 13C NMR (75.46 MHz, CDCl3) δ = 26.2, 32.3 (d, J = 54
Hz), 115.6, 128.9 (d, J = 12 Hz), 129.3 (d, J = 75 Hz), 132.4 (d, J = 10 Hz), 136.8
75
General Synthesis of Acyclic Tertiary Phosphine Sulfides
(d, J = 17 Hz), 138.4; 31P NMR (121.47 MHz, CDCl3) δ = 45.1 (m); MS (70 eV,
EI): m/z (%): 284 [M+, 1], 230 (3), 174 (5), 107 (29), 63 (100); HRMS calcd for
C14H18ClPS, 284.0555, found: 284.0558; Anal Calcd for C14H18ClPS, C, 59.04; H,
6.37. found: C, 59.00; H, 6.39; IR (CHCl3) (ν, cm-1): 792, 908, 990, 1436, 1480,
1575, 1637.
Ethyl(methyl)phenylphosphine sulfide32 (8a): yield = 45 %; solid, m.p.: 3234°C (from ethanol) Lit.32a: 33-34 °C; 1H NMR (300 MHz, CDCl3) δ = 0.98-1.20
(m, 3H), 1.87 (d, 3H, J = 12.9 Hz), 1.98-2.10 (m, 2H), 7.35-7.50 (m, 3H), 7.747.86 (m, 2H); 13C NMR (75.46 MHz, CDCl3)
= 6.4 (d, J = 4 Hz), 20.1 (d, J =
56 Hz), 28.0 (d, J = 56 Hz), 128.5 (d, J = 12 Hz), 130.4 (d, J = 10 Hz), 131.4 (d, J
= 3 Hz), 132.0 (d, J = 77 Hz); 31P NMR (121.47 MHz, CDCl3 δ = 42.0 (m); MS
(70 eV, EI): m/z (%): 184 [M+, 75], 156 (100), 141 (36), 109 (15), 78 (20), 63
(18); HRMS calcd for C9H13PS, 184.0476, found: 184.0474; Anal Calcd for
C9H13PS, C, 58.67; H, 7.11. found: C, 58.61; H, 7.13; IR (neat) (ν, cm-1): 694,
744, 1105, 1456.
Butyl(methyl)phenylphosphine sulfide33 (8b): yield = 45 %; colorless oil; 1H
NMR (300 MHz, CDCl3) δ = 0.88 (t, 3H, J = 7.1 Hz), 1.30-1.54 (m, 2H), 1.541.76 (m, 2H), 1.95 (d, 3H, J = 12.8 Hz), 2.02-2.16 (m, 2H), 7.42-7.60 (m, 3H),
7.84-7.94 (m, 2H); 13C NMR (75.46 MHz, CDCl3) δ = 13.6, 20.8 (d, J = 56 Hz),
23.7 (d, J = 17 Hz), 24.5 (d, J = 3 Hz), 34.7 (d, J = 55 Hz), 128.6 (d, J = 12 Hz),
130.4 (d, J = 10 Hz), 131.4 (d, J = 3 Hz), 132.6 (d, J = 77 Hz); 31P NMR (121.47
MHz, CDCl3) δ = 39.7 (m); MS (70 eV, EI): m/z (%): 212 [M+, 38], 156 (100),
141 (24), 123 (11), 78 (14), 63 (10); HRMS calcd for C11H17PS, 212.0789, found:
212.0787; Anal Calcd for C11H17PS, C, 62.23; H, 8.07. found: C, 62.14; H, 8.10;
IR (neat) (ν, cm-1): 689, 739, 1106, 1433, 1456.
76
RESULTS and DISCUSSION : Chapter 6
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(a) Gray, G. A.; Cremer, S. E.; Marsi, K. L. J. Am. Chem. Soc. 1976, 98,
2109. (b) Abdur-Rashid, K.; Fong, T. P.; Greaves, B.; Gusev, D. G.;
Hinman, J. G.; Landau, S. E.; Lough, A. J.; Morris, R. H. J. Am. Chem.
Soc. 2000, 122, 9155. (c) Von Fluck, E.; Binder, H. Z. Anorg. Allg. Chem.
1967, 354, 139.
(31)
(a) Quin, L. D.; Gordon, M. D.; Lee, S. O. Org. Magn. Res. 1974, 6, 503.
(b) Aladzheva, I. M.; Odinets, I. L.; Petrovskii, P. V.; Mastryukova, T. A.;
Kabachnik, M. I. Russ. J. Gen. Chem. E.N. 1993, 63, 431.
79
General Synthesis of Acyclic Tertiary Phosphine Sulfides
(32)
(a) Harwood, H. J.; Pollart, K. A. J. Org. Chem., 1963, 28, 3430. (b)
Leung, P. H.; Willis, A. C.; Wild, S. B. Inorg. Chem. 1992, 31, 1406. (c)
Wolfsberger, W. Z.Naturforsch. 1988, 43b, 295-298. (d) Bruzik, K. S.;
Stec, W. J. J. Org. Chem. 1990, 55, 6131.
(33)
Omelanczuk, J.; Perlikowska, W.; Mikolajczyk, M. J. Chem. Soc., Chem.
Commun. 1980, 24.
80
RESULTS and DISCUSSION : Chapter 7
Chapter 7
ONE-POT SYNTHESIS OF SECONDARY
PHOSPHINES AND THEIR BORANE COMPLEXES
7.1 Introduction
Secondary phosphines are useful intermediates in organic synthesis and represent
versatile synthons for the preparation of chiral mono- and bidentate phosphinic
ligands.1 However, the synthetic procedures for preparing such secondary
phosphines are, as a rule, multistep and laborious with very low overall yields in
the case of alkyl asymmetric secondary phosphines. Some indirect methods have
been developed for the synthesis of secondary phosphines in which a
monochlorophosphine is synthesised and subsequently converted into the desired
phosphine by reduction with lithium alanate, sodium borohydride, or sodium.2
Unfortunately, only a few monochlorophosphines are readily available by reaction
of PCl3 with Grignard reagents: in practice, this synthetic route is easy when the
desired phosphines contains aryl groups, but becomes more complicated when
they contain only alkyl groups, and further difficulties are encountered when the
phosphines contain two different alkyl groups.
Another factor complicating the synthesis of secondary phosphines is their very
high air-sensitivity, which makes them very difficult to handle and leads to the
need for special equipment and experience that may not be available in every
laboratory. To overcome this problem, secondary phosphines are often
transformed into the corresponding phosphine–borane complexes, which are airinsensitive, present particular and very interesting reactivities, and are smoothly
cleaved. In the last decade there has been considerable interest in the preparation
and controlled reactivity of phosphine–borane complexes in particular those
81
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
involving secondary phosphines. Various applications for these complexes have
been identified, including their use in carbonyl additions,3 alkylation,3,4
hydrophosphination,5 and conjugate addition processes,6 as well as in metalmediated couplings.7 Two recent reviews8 highlight the importance of protecting
secondary phosphines in the synthesis of chiral phosphine ligands as well as the
expanded range of controlled synthetic possibilities available with phosphineborane complexes in comparison to the parent phosphines. Secondary phosphineboranes are generally obtained by one of the following procedures: reaction of the
parent free phosphine with BH3·THF or BH3·SMe2 complexes;9 directly from
parent phosphine oxides by in situ reduction with LiAlH4 in the presence of
NaBH4 and CeCl3;10 or by reacting parent phosphine oxides with a large excess of
BH3·SMe2 together with small amount of water.11 Recently, a general synthesis of
phosphine-borane complexes from parent free phosphines and NaBH4/acetic acid
has also been reported.12
7.2 Results and discussion
7.2.1 Developing of synthetic procedure
As reported in Chapter 6, we studied13 the reaction between reagent 1 and monoGrignard reagents. The symmetric tertiary phosphines, or their corresponding
sulfides, were obtained in very high yield, and the asymmetric tertiary, or their
sulfides, were obtained in 45% yield by addition of equimolar amounts of
different Grignard reagents to a solution of 1 in two steps.
These findings prompted us to examine whether a similar one-pot procedure,
employing the same phosphorus atom donor reagent 1, could be used to
synthesize
acyclic
symmetric
and
asymmetric
diaryl-,
arylalkyl-,
and
dialkylphosphines, and their borane complexes.
The simultaneous addition, at room temperature, of equivalent amounts of the
Grignard reagents R1MgBr and R2MgBr to a solution of benzothiadiphosphole (1)
gave, after quenching with acidic water, symmetrical or asymmetrical secondary
phosphines 2 and compound 3 (Scheme 7.1). The intermediate of this reaction
82
RESULTS and DISCUSSION : Chapter 7
was hypothesized to be a pentacoordinate phosphorus species such as A as
reported previously reported.13
The proposed synthesis affords symmetrical secondary phosphines 2a-d (R1=R2)
in high yield (80-85%) and asymmetrical secondary phosphines (R1≠R2) in yields
close to the maximum value of 50% imposed by statistical factors (Chapter 6).13
In order to overcome this statistical limit and to obtain the highest yields of
asymmetric secondary phosphines we carried out the reaction with sequential
addition of the two different RMgBr reagents. We found that, with this procedure,
asymmetric secondary phosphines 2e-h were obtained in 70-75% yields.14 As
previously reported in Chapter 5 and 6, the byproduct 3 was recovered by basicacid exstraction.
PCl3
P2
P 1) R1MgBr
S
S
2
P 2) R MgBr
S
P1 R2
S
1
H3O+
MgBr
R1
A
PH
R1R2PH
2 a-h
(70-85%)
+
SH
SH
3 (90%)
MgBr
1) CH3COOH
PCl3
2) BH3 THF
PH
SH
+ R1R2PH BH3
4 a-h (70-85%)
SH
3 (90%)
a
b
c
d
e
f
g
R1
Et n-Bu n-Pent Ph
Me
Et
R2
Et n-Bu n-Pent Ph
Ph
Ph Ph
h
n-Bu Et
n-Hex
Scheme 7.1: Synthesis of secondary phosphines and their borane complexes.
83
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
The growing interest in the protection of secondary phosphines as phosphineborane complexes prompted us to investigate whether the borane complexes of
secondary phosphines could be obtained using our one-pot procedure without
separation of free phosphine precursor. We found that treatment of the reaction
mixture containing intermediates such as A with acetic acid followed by in situ
addition of BH3·THF complex (or BH3·Me2S or NaBH4/acetic acid) did indeed
afford phosphine–borane complexes 4 in high yields. Unexpectedly, we found that
the secondary phosphine 3 was not complexed; this is of fundamental importance
because it enabled easy recycling of 3 by treatment with PCl3, which afforded the
starting reagent 1. It is noteworthy that reported syntheses8b,11,12 of phosphineborane complexes require, as starting material, the isolation of free phosphines or
their derivatives. This method represent the first reported procedure for
synthesizing secondary phosphine-boranes that does not require isolation of any
phosphine derivatives as precursors. In this procedure, the three borane sources
can be used without distinction.14 However, it should be noted that secondary
dialkylphosphines were easily and quantitatively tranformed into their BH3
complexes by simple addition of one equivalent of BH3·THF to the reaction
mixture, whereas in the case of phosphines bearing phenyl groups, the
complexation was slower and possibly incomplete because of the instability in the
time of BH3·THF solution. This latter limitation was easily overcome by adding
further amounts of BH3·THF solution in successive steps until the reaction was
complete. This reaction is clean and does not use BH3·Me2S, which has a strong
odour that is difficult to eradicate nor does it use the NaBH4/AcOH system, which
requires the removal of residue salts.
7.2.2 Study of intermediates
To evaluate whether secondary phosphanes are also formed using Grignard
reagents bearing bulky groups, we attempted to react 1 with t-butylmagnesium
chloride (Scheme 7.2).
84
RESULTS and DISCUSSION : Chapter 7
P
P
R1MgX
S
∆T (90-100°C
4-5 min)
P
S
S
P
S
R1
1
XMg
1
1) 2 R2MgX
2) H2O
6*a, b
R2PH
PH
+
SH
5
SH 3
P
S
S
P
P
R1MgX
1
S
R2: n-Bu, Ph
X = Br, Cl
S
P
P R1
S R1
S
R1
XMg
a : R1 = t-Bu
b : R1 = t-Pent
c : R1 = Ph3C
d : R1 = i-Pr
e : R1 = c-Hex
f : R1 = Ph
g : R1 = n-Bu
P
R1MgX
6d-g
MgX
MgX
7f, g
H3O+
PH
R2PH
5f, g
+
SH
SH 3
Scheme 7.2: Intermediates of the reactions between above Grignard reagents and
benzothiadiphosphole 1.
GC-MS analysis of the reaction mixture showed only starting reagent 1, indicating
that the reaction between 1 and t-butylmagnesium chloride does not proceed, even
in the presence of an excess of Grignard reagent. Surprisingly, however, when we
subsequently added a less hindered Grignard reagent, R2MgX (Scheme 7.2) to the
reaction mixture containing 1 and t-butylmagnesium chloride, GC-MS analysis of
the reaction mixture again showed only compound 1, indicating that 1 also does
not react with this new Grignard reagent. Given that, in the absence of tbutylmagnesium chloride, R2MgX easily reacts14,15 with 1 to afford the
corresponding secondary symmetrical phosphane R22PH 5, our finding of no
apparent reaction between 1 and R2MgX was unexpected. A plausible explanation
for this would be that in the reaction mixture, 1 complexes with the t-butyl
Grignard to form an instable intermediate, and that this intermediate decomposes
85
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
in the GC injector such that the GC-MS analysis indicates that only compound 1
is present. Thus, we conjectured that the t-butylmagnesium chloride may have
complexed with the S-P bond of 1, thus hindering the subsequent attack of the less
hindered Grignard reagent. To gain more information about the hypothesized
interaction between reagent 1 and t-butylmagnesium chloride, we recorded a
31
P
NMR spectrum of the final crude reaction mixture. As expected, no signals
characteristic of reagent 1 were observed in the spectrum, but two new sets of
doublets (δ= 38.1 ppm (d, 1J(P,P) = 275 Hz), 9.6 ppm (d, 1J(P,P) = 275 Hz)
strongly upfield with respect to those of 1 (δ= 86.8 ppm (d, 1J(P,P) = 208 Hz),
66.7 ppm (d, 1J(P,P) = 208 Hz) were observed, suggesting the presence of a new
species containing a P-P bond. In addition, these latter signals remained for
several hours indicating the good stability of this intermediate. The 1H NMR
spectrum of the crude reaction mixture in [D8]THF contains signals characteristic
of the presence of two non-equivalent aromatic rings as well as a doublet with a
coupling constant of 14 Hz in the region of t-butylic protons, which is ascribed to
a 3JP-H coupling. This was confirmed by examination of the
13
C NMR spectrum,
which contained two doublets of doublets, centered at 37.2 and 29.9 ppm, which
can be assigned, respectively, to the tertiary and methylic carbon atoms of the tbutyl group each coupled with two phosphorus atoms linked in a P-P bond.
Furthermore, to determine which phosphorus is adjacent to the t-butyl moiety, we
carried out a 1H, 31P heteronuclear multiple bond correlation experiment (HMBC,
Figure 7.1) optimized for coupling constants of 12.5 Hz (close to the observed
three bond 3J P-H coupling constant of the methyl signal of the t-butyl moiety).
The HMBC spectrum showed a cross peak indicating a correlation between the
proton resonance of the methyl doublet at 1.14 ppm with that of the 31P doublet at
38.1 ppm.
86
RESULTS and DISCUSSION : Chapter 7
Figure 7.1: 1H, 31P HMBC spectrum of intermediate 6*a in [D8]THF.
The spectrum additionally showed cross couplings in the aromatic region
indicating connections with the phosphorus atom signal at 9.6 ppm (Figure 7.1).
The NMR spectral data are consistent with a structure such as 6*a, represented in
Scheme 7.2, which contains a P-P-C(CH)3 structure and is characterized by
nonsymmetric aromatic rings. Such a configuration could form if one of the
sulphur atoms in 1 coordinates with the magnesium atom of t-butylmagnesium
chloride. To verify the thermal instability of this intermediate, as indicated by the
GC-MS data, the crude reaction mixture containing only 6*a was heated to 90100°C and analyzed by
31
P NMR spectroscopy. After about 4-5 minutes at this
temperature it was observed the disappearance of the signals corresponding to 6*a
and the concomitant appearance of signals related to starting compound 1 (Figure
7.2).
The fact that simple heating at 90-100 °C is sufficient to break the phosphoruscarbon bond, which is typically a very strong bond, supports the hypothesis that
the intermediate has a structure like that of 6*a (Scheme 7.2), in which the
magnesium atom is coordinated both, with sulfur atom and, with a labile
interaction, with the carbon atom of the t-butyl group.
87
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
Starting reagent 1
Intermediate 4*a
Reaction mixture containing intermediate 4*a
after heating at 90-100°C for 4-5 min. that
shows reformation of starting reagent 1.
150
Figure 7.2:
100
50
0
- 50
- 100
- 150
ppm
31
P NMR spectra of the reaction between benzothiadiphosphole 1 and
t-butylmagnesium chloride.
In order to check whether the behaviour showed by the reaction between
compound 1 and t-butylmagnesium chloride could be observed also in other cases,
we carried out the reaction with Grignard reagents characterized by different steric
hindrance (Scheme 7.2). We found that the reaction between compound 1 and tpentylmagnesium chloride produces intermediate 6*b which, when heated, came
back to starting reagents ( see exsperimental section), as previously observed for
6*a.
The reaction with tritylmagnesium chloride (case c) did not occur. When we
carried out the reaction between 1 and one equivalent of phenylmagnesium
bromide (case f), or n-butylmagnesium bromide (case g) we observed in the
31
P
NMR spectrum a couple of doublets ascribed to intermediate 6f (δ= 27.6 and 14.0
ppm (1J(P,P) = 265 Hz ) or 6g (15.8 and 12.2 ppm (1J(P,P) = 258 Hz). In these
cases, after addition of further amounts of the same Grignard reagent, we
observed the disappearance of the first doublets and the concomitant appearance
of a second couple of doublets which were stable and are in accord with the new
pentacoordinate phosphorus species such as 7f (δ= -8.3 and -45.3 ppm (1J(P,P) =
179 Hz) and 7g (-31.6 and -43.3 ppm (1J(P,P)=169 Hz). After addition of water to
88
RESULTS and DISCUSSION : Chapter 7
these reaction mixtures we observed the immediate disappearance of signals of 7f,
(or 7g) and the concomitant appearance of signals of 5f, (or 5g) and 3 (figure 7.3).
It is interesting to note that a simple heating at 90-100 °C of a mixture of
intermediates 6f,g and 7f,g is not able to break the phosphorus-carbon bonds
derived from the reaction with the Grignard reagent, to give 1. This might indicate
a different strenght of the phosphorus-carbon bond both for 6f,g and 7f,g with
respect to 6*a,b, in agreement also with the observed trend, toward up-fields, of
the chemical shifts of the corresponding signals. Then, in 6f,g (Scheme 7.2) the CMg bond is completely broken and, consequently, a total coordination (only
partial in case 6*a, b) between sulphur and MgX group occurs. In agreement with
this proposed mechanism and the two different structures 6* and 6, we have
observed that the attack of the second equivalent of RMgX (R = phenyl, n-butyl)
to 6 is favoured respect to that of the first equivalent of the same Grignard to 1.
Infact, the
31
P NMR spectrum obtained after addition of only one equivalent of
phenylmagnesium- or n-butylmagnesium bromide to compound 1 showed
presence of signals of both, 6f and 7f or 6g and 7g, respectively, together with
those of unreacted 1. This behaviour can be due to the complete coordination
between sulphur and magnesium atoms in intermediates 6f,g that make the
adjacent phosphorus atom more prone to undergo the second attack of the
Grignard reagent with respect to the first one.
89
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
a
b
c
d
150
Figure 7.3:
100
50
0
-50
-100
- 150 ppm
31
P NMR spectra of the reaction between benzothiadiphosphole 1 and n-
butylmagnesium bromide carried out in the NMR tube in THF. a.: spectrum of the starting reagent
1. b.: after addition of one equivalent of the Grignard reagent respect to 1 (presence of
intermediates 6g and traces of 7g and starting material 1). c.: after addition of a further equivalent
of Grignard reagent (only presence of 7g). d.: spectrum of the reaction mixture containing only 7g
after addition of acidic water (formation of dibutylphosphine (5g) and compound 3).
In the case of i-propylmagnesium chloride (case d) and c-hexylmagnesium
chloride (case e) we observed only signals related to intermediates 6d and 6e,
which resulted unchanged after heating at 90-100 °C even after 5-10 minutes.
When the reaction was carried out with two or more equivalents of ipropylmagnesium chloride and c-hexylmagnesium chloride the spectrum again
showed only presence of 6d and 6e without signals of 7d and 7e. Probably, the
steric hindrance of this Grignard reagents are between that of cases a, b and f, g
then the presence of the i-propylic and c-hexylic moiety on 6d and 6e,
respectively, do not permit the attack of the second molecule of ipropylmagnesium chloride or c-hexylmagnesium chloride, so explaining the
absence of formation of the corresponding intermediates 7d and 7e. Probably, we
did not observed signals related to intermediates 6*d-g because the limited steric
90
RESULTS and DISCUSSION : Chapter 7
hindrance of the Grignard reagents makes these intermediates not detectable being
they transformed, immediately after their formation, into 6d-g.
7.2.3 Synthesis of secondary phosphines containing bulky
group.
We found that using i-propylmagnesium chloride or c-hexylmagnesium chloride it
was only possible to obtain the intermediates 6d,e, this encouraging us to try to
obtain secondary phosphine borane complexes using the previous reported
procedure.
In this case, in order to obtain good yields, it is necessary to add as the first step
the Grignard reagent containing the bulkiest group and the second in the
successive step, leaving an opportune reaction time between the two steps. In fact
for bulky groups (as i-propyl and c-hexyl) 3 or 4 minutes of reaction are necessary
to completely form the intermediate 6d,e-like. After the addition of the ipropylmagnesium chloride or c-hexylmagnesium chloride in this first step, the
high steric hindrance of these moieties meant that only Grignard reagents with not
high steric hindrance, such as phenylmagnesium bromide or methylmagnesium
bromide,
could
be
used
in
the
following
step.
The
use
of
o-
metoxyphenylmagnesium bromide is possible only when c-hexylmagnesium
chloride is used in the first step. The hindrance of i-propyl group is too high to
permit the successive reaction with o-metoxyphenylmagnesium bromide. As
previously reported, (i-propyl)2PH and (c-hexyl)2PH cannot be obtained by adding
an excess of the corresponding Grignard reagent. This means that it is possible to
add an excess of i-propylmagnesium bromide and c-hexylmagnesium chloride in
the first step to increase the first step reaction rate without obtaining the
corresponding symmetric secondary phosphines as a by-product. In general, this
permits improvement of the yield in the asymmetric secondary phosphine (2i-k)
bearing bulky groups to 80-85% instead of 70-75% when both Grignard reagents
used have small steric hindrance.14 With the exception of (c-hexyl)(2metoxyphenyl)PH 2l where the hindrance of 2-metoxyphenyl group permits the
reaction with the intermediate 6e, but at the same time makes this reaction very
slow and difficult, giving secondary phosphine in a lower yield (70-75%).
91
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
PCl3
P2
P 1) R1MgBr
S
S
2
P 2) R MgBr
S
R1R2PH
P1 R2
S
1
PH
H3O+
MgBr
+
SH
2 a-p
R1
SH
A
3 (90%)
MgBr
1) CH3COOH
PCl3
2) BH3 THF
PH
SH
+ R1R2PH BH3
4 a-p (70-85%)
SH
3 (90%)
a
b
c
d
e
f
g
R1
Et n-Bu n-Pent Ph
Me
Et
R2
Et n-Bu n-Pent Ph
Ph
Ph Ph
m
n
o
R1
2-MeOPh 2-MePh 4-MePh
R2
Me
2-MePh 4-MePh
h
n-Bu Et
i
i-Pr
n-Hex Ph
j
k
l
c-Hex c-Hex c-Hex
Me
Ph
2-MeOPh
p
-(CH2)5-
Scheme 7.3 General synthesis of secondary phosphines.
When 2-metoxyphenylmagnesium bromide is added to 1 as a first Grignard
reagent, its steric hindrance does not block the successive reaction of
methylmagnesium bromide, giving the secondary phosphine 2m in a 70-75%
yield. Its reactivity can be compared with the reactivity of low steric hindrance
groups.
We also obtained symmetric secondary phosphines containing the substituted
phenyl group (o-tolyl)2PH 2n and (p-tolyl)2PH 2o in high yields (80-85%).
92
RESULTS and DISCUSSION : Chapter 7
It should be noted that phosphines 2i-o, were analyzed only by
31
P NMR
spectroscopy and GC-MS analysis and were not isolated. They were isolated as
borane complexes 4i-o, which are stable derivatives and fully characterized.
To explore the generality of this procedure for synthesizing tertiary phosphineborane complexes, we also used it to synthesize the borane complex of a cyclic
secondary phosphine, namely the 1-phosphinane borane complex (4p), which was
obtained in 80% yield.
7.3 Conclusion
In conclusion, this method represents a general protocol for the synthesis, in high
yields, of acyclic-, cyclic-, symmetrical and asymmetrical secondary phosphines
and their borane complexes using an almost identical, but independent, procedure.
This generality arises because the method uses a phosphorus atom donor 1 and
easily available Grignard reagents, and overcomes the limitations typical of the
classical syntheses of secondary phosphines, which involve multistep syntheses
and are limited by the availability of commercial sources of the organic
phosphorus compounds that are used as starting reagents. In addition, using this
one-pot procedure to obtain phosphine-borane complexes, free compound 3 was
recovered and recycled to starting reagent 1, making the whole process highly
atom-economic and environmentally friendly.
Additionally, the reaction mechanism was studied identifying the intermediates
involved. Different behaviour was observed depending on the steric hindrance of
the used Grignard reagent. In fact, with bulky reagents, as t-butyl- and tpentylmagnesium chloride, the reaction gave only formation of four-center
intermediates 6*a, b whereas with i-propylmagnesium chloride and chexylmagnesium chloride the only intermediates 6d,e were observed and, in the
other cases, the reaction can otherwise proceed toward intermediates 7e, f.
93
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
7.4 Experimental section
General: 1H, 13C, and 31P NMR spectra were recorded at 300 (or 400 or 600), at
75.46 (or 100.56 or 150.82) and 120.75 (or 161.89 or 242.77) MHz, respectively,
in CDCl3 or THF-d8. Chemical shifts are referenced to internal standard TMS (1H
NMR), to solvent (77.0 ppm for 13C NMR) or are referenced to solvent (THF-d8,
1.8 ppm and 26.7 ppm for 1H and 13C NMR, respectively) and to external standard
85% H3PO4 (31P NMR). J values are given in Hz. MS spectra were recorded at an
ionisation voltage of 70 eV. Flash chromatography (FC) was performed on silica
gel (0.040-0.063 mm). Melting points are uncorrected. IR spectra of compounds
11 and 12 showed characteristic bands (~2440 and 2400-2380, respectively, P-H),
near 2370 and 2350 (BH3 as. and symm str.), 1190-1120 and 1080-1040 (BH3 as.
and symm def.), 1000-900 (P-H def.), 790-720 (P-C). THF was distilled from
sodium benzophenone ketyl and all solvents were purified appropriately before
use and degassed immediately prior to use. All Grignard reagents used, both
commercially available and prepared from the corresponding alkyl halide and
magnesium turnings, were titrated immediately prior to use by standard
methods.16 Except tritylmagnesium chloride (Ph3CMgCl), which was prepared
according to Gilman.17 Air and moisture sensitive solutions and reagents were
handled in a dried apparatus under a dry argon atmosphere using standard
Schlenk-type techniques. Reaction between benzothiadiphosphole 1 and
tritylmagnesium chloride does not occur.
Preparation of phosphines 2a-p. Typical procedure A: Solutions of the two
Grignard reagents (R1MgBr: 1.0 mmol, R2MgBr: 1.0 mmol)) were sequentially
added (1-2 min. between the addition of the first and the second Grignard reagent)
to a solution of benzothiadiphosphole (1) (1.0 mmol) in anhydrous THF and under
an argon atmosphere (when R1=R2 the addition of two equivalents of the Grignard
reagent is in one step). After about 20-30 min the solvent was partially evaporated
and the reaction mixture was treated with degassed acidic (HCl) aqueous solution.
Extraction with CH2Cl2 gave a mixture of phosphines and of the residue 3. An
94
RESULTS and DISCUSSION : Chapter 7
easy separation of these compounds was carried out by treating the organic
solution with degassed aqueous NaOH; in this way the sodium salt of compound 3
is dissolved in the aqueous solution, whereas the organic one contains the
phosphines 2 which were immediately purified by bulb to bulb distillation.
Compound 315 was recovered (90%) from the basic aqueous layer by acidification
and extraction with dichloromethane, purified by distillation and stored under
argon. By simple treatment of a dry solution of compound 3 with an equimolar
amount of PCl3 the starting reagent 1 was regenerated in almost pure form so that
it can be reused without further purification.
When Grinard reagents bearing bulky groups (as i-propylmagnesium chloride or
c-hexylmagnesium chloride) are used, it is necessary adding this Grinard reagents
in the first step. The quantity should be around 1.3-2 equivalent respect 1, this is
possible because of impossible to obtain the second attack on intermediate 4d,e.
Also the time between the two steps should be longer (3 or 4 minutes) to permit
the completion formation of 4d,e.
Phosphines 2i-o, were analyzed in the reaction mixture only by
31
P NMR
spectroscopy and GC-MS analysis, and were not isolated. They were isolated as
borane complexes 4i-o, which are stable and fully characterized.
Diethylphosphine 2a: colourless oil, b.p. 83-88 °C/760 mmHg (lit.18: 85 °C/760
mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.90 (br. dm, 1JP-H = 190 Hz,
1H), 1.20-0.90 (m, 10 H) ppm; 31P NMR (120.76 MHz, CDCl3, 25 °C): δ = −55.5
(dm, 1JP-H = 190 Hz), GC-MS (m/z, %): 90 (M+, 15), 89 (M – 1, 100), 61 (0.7);
HRMS calcd. for C4H11P, 90.0598; found: 90.0595.
Dibutylphosphine 2b: colourless oil, b.p. 75-80 °C/18-20 mmHg (lit.19: 71-73
°C/17 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 2.98 (br. dm, 1JP-H = 189
Hz, 1 H), 2.40-1.05 (m, 12 H), 1.05-0.75 (m, 6 H) ppm; 31P NMR (120.76 MHz,
CDCl3, 25 °C): δ = −69.0 (dm, 1JP-H = 189 Hz), GC-MS (m/z, %): 146 (M+, 4),
117 (5), 104 (3), 90 (2), 89 (3), 75 (2), 62 (100), 57 (15); HRMS calcd. for
C8H19P, 146.1224; found: 146.1229.
95
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
Dipentylphosphine 2c: colourless oil, b.p. 110-115 °C/18-20 mmHg (lit.20a: 100
°C/15 mmHg, lit.20b: 110 °C/15 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ =
2.97 (br. dm, 1JP-H = 194 Hz, 1 H), 2.40-1.15 (m, 16 H), 1.00-0.80 (m, 6 H), ppm;
31
P NMR (120.76 MHz, CDCl3, 25 °C): δ = −69.1 (dm, 1JP-H = 194 Hz), GC-MS
(m/z, %): 174 (M+, 4), 159 (1), 145 (1), 131 (1), 118 (3), 103 (9), 76 (15), 62
(100), 55 (14); HRMS calcd for C10H23P, 174.1537; found: 174.1539.
Diphenylphosphine 2d: colourless oil, b.p. 159-164 °C/18-20 mmHg (lit.21: 160162 °C/20 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.40-6.50 (m, 10 H),
5.20-3.50 (br. s. 1H), ppm;
31
P NMR (120.76 MHz, CDCl3, 25 °C): δ = −41.0
(dm, 1JP-H = 219 Hz), GC-MS (m/z, %): 186 (M+, 35), 152 (5), 115 (4), 108 (100),
92 (15); HRMS calcd for C12H11P, 186.0598; found: 186.0594.
Methyl(phenyl)phosphine 2e: colourless oil, b.p. 67-71 °C/18-20 mmHg (lit.22:
62.5-63 °C/13 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.92-6.80 (m, 5
H), 4.32 (br. dm, 1JP-H = 203 Hz, 1H), 1.40-1.30 (m, 3 H) ppm; 31P NMR (120.76
MHz, CDCl3, 25 °C): δ = −71.5 (dm, 1JP-H = 203 Hz), GC-MS (m/z, %): 124 (M+,
100), 109 (99), 78 (37), 63 (27); HRMS calcd for C7H9P, 124.0442; found:
124.0445.
Ethyl(phenyl)phosphine 2f: colourless oil, b.p. 90-93 °C/18-20 mmHg (lit.23: 9292.5 °C/23 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.58-7.00 (m, 5 H),
4.01 (dt, 1JP-H = 204 Hz, 2JP-H = 6.8 Hz, 1 H), 1.90-1.28 (m, 2 H) 0.90-0.80 (m, J =
1 H) ppm;
31
P NMR (120.76 MHz, CDCl3, 25 °C): δ = −44.0 (dm, 1JP-H = 204
Hz); GC-MS (m/z, %): 138 (M+, 92), 108 (100), 78 (46); HRMS calcd for C8H11P,
138.0598; found: 138.0601.
Butyl(phenyl)phosphine 2g: colourless oil, b.p. 110-114 °C/18-20 mmHg (lit.24:
110 °C/18 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.0-6.0 (m, 5 H),
3.32 (dm, 1JP-H = 227 Hz, 1 H), 1.72-0.12 (m, 9 H) ppm; 31P NMR (120.76 MHz,
CDCl3, 25 °C): δ = −53.4 (dm, 1JP-H = 227 Hz),
96
RESULTS and DISCUSSION : Chapter 7
GC-MS (m/z, %): 166 (M+, 40), 137 (6), 124 (100), 109 (56), 108 (50); HRMS
calcd for C10H15P, 166.0911; found: 166.0907.
Ethyl(hexyl)phosphine 2h: colourless oil, b.p. 78-83 °C/18-20 mmHg (lit.25: 85
°C/23 mmHg), 1H NMR (300 MHz, CDCl3, 25 °C): δ = 3.02 (dm, 1JP-H = 185 Hz,
1H), 1.62-1.18 (m, 12 H), 1.18-0.90 (m, 3 H) ppm;
31
P NMR (120.76 MHz,
CDCl3, 25 °C): δ = −61.3 (dm, 1JP-H = 185 Hz), GC-MS (m/z, %): 146 (M+, 15),
131 (4), 117 (14), 89 (29), 76 (100), 62 (61); HRMS calcd for C8H19P, 146.1224;
found: 146.1229.
Isopropyl(phenyl)phosphine 2i26 :
31
P NMR {1H} (161.9 MHz, THF-d8) δ =-
25.1 (dm, JP-H = 201 Hz); GC-MS (m/z, %): 152 [M+, 40], 108 (100) 83 (27) 57
(44).
Cyclohexyl(methyl)phosphine 2j :
31
P NMR {1H} (161.9 MHz, THF-d8) δ =-
46.1 (dm, JP-H = 177 Hz); GC-MS (m/z, %): 130 (M+, 13), 83 (29), 55 (100).
Cyclohexyl(phenyl)phosphine 2k : 31P NMR (161.89 MHz, CDCl3, 25 °C) δ = 29.8 (dm, JP-H=196 Hz); GC-MS (m/z, %): 192 (M+, 1), 110 (5), 83 (6), 55 (100).
Cyclohexyl(2-methoxyphenyl)phosphine 2l :
31
P{1H}NMR (161.89 MHz,
CDCl3, 25 °C): δ= -42.6 (dm, JP-H = 137 Hz); GC-MS (m/z, %): 222 (M+, 22), 140
(100), 109 (40), 83 (75).
(2-Methoxyphenyl)(methyl)phosphine 2m :
31
P{1H}NMR (161.89 MHz,
CDCl3, 25 °C): δ=-83.1 (dm, JP-H= 205 Hz); GC-MS (m/z, %): 154 (M+, 77), 139
(37), 109 (65), 91 (100), 77 (73).
Bis(2-methylphenyl)phosphine 2n26 :
31
P{1H}NMR (161.89 MHz, THF-d8, 25
°C): δ= -58.9 (dm, J = 220 Hz); GC-MS (m/z, %): 214 (M+, 17), 122 (53), 91
(25), 78 (100).
97
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
Bis(4-methylphenyl)phosphine 2o26 : 31P{1H}NMR (161.89 MHz, THF, 25 °C):
δ= -42.2 (dm, J = 215 Hz); GC-MS (m/z, %): 214 (M+, 83), 183 (10), 122 (100),
78 (44).
Phosphinane 2p27 : 31P{1H}NMR (161.89 MHz, THF, 25 °C): δ= -65.0 (dm, J =
190 Hz); MS (70 eV, EI): m/z : 102 (M+, 100), 87 (23), 74 (95), 72 (14), 69 (13),
60 (14), 57 (21).
Preparation of phosphine boranes 4a-h. Typical procedure: Solutions of the
two Grignard reagents (R1MgBr: 1.0 mmol, and R2MgBr: 1.0 mmol) were
sequentially added (1-2 min. between the addition of the first and the second
Grignard reagent) to a solution of benzothiadiphosphole (1) (1.0 mmol) in
anhydrous THF and under an argon atmosphere (when R1=R2 the addition of two
equivalents of the Grignard reagent is in one step). After 20-30 min. the reaction
mixture was treated with acid acetic glacial (2-3 mmol) and stirred for 5 min. The
flask was immersed in an ice bath and BH3-THF complex (1.5 mmol) was added
during 2-3 h. The ice-bath was removed and the solvent was partially removed.
The reaction mixture was treated with degassed acidic (HCl) aqueous solution.
Extraction under argon atmosphere with CH2Cl2 gave a mixture of phosphine
borane and of the residue 3. An easy separation of these compounds was carried
out by treating, under argon atmosphere, the organic solution with degassed
aqueous NaOH; in this way the sodium salt of compound 3 is dissolved in the
aqueous solution, whereas the organic one contains the phosphine borane complex
4 which was purified by chromatography on silica gel (n-hexane:EtOAc 95/5).
Compound 3 can be recovered (90%) from the basic aqueous layer by
acidification and extraction with dichloromethane, treatment with anhydrous
Na2SO4, and concentration under vacuum (all these manipulations require argon
atmosphere, in order to avoid oxidation of compound 3). Compound 3 was
purified by distillation and stored under argon. By simple treatment of the dry
solution of compound 3 with an equimolar amount of PCl3 the starting reagent 1
was regenerated in almost pure form so that it can be reused without further
purification.
98
RESULTS and DISCUSSION : Chapter 7
When Grinard reagents bearing bulky groups (as i-propylmagnesium chloride or
c-hexylmagnesium chloride) are used, it is necessary adding this Grinard reagents
in the first step. The quantity should be around 1.3-2 equivalent respect 1, this is
possible because of impossible to obtain the second attack on intermediate 4d,e.
Also the time between the two steps should be longer (3 or 4 minutes) to permit
the completion formation of 4d,e.
Diethylphosphine borane 4a28: colourless oil, RF = 0.35 (n-hexane : Ethyl
acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.48 (d of sextets, 1JP-H =
355.3 Hz, J = 6.0 Hz, 1 H), 1.87-1.65 (m, 4 H), 1.22 (t, J = 16.8 Hz, J = 7.5 Hz, 3
H), 0.50 (br. q of doublets, J B-H = 95.8 Hz, J = 14.1 Hz, 3 H) ppm;
13
C NMR
(100.56 MHz, CDCl3, 25 °C): δ = 13.3 (d, J = 36.3 Hz), 8.6 (d, J = 3.7 Hz), 31P
NMR (161.89 MHz, CDCl3, 25 °C): δ = 1.8 (q, JB-P = 52.4 Hz); 31P{1H}NMR: δ
= 1.8 (dm, 1JP-H = 355.3 Hz); GC-MS (m/z, %): 90 (M+-BH3, 15), 89 (M – 1,
100), 61 (0.7).
Dibutylphosphine borane 4b12: colourless oil, RF = 0.45 (n-hexane : Ethyl
acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.54 (d of sextets, 1JP-H =
355.2 Hz, J = 5.9 Hz, 1 H), 1.85-1.35 (m, 12 H), 0,94 (t, J = 7.3 Hz, 6 H), 0.51
(br. q, J B-H ~ 98 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 26.5
(d, J = 3.2 Hz), 23.8 (d, J = 12.1 Hz), 20.2 (d, J = 36.4 Hz), 13.5;
31
P NMR
(161.89 MHz, CDCl3, 25 °C): δ = -8.0 (br q, JB-P = 53 Hz); 31P{1H}NMR: δ = 8.0 (dm, 1JP-H = 355.2 Hz); GC-MS (m/z, %): 146 (M+-BH3, 4), 117 (5), 104 (3),
90 (2), 89 (3), 75 (2), 62 (100), 57 (15).
Dipentylphosphine borane 4c: colourless oil, RF = 0.48 (n-hexane : Ethyl acetate
85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.53 (d of sextets, 1JP-H = 354.6
Hz, J = 6.0 Hz, 1 H), 1.81-1.23 (m, 16 H), 0.91 (t, J = 7.0 Hz, 6 H), 0.50 (br. q, J
B-H
~ 100 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 33.0 (d, J =
11.9 Hz), 24.1 (d, J = 3.1 Hz), 22.3, 20.6 (d, J = 35.2 Hz), 14.0, 31P NMR (161.89
MHz, CDCl3, 25 °C): δ = -7.9 (br. q, J B-P ~ 48.0 Hz);
31
P{1H}NMR: δ = -7.9
99
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
(dm, 1JP-H = 354.6 Hz); GC-MS (m/z, %): 174 (M+-BH3, 4), 159 (1), 145 (1), 131
(1), 118 (3), 103 (9), 76 (15), 62 (100), 55 (14).
Diphenylphosphine borane 4d: greasy solid, m.p.: 42-44 °C, (Lit.10b: 43-44 °C);
RF = 0.40 (n-hexane : Ethyl acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 7.71-7.63 (m, 4 H), 7.54-7.42 (m, 6 H), 6.30 (dq, 1JP-H = 378.8 Hz, J = 6.9 Hz, 1
H), 1.07 (br. q, J B-H ~ 97 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ
= 133.0 (d, J = 9.9 Hz), 131.6 (d, J = 1.6 Hz), 129.1 (d, J = 9.8 Hz), 126.2 (d, J =
57.4 Hz); 31P NMR (161.89 MHz, CDCl3, 25 °C): δ = 1.9 (br. q, J B-P ~ 50 Hz);
31
P{1H}NMR: δ = 1.9 (dm, 1JP-H = 378.8 Hz); GC-MS (m/z, %): 186 (M+-BH3,
35), 152 (5), 115 (4), 108 (100), 92 (15).
Methyl(phenyl)phosphine borane 4e29: colourless oil, RF = 0.35 (n-hexane :
Ethyl acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.73-7.67 (m, 2 H),
7.55-7.44 (m, 3 H), 5.32 (d of septets, 1JP-H = 371.2 Hz, J = 5.9 Hz, 1 H), 1.62 (dd,
J = 10.8 Hz, J = 5.9 Hz, 3 H), 0.83 (br. q, J B-H ~ 100 Hz, 3 H) ppm;
13
C NMR
(100.56 MHz, CDCl3, 25 °C): δ = 132.8 (d, J = 8.9 Hz), 132.2 (d, J = 2.9 Hz),
129.5 (d, J = 9.8 Hz), 126.9 (d, J = 56.8 Hz), 8.6 (d, J = 38.8 Hz),
31
P NMR
(161.89 MHz, CDCl3, 25 °C): δ = -14.4 (br. q, J B-P ~ 48 Hz); 31P{1H}NMR: δ = 2.3 (dm, 1JP-H = 371.2 Hz); GC-MS (m/z, %): 124 (M+-BH3, 100), 109 (99), 78
(37), 63 (27).
Ethyl(phenyl)phosphine borane 4f29: colourless oil, RF = 0.37 (n-hexane : Ethyl
acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.72-7.63 (m, 2 H), 7.587.32 (m, 3 H), 5.38 (d of sextets, 1JP-H = 367.8 Hz, J = 5.9 Hz, 1 H), 2.00-1.86 (m,
2 H), 1.13 (dt, J = 17.8 Hz, J = 7.9 Hz, 3 H), 0.81 (br. q, J B-H ~ 97 Hz, 3 H) ppm;
13
C NMR (100.56 MHz, CDCl3, 25 °C): δ = 133.1 (d, J = 8.9 Hz), 132.0 (d, J =
1.9 Hz), 129.3 (d, J = 9.9 Hz), 125.6 (d, J = 54.9 Hz), 17.2 (d, J = 36.7.9 Hz), 8.9
(d, J = 3.1 Hz), 31P NMR (161.89 MHz, CDCl3, 25 °C): δ = 2.2 (br. q, J B-P ~ 45
Hz); 31P{1H}NMR: δ = -2.3 (dm, 1JP-H = 367.8 Hz); GC-MS (m/z, %): 138 (M+BH3, 92), 108 (100), 78 (46).
100
RESULTS and DISCUSSION : Chapter 7
Butyl(phenyl)phosphine borane 4g: colourless oil, RF = 0.34 (n-hexane : Ethyl
acetate 85/15); 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.75-7.62 (m, 2 H), 7.577.38 (m, 3 H), 5.41 (d of sextets, 1JP-H = 366.4 Hz, J = 6.4 Hz, 1 H), 2.10-1.80 (m,
2 H), 1.65-1.45 (m, 2 H), 1.45-1.33 (m, 2 H), 0.90 (t, J = 7.2 Hz, 3 H), 0.78 (br. q,
J B-H ~ 94 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 132.8 (d, J =
8.9 Hz), 131.6 (d, J = 2.5 Hz), 129.0 (d, J = 9.8 Hz), 125.8 (d, J = 55.5 Hz), 26.4
(d, J = 3.4 Hz), 23.7 (d, J = 12.7 Hz), 23.3 (d, J = 35.8 Hz), 13.5,
31
P NMR
(161.89 MHz, CDCl3, 25 °C): δ = -2.3 (br. q, J B-P ~ 45 Hz); 31P{1H}NMR: δ = 2.3 (dm, 1JP-H = 366.4 Hz); GC-MS (m/z, %): 166 (M+-BH3, 40), 137 (6), 124
(100), 109 (56), 108 (50).
Ethyl(hexyl)phosphine borane 4h: colourless oil, RF = 0.50 (n-hexane : Ethyl
acetate 95/5); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.51 (d of sextets, 1JP-H =
355.0 Hz, J = 5.3 Hz, 1 H), 1.89-1.60 (m, 4 H), 1.47-1.24 (m, 8 H), 1.21 (dt, J =
16.7 Hz, J = 7.7 Hz, 3 H), 0.89 (t, J = 6.9 Hz, 3 H), 0.51 (br. q, J B-H ~ 103 Hz, 3
H) ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 31.2, 30.4 (d, J = 11.4 Hz),
24.4 (d, J = 2.7 Hz), 22.4, 20.0 (d, J = 35.5 Hz), 14.0, 13.7 (d, J = 36.3 Hz), 8.6
(d, J = 2.9 Hz), 31P NMR (161.89 MHz, CDCl3, 25 °C): δ = -3.0 (br. q, J B-P ~ 51.5
Hz); 31P{1H}NMR: δ = -3.0 (dm, 1JP-H = 355.0 Hz); GC-MS (m/z, %): 146 (M+BH3, 15), 131 (4), 117 (14), 89 (29), 76 (100), 62 (61).
Isopropyl(phenyl)phosphine borane 4i11 : colourless oil, (n-hexane : diethyl
ether 90/10), 1H NMR (400 MHz, CDCl3, 25 °C) δ= 7.78–7.63 (m, 2 H), 7.60–
7.44 (m, 3 H), 5.30 (dq, 1 H, JP-H = 377 Hz), 2.35–2.16 (m, 1 H), 1.36–1.09 (m, 6
H), 0.63 (br q, J ~ 102 Hz, 3 H);
13
C NMR (100.56 MHz, CDCl3, 25 °C): δ =
133.7 (d, J = 8 Hz), 132.1 (d, J = 2 Hz), 129.2 (d, J = 10 Hz), 125.1 (d, J = 53
Hz), 24.2 (d, J = 35 Hz), 18.2 (d, J = 50 Hz); 31P NMR (161.89 MHz, CDCl3, 25
°C): δ= 16.3 (br. q, J
B-P
~ 44 Hz);
31
P{1H}NMR: δ= 16.3(dm, JP-H = 377 Hz,);
GC-MS (m/z, %): 152 [M+ -BH3, 40], 108 (100) 83 (27) 57 (44).
Cyclohexyl(methyl)phosphine borane 4j : colourless oil, (n-hexane : diethyl
ether 90/10), 1H NMR (400 MHz, CDCl3, 25 °C) δ: 4.47 (dsext, 1 H, J = 357 Hz,
101
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
J = 6 Hz), 1.98–1.88 (m, 2 H), 1.88–1.80 (m, 2 H), 1.77–1.69 (m, 2 H), 1.69–1.63
(m, 1 H), 1.40–1.20 (m, 4 H), 1.32 (dd, 3 H, J = 11 Hz, J = 6 Hz), 0.49 (br q, J ~
98 Hz, 3 H); 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 31.4 (d, J = 36 Hz), 28.0
(d, J = 12 Hz), 26.3 (d, J = 12 Hz), 25.7, 2.9 (d, J = 36 Hz);
MHz, CDCl3, 25 °C): δ= -5.7 (br. q, J
B-P
~ 50 Hz);
31
31
P NMR (161.89
P{1H}NMR: δ= -5.7 (dm,
JP-H = 357 Hz). GC-MS (m/z, %): 130 (M+ -BH3, 13), 83 (29), 55 (100).
Cyclohexyl(phenyl)phosphine borane 4k11 : colourless oil, (n-hexane : diethyl
ether 90/10), 1H NMR (400 MHz, CDCl3, 25 °C) δ= 7.77–7.42 (m, 5 H), 5.24 (dq,
1 H, JP-H = 364 Hz), 2.10–1.63 (m, 6 H), 1.46–1.12 (m, 5 H), 0.80 (br q, J ~99 Hz,
3 H); 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 133.7 (d, J = 8 Hz), 132.4 (d, J
= 2 Hz), 129.1 (d, J = 10 Hz), 125.1 (d, J = 53 Hz), 33.7 (d, J = 37 Hz), 27.0 (d, J
= 9 Hz), 26.8 (d, J = 10 Hz), 26.0;
31
P NMR (161.89 MHz, CDCl3, 25 °C): δ=
13.1 (dm, JP-H = 364 Hz); GC-MS (m/z, %): 192 (M+ -BH3, 1), 110 (5), 83 (6), 55
(100).
Cyclohexyl(2-methoxyphenyl)phosphine borane 4l30 : colourless oil, (n-hexane
: diethyl ether 90/10), 1H NMR (400 MHz, CDCl3, 25 °C) δ: 7.75-7.67 (m, 1 H),
7.52-7.45 (m, 1 H), 7.10-7.00 (m, 1 H), 6.95-6.90 (m, 1 H), 5.51 (d, J = 381Hz, 1
H), 3.90 (s, 3 H), 2.20-1.65 (m, 6 H), 1.45-1.15 (m, 5 H), 0.67 (br. q, J ~100 Hz, 3
H); 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 160.6, 135.7 (d, J =13 Hz), 133.4,
121.1 (d, J =11 Hz), 113.1 (d, J =52 Hz), 110.5 (d, J = 4 Hz), 55.7, 31.7 (d, J =37
Hz), 26.7 (d, J = 10 Hz), 26.5 (d, J = 9 Hz), 25.7; 31P NMR (161.89 MHz, CDCl3,
25 °C): δ= -8.2 (br. q, J B-P ~ 51 Hz); 31P{1H}NMR (161.89 MHz, CDCl3, 25 °C):
δ= – 8.2 (dm, J
PH=
381 Hz); GC-MS (m/z, %): 222 (M+ -BH3, 22), 140 (100),
109 (40), 83 (75).
(2-Methoxyphenyl)(methyl)phosphine borane 4m31 : colourless oil, (n-hexane :
diethyl ether 90/10), 1H NMR (300 MHz, CDCl3, 25 °C) δ = 7.80-7.70 (m, H),
7.53-7.45 (m, 1 H), 7.10-7.00 (m, 1 H), 6.98-6.88 (m, 1 H), 5.67 (dsept, J = 385
Hz, J = 6 Hz, 1 H), 3.89 (s, 3 H), 1.54 (dd, J = 11 Hz, J = 6 Hz, 3 H), 0.76 (br q, J
~ 95 Hz, 3 H); 13C NMR (75.46 MHz, CDCl3, 25 °C): δ =160.8, 134.9 (d, J = 15
102
RESULTS and DISCUSSION : Chapter 7
Hz), 133.9, 121.2 (d, J = 12 Hz), 114.3 (d, J = 55 Hz), 110.5 (d, J = 4 Hz), 55.8,
7.1 (d, J = 40 Hz); 31P NMR (161.89 MHz, CDCl3, 25 °C): δ= -29.3 (br. q, J B-P ~
48 Hz); 31P{1H}NMR (161.89 MHz, CDCl3, 25 °C): δ= -30.4 (dm, J = 385 Hz);
GC-MS (m/z, %): 154 (M+ -BH3, 77), 139 (37), 109 (65), 91 (100), 77 (73).
Bis(2-methylphenyl)phosphine borane 4n : colourless oil, (n-hexane : diethyl
ether 90/10), 1H NMR (400 MHz, CDCl3, 25 °C) δ = 7.62 (dd, J = 14 Hz, J = 8
Hz, 2 H), 7.42 (app. t, J = 7 Hz, 2 H), 7.32-7.22 (m, 4 H), 6.49 (dq, J = 376 Hz, J
= 7 Hz, 1 H), 2.34 (s, 6 H), 1.11 (br q, J ~ 92 Hz, 3 H); 13C NMR (100.56 MHz,
CDCl3, 25 °C): δ = 141.5 (d, J = 4 Hz), 134.0 (d, J = 15 Hz), 131.7 (d, J = 2 Hz),
131.0 (d, J = 8 Hz), 126.5 (d, J = 12 Hz), 125.0 (d, J = 54 Hz), 20.9 (d, J = 5 Hz);
31
P NMR (161.89 MHz, CDCl3, 25 °C): δ= -14.1 (br. q, J
31
P{1H}NMR (161.89 MHz, CDCl3, 25 °C): δ= -14.1 (dm, J = 376 Hz); GC-MS
B-P
~ 48 Hz);
(m/z, %): 214 (M+ -BH3, 17), 122 (53), 91 (25), 78 (100).
Bis(4-methylphenyl)phosphine borane 4o26 : colourless oil, (n-hexane : diethyl
ether 90/10), 1H NMR (400 MHz, THF-d8, 25 °C) δ = 7.65-7-60 (m, 4 H), 7.30 (d,
J = 8 Hz, 4 H), 6.30 (dq, J = 379 Hz, J = 7 Hz, 1 H), 2.39 (s, 6 H), 1.10 (br q, J ~
94 Hz, 3 H);
13
C NMR (100.56 MHz, THF-d8, 25 °C): δ = 142.9 (d, J = 4 Hz),
133.9 (d, J = 16 Hz), 130.6 (d, J = 17 Hz), 125.2 (d, J = 92 Hz), 21.6; 31P NMR
(161.89 MHz, THF-d8, 25 °C): δ= -1.1 (br. q, J
B-P
~ 50 Hz);
31
P{1H}NMR
(161.89 MHz, THF-d8, 25 °C): δ= -1.1 (dm, J = 379 Hz); GC-MS (m/z, %): 214
(M+ -BH3, 83), 183 (10), 122 (100), 78 (44).
Phosphinane borane 4p : colourless oil, (n-hexane : diethyl ether 90/10), 1H
NMR (400 MHz, CDCl3, 25 °C) δ = 4.61 (d, J = 354 Hz, 1 H), 2.20-1.93 (m, 4
H), 1.69-1.50 (m, 6 H), 0.52 (br q, J ~ 97 Hz, 3 H);
13
C NMR (100.56 MHz,
CDCl3, 25 °C): δ = 26.5 (d, J = 5 Hz), 24.9 (d, J = 8 Hz), 19.6 (d, J = 35 Hz); 31P
NMR (161.89 MHz, CDCl3, 25 °C): δ= -12.5 (br. q, J B-P ~ 52 Hz); 31P{1H}NMR
(161.89 MHz, THF-d8, 25 °C): δ= -12.5 (dm, J = 358 Hz); GC-MS (m/z, %): 102
(M+ -BH3, 100), 87 (23), 74 (95), 72 (14), 69 (13), 60 (14), 57 (21).
103
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
Formation of intermediate 6*a and spectra of experiments showing its
thermal instability.
To a solution of compound 1 (0.030g, 0.098 mmol), dissolved in 3 mL of THF-d8,
a solution of t-butylmagnesium chloride (1.5 eq., 1.0 M in THF) was added. After
about 5-10 min. the reaction mixture, analyzed by GC-MS analysis (in the
presence of an internal standard), showed only presence of all the starting reagent
1. A sample of the same crude reaction mixture, analyzed by
31
P NMR
spectroscopy, showed presence of signals of 6*a, which was characterized also by
1
H NMR,
13
C NMR and 1H-31P HMBC (figure 7.1 of main text). The remaining
reaction mixture, after heating at 90-100°C for 4-5 min. showed, at
31
P NMR
analysis, complete disappearance of signals related to 6*a, and concomitant
appearance of those of starting reagent 1. All attempts of crystallization of 6*a do
not permitted to obtain crystals suitable for X-Rays diffraction analysis.
Intermediate 6*a: 1H NMR (600 MHz, THF-d8, 25°C): δ (ppm) = 7.58 (d, J
=10.7 Hz, 1H), 7.53 (d, J =7.9 Hz, 1H), 7.29 (d, J =6.5 Hz, 1H), 7.20 (d, J =8.4
Hz, 1H), 6.94 (d, J =8.3 Hz, 1H), 6.21 (br. d, J ~3 Hz, 1H), 2.34 (s, 3H), 2.04 (s,
3H), 1.14 (d, 3J(P,H)=14 Hz, 9H) ppm; 13C NMR (150.82 MHz, THF-d8, 25°C): δ
(ppm) = 152.5 (dd, J=4 Hz, J=1 Hz), 149.7 (d, J=25 Hz), 143.6 (dd, J=26 Hz, J=2
Hz), 137.8, 136.4, 136.0 (d, J=9 Hz), 135.3 (d, J=33 Hz), 133.4 (d, J=4 Hz),
132.4, 131.7, 130.3, 126.7 (d, J=6 Hz), 37.2 (dd, 1J(P,C)=31 Hz, 2J(P,C)=18 Hz,
C(CH3)3), 29.3 (dd, 2J(P,C)=14 Hz, 3J(P,C)=6 Hz, C(CH3)3), 22.5 (s, CH3), 22.3
(s, CH3);
1
31
P NMR (242.77 MHz, THF-d8, 25°C, H3PO4 ext. std.): δ=38.1 (d,
J(P,P)=275 Hz), 9.6 (d, 1J(P,P)=275 Hz).
Formation of intermediate 6*b and spectra of experiments showing its
thermal instability.
Intermediate 6*b was formed directly in the NMR tube by adding, under argon
atmosphere, 0.15 mL of t-pentylmagnesium chloride (0.15 mmol, 1.0 M solution
in diethyl ether) to compound 1 (0.035g, 0.11 mmol) dissolved in 1.0 mL of THFd8. After 5-10 minutes, the signals of starting reagent 1 (fig.7.4 spectrum a)
disappeared and concomitantly appeared signals related to intermediate 6*b
104
RESULTS and DISCUSSION : Chapter 7
(fig.7.4 spectrum b) which was characterized by 1H,
13
C NMR and
31
P NMR
spectroscopy. Then the reaction mixture was transferred, under argon atmosphere,
in a tree-necked round-bottom flask and heated for 1-2 min. at 90-100 °C then
dissolved in THF and analyzed by 31P NMR spectroscopy (fig.7.4 spectrum c) in
which signals of compound 1 reappeared (in another experiment, when the
solution was heated for more time, about 4-5 min., the spectrum showed complete
disappearance of intermediate 6*b). To the obtained mixture a further amount of
t-pentylmagnesium chloride was added and the corresponding spectrum showed
disappearance of signals of 1 (fig.7.4 spectrum d) which reappeared by further
heating of the reaction mixture (fig.7.4 spectrum d). All attempts of crystallization
of 6*b do not permitted to obtain crystals suitable for X-Rays diffraction analysis.
Intermediate 6*b: 1H NMR (400 MHz, [THF-d8, 25°C): δ (ppm) = 7.54 (d, J
=8.5 Hz, 1H), 7.46 (d, J =8.0 Hz, 2H), 7.12 (d, J =8.0 Hz, 1H), 6.74 (d, J =7.8 Hz,
1H), 6.07 (br. d, J ~2 Hz, 1H), 2.38 (s, 3H), 2.02 (s, 3H), 1.60-1.45 (m, 2H), 1.10
(d, J(P,H)=11 Hz, 6H), 1.06-0.97 (m, 3 H);
13
C NMR (100.56 MHz, THF-d8,
25°C): δ (ppm) = 151.3 (d, J=4 Hz), 148.2 (d, J=26 Hz), 142.4 (d, J=27 Hz),
136.5, 135.0, 134.5 (d, J=10 Hz), 133.8 (d, J=33 Hz), 132.1, 130.9, 130.2, 128.9,
125.2 (d, J=6 Hz), 39.0 (dd, 1J(P,C)=37 Hz, 2J(P,C)=11 Hz, C(CH3)2), 32.9 (d, J =
6 Hz), 23.6 (dd, 2J(P,C)=12 Hz, 3J(P,C)=6 Hz, C(CH3)2), 23.0 (dd, 2J(P,C)=12
Hz, 3J(P,C)=7 Hz, C(CH3)2), 20.3 (s, CH3), 20.1 (s, CH3), 8.3 (d, J = 12 Hz, CH3);
31
P NMR (242.77 MHz, THF-d8, 25°C, H3PO4 ext. std.): δ = 40.4 (d, 1J(P,P)=281
Hz), 12.1 (d, 1J(P,P)=281 Hz).
105
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
a. Starting reagent 1
b. Intermediate 4*b
c.
Reaction
mixture
containing
intermediate 4*b after heating at 90100°C for 1-2 min. that shows
reformation of starting reagent 1.
d. Reaction mixture showed in c.
after addition of a further amount of
t-pentylmagnesium chloride
e. Reaction mixture showed in d.
after heating at 90-100°C for 1-2
min.
Figure 7.4: 31P NMR spectra of the reaction between benzothiadiphosphole 1 and
t-pentylmagnesium chloride.
Formation of intermediates 6d and 6e: The reaction between compound 1 and ipropylmagnesium chloride or c-hexylmagnesium chloride (1.5 equivalents),
analyzed by 31P NMR spectroscopy, showed presence of a couple of doublets (see
below) which, after heating of the reaction mixture for 3-5 min at 90-100 °C,
remained unchanged. In addition, when the reaction was carried out with an two
or more equivalents of i-propylmagnesium chloride or c-hexylmagnesium
chloride, respectively, the spectrum showed only presence of 6d or6e without
signals of 7d or 7e.
Intermediate 6d: 31P NMR (161.89 MHz, THF, 25°C, H3PO4 ext. std.): δ= 28.5
(d, 1J(P,P)=266 Hz), 15.1 (d, 1J(P,P)=266 Hz).
106
RESULTS and DISCUSSION : Chapter 7
Intermediate 6e:
31
P NMR (161.89 MHz, THF, 25°C, H3PO4 ext. std.): δ= 22.7
1
(d, J(P,P)=265 Hz), 12.8 (d, 1J(P,P)=265 Hz).
Formation of intermediates 6f, g and 7f, g:
To a solution of compound 1 (0.306g, 1.0 mmol), dissolved in 10 mL of THF, 1.5
equivalents of phenylmagnesium bromide (or n-butylmagnesium bromide) were
added. After 1 min. the 31P NMR spectrum of the crude reaction mixture showed
presence of starting material 1 together with compound 6f (or 6g) and traces of 7f
(or 7g).
When the reaction was carried out using two equivalents of Grignard reagent the
corresponding 31P NMR spectrum showed only presence of intermediate 7f,g.
Intermediate 6f:
31
P NMR (161.89 MHz, THF, 25°C, H3PO4 ext. std.): δ= 27.6
1
(d, J(P,P)=265 Hz), 14.0 (d, 1J(P,P)=265 Hz).
Intermediate 6g: 31P NMR (161.89 MHz, THF, 25°C, H3PO4 ext. std.): δ= 15.8
(d, 1J(P,P)=258 Hz), 12.2 (d, 1J(P,P)=258 Hz).
Intermediate 7f:
31
P NMR (161.89 MHz, THF, 25°C, H3PO4 ext. std.): δ= -8.3
(d, 1J(P,P)=179 Hz), -45.3 (d, 1J(P,P)=179 Hz).
Intermediate 7g: 31P NMR (161.89 MHz, THF, 25°C, H3PO4 ext. std.): δ= -31.6
(d, 1J(P,P)=169 Hz), -43.3 (d, 1J(P,P)=169 Hz).
7.5 References
(1)
(a) Pietrusiewicz, K. M.; Zablocka, M. Chem. Rev. 1994, 94, 1375-1411.
(b) Engel, R. Synthesis of Carbon-Phosphorus Bonds; CRC Press, Inc.:
Boca Raton, FL, 1988.
(2)
(a) Van Hooijdonk, M. C. J. M.; Gerritsen, G.; Brandsma, L. Phosphorus
Sulfur Silicon Relat. Elem. 2000, 162, 39-49. (b) Stankiewicz, M.; Nycz,
J.; Rachon, J. Heteroatom Chem. 2002, 13, 330-339.
(3)
Imamoto, T. Pure Appl. Chem. 1993, 65, 655-660.
(4)
McKinstry, L.; Livinghouse, T. Tetrahedron 1995, 51, 7655-7666.
107
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
(5)
(a) Bourumeau, K.; Gaumount, A. C.; Denis, J. M. Tetrahedron Lett.
1997, 38, 1923-1926. (b) Bourumeau, K.; Gaumount, A. C.; Denis, J. M.
J. Organomet. Chem. 1997, 529, 205-213.
(6)
Leautey, M.; Deliencourt, G. C.; Jubault, P.; Pannecoucke, X.; Quirion, J.
C. Tetrahedron Lett. 2002, 43, 9237-9240.
(7)
Al-Masum, M.; Kumaraswamy, G.; Livinghouse, T. J. Org. Chem. 2000,
65, 4776-4778.
(8)
(a) Brunel, J. M.; Faure, B.; Maffei, M. Coordination Chemistry Reviews
1998, 178-180, 665-698; (b) Ohff, M.; Holz, J.; Quirmhach, M.; Borner,
A. Synthesis 1998, 1391-1415.
(9)
Beres, J.; Dodds, A.; Morabito, A. J.; Adams, R. M. Inorg. Chem. 1971,
10, 2072-.2074.
(10)
(a) Imamoto, Kusumoto, T.; T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc.
1985, 107, 5301-5303; (b) Imamoto, T.; Oshiki, T.; Onozawa, T.;
Kusumoto, T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244-5252.
(11)
Stankevic, M.; Pietrusiewicz, K. M. Synlett 2003, 7, 1012-1016.
(12)
McNulty, J.; Zhou, Y. Tetrahedron Lett. 2004, 45, 407-409.
(13)
Baccolini, G.; Boga, C.; Mazzacurati, M. J. Org. Chem. 2005, 70, 47744777.
(14)
G. Baccolini, C. Boga, M. Mazzacurati, F. Sangirardi Org. Lett. 2006, 8,
1677-1680.
(15)
G. Baccolini, C. Boga, M. Galeotti, Angew. Chem. 2004, 116, 3120-3122;
Angew. Chem. Int. Ed. 2004, 43, 3058-3060.
(16)
Bergbreiter, D. E.; Pendergrass, E. J. Org. Chem., 1981, 46, 219-20.
(17)
H. Gilman, E. A. Zoellner, J. Am. Chem. Soc., 1929, 51, 3493-3496.
(18)
Hewertson, W.; Watson, H. R. J. Chem. Soc. 1962, 1490-1494.
(19)
Sander, M. Chem. Ber., 1960, 93, 1220-1230.
(20)
(a) Arbuzova, S. N.; Brandsma, L.; Gusarova, N.K.; Tropimov, B. A. Rec.
Trav. Chim. Pays-Bas. 1994, 113, 575-576; (b) Brandsma, L.; Gusarova,
N. K.; Gusarov, A. V.; Verkruijsse, H. D.; Tropimov, B. A. Synth.
Commun. 1994, 24, 3219-3224.
108
RESULTS and DISCUSSION : Chapter 7
(21)
Cristau, H.-J.; Chene, A.; Christol, H. J. Organomet. Chem., 1980, 185,
283-296.
(22)
Dahl, O. Acta. Chem. Scand., 1971, 25, 3163-3171.
(23)
(a) Tsvetkov, E. N.; Bondarenko, N. A.; Malakhova, I. G.; Kabachnik, M.
I. J. Gen. Chem. USSR (Engl. Transl.), 1985, 55, 8-22. (b) Tsvetkov, E.
N.; Bondarenko, N. A.; Malakhova, I. G.; Kabachnik, M. I. Synthesis,
1986, 198-208.
(24)
Van Doorn, J. A.; Meijboom, N. Phosphorus, Sulphur Silicon Relat.
Elem.. 1989, 42, 211.
(25)
Majewski, P. Synthesis. 1987, 554-555.
(26)
Busacca, C. A.; Lorenz, J. C.; Grinberg, N.; Haddad, N.; Hrapchak, M.;
Latli, B.; Lee, H.; Sabila, P.; Saha, A.; Sarvestani, M.; Shen, S.;
Varsolana, R.; Wei, X.; Senanayake, C. H. Org. Lett.. 2005, 7, 4277.
(27)
(a) J. B. Lambert, W. L. Oliver, Tetrahedron 1971, 27, 4245. (b) D . M.
Schubert, A. D. Norman, Inorg. Chem. 1984, 23, 4130. (c) D. M.
Schubert, P. F. Brandt, A. D. Norman, Inorg. Chem. 1996, 35, 6204. (d) P.
F. Brandt, D. M. Schubert, A. D. Norman, Inorg. Chem. 1997, 36, 1728.
(28)
Davis, J.; Drake, J. E. J. Chem. Soc. (A) 1971, 2094.
(29)
Lebel, H.; Morin, S.; Paquet, V. Org. Lett.. 2003, 5, 2347.
(30)
Immoto, T.; Matsuo, M.; Nonomura, T.; Kishikawa, K.; Yanagawa, M.
Heteroatom Chem. 1993, 4, 475.
(31)
Wolfe, B.; Livinghouse, T.; J. Org. Chem., 2001, 66, 1514.
109
One-Pot Synthesis of Secondary Phosphines and their Borane Complexes
110
RESULTS and DISCUSSION : Chapter 8
Chapter 8
SYNTHESIS OF TERTIARY PHOSPHINE-BORANE
COMPLEXES
8.1 Introduction
Phosphine-borane complexes are an important class of compounds that have
attracted increasing interest since the first reported synthesis over 50 years ago.1
In phosphine-boranes, the BH3 is not only a valuable and protective group that can
be easily removed, it also imparts useful reactivity features not found in typical
tetracoordinated phosphorus derivatives.2 Phosphine-borane complexes are now
used in a variety of applications, including alkylations,3,4 conjugate addition
processes,5 and deprotonation followed by metal-mediated coupling.6 Moreover,
numerous recent studies have demonstrated the importance of tertiary phosphineborane complexes in the synthesis of chiral phosphorus ligands, and have
expanded the range of synthetic procedures by using air-stable phosphine-boranes
instead of the analogous phosphines.6,7 Tertiary phosphine-boranes are generally
obtained by reaction of the parent free phosphine with BH3.THF, BH3.SMe2
complexes or NaBH4/acetic acid,8 or directly from parent phosphine oxides by in
situ reduction with LiAlH4 in the presence of NaBH4 and CeCl3.9 However,
currently available methods for the synthesis of acyclic and cyclic tertiary
phosphines are usually long and tedious procedures involving multiple steps,10-21
and are difficult and dangerous in some cases because they require pyrophoric and
air-sensitive reagents such as primary and secondary phosphines and
halophosphines. Moreover, in the case of acyclic tertiary asymmetrical
phosphines, available synthetic procedures result in poor yields.10
111
Synthesis of Tertiary Phosphine-Borane Complexes
8.2 Results and discussion
Using the previously reported22 procedure (Chapter 6) for obtaining acyclic
tertiary phosphines 5a-c, we reacted 1 with three equivalents of mono-Grignard
reagents. We then found that treatment of this reaction mixture with BH3.THF
directly afforded the tertiary phosphine-borane complexes 6a-c in high yield (8590%) without isolation of the free phosphines (Scheme 8.1). Simultaneous with
the formation of the tertiary phosphines, we observed the formation of the
magnesium salt of compound 3, which is the residue of 1. As a consequence, after
completion of the complexation of the tertiary phosphines to give the
corresponding borane complexes, the precursor magnesium salt of 3 can be
transformed in situ into reagent 1 by addition of a small excess of PCl3. Compared
to the previous procedure23 for recycling 1, which involved treatment of the
reaction mixture containing the magnesium salt of 3 with acidic water followed by
the isolation of 3, this new in situ recycling process is very easy and fast.
The procedure reported here is made possible by the chemical stability of tertiary
phosphine borane complexes also in the presence of PCl3, which can be added
directly to the reaction mixture. It should be noted that this procedure cannot be
applied to secondary phosphine borane complexes due to the high reactivity of the
P-H bond with PCl3, which causes a reduction in the yields.
The reformed reagent 1 is almost quantitatively separated from the reaction
mixture by simple crystallization24 whereas the phosphine-borane complex,
present in the mother liquor, is purified by chromatography.
112
RESULTS and DISCUSSION : Chapter 8
P2
S
P2
P2
1
3
1) R MgBr
3) R MgBr
S
P1 2) R2MgBr
S
S
1
MgBr
S
P1 R2
P1
S
R1
MgBr
A
R1
R3
MgBr
R2
R1R2R3P
5a-i
A'
MgBr
MgBr
1) BH3 THF
2) PCl3
P2
S
P1
+ R1R2R3P.BH3
R1 = R2 = R3 (85-90%)
R1 = R2 = R3 (75-80%)
R1 = R2 = R3 (45-55%)
S
6a-i
1 (90%)
a
b
c
d
e
f
g
h
i
R1
n-Bu n-Hex
Ph
n-Hex
Et
c-Hexyl
i-Pr
R2
n-Bu n-Hex
Ph
n-Hex
Et
Me
Me
n-Bu
-
3
n-Bu n-Hex
Ph
n-Bu
n-Pent Me
Me
Et
Et
R
n-Hex R1-R2 = -(CH2)5-
Scheme 2 Synthesis of tertiary phosphine borane complexes with in situ recycling starting
reagent 1.
In the case of the synthesis of symmetrical (R1 = R2 ≠ R3) (5d,e) and asymmetrical
(R1 ≠ R2 ≠ R3) (5h) tertiary phosphines, two Grignard reagents (R1MgBr and
R2MgBr) were added in the first step and, after 4-5 min, the third Grignard
reagent (R3MgBr) was added. In this manner it was possible to obtain the
symmetrical tertiary phosphine-borane complexes 6d,e (R12R3PBH3) in high yield
(75-80%) and the asymmetrical tertiary phosphine-borane complex 6h
(R1R2R3PBH3) in moderate yield (45%). To further increase the yield of the
desired product beyond the statistical limit22 (Chapter 6), we tried a procedure
similar to that previously reported for the synthesis of secondary asymmetrical
phosphines,25 in which the three different mono-Grignard reagents were added in
three successive steps with very short reaction times between the steps. We found
that the best yields were obtained by a 1 min reaction time between the addition of
the first and second Grignard reagents, followed by a 2 min reaction time between
the addition of the second and third Grignard reagents. In this way, the
113
Synthesis of Tertiary Phosphine-Borane Complexes
asymmetrical tertiary phosphine-borane complex 6h was obtained in 55% yield,
which is over the statistical limit.
It is important to note that Grignard reagents with a bulky moiety, such as c-hexyl
and i-propyl, must be used in the first attack on reagent 1. After the addition of the
c-hexyl or i-propyl groups in this first step, the high steric hindrance of these
moieties meant that only Grignard reagents with very small steric hindrance, such
as methylmagnesium bromide, could be used in the following step. In this manner
it
was
possible
to
obtain
cyclohexyl(dimethyl)phosphine
(5f)
and
isopropyl(dimethyl)phosphine (5g) and their complexes with BH3.
To explore the generality of this procedure for synthesizing tertiary phosphineborane complexes, we also used it to synthesize the borane complex of a cyclic
tertiary phosphine, namely the 1-ethylphosphinane borane complex (6i), which
was obtained in 70% yield.
It is noteworthy that the complexation of secondary phosphines25 requires addition
of acetic before BH3.THF, in order to break the pentacoordinated intermediate A,
which is more stable than the hexacoordinated intermediate A’, which
spontaneously collapses. Acetic acid is also necessary as a proton source to form
the P-H bond in secondary phosphines. Obviously, in our complexation procedure
of tertiary phosphines, the addition of acetic acid is not necessary because in this
case the hexacoordinate intermediate A’ is the direct precursor of tertiary
phosphine.
We chose BH3.THF as the complexation agent because after complexation of the
tertiary phosphines at –8 to –5°C, the excess BH3 could be easily removed simply
by allowing the reaction mixture to stand at room temperature. In fact, the
decomposition at room temperature of the BH3.THF complex produces gaseous
BH3 and THF (the reaction solvent). The use of other complexation agents, as
BH3.Me2S or NaBH4/acetic acid, must be avoided because the PCl3 added in situ
in the recycling step from magnesium salt of compound 3 to starting reagent 1,
could react with these borane sources, that are not easy to remove at room
temperature.
The easy obtainement of tertiary phosphines through our procedure can be
explained by the intervention of hypervalent phosphorus intermediates (penta- and
114
RESULTS and DISCUSSION : Chapter 8
hexacoordinated) such A and A’ (see Schemes 8.1). The formation of such
intermediates is favored by the “dibenzo-butterfly” structure of 1, as we reported
for the synthesis of cyclic tertiary phosphines.26
Previously22,26 we thought that the hexacoordinated intermediate A’ required a
nucleophilic attack, for example by water or an acid, in order to decompose it.
During the present study, however, we observed by
31
P NMR spectroscopy that
A’ is unstable and spontaneously collapses to give the corresponding tertiary
phosphines, presumably due to its high steric hindrance. Consequently, about 30
minutes after the addition of the final Grignard reagent, BH3.THF can be added to
the reaction mixture to obtain the complexation of the tertiary phosphines formed
by the spontaneous decomposition of A’. It is important to wait until the reaction
between intermediate A and the final Grignard reagent, producing the tertiary
phosphine, has gone to completion (at least 30 minutes) before adding BH3.THF.
If this reaction has not gone to completion, the BH3 may complex with the
hypercoordinated intermediates, thereby hindering the evolution of the process
toward the desired products.
To gain more information about the mechanism of this reaction, we performed the
reaction between 1 and n-butylmagnesium bromide in an NMR tube, and
monitored the progress of the reaction using
31
P NMR spectroscopy. After the
addition of two equivalents of n-butylmagnesium bromide to a THF solution
containing one equivalent of 1, we observed the formation of the pentacoordinated
intermediate A [δ= -31.6 (d, 1J(P,P)=169 Hz), -43.3 (d, 1J(P,P)=169 Hz) ppm]
(figure 8.1); this intermediate was stable and could remain in solution in the NMR
tube for about 1 h.
115
Synthesis of Tertiary Phosphine-Borane Complexes
Figure 8.1:
31
P NMR spectra of the reaction between benzothiadiphosphole 1 and n-
butylmagnesium bromide carried out in the NMR tube in THF. a.: spectrum of the starting reagent
1. b.: after addition of two equivalent of the Grignard reagent respect to 1 (presence of
intermediates A). c.: after addition of a further equivalent of Grignard reagent (presence of A and
A’ (red)). d.: spectrum of the reaction mixture after time (presence of 5a δ= -31.6 ppm,
magnesium salt of 3, δ= -57.7 ppm and traces of A). e.: after addition of acidic water (formation of
tributylphosphine (5a), compound 3 δ= -52.0 ppm and traces of dibutylphosphine).
116
RESULTS and DISCUSSION : Chapter 8
Then, after addition of a small excess of n-butylmagnesium bromide, we observed
the slow disappearance of the pentacoordinated intermediate signals and the
concomitant appearance of two signals corresponding to the tributylphosphine 5a
(δ= -31.6 ppm) and the magnesium salt of 3 (δ= -57.7 ppm), respectively.
Concomitant signals at δ= 60.1 (d, 1J(P,P)=225 Hz) and -48.7 (d, 1J(P,P)=225 Hz)
ppm were ascribed to the hexacoordinated intermediate A’, and were observed
only during the initial stage of the reaction because this intermediate readily
decomposes to form the tertiary phosphine 5a and the magnesium salt of 3. These
findings are of great importance because they represent the first observation of the
hexacoordinated intermediate A’, which until now has only been hypothesized,
and hence afford us a complete picture of the reaction mechanism.
8.3 Conclusion
In conclusion, a one-pot method for synthesizing tertiary phosphine borane
complexes without previous isolation of free phosphines is reported. The method
is general, in that it can be used to obtain acyclic-, cyclic-, symmetrical and
asymmetrical phosphine-borane complexes. The most important aspect of this
procedure is that the starting reagent 1 is re-formed directly in the reaction
mixture and then recovered by simple crystallization, making the full process both
highly atom-economic and environmentally friendly. It should be noted that this
improved synthetic procedure avoids the long and tedious work-up associated
with the use of air- and moisture-sensitive compounds. In addition, the
observation
of
all
hypervalent
phosphorus
intermediates
(penta-
and
hexacoordinated) permitted a clear identification of the mechanism of this
reaction.
117
Synthesis of Tertiary Phosphine-Borane Complexes
8.4 Experimental section
General: 1H,
13
C, and
31
P NMR spectra were recorded at 400, at 100.56 and
161.89 MHz, respectively. Chemical shifts are referenced to internal standard
TMS (1H NMR), to solvent (77.0 ppm for
13
C NMR) and to external standard
85% H3PO4 (31P NMR). J values are given in Hz. MS spectra were recorded at an
ionisation voltage of 70 eV. Flash chromatography (FC) was performed on silica
gel (0.040-0.063 mm). Melting points are uncorrected. IR spectra of compounds
6a-i showed characteristic bands near 2370 and 2350 (BH3 as. and symm str.),
1190-1120 and 1080-1040 (BH3 as. and symm def.), 790-720 (P-C). THF was
distilled from sodium benzophenone ketyl and all solvents were purified
appropriately before use and degassed immediately prior to use. All Grignard
reagents used were commercially available and were titrated immediately prior to
use by standard methods.27 Air and moisture sensitive solutions and reagents were
handled in a dried apparatus under a dry argon atmosphere using standard
Schlenk-type techniques.
Preparation of acyclic tertiary phosphine boranes 6a-h. Typical two-step
procedure: To a solution of benzothiadiphosphole (1) (0.306 g, 1.0 mmol) in
anhydrous THF (10 mL) under a dry argon atmosphere, the first Grignard reagent
(R1MgBr, 2.4 mmol) was added. After 4-5 min., the second Grignard reagent
(R2MgBr, 1.2 mmol) was added. After about 30-40 min, the flask was immersed
in a salt-ice bath (-5 to -8°C) and BH3-THF complex (1.5-2.0 mmol) was added
portion-wise (first 1 mmol, then after about 1 h, 0.5 mmol was added each 30
min). The salt-ice bath was removed and the reaction mixture was allowed to
stand at room temperature. The resulting solution was stirred under gentle
pressure of argon (in order to remove the excess of BH3), and then PCl3 was
added (1.5 mmol). After 5-10 min, the reaction mixture was treated with acidic
(HCl) aqueous solution (0.5 mL) and the solvent was partially removed under
vacuum. Extraction with CH2Cl2, treatment with anhydrous Na2SO4, and
concentration under vacuum gave a mixture of phosphine-borane complex and
reagent 1. Compound 1 was recovered by crystallization from CH2Cl2/diethyl
118
RESULTS and DISCUSSION : Chapter 8
ether in 70-80% yield. Flash chromatography (FC) of the concentrated mother
liquor gave phosphine-borane complex 6d, e in 75-80% yield, and a further
amount of 1 in 10-20% yield.
The tertiary phosphine-borane complex 6h was obtained in 45% yield (it was
easily separated from the other possible phosphine-borane complexes by FC)
following the method described above for preparing 6d,e, except that in this case
two different Grignard reagents, R1MgBr (1.2 mmol) and R2MgBr (1.2 mmol),
were added to 1 in the first step (instead of 2.4 mmol of the same organometallic),
and the third Grignard reagent R3MgBr (1.2 mmol) was added in the second step.
When R1=R2=R3, the three Grignard reagents (3.2 mmol) were simultaneously
added to a solution of benzothiadiphosphole (1) and the phosphine-borane
complexes 6a-c were obtained in 85-90% yields.
For the synthesis of tertiary phosphines containing bulky moieties, such as
dimethyl(c-hexyl)phosphine borane (6f) and dimethyl(i-propyl)phosphine borane
(6g), the Grignard reagent with the bulky group was added first.
Preparation of unsymmetric tertiary phosphine borane 6h; three-step
procedure: The first and the second Grignard reagents (R1MgBr, 1.0 mmol +
R2MgBr, 1.0 mmol) were sequentially added (1 min between the two steps) to a
solution of benzothiadiphosphole (1) (0.306 g, 1.0 mmol) in anhydrous THF (10
mL) and under a dry argon atmosphere. After 2 min., the third Grignard reagent
(R3MgBr, 1.2 mmol) was added. After about 30-40 min, the flask was immersed
in an salt-ice bath (-5 to -8°C) and BH3.THF complex (1.5-2.0 mmol) was added
portion-wise (firstly 1 mmol, then after about 1h, 0.5 mmol each 30 min). The
salt-ice bath was removed and the reaction mixture was allowed to stand at room
temperature. The resulting solution was stirred under gentle pressure of argon (in
order to remove the excess of BH3), than PCl3 was added (1.5 mmol). After 5-10
min, the reaction mixture was treated with acidic (HCl) aqueous solution (0.5 ml)
and the solvent was partially removed under vacuum. Extraction with CH2Cl2,
treatment with anhydrous Na2SO4, and concentration under vacuum gave a
mixture of phosphine-borane complex and reagent 1. Compound 1 was recovered
by crystallization from CH2Cl2 /diethyl ether in 70-80% yield. FC of the mother
119
Synthesis of Tertiary Phosphine-Borane Complexes
liquor gave unsymmetrical phosphine-borane complex 6h in 55% yield, and
futher amount of compound 1 in 10-20% yield.
Preparation of 1-ethylphosphinane borane 6i: The bis-Grignard reagent
BrMg(CH2)5MgBr (1 mmol) was added to a solution of 1 (0.306 g, 1 mmol) in
THF (10 mL), at room temperature. The mixture was stirred for 15 min, then
ethylmagnesium bromide (1 mmol) was added. The reaction mixture was stirred
for 1 h after that the flask was immersed in an salt-ice bath (-5 to -8°C) and
BH3.THF complex (1.5-2.0 mmol) was added portion-wise (firstly 1 mmol, then
after about 1h, 0.5 mmol each 30 min). The salt-ice bath was removed and the
reaction mixture was allowed to stand at room temperature. The resulting solution
was stirred under gentle pressure of argon (in order to remove the excess of BH3),
than PCl3 was added (1.5 mmol). After 5-10 min, the reaction mixture was treated
with acidic (HCl) aqueous solution (0.5 mL) and the solvent was partially
removed under vacuum. Extraction with CH2Cl2, treatment with anhydrous
Na2SO4, and concentration under vacuum gave a mixture of phosphine-borane
complex and reagent 1. Compound 1 was recovered by crystallization from
CH2Cl2 /diethyl ether in 70-80% yield.
FC of the mother liquor gave 1-ethylphosphinane borane complex (6i) in 70%
yield, and further amount of compound 1 in 10-20% yield.
Tributylphosphine borane (6a): colourless oil, RF = 0.10 (n-hexane : ethyl
acetate 85/15);
1
H NMR (400 MHz, CDCl3, 25 °C): δ = 1.62-1.52 (m, 6 H),
1.53-1.35 (m, 12H), 0,93 (t, J = 7.0 Hz, 9 H), 0.38 (br. q, J B-H ~ 82 Hz, 3 H) ppm;
13
C NMR (100.56 MHz, CDCl3, 25 °C): δ = 24.9 (d, J = 2.2 Hz), 24.6 (d, J = 12.3
Hz), 24.0 (d, J = 34.9 Hz), 13.8; 31P NMR (161.89 MHz, CDCl3, 25 °C): δ = 15.0
(br q, JB-P = 54 Hz); MS (70 eV, EI): m/z : 262 [M+ -BH3, 66], 183 (100), 152
(20), 108 (81), 77 (29), 51 (77).
Trihexylphosphine borane (6b): colourless oil, RF = 0.25 (n-hexane : ethyl
acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.60-1.43 (m, 10 H),
1.42-1.24 (m, 20 H), 0.89 (t, J = 6.9 Hz, 9 H), 0.50 (br. q, J B-H ~ 100 Hz, 3 H)
120
RESULTS and DISCUSSION : Chapter 8
ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 31.6, 31.2 (d, J = 12.2 Hz), 23.4
(d, J = 35.0 Hz), 22.9 (d, J = 2.1 Hz), 22.8, 14.3, 31P NMR (161.89 MHz, CDCl3,
25 °C): δ = 15.0 (m). MS (70 eV, EI): m/z : 286 [M+ -BH3, 30], 271 (19), 257
(60), 229 (100), 202 (41), 187 (25), 159 (39), 146 (40), 132 (56), 117 (23), 90
(28), 76 (72), 62 (44).
Triphenylphosphine borane (6c): white solid, m.p.: 186-187 °C; RF = 0.39 (nhexane : ethyl acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 7.61-7.55
(m, 6 H), 7.53-7.48 (m, 3 H), 7.47-7.41 (m, 6H), 1.30 (br. q, J B-H ~ 83 Hz, 3 H)
ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 133.5 (d, J = 10.3 Hz), 131.6 (d,
J = 2.4 Hz), 129.5 (d, J = 58.4 Hz), 129.1 (d, J = 10.4 Hz);
31
P NMR (161.89
MHz, CDCl3, 25 °C): δ = 21.2 (m). MS (70 eV, EI): m/z : 202 [M+ -BH3, 41], 173
(28), 160 (20), 146 (47), 118 (39), 76 (100), 55 (40).
Dihexyl(butyl)phosphine borane (6d): colourless oil, RF = 0.35 (n-hexane :
ethyl acetate 85/15); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.52-1.45 (m, 6 H),
1.43-1.27 (m, 12 H), 1.26-1.19 (m, 8 H), 0.86 (t, J = 7.5 Hz, 3H), 0.82 (t, J = 6.8
Hz, 6H), 0.31 (br. q, J B-H ~ 82 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25
°C): δ = 31.6, 31.3 (d, J = 12.7 Hz), 25.0 (d, J = 1.6 Hz), 24.7 (d, J = 12.3 Hz),
23.4 (d, J = 34.6 Hz), 23.1 (d, J = 34.2 Hz), 22.9 (d, J = 1.5 Hz), 22.8, 14.3, 13.9,
31
P NMR (161.89 MHz, CDCl3, 25 °C): δ = 15.2 (m). MS (70 eV, EI): m/z : 258
[M+ -BH3, 33], 229 (16), 201 (20), 174 (37), 132 (25), 118 (23), 104 (436), 76
(100), 62 (81), 55 (81).
Diethyl(pentyl)phosphine borane (6e): colourless oil, RF = 0.37 (n-hexane :
ethyl acetate 90/10); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.66-1.54 (m, 4 H),
1.56-1.43 (m, 4 H), 1.40-1.30 (m, 4 H), 1.12 (dt, J = 15.3 Hz, J = 7.6 Hz, 6 H),
0.90 (t, J = 7.3 Hz, 3 H), 0.37 (br. q, J B-H ~ 94 Hz, 3 H) ppm; 13C NMR (100.56
MHz, CDCl3, 25 °C): δ = 33.4 (d, J = 12.0 Hz), 22.1, 22.2, 22.3 (d, J = 2.2 Hz),
15.6 (d, J = 37.3 Hz), 13.8, 6.7 (d, J = 2.9 Hz), 31P NMR (161.89 MHz, CDCl3, 25
°C): δ = 19.2 (br. q, J B-P ~ 59 Hz). MS (70 eV, EI): m/z : 160 [M+ -BH3, 34], 143
(12), 117 (20), 104 (49), 90 (47), 76 (100), 59 (33).
121
Synthesis of Tertiary Phosphine-Borane Complexes
Dimethyl(c-hexyl)phosphine borane (6f)28: yellow grease oil, RF = 0.29 (nhexane : ethyl acetate 80/20); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.94-1.50
(m’s, 7 H), 1.34-1.15 (m, 4 H), 1.23 (d, J = 10.3 Hz, 6 H), 0.42 (br. dq, J B-H ~ 95
Hz, J P-H ~ 15 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25 °C): δ = 34.8 (d,
J = 37.2 Hz), 26.8 (d, J = 10.6 Hz), 26.42, 26.13, 8.93 (d, J = 37.5 Hz); 31P NMR
(161.89 MHz, CDCl3, 25 °C): δ = 9.6 (br. q, J B-P ~ 62 Hz). MS (70 eV, EI): m/z :
144 [M+ -BH3, 13], 129 (2), 103 (7), 83 (18), 64 (65), 55 (100).
Dimethyl(i-propyl) phosphine borane (6g)28,29: grease solid, RF = 0.22 (nhexane : ethyl acetate 80/20); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.88-1.76
(m, 1 H), 1.24 (d, J = 10.0 Hz, 6 H), 1.16 (dd, J = 15.1 Hz, J = 7.2 Hz, 6 H), 0.43
(br. dq, J B-H ~ 95 Hz, J P-H ~ 16 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25
°C): δ = 24.9 (d, J = 36.4 Hz), 16.7 (d, J = 26.6 Hz), 8.8 (d, J = 36.5 Hz),
31
P
NMR (161.89 MHz, CDCl3, 25 °C): δ = 13.4 (br. q, J B-P ~ 61 Hz). MS (70 eV,
EI): m/z : 104 [M+ -BH3, 80], 89 (15), 74 (32), 62 (100).
Hexyl(butyl)(ethyl) phosphine borane (6h): colourless oil, RF = 0.31 (n-hexane
: ethyl acetate 90/10); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.68-1.25 (m, 18
H), 1.12 (dt, J = 8.0 Hz, J = 15.6Hz, 3 H), 0.93 (t, J = 7.2 Hz, 3 H), 0.89 (t, J = 7.0
Hz, 3 H), 0.62 (br. q, J B-H ~ 97 Hz, 3 H) ppm; 13C NMR (100.56 MHz, CDCl3, 25
°C): δ = 31.6, 31.3 (d, J = 13.0 Hz), 25.0 (d, J = 2.7 Hz), 24.7 (d, J = 12.8 Hz),
22.9 (d, J = 34.5 Hz), 22.8 (d, J = 2.3 Hz), 22.8, 22.7 (d, J = 34.1 Hz), 16.4 (d, J =
34.6 Hz), 14.3, 13.9, 7.1 (d, J = 2.6 Hz), 31P NMR (161.89 MHz, CDCl3, 25 °C): δ
= 17.2 (br. q, J B-P ~ 56 Hz). MS (70 eV, EI): m/z : 202 [M+ -BH3, 34], 187 (12),
173 (57), 145 (55), 131 (13), 118 (29), 103 (18), 90 (100), 76 (84), 62 (59), 55
(16).
1-ethylphosphinane borane (6i): colourless oil, RF = 0.27 (n-hexane : ethyl
acetate 80/20); 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.97-1.42 (m, 12 H), 1.14
(dt, J = 7.8 Hz, J = 16.1 Hz, 3 H), 0.43 (br. q, J B-H ~ 93 Hz, 3 H) ppm; 13C NMR
(100.56 MHz, CDCl3, 25 °C): δ = 24.6 (d, J = 5.8 Hz), 21.3 (d, J = 11.0 Hz), 21.1
(d, J = 39.4 Hz), 16.3 (d, J = 35.7 Hz), 6.4 (d, J = 1.69 Hz);
122
31
P NMR (161.89
RESULTS and DISCUSSION : Chapter 8
MHz, CDCl3, 25 °C): δ = 5.6 (br. q, J B-P ~ 63 Hz). MS (70 eV, EI): m/z : 160 [M+
-BH3, 37], 143 (12), 117 (20), 104 (52), 90 (47), 76 (100), 59 (33).
8.5 References
(1)
Burg, A. B.; Wagner, R. I. J. Am. Chem. Soc. 1953, 75, 3872.
(2)
(a) Brunel, J. M.; Faure, B.; Maffei, M. Coord. Chem. Rev. 1998, 178,
665; (b) Ohff, M.; Holz, J.; Quirmhach, M.; Borner, A. Synthesis 1998,
1391.
(3)
Imamoto, T. Pure Appl. Chem. 1993, 65, 655.
(4)
McKinstry, L.; Livinghouse, T. Tetrahedron 1995, 51, 7655.
(5)
Leautey, M.; Deliencourt, G. C.; Jubault, P.; Pannecoucke, X.; Quirion, J.
C. Tetrahedron Lett. 2002, 43, 9237.
(6)
(a) Gridnev, I. D.; Yamanoi, Y.; Higashi, N.; Tsuruta, H.; Yasutake, M.;
Imamoto, T., Adv. Synth. Catal., 2001, 343, 118; (b) Yamanoi, Y.;
Imamoto, T., J. Org. Chem. 1999, 64, 2988; (c) Al-Masum, M.;
Kumaraswamy, G.; Livinghouse, T. J. Org. Chem. 2000, 65, 4776; (d)
Cedric, G.; Canipa, S. J.; O'Brien, P.; Taylor, S.; J. Am. Chem. Soc. 2006,
128, 9336.
(7)
(a) Ohashi, A., Kikuchi, S., Yasutake, M., Imamoto, T. Eur. J. Org.
Chem. 2002, 2535; (b) Johansson, M. J., Kann, N. C. Mini-Rev. Org.
Chem. 2004, 1, 233.
(8)
(a) Beres, J.; Dodds, A.; Morabito, A. J.; Adams, R. M. Inorg. Chem.
1971, 10, 2072; (b) Imamoto, Kusumoto, T.; T.; Suzuki, N.; Sato, K. J.
Am. Chem. Soc. 1985, 107, 5301; (c) Imamoto, T.; Oshiki, T.; Onozawa,
T.; Kusumoto, T.; Sato, K. J. Am. Chem. Soc. 1990, 112, 5244.
(9)
Stankevic, M.; Pietrusiewicz, K. M. Synlett 2003, 7, 1012.
(10) (a) Organic Phosphorus Compounds Kosolapoff, G. M. and Maier, L.
Eds.; Wiley-Interscience, New York, 1972-1975, Vol. 1-7. (b) Smith, D. J.
Phosphines,
Phosphonium
Salts,
and
Halogeno
Phosphines,
in
Comprensive Organic Chemistry, Barton, D.; Ollis, W. D.; Stoddart, J. F.
123
Synthesis of Tertiary Phosphine-Borane Complexes
Eds., Pergamon Press: New York, 1979, Vol 2, pp. 1128-1138. (c) Engel,
R. Synthesis of carbon-Phosphorus Bonds, CRC Press: Boca Raton, 1987
(d) Pietrusiewicz, K. M., Zabloka, M. Chem. Rev.1994, 94,1375; (e)
Gelman, D.; Jiang, L.; Buchwald, S. L.; Org. Lett. 2002, 4, 3541.
(11) (a) Wittig, G.; Braun, H.; Cristau, H. J. Justus Liebigs Ann. Chem. 1971,
751, 17; (b) Fild, M.; Smchutzler, R. in Organic Phosphorus Compounds
G.M. Kosolapoff, G. M. and Maier, L. Eds., Wiley-Interscience: New
York, 1972, Vol. 4, Chapter 1.
(12) (a) Hall, C. R.; Inch, T. D. Tetrahedron 1980, 36, 2059. (b) Koisumi, T.;
Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E. Tetrahedron Lett. 1981, 22,
477; (c) Koisumi, T.; Yanada, R.; Takagi, H.; Hirai, H.; Yoshii, E.
Tetrahedron Lett. 1981, 22, 571.
(13) Bailey, W. J.; Buckler, S. A.; Marktscheffel, F. J. Org. Chem. 1960, 25,
1996.
(14) Grayson, M.; Keough, P. T.; Johnson, G. A. J. Am. Chem. Soc. 1959, 81,
4803.
(15) Hellman, H.; Schumaker, O. Angew. Chem. 1960, 72, 211.
(16) (a) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315. (b)
Stadler, A.; Kappe, C. O. Org. Lett. 2002, 4, 3541. (c) Jolly, W. L. Inorg.
Synth. 1968, 11, 126.
(17) Lebel H.; Morin, S.; Parquet, V. Org. Lett. 2003, 5, 2347; (b) Yang, C.;
Lee, H. M.; Nolan, S. P. Org. Lett. 2001, 3, 1511; (c) Payne, N. C.;
Stephan, D. W. Can. J. Chem. 1980, 58, 15.
(18) (a) Engel, R. Handbook of Organophosphorus Chemistry; Marcel Dekker:
New York, 1992; Chapt. 5.(b) Imamoto, T.; Kikuki, S.-I.; Miura, T.;
Wada, Y. Org. Lett. 2001, 3, 87. (c) Korpiun, O.; Lewis, R. A.; Chickos,
J.; Mislow, K. J. Am. Chem. Soc. 1968, 90, 4842.
(19) (a)
Dimroth,
K.
Heterocyclic
Ring
containing
Phosphorus.
In
Comprehensive Heterocyclic Chemistry, Pergamon Press: New York
1984, Vol 1 A. R. Katrizky, C. W. Rees, Eds.; pp.494-523. (b)
Featherman, S. F.; Lee, S. O.; Quin, L. D. J. Org. Chem. 1974, 39, 2899.
124
RESULTS and DISCUSSION : Chapter 8
(20) (a) Issleib, K.; Hausler, S. Chem. Ber. 1961, 94, 113. (b) Wagner, R.I U.S.
Patent 3086053,1963; Chem.Abstr. 1964, 60, 559.
(21) (a) Issleib, K.; Krech, K.; Gruber, K. Chem. Ber. 1963, 96, 2186. (b)
Davies, H.; Downer, J. D.; Kirby, P. J. Chem. Soc.C. 1966, 245. (c)
Douglass, M. R.; Mark, T. J. J.Am.Chem.Soc. 2000, 122, 1824. (d)
Hackney, M. L. J.; Schubert, D. M.; Brandt, P. F.; Haltiwanger, R. C.;
Norman, A. D. Inorg.Chem. 1997, 36, 1867.
(22) Baccolini, G.; Boga, C.; Mazzacurati, M. J. Org. Chem. 2005, 70, 47744777.
(23) Baccolini; G.; Boga, C.; Galeotti, M. Angew. Chem. Int. Ed. 2004, 43,
3058.
(24) The small amount of 1 that does not crystallize and stay in the solution, it
is separated by chromatography during the purification step of the
phosphine borane complex (see experimental section).
(25) Baccolini; G.; Boga, C.; Mazzacurati, M.; Sangirardi, F.; Org. Lett. 2006,
8, 1677.
(26) (a) Baccolini, G.; Boga, C.; Negri, U. Synlett 2000, 1685; (b) Baccolini,
G.; Boga, C.; Buscaroli, R. A. Eur. J. Org. Chem. 2001, 3421.
(27) Bergbreiter, D. E.; Pendergrass, E. J. Org. Chem., 1981, 46, 219.
(28) Gridnev, I. D.; Yamanoi, Y.; Higashi, N.; Tsuruta, H.; Yasutake, M.;
Imamoto, T., Adv. Synth. Catal., 2001, 343, 118.
(29) Yamanoi, Y.; Imamoto, T., J. Org. Chem., 1999, 64, 2988.
125
Synthesis of Tertiary Phosphine-Borane Complexes
126
RESULTS and DISCUSSION : Chapter 9
Chapter 9
CATALYTIC TRANSPORT SYSTEM OF ELEMENTS:
SYNTHESIS OF ARSINE AND STIBINE
DERIVATIVES
9.1 Introduction
The heterocyclic chemistry of arsenic and antimony has its roots in medicinal
chemistry of the early 1900s. With the discovery that an organoarsenic compound
provided a cure for syphilis, many new arsenic compounds were prepared and
tested for their potential medicinal properties. Interest in organoantimony
compounds arose only after the chemotherapeutical properties of organoarsenic
were discovered.1
Organoarsenic and organoantimony have received much less attention than the
analogous organophosphorus compounds in past years. Only recently these
compounds have been revaluated for their coordination properties and application
as ligands in coordination chemistry.2 Unfortunately the number of available
syntheses is low and often required multi-step reactions.3
9.2 Results and discussion
In previous studies it was reported4 that the formation of cyclic tertiary
phosphines such as 2 is achieved in very high yields and in a one-pot reaction by
simultaneous addition of a bis-Grignard and a mono-Grignard reagent to the
reagent 1a (Chapter 4). Treatment of the resulting reaction mixture with aqueous
acid gave cyclic phosphines 2 and the end product 3, which is the residue of 1a.
127
Catalytic transport system of elements: Synthesis of Arsine and Stibine
Treatment of 3 with PCl3 quantitatively and immediately regenerates the starting
reagent 1a (Scheme 9.1).
PCl3
P
S
1) BrMg(CH2)3(CH2)nMgBr;
RMgBr
2) H3O+
P
S
1
PH
P
R
n
+
2 (60-70%)
SH
SH
3 (90%)
n = 1, 2
R = Alkyl, Alkenyl, Ph
Scheme 9.1 Synthesis of cyclic tertiary phosphines with recycling of reagent 1.
Additional studies on the above reported reaction, showed that this reaction could
be considered an unusual ‘transport’ system of elements (Scheme 9.2) formed by
two molecules. The first is a benzothiadiphosphole derivative (1a), the phosphorus
donor reagent that can react with different Grignard reagents. In the case of the
simultaneous addition of an equimolar amount of bis- and a mono-Grignard
reagent to 1a, cyclic tertiary phosphines (5,6a) are easily obtained.
The second is the by-product 4 that is the residue of the reagent 1a obtained after
expulsion of the phosphorus atom, when tertiary phosphines (5,6a) are produced in
a 70-80% yield.
128
RESULTS and DISCUSSION : Chapter 9
PCl3
ECl3
+
MgBr
P
P
P
S
S
-
1a
S
+
MgBr
1b,c
4
BrMg(CH2)3(CH2)nMgBr,
CH3MgBr
a: E = P
b: E = As
c: E = Sb
P
E
S
S
-
S
BrMg+
n = 1: 5a-c
n = 2: 6a-c
P
n
5a
6a
E
n
BrMg(CH2)3(CH2)nMgBr,
CH3MgBr
5 b,c
6 b,c
Scheme 9.2 Catalytic cycle using the catalyst 4.
The compound 4 is the magnesium salt of 3, that in previous reactions was
recovered as the analogous acid derivatives 3 (Scheme 9.3). This compound 4 is
easily retransformed into the starting reagent 1 by simple addition of PCl3. When
the addition of PCl3 is done directly into the reaction mixture, after formation of
phosphines, the starting reagent 1a is directly regenerated without previous
separation of the salt 4. In this way the reagent 1a can react again with the bis- and
mono-Grignard reagents producing phosphines 5,6a and the by-product 4.
Therefore it is possible to repeat this transport process of the P atom theoretically
an infinite number of times.
The only limitation to the number of cycles is due to the quantity of starting
material. In fact in every cycle 90% of initial 1a is obtained, this means that after
some cycles the quantity of 1a is low (in respect to the other components of
reaction mixture) and measuring out the amount of Grignard reagents to add is
very difficult.
It is important to note that the molecule 4 is the true carrier of the P element and
might be considered a “catalyst” both, for its ability to obtain products which are
quite difficult to synthesize by other methods, and for the fact that it can be
completely recovered at the end of the process.
129
Catalytic transport system of elements: Synthesis of Arsine and Stibine
+
MgBr
H3O+
P
-
-
S
BrMg+
S
MgBr
H
P
SH HS
+
4
3
Scheme 9.3 Addition of H3O+ to compound 4 produces 3
These results about phosphorus donation were explained5 by the intervention of a
pentacoordinate phosphorus intermediates such as A, which was also isolated and
characterized by 31P NMR, and a hexacoordinate species such as B very instable
(Scheme 9.4) in which the folded “dibenzo-butterfly” moiety of reagent 1a,
greatly favours their formation.6
In fact, it is reported that in the hypervalent phosphorus species the presence of
rings is a factor of enormous stability, reducing overcrowding.6 For every cycle in
a pentacoordinate species the stabilization is improved by a high factor (about
106- 108) in respect to the pentacoordinate species without the cycle. If an
additional small ring is generated during the reaction, as in the case of bisGrignard reagent, a further stabilization of these hypervalent intermediates is
achieved. As a consequence, the reaction of bis-Grignard reagent that gives a new
cycle around the phosphorus atom is highly preferred over the reaction of a monoGrignard reagent in which there is not this cyclization. For this reason it is
possible to carry out the reaction with the simultaneous addition of both bis- and
mono-Grignard reagents always obtaining the same product 5,6a in very high
yields as occurs in the case of the subsequent addition of the two reagents.
130
RESULTS and DISCUSSION : Chapter 9
+
S
P
-
S
BrMg+
P
S
MgBr
PCl3
P
1a
-
S
MgBr
+
4
BrMg(CH2)3(CH2)nMgBr
P2
S
S
P2
P1
S P R
1
S
RMgBr
n
MgBr
MgBr
n
MgBr
MgBr
A
MgBr
B
n=1,2
+
P
n
MgBr
+
P
-
-
S
BrMg+
5a
6a
S
MgBr
+
4
Scheme 9.4 Mechanism of reaction.
The reaction between benzothiadiphosphole 1, pentamethylenbis-(magnesium bromide) and
methylmagnesium bromide was carried out in the NMR tube in THF and followed by 31P NMR
spectroscopy. After addition of one equivalent of bis-Grignard reagent respect to 1 only the
presence of intermediates A [δ= -43.2 (d, J= 190 Hz), -46.7 (d, J= 190 Hz) ppm] was observed.
Then after addition of a further equivalent of mono-Grignard reagent, the hexacoordinated
intermediate B was observed in very low concentration (tentatively assigned [δ= 56.9 (d, J= 216
Hz), -56.8 (d, J= 216 Hz) ppm]). The spectrum of the reaction mixture after time showed presence
of 6a [δ= -41.7 ppm] and catalyst 4 [δ= -57.7 ppm].
In addition, this process is highly favoured when organomagnesium derivatives
are used, while it is highly disfavoured when zinc or lithium derivatives are used.
The probable effect of Mg ions can be easily explained by imaging that the
coordination of the magnesium atom to a sulfur atom would activate P1 of
131
Catalytic transport system of elements: Synthesis of Arsine and Stibine
intermediate A toward a further nucleophilic attack to give the instable
hexacoordinate B. A further indication of the importance of the magnesium in this
process lies in the fact that when we carried out the reaction between 1a and
phenylzinc bromide, any phosphinic product such as 5,6a was recovered and the
use of analogous lithium reagent gave only ring opened products of 1a.
These findings, together with the possibility of easily transforming the residue 4 in
the starting reagent 1a by the simple addition of PCl3 prompted us to use 4 to
obtain similar transport processes with other elements in which the formation of
hypervalent species is easy as in the case P element. These elements are As and Sb
which have analogous atom electron configuration. In fact, by simple treatment of
compound 4 with AsCl3 and SbCl3, the arsenic-heterocycle 1b and the
antimonium-heterocycle 1c were obtained. These heterocyclic compounds 1b,c, as
reported for 1a, can be used as arsenic and antimonium donor reagents for the
synthesis of tertiary cyclic arsine 5,6b in 70-75% yield and tertiary cyclic stibine
5,6c in 65-68% yield in a continuous cycle such as that depicted in Scheme 9.2.
The reported mechanism in Scheme 9.4 can also be used to explain reaction in
which As and Sb are involved and in general other elements which can have stable
hypercoordinated species.
When the same process was carried out in order to obtain C or Bi derivative
(treating catalyst 4 with CH3CCl3 for C and BiCl3 for Bi) we obtained the
corresponding intermediate 1d,e (scheme 9.5) but the subsequent addition of bisand mono-Grignard reagents did not generate the corresponding cyclic compounds
5d,e and 6d,e. This is in accord with the fact that in the case of C the hypervalent
species, penta and hexacoordinated, are very unstable or impossible, while in the
case of Bi these hypervalent species are predicted to be very stable and substituted
by ionic species.
As follows the compound 4 can be compared with a catalyst, because it is used to
catalyse different processes that cannot work without it and it is recovered at the
end of the reaction. Instead the compounds 1a,b,c could be seen as activated forms
of the catalyst 4.
132
RESULTS and DISCUSSION : Chapter 9
CH3CCl3
BiCl3
+
MgBr
P
C
S
S
CH3
P
SBrMg+
1d
P
Bi
S
S
-
S
+
MgBr
1e
4
BrMg(CH2)3(CH2)nMgBr,
CH3MgBr
C
n = 1: 5d,e
n = 2: 6d,e
5d
6d
n
Bi
n
BrMg(CH2)3(CH2)nMgBr,
CH3MgBr
5e
6e
Scheme 9.5 Carbon and bismuth heterocyclic derivatives 1d,e.
9.2.1 Penta and hexacoordinated phosphorus intermediate: a
possible explanation of ribozyme and enzyme phosphoryl
transfer reactions
The quite unique ability of enzymes to provide an enormous rate of enhancements
(107-1019–fold ) of very important biological transformations is principally due to
the high stabilization of high–energy transition states or intermediates along a new
reaction coordinate. This very complex reaction is guided probably by multiple
interactions at enzyme specific sites with the reactants. Numerous studies reveal
that several enzymatic phosphoryl transfer processes are shown to take place via
cyclic pentacoordinate phosphorus transition state species.7 Also phosphoryl
transfer reactions as hydrolyses of RNA 7, energy transfer and DNA formation via
ATP
8
and many others processes go through the pentacoordinated phosphorus
intermediates.9
It has also been recently reported that phospho-enzyme intermediates (E-P) in the
action of protein tyrosinephosphatase (PTPs, signaling enzymes that control a
diverse array of cellular processes) is assumed to be pentacoordinate forming
133
Catalytic transport system of elements: Synthesis of Arsine and Stibine
several cycles around the P atom by interaction with the enzyme site (Figure
9.1).9,10
O
R
AA
O
H2N
H2N
OO
H2
N
P
-
O
H2N
S-
AA
O-
H
NH
N
H2
O
H
O
AA
AA
AA
Figure 9.1 Transition state for the phospho-enzyme intermediate formation in PTPs.9
In addition, the most simple biological reactions involving ribozymes, RNA
molecules, or the so called enzyme-like molecules, proceed through a cyclic
phosphorus pentacoordinated intermediate or transition state.11
Additionally, as recently reported,12 the easy formation of hexacoordinated
phosphorus specie from a pentacoordinated species may also have an important
role in formulating a possible mechanism in the active site of ribozymes or
phosphoryl transfer enzymes. The energy associated with the conversion from
five to six coordinate phosphorus species is found to be very small. In addition,
the hexacoordinate state exhibits greater instability than pentacoordinate
analogous species and this permit a easy collapse of the molecula. In fact, in
hexacoordinate states the increase in coordination geometry will result in a
loosening of all bonds to the phosphorus atom and allow the leaving group or
groups to depart more readily than in pentacoordinate analogous species.
However, the full details of the mechanism of action of these enzymes or enzymelike molecules and the factors which determine this very high rate of enhancement
of this process remains to be elucidated.
134
RESULTS and DISCUSSION : Chapter 9
In the previous reaction presented (paragraph 9.2), the formation of cyclic
pentacoordinated and hexacoordinated intermediates was demonstrated to be
important in achieving a high velocity and selectivity of the processes.
In effect, when an equimolar amount of bis- and mono-Grignard reagents were
added simultaneously to the solution containing the “catalyst” 4 and PCl3, cyclic
tertiary phosphines 5,6a were obtained as prevalent products, in few minutes (3-5
minutes) (case X, scheme 9.6). These results are in contrast with the same reaction
carried out without “catalyst” 4. In fact, when bis- and mono-Grignard reagents
were simultaneously added to PCl3 (case Y, scheme 9.6) no traces of cyclic
tertiary phosphines 5,6a were found. In the resulting reaction mixture analyzed
after 2h of reaction, only a mix of several open products were identified.
These different results are due to the structural characteristics of “activated” form
of 4 (1a) in respect to PCl3. In case X, the rigid folded structure of 1a with its
bicyclic condensed system favours the formation of hypervalent intermediates
(paragraph 9.2).6 In the first stage, we have formation of a pentacoordinate
phosphorus intermediates such as A, followed in the second stage, by the
formation of a hexacoordinate specie such as B (scheme 9.4).
The selectivity of this process is driven by the formation of an additional cycle
around the P atom, in the pentacoordinated intermediate A, providing an
enormous enhancement of the additional reaction rate of a bis-Grignard reagent in
respect to the mono-Grignard reagent.
Otherwise, when no cyclic pentacoordinated phosphorus intermediate is involved,
in the reaction mechanism, the formation of cyclic phosphorus compounds, such
as 5,6a is not observed as in the reported case Y, scheme 9.6. This behaviour is in
accord with the observation that only when rings are present in a tetracoordinated
phosphorus, or when such rings are easily formed during the reaction, the
formation of pentacoordinated intermediate is favoured, gaining both in
thermodynamic and kinetic advantage.13 Consequently, the intervention of cyclic
pentacoordinated intermediate allows the easily formation of cyclic phosphorus
compounds (case X), also when the acyclic corresponding derivatives are
generally favoured (case Y).
135
Catalytic transport system of elements: Synthesis of Arsine and Stibine
X: WITH "CATALYST" 4
+
MgBr
+
P
PCl3
BrMg(CH2)3(CH2)nMgBr
CH3MgBr
-
-
S
S
MgBr BrMg+
+
n
MgBr
P
+
5a
6a
+
4
P
S
S
MgBr BrMg+
-
+
4
n = 1: 5a
n = 2: 6a
P
S P S
1a
Y: WITHOUT "CATALYST" 4
PCl3
BrMg(CH2)3(CH2)nMgBr
CH3MgBr
mix of open products
Scheme 9.6 Reaction conducted with catalyst 4 (X) and without catalyst 4 (Y).
In addition, we found that pentacoordinated intermediate A is stable enough to
stay in solution (1 hour) without decomposing. Therefore it is necessary to add a
nucleophile to obtain the decomposition of intermediate A. This is explained with
the formation of hexacoordinated intermediate B (for addition of a further
nucleophile on intermediate A) that is unstable12 and immediately collapses
producing the cyclic tertiary phosphines 5,6a and the starting “catalyst” 4 (scheme
9.4). As follows the resulting process (case X) is extremely fast, compared with
the no-catalysed process (case Y). In fact when the reaction, with the catalyst 4,
was conducted adding simultaneously the bis- and mono-Grignard reagents, the
reaction was completed only after few minutes (3-5 min), making it very difficult
to individuate (by 31P NMR spectroscopy) the pentacoordinated intermediate A.
Using this observation it could be possible to explain the high selectivity and
reaction rate of the reaction catalyzed by enzyme or enzyme-like molecules in
which cyclic phosphorus pentacoordinated intermediates are involved, but also to
determinate the important role of hexacoordinated species.
136
RESULTS and DISCUSSION : Chapter 9
In addition, the reactions catalyzed by enzyme-like molecules, as well as
enzymatic processes often require divalent metal ions such as Mg2+ as cofactors.
For example recent structural determination of a crystal obtained in a phosphoryl
tranfer process catalyzed by β-phosphoglucomutase (β-PGM) having Mg(II) as
cofactor reveals as intermediate a pentacoordinated phosphorus stabilized also by
coordination with magnesium ions.9
This behavior is in agreement with the role of magnesium ions assumed in our
reaction. In fact in our “pattern”, the coordination of the magnesium ions to the
sulfur atom would activate the pentacoordinated phosphorus, in the intermediate
A, to receive a nucleophilic attack giving the hexacoordinated intermediate B.
Moreover, as previously reported (paragraph 9.2), our “pattern” is applicable to
other elements such as arsenic and antimony that have an analogous atom electron
configuration of phosphorus. Therefore it could be possible to predict that the
biological processes in which pentacoordinated intermediates are involved, can
also work with these elements instead of phosphorus. Nevertheless the penta and
hexacoordinated species of arsenic and antimony derivatives are more stable than
the analogous phosphorus derivative, consequently the reaction is much slower.
9.3 Conclusion
The discovery and isolation of compound 4 permitted a study of a new cyclic
catalytic process to obtain cyclic tertiary phosphines . The new catalyst 4 was
applied also in the synthesis of tertiary arsine and stibine in good-high yields.
Those reactions were explained with the intervention of penta and
hexacoordinated intermediates, that were identified by 31P NMR spectroscopy.
In addition the heterocyclic compounds containing carbon and bismuth 1d,e
(“activated” form of catalyst 4) were synthesized. Nevertheless, due to the
impossibility of the carbon atom to form stable hypervalent species and the high
tendency of the bismuth atom to form extremely stable hypervalent species, their
use in the synthesis of organo-compound derivatives was not possible.
137
Catalytic transport system of elements: Synthesis of Arsine and Stibine
In addition, studying the role of hypervalent intermediate species in the above
reactions, it was possible to hypothesize a “pattern” that can be applied in the
explanation of the mechanism of ribozyme and enzyme phosphoryl transfer
reactions, in which cyclic pentacoordinated intermediates are involved.
9.4 Experimental Section
General. NMR spectra were recorded at 300 (400) and 121.45 (161.9) MHz for
1
H and 31P, respectively. Chemical shifts are referenced to solvent THF (1H NMR,
1.8 ppm and 13C NMR, 26.7 ppm), and external standard 85% H3PO4 (31P NMR).
J values are given in Hz. THF was distilled from sodium benzophenone ketyl. All
Grignard reagents used, both commercially available and prepared from the
corresponding alkyl halide and magnesium turnings, were titrated immediately
prior to use by standard methods.14 Air and moisture sensitive solutions and
reagents were performed under dry argon atmosphere using standard Schlenk-type
techniques. All solvents were purified appropriately before use and degassed
immediately prior to use. Benzothiadiphosphole 1a was synthesized as decribed
(Appendix 1).15 From reagent 1a and catalyst 4, compound 5 is obtained easily, as
reported in Appendix 2.16
Isolation and characterization of compound 4:
After reaction of reagent 1 with bis- and mono- Grignard reagent (see preparation
of compounds 5,6), and concentration of solution by vacuum pump (1/5 of the
starting volume), the resulting suspension was filtered carefully under argon
atmosphere. The white salt (4) was washed one time with 1-2 ml of anhydrous
THF (the compound 4 is almost insoluble in THF, but reacts with traces of water
to produce compound 3). Compound 4 was conserved as suspension in anhydrous
THF under argon (in this way it can be preserved for 2-3 days).
White solid; 1H-NMR (400 MHz, THF d8): δ = 7.42 (br s, 1H), 7.28 (br s, 1H),
7.05 (br s, J ∼ 6.6 Hz, 1 H), 7.00 (br s, J ∼ 6.6 Hz, 1 H), 6.54 (d, J = 6.8 Hz, 1 H),
6.48 (d, J ∼ 6.8 Hz, 1 H), 2.20 (s, 3 H), 2.11 (s, 3 H);
138
13
C-NMR (100.56 MHz,
RESULTS and DISCUSSION : Chapter 9
THF d8): δ = 146.8, 146.1, 143.0 (d, J = 28 Hz,), 141.9 (d, J = 30 Hz), 135.9 (d, J
∼ 91 Hz,), 134.1 (d, J ∼ 91 Hz,), 135.2, 134.6, 133.4, 129.7, 127.1, 126.0, 22.7,
22.6; 31P-NMR (161.9 MHz, THF d8) δ = -79.4 (m).
Preparation of new heterocycles 1b and 1c:
To a suspension of compound 4 (0.588g, 1.0 mmol) in THF (10 mL) under argon
atmosphere, one equivalent of arsenic trichloride or antimony trichloride, in the
case of the formation of compound 1b or 1c, respectively, was added (particular
care must be taken in the manipulation of these reagents because of their toxicity).
The solution turned immediately pale yellow (or pale green in the case of the
formation of compound 1c). After 20 min. the solvent was removed giving
quantitatively compound 1b (or 1c) which were immediately characterized and
stored under argon atmosphere.
Compound 1c has to conserve in diluted solution of THF, because it easily forms
a solid precipitate that is insoluble.
When bismuth trichloride was added to 4, immediately the formation of a red salt
1e (almost insoluble) was observed.
In the case of addition of CH3CCl3 to 4, the reaction was very slow and the
resulting yield in 1d was very poor. As a consequence, the heterocycle 1d was not
isolated but only identified in the reaction mixture by GC-MS and
31
P NMR
spectroscopy, with reference to the same compound synthesized via the procedure
reported in Appendix 3. Also in the reaction with bis- and mono-Grignard
reagents, the compound 1d was synthesized using the procedure reported in
Appendix 3.
2,10-dimethyl[1,3,2]benzothiaphospharsolo[2,3-b][1,3,2]
benzothiaphospharsole (1b)
1
H-NMR (400 MHz, THF d8): δ = 7.54 (d, J = 9.5 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 2
H), 6.96 (d, J = 8.0 Hz, 2 H), 2.28 (s, 6 H); 13C-NMR (100.56 MHz, THF d8): δ =
145.3, 143.8 (d, J = 33 Hz,), 137.0 (d, J = 8.9 Hz), 134.8 (d, J = 30 Hz,), 132.2,
127.6 (d, J = 2.5 Hz,), 22.2; 31P-NMR (161.9 MHz, THF d8) δ = 78.6 (t, JPH = 8.7
139
Catalytic transport system of elements: Synthesis of Arsine and Stibine
Hz); GC-MS (m/z, %): 350 (M+, 35), 243 (100), 107 (14); HRMS (m/z): [M]+
calcd for C14H12AsPS2, 349.9334; found, 349.9332.
2,10-dimethyl[1,3,2]benzothiaphosphastibolo[2,3-b][1,3,2]
benzothiaphosphastibole (1c)
1
H-NMR (400 MHz, THF d8): δ = 7.54 (d, J = 10.3 Hz, 2 H), 7.22 (d, J = 8.1 Hz,
2 H), 6.84 (d, J = 8.0 Hz, 2 H), 2.26 (s, 6 H); 13C-NMR (100.56 MHz, THF d8): δ
= 147.6, 137.6 (d, J = 30.6 Hz,), 135.5 (d, J = 9.5 Hz), 133.7 (d, J = 68.7 Hz,),
131.4, 130.7, 21.9; 31P-NMR (161.9 MHz, THF d8) δ = 52.7 (br s, line width 410
Hz); GC-MS (m/z, %): 396 (M+, 23), 243 (100), 153 (6), 121 (12); HRMS (m/z):
[M]+ calcd for C14H12PS2Sb, 395.9156; found, 395.9152.
2,10-dimethyl[1,3,2]benzothiaphosphabismutholo[2,3-b][1,3,2]
benzothiaphosphabismuthole (1e)
1
H-NMR (400 MHz, THF d8): δ = 7.71 (d, J = 14.0 Hz, 2H), 7.25-7.08 (m, 4H),
2.29 (s, 6H). 31P-NMR (161.9 MHz, THF d8) δ = 35.0 (t, JPH = 14.0 Hz).
Preparation of compounds 5 (or 6) with concomitant recycle of the reagent 1
A solution of bis-Grignard reagent BrMg(CH2)3(CH2)nMgBr (2.0 mmol, n =1, or
2) in THF was added, at room temperature, to a solution of benzothiadiphosphole
(1a) (2.0 mmol) in anhydrous THF (20 mL) and under an argon atmosphere. The
mixture was stirred for 15 min. to complete the phospholane ring formation, or for
90 min. in the case of phosphinane formation. A solution of methylmagnesium
bromide (2.0 mmol) in THF was then slowly added dropwise. The reaction was
monitored by GC-MS and 31P NMR spectrometry: when the signals of reagent 1a
disappeared, with concomitant appearance of that of cyclic phosphine 5a (or 6a),
an equivalent amount of PCl3 was added to the crude reaction mixture and the
concomitant formation of starting reagent 1a was detected. The yield is nearly
quantitative, and the cycle can be repeated more times, thus allowing to a
continuous increase in the yield of cyclic phosphine. The isolation of the reaction
products can be easily obtained by partial removal of the solvent and treatment of
the reaction mixture with degassed acidic (HCl) aqueous solution. Extraction with
140
RESULTS and DISCUSSION : Chapter 9
CH2Cl2 gave a mixture of phosphine and of the residue 3. An easy separation of
these compounds was carried out by treating the organic solution with degassed
aqueous NaOH; in this way the sodium salt of compound 3 is dissolved in the
aqueous solution, whereas the organic one contains the phosphine which was
immediately purified by bulb-to-bulb distillation. Compound 3 was recovered
(90%) from the basic aqueous layer by acidification and extraction with
dichloromethane, purified by distillation and stored under argon.
After addition of equivalent amount of bis-Grignard and mono-Grignard reagent
(Scheme 9.2) to a solution containing compound 1b or 1c, in a manner similar to
that described above, the reaction was monitored by
31
P NMR and GC-MS
spectrometry and when the formation of the corresponding cyclic arsine or stibine
and concomitant disappearance of starting reagent 1 was detected, the reaction
mixture containing the intermediate 4 was treated with an equivalent amount of
AsCl3 (or SbCl3) and the concomitant formation of starting reagent 1b (or 1c) was
detected. Also in this case the yield is nearly quantitative, and the cycle can be
repeated more times, thus avoiding the step-by-step separation of reaction
products which imply a decrease of yield since compounds 1b, 1c, and 5 are
stable in solution but, once isolated, are air-sensitive and tend to transform into
the corresponding oxides.
1-methylphosholane 5a : Colourless oil, bp 122-125°C (760 mmHg), Lit.17 122124°C (760 mmHg); 1H-NMR (300 MHz, CDCl3): δ: 2.20-1.20 (m, 8 H), 1.28 (d,
3 H, J = 2.7 Hz); 31P-NMR (121.45 MHz, CDCl3) δ - 38.5. (m); GC-MS (m/z, %):
102 (M+, 85), 87 (100), 59 (50), 56 (45), 46 (63); HRMS (m/z): [M]+ calcd for
C5H11P, 102.0598; found, 102.0601; analysis (% calcd, % found for C5H11P): C
(58.81, 58.79), H (10.86, 10.88).
1-methylarsolane 5b : Colourless oil, bp 66-69°C (15-18 mmHg), Lit.18 65-66°C
(15 mmHg); 1H-NMR (300 MHz, CDCl3): δ: 1.75-1.25 (m, 8 H), 0.83 (s, 3 H);
GC-MS (m/z, %): 146 (M+, 100), 131 (39), 132 (23), 103 (57), 90 (18), 55 (31);
HRMS (m/z): [M]+ calcd for C5H11As, 146.0624; found, 146.0626; analysis (%
calcd, % found for C5H11As): C (41.11, 40.94), H (7.59, 7.56).
141
Catalytic transport system of elements: Synthesis of Arsine and Stibine
1-methylstibolane 5c : Colourless oil, bp 57-60°C (15-18 mmHg), Lit.19 67-68°C
(30 mmHg); 1H-NMR (300 MHz, CDCl3): δ: 1.80-1.00 (m, 8 H), 0.52 (s, 3 H);
GC-MS (m/z, %): 192 [194] (M+, 75), 177 (44), 149 (58), 136 (100); HRMS
(m/z): [M]+ calcd for C5H11Sb, 191.9899; found, 191.9897; analysis (% calcd, %
found for C5H11Sb): C (31.13, 31.24), H (5.75, 5.77).
1-methylphosphinane 6a : Colourless oil, bp 145-147°C (760 mmHg), Lit.20
146°C (760 mmHg); 1H-NMR (300 MHz, CDCl3): δ: 1.85-1.00 (m, 10 H), 1.32
(d, 3 H, J = 3.0 Hz); 31P-NMR (121.45 MHz, CDCl3) δ - 53.5. (m); GC-MS (m/z,
%): 116 (M+, 100), 101 (45), 73 (50), 70 (25), 46 (63); HRMS (m/z): [M]+ calcd
for C6H13P, 116.0755; found, 116.0752; analysis (% calcd, % found for C6H13P):
C (62.05, 62.03), H (11.28, 11.31).
1-methylarsinane 6b : Colourless oil, bp 70-75°C (15-18 mmHg), Lit.21 153155°C (760 mmHg); 1H-NMR (300 MHz, CDCl3): δ: 1.75-1.25 (m, 10 H), 0.90
(s, 3 H); GC-MS (m/z, %): 160 (M+, 100), 145 (42), 69 (33); HRMS (m/z): [M]+
calcd for C6H13Sb, 160.0233; found, 160.0230; analysis (% calcd, % found for
C6H13Sb): C (45.02, 44.85), H (8.18, 8.15).
1-methylstibinane 6c : Colourless oil, bp 74-79°C (15-18 mmHg), Lit.19 77-79°C
(19 mmHg); 1H-NMR (300 MHz, CDCl3): δ: 1.80-1.00 (m, 10 H), 0.66 (s, 3 H);
GC-MS (m/z, %): 206 [208] (M+, 56), 191 (39), 163 (36), 136 (100), 121 (42), 69
(82); HRMS (m/z): [M]+ calcd for C6H13Sb, 206.0055; found, 206.0052; analysis
(% calcd, % found for C6H13Sb): C (34.83, 34.95), H (6.33, 6.35).
142
RESULTS and DISCUSSION : Chapter 9
9.5 References
(1)
Haiduc, I.; Zucherman, J. J. Basic Organometallic Chemistry; Walter de
Gruyter, New York, 1985.
(2)
Warner, H. Angew. Chem., Int. Ed. 2004, 43, 938.
(3)
(a) Atkinson, R. E. Heterocyclic Rings Containing Arsenic, Antimony or
Bismuth, Comprehensive Heterocyclic Chemistry – I Edition, 1984, Vol. I,
pag. 539; (b) Ashe, A. J. Six-membered Rings with one Arsenic, Antimony,
or Bismuth Atom, Comprehensive Heterocyclic Chemistry – II Edition,
1985-1995, Vol. V, pag. 669 and 824.
(4)
Baccolini, G., Boga, C., Negri, U., Synlett 2000, 11, 1685.
(5)
(a) Baccolini, G., Boga, C., Buscaroli, R. A., Eur. J. Org. Chem. 2001,
3421. (b) Baccolini, G., Boga, C., Mazzacurati, M., submitted article
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(6)
(a) Westheimer, F., Acc. Chem Res., 1968, 1, 70. (b) Tennis, E. A.,
Westheimer, F., J. Am, Chem. Soc., 1966, 88, 3432. (c) Haake, P. C.,
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F., Tennis, E., Williams, L. D., Westheimer, F., J. Am, Chem. Soc., 1969,
91, 6066.
(7)
(a) Perreault, D. M.; Anslyn, E. V. Angew. Chem., Int. Ed. 1997, 36, 432;
(b) Raines, R. T. Ribonuclease A. Chem. Rev. 1998, 98, 1045; (c) Takagi,
Y.; Warashina, M.; Stec, W. J.; Yoshinari, K.; Taira, K. Nucleic Acids Res.
2001, 29, 1815.
(8)
Voet, D.; Voet, J. G.; Pratt, C. W. Fundamentals of Biochemistry; John
Wiley and Sons: New York, 1998.
(9)
Swamy K. C. K.; Kumar, N. S. Acc. Chem. Res., 2006, 39, 324.
(10)
Zhang, Z.-Y. Acc. Chem. Res. 2003, 36, 385.
(11)
(a) Doudna, J. A.; Chech, T. R. Nature, 2002, 418, 222; (b) Steitz, T. A.;
Moore, P. B. Trend in Biochemical Science, 2003, 28, 411.
(12)
(a) Holms, R.R. Acc. Chem. Res., 1998, 31, 535; (b) Holms, R.R. Acc.
Chem. Res., 2004, 37, 746.
143
Catalytic transport system of elements: Synthesis of Arsine and Stibine
(13)
(a) F. Ramirez, Acc. Chem. Res., 1968, 1, 168; (b) D. B. Denney, D. J.
Denney, B. C. Chang, K. L. Marsi, J. Am, Chem. Soc., 1970, 91, 5243.
(14)
Bergbreiter, D. E., Pendergrass, E. J. Org. Chem. 1981, 46, 219.
(15)
(a) Baccolini, G., Mezzina, E., Todesco, P. E., Foresti, E. J. Chem. Soc.,
Chem. Commun., 1988, 304. (b) Baccolini, G., Beghelli, M., Boga, C.
Heteroatom Chem., 1997, 8, 551.
(16)
Baccolini, G., Boga, C., Galeotti, M. Angewandte Chemie, Int. Ed. 2004,
43, 3058.
(17)
Fell, B., Bahrmann, H. Synthesis 1974, 119.
(18)
Mickiewicz, M., Wild, S. B, J. Chem. Soc., Dalton Trans. 1977, 704.
(19)
Meinema, H. A., Martens, H. F., Noltes, J. G. J. Organomet. Chem. 1976,
10, 183.
(20)
Marsi, K. L.; Oberlander, J, E. J. Am. Chem. Soc. 1973, 95, 200.
(21)
Lambert, J. B., Sun, H.-N. J. Organomet. Chem. 1976, 117, 17.
144
RESULTS and DISCUSSION : Chapter 10
Chapter 10
GENERAL ONE-POT SYNTHESIS OF
1,2,5-DITHIAPHOSPHEPINES AND THEIR
PRECURSOR PHOSPHINETHIOLS
10.1 Introduction
The synthesis of heterocyclic systems containing phosphorus is of considerable
current interest, principally because they play a central role in coordination
chemistry and homogeneous catalysis.1 In addition, cyclic systems containing
both phosphorus and sulfur should be particularly interesting as bidentate or
polydentate ligands but this type of compounds has received much less attention.
Also phoshinethiols are of considerable interest because recently attention has
increasingly been paid to the coordination chemistry of polydentate ligands
incorporating both thiolate and tertiary phosphine donor sites, as their
combination is likely to confer unusual structures and reactivities on their metal
complexes.2
10.2 Results and discussion
In the past years, in order to find further information about the reaction between
compound 1 and bis-Grignard reagents a new type of transformation has been
observed which occurs when the intermediate A reacts with RMgBr with high
steric hindrance of the R group (Scheme 10.1). In these cases (cases a, c, d) there
is the prevalent formation3 of the new heterocyclic compounds 6 (75-80%) with
the concomitant formation of cyclic phosphine sulfides 7. When RMgX is
sterically less demanding (case b) and the intermediate A was allowed to stand for
145
Synthesis of 1,2,5-Dithiaphosphepines and Their Precursor Phosphinethiols
about 3 hours at room temperature before the reaction with RMgBr there is the
formation of both 6 and 4 (tertiary phosphine) in a ratio depending on the reaction
time of the first step of the reaction with the formation of intermediate A. In fact,
when PhMgBr is immediately added to A, 4 is the only product, while when
PhMgBr is added to A after about 3 hours at ambient temperature also 6b is found
in 50% yield. This fact indicates that the pathway for formation of 6 is more
complex than the one for explaining the formation of 4.
R
P
SH HS
+
P
R
5
4
1) 30 min, r.t.
2) RMgBr
3) H3O+
S
1) 3 h, r.t.
2) RMgBr
3) S8
P1
P
BrMg(CH2)5MgBr
2
S P
n
S
MgBr
MgBr A
P
S
S
+
S S
6 e-f
+
S
6 a-d
1) 3 h, r.t.
2) R'ONa
3) S8
S R'O
P
R S
P
P
S
H
P
S
H
7
a) R = CH(CH3)(CH2)2CH3
b) R = Ph
c) R = 2-Chlorophenyl
d) R = CH(CH3)CH=CH2
e) R' = CH2CH3
f) R' = CH2CH(CH3)CH2CH3
g) R = CH2(CH2)2CH3
h) R = CH2(CH2)3CH3
7
Scheme 10.1 Synthesis of 1,2,5-Dithiaphosphepines
Presumably the new intermediate might be the isomeric ionic form A' (Scheme
10.2) which might explain the inversion of reactivity of the two P atoms. In this
manner, the nucleophilic attack of the second reagent can occur on the P2 atom
which is now a very reactive phosphenium ion.4 After this attack and addition of
S8 and water, the P1 phosphoranide,5 an unstable hypervalent species, collapses to
form compounds 6 and 7. The decomposition pathway is still unclear. A
possibility is the formation of phosphinethiols such as 9 and 11 and their
subsequent oxidation by S8 , as reported in Scheme 10.3 and explained below.
146
RESULTS and DISCUSSION : Chapter 10
P1
S
P2
n
S
MgBr
MgBr A
S
P+
P
n
S
MgBr
MgBr A'
Scheme 10.2 The isomeric ionic form A'
In a similar manner we obtained the 11-alkoxy derivatives 6e,f using alcoholates
as nucleophilic reagents.
Compounds 6 represent the first examples of derivatives with a new heterocyclic
system, namely 11H-dibenzo[c,f][1,2,5] dithiaphosphepine 11-thione derivatives.
The only related compound reported in the literature6 is the 11-phenyl-11-oxoderivative, obtained by a two-step procedure from lithium 2-lithiobenzenethiolate
at -78°C with phenylphosphonic dichloride. Then the 2-mercaptophenyl
phosphane oxide obtained is oxidized to the cyclic disulfide by DMSO at 90°C. It
is clear that with this reported procedure it is necessary to use, for every cyclic
disulfide, various RPOCl2 reagents, which are very difficult to prepare when R is
a simple alkyl group. On the other hand, in this case it is possible to obtain
compounds 6 bearing several R or OR' groups only using different monoGrignard reagents or sodium alcoholates in a one-pot two-step procedure carried
out at room temperature.
With the purpose to check whether the new method to obtain dibenzo[c,f][1,2,5]
dithiaphosphepine 11-thione derivatives can be generalized, the reaction was
carried out using mono-Grignard reagents RMgBr having not relevant steric
hindrance, namely n-butyl- and n-pentylmagnesium bromide (cases g, h). Also in
these cases, the corresponding products 6g and 6h were obtained, thus confirming
the possibility to prepare, through this new synthetic approach, a wide number of
dithiaphosphepines.
In order to confirm unequivocally the structure of these new series of heterocyclic
compounds by X-rays diffraction we repeated the reaction to prepare compound
6b and were able to obtain suitable crystals for a single crystal X-ray diffraction
study.
147
Synthesis of 1,2,5-Dithiaphosphepines and Their Precursor Phosphinethiols
Compound 6b (Figure 10.1) contains an unusual seven-membered heterocycle in
which a phosphorus and two sulfur atoms forming an S-S bond are present. The
molecule is asymmetric and the central heterocycle is rather distorted, presumably
in order to optimize the bonding interactions. The S-S distance [2.033(2) Å] is
comparable to that found in S8 [2.059 Å] and the P-S distance [1.936(2) Å]
indicates double bond order. In letterature only one other compound showing a
similar seven-membered ring has been reported in the literature: [OPS3]2 where
PS3= [P(C6H4-2-S)3]7 (see Figure 10.2). In the latter case the molecule is dimeric
and the phosphorus atoms are oxidized.
Figure 10.1. ORTEP drawing of 8b.
148
RESULTS and DISCUSSION : Chapter 10
S
P
S
O
S
S
O
S
P
S
Figure 10.2
With the aim to obtain compound 8,8 which is the phosphinic form of 6b, the
reaction has been carried out in a similar manner but without the final treatment
with sulfur. The final reaction mixture was treated with aqueous acid to recover
also the secondary cyclic phosphane 10, but surprisingly the phosphanethiol 9 was
obtained together with phosphane 10, which can be completely purified by bulbto-bulb distillation. Compound 9 was separated from the residue by column
chromatography and obtained in 50% yield. Compound 8 was not obtained. Small
amounts of 4 (R=Ph) and 5 were also observed.
When compound 9 was treated with a stoichiometric amount of elemental sulfur
the corresponding sulfide 11 was obtained quantitatively and completely
characterized. Further treatment of 11 with sulphur gave the heterocyclic
compound 6b.8
149
Synthesis of 1,2,5-Dithiaphosphepines and Their Precursor Phosphinethiols
Ph
P
1) 3 h, r.t.
2) PhMgBr
3) H3O+
S
S
8
P
S
1) 3 h, r.t.
2) PhMgBr
3) H3O+
P1
BrMg(CH2)5MgBr
S
P
P2
S
MgBr
MgBr A
S
n
Ph
P
SH HS
9
+
P
H
10
S8
1) 3 h, r.t.
2) PhMgBr
3) S8
Ph S
P
+
P
H
S
7
Ph S
P
S S
6b
S8
SH HS
11
Scheme 10.3 Synthesis of Phosphinethiols.
In addition, compounds 9 and 11 were found, when analyzed by GC-MS, showed
mainly the presence of compounds 8 and 6b, respectively, thus revealing a
probable oxidation reaction from the thiolic to the disulfidic form in the mass
injector.
The importance of this new simple route to phosphinethiols suggests us to try to
synthesize also alkyl derivatives, that probably are less stable than the phenyl
ones: work is still in progress to this objective.
10.3 Conclusion
In conclusion, with these new transformations of compound 1 it is possible to
have a general method to produce the 1,2,5-dithiaphosphepinic system and to
obtain also its precursor phosphanethiols 9 and 11,8 which are known as pincer
ligands. Recently, the chemistry of this kind of S-P-S pincer ligands has attracted
increasing interest, augmented by the observation of unusual structures containing
150
RESULTS and DISCUSSION : Chapter 10
a ‘dibenzo-butterfly’ moiety, very similar to our intermediate A, in the resulting
transition metal complexes.2
10.4 Exsperimental section
General: 1H, 13C and 31P NMR spectra were recorded on a Varian Gemini 300 (or
Inova 400) spectrometer at 300 (or 400) MHz, 75.46 (or 100.56) MHz and 120.75
(or 161.90) MHz, respectively, in CDCl3. Chemical shifts are referenced to
internal standard TMS (1H NMR), to solvent (77.0 ppm for
13
C NMR), and to
31
external standard 85% H3PO4 ( P NMR). J values are given in Hz. Multiplicities
were obtained from DEPT experiments (the symbols used are as follows: (+) for
CH and CH3, (-) for CH2) I.R. spectra were recorded on a Perkin-Elmer
spectrometer mod. 1600 FT-IR. MS spectra were recorded at an ionisation voltage
of 70 eV on a VG 7070 E spectrometer. GC-MS analyses were performed on a
HP-5890 gas chromatograph equipped with a methyl silicone capillary column
and an HP-5970 mass detector. Thin-layer chromatography was performed on
Merck Kieselgel 60 F254. Melting points were measured with a Büchi apparatus
and are uncorrected. THF was distilled from sodium benzophenone ketyl. All
Grignard reagents used, both commercially available and prepared from the
corresponding alkyl halide and magnesium turnings, were titrated immediately
prior to use by standard methods.9
Typical procedure for the synthesis of compounds 6: A solution of
BrMg(CH2)5MgBr (1.0 mmol) in THF was added dropwise under dry nitrogen
atmosphere to a solution of 1 (1.0 mmol) in THF (15-25 mL) at room temperature.
The mixture was stirred for 30 min and allowed to stand for an additional 150
min, always at room temperature. A solution of mono-Grignard reagent (1.1
mmol) (or alcoholate, 2.0 mmol) was then added. The reaction mixture was
allowed to stand for 25 h at room temperature then treated with elemental sulfur
(2.0 mmol) for 60 min., quenched with water and extracted with CH2Cl2. The
organic layer was dried over anhydrous sodium sulfate and concentrated ‘in
vacuo’. Compounds 6 were isolated by FC on a silica gel column. According to
151
Synthesis of 1,2,5-Dithiaphosphepines and Their Precursor Phosphinethiols
spectral data their purity is higher than 98%. Characterization data for compounds
6a,c,d,e,f were reported previously.3
2,9-Dimethyl-11-(butyl)-11H-11λ5-dibenzo[c,f][1,2,5]dithiaphosphepine-11thione (6g):
greasy solid, 35 % yield, Rf = 0.44 (petroleum light : dichloromethane 2 : 1); δH
(300 MHz, CDCl3): 8.74 (dd, 2H, JP-H = 17.0 Hz, JH-H= 2.2 Hz), 7.36 (dd, 2H, J =
7.5 Hz, J = 4.4 Hz), 7.26-7.16 (m, 2H), 2.85-2.70 (m, 2H), 2.45 (s, 6H, CH3),
2.40-1.40 (m, 4H), 0.90-0.70 (m, 3 H); δC (75.56 MHz, CDCl3): 139.8 (d, J = 12.2
Hz), 139.3 (d, J = 12.4 Hz), 138.2 (d, J = 5.8 Hz), 133.7 (d, J = 75.6 Hz), 132.4
(d, J = 2.4 Hz), 131.3 (d, J = 8.9 Hz), 40.1 (d, J = 56.0 Hz), 24.2 (d, J = 3.4 Hz,),
23.4 (d, J = 18.1 Hz), 21.3, 13.6; δP (121.47 MHz, CDCl3): 53.7; MS (m/z, %):
364 (M+, 25), 331 (25), 308 (30), 275 (100), 243 (50), 211 (18), 185 (21); IR, ν
(cm-1): 617, 728, 1111, 1450, 1583; HRMS calcd. For C18H21PS3: 364.0543,
found: 364.0541.
2,9-Dimethyl-11-(pentyl)-11H-11λ5-dibenzo[c,f][1,2,5]dithiaphosphepine-11thione (6h):
greasy solid, 45 % yield, Rf = 0.44 (petroleum light : dichloromethane 2 : 1); δH
(300 MHz, CDCl3): 8.74 (dd, 2H, JP-H = 16.3 Hz, JH-H= 1.6 Hz), 7.37 (dd, 2H, J =
7.8 Hz, J = 4.7 Hz), 7.25-7.16 (m, 2H), 2.80-2.62 (m, 2H), 2.45 (s, 6H, CH3),
1.70-1.00 (m, 4H), 0.98-0.88 (m, 2H), 0.83-0.74 (m, 3H); δC (75.56 MHz,
CDCl3): 139.8 (d, J = 12.2 Hz), 139.3 (d, J = 12.2 Hz), 138.2 (d, J = 5.4 Hz),
133.8 (d, J = 75.7 Hz), 132.4 (d, J = 3.2 Hz), 131.4 (d, J = 9.1 Hz), 40.2 (d, J =
55.6 Hz), 32.4 (d, J = 17.8 Hz), 22.1, 22.0 (d, J = 3.6 Hz), 21.4, 13.9; δP (121.47
MHz, CDCl3): 53.6; MS (m/z, %): 378 (M+, 24), 345 (30), 308 (32), 275 (100),
243 (31), 211 (16), 185 (25); IR, ν (cm-1): 613, 717, 1117, 1456, 1583; HRMS
calcd. For C19H23PS3: 378.0700, found: 378.0698.
152
RESULTS and DISCUSSION : Chapter 10
Physical and crystallographic data of 11-(phenyl)-2,9-dimethyl-11H-11λ5dibenzo[c,f][1,2,5]dithiaphosphepine-11-thione (6b):
The reaction was carried out following the typical procedure described above.
Compound 6b was obtained in 50% yield, m. p.: 162-164 °C (from
dichloromethane) Rf = 0.45 (petroleum light : dichloromethane 2 : 1); δH (300
MHz, CDCl3): 8.58 (dm, 2H, 3JP-H = 16.6 Hz), 7.42-7.20 (m, 9H), 2.43 (s, 6H,
CH3); δC (75.56 MHz, CDCl3): 139.8 (d, J = 70.1 Hz), 139.5 (d, J = 12.8 Hz),
139.1 (d, J = 13.1 Hz), 139.0 (d, J = 7.4 Hz), 133.7 (d, J = 83.0 Hz), 132.8 (d, J =
2.9 Hz), 131.3 (d, J = 8.9 Hz), 130.7 (d, J = 3.3 Hz), 130.3 (d, J = 11.3 Hz), 128.3
(d, J = 13.3 Hz), 21.3; δP (121.47 MHz, CDCl3): 49.0; MS (m/z, %): 384 (M+,
59), 352 (14), 320 (74), 275 (70), 243 (100), 211 (51), 185 (62); IR, ν (cm-1): 488
(S-S), 690 and 745 (P=S), 1100 (PC), 1583; HRMS calcd. for C20H17PS3:
384.0230, found: 384.0221.
Crystal structure of 6b: C20H17PS3, Fw = 384.49, monoclinic, space group Cc, a =
9.351(2), b = 16.050(3), c = 12.474(3) Å, β = 102.93(3)°, V = 1824.5(6) Å3, Z = 4,
D = 1.400 Mg/m3, µ(Mo-Kα)= 0.493 mm-1, R1 = 0.0348, [I > 2σ(I)], absolute
structure parameter = 0.05(11), Rw = 0.0911 (all data), GOF = 1.002.
Synthesis of compounds 9 and 11: A solution of BrMg(CH2)5MgBr (1.0 mmol)
in THF was added dropwise under a dry nitrogen atmosphere to a solution of 1
(1.0 mmol) in THF (15-25 mL) at room temperature. The mixture was stirred for
30 min and allowed to stand for an additional 150 min at room temperature. A
solution of phenylmagnesium bromide (1.1 mmol) was then added. The reaction
mixture was allowed to stand for 25 h at room temperature then treated with
aqueous acid and extracted with CH2Cl2. The organic layer was dried over
anhydrous sodium sulfate and concentrated ‘in vacuo’. Compound 9 was isolated
by FC on a silica gel column (eluent: petroleum light: dichloromethane 2 : 1). It
contains small amounts ( about 3%) of its oxide 12, probably formed during the
work-up and/or the chromatographic purification process. The oxide 12 was
characterized only by 1H, 31P NMR and MS spectroscopy as reported below.
Treatment of a solution of 9 in dichloromethane with an equimolar amount of
elemental sulfur gave quantitatively the corresponding sulphide 11, which was
153
Synthesis of 1,2,5-Dithiaphosphepines and Their Precursor Phosphinethiols
isolated and fully characterized. Further addition of sulfur to this solution gave
formation of compound 6b. Also when the solution containing pure 9 was treated
with a large excess of elemental sulfur, the reaction, monitored by 1H NMR
analysis, showed the presence of both 11 and 6b, with gradual decreasing of 11
and the parallel increasing of 6b until the presence of the latter alone.
4-Methyl-2-[(5-methyl-2-sulfanylphenyl)(phenyl)phosphino]benzenethiol (9):
50% yield, Rf = 0.10 (petroleum light : dichloromethane 1 : 2); δH (400 MHz,
CDCl3): 7.42-7.34 (m, 3H), 7.32-7.24 (m, 4H), 7.08-7.03 (m, 2H), 6.61-6.57 (m,
2H), 3.94 (d, 2H, J = 1.3 Hz, disappears after addition of D2O), 2.17 (s, 6H); δC
(100.56 MHz, CDCl3) (selected data): 136.0, 134.7 (d, J = 6.5 Hz), 134.4, 134.2
(d, J = 20.2 Hz), 130.9 (d, J = 3.2 Hz), 130.5, 129.2, 128.8 (d, J = 7.3 Hz), 21.1;
δP (161.90 MHz, CDCl3): -18.3; MS (m/z, %): 353 (M+-1, 2), 352 (9), 320 (6),
243 (100), 211 (17); IR, ν (cm-1): 696, 746, 807, 1038, 1111, 1263, 1434, 1453,
2487, 2547; HRMS calcd. for C20H19PS2: 354.0666, found: 354.0662.
4-Methyl-2-[(5-methyl-2-sulfanylphenyl)(phenyl)phosphorothioyl]benzene
thiol (11): m. p.: 169-171 °C (from dichloromethane), quantitative yield from
11b, Rf = 0.30 (petroleum light : dichloromethane 1 : 2); δH (400 MHz, CDCl3):
7.80 (dd, 2H, J = 13.7 Hz, J = 7.1 Hz), 7.64-7.44 (m, 3H), 7.38-7.28 (m, 2H),
7.22-7.14 (m, 2H), 6.95 (dd, 2H, J = 15.2 Hz, J = 1.3 Hz), 6.13 (s, 2H, disappears
after addition of D2O), 2.18 (s, 6H); δC (100.56 MHz, CDCl3): 135.3 (d, J = 7.3
Hz), 135.0 (d, J = 11.3 Hz), 134.6 (d, J = 11.3 Hz), 133.2 (d, J = 10.5 Hz), 133.0
(d, J = 9.7 Hz), 132.8 (d, J = 2.4 Hz), 132.1 (d, J = 3.2 Hz), 129.4 (d, J = 86.6
Hz), 128.6 (d, J = 13.0 Hz), 127.4 (d, J = 89.1 Hz), 21.0; δP (161.90 MHz,
CDCl3): 44.5; MS (m/z, %): 386 (M+, 12), 385 (20), 384 (80), 352 (10), 320
(100), 275 (97), 243 (86), 185 (85); IR, ν (cm-1): 692, 715, 730, 814, 905, 1118,
1267, 1380, 1434, 1464, 2373; HRMS calcd. for C20H19PS3: 386.0387, found:
386.0384.
4-Methyl-2-[(5-methyl-2-sulfanylphenyl)(phenyl)phosphoryl]benzenethiol
(12): δH (400 MHz, CDCl3): 7.70-7.05 (m, 9H), 6.79 (d, 2H, J = 14.3 Hz), 5.95 (s,
154
RESULTS and DISCUSSION : Chapter 10
2H, disappears after addition of D2O), 2.19 (s, 6H); δP (161.90 MHz, CDCl3):
39.0; MS (m/z, %): 370 (M+, 11), 369 (25), 368 (100), 335 (13), 259 (63), 244
(18), 211 (22).
10.4 References
(1)
(a) Noyori, R. Asymmetric Catalysis in Organic Synthesis, Wiley: New
York, 1994; (b) Burk, M. J.; Gross, M. F.; Martinez, J. P. J Am Chem Soc,
1995, 117, 9375; (c) Jiang, Q.; Xiao, D.; Zhang, Z.; Cao, P.; Zang, X.
Angew Chem Int Ed, 1999, 38, 516.
(2)
(a) Lee, C.-M.; Chen, C.-H.; Ke, S.-C.; Lee, G.-H.; Liaw, W.-F. J Am
Chem Soc, 2004, 126, 8406; (b) Cerrada, E.; Falvello, L. R.; Hursthouse,
M. B.; Laguna, M.; Luquín, A.; Pozo-Gonzalo, C. Eur J Inorg Chem,
2002, 826.
(3)
Baccolini; G.; Boga, C.; Guizzardi, G.; Ponzano, S. Tetrahedron Lett,
2002, 43, 9299.
(4)
For a review about phosphenium ions see: Cowley, A. H.; Kempt, R. A.
Chem Rev, 1985, 85, 367.
(5)
For a review about phosphoranides see: Dillon, K. B. Chem Rev, 1994, 94,
1441.
(6)
Block, E.; Ofori-Okai, G.; Zubieta, J. J Am Chem Soc, 1989, 111, 2327.
(7)
Clark, K. A.; George, T. A.; Brett, T. J.; Ross II, C. R.; Shoemaker, R. K.
Inorg Chem , 2000, 39, 2252.
(8)
Baccolini; G.; Boga, C.; Mazzacurati, M.; Monari, M. Heteroatom Chem.,
2005, 16, 339.
(9)
Bergbreiter, D. E.; Pendergrass, E. J Org Chem, 1981, 46, 219.
155
Synthesis of 1,2,5-Dithiaphosphepines and Their Precursor Phosphinethiols
156
RESULTS and DISCUSSION : Chapter 11
Chapter 11
SYNTHESIS AND EVALUATION OF A NEW SERIES OF
LIGANDS DERIVING FROM MeOXuPHOS IN THE
ASYMMETRIC HYDROGENATION OF KETONES
11.1 Introduction
A large number of optically active compounds contain a hydrogen atom at the
stereogenic centre. This hydrogen atom can be introduced into appropriate
unsaturated prochiral precursors by asymmetric hydroboration,1 hydrosilylation2 and
transfer hydrogenation using organic hydrogen donors3 as well as hydrogenation
using hydrogen gas.4
Catalytic asymmetric hydrogenation of polar bonds is a key reaction in the fine
chemical industry. Ruthenium complexes exhibit good reactivity and selectivity,
especially in the catalytic reduction of polar bonds and with amino ligands these are
much more active than other metal complexes for the H2-hydrogenation of ketones,
particularly those devoid of heteroatom functionality, this high activity often comes
with high enantioselectivity.5
The most recent mechanism of polar bond reduction by ruthenium complexes, was
proposed by Noyori,4, 6 the “metal-ligand bifunctional catalysis” operates by hydride
transfer to the substrate in the outer coordination sphere of the Ru complex. In these
cases the ancillary ligand provides a proton that can be transferred when the hydride
is transferred.7
157
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
O
D
H
H
L
[Ru]
I
H
L
H
[Ru]
C
1
A
O
C
H
H
L
[Ru]
IV
II
C
B
L
H2
H
O
C
[Ru]
III
H
2
Scheme 11.1: General scheme for H2-hydrogenation of polar bonds by the “metal-ligand bifunctional
catalysis” mechanism.
This mechanism can be subdivided in four stages (Scheme 11.1). In step A the
substrate 1 coordinates by forming an interaction between the oxygen and carbon
atoms and the proton and the hydride of the complex I. This interaction produces a
six membered-cyclic intermediate II from which the simultaneous transfer of the
hydride and the proton (step B) produced the substrate 2 and the ruthenium complex
with a vacant coordination site, III. Hydrogen gas can then coordinate at this open
site (step C) producing intermediate IV. The coordinated H2 molecule to the complex
heterolytically breaks (step D) to generate the starting hydride complex I.7
The hydride affinities of the polar bonds are low, consequently the ruthenium
complex must be sufficiently hydridic to promote the hydride transfer reaction. For
this reason usually, they contain ancillary ligands that stabilize the positive charge
that is left on the metal after the hydride transfer step (Scheme 11.1, III). These
ligands could include strongly basic hydride, phosphine, and cyclopentadienide
ligands with electropositive donor elements.7
158
RESULTS and DISCUSSION : Chapter 11
11.1.1 Monodentate Phosphorus Ligands in Catalysis for
Asymmetric Hydrogenation
Chiral monophosphines were the first ligands successfully applied in the pioneering
studies on enantioselective hydrogenation.8 This area has been dominated by chiral
bidentate ligands for more than three decades.9 As a common view, bidentate ligands
were considered a condition necessary to achieve high stereoselectivity in catalytic
asymmetric hydrogenation reactions. An enormous number of chiral bidentate ligands
have been developed for enantioselective hydrogenation, but only a limited number
including DIOP 1, BINAP 2 and DuPhos 3 and its analogues (Figure 11.1) are
commercially available, and even fewer are used in industrial processes.10
O
O
P
PPh2
PPh2
PPh2
PPh2
P
DIOP 1
BINAP 2
DuPhos 3
Figure 11.1: Biphosphorus ligands
One of the major disadvantages of bidentate phosphorus ligands, especially
phosphines, is their often inconvenient synthesis. This, in turn, makes them relatively
expensive. In addition, it is very difficult to establish a library of bidentate ligands for
fine-tuning to a specific target molecule.11
Recent progresses have shown that the use of a bidentate ligand is not essential to
obtain good stereodiscrimination. Chiral monodentate phosphorus ligands have been
proven to be able to induce excellent enantioselectivity in rhodium-catalyzed
asymmetric hydrogenation reactions, comparable to or better than those reached by
bidentate ligands.12 Thus monodentate phosphines,13 phosphonites,14 phosphites,15
159
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
and phosphoramidites16,17,18 have been successfully applied in rhodium-catalyzed
asymmetric hydrogenation (Figure 11.2).
O
O
P tBu
O
P
4
P OR
O
(s)- 5
(s)- 6
R = iPr, Ph, (R)-CH(Me)Ph
Me
N Me
Me
O
N
P
Me
O
O
O
P
P N
O
O
(s)- MonoPhos 7
(s)-SIPHOS 9
8
Figure 11.2: Monophosphorus ligands.
Fiaud reported monophosphine ligand 4 which was examined as a chiral ligand in the
hydrogenation of N-acetyl dehydrophenylalanine methyl ester with complete
conversion and 82% ee’s.13 Orpen and Pringle have developed a series of
biarylphosphonite ligands such as 5 which achieve up to 92% ee’s for the asymmetric
hydrogenation of methyl (2-acetamide)acrylate.12 Reetz reported a series of
monophosphite ligands such as 6 which have provided up to 99% ee’s for the
asymmetric
hydrogenation
of
dimethyl
itaconate.15
Feringa
developed
a
phosphoramidite ligand known as MonoPhos 7, which showed excellent reactivities
and enantioselectivities for the hydrogenation of dehydroamino acid derivatives and
160
RESULTS and DISCUSSION : Chapter 11
arylenamides.14 Recently he has also reported a new class of achiral catechol- based
phosphoramidites 8 that were applied to obtain up to 99% ee in the hydrogenation of
the same classes of substrates reported above.15
Finally, Zhou reported a
monophosphoramidite ligand SIPHOS 9 on the basis of a chiral 1,1’-spirobiindane7,7’-diol. Up to 99% ee’s have been obtained in asymmetric hydrogenation of αdehydroamino acids, aryllenamides, and itaconares.18
11.1.2 A New family of Monodentate Phosphorus Ligand: XuPHOS
The XuPHOS ligands represent a new series of monodentate phosphorus BINOLderived ligands containing a substituted aromatic ring attached to the phosphorus
atom (Figure 11.3).
X
O
P
O
X= H, Ph, OMe, Br, Me
XuPHOS
Figure 11.3: XuPHOS ligands.
During the preliminary studies on this new series of monodentate phosphorus ligands,
the ortho-bromo and ortho-methoxy ligands gave good results in the asymmetric
reduction of ketones by hydrogenation.19
Consequently, the BrXuPHOS ligand was chosen to extend the investigations to
further substrates. The best results were obtained for the reduction of methyl ketone
containing an ortho-substituted aromatic ring, where it was possible to obtain the
alcohol derivative with 99% e.e.20 Moreover It was found that the best e.e. results
were obtained when both phosphorus and diamine ligands in the complex had the
161
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
same combination of configurations. In fact, the (S,S,SS) complex gave a 90% (R) e.e.
in the reduction of acetophenone, while the corresponding complex of (S,S,RR)
configuration gave only 33% (S) e.e. 19
The structural analogy of this complex with the Noyori complex suggests that the
reduction mechanism for the XuPHOS-Ru-DPEN complex involves “metal-ligand
bifunctional catalysis”. Therefore the oxygen atom of the C=O interacts with an axial
hydrogen of the amino group belonging to DPEN, while the carbon atom of the C=O
interacts with the hydride on the ruthenium atom. The high stereocontrol of the
catalyst can be explained with the two BINOL groups attached on the phosphorus
atoms causing a sterical hindrance, consequently the smallest group on the substrate,
is favoured to occupy the region of space between the binaphtyl groups (Figure 11.4,
B).20
O O
O O
Br P
Ru
P
Br
O O
Br P
H 2N
NH 2
H2N
Ph
Ph
Ph
A
CH 3
H
Ru
O O
P
O Br
H
NH
Ph
B
Figure 11.4: (A) Catalyst structure; (B) Favoured ketone approach.20
The first results using the Ru-MeOXuPHOS complex were comparable to the RuBrOXuPHOS complex. Acetophenone was reduced with full conversion and 88%
e.e.,19 but unfortunately it was not studied as much as the ortho-bromo derivative.
162
RESULTS and DISCUSSION : Chapter 11
11.2 Results and discussion
The aim of this project was to synthesize and evaluate a new series of ortho-OR
ligands derived from MeO XuPHOS in order to study the effect of the ortho-OR
group on the activity and selectivity of the catalysts.
In order to determine which structural hindrance was necessary for a successful
ligand, the synthesis of a series of ortho-OR ligands with R= Me, Et, tBu, Ph,
SiPh2tBu (Figure 11.5) was attempted.
The synthesized ligands were used to prepare ruthenium (II) diamine catalysts which
were tested in ketone reduction by hydrogenation.
Si
O
O
O
O
P
O
O
P
O
O
P
O
O
(S)-MeOXuPHOS
O
P
O
O
O
P
O
Figure 11.5: (S)-MeOXuPHOS and its derived ligands.
163
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
11.2.1 Synthesis of ligands and corresponding Ru-DPEN
complexes
In order to became familiar with the synthesis procedure, the known synthesis of the
(S)- and (R)- MeOXuPHOS ligand and the MeOXuPHOS-Ru-DPEN complex were
reproduced,19 after that the catalyst was used to carry out the hydrogenation of
different ketones, in order to obtain more information about its reactivity.
N
O
Br
O
N
O
P
O
(S)-BINOL
P
n-BuLi, -78°C
toluene, reflux 48h
ClP(NMe2)2, 0°C
O
y = 60%
y =28%
10
(S)-MeOXuPHOS
11
O
O
P
O
O
P
O
O
Cl
[RuCl2(C6H6)]2
DMF, 100°C, 10 min
Ru
(S, S)-DPEN, r.t., 3h
Cl
NH2
NH2
O
y = 89%
P
O
O
(S,S,SS)-MeOXuPHOS-Ru-DPEN 12
Scheme 11.2: Synthetic route to the (S)- and (R)- MeOXuPHOS ligand and the (S,S,SS)- and
(R,R,RR)- MeOXuPHOS-Ru-DPEN complex.
A new procedure of complex synthesis was attempted in order to simplify the
purification step. The removal of the DMF solvent was problematic, causing a
decrease of the purity of the complex catalyst.
164
RESULTS and DISCUSSION : Chapter 11
A synthetic procedure recently published by R. H. Morris and co-workers was
attempted to synthesize the RuHCl(diphosphonite)(diamine) complexes in a one-pot
two step procedure, where they had used RuHCl(PPh3)3, BINOP as the phosphorus
ligand, and DPEN.21 Therefore, the reaction was repeated trying different solvents,
toluene and THF as reported in Scheme 11.3.
O
RuHCl(PPh3)3
Toluene, 65°C, 1 h
(S, S)-DPEN, r.t., 3h
O
P
O
O
P
O
Cl
NH2
Ru
O
RuHCl(PPh3)3
THF, 65°C, 1 h
(S, S)-DPEN, r.t., 3h
Cl
NH2
O
P
O
O
(S)-MeO XuPHOS 11
(S,S,SS)-MeO XuPHOS-Ru-DPEN
12
Scheme 11.3: Synthesis of (S,S,SS)-MeOXuPHOS-Ru-DPEN complex using the R. H. Morris and coworkers’ procedure.21
Only the reaction carried out in THF led to traces of the complex 12. Possibly, in the
case reported by Morris, the reaction worked because the phosphorus ligand was
bidentate; the structure of the ligand could be favoured by the substitution of PPh3
with the ligand on the metallic centre.
This result suggested that the complex could be formed in a different solvent than
DMF. Consequently the complexation reaction was carried out in THF using the
Morris procedure, but [RuCl2(C6H6)]2 was used instead of RuHCl(PPh3)3 as a starting
material (Scheme 11.3). In this case the MeOXuPHOS-Ru-DPEN complex was
obtained and problem of removing the solvent from the complex was avoided.
165
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
O
O
P
O
O
P
O
Cl
[RuCl2(C6H6)]2
THF, reflux, 1 h
(S, S)-DPEN, r.t.,
overnight
O
y = 92%
NH2
Ru
Cl
NH2
O
P
O
O
(S)-MeO XuPHOS
11
(S,S,SS)-MeO XuPHOS-Ru-DPEN
12
Scheme 11.3: Synthesis of the (S,S,SS)-MeOXuPHOS-Ru-DPEN complex in THF.
Following a procedure close to the synthesis of the MeOXuPHOS ligand, the
synthetic route to the tBuPh2SiOXuPHOS ligand reported in Scheme 11.4 was
proposed. In this case the (2-bromophenoxy)(tert-butyl)diphenylsilane (13) was not
commercially available, but was obtained by o-silylation of ortho-bromophenol
(Scheme 11.4).22 The products 14 and 15 were obtained using the same procedure to
prepare MeOXuPHOS ligand (Scheme 11.4).
166
RESULTS and DISCUSSION : Chapter 11
OH
O
Br
tBuPh2SiCl, imidazole
Si
N
n-BuLi, -78°C
Br
y = 93%
N
N
P
Si
O
N
ClP(NMe2)2, 0°C
DMF, r.t., 20 h
Si
O
P
14
13
Si
O
(rac)-BINOL
toluene, reflux 24 h
O
P
O
(rac)-tBuPh2SiO XuPHOS
15
Scheme 11.4: Synthetic route to tBuPh2SiOXuPHOS ligand
In the first attempt, the synthesis of 14 was carried out using a small amount of crude
product 13 containing the starting material tBuPh2SiCl. Purification of the final
product 15 was attempted by crystallization. However, due to the small quantity of
compound 15 it was not possible to separate it from the tBuPh2SiCl.
During the development of the synthesis on a larger scale, obtaining compound 14
cleanly from its corresponding oxidized compound proved difficult.
Due to the difficulties encountered in the synthesis, and also because of the instability
of the O-Si bond, the synthesis of tBuPh2SiOXuPHOS ligand was abandoned.
In the case of MeOXuPHOS ligand, the available starting material was diphenyl
ether, therefore the synthetic route reported in Scheme 11.5 was adopted.
167
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
O
1. n-BuLi, 0°C
N
2. r.t., 20 h
N
P
O
P
O
O
(S)-BINOL
O
toluene, reflux 20h
3. ClP(NMe2)2, 0°C
y = 81%
(S)-PhOXuPHOS
16
17
O
O
P
O
O
P
O
O
Cl
[RuCl2(C6H6)]2 DMF,
100°C, 10 min
Ru
(S, S)-DPEN, r.t., 3h
Cl
y = 72%
NH2
NH2
O
P
O
O
(S,S,SS)-PhO XuPHOS-Ru-DPEN 18
Scheme 11.5: Synthetic route to the (S)-PhOXuPHOS ligand and the (S,S,SS)-PhOXuPHOS-RuDPEN complex.
The first step was different from the synthetic approach used to prepare the
MeOXuPHOS ligand as it consisted of an ortholithiation. Consequently, the reaction
was tested using the electrophilic reagent CO2. The test reaction to obtain 2phenoxybenzoic acid gave an impure product. Nevertheless the equivalent reaction
was carried out using ClP(NMe2)2. The reaction gave a product not as clean as in the
case of the bromo-lithium exchange.
The condensation reaction between 16 and (S)-BINOL gave 17 impure of BINOL.
168
RESULTS and DISCUSSION : Chapter 11
The compound 18 was purified by crystallisation from toluene, however only BINOL
crystals were obtained. This indicates that the formation of compound 18 is difficult,
probably because of the big sterical hindrance caused by the phenyl groups.
Nevertheless, the Ru complex was synthesised using the impure (S)-PhOXuPHOS
ligand. The obtained complex 18 was also impure.
It was not possible to quantify by 1H-NMR spectrum the percentage of impurity,
because the proton chemical shift of 17 and 18 were very similar to the protons in
BINOL and as a result some signals were overlapped. The impure (S,S,SS)PhOXuPHOS-Ru-DPEN complex 18 was tested on the reduction of acetophenone by
H2-hydrogenation; the result is reported in section 11.2.2.
Based on the analogy of the PhOXuPHOS ligand’s synthetic route, the synthetic
route reported in Scheme 11.6 was proposed.
Compound 19 was not commercially available; therefore a synthetic route was
necessary to synthesise it. Two different approaches were tried, a nucleophilic
aromatic substitution via a benzyne mechanism23 (Scheme 11.7 A) and a palladiumcatalysed carbon-oxygen bond formation24 (Scheme 11.7 B). In both cases, the yield
in 19 was low.
N
O
1. n-BuLi, 0°C
N
P
O
(S)-BINOL
toluene, reflux 20h
2. r.t., 20 h
O
P
O
O
3. ClP(NMe2)2, 0°C
19
20
(S)-tBuOXuPHOS
21
Scheme 11.6: Initially proposed synthetic route for the tBuOXuPHOS ligand.
The successive step gave compound 20 only in traces. Due to the difficulties that
occurred in the synthesis reported above, the synthesis of tBuOXuPHOS ligand was
abandoned.
169
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
Br
O
tBuOK
A.
DMSO, r.t., 24 h
y = 14%
19
O
Br
B.
tBuONa, Pd(OAc)2, P(tBu)3
toluene, reflux 8h
y = 21%
19
Scheme 11.7: Synthetic route to 19.
Also in this case, based on the analogy of the PhOXuPHOS and tBuOXuPHOS
ligands’ synthetic route, the proposed synthetic route for (S)-EtOXuPHOS is reported
in Scheme 11.8.
N
O
1. n-BuLi, 0°C
N
P
O
(S)-BINOL
O
P
O
toluene, reflux 20h
2. r.t., 20 h
O
3. ClP(NMe2)2, 0°C
22
(S)-EtOXuPHOS
23
Scheme 11.8: Initially proposed synthetic route for EtOXuPHOS ligand.
The available starting material was phenetole, and the ortholithiation was attempted,
as in the two cases reported above. Unfortunately the reaction gave only a small
amount of the product 22.
170
RESULTS and DISCUSSION : Chapter 11
11.2.2 Asymmetric hydrogenation of ketones
In order to check the activity of the synthesised catalyst (S,S,SS)-MeOXuPHOS-RuDPEN (with standard method), the asymmetric hydrogenation of acetophenone was
carried out (reaction conditions: S/C:500; Time:20h; P:40bar; r.t.). The test gave
moderate ee’s of 75% (R) , but the conversion was low (21%). The catalyst was made
impure by DMF, probably for this reason it was not possible to obtain good results.
Nevertheless it was decided to proceed with testing of other ketone substrates using
this catalyst.
In addition the (S,S,SS)-MeOXuPHOS-Ru-DPEN complex, obtained using THF as
solvent (Scheme 11.2), was used to carry out the same reaction reported above
(reaction condition: S/C:500; Time:20h; P:40bar; r.t.). The reaction gave the same
ee’s (76% (R)) as the previous case, but the conversion was improved (60%). Also in
this case the catalyst was impure, perhaps for this reason it was not possible to
improve the results.
Further ketones were reduced using the same complex and the results are reported in
table 11.1. In all cases, except one, the conversion was very low, probably for the
reason previously reported. The ee’s were generally low as well, except in the cases
of hydrogenation of 2-iodoacetophenone and 2-acetonaphtone which gave 70% (R)
and 79% (R) respectively.
171
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
Ketone
Br
I
Conv.
e.e.
(%)a
(%)a
r.t.
4.6
47 (R)
50
r.t.
10.3
70 (R)
20
50
r.t.
93
79 (R)
500
20
50
r.t.
21
52 (R)
500
20
50
r.t
33
54 (R)
500
20
50
r.t
32
0
S/C
t/h
P / bar
T
500
20
50
500
20
500
O
O
O
O
O
O
Reaction was conducted in 2-propanol with a 0.15 M solution of ketone, 10 equiv of
base (tBuOK) wrt catalyst. (a) Determined by chiral GC
Table 11.1: Asymmetric hydrogenation of ketones using (S,S,SS)-MeOXuPHOS-Ru-DPEN.
The complex derived from the PhOXuPHOS ligand was not clean, nevertheless it
was decided to examine its activity. The conversion and the ee’s were very low (table
11.2). It was envisaged that these poor results could be explained by the high
hindrance of the phenyl group.
172
RESULTS and DISCUSSION : Chapter 11
Ketone
S/C
t/h
P / bar
T
500
20
50
r.t.
Conv.
e.e.
(%)a
(%)a
2.5
44 (R)
O
Reaction was conducted in 2-propanol with a 0.15 M solution of ketone, 10 equiv of
base (tBuOK) wrt catalyst. (a) Determined by chiral GC
Table 11.2: Asymmetric hydrogenation of acetophenone using (S,S,SS)-PhOXuPHOS-Ru-DPEN.
11.3 Conclusion
The results obtained from the PhOXuPHOS-Ru-DPEN complex, demonstrated that a
bulky group as a substitute decreases the performance of the catalyst in the
steroselectivity and, presumably, also in the activity.
Consequently, it could be interesting to try to decrease the sterical hindrance, using a
smaller R group such as an ethyl group. For this reason it might be necessary to
change the proposed initially synthetic route for EtOXuPHOS (Scheme 11.8). A
proposal is reported below (Scheme 11.9).
Promising results obtained in the asymmetric hydrogenation of ketones (Table 11.2)
suggest that using pure MeOXuPHOS-Ru-DPEN complex, it would be possible to
improve both the conversion and ee’s, in particular for the substrates, 2iodoacetophenone and 2-acetonaphtone that have shown to give good ee’s.
Moreover the new procedure to synthesise the complex in THF gave good results,
consequently it could be useful to repeat it in order to find the best reaction and
purification conditions.
173
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
N
O
OH
Br
Br
C2H5Cl
K2CO3, acetone, 8h-reflux
N
N
P
n-BuLi, -78°C
ClP(NMe2)2, 0°C
N
O
P
O
P
O
O
(S)-BINOL
toluene, reflux 20h
O
(S)-EtOXuPHOS
Scheme 11.9: New proposed synthetic route for EtOXuPHOS ligand.
11.4 Experimental Section
General: All reactions, unless otherwise stated, were run under an atmosphere of
argon inflame or oven dried glassware (round bottomed flasks or Schlenk tubes).
Room temperature refers to ambient room temperature (20-22 °C), 0 °C refers to an
ice slush bath and -78 °C refers to a dry ice-acetone bath. Heated experiments were
conducted using thermostatically controlled oil baths. Reactions were monitored by
Thin Layer Chromatography (TLC) using aluminium backed silica gel 60 (F254)
plates, visualized using UV254 nm and PMA, potassium permanganate or ninhydrin
dips as appropriate. Flash column chromatography was carried out routinely using 60
Å silica gel (Merck). NMR spectra were recorded on a Bruker DPX-300 (300 MHz)
or DPX-400 (400 MHz) spectrometer. Chemical shifts are reported in δ units, parts
per million downfield from (CH3)4Si. Coupling constants (J) are measured in hertz.
Enantiomeric excesses were determined by GC analysis (Hewlett Packard 5890A gas
chromatography,
Cyclodextrin-β-236M-19
(CHROMPAC,
50m))
as
Elemental analyses were performed using the Exeter Analytical Model CE440.
174
stated.
RESULTS and DISCUSSION : Chapter 11
Synthesis of ortho-bis(dimethylaminophosphino)anisole (10)19
In an oven-dried 100 mL round bottom flask twice purged with nitrogen, 2bromoanisole (1.496 g, 8 mmol, 1.4 mL) was dissolved in freshly distilled diethyl
ether (25 mL) and it was allowed to cool to –78 °C. To the resulting solution was
added n-butyllithium (1.6 M, 8.8 mmol, 5.5 ml, 1.1 eq) and the mixture was allowed
to stir for 30 min whilst being maintained at –78 °C. The reaction mixture was then
allowed to warm to 0 °C and bis-(dimethylamino)chlorophosphane (8.8 mmol, 1.33
g, 1.3 mL, 1.1 eq) was added dropwise via a nitrogen purged syringe and the reaction
mixture was allowed to stir 20-30 min at room temperature. The resulting white
suspension was washed with saturated degassed sodium hydrogen carbonate solution
(25 mL), diluted with diethyl ether (25 mL) and transferred into a separating funnel,
the organic layer was collected and the aqueous layer back extracted with a further
aliquot of ether (5 mL). The combined organic layers were dried over anhydrous
magnesium sulphate for half an hour, filtered and concentrated under reduced
pressure to give the crude product as a pale green oil (1.09, 60%).
1
H NMR (300 MHz, CDCl3) δ= 7.70-7.66 (m, 1H), 7.29-7.22 (m, 1H), 7.09-7.07 (m,
1H), 6.65 (dd, J= 4.3Hz, J 8.1Hz,1H), 3.77 (s, 3H), 2.58 (d, JPH= 18.4Hz, 12H); 31P
NMR (162 MHz, CDCl3) δ= 97.7
Synthesis of (S)-MeOXuPHOS (11) 19
To a solution containing 2-bis-(dimethylaminophosphino)-anisole (1.01g, 4.42 mmol)
dissolved in toluene (25 mL) was added the (S)-bi-2-naphthol (1.26 g, 4.42 mmol)
dissolved in anhydrous toluene (25 mL). The reaction flask was placed in an oil bath
and stirred at room temperature for 10 min. It was heated up to reflux for 24 h. The
reaction was monitored by
31
P NMR, and also the releasing dimethylamine gas was
monitored by pH paper. After the reaction finished, it was allowed to cool down to
room temperature. Solvent was removed to get a off-white solid and dried under high
vacuum. The white solid was purified by recrystallization from toluene (529 mg,
28%).
175
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
1
H NMR (300 MHz, CDCl3) δ= 7.96-7.93 (1H, m), 7.83-7.79 (1H, m), 7.60 (t, J
8.1Hz, 2H), 7.49-7.35 (m, 4H), 7.33-7.18 (m, 3H), 7.13-7.09 (m, 1H), 6.96-6.85 (m,
1H), 6.80-6.77 (m,1H), 6.69-6.64 (m,1H), 3.96 (s, 3H); 31P NMR (162 MHz, CDCl3)
δ= 180.
Synthesis of (S,S,SS)- MeOXuPHOS-Ru-DPEN complex (12) 19
[RuCl2(C6H6)]2 (100mg, 0.200mmol) and (S)-MeOXuPHOS (338mg, 0.800mmol,
4e.q.) were placed in a 25-mL Schlenk flask. After the air in the flask was replaced
with argon, anhydrous DMF (10 ml) was added, the mixture was degassed and stirred
under argon at 100 °C for 10 min to form a reddish brown solution. After the solution
was cooled to 25 °C, (S, S)-DPEN (85mg, 0.400mmol) was added and the mixture
was degassed again before it was stirred for 3h. After the reaction finished, the
solvent was removed under reduced pressure., and CH2Cl2 was added in for several
times into the reaction mixture, and at each time it was turned on the high vacuum
and back to argon. The resulting dark green (yellow) solid was dried under the high
vacuum to give the metal complex (S,S,SS)- MeOXuPHOS-Ru-DPEN (438 mg,
89%).
1
H NMR (400MHz, CDCl3): δ= 7.72 (d, J 7.95Hz, 2H), 7.66 (d, J 7.91Hz, 2H), 7.61
(t, J 12.00Hz, 2H), 7.49 (d, J 8.83Hz, 2H), 7.44 (t, J 8.23Hz, 2H), 7.35 (t, J 7.99Hz,
2H), 7.28-7.24 (m, 8H), 7.16-7.13 (m, 8H), 7.10 7.06 (m, 6H), 7.02-7.00 (m, 6H),
6.87 (t, 2H), 4.58 (m, 2H), 4.47-4.45 (m, 2H), 4.14-4.10 (m, 2H), 3.97 (s, 6H);
31
P
NMR (162 MHz, CDCl3) δ= 206.3.
Synthesis of (S,S,SS)-MeOXuPHOS-Ru-DPEN complex (12) using THF.
[RuCl2(C6H6)]2 (25 mg, 0.05 mmol) and (S)-MeOXuPHOS (85 mg, 0.20 mmol,
4e.q.) were placed in a 50-mL Schlenk flask. After the air in the flask was replaced
with argon, anhydrous THF (15 ml) was added, the mixture was degassed and stirred
under argon at reflux for 1 h to form a yellow brown solution. After the solution was
cooled to 25 °C, (S, S)-DPEN (21 mg, 0.10 mmol) was added and the mixture was
degassed again before it was stirred overnight. After the reaction finished, the solvent
176
RESULTS and DISCUSSION : Chapter 11
was removed under reduced pressure. The resulting yellow brown solid was dried
under the high vacuum to give (S,S,SS)-MeOXuPHOS-Ru-DPEN complex (107 mg,
92 %).
31
P NMR (162 MHz, CDCl3) δ= 206.8.
Synthesis of (2-bromophenoxy)(tert-butyl)diphenylsilane (13)22
To an ice-cold bath of 2-bromophenol (1.81 g, 10.48 mmol, 1.2 ml) in DMF (75 mL)
was added tBuPh2SiCl ( 3.17 g, 11.53 mmol, 1.1 eq, 3.0 ml) and imidazole (1.5 g,
22.01 mmol, 2.1 eq). The mixture was allowed to stir at ambient temperature
overnight. After the reaction finished, the mixture was diluted with ethyl acetate (70
ml) and washed with water and brine, dried over magnesium sulphate for half an
hour, than concentrated in vacuo. The crude product was purify by chromatography
(SiO2, hexane, r.f. (AcOEt/Hexane 5:95) = 0.42) to give a white solid (3.97 g, 93%).
IR: vmax solid/cm-1 = 2928, 2855, 1476, 1296, 1028, 929; 1H NMR (300 MHz,
CDCl3) δ= 7.75-7.69 (m, 4H), 7.42 (dd, J 1.7 Hz, J 7.7 Hz, 1H), 7.44-7.35 (m, 6H),
6.83 (ddd app. dt, J 1.7 Hz, J 7.3 Hz, 1H), 6.71 (ddd app. dt, J 1.7 Hz, J 7.9 Hz, 1H),
6.45 (dd, J 1.5 Hz, J 8.1 Hz, 1H), 1.14 (s, 9H); 13C NMR (75 MHz, CDCl3) δ= 152.0,
135.3, 133.0, 132.0, 129.8, 127.7 (2 CH), 121.8, 119.6, 114.4, 26.2, 19.5; Anal.
Calculated for C22H23BrOSi: C, 64.23; H, 5.63. Found: C. 64.20; H, 5.53.
Synthesis of 2-bis(dimethylaminophosphino)terbutyl diphenylsililoxybenzene (14)
In a dried 100 mL Schlenk flask twice purged with nitrogen, (2-bromophenoxy)(tertbutyl)diphenylsilane (1.5 g, 3.69 mmol) was dissolved in freshly distilled diethyl
ether (35 mL) and it was allowed to cool to –78 °C. To the resulting solution was
added n-butyllithium (1.6 M, 4.06 mmol, 2.5 mL, 1.1 eq) and the mixture was
allowed to stir for 30 min whilst being maintained at –78 °C. The reaction mixture
was then allowed to warm to 0 °C and bis-(dimethylamino)chlorophosphane (0.612 g,
4.06 mmol, 0.6 mL, 1.1 eq) was added dropwise via a nitrogen purged syringe and
the reaction mixture was allowed to stir 20-30 min at ambient temperature. The
resulting white suspension was washed with saturated degassed sodium hydrogen
177
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
carbonate solution (35 mL), diluted with diethyl ether (35 mL) and transferred to a
separating funnel, the organic layer was collected and the aqueous layer back
extracted with a further aliquot of ether (5 mL). The combined organic layers were
dried over magnesium sulphate for half an hour, filtered and concentrated under
reduced pressure to give the crude product as pale yellow oil. It was not possible to
purified the product.
IR: vmax neat/cm-1 = 3063, 2932, 2850, 1467, 1418, 1026; 1H NMR (300 MHz,
CDCl3) δ= 7.75-7.68 (m, 4H), 7.52 (dd, J 1.9 Hz, J 7.9 Hz, 1H), 7.40-7.35 (m, 6H),
6.84 (ddd app. dt, J 1.7Hz, J 7.5Hz, 1H), 6.71 (ddd app. dt, J 1.5Hz, J 7.7Hz,1H), 6.45
(dd, J 1.5 Hz, J 8.1 Hz, 1H), 2.47 (d, JP-H 9.4Hz, 12H), 1.14 (s, 9H); 31P NMR (162
MHz, CDCl3) δ= 126.
Oxidized derivative of 14: 31P NMR (162 MHz, CDCl3) δ= 39.
Synthesis of (Rac)-tBuPh2SiOXuPHOS (15)
To
a
solution
containing
2-bis(dimethylaminophosphino)terbutyl
diphenylsililoxybenzene (88 mg, 1.9 mmol) dissolved in toluene (15 mL) was
charged the (Rac)-bi-2-naphthol (56 mg, 1.9 mmol) dissolved in anhydrous toluene
(60 mL). The reaction flask was placed in an oil bath and stirred at room temperature
for 10 min. It was heated up to reflux for 24 h. The reaction was monitored by
31
P
NMR, and also the releasing dimethylamine gas was monitored by pH paper. After
the reaction finished, it was allowed to cool down to room temperature. Solvent was
removed to get a white solid and dried under high vacuum. It was not possible to
purify the product.
31
P NMR (162 MHz, CDCl3) δ= 138.
Synthesis of ortho-bis(dimethylaminophosphino)diphenyl ether (16)
In a dried 100 mL Schlenk flask twice purged with nitrogen, diphenyl ether (1.07 g,
6.3 mmol) was dissolved in freshly distilled diethyl ether (20 mL) and it was allowed
to cool to 0 °C. To the resulting solution was added n-butyllithium (1.6 M, 6.3 mmol,
3.9 mL, 1 eq) and the mixture was allowed to stir at ambient temperature overnight.
178
RESULTS and DISCUSSION : Chapter 11
The reaction mixture was then allowed to warm to 0 °C and bis(dimethylamino)chlorophosphane (6.9 mmol, 1.04 g, 1 mL, 1.1 eq) was added
dropwise via a nitrogen purged syringe and the reaction mixture was allowed to stir
20-30 min at ambient temperature. The resulting white suspension was washed with
saturated degassed sodium hydrogen carbonate solution (25 mL), diluted with diethyl
ether (25 mL) and transferred to a separating funnel, the organic layer was collected
and the aqueous layer back extracted with a further aliquot of ether (5 mL). The
combined organic layers were dried over magnesium sulphate for half an hour,
filtered and concentrated under reduced pressure to give the crude product as pale
yellow oil (1.723 g, 81%). It was not possible to purify the product.
IR: vmax neat/cm-1 = 3052, 2861, 2774, 1581, 1478, 955; 1H NMR (300 MHz,
CDCl3) δ= 7.52-7.45 (m, 1H), 7.35-6.92 (m, 7H), 6.88-6.81 (m, 1H), 2.68 (d, JPH
Hz, 12H); 31P NMR (162 MHz, CDCl3) δ= 95.9.
Synthesis of (S)-PhOXuPHOS (17)
To a solution containing ortho-bis(dimethylaminophosphino)diphenyl ether (406 mg,
1.48 mmol) dissolved in toluene (10 mL) was charged the (S)-bi-2-naphthol (423 mg,
1.48 mmol) dissolved in anhydrous toluene (30 mL). The reaction flask was placed in
an oil bath and stirred at room temperature for 10 min. It was heated up to reflux for
20 h. The reaction was monitored by 31P NMR, and also the releasing dimethylamine
gas was monitored by pH paper. After the reaction finished, it was allowed to cool
down to room temperature. Solvent was removed to get an oil that was washed with
diethyl ether. After solvent was removed, a white solid was obtained that was dried
under high vacuum. It was not possible to purify the product.
31
P NMR (162 MHz, CDCl3) δ= 178.
Synthesis of (S, S,SS)-PhOXuPHOS-Ru-DPEN complex (18)
[RuCl2(C6H6)]2 (28 mg, 0.057 mmol) and (S)-PhOXuPHOS (111 mg, 0.230 mmol, 4
e.q.) were placed in a 50-mL Schlenk flask. After the air in the flask was replaced
with argon, anhydrous DMF (5 ml) was added, the mixture was degassed and stirred
179
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
under argon at 100 °C for 10 min to form a reddish brown solution. After the solution
was cooled to 25 °C, (S, S)-DPEN (23 mg, 0.110 mmol) was added and the mixture
was degassed again before it was stirred for 3h. After the reaction finished, the
solvent was removed under argon flow, and CH2Cl2 was added in for several times
into the reaction mixture, and at each time it was turned on the high vacuum and back
to argon. The resulting brown solid was dried under the high vacuum to give the
metal complex (105 mg, 72 %). It was not possible to purify the product.
31
P NMR (162 MHz, CDCl3) δ= 210.
Synthesis of 1- tert butoxy benzene; procedure B (19) 23
In a schlenk flask under argon, at a solution of 2-bromobenzene (2,98 g, 17.2 mmol, 2
mL) and sodium tert-butoxide (2 g, 20.64 mmol) in toluene (60 mL), was added
Pd(OAc)2 (0.047g, 0.21mmol) and P(tBu)3 (0.127 g, 0.63 mmol, 0.15 mL). The
mixture was stirred at reflux for 8 h. After the reaction finished, the mixture was
diluted with ethyl acetate (50 mL) and washed with water (50 mL), dried over
magnesium sulphate for half an hour, filtered and concentrated under reduced
pressure to give the crude product that was purified by chromatography (SiO2,
Hexane). The product was as oil (0.55 g, 21%).
1
H NMR (300 MHz, CDCl3) δ= 7.26 (t, J 7.5 Hz, 2H), 7.08 (t, J 7.5 Hz, 1H), 6.99 (d,
J 7.5 Hz, 2H), 1.34 (s, 9H);
13
C NMR (75 MHz, CDCl3) δ= 155.1, 128.5, 124.0,
123.1, 78.1, 28.6.
Synthesis of ortho-bis(dimethylaminophosphino) tert butoxy benzene (20)
In a dried 100 mL Schlenk flask twice purged with nitrogen, 1- tert butoxy benzene
(0.5 g, 3.3 mmol) was dissolved in freshly distilled diethyl ether (10 mL) and it was
allowed to cool to 0 °C. To the resulting solution was added n-butyllithium (1.6 M,
3.3 mmol, 2.1 mL, 1 eq) and the mixture was allowed to stir at ambient temperature
overnight. The reaction mixture was then allowed to warm to 0 °C and bis(dimethylamino)chlorophosphane (3.7 mmol, 0.56 g, 0.55 mL, 1.1 eq) was added
dropwise via a nitrogen purged syringe and the reaction mixture was allowed to stir
180
RESULTS and DISCUSSION : Chapter 11
20-30 min at ambient temperature. The resulting white suspension was washed with
saturated degassed sodium hydrogen carbonate solution (10 mL), diluted with diethyl
ether (10 mL) and transferred to a separating funnel, the organic layer was collected
and the aqueous layer back extracted with a further aliquot of ether (5 mL). The
combined organic layers were dried over magnesium sulphate for half an hour,
filtered and concentrated under reduced pressure to give the crude product as pale
yellow oil. The product was obtained only in trace.
Synthesis of ortho-bis(dimethylaminophosphino) phenetole (22)
In a dried 100 mL Schlenk flask twice purged with nitrogen, phenetole (0.41 g, 3.3
mmol) was dissolved in freshly distilled diethyl ether (10 mL) and it was allowed to
cool to 0 °C. To the resulting solution was added n-butyllithium (1.6 M, 3.3 mmol,
2.1 mL, 1 eq) and the mixture was allowed to stir at ambient temperature overnight.
The reaction mixture was then allowed to warm to 0 °C and bis(dimethylamino)chlorophosphane (3.7 mmol, 0.56 g, 0.55 mL, 1.1 eq) was added
dropwise via a nitrogen purged syringe and the reaction mixture was allowed to stir
20-30 min at ambient temperature. The resulting white suspension was washed with
saturated degassed sodium hydrogen carbonate solution (10mL), diluted with diethyl
ether (10 mL) and transferred to a separating funnel, the organic layer was collected
and the aqueous layer back extracted with a further aliquot of ether (5 mL). The
combined organic layers were dried over magnesium sulphate for half an hour,
filtered and concentrated under reduced pressure to give the crude product as read oil.
The product was obtained only in trace.
General procedure for the asymmetric hydrogenation catalysed by (S,S,SS) and
(R,R,RR)-MeOXuPHOS-Ru-DPEN and (S,S,SS)-PhOXuPHOS-Ru-DPEN 19
In a dried round bottom flask (150 mL), acetophenone (0.48 mL, 0.5 g, 4.16 mmol)
and (CH3)3COK (9 mg, 0.083 mmol, 0.5 mol %) were dissolved in dry and degassed
2-propanol (28 mL). (S,S,SS)-MeOXuPHOS-Ru-DPEN (10 mg, 0.0083 mmol, 0.05
mol %) was dissolved in anhydrous and degassed CH2Cl2 (1 mL), which was used as
181
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
the catalyst stock solution and was transferred into the reaction solution above under
argon. The mixture was degassed by three vacuum-filling with argon cycles and then
it was quickly transferred into the autoclave. It was purged with hydrogen for 10
seconds and finally the hydrogen was introduced to 50 bar. The reaction mixture was
stirred vigorously at 20-22 oC (or 0 oC refers to an ice slush bath) for 20h. The
mixture was filtered through a pad of silica gel and the pad was washed with a 50%
solution of ethyl acetate in hexane (120 mL). The filtrate was concentrated under
reduced pressure to afford the reduction product.
11.5 References
(1)
(a) Nagata, T., Yorozu, K., Yamada, T., Mukaiyama, T., Angew. Chem. Int.
Ed., 1995, 34, 2146; (b) Brown, H. C., Ramachandran, P. V., Acc. Chem.
Res., 1992, 25, 16.
(2)
(a) Yun, J., Buchwald, S. L., J. Am. Chem. Soc., 1999, 121, 5640; (b) Lee, S.,
Lim, C. W., Song, C. E., Kim, I. O., Tetrahedron: Asymmetry, 1997, 8, 4027;
(c) Hayashi, T., Hayashi, C., Uozumi, Y., Tetrahedron: Asymmetry, 1995, 6,
2503; (d) Sawamura, M., Kuwano, R., Ito,Y., Angew. Chem. Int. Ed., 1994,
33, 112.
(3)
(a) Palmer, J. M., Wills, M., Tetrahedron: Asymmetry, 1999, 10, 2045; (b)
Noyori R., Hashiguchi, S., Acc. Chem. Res., 1997, 30, 97.
(4)
Noyori R., Ohkuma, T., Angew. Chem. Int. Ed., 2001, 40, 40.
(5)
Noyori R., Angew. Chem. Int. Ed., 2002, 41, 2008.
(6)
Haack, K. J., Hashiguchi, A. F., Ikariya, T., Noyori, R., Angew. Chem. Int.
Ed., 1997, 36, 285.
(7)
Clapham, S. E., Hadzovic, A., Morris, R. H., Coordination Chemistry
Reviews, 2004, 248, 2201.
182
RESULTS and DISCUSSION : Chapter 11
(8)
(a) Knowles, W. S., Sabacky, M. J., J. Chem. Soc. Chem. Commun., 1968,
1445; (b) Knowles, W. S., Acc. Chem. Rev., 1983, 16, 106.
(9)
Tang, W., Zhang, X., Chem. Rev., 2003, 103, 3029.
(10)
(a)Blaser, H.-U., Mala, C., Pugin, B., Spindler, F., Steiner, H., Studer, M.,
Adv. Synth. Catal., 2003, 345, 103. (b) (a) Blaser, H.-U., Spindler, F., Studer,
M., Appl. Catal. A, 2001, 221, 119.
(11)
Bernsmann, H., van den Berg, M., Hoen, R., Minnaard, A. J., Mehler, G.,
Reetz, M. T., De Vries, J. G., Feringa, B. L., J. Org. Chem., 2005, 70, 943.
(12)
(a)Komarov, I. V., Borner, A., Angew. Chem. Int. Ed., 2001, 40, 1197. (b)
Jerphagnon, T., Renaud, J.-L., Bruneau, C., Tetrahedron: Asymmetry, 2004,
15, 2101.
(13)
Guillen, F., Fiaud, J. C., Tetrahedron Letters , 1999, 40, 2939.
(14)
Claver, C., Fernandez, E., Gillon, A., Heslop, K., Hyett, D. J., Martorell, A.,
Orpen, A. G., Pringle, P. G., J. Chem. Soc. Chem. Commun., 2000, 961.
(15)
Reetz, M. T., Mehler, G., Angew. Chem. Int. Ed., 2000, 39, 3889.
(16)
Van den Berg, M., Minnaard, A. J., Schudde, E. P., van Esch, J., de Vries, A.
H. M., de Vries, J., Feringa, B. L., J. Am. Chem. Soc., 2000, 122, 11539.
(17)
Hoen, R., van den Berg, M., Bernsmann, H., Minnaard, A. J., de Vries, J. G.,
Feringa, B., Org. Lett., 2004, 6, 1433.
(18)
(a) Hu, A. G., Fu, Y., Xie, J. H., Zhou, H., Wang, L. X., Zhou, Q. L., Angew.
Chem. Int. Ed., 2002, 41, 2348; (b) Fu, Y., Xie, J. H., Hu, A. G., Zhou, H.,
Wang, L. X., Zhou, Q. L., J. Chem. Soc. Chem. Commun., 2002, 480.
(19)
Xu J., Alcock N. W., Clarkson G. J., Docherty G., Woodward G., Wills M.,
Org. Lett. 2004, 6, 4105.
(20)
Xu J., Alcock N. W., Clarkson G. J., Docherty G., Woodward G., Wills M., J.
Org. Chem. 2005, 70, 8079.
(21)
R. Guo, C. Elpelt, X. Chen, D. Song, R. H. Morris, Chem. Commun., 2005,
3050.
(22)
Ino A., Murabayashi A., Tetrahedron, 2001, 57,1897.
(23)
J. D. Cram, B. Ruckeborn, G. R. Knox, J. Am. Chem. Soc., 1960, 82, 6412.
183
Synthesis and Evaluation of a New Series of Ligands Deriving from MeOXuPHOS
(24)
Watanabe, M.; Nishiyama, M.; Koie, Y.; Tetrahedron Letters , 1999, 40,
8837.
184
RESULTS and DISCUSSION : Chapter 12
Chapter 12
RUTHENIUM-CATALYZED HYDROGENATION OF
KETONES AND AROMATIC RINGS
12.1 Introduction
The arene hydrogenation by molecular catalysis is a current area of research in
which many highly innovative catalysts have been evaluated. Arene
hydrogenation has many applications ranging from small scale synthesis to
industrial processes such as the synthesis of cyclohexane and the removal of
aromatic compounds from fuels.1
The reduction of aromatic rings can be obtained by numerous methods:
heterogeneous and homogeneous catalysis, dissolving metal reduction (Na/K in
liquid NH3).2 Usually, heterogeneous catalytic hydrogenation is carried out under
drastic conditions (high pressure and temperature) and the metals used are RaneyNi, Pd, Ru and Rh. Recently, new research has made progress in the reaction
conditions using moderate temperatures, low pressure and water as solvent, but
the problem still is the quantity of catalyst used; around 10% w/w. In a recent
paper, Tsukinoki et al.3 found a new heterogeneous method to reduce aromatic
rings in high yields under mild conditions. They performed a method using
Raney-Ni-Al alloy as catalyst, and dilute aqueous alkaline solution (KOH) in
water at 90°C. More recently, Sajiki et al. used Rh/C for a similar reaction that
proceeds at 80°C, in water under 5 atm of H2.4
To compare, the homogeneous catalysis is not studied as much as the
heterogeneous, generally it is carried out under milder conditions than those for
heterogeneous hydrogenation, and sometimes in atmospheric hydrogen pressure
and at room temperature. One of the first catalysts, organocobalt molecule, η3-
185
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
C3H5Co[P(OCH3)3]3 discovered by Muetterties in 1973 has been used as catalyst
for the hydrogenation of aromatic hydrocarbons.5 Reaction conditions were mild
(1 atm hydrogen, room temperature) and the cobalt-catalyst was demonstrated to
be stereoselective and chemoselective. Unfortunately, there were limiting factors
such as steric (arene-substitution), electronic (strongly electron-withdrawing
groups such as F and NO2) and protonic substituents (OH, COOH).
The generally accepted mechanism for the hydrogenation of arenes was proposed
in 1974.6 The mechanism took place in a number of metal-arene complexes and
the so called “arene-exchange mechanism” is shown in figure 12.1.
= a metal-ligand combination
+L
+ H2
H
H
H
H
+ H2
+ H2
H
H
Figure 12.1: General scheme for arene hydrogenation catalysis by the “arene-exchange
mechanism”.8
Typically, heterogeneous catalysts use metals supported on fixed beds, or metal
colloids and nanoparticles, which can be used under milder conditions.7 A number
of molecular compounds have been reported to homogeneously catalyse the
hydrogenation of arene, although many have since been shown to be precursors to
heterogeneous catalysis.8 Actually, the active catalysis was later discovered to be
colloidal and compared to many of the apparently homogeneous catalyses that
have been reported, these colloidal catalysts operated under much milder
conditions and are often more active, in discordance with the general assumption
186
RESULTS and DISCUSSION : Chapter 12
that homogeneous catalysis are more active than heterogeneous catalysis under
ambient conditions.8
12.2 Results and discussion
During the study of hydrogenation reaction catalyzed by RuCl3 and sodium
alkoxide, a new catalyst was discovered. It was shown to be active in reducing
ketones and aromatic rings at the same time.
The aim of this project was to find the best reaction conditions using this new
catalyst. Moreover an initial study of improvement of the ligand was attempted.
12.2.1 Hydrogenation reaction catalyzed by RuCl3, 1,1,1Tris(hydroxymethyl)ethane and bases
Sodium alkoxide was used as a base in the hydrogenation reaction of
acetophenone catalyzed by RuCl3 (tab 12.1, entry 1). Unexpectedly, we got not
only the reduction of the ketone group, but the aromatic rings as well. As a result
the crude reaction was composed of three products: 1-phenyl-ethanol, 1cyclohexyl-ethanol and cyclohexyl methyl ketone, in the ratio reported in tab.
12.1 entry 1.
187
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
Entry
Substrate
Catalyst
Conv (%)a 20h
Base
OH
OH
O
O
1
RuCl3
3.5 eq CH3ONa
29
4
6.5
RuCl3
No base
30
16
6
3.5 eq CH3ONa
46
44
10
No base
13
6
2
O
2
O
OH
RuCl3 +
3
OH
OH
O
4
OH
RuCl3 +
OH
OH
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1mol% of catalyst wrt
substrate, eq. base wrt catalyst, pressure of H2 10 bar, room temperature. (a) Determined by 1H
NMR.
Table 12.1: Hydrogenation of acetophenone using ruthenium-catalyst and sodium alkoxides.
In order to determinate the role of sodium methoxide, the reaction was repeated
using any base (entry 2, table 12.1). The conversion was a slight better than the
previous result (entry 1), indicating apparently, that the base did not play an
important function in the catalysis.
Nevertheless, the reaction was repeated again using the same conditions used in
entry 1, and adding the 1,1,1-tris(hydroxymethyl)ethane (entry 3, table 12.1). The
result this time was much better than the previous two attempts and complete
conversion was obtained. As for the reaction, entry 1, the reaction, entry 3, was
repeated without base as well (entry 4, table 12.1). But this time the result was
inferior in respect to all previous tests (entry 1,2, 3, table 12.1).
This improved result could be explained with the formation of a complex between
RuCl3 and the 1,1,1-tris(hydroxymethyl)ethane promoted by the base with the
elimination of NaCl, as reported in figure 12.2.
188
RESULTS and DISCUSSION : Chapter 12
OH
RuCl3
OH
+
3.5 eq CH3ONa
CH3OH
OH
O
Ru
O
+
NaCl
O
1
Figure 12.2: Formation of new ruthenium-1,1,1-tris(hydroxymethyl)ethane complex.
To demonstrate the importance of this base, the reaction was repeated using 3.5 eq
(entry 1, table 12.2) and 2 eq. of base (entry 2, table 12.2). As the results show,
reported in table 12.2, the reaction conducted using 2 eq of base (entry 2) was
much slower than the reaction where 3.5 eq of base was added (entry 1). This
indicates that almost 3 times the stoichiometric amount of base is necessary for
the complex formation.
Entry Substrate
Catalyst
Conv (%)a 21h
Base
OH
O
OH
RuCl3 +
1
O
OH
OH
3.5 eq CH3ONa
7
92.6
0.4
2 eq CH3ONa
26
59
14
3 eq Et3N
CH2Cl2
0.6M
8
7
CH3OH
0.6M
8
4
OH
O
OH
RuCl3 +
2
OH
OH
O
OH
RuCl3 +
3
OH
OH
O
3 eq
OH
4
RuCl3 +
OH
OH
H2N
COONa
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1 mol% of catalyst wrt
substrate, the quantity of base wrt catalyst, pressure of H2: 10 bar, room temperature. (a)
Determined by 1H NMR.
Table 12.2: Hydrogenation of acetophenone using ruthenium-catalyst and sodium alkoxides.
The use of different bases was analysed, in particular using Et3N and sodium
glycinate (entry 3 and 4 respectively, table 12.2), but the results reported in table
189
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
12.2 show a conversion decrement, indicating that the best base for the catalyst
formation was sodium alkoxide.
To evaluate the catalyst activity, the reaction was carried out using 0.1mol%
instead of 1mol% of catalyst (entry 2, table 12.3). Also in this case the conversion
was complete, but the reaction trend showed slower reaction rate in the reduction
of substrate.
Entry
Substrate
Catalyst
Catalyst
%
Pressure
(bar)
Conv (%)a 21h
OH
O
OH
O
OH
RuCl3 +
1
OH
1
10
7
92.6
0.4
0.1
10
65
33
2
0.1
20
36
58
6
OH
O
OH
RuCl3 +
2
OH
OH
O
OH
RuCl3 +
3
OH
OH
Reactions were conducted in methanol with a 0.6 M solution of ketone, mol% catalyst wrt
substrate, 3.5 eq CH3ONa wrt catalyst, room temperature. (a) Determined by 1H NMR.
Table 12.3: Hydrogenation of acetophenone using ruthenium-catalyst and sodium alkoxides.
In addition, the influence of the pressure was studied: the reaction was carried out
under a pressure of 20 bar instead of 10 bar (entry 2 and 3 respectively, table
12.3), and as expected, the reaction rate increased with the increment of pressure.
.
In order to study the catalyst activity on ketone reduction different substrates were
considered. Cyclohexyl methyl ketone was chosen as it lacks carbon-carbon
double bonds that could be reduced by the catalyst. The reduction of cyclohexyl
methyl ketone (entry 1, table 12.4), was followed by 1H NMR spectroscopy, and
the reaction trend shows that in the first 6 hours the reaction velocity was quite
high with a 61% conversion, but subsequent to this time and even after 20 hours,
the conversion was not completed.
190
RESULTS and DISCUSSION : Chapter 12
Entry Substrate
Catalyst
O
Conv (%)a
2h
Conv (%)a
4h
Conv (%)a
6h
Conv (%)a
20h
22
39
61
95
OH
RuCl3 +
1
OH
OH
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1 mol% catalyst wrt
substrate, 3.5 eq CH3ONa wrt catalyst, pressure of H2: 10 bar, room temperature. (a) Determined
by 1H NMR.
Table 12.4: Hydrogenation of cyclohexyl methyl ketone using ruthenium-catalyst and sodium
alkoxides.
The catalytic activity was tested on aromatic substrate as well, in particular
quinoline was used. The optimized reaction conditions were applied for both
entry 1 and 2, table 12.5 and in both cases the conversion after 20 hours was low
and selective for only reduction of pyridine ring. It should be noted that when a
high pressure was applied (30 bar, entry 2), traces of completed reduction product
were observed.
Entry
Substrate
Catalyst
Pressure
(bar)
Conv. (%)a 6h
N
H
R
Conv. (%)a 20h
N
H
R
N
H
R
N
H
R
OH
RuCl3 +
1
OH
N
10
-
-
32
30
7
-
25
OH
RuCl3 +
2
OH
N
-
OH
OH
traces
OH
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1mol% catalyst wrt
substrate, 3.5 eq CH3ONa wrt catalyst, room temperature. (a) Determined by 1H NMR.
Table 12.5: Hydrogenation of aromatic substrates using ruthenium-catalyst and sodium alkoxide.
Subsequently, an optical pure diol ((S, S)-1,2-diphenyl-1,2-ethanediol) was tested
as a ligand instead of the triol (1,1,1-Tris(hydroxymethyl)ethane). The conversion
was lower (entry 2, table 12.6) in respect to the reaction carried out with the triol
(entry 1, table 12.6). In order to verify the possibility of enantioselectivity induced
by the chiral ligand used, the crude reaction was analysed by chiral GC, but the
result showed no enantioselectivity.
191
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
Entry
Substrate
O
1
Conv (%)a
20h
Catalyst
OH
RuCl3 +
OH
95
OH
O
2
RuCl3 +
HO
OH
Ph
Ph
71
(0% ee’)
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1mol% catalyst wrt
substrate, 3.5 eq CH3ONa wrt catalyst, pressure of H2 10 bar, room temperature. (a) Determined
by 1H NMR.
Table 12.6: Hydrogenation of cyclohexyl methyl ketone using ruthenium-catalyst and sodium
alkoxides
The temperature was identified as an important parameter in the reaction, and
some tests were carried out at different temperatures from 14-18°C to 35°C (entry
1-3, table 12.7). Simultaneously, a new procedure for “activating catalyst” was
attempted; the catalyst was heated at 35°C, 50 bar for 5h, than after cooling down
the solution, the substrate was added. The best compromise temperature for the
reaction was found to be 25°C. Also the “activating catalyst” procedure seems to
improve the catalyst activity.
Other tests, using different bases, were carried out. In particular sodium hydroxide
was used as a base instead of sodium methoxide (entry 4, table 12.7). In this case,
the conversion was completed and comparable to the result obtained in entry 1,
table 12.2. Sodium hydroxide demonstrates that other strong bases can be used
instead of sodium alkoxide. The excess of base (in respect to the previous
reactions, 4.2 eq NaOH instead 3.5 eq CH3ONa) could also improve the catalyst
activity because, as reported by Dyson,8a in some cases of arene hydrogenation
catalysis, efficiency increases with increasing pH.
The best result was found by adding water after catalyst formation (entry 5),
(same reaction condition of entry 4, table 12.7), in this case the conversion was
complete and only 1-cyclohexyl-ethanol was obtained.
192
RESULTS and DISCUSSION : Chapter 12
Entry
Catalyst
Base
Conv (%)a 16h
Temperature
OH
3.5 eq CH3ONa
Room
temperature (1418°C)
49
20
16
3.5 eq CH3ONa
25°C
50.7
23.8
24.8
3.5 eq CH3ONa
35°C
42.5
26
16.6
4.2 eq NaOH
25°C
15.6
80.8
3.6
4.2 eq NaOH
25°C
-
100d
-
OH
1
RuCl3 +
OH
O
OH
OH
OH
2
RuCl3 +
OH
OH
OH
3
RuCl3 +
OH
OH
OH
4
RuCl3 +
OH
OH
OH
5
RuCl3 +
OH
OH
Reactions were conducted in methanol with a 0.1 M solution of ketone, 1 mol% catalyst wrt
substrate and the catalyst was heated at 35°C, 50 bar for 5h before to add the substrate (“catalyst
activation”), eq base wrt catalyst, substrate: acetophenone, pressure 10 bar; Mechanical stirrer
(rpm 685 MAX). (a) Determined by 1H NMR; (b) reactions were conducted without previous
“catalyst activation”; (c) Reactions were conducted in methanol with a 0.6 M solution of ketone,
for 21h; (d) solvent:: methanol 95ml and water 30ml.
Table 2.7: Hydrogenation of aromatic substrates using ruthenium-catalyst
12.2.2 Synthesis of phosphorus ligands
The possibility of introducing phosphorus groups in the ligand was analyzed. In
fact phosphorus and amine compounds are good ligands often used with transition
metal for the catalytic reduction of aromatic rings.9
Initially PPh3 was used; two tests were carried out, the first using RuCl3 and three
equivalents of PPh3 (entry 1, table 12.8), but the conversion was much lower than
the same reaction carried out without phophorus ligands (entry 2, table 12.1).
193
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
Entry
Substrate
Catalyst
Conv. (%)a 20h
Base
O
OH
OH
O
RuCl3
+ 3eq PPh3
1
-
2.6
2.4
1
3.5 eq
CH3ONa
18
6
4.5
OH
O
RuCl3 +
2
OH
OH
+ 1eq PPh3
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1mol% catalyst wrt
substrate, eq CH3ONa wrt catalyst, pressure of H2 10 bar, room temperature. (a) Determined by
1
H NMR.
Table 12.8: Hydrogenation of acetophenone using ruthenium-catalyst and sodium alkoxides.
The second experiment was done adding 1 equivalent of PPh3 to RuCl3,
1,1,1-tris(hydroxymethyl)ethane, and sodium methoxide (entry 2, table 12.8),
however as in the previous reaction (entry 1), the conversion was lower than the
corresponding reaction conducted without PPh3 (entry 3, table 12.1).
Nevertheless, the phosphorus group was introduced in the ligand structure. The
ligand 2 (figure 12.3) was obtained from 3-methyl-3-oxetanemethanol using
LiPPh2 as nucleophilic reagent, after previous alcohol deprotonation by n-BuLi.
The product 2 was purified by crystallization from toluene and pentene.
OH
O
OH
1) 1eq. n-BuLi
2) 1.2 eq. LiPPh2, THF, 0°C
3) r.t., overnight
y= 37%
OH
PPh2
2
Figure 12.3: Synthesis of 2-((diphenylphosphino)methyl)-2-methylpropane-1,3-diol.
It was tested in the reduction of acetophenone and the conversion was very poor
(entry 1, table 12.9),. The amount of base was reduced because in the ligand there
were only two OH to deprotonate.
194
RESULTS and DISCUSSION : Chapter 12
Entry
Substrate
Catalyst
Conv. (%)a 20h
Base
O
OH
OH
O
OH
RuCl3 +
1
2 eq CH3ONa
OH
4.5
1.5
1
PPh2
Reactions were conducted in methanol with a 0.6 M solution of ketone, 1mol% catalyst wrt
substrate, eq CH3ONa wrt catalyst, pressure of H2 10 bar, room temperature. (a) Determined by
1
H NMR.
Table 12.9: Hydrogenation of acetophenone using ruthenium-ligand 2 complex.
Therefore also an amino group was also introduced in the ligand, and compound 7
was synthesized using the following procedure (figure 12.4). After synthesis of
compound
3,
from
3-methyl-3-oxetanemethanol
by
easily
nucleophilic
substitution with MsCl, NaN3 was used as nitrogen nucleophile to obtain 4. The
crude reaction of 4 was immediately converted into the amine 5 because of the
instability of 4. The azide 4 was converted into amine 5 using Staudinger Reaction
(mild azide reduction) as reported in literature10 and the reaction product 5 was
purified by chromatography.
OH
OMs
N3
NaN3
MsCl, Et3N
O
DCM, r.t., overnight
y= 83%
O
3
N3
y= 84%
NH2
4
2) H2O, reflux, 2h
y= 63%
NHTs
O
NHTs
O
5
DCM, r.t., overnight
y= 54%
6
O
6
OH
1) 1eq. n-BuLi
2) 1.1 eq. LiPPh2, THF, 0°C
3) r.t., overnight
4
TsCl, Et3N
1) PPh3, Et2O, r.t.
O
O
DMF, 40°C, overnight
NHTs
PPh2
7
Figure 12.4: Synthesis route for ligand 7.
195
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
The ligand 7 (figure 12.5) was obtained from compound 6 using the same
procedure utilized for obtaining ligand 2. Unfortunately, compound 7 was
obtained as white oil impure with starting material 6 and HPPh2. Despite that the
ligand (7) was not pure, the hydrogenation reaction carried out using 7 as ligand
was attempted. The conversion was very low (entry 1, table 12.10).
Entry
Substrate
Catalyst
Temperature
Conv (%)a 21h
Pressure
OH
O
1
O
OH
OH
RuCl3 +
NHTs
25°C
10 bar
3
1.3
1
PPh2
Reactions were conducted in methanol with a 0.1 M solution of ketone, 1mol% catalyst wrt
substrate , 3.5 eq CH3ONa wrt catalyst, Mechanical (rpm 685 MAX). (a) Determined by 1H NMR.
Table 12.10: Hydrogenation of acetophenone using ruthenium-ligand 7 complex.
12.3 Conclusion
During the optimization of reaction conditions, temperature was found to be very
important for the catalyst activity (25°C). Pressure does not seem to have a strong
influence on the conversion, but the stirrer has a big effect. For this reason, the
stirrer and the concentration of substrate should be studied more, because we
hypothesise that the catalyst does not operate effectively in homogeneous phase,
but in colloidal phase (heterogeneous). In a recent review of Dyson8, it has been
reported that a large number of catalysts for arene hydrogenation work in colloidal
phase.
Sodium hydroxide showed to be a good base, and more easy to handle than
sodium methoxide. The ratio base wrt catalyst seems to be a influence parameter
on the reaction, probably because a higher pH of reaction could improve the
catalyst activity.8 Nevertheless, the best reaction conditions were obtained using
NaOH as base and adding water and methanol together as solvent, in this case a
complete conversion in 1-cyclohexyl-ethanol was obtained. Actually, water seems
196
RESULTS and DISCUSSION : Chapter 12
to be a good solvent for the catalyst, this was also demonstrated as no catalyst was
found on the bottom of the autoclave like in the previous cases (see figure 2.11,
experimental section).
Phosphorus ligands (2 and 7) were used instead of triol, in order to improve the
catalytic performance but, as the results show, phosphines and amine compounds
are not good ligands for this type of catalyst.
Also diol was tested as a ligand and the result obtained in the hydrogenation
reaction of cyclohexyl methyl ketone (entry 1, table 12.4) was good (71% conv.
vs 95% conv. of triol). This data suggests further study of alcohol ligands as they
seem to be more active.
12.4 Experimental Section
General: All reactions, unless otherwise stated, were run under an atmosphere of
argon in flame or oven dried glassware (round bottomed flasks or Schlenk tubes).
Room temperature refers to ambient room temperature (20-22 °C); 0 °C refers to
an ice slush bath. Heated experiments were conducted using thermostatically
controlled oil baths. Reactions were monitored by Thin Layer Chromatography
(TLC) using aluminium backed silica gel 60 (F254) plates, visualized using
UV254 nm and PMA, potassium permanganate or ninhydrin dips as appropriate.
Flash column chromatography was carried out routinely using 60 Å silica gel
(Merck). NMR spectra were recorded on a Bruker DPX-300 (300 MHz) or DPX400 (400 MHz) spectrometer. Chemical shifts are reported in δ units, parts per
million downfield from (CH3)4Si. Coupling constants (J) are measured in hertz.
Enantiomeric excesses were determined by GC analysis (Hewlett Packard 5890A
gas chromatography, Cyclodextrin-β-236M-19 (CHROMPAC, 50m)) as stated.
Elemental analyses were performed using the Exeter Analytical Model CE440.
The hydrogenation reactions were conducted in a high pressure autoclave (300
ml) which is commercially available from the Parr Ltd. Company.
NaH 60% in mineral oil was used after washed 3 times with anhydrous pentane,
immediately before use (the quantity of NaH reported refers to NaH 60% in
mineral oil).
197
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
General procedure for the hydrogenation catalysed by RuCl3, 1,1,1Tris(hydroxymethyl)ethane and sodium methoxide.
In a dried round bottom flask, anhydrous methanol (10 mL) was added to NaH
(17 mg, 0.437 mmol, 3.5 eq). In another dried round bottom flask, RuCl3.3H2O
(26 mg, 0.125 mmol, 1 mol%) and 1,1,1-tris(hydroxymethyl)ethane (15 mg, 0.125
mmol) were dissolved in anhydrous methanol (10 mL), then stirred for 5 min. The
solution of sodium methoxide was added and the mixture was allowed to stir for
30 min, the colour change from black to dark brown. Then acetophenone (1.15
mL, 12.48 mmol) was added to solution of catalyst. The mixture was transferred
into the autoclave. It was purged with hydrogen for 10 seconds and finally the
hydrogen was introduced to 10 bar. The reaction mixture was stirred vigorously at
the temperature and for the time each time indicated. The mixture was filtered
through a pad of silica gel and the pad was washed with a 50% solution of ethyl
acetate in hexane (50 mL). The filtrate was concentrated under reduced pressure
to afford the reduction reaction crude.
2-((diphenylphosphino)methyl)-2-methylpropane-1,3-diol (2) 10
To a solution of 3-methyl-3-oxetanemethanol (0.25g, 0.25mL, 2.5mmol) in THF
(5mL) was added dropwise at 0ºC, n-BuLi (1mL, 2.5mmol, 1.0eq). The solution
was allowed to stir at room temperature for 1h. To a solution of Ph2PH (0.56g,
0.52mL, 3mmol, 1.2eq) in THF (6 ml) at 0ºC was added drop wise n-BuLi
(1.2mL, 3mmol, 1.2eq), and the solution was allowed to stir at room temperature
for 1h.
Than to the first solution was cooled again at 0ºC, and the solution of Ph2PLi was
added drop wise. The resulting red-orange mixture was stirred at room
temperature overnight. Than the solvent was removed under reduce pressure. To
the residue oil was added water (5ml, degassed) and extract with ether (10ml,
degassed). The aqueous layer was washed two times with ether (2 x 10ml,
degassed). The organic layers were dried over MgSO4.
The product was obtained as a white crystalline solid (0.26g, 37%), for
crystallization from toluene and pentane.
198
RESULTS and DISCUSSION : Chapter 12
mp= 95-97°C, ν (solid)/cm-1: 3298, 1437, 1178, 1026; 1H NMR (300 MHz,
CDCl3): δ= 7.51-7.50 (2H, m, Ar-H), 7.34-7.32 (3H, m, Ar-H), 3.63 (2H, d,
J=11.93 Hz, CH2O), 3.56 (2H, d, J=11.49 Hz, CH2O), 4.62 (2H, d, 2JP-H =3.39
Hz, CH2OH), 0.89 (3H, t, CH3); 13C NMR (75 MHz, CDCl3): δ= 164.23 (d, 1JP-C=
48 Hz, C-Ar), 132.87 (d, 2JP-C =19 Hz, 2CH-Ar), 128.81 (s, CH-Ar), 128.57 (d,
3
JP-C =7.5 Hz, 2CH-Ar), 70.79 (d, 3JP-C =8.6 Hz, 2CH2), 39.99 (d, 2JP-C =11.1 Hz,
C), 34.15 (d, 1JP-C =14.9 Hz, CH2), 20.45 (d, 3JP-C =9.8 Hz, CH3); 31P NMR (121
MHz, CDCl3) δ= -26.02. HRMS: calc. for C17H21O2P: 288.1279. Found:
288.1288. MS: m/z (EI)= 288(M+,13), 199(100), 183(63), 108(33), 91(27). Anal.
Calculated for C17H21O2P: C 70.82; H 7.34; P 10.74. Found: C 70.52; H 7.29; P
11.02.
(3-methyloxetan-3-yl)methylmethanesulfonate (3)
To a solution of 3-methyl-3-oxetanemethanol (0.25g, 0.25mL, 2.5mmol) in DCM
at 0ºC were added Et3N (0.76g, 1mL, 7.5mmol, 3eq) and dropwise
methanesulfonate chloride (0.37g, 0.25mL, 3.25mmol, 1.3eq). The mixture was
stirred for 30 minute at 0ºC then overnight at room temperature.
The mixture solution was quenched with saturated solution of NaHCO3 (40mL).
The organic layer was collected and the aqueous layer was further extracted with
ether (2 X 20mL). The combined organic layers were dried over MgSO4 and
concentrated to give the crude, that was purify by chromatography
(Rf.(Et2O)=0.15) to give a pale yellow solid (3.37g, 83%);
mp= 42-43°C, ν (solid)/cm-1: 2966, 2883, 1339, 1165; 1H NMR (300 MHz,
CDCl3): δ= 4.52 (2H, d, J 6.2Hz, CH2O), 4.43 (2H, d, J 6.2Hz, CH2O), 4.32 (2H,
s, CH2OS), 3.07 (3H, s, CH3S), 1.39 (3H, s, CH3);
13
C NMR (75 MHz, CDCl3):
δ= 78.82 (s, 2CH2O), 73.28 (s, CH2OS), 39.28 (s, C), 37.34 (s, CH3S), 20.63 (s,
CH3); Anal. Calculated for C6H12O4S: C, 39.99; H, 6.71. Found: C.39.86; H, 6.63.
3-(azidomethyl)-3-methyloxetane (4) 10
To
a
solution
of
(3-methyloxetan-3-yl)methylmethanesulfonate
(1.50g,
8.32mmol) in DMF (45mL) at 40ºC was added NaN3 (2.71g, 41.62mmol, 5eq),
and then the reaction mixture was allowed to stir at 40ºC overnight.
199
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
Diethyl ether (45mL) and water (45mL) were then added. The organic phase was
extracted with diethyl ether (2 x 45mL). The combined organic layers were dried
over MgSO4, and concentrated under reduced pressure to give the crude product
as a pale yellow oil (0.88g, 84%);
V (neat)/cm-1: 2932, 2869, 2094; 1H NMR (300 MHz, CDCl3): δ=4.46 (2H, d,
J=6.0Hz, CH2O), 4.39 (2H, d, J=6.2Hz, CH2O), 3.55 (2H, s, CH2N3),1.34 (3H, s,
CH3); 13C NMR (100Hz, CDCl3): δ= 80.0, 58.5, 40.2, 21.6.
(3-methyloxetan-3-yl)methanamine (5) 10
PPh3 (10.94g, 41.74mmol, 6eq) was added to a stirred solution of crude product
3-(azidomethyl)-3-methyloxetane (0.88g, 6.95mmol) in diethyl ether (250mL).
The reaction mixture was then stirred under nitrogen at room temperature
overnight. To the mixture was then additioned of water (1mL) and it was refluxed
for 2h. The solvent was removed under reduced pressure. The residue was
purified by filtration on silica pad with diethyl ether to remove the phosphorus
compounds, then with methanol to obtain the product as a brown oil (0.44g, 63%)
V (neat)/cm-1: 3357, 2959, 2872, 1570, 1316; 1H NMR (400MHz, CDCl3): δ=
4.44 (2H, d, J=5.8Hz, CH2O), 4.37 (2H, d, J=5.8HZ, CH2O), 2.88 (2H, s,
CH2NH2), 1.40 (2H, br s, NH2), 1.28 (3H, s, CH3); 13C NMR (100MHz, CDCl3):
δ= 80.39 (2C), 49.3, 40.5, 21.3.
4-methyl-n-((3-methyloxetan-3-yl)methyl)benzenesulfonamide (6)
To a solution of (3-methyloxetan-3-yl)methanamine (0.44g, 4.39mmol) in CH2Cl2
at 0ºC were added Et3N (0.76g, 1mL, 7.5mmol, 1.7eq) and drop wise
p-toluenesulfonyl chloride (0.84g, 4.39mmol, 1eq). The mixture was stirred for 30
minute at 0ºC than overnight at room temperature.
The mixture solution was quenched with water (10mL) and extracted with CH2Cl2
(2 x 10mL). The combined organic layers were dried over MgSO4 and
concentrated to give the crude, that was purify by chromatography
(Rf.(Et2O)=0.35) to give a white solid (0.60g, 54%);
mp= 90-91°C; V (solid)/cm-1: 3172, 2953, 2885 , 2360, 1327,1157; 1H NMR
(400MHz, CDCl3): δ= 7.76 (2H, d, J=8.3Hz, Ar-H), 7.33 (2H, d, J=8.0Hz, Ar-H),
200
RESULTS and DISCUSSION : Chapter 12
4.71 (1H, br s, NH), 4.35 (2H, d, J=6.0Hz, CH2O), 4.33 (2H, d, J=6.3Hz, CH2O),
3.12 (2H, d, J=6.8Hz, CH2NH), 2.44 (3H, s, CH3-Ar), 1.26 (3H, s, CH3-C);
13
C
NMR (100MHz, CDCl3): δ= 143.73 (1C, s, C-Ar), 136.75 (1C, s, C-Ar), 129.87
(2C, s, CH-Ar), 127.12 (2C, s, CH-Ar), 79.93 (2C, S, CH2O), 49.87 (1C, s,
CH2NH), 39.44 (1C, s, C-CH3), 21.55 (2C, s, CH3-C+CH3-Ar).
HRMS: calc. for C12H17NO3S: 256.1005. Found: 256.1007 MS: m/z (EI)=
256(M+,6), 183(6), 154(29), 90(100), 70(54). Anal. Calculated for C12H17NO3S:
C 56.45; H 6.71; N 5.49. Found: C 56.40; H 6.68; N 5.35.
n-{2-[(Diphenylphosphanyl)-methyl]-3-hydroxy-2-methyl-propyl}-4-methylbenzenesulfonamide (7) 10
To a solution of 4-methyl-n-((3-methyloxetan-3-yl)methyl)benzenesulfonamide
(0.30g, 1.2 mmol) in THF (10 ml), n-BuLi (0.75 mL, 1.2 mmol) was added drop
wise at 0ºC. The solution was allowed to stir at room temperature for 1h. To a
solution of Ph2PH (0.26g, 0.24mL, 1.4mmol, 1.1 eq) in THF (5 mL) at 0ºC nBuLi (0.87 mL, 1.4 mmol) was added dropwise, and the solution was allowed to
stir at room temperature for 1h.
Then the first solution was cooled again at 0ºC, and the solution of Ph2PLi was
added drop wise. The resulting red-orange mixture was stirred at room
temperature overnight. Then the solvent was removed under reduced pressure.
The residue oil was treated with water (5ml, degassed) and extract with ether
(10mL, degassed). The aqueous layer was washed two times with diethyl ether (2
x 10mL, degassed). The organic layers were dried over MgSO4.
The product was difficult to purify and was obtained as a white oil impure of
starting material and of diphenylphosphine (crude: 0.54g).
1
H NMR (400 MHz, CDCl3): δ= 7.58 (2H, d, J=8.28 Hz, Ar-H Ts), 7.49-7.41 (4H,
m, Ar-H), 7.35-7.30 (6H, m, Ar-H), 7.27 (2H, d, J=8.40 Hz, Ar-H Ts), 4.49 (1H, t,
J=6.78 Hz, NH), 3.61 (1H, d, J=11.54 Hz, CH2OH), 3.35 (1H, d, J=11.54 Hz,
CH2OH), 2.83 (1H, q, J=13.55 Hz, J=7.28 Hz, CH2NH), 2.77 (1H, q, J=13.55 Hz,
J=7.28 Hz, CH2NH), 2.42 (3H, s, CH3-Ts), 2.13 (2H, d, J=3.01 Hz, CH2-P), 0.91
(3H, s, CH3-C); 31P NMR (121 MHz, CDCl3) δ= -28.0.
201
Ruthenium-catalyzed Hydrogenation of Ketones and Aromatic Rings
12.4 References
(1)
(a) Donohoe Y. J., Garg R., Stevenson C. A., Tetrahedron: Asymmetry,
1996, 7, 317; (b) Corma A., Martinez A., Martinez-Soria V., J. Catal.,
1997, 169, 480.
(2)
March J., Advanced Organic Chemistry, John Wiley & Sons, New York,
1992, pp. 780-783.
(3)
Tsukinoki T., Kanga T., Liu G. B., Tsuziki H., Tashiro M., Tetrahedron
lett., 2000, 41, 5865.
(4)
Maegawa T., Akashi A., Sajihi H., Synlett, 2006, 1440.
(5)
Muetterties E. L., Bleeke J. R., Acc. Chem. Rev.,1979, 12, 324.
(6)
Bennet M. A., Smith A. K., J. Chem. Soc., Dalton Trans., 1974, 233.
(7)
(a) Davies S. C., Klabunde K. J., Chem. Rev., 1982, 82, 153; (b) Lewis L.
N., Chem. Rev., 1993, 93, 2693.
(8)
(a) Dyson P. J., J. Chem. Soc., Dalton Trans., 2003, 2964; (b) Gelbach T.
J., Dyson P. J., J. Organomet. Chem., 2005, 690, 3552.
(9)
(a) Boxwell C. J., Dyson P. J., Ellis D. J., Welton T., J. Am. Chem. Soc.,
2002, 124, 9334; (b) Maillet C., Praveen T., Janvier P., Minguet S., Evain
M., Saluzzo C., Tommasino M. L., Bujoli B., J. Org. Chem. 2002, 67,
8191.
(10)
Jacobi A., Huttner G., Winterhalter U., Cunskis S., Eur. J. Inorg. Chem.
1998, 675.
202
Appendix
Appendix 1
Appendix 1
1.1 One pot three-steps procedure for reagent fused benzo1,2,3-thiadiphosphole
The reaction was conducted in a 150 mL three-necked flask equipped with a
condenser, a dropping funnel, and with inlet for dry N2. A mixture of pmethylthioanisole (0.04 mol) and AlCl3 (0.03 mol) was stirred under N2 for about
10 minutes (until the AlCl3 was completed soluble) during which the colour
changed to yellow-pink. Then PCl3 (0.04 mol) was added, and the resulting redbrown solution stirred for 10 minutes. After that other PCl3 (0.012 mol) was
added, the N2 flow stopped and the mixture heated to reflux (90-100°C) for 6-8
hours.
The reaction was monitored using GC-MS. When the reaction was finished the
solution was cooled down to 0°C and CH2Cl2 (30 mL) was added. The resulting
solution was treated under stirring with water. Extraction with CH2Cl2 (30 mL)
and subsequent crystallization of the crude product from CH2Cl2-Et2O gave pure
reagent 1.
40-60%; White crystals; m.p. = 157-159°C; 1H NMR (300 MHz, CDCl3): 7.41 (d,
2H, JPH = 8.0 Hz), 7.25 (d, 2H, 1JHH = 7.5 Hz), 6.98 (d, 2H, 1JHH = 7.5 Hz), 2.28
(s, 6H);
13
C NMR (300 MHz, CDCl3 75.46): 141.6, 139.96 (d, JPC = 29.6 Hz),
135.5 (d, JPC = 7.4 Hz), 131.7 (d, JPC = 27.7 Hz), 130.5, 124.9, 20.8;
31
P NMR
(121.47 MHz, CDCl3, ext. 85% H3PO4): 65.4 (d, JPP 211.5 Hz ), 88.3 (d, JPP 211.5
Hz); GC-MS (m/z, %): 243 (M+), 211, 153, 121, 77, 63; HRMS (EI) calcd for
C14H12P2S2 : 305.9855, found: 305.9859.1
2,10-dimethyl[1,2,3]benzothiadiphospholo[2,3-b][1,2,3]benzothiadiphosphole
12-oxide (1’) :
31
P NMR (161.90 MHz, CDCl3, ext. 85% H3PO4): 20.0 (d, JPP
256.6 Hz ), 100.9 (d, JPP 256.6 Hz).
205
Appendix 1
(1)
(a) Baccolini, G., Mezzina, E., Todesco, P. E., Foresti, E. J. Chem. Soc.,
Chem. Commun., 1988, 304. (b) Baccolini, G., Beghelli, M., Boga, C.
Heteroatom Chem., 1997, 8, 551.
206
Appendix 2
Appendix 2
2.1
Characterization
of
4-methyl-2-[(5-methyl-2-
sulfanylphenyl) phosphanyl]benzenethiol (A)
After the reaction between reagent 1 and Grignard reagents, the solvent is partially
evaporated and the reaction mixture is treated with aqueous acid solution (HCl).
Extraction with CH2Cl2 give a mixture of phosphines and the residue A. The
phosphines are easily separated from A by treating the organic solution with
aqueous NaOH; after this treatment, the sodium salt of A is dissolved in the
aqueous solution, whereas the phosphines are in the organic phase. Compound A
is recovered (90%) from the basic aqueous layer by acidification and extraction
with dichloromethane, and is then purified by distillation and stored under argon.
Simple treatment of a dry solution of compound A with an equimolar amount of
PCl3 led to the regeneration of the starting reagent 1 in almost pure form, allowing
it to be reused without further purification.1
4-Methyl-2-[(5-methyl-2-sulfanylphenyl)phosphanyl]benzenethiol1 (A): 90%,
colorless liquid, b.p. 110–1158C (0.5 mmHg);1H NMR (400 MHz, CDCl3, TMS):
2.23 (s, 6H, CH3), 4.30 (br s, 2H, exch. with D2O, SH), 5.29 (d, 1H, JPH=228 Hz,
PH), 6.99–7.07 (m, 2H), 7.07–7.12 (m, 2H), 7.63–7.72 (m, 2H); 31P NMR (161.89
MHz, CDCl3, ext. 85% H3PO4): -52.0 ppm (br d, JPH=228 Hz). HRMS (EI) calcd
for C14H15PS2 : 278.0353, found: 278.0355.
207
Appendix 2
2.2
Reduction
of
2,2’-(oxidophosphoranediyl)bis(4-
methylbenzenethiol) (A’)
After a long storage (also under argon) or after extraction, it is possible to find
compound A impure of corresponding oxidized derivate A’. In these cases it is not
necessary purified again compound A by distillation, because also the oxide
derivative A’ can react with PCl3 to produce the corresponding oxidized
compound of reagent 1 (1’).
Reduction procedure of a mixture of 1 and 1’: To a mixture containing both
compounds 1 and 1’ was added toluene as solvent and an excess of HSiCl3
(respect to the quantity of 1’). The solution was heated to reflux for 2-3 hours,
until the reduction was completed (reaction followed by 31P NMR spectroscopy).
Then the solution was cooled down and added 1-2 ml of water (to remove the
excess of HSiCl3). The mixture was extracted with CH2Cl2, and reagent was recrystallized from a solution of CH2Cl2 and Et2O.
2,2’-(oxidophosphoranediyl)bis(4-methylbenzenethiol)
(A’):
white
grease
solid; 1H NMR (300 MHz, CDCl3, TMS): 2.30 (s, 6H) 7.26-7.18 (m, 2H), 7.347.27 (m, 2H), 7.43-7.52 (m, 2H) 8.29 (d, 1H, JPH= 509 Hz, PH); 13C NMR (75.46
MHz, CDCl3): 136.3 (d, J=12 Hz), 134.3 (d, J=12 Hz), 133.8 (d, J=11 Hz), 133.5
(d, J=2.4 Hz), 132.9 (d, J=9 Hz), 129.1 (d, J=106 Hz), 20.6;
31
P NMR (121.45
MHz, CDCl3, ext. 85% H3PO4): 19.0 ppm (br d, JPH= 509Hz).
(1)
Baccolini, G., Boga, C., Galeotti, M. Angewandte Chemie, Int. Ed. 2004,
43, 3058.
208
Appendix 3
Appendix 3
3.1
Synthesis
of
cis-2,6,10-trimethyl[1,3]
benzathiophospholo-[2,3b]benzathiophosphole
To a stirred slurry of anhydrous AlCl3 (16.8 mmol) in 1,2-dichloroethane (15 mI)
was added dropwise CH3COCl (10 mmol) the temperature being kept at 5-10 °C.
fused benzo-1,2,3-thiadiphospholes (7.2 mmol) was then added similarly over ca.
10 min. The mixture was brought to, and held at 25°C with stirring for 20 min.
The reaction was monitored by t.l.c. (light petroleum as eluant) and GC-MS
spectrometry. The cis-product was purified by filtration of the mixture on a
Florisil column with cyclohexane-CH2Cl2 (90:10) as eluant and obtained in 79%
yield.
cis-2,6,10-trimethyl[1,3] benzathiophopholo-[2,3b]benzathiophosphole 1:
white solid, p.f. 160-163°C; 1H NMR(200Hz, CDCl3) δ= 2.21 (d, JHP 16.4 Hz,
3H), 2.29 (s, 6H), 7.01-7.08(m,4H),7.27 (bd, JHP 7.0 Hz, 2H); 13C NMR(50.30Hz,
CDCl3) δ= 20.7, 27.8 (d, JCP 28.5 Hz), 71.3 (d, JCP 23.6 Hz), 121.7, 130.7, 130.7
(d, JCP 23.5 Hz), 135.4 (d, JCP 7.2 Hz), 136.6 (d, JCP 14.8 Hz), 142.9(d, JCP 2.8
Hz), 31P NMR{1H}(32.20Hz, CDCl3, ext. 85% H3PO4) δ= 63.4; HRMS (EI) calcd
for C14H15PS2 : 302.0353, found: 302.0353; Elem. Anal.: found H, 5.03; C, 63.54;
P, 10.25; S, 21.18. C16H15PS2 calcd H, 5.00; C, 63.55; P, 10.24; S,21.19%.
(1)
Baccolini, G., Mezzina, E., J. Chem. Soc., Perkin trans 1 1990, 19.
209
Appendix 3
210
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