Journal Name ARTICLE TYPE Catalytic amide formation from non-activated carboxylic acids and amines.

Journal Name ARTICLE TYPE Catalytic amide formation from non-activated carboxylic acids and amines.
Journal Name
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Cite this: DOI: 10.1039/c0xx00000x
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Catalytic amide formation from non-activated carboxylic acids and
amines.
Helena Lundberg a, Fredrik Tinnisa, Nicklas Selander*a and Hans Adolfsson*a
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
10
The amide functionality is found in a wide variety of biological and synthetic structures such as proteins,
polymers, pesticides and pharmaceuticals. Due to the fact that synthetic amides are still mainly produced
by the aid of coupling reagents with poor atom-economy, the direct catalytic formation of amides from
carboxylic acids and amines has become a field of emerging importance. A general, efficient and
selective catalytic method for this transformation would meet well with the increasing criterias for green
chemistry. This review covers catalytic and synthetically relevant methods for direct condensation of
carboxylic acids and amines. A comprehensive overview of homogeneous and heterogeneous catalytic
methods is presented, covering biocatalysis, Lewis acid catalysts based on boron and metals as well an
assortment of other types of catalysts.
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1. Introduction
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The amide functionality is one of the most fundamental chemical
building blocks found in Nature. It constitutes the backbone of
the biologically crucial proteins, and it is present in a vast number
of synthetic structures. For example, the amide bond is found in
up to 25% of all pharmaceuticals on the market,1 and it was
present in 2/3 of drug candidates which were surveyed by three
leading pharmaceutical companies in 2006.2 It has been estimated
that 16% of all reactions involved in the synthesis of modern
pharmaceuticals was the acylation of an amine, which makes it
the most commonly performed reaction in this field.3 Polymers
based on the amide linkage are of importance in a wide range of
applications, from everyday materials such as nylons, to more
advanced uses in drug delivery systems, adhesives and wound
healing.4 In addition, the amide bond is commonly found as a key
structural element in agrochemicals and in products from the fine
chemicals industry.
Formally, the amide bond is formed through the condensation
of a carboxylic acid and an amine with the release of one
equivalent of water. This reaction has been considered
challenging due to the competing acid-base reaction, which
occurs when the amine and the carboxylic acid are mixed.
Although the amide bond can be formed from the corresponding
ammonium carboxylate salt upon heating, this reaction has
generally been considered to be of limited preparative value.5
Furthermore, the high activation barrier for the direct coupling of
a carboxylic acid and an amine can only be overcome using
forcing reaction conditions.6 In order to circumvent these
problems, the amide bond is usually formed via an activated
carboxylic acid. The carboxylic activation is usually taking place
with the aid of a coupling reagent,7 or alternatively by turning the
This journal is © The Royal Society of Chemistry [year]
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carboxylic acid into the corresponding acid chloride (the
Schotten-Baumann reaction). The use of coupling reagents
usually results in mild reaction conditions and good yields, but
requires stoichiometric amounts of the reagent. Hence, at least
one equivalent of waste is generated per product molecule
formed, leading to an overall low atom economy. The removal of
this waste from the reaction mixture is also a tedious and
expensive process in addition to the cost and toxicity of the
coupling reagent itself. Due to these issues, as well as the
importance of the amide bond in the pharmaceutical industry, a
catalytic and waste-free production of amides was voted a
highlighted area of research by the American Chemical Society’s
(ACS) Green Chemistry Institute (GCI) Pharmaceutical
Roundtable (PR) in 2005.8
Many catalytic methods for the formation of amides have been
developed, utilising starting materials such as alcohols,
aldehydes, nitriles and aryl halides.9 However, relatively few
protocols are known where carboxylic acids are used as starting
materials, even though this catalytic transformation could easily
be envisioned to be highly valuable in e.g. peptide synthesis. In
recent time, the direct catalytic amidation of non-activated
carboxylic acids has attracted more attention, with an increasing
number of groups focusing on this area of research. Although
several reviews cover parts of the material presented herein,10
there is to the best of our knowledge none which compiles all
types of catalytic methods for direct amidation. Thus, the aim of
this review is to provide an easily accessible and comprehensive
overview of synthetically relevant literature on all types of
catalysts for direct amidation, ranging from biocatalysis, Lewis
acid catalysts based on boron reagents and different metal
complexes, as well as other catalyst types. Both homogeneous
and heterogeneous catalytic protocols are included, and the scope
[journal], [year], [vol], 00–00 | 1
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and limitations of the different systems are discussed. To date,
most catalytic protocols for direct amidation require elevated
reaction temperatures and water scavengers and/or suffer from a
limited substrate scope. We hope that this review will inspire the
research community to continue to develop novel and general
catalytic methods for a broad range of substrates under ambient
reaction conditions for this highly important synthetic
transformation.
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3. Biocatalysis
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2. Comments on thermal amidation
As mentioned above, it is well-known that amides can be formed
by the thermal treatment of a carboxylic acid and an amine
without any catalyst present, generally at reaction temperatures of
>140 ºC.11 Recently, it was shown that a significant amount of the
amide product can be formed even at lower temperatures, usually
with azeotropic removal of water.12,13,14 The yields of the thermal
amidation reaction is highly substrate dependent, as well as
dependent on temperature, substrate concentration, solvent and
other reaction parameters. As an example, the thermal yield of N(4-methylbenzyl)-3-phenylpropanamide at 110 ºC under neat
conditions was reported to be 58%, whereas the same product
was formed quantitatively in toluene at 2 M concentration with
the same reaction time and temperature (Scheme 1).13 For
comparison, the structurally similar N-benzylphenylacetamide
was formed in only 13% yield or less, when phenylacetic acid
and benzylamine were allowed to react in THF at 70 ºC at a
concentration of 0.4 M and a reaction time of 24 hours.15 The
literature on thermal amidation is not covered in this review
unless the non-catalysed reaction is specifically mentioned by the
authors.
synthetic utility, practicality and substrate scope of the methods
are more important factors to consider in the assessment of the
scientific impact.
70
Enzymes are Nature’s own catalysts for a wide variety of
reactions, and amide bond formation for the build-up of proteins
and other biologically important amides is one of the most
central. The highly selective actions of enzymes under ambient
conditions, as in most crucial biological processes, have inspired
many research groups to utilize biocatalysts for synthetic
purposes. Not surprisingly, enzymatic systems have been applied
for the catalytic formation of a range of different amides and their
derivatives.
3.1 Catalytic formation of primary amides
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Lipases make up the most common enzyme class used for the
synthetic formation of amides from carboxylic acids and amines,
with a few exceptions. For example, the amidation of the Cterminus of dipeptides, using a peptide amidase extracted from
orange peel was reported by Čeřovský and Kula.16 By employing
a slight excess of ammonium hydrogen carbonate as ammonia
source, the authors reported yields of 22-34% of the primary
amide-dipeptides after 72 hours of reaction time at 40 ºC in
acetonitrile containing 5% water (Scheme 2). The enzyme
loading was 80 mg/mmol substrate at a substrate concentration of
0.05 M. The authors claimed that the limiting factor of the
reaction, in terms of yield, was the solubility of the dipeptides. It
was therefore important to prevent the precipitation of the
ammonium dipeptide salt by finding the optimal solvent system
for a specific substrate, as well as using an ammonia source
which gives rise to a pH suitable for the enzyme activity.
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35
95
40
Scheme 1. Condition dependence in thermal amidation
(Williams, 2012)
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It should be pointed out that the thermal reaction, which
indeed gives the targeted amide product, is sometimes not
investigated or commented upon throughout the literature. In
general, the thermal amide bond formation is not a synthetic
problem unless the process involves a kinetic resolution of the
starting material. Although the background reaction can be
substantial under certain reaction conditions, and sometimes
raises the question regarding the importance of the catalyst, an
added catalyst is often shown to enhance the reaction rate further.
At lower reaction temperatures, the thermal amidation is most
often negligible and the product formation can solely be
attributed to the catalytic action. The marked dependence on
substrates and reaction conditions for the amide bond formation
makes the comparison between different catalytic methods
difficult and sometimes not even meaningful at all. Rather, the
2 | Journal Name, [year], [vol], 00–00
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Scheme 2. Selected primary peptide amides formed using a
peptide amidase catalyst (Čeřovský, 1998).
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In 2001, the same authors demonstrated that the C-terminals of
not only dipeptides but also of different tri- tetra- and
pentapeptides could be turned into the primary amide
functionality with the amidase catalyst.17 The enzyme activity
was reported to drop significantly when more than four amino
acids were linked together, resulting in a low yield of the Bocprotected pentapeptide Leu-enkephalin (<10%). Peptides derived
from D-amino acids were not converted into amides by the
enzyme catalyst.
Another useful protocol for the amidation of peptide CThis journal is © The Royal Society of Chemistry [year]
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terminals was published by Nuijens et al.18 The authors used
Candida Antarctica lipase B (CAL-B) and cross-linked Subtilisin
A protease (Alcalase-CLEA) for the C-terminal amidation of
Cbz-protected amino acids, as well as a number of different di-,
tri- and tetrapeptides in high yields (Scheme 3). The amide
nitrogen was delivered from either ammonium benzoate or
directly from the ammonium salts of the amino acids or peptide
starting materials. The reactions were run in toluene with a
catalyst loading of 100 mg of CAL-B to 50 mg peptide substrate,
or in a DMF/t-butanol mixture with a catalyst loading of 50 mg
Alcalase-CLEA to 0.1 mmol peptide in the presence of 3Å
molecular sieves. Transamidation and hydrolysis of the starting
materials were successfully avoided in the majority of the cases.
15
Cbz
CAL-B
OH
N
H
R1
C6H5CO2NH4/NH3
R2
O
H
N
toluene
O
n
Cbz
70
NH2
N
H
R1
16h, 50 °C
65
R2
O
H
N
(Litjens, 1999).
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O
n
n=0, 1 or 2
20
25
Amino acid / peptide
Yield (%)
NH3 source
Cbz-Pro-OH
99
ammonium benzoate
Cbz-Val-Pro-Pro-OH
90
Cbz-Gly-Leu-Ala-OH
65
Cbz-Gly-Phe-Ala-OH
82
Cbz-Gly-Ile-Ala-OH
85
Cbz
30
H
N
R1
NH4
R2
O
N
H
n
ammonia gas
56
Cbz-Val-Val-Pro-OH
O
O
80
Alcalase-CLEA
t-butanol/DMF
Cbz
R1
(82.5/17.5, v/v)
85
R2
O
H
N
NH2
N
H
n
O
16h, 50 °C
n=1 or 2
90
35
40
Peptide
Yield (%)
Cbz-Ile-Met-OH
89
Cbz-Ala-Phe-OH
87
Cbz-Gly-Leu-Ala-OH
89
Cbz-Gly-Pro-Ala-OH
85
Cbz-Gly-Ile-Ala-OH
78
Cbz-Pro-Leu-Gly-OH
53
95
The reaction time was 3-5 days and the synthesis was performed
under dilute conditions in methyl isobutylketone (MIBK), using a
slight excess of ammonium carbamate and a catalyst loading of
20 mg enzyme per mmol substrate. The authors also
demonstrated that the reaction time could be significantly reduced
using diisopropyl ether as solvent, allowing for a higher substrate
concentration to be used. The amidation of oleic acid was
complete after 6 hours of reaction time, using molecular sieves as
water scavenger and the oleamide product was isolated by
recrystallization in 79% yield. However, the catalyst loading for
the new protocol was slightly higher compared to the MIBK
protocol: 35 mg/mmol substrate.20
Novozym® 435 was employed in a continuous plug flow
reactor to synthesise oleamide from oleic acid and ammonium
carbamate in 2-methyl-2-butanol.21 With this experimental setup,
the authors claimed that the enzyme cost makes up only 4% of
the total cost by assuming a one year lifetime of the enzyme and a
productivity of 4500 kg amide/kg enzyme. It was argued that the
volumetric productivity of this setup was a 4- to a 100-fold
improvement compared to the earlier developed batch methods.
Novozym® 435 was also used by Levinson et al. to catalyse the
formation of the corresponding primary amides of oleic acid,
lesquerolic and ricinoleic acid, using ammonium carbamate as
ammonia source.22 After 24 hours at 55 ºC and a 1:1 molar ratio
of carbamate to acid, the amides were formed in near quantitative
yields with a catalyst loading of 100 mg immobilized enzyme to
1 mmol substrate. The same methodology was also efficient for
the direct amidation of 10-hydroxystearic acid and 10-ketostearic
acid in 2-methyl-2-butanol to obtain the corresponding primary
amides in 94% and 92% yield respectively.23 Furthermore, it was
shown that multi-hydroxylated fatty acids were efficiently
converted into the corresponding amides employing the same
method.24 A comparison between enzymatic amidation protocols
for oleic acid with Novozym® 435 as catalyst is given in Scheme
5.
Scheme 3. Selected amidation of peptides catalysed by lipases
(Nuijens, 2012).
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The formation of primary amides from carboxylic acids using
ammonium carbamate as source of ammonia and CAL-B
immobilized on a macroporous acrylic resin (Novozym® 435) as
biocatalyst was reported by Litjens et al.19,20 At reaction
temperatures of 35-60 ºC, the amide products were formed from a
range of carboxylic acids in 24-94% yield (Scheme 4).
105
Scheme 5. Overview of CAL-B -based methods for the formation
of oleamide.
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Scheme 4. Catalytic amidation of carboxylic acids by CAL-B
This journal is © The Royal Society of Chemistry [year]
The direct amidation with Novozym® 435 as catalyst can also
be performed in an ionic liquid, as demonstrated by Lau et al. A
quantitative yield was obtained for octanamide in 1-butyl-3methylimidazolium
tetrafluoroborate
([C4mim][BF4])
by
bubbling ammonia gas through a solution of octanoic acid for 4
days at 40 ºC. The catalyst loading was 0.17 mg immobilized
Journal Name, [year], [vol], 00–00 | 3
enzyme to 1 mmol substrate.25
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In addition to the enzymatic methods above, the
microorganisms Bacillus cereus,26,27 Streptomyces halstedii,28
and Bacillus subtilis29 have been used to form primary amides
from carboxylic acids.
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3.2 Secondary and tertiary amides
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The first report on the enzymatic formation of secondary amides
was published in 1991 by Tuccio et al.30 A series of carboxylic
acids were converted into the corresponding n-octylamides using
Porcine pancreas lipase (PPL), Candida cylindracea lipase
(CCL) and two mycelia preparations of Rhizopus arrhizus (RAL)
and Penicillum cyclopium (PCL) with lipasic activity. The best
result was obtained with RAL and palmitic acid (50% yield) at 40
ºC for 7 days with a 2:1 ratio of acid to amine, and a catalyst
loading of 2000 lipasic units of enzyme to 1 mmol carboxylic
acid. A clear correlation between the length of the carbon chain in
the carboxylic acid substrate and product yield was observed;
only 25% yield of the product was obtained with acetic acid
(Scheme 6). In addition to the desired secondary amides, imide
and amidine by-products were formed in low yields during the
reaction.
O
25
OH
1 mmol
30
35
40
45
50
NH2
7
0.5 mmol
hexane, 0.02 M (acid)
4 Å MS
R
Yield (%)
CH3
25
C3H7
30
C7H15
35
C15H23
40
C15H31
50
75
80
O
Rhizopus arrhizus lipase
+
R
70
R
N
H
7
Scheme 6. Rhizopus arrhizus lipase-catalysed amidation of
carboxylic acids of different chain lengths (Tuccio, 1991).
In 2002, the first protocol employing a protease as biocatalyst
for the direct amidation of carboxylic acids was published by
Ulijn et al.31 It was also the first paper to describe the catalytic
formation of peptides from two amino acids under synthetically
useful reaction conditions. The amine component of the reaction,
L-phenylalanine, was attached to a PEGA1900-support via a Wang
linker and then reacted with a variety of protected amino acids in
aqueous media with thermolysin as catalyst. The peptides were
obtained in good to excellent yields after hydrolysis, using a
catalyst loading of 25 mg per mmol substrate. Amino acids with
non-polar side chains gave the highest conversions, and
interestingly, no product was observed with the non-natural
amino acid Fmoc-norleucine (Scheme 7). An important factor for
the success of this method is that the ionization of the supported
amine substrate can be supressed by the proximity to the
positively charged resin.
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105
Scheme 7. Selected dipeptides formed in thermolysin-catalysed
amidation (Ulijn, 2002).
The enzyme-catalysed formation of surfactants based on
biologically derived starting materials has been rather wellinvestigated. The first example of this was published in 1997,
when Maugard et al. reported on the bio-catalysed synthesis of
surfactants from oleic acid and the sugar N-methyl-glucamine.32
Yields of up to 97% were obtained at 90 ºC with immobilized
Candida Antarctica lipase B (Novozym® 435) after 50 hours of
reaction time. The molar ratio of acid to amine was 1:1 in 2methyl-2-butanol with a catalyst loading of 57 mg immobilized
enzyme to 1 mmol substrate. The authors reported that the amide
coupling also worked well using decanoic acid or N-methylgalactamine as substrates (Scheme 8). A high selectivity between
amidation and esterification of the primary alcohol of the
glucamine could be achieved by controlling the acid/amine ratio,
and hence the pH, of the reaction medium. Kinetic studies
showed that an excess of the carboxylic acid favoured the ester
formation whereas an excess of the amine component favoured
the amide product.33 The same selectivity trend was observed
when the reaction was performed in hexane with immobilized
Rhizomucor miehei lipase (Lipozyme®) in place of CAL-B.
However, lower conversions into the amide product were
observed when Lipozyme® was employed as catalyst.34 The
mechanism and origin of selectivity of the immobilized CAL-B
was investigated, as well as the kinetics of O- vs N-acylation of
myristic acid with 2-butanol and sec-butylamine.35,36
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Scheme 8. Amide formation from oleic acid and N-methylglucamine (Maugard, 1997).
This journal is © The Royal Society of Chemistry [year]
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The catalytic amidation of ethanolamine with fatty acids was
studied by Fernandez-Perez and Otero. It was found that high
yields (90-94%) of the amide surfactants could be obtained using
Novozym® 435 as amidation catalyst.37 An equimolar ratio of
ethanolamine and carboxylic acid was used in dioxane,
acetonitrile or n-hexane at 40 ºC (Scheme 9). The catalyst loading
was generally 125 mg/mmol substrate, and the reaction was
found to be highly selective for N- over O-acylation. However, 46% of the diacylated product was formed in dioxane and
acetonitrile as solvent. Not too surprisingly, the diacylated
product was favoured by an excess of the fatty acid; a 2-4 molar
excess of the carboxylic acid gave rise to 70-90% yield of the
N,O-diacylated product.
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The effect of microwave irradiation on the enzyme-catalysed
(Novozym® 435) formation of ethanolamides from fatty acids
was investigated by Kidwai and co-workers.42 It was found that
the reaction proceeded considerably faster with microwave
induced synthesis as compared to conventional heating (reaction
times of minutes instead of hours). Furthermore, when the
reactants were impregnated on the supported enzyme, the
amidation reaction was more efficient compared to performing
the reaction in solution (Scheme 10). The optimized catalyst
loading was reported to be 8 mg/mmol substrate.
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15
O
HO
NH2 +
R
CAL-B
OH solvent, 40 °C
O
75
HO
N
H
R
1 : 1 ratio
20
Acid
R
Yield (%)
80
Palmitic acid
25
Myristic acid
Lauric acid
Capric acid
30
14
12
10
8
90
90
90
94
Scheme 9. Amidation of ethanolamine with long-chain
carboxylic acids (Fernandez-Perez, 2001).
35
40
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Additional studies by Fernandez-Perez and Otero on secondary
amines concluded that an excess of diethanolamine resulted in
full chemoselectivity in favour of the tertiary amide product.38 It
was also found that the monoacylated ester was a rapidly formed
intermediate in dioxane, which subsequently was transformed
into the thermodynamically more stable amide. However, no such
ester intermediate was observed when the reaction was performed
in n-hexane.
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This journal is © The Royal Society of Chemistry [year]
Kidwai et al. also found that primary amides as well as N-methyland N-ethylamides could be formed with Novozym® 435 using
PEG200, PEG400 and PEG600 as solvents.43 With equimolar
amounts of the amine and carboxylic acid, the amides were
formed in 60-88% yield from lauric, capric, myristic and palmitic
acid. Molecular sieves were used as a water scavenger at room
temperature and the catalyst loading was reported to be 25
mg/mmol substrate. The results from the PEG reactions were
shown to be comparable to, and sometimes better than, results
from reactions in ionic liquids or t-butanol. The authors showed
that the immobilized enzyme could be reused up to 8 times with
only 5% difference in yield between the first and the eighth run.
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Tufvesson et al. published a large scale synthesis of the
ethanolamide of lauric acid (100g lauric acid, 0.5 mol), using
Novozym® 435 as catalyst (5 g) and an equimolar mixture of
acid and amine.39 By running the reaction at 90 ºC and adding the
ethanolamine in portions to keep it protonated at all times, water
could be distilled off under vacuum to afford the surfactant amide
in 95% yield. Surfactant ethanolamides were also synthesised by
Plastina et al.40 Novozym® 435 was used as catalyst to afford six
different ethanolamides from fatty acids in yields ranging from
80-88%. The reaction was performed in hexane at 40 ºC, with a
catalyst loading of 250 mg/mmol substrate and a 1:1 molar ratio
of amine to acid. The immobilized enzyme was also used by
Wang et al. for the amidation of oleic acid with ethanolamine on
a 50 mmol scale, yielding 74% of the amide after
recrystallization.41 The catalyst loading was 30% and the
reactants were used in a 1:1 molar ratio.
Scheme 10. Amidation of ethanolamine with conventional vs.
MW heating (Kidwai, 2009).
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Novozym® 435 has also been used for the amidation of (E)7,10-dihydroxydec-8-enoic acid with N-methylethanolamine,
resulting in a yield of 95% after 72 hours at 50 ºC in isoamyl
alcohol.44 In addition, the same catalyst was employed for the
biosynthesis of 18 different N-alkylamides under solvent-free
conditions and reduced pressure. The products were obtained in
77-82% yield, and four of them were found to have biological
activity against root-knot nematode (Meloidogyne incognita).45
3.3 Hydroxamic acids and acyl hydrazines
One of the first reports on the enzymatic synthesis of hydroxamic
acids from a sodium acyl salt and hydroxylamine was reported by
Lipmann and Tuttle in 1950.46 With the use of a hog liver
esterase and the pancreas lipase Pancreatine Parke-Davis, the
authors reported on the formation of hydroxamic acids in yields
typically around 10% after 60 minutes incubation time at 37 ºC at
neutral pH. It was found that the two enzymes functioned
optimally with carbon chains of different lengths; the hog liver
esterase worked best with sodium octanoate, whereas the longer
chain of sodium dodecanoate suited the pancrease lipase better.
Hydroxylamine was used in large excess in all the reported
Journal Name, [year], [vol], 00–00 | 5
examples.
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A synthetically useful method for the synthesis of aliphatic
hydroxamic acids was reported by Servat et al.47 Yields around
75% were obtained for a range of aliphatic acids with a chain
length of 8-22 carbons (Figure 1), using Lipozyme® as catalyst.
The reaction was performed at 37 ºC with a reaction time of 24
hours, with a five-fold excess of the hydroxylamine to acid
substrate in a phosphate buffer (pH 7) and a catalyst loading of
250 mg immobilized enzyme per 1 mmol substrate.
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agent/catalyst, which produces both enantiomers of the substrate
throughout the reaction. The combination of the two enables a
theoretical maximum yield of 100% of the fully enantiomerically
enriched product.
The first example of enzymatic kinetic resolution of a chiral
carboxylic acid in the amidation with an amine was published by
Litjens et al. in 1999.20 The authors demonstrated that 4methyloctanoic acid could be resolved by turning it into the
primary amide using Novozym® 435 (20 mg immobilized
enzyme per 1 mmol substrate, Scheme 12). An excess of
ammonium carbamate was used as source of ammonia, resulting
in 52% conversion and 95% ee in favour of the (R)-enantiomer.
The ee was determined by measurements on the remaining
unreacted carboxylic acid.
75
20
Figure 1. Substrates used for the formation of hydroxamic acids
by Servat et al. (1990).
25
30
35
Sheldon and co-workers reported on the gram-scale formation
of N-hydroxyoctanamide from octanoic acid and hydroxylamine
(93% yield), using Novozym® 435 in organic solvents at 40 ºC.
The catalyst loading was 1.44 mg immobilized enzyme to 1
mmol substrate using a slight excess of the aqueous
hydroxylamine (1.24 equiv).48 It was found that the reaction
performed equally well with T. lanuginosus lipase immobilized
on Accurel EP 100 as catalyst. Furthermore, Obenzylhydroxylamine, as well as different hydrazines could be
used as coupling partners to form the corresponding carboxylic
derivatives in excellent yields in t-butanol at 40 ºC (Scheme 11).
When hydrazine was used as substrate in the reaction with an
excess of octanoic acid, N,N’-dioctoylhydrazine was obtained in
good yields.49
80
Scheme 12. Kinetic resolution of 4-methyloctanoic acid with
CAL-B (Litjens, 1999).
85
90
95
40
100
45
105
50
Scheme 11. Enzymatic synthesis of hydroxamic acids and acyl
hydrazines from octanoic acid (Sheldon and co-workers, 2000).
3.4 Kinetic resolution of amines or carboxylic acids
55
In a kinetic resolution (KR), a chiral catalyst discriminates
between two enantiomers of a substrate by reacting faster with
one of the isomers. If the catalyst is completely selective, the
maximum yield of the process is 50% with a product of 100%
enantiomeric excess (ee). In a dynamic kinetic resolution (DKR),
a selective chiral catalyst is combined with a racemising
6 | Journal Name, [year], [vol], 00–00
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Sheldon and co-workers showed that racemic ibuprofen could
be kinetically resolved as its hydroxamic acid with Candida
rugosa lipase (ChiroCLEC-CR) in 41% yield with >92% ee as
the (S)-isomer (catalyst loading of 50 mg per mmol substrate).
The racemic acid could also be resolved as its octanoylhydrazine
derivative with the best result arising from the use of
Pseudomonas lipoprotein lipase in 50% yield with 82% ee as the
(R)-enantiomer (Figure 2).49
The enzymatic dipeptide synthesis from protected amino acids
on solid support, reported by Ulijn et al., was also shown to be
active in kinetic resolution.31 The authors showed that the
protease catalyst was selective for only one of the stereoisomer of
phenylalanine, producing only the L,L-diastereomer when Lphenylalanine on solid support was reacted with Fmoc-protected
D,L-phenylalanine (Figure 2).
The enzymatic kinetic resolution of chiral amines by amidation
with carboxylic acids was first published by Tuccio et al. in
1991.30 It was found that the kinetic resolution of racemic 2aminooctane with palmitic acid could be performed, using
Rhizopus arrhizus lipase as catalyst. The (R)-enantiomer of the
amine preferentially reacted with the acid, resulting in a yield of
30% and an enantiomeric excess of 70% of the amide product
(Figure 2). Further studies by Irimescu and Kato showed that
Novozym® 435 could be employed for the kinetic resolution of
1-phenylethylamine and 2-phenyl-1-propylamine in the
amidation reaction with octanoic, dodecanoic and 4-pentenoic
acid. The reaction was performed in ionic liquids under reduced
pressure (5 mm Hg) and a catalyst loading of 23 mg/1 mmol
substrate.50 When 1-phenylethylamine was used as substrate, the
amide products were obtained with excellent enantioselectivities
This journal is © The Royal Society of Chemistry [year]
5
10
15
20
25
30
35
40
(97->99% ee) in yields ranging from 8 to 49%. The analogous
reaction with 2-phenyl-1-propylamine displayed considerably
lower selectivity; 59.8% ee was obtained under solvent free
conditions (Figure 2). Further studies revealed that the amide
from 1-phenylethylamine and 4-pentenoic acid was obtained in
low to moderate yields (5-21%) and excellent enantioselectivities
(>99% ee in favor of the (R)-isomer).51 The highest yield was
obtained in 1-butyl-2,3-methylimidazolium trifluormethane
sulphonate ([bdmim]tfms), when the reaction was performed
under reduced pressure at slightly elevated temperature.
Performing the reaction with 3 mmol carboxylic acid resulted in
41% conversion and >99% ee of the resulting amide. Prasad et al.
reported on the kinetic resolution of racemic 2-ethylhexyalmine
in the amidation reaction with six different carboxylic acids,
using CAL-B immobilized on accurel as catalyst at 90 ºC under
solvent free conditions and vacuum.52 The amides were obtained
in 40-45% yield with >99% ee employing a catalyst loading of
120 mg/mmol carboxylic acid and 2 equivalents of the amine
(Figure 2). Bertrand and co-workers reported on the use of
Novozym® 435 for the kinetic resolution of racemic amines at 80
ºC in heptanes with a 1:1 molar ratio of carboxylic acid to amine
(catalyst loading of 200 mg/mmol substrate).53 The authors
demonstrated that the enzyme could be used for the kinetic
resolution of 2-amino-4-phenylbutane with four different
carboxylic acids, resulting in high yields and excellent
enantioselectivities for the (R)-isomer of the amides. Lauric acid
was also used as acylating agent for a range of amines, resulting
in good yields with good to excellent ee’s of most amides.
However, the resolution of 2-phenylethylamine resulted in a
moderate 65% ee of the corresponding amide (Figure 2).
Furthermore, the authors showed that the immobilized enzyme
could be recycled five times, with only negligible changes in
yield and enantioselectivity of the amide product.
Bertrand and co-workers reported on the dynamic kinetic
resolution (DKR) of amines using the Novozym® 435 catalyst, in
combination with AIBN and a thiol at 80 ºC in heptane. This is
the first and only example of DKR in direct amidation. The
amidation of 4-phenyl-2-aminobutane, using lauric acid as acyl
donor, resulted in 71% isolated yield and >99% ee of the amide,
in favor of the (R)-enantiomer. The mechanism was suggested to
go via a free radical racemization of the amine (Scheme 13).54
60
65
70
of amidase and protease catalysts, lipases stand out as the most
well-established catalyst type for the transformation. Among
these, Candida antarctica lipase B is most often the biocatalyst of
choice, working well in several solvents, at different temperatures
and with a variety of substrates.
Biocatalysts are usually very selective and the enzymecatalysed protocols generally show good selectivity for N- versus
O-acylation. In addition, there are several examples of highly
selective kinetic resolution and even an example of dynamic
kinetic resolution. A drawback with enzyme-based catalysts is the
pre-determined preference for either the (R)- or (S)-isomer, which
can be of concern if the opposite enantiomer is the synthetic
target. Moreover, the synthetic scope is often limited to substrates
with similar structures and the reaction times are sometimes in
terms of days. These issues could be addressed e.g. by directed
evolution,55 and bioengineering.
75
80
Many biocatalytic protocols employ enzymes immobilized on
a solid support, e.g. Novozym® 435. The use of a solid-supported
enzyme makes it possible to recycle the catalyst and also enables
the use of flow reactors. This has been demonstrated in the
literature and those processes are valuable contributions towards
greener and more cost-effective syntheses of amides.
85
90
95
100
45
105
50
Scheme 13. Free radical mediated dynamic kinetic resolution of
an amine using CAL-B as catalyst (Bertrand, 2007).
3.5 Summary and conclusions on biocatalysis
55
110
The enzyme-catalysed amide bond formation has been explored
by several groups for the formation of primary, secondary and
tertiary amides, as well as carboxylic derivatives of
hydroxylamines and hydrazines. Even though there are examples
115
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 7
Litjens et al. 1999
Prasad et al. 2005
(Candida antarctica lipase B)
O
(Candida antarctica lipase B)
5
O
NH2
N
H
42.5%
52%
10
N
H
H
N
15
>99% ee
O
N
H
6
>99% ee
ee calculated on unreacted acid
3
40%
O
44%
Pseudomonas lipoprotein lipase)
N
H
2
>99% ee
O
Sheldon and co-workers 2001
(Candida rugosa lipase and
N
H
44%
>99% ee
95% ee (calculated on unreacted acid)
O
O
N
H
42.5%
45.5%
>99% ee
>99% ee
4
OH
Bertrand and co-workers 2007
O
(Candida antarctica lipase B)
O
41%
>92% ee
H
N
20
O
O
N
H
HN
98.6% ee
Ulijn et al. 2002
HN
(Thermolysin)
Ph
O
45%
Fmoc
38%
O
HN
>99% de
HN
10
99.5% ee
O
HN
10
HN
10
O
10
Ph
NEt2
35
HN
O
40
HN
10
Ph
Tuccio et al. 1991
(Rhizopus arrhizus lipase)
10
42%
>98.0% ee
>99.5% ee
O
49.5%
44%
49.5%
46%
46%
99.8% ee
99.0% ee
98.0% ee
99.0% ee
O
14
O
O
HN
HN
10
O
30%
65.0% ee
O
HN
45%
96.9% ee
Fmoc O
NH
55%
49%
>99.5% ee
5
4
OH
N
Ph
10
Ph
>99.5% ee
10
HN
14
O
HN
10
O
Ph
O
O
HN
45% (NMR)
48%
97.1% ee
25
10
Ph
44% (NMR)
82% ee
HN
6
Ph
6
50%
30
HN
2
O
O
O
12
HN
12
>70% ee
45
Irimescu et al. 2004
39%
(Candida antarctica lipase B)
O
O
HN
50
HN
6
Ph
10
96.7% ee
HN
12
Ph
>99.0% ee
H
N
55
O
2.
42%
94.0% ee
O
HN
48.9%
97.1% ee
48%
O
Ph
31.6%
Figure
>98.0% ee
8%
Ph
47%
>99.0% ee
>99.5% ee
38.2%
59.8% ee
Enantiomerically
enriched
8 | Journal Name, [year], [vol], 00–00
amides
from
enzyme-catalysed
kinetic
resolution
of
racemic
substrates.
This journal is © The Royal Society of Chemistry [year]
4. Boron-based catalysts for amidation reactions
5
10
15
The stoichiometric use of boron-based compounds for the direct
amidation of non-activated carboxylic acids with amines has been
known since the 1960’s.56 However, in the last few decades, the
use of boron-based compounds as catalysts has gained a
considerable interest. The Lewis acidity of the boron-based
catalysts can efficiently be fine-tuned by substituent effects for
the activation of carboxylic acids. In general, boronic acids and
their derivatives show a high functional group tolerance and are
more stable in the presence of water compared to other Lewis
acids, making them promising catalysts for the direct amidation
reaction. However, these types of catalysts commonly require
removal of formed water as well as elevated temperatures in
order to enable high yields of amide product. Both heterogeneous
and homogeneous systems have been developed for boron-based
catalysts.
4.1 Homogeneous boron-catalysed protocols
20
25
The range of soluble boron compounds used as catalysts for the
direct amidation of carboxylic acids and amines encompasses
boric acid, boric esters, and boronic acids. Of the latter, especially
electron-deficient compounds have found their use as catalysts,
however, high catalytic activity has also been found in
arylboronic acids containing electron-donating groups.
Furthermore, bifunctional arylboronic acids substituted with a
tertiary amine have successfully been employed as catalysts.
4.1.1 Formation of primary amides
30
35
To date, only one boron-based catalytic system is known for the
formation of a primary amide from one single substrate.
Shteinberg demonstrated that boric acid in combination with
PEG-400 are effective in the catalytic amidation of 4nitrobenzoic acid using gaseous ammonia.57 Interestingly, neither
boric acid nor PEG-400 was catalytically active alone in the
absence of the other component. Under optimized conditions,
using 2 mol% boric acid and 1 mol% PEG-400 in refluxing 1,2,4trichlorobenzene (bp 170-175 ºC), 4-nitrobenzamide was formed
in 92% yield after 10 hours (Scheme 14).58
60
acids were efficient catalysts for the amide formation in refluxing
toluene, xylene or mesitylene with molecular sieves present in a
soxhlet thimble. With 1-10 mol% of the added 3,4,5trifluorobenzeneboronic acid catalyst, good to excellent yields of
secondary and tertiary amides were obtained from aliphatic and
aromatic acids with aliphatic and aromatic amines (Scheme 15).
65
70
75
80
85
90
95
Scheme 15. Selected substrates from Yamamoto and coworkers
(1996).
40
100
45
50
Scheme 14. Formation of 4-nitrobenzamide by boric acid/PEGcatalysis (Shteinberg, 2003 and 2005).
Additionally, PEG of different chain lengths were shown to work
well as co-catalysts with boric acid for the formation of primary
amides.59,60
4.1.2 Secondary and tertiary amides
55
The first boron-based catalytic protocol for the formation of
secondary and tertiary amides was reported by Yamamoto and
co-workers in 1996.61 It was found that electron-poor arylboronic
This journal is © The Royal Society of Chemistry [year]
105
110
Lactams from 6-aminocapric acid and 5-aminovaleric acid, as
well as dimers of unprotected proline were also obtained in good
yields using this methodology. The benzyl amides of
enantiomerically pure α-hydroxy-iso-butyric acid and α-hydroxyiso-propanoic acid were formed without any racemisation,
whereas the enantiopurity of the mandelic acid product was
somewhat reduced during the amide bond formation. The same
catalyst was also employed for the poly-condensation reaction of
amides to form aliphatic and aromatic polyamides,62 and for the
synthesis of acyl azides.63 For sterically more demanding
substrates
such
as
cyclohexylcarboxylic
acid
and
adamantylcarboxylic
acid,
boron
catalysts
with
a
tetrachlorocatechol moiety (Figure 3) were found to be more
efficient.64
[journal], [year], [vol], 00–00 | 9
60
5
Figure 3. Tetrachlorocatechol-based boron catalysts developed
by Yamamoto and co-workers (2006).
10
15
20
Ishihara and co-workers recently demonstrated that
alkylboronic acids are effective catalysts for the amidation of αhydroxy carboxylic acids in refluxing toluene with azeotropic
removal of water (Scheme 16).65 Interestingly, the addition of
water (2-20 mol%) and benzoic acid was found to increase the
product yield, possibly by promoting ligand exchange between
the product and starting material. (R)-Mandelic acid was found to
give partly racemised amides when the reaction was performed in
refluxing toluene, whereas (S)-3-phenyllactic acid did not show
any decrease in amide enantiopurity under the same reaction
conditions. In refluxing 1,2-dichloroethane (bp 83 ºC), the
racemisation of mandelic amides was found to be less
pronounced.
OH
25
R
O
1
R
+
OH
amine
B
1:1 molar ratio
70
75
80
R= Me or Bu
OH (1-10 mol%)
PhCO2H (0-50 mol%)
H2O (~2-20 mol%)
toluene, azeotropic reflux
OH
65
O
R1
N
OH
R2
85
R3
30
O
O
NHBn
Ph
5
OH
35
OH
In 2006, Whiting and co-workers presented an investigation on
the kinetics of the direct thermal amidation of carboxylic acids
and amines.70 The results of the purely thermal reaction were
compared to reactions run with boric and boronic acid catalysts.
It was concluded that the addition of boronic acid enhanced the
reaction rate and in particular, bifunctional boronic acid catalysts
were highlighted as a promising type of catalysts for the reaction.
The electronic effects of substituted analogues of the bifunctional
catalyst were investigated, showing an enhanced catalytic activity
for arylboronic acids having a CF3-group in the para position.
The opposite effect was observed when the electron donating
methoxy group was situated in ortho position (Figure 4).71
Ph
Figure 4. Developed Bi-functional catalysts (Whiting, 2006)
96%
92%, >99% ee
Scheme 17. Large scale amidation with boric acid catalysis
(Tang, 2005).
90
Ph
N
H
presence of 1 mol% boric acid in refluxing toluene or xylene to
furnish the amide products in 60-99% isolated yields (Scheme
17).66,67 A Dean-Stark trap was used for the removal of water and
the protocol was efficient also for substrates containing free
hydroxylgroups with full selectivity for N-acylation. The
methodology was later used for the synthesis of several active
pharmaceutical compounds,68 as well as for the synthesis of
substituted cinnamides.69
95
MeO
O
Ph
40
OH
N
H
98%, 79% ee
45
50
OMe
O
Ph
OH
N
H
OMe
97%
100
Scheme 16. Amidation of α-hydroxycarboxylic acids with
alkylboronic acid catalysis (Ishihara, 2013).
The benzyl amide of salicylic acid was formed in a quantitative
yield with the alkylboronic acid catalyst in refluxing o-xylene. A
high selectivity for the amide bond formation over esterification
was observed with methylboronic acid as catalyst in the reaction
of mandelic acid and 6-aminohexanol as substrates. The thermal
background
reaction
of mandelic acid
with
3,5dimethylpiperidine was found to be non-existent in refluxing
toluene after 14 hours.
105
110
55
The use of boric acid as catalyst for the formation of secondary
and tertiary amides was recently studied by Tang. Both aliphatic
and aromatic carboxylic acids and amines were coupled in the
10 | Journal Name, [year], [vol], 00–00
115
Recently, Whiting and co-workers developed a catalytic
protocol for the coupling of amino acids protected at the C- or Nterminus, with benzylamine or phenylacetic acid.72 It was shown
that 3,4,5-trifluorophenylboronic acid, developed by Yamamoto
in 1996, and o-nitrophenylboronic acid were the most efficient
catalysts in refluxing fluorobenzene (bp 85 ºC) using molecular
sieves as water scavenger. The benzyl amide of Boc-protected
proline was obtained in 90% isolated yield (>99% ee) with
Yamamoto’s catalyst, whereas the o-nitrophenylboronic acid
catalyst furnished the benzyl amide of Boc-protected
phenylalanine in 91% isolated yield (79% ee). Similarly, the
amides from phenylacetic acid and the methyl ester
hydrochlorides of phenylalanine and valine were obtained in 78%
(64% ee) and 68% (>99% ee) yields respectively, employing
Yamamoto’s catalyst. The catalyst loading was 25 mol% in all
cases. The same arylboronic acids were also employed in the
synthesis of dipeptides from two protected amino acids, resulting
in yields of 20-62% with 100% catalyst loading at 65 ºC. Lower
catalyst loadings resulted in lower yields of the product. Although
this is a stoichiometric transformation, it represents the only
example of linear dipeptides being formed with a boron-based
This journal is © The Royal Society of Chemistry [year]
5
mediator. In some cases, higher yields were obtained when the
reaction was performed in the presence of two boronic acids (50
mol% of each). The stereochemical purity of the starting
materials was reported to be retained in the peptide products
(Scheme 18).
60
R''
Cl
H3N
O
Catalyst A - C (100 mol%)
R'
10
R'
RHN
65 °C, 3Å MS, 32 h
O
O
fluorobenzene
Scheme 19. Room-temperature amidation of (S)-Ibuprofen (Hall,
2008).
O
H
N
iPr2NEt (1 eq.)
OH
RHN
15
65
OR'''
OR'''
R''
70
Mechanistic studies using DFT calculations suggested the
involvement of acyl boronic species as intermediates for the
catalytic activation of the carboxylic acids (Figure 5).74,75
Catalysts
OH
F
B
NO2
OH
B
OH
OH
B
OH
75
OH
F
F
20
B
A
C
Figure 5. Proposed acylborate intermediates (Marcelli, 2010 and
Guo, 2013)
80
Bn
Boc
25
N
H
H
N
O
Bn
O
OMe
Ac
Bn
31%, catalyst A
N
H
O
H
N
Interestingly, kinetic and spectroscopic investigations revealed
that an increased electron density of the iodo substituent by
addition of a methoxy group in para position increased both the
yield and reaction rate of the amidation (Scheme 20).76
OEt
O
47%, catalyst B
85
58%, catalyst B
Bn
30
Ac
35
N
H
O
H
N
O
Bn
OMe
Bn
48%, catalyst B
Bn
Ac
N
H
Cbz
H
N
N
H
O
H
N
O
OMe
90
Bn
62%, catalyst B & C (50/50)
O
Bn
OMe
O
Boc
N
H
H
N
O
95
OMe
O
40
20%, catalyst B
<2%, catalyst B
51%, catalyst B & C (50/50)
55%, catalyst B & C (50/50)
100
Scheme 18. Selected dipeptides (Whiting, 2013).
45
50
55
All the boron-based catalysts described so far require elevated
reaction temperatures in order to produce good yields of the
amide product. However, in 2008, Hall and co-workers found that
ortho-substituted phenylboronic acids, in particular oiodophenylboronic acid, were efficient catalysts at room
temperature.73 Although the protocol includes longer reaction
times (48 h) and a higher dilution (0.07 M) compared to earlier
examples, a range of different amides with yields up to 90% were
obtained at only 25 ºC in THF or DCM. Importantly, the
conditions were mild enough to leave the labile stereocenter in
enantiomerically pure (S)-ibuprofen essentially untouched (<5%
racemisation) in the reactions with benzylamine and (R)-(+)-αmethylbenzylamine (Scheme 19).
This journal is © The Royal Society of Chemistry [year]
105
110
115
Scheme 20. Effect of the electronically modified oiodophenylboronic acid catalyst in the amidation (Hall, 2012).
Journal Name, [year], [vol], 00–00 | 11
4.1.3 Kinetic resolution of amines
5
In 2008, Whiting and co-workers published the first, and so far
only, example of a kinetic resolution of amines using a chiral
boronic acid catalyst in the amidation reaction with carboxylic
acids.77 The chiral catalyst, comprising a ferrocene backbone,
gave an ee of 41% (21% yield) in the resolution of racemic 1phenylethylamine with benzoic acid in fluorobenzene. The chiral
induction was less efficient for the resolution with 4phenylbutanoic acid (Scheme 21).
60
65
secondary and tertiary amides were formed in 87-98% yield.
Lower yields were obtained when aniline or amines with a
boiling point lower than toluene were used. The authors
demonstrated that the catalyst could be recycled at least three
times without any loss of activity. However, the employed
reaction conditions were found to completely racemise the
stereocenters in the dipeptide of Cbz-protected phenylalanine and
the tert-butyl ester of alanine.
10
70
Figure 7. 3-borono-N-alkylpyridinium salt catalysts developed
by Wang and co-workers (2001).
15
75
20
80
25
Scheme 21. Kinetic resolution of primary amines by a chiral
boron-based catalyst (Whiting, 2008).
4.2 Recyclable boronic acid catalysts
30
35
40
Furthermore, Yamamoto and co-workers demonstrated that the 4boronopyridinium catalysts showed a higher thermostability as
compared to the 3-boronopyridinium analogues.81,82 The Nmethylpyridinium boronic acids displayed an enhanced catalytic
activity and could be recycled by the use of ionic liquids.
Polystyrene-bound catalysts of the same type worked well in
regular solvents and could be recycled by filtration (Figure 8).
A polyfluorinated and recyclable boronic acid catalyst was
developed by Yamamoto and co-workers.78 It was found that 3,5bis(perfluorodecyl)phenylboronic acid (Figure 6) was the most
active amidation catalyst in refluxing toluene by using molecular
sieves in a Soxhlet thimble for the removal of water. When the
reaction was performed in a fluorous biphasic system, the catalyst
could
be
recovered
by
extraction
with
perfluoromethylcyclohexane, and the fluorous phase could be reused. Alternatively, the catalyst, which becomes insoluble at
room temperature, could be recycled by decantation of the
product-containing layer. By employment of the latter recycling
procedure, the catalyst was re-used ten times without any loss of
activity in the coupling of cyclohexanecarboxylic acid and
benzylamine.
I
N
85
B(OH)2
recyclable by ionic liquids
90
Cl
Br
2N
N
B(OH)2
B(OH)2
95
Br
NTf2
4N
2N
B(OH)2
B(OH)2
100
recyclable by filtration
Figure 8. Recyclable boron-based catalysts (Yamamoto, 2005).
45
105
Figure 6. A polyfluorinated boronic acid catalyst developed by
Yamamoto and co-workers (2001).
50
55
The same group also reported on the use of cationic 4-borono-Nmethylpyridinium iodide as an efficient catalyst for the amide
condensation in polar solvents.79 This finding was in parallel to
similar catalysts from Wang and co-workers, who published the
synthesis and use of 3-borono-N-methylpyridinium salt as well as
an N-polystyrene resin-bound 3-boronopyridinium catalyst
(Figure 7).80 With 1-5 mol% of the immobilized catalyst,
110
115
12 | Journal Name, [year], [vol], 00–00
4.3 Summary and conclusions on boron-based catalysts
Boron-based catalysts generally work well with a fairly broad
substrate scope, including hydroxy-substituted reactants. Boronic
acids have also been demonstrated to be efficient catalysts for the
synthesis of lactams by intramolecular direct amidation. The
yields are usually high and there are several examples where the
catalyst can be recycled without loss of activity. The only
example of a non-biological chiral catalyst for kinetic resolution
of amines in the direct amidation is based on boron.77 A drawback
for many of the boron-based catalysts is that they often require
elevated reaction temperatures (85 ºC or more), which may result
This journal is © The Royal Society of Chemistry [year]
5
10
15
in problems with racemisation and limits the substrate scope.
There are two notable exceptions of boronic acid catalysts that
perform well at room temperature, thereby circumventing the
racemisation issue.73 However, in this case, the reactant
concentrations must be low and a fairly large amount of
molecular sieves is required to drive the reaction which limits
large scale applications.
Although most boronic acids are stable towards water, its
removal is crucial to drive the reaction forward for the majority
of the methods presented above, which might be troublesome for
large-scale applications. Another challenge for the development
of new boron-based catalysts includes the catalytic coupling of
amino acids and peptides, which to date is limited to dimerization
or stoichiometric methods. The boron-based catalysts also seem
to fail when it comes to the formation of primary amides. An
exception is the protocol employing catalytic amounts of boric
acid/PEG-400 which can be used to form the benzanilide of 4nitrobenzoic acid under rather harsh conditions.57
60
Scheme 22. Titanium-catalysed formation of 4-nitrobenzanilide
(Shteinberg, 2003).
65
70
75
20
25
30
35
5. Metal catalysis
The use of metal-based catalysts for the direct amidation of
carboxylic acids and amines has mainly received attention in the
last few years, and remain an underdeveloped area. In general,
oxophilic early transition metals are employed as catalysts, and
both homogenous and heterogeneous catalytic protocols are
available.
80
5.1 Homogeneous metal-catalysed protocols
85
Group IV metals represent the dominant class of metal-based
catalysts employed for the direct amidation of non-activated
carboxylic acids under homogeneous conditions. Nevertheless,
other transition metals as well as main group metals have also
found use as catalysts. In contrast to most other areas where
metal-based catalysts are used, amidations are performed using
simple metal salts without incorporation of more sophisticated
ligands than simple counter ions (i.e. halides, alkoxides or
acetates). Therefore, one can foresee that more developed metal
complexes, containing ligands with a tuning ability, will be
evaluated as amidation catalysts in the future.
Scheme 23. Formation of primary and tertiary amides using
carbamates as amine sources (Adolfsson, 2012).
5.1.2 Secondary and tertiary amides
90
95
40
5.1.1 Primary amides
45
50
The metal-catalysed formation of primary amides from
carboxylic acids and ammonia is less explored than the synthesis
of secondary or tertiary amides. The first report was published by
Shteinberg in 2003, who used Ti(OBu)4 in combination with
PEG-400 for the reaction of 4-nitrobenzoic acid and ammonia.57
The amide was formed in 90% yield using 2 mol% of the
titanium complex and 0.9 mol% PEG-400 in refluxing
trichlorobenzene (Scheme 22). Neither Ti(OBu)4 nor PEG-400
were active as catalysts on their own.
100
105
110
55
This journal is © The Royal Society of Chemistry [year]
In 2012, Adolfsson and co-workers reported that the
tetrachloride complexes of titanium and zirconium catalysed the
formation of primary amides, using ammonium carbamate as the
source of ammonia.83 Although a higher catalyst loading was
employed, compared to Shteinberg’s protocol, the reaction was
performed at a lower reaction temperature. Nine primary amides
were formed in 67-99% yield, using 20 mol% of the catalyst at
100-120 ºC in the presence of molecular sieves. The authors also
showed that N,N-dimethylammonium N,N-dimethylcarbamate
worked well as a source of dimethylamine to afford nine different
dimethylamides in 61-99% yield under similar reaction
conditions (Scheme 23). The thermal amidation reaction, in the
absence of catalyst, furnished the primary amides and dimethyl
amides in 2-14% and 5-17% yield, respectively.
The use of metal complexes as Lewis acidic mediators for the
formation of secondary and tertiary amides goes back to the
1970’s, when Wilson and Weingardten used stoichiometric
amounts of TiCl4 to form carboxamides from non-activated
carboxylic acids and amines.84 In 1972, the first patent was filed
for a catalytic process describing the production of amides from
different long chain fatty acids and amines.85 The authors used
0.6-1 mol% of metal complexes based on Ti(IV), Zr(IV) and
Ta(V) as catalysts, with reaction temperatures of 120-200 ºC, and
reached near-quantitative yields in a couple of hours of reaction
time. In 1979, another patent was filed for the catalytic
production of N,N-dimethyl-m-toluamide from the corresponding
carboxylic acid and amine.86 At elevated reaction temperatures
(150-300 ºC), the amide was formed from a mixture with 2:1
molar ratio of carboxylic acid to amine with typically 0.2-0.5
mol% of different Ti(IV)-complexes as catalysts with the removal
of water.
In the beginning of the 1980’s, Steliou et al. reported on the
formation of five- to seven-membered lactams in near
quantitative yield (95%) with 10 mol% Bu2SnO in refluxing
xylene and a Dean-Stark trap for the removal of water (Scheme
24).87,88 Although the method failed for the synthesis of β-lactams
Journal Name, [year], [vol], 00–00 | 13
and macrocyclic lactams, one example of a bridged lactam was
reported with the use of a stoichiometric amount of the tin
complex.
60
5
65
the substrate was refluxed in aniline (bp 184 ºC) for two hours.91
Furthermore, it was demonstrated that substituted anilines were
effective as coupling partners with benzoic acid under the same
reaction conditions.92 Anilines substituted with electron donating
groups were generally giving rise to higher conversions than
electron poor anilines, with the exception of aminophenols, where
the OH-group seemed to retard the reaction. Selected examples
are given in Figure 9.
10
70
15
75
Scheme 24. Tin-catalysed/mediated lactamisation reactions
(Steliou, 1983).
20
25
In 1988, Mader and Helquist reported on the lactamisation of
linear amino acids using 50 mol% of Ti(OiPr)4 in refluxing
dichloroethane (bp 83 ºC).89 The lactams were obtained in 3593% yield with a ring size of 5-7 atoms (Scheme 25). When the
catalyst loading was reduced to 10-25 mol%, lower yields of the
lactams were observed. Moreover, the method failed for the
formation of linear amides.
O
30
R2
35
N
H
n
R1
Ti(Oi Pr)4 50 mol%
OH
85
O
NH
O
80
NH
93%
O
90
81%
O
N
1,2-dichloroethane
reflux, 0.34M, 3-26 h
NH
85%
O
75% O
95
NH
N
40
86%
35%
Scheme 25. Ti(OiPr)4-catalysed lactamisations (Helquist, 1988).
45
50
55
The first catalytic intermolecular amidation protocol was
published by Shteinberg et al., employing Ti(OBu)4 as a catalyst
for the acylation of aniline with various carboxylic acids.90 By the
use of a 2 mol% catalyst loading in refluxing o-xylene (bp 145
ºC), the authors showed that the titanium butoxide complex was a
superior catalyst, 85% yield compared to TiCl4 (39%), SnCl4
(26%), Bu2SnO (22%) and BF3⋅OEt2 (10%) in the amidation of
benzoic acid and aniline. The efficacy of the Ti(OBu)4 catalyst
was demonstrated in 21 examples where the amide yields ranged
from 38 to 98% with a thermal reaction contributing to 0-5%.
Lower yields were obtained with di-carboxylic acids, and a free
hydroxyl group in the para-position of the benzoic acid substrate
was found to inhibit the reaction. However, the authors found that
2 mol% of the titanium complex catalysed the formation of the
anilide product 3-hydroxy-2-naphthoic acid in 80% yield, when
14 | Journal Name, [year], [vol], 00–00
100
105
110
115
Figure 9. Selected examples for the Ti(OBu)4-catalysed
amidation of benzoic acids and anilines (Shteinberg, 1988 and
1989).
The amidation of benzoic acid with aniline performed optimal in
non-polar aprotic media under an azeotropic removal of water. In
the presence of polar solvents such as DMF, DMSO, HMPA and
sulfolane, the amidation reaction was inhibited even at 10 mol%
concentration in o-xylene.93
Shteinberg et al. observed that batches of the Ti(OBu)4 catalyst
which had been standing on the shelf for some time seemed to
perform better than freshly distilled ones. The authors attributed
this effect to the involvement of water at some stage in the
reaction and therefore investigated the catalytic activity of aged
batches of the catalyst.94 Reproducible results were obtained
when the aging of the catalyst was performed under controlled
conditions in a moist cell.95 The most active catalyst was obtained
after 5.5 hours of aging, with an estimated absorption of about 1.8
mol-equivalents of water. A yield of 45% was observed in the
formation of benzanilide using the aged catalyst, whereas freshly
distilled catalyst furnished the same product in only 15% yield
under otherwise identical reaction conditions. It was suggested
that the water hydrolyses the butoxide ligands of the catalyst to
This journal is © The Royal Society of Chemistry [year]
5
form linear oligomers of polytitanate which were assumed to be
the most active form of the catalyst. A higher degree of water
absorption led to a lower catalyst activity which was explained by
a cross-linking of the linear oligomers that are less soluble in the
reaction medium. Alternatively, the activation of the catalyst
could be performed by pre-treating the catalyst with benzoic acid
prior to the reaction.96 The reaction progress of the amidation was
also found to be highly dependent on a high mass transfer rate of
water.97
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15
20
25
The N-formylation of amines using neat formic acid and
zinc(II) chloride as catalyst was investigated by Shekhar et al.98,99
Electron rich aniline derivatives were reported to be highly
reactive, furnishing the formamide products in 80-98% yield after
10-90 min at 70°C using 10 mol% of ZnCl2 (Scheme 26).
Electron-poor aryl amines and secondary amines however,
required longer reaction times (4-15h) in order to obtain useful
yields. Other Lewis acidic metal salts such as SnCl2, LaCl3 and
La(OTf)3 were equally efficient as catalysts for the synthesis of
formanilide (>90% yield in all cases). In absence of a catalyst, the
reaction did not proceed. Moreover, the amidation of longer chain
carboxylic acids with aniline was less effective under the reported
reaction conditions; when acetic acid was used, the amide was
formed in 55% yield after 12 hours while decanoic acid remained
unreacted.
ZnCl2 10 mol%
RNH2 + HCOOH
neat, 70 ºC
70
catalyst. However, the authors found that the reaction rate was
dramatically increased by the addition of various metal
complexes in catalytic amounts. The most efficient catalysts were
identified as ZrCl4 and ZrCp2Cl2, which led to high conversions
after four hours of reaction time using a 5 mol% catalyst loading
(Scheme 27). The yields of the catalysed reactions were in almost
all cases higher than for the thermal reactions of the same
substrates. The pharmaceuticals paracetamol and moclobemide
were synthesized with full conversion using zirconium catalysis,
as compared to 37% and 14% yield of the thermal reaction,
respectively. The benzyl amide of N-Boc-proline was also formed
in a moderate isolated yield of 56%, and with retained
stereochemical purity. The thermal reaction for this substrate was
found to be non-existing at 100 ºC.
75
80
85
RNHCHO
30
NHCHO
N
NHCHO
NCHO
N
96%, 10 min
90
O
96%, 30 min
80%, 240 min
35
S
NHCHO
NHCHO
95
CO2Et
40
95%, 200 min
60%, 60 min
Scheme 26. ZnCl2-catalysed N-formylation (Shekhar, 2009).
45
50
Another method for the catalytic N-formylation of anilines
with formic acid was published by Azizi et al.100 Tin(II) chloride
was used as catalyst in the form of a deep eutectic solvent
(DES)101 for the formylation of a series of anilines. The
formanilide products were obtained in up to excellent yields
using 30 mol% of the tin(II) chloride-choline chloride DES
catalyst at 70 ºC. Formic acid was found to be a superior
formylating reagent compared to trimethyl orthoformate.
100
105
110
55
Williams and co-workers reported on the thermal amidation of
carboxylic acids and amines, which was found to take place to a
fairly high extent at 110 ºC in toluene.13 In the reaction of 3phenylpropionic
acid
and
4-methylbenzylamine,
the
corresponding amide was formed in 20% yield after 4 hours, and
a full conversion was obtained after 20 hours in the absence of a
This journal is © The Royal Society of Chemistry [year]
115
Scheme 27. Selected examples of amides formed by Williams’
catalytic protocol (2012).
Simultaneously, and in parallel to the work of Williams,
Adolfsson and co-workers reported that ZrCl4 worked well as
catalyst at 70 ºC in THF when molecular sieves were present as a
water scavenger.14 The authors found that the thermal
background reaction at 70 ºC was considerably lower than that
taking place at 110 ºC, which was reported by Williams. For
phenylacetic acid, the corresponding benzylamide was formed in
10-13% yield after 24 hours, depending on the acid to amine
ratio. The authors reported 24 examples of secondary and tertiary
amides being formed in 62-99% yield with a 2-10 mol% catalyst
loading (Scheme 28). No racemisation of the stereocenter in Bocprotected alanine and proline was detected in the coupling with
benzylamine, nor for the amide resulting from the coupling of
(R)-1-phenylethylamine with phenylacetic acid. Furthermore, the
benzylamide of the anti-inflammatory drug indomethacin was
formed in 97% isolated yield employing 2 mol% of ZrCl4. The
zirconium-catalysed amidation reaction was found to be suitable
for larger scale syntheses; a comparable yield for N-benzyl-2phenylacetamide was obtained on a 40 mmol scale.
Journal Name, [year], [vol], 00–00 | 15
O
R1
+
OH
R2
H
N
R3
5
R1
THF, 0.4 M, 70 °C
N
H
Ph
99%
Ph
65
N
H
O
Ph
70%, 100°C
N
Boc
>99%
N
H
Ph
70
O
O
3
94%
11
O
H
N
O
15
R3
O
O
10
N
R2
4Å MS, 24 h
Ph
60
O
ZrCl4 2-10 mol%
N
H
Ph
73%
95%
N
H
N
Ph
>99% ee
Boc
20
25
30
35
40
75
Scheme 28. Zirconium-catalysed amidation, selected examples
(Adolfsson, 2012).
The authors also demonstrated the efficacy of Ti(OiPr)4 as
catalyst in the amidation reaction. A range of amides was
obtained using a 10 mol% loading at 70 ºC with 4Å molecular
sieves as water scavenger.102 These results were in contrast to the
early work of Helquist and Mader who observed no product for
the intermolecular amide formation with the same catalyst.89
Terada et al. reported on the catalytic activity of metal salts in
the amidation of long-chain aliphatic carboxylic acids and amines
in refluxing mesitylene (bp 163 ºC).103 Several metal chloride
complexes were examined, and it was found that FeCl3•6H2O was
the most efficient catalyst, followed by ZnCl2, NiCl2•6H2O and
MnCl3•6H2O. The reaction worked best in high boiling solvents
at refluxing conditions with a Dean-Stark apparatus for the
azeotropic removal of water. The aliphatic amides were formed in
47-93% yield after 6 hours using 2 mol% of FeCl3•6H2O as
catalyst (Figure 10). In contrast to many other metal and enzyme
catalysts, the reaction was only effective with carboxylic acids as
substrates; the aminolysis of methyl palmitate with decylamine
did not occur under the applied reaction conditions.
80
Figure 10. Substrate scope for the FeCl3-catalysed synthesis of
aliphatic amides (Terada, 2008).
85
90
95
100
45
105
50
110
55
115
16 | Journal Name, [year], [vol], 00–00
Brahmachari et al. found that zinc acetate worked well as
catalyst for the acetylation of amines in acetic acid under reflux
(with 25-30 mol% catalyst loading), and under microwave
irradiation (with 0.9 mol% loading and 300 W).104,105 Primary
and secondary amines, both aromatic and aliphatic ones, were
acetylated in good to excellent yields. The reaction was found to
be highly selective for N-acetylation in the presence of other
nucleophiles such as alcohols and thiols. Furthermore, it was
demonstrated that the acetylation of amines worked well with the
acetate complexes of sodium, calcium, magnesium, manganese
and copper as catalysts. The authors discovered that the Nacetylation also worked well when Zn(OAc)2 was used in a
stoichiometric amount in the absence of acetic acid. An analysis
of the residual metal showed that ZnO had formed during the
reaction. Since the metal acetate could be recovered after the
catalysis in acetic acid, it was presumed that the metal oxide
could be used as pre-catalyst to form the metal acetate in situ.
This assumption proved to be correct and the authors
demonstrated that ZnO, Cr2O3, Al2O3, CaO and MgO could be
used as pre-catalysts in the acetylation reaction.
A reusable homogenous catalyst system was developed by De
Oliveira et al. A variety of amides were formed in 82-97% yield
from fatty acids and pyrrolidine with 5 mol% of CdO or SnCl2
using an ionic liquid (1-n-butyl-3-methylimidazolium
bis(trifluoromethylsulfonyl)imide) as reaction medium.106 The
metal catalysts could be reused up to 8 times by recycling of the
ionic liquid after decantation and extraction of the amide
products. In addition, Sb(OEt)3 was mentioned by Yamamoto and
co-workers to be catalytically active for the amidation of a
handful of substrates.107
This journal is © The Royal Society of Chemistry [year]
5.2 Heterogeneous metal-containing catalysts
5
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15
20
25
The main advantage of heterogeneous catalysis is the possibility
of facile separation of the catalyst from the reaction medium and
the potential recyclability, overall leading to a better atom
economy. The development of heterogeneous catalysts for the
direct amidation of carboxylic acids started already in the 1970’s
and originates largely from origin of life experiments, studying
the formation of peptides from amino acids aided by minerals and
clays. The proposed models used different techniques in attempts
to mimic the primitive earth, and the general idea was that amino
acids were adsorbed to the mineral surface to form active esters
for further condensation. In the synthetic protocols investigating
this hypothesis, the yields of peptides were in general in the order
of a few percent and the reaction times were measured in days to
months. For this reason, the literature in this field is not covered
by this review but can be found elsewhere.108 The catalytic
formation of peptides from non-activated amino acids is not an
easy task, and to date there are no general catalytic methods for
this transformation, neither homogeneous nor heterogeneous.
However, several heterogeneous catalytic protocols for direct
amidation of other types of carboxylic acids and amines have
been developed. Little is known about the operating mechanisms
of the heterogeneous catalysts. Hence, this section covers all
catalytic protocols which contain metal ions, without speculations
on whether the catalytic effect is due to the incorporated metal or
not.
5.2.1 Synthesis of primary amides
30
35
40
Only a few heterogeneous metal-catalysed syntheses of primary
amides have been reported in the literature. Reddy et al.
published a ZrOCl2⋅8H2O-catalysed amidation protocol under
microwave irradiation (80 oC, 100 W) for the formation of
primary amides from 25 different carboxylic acids using urea as
nitrogen source.109 The authors reported yields of 73-94% in only
20-80 seconds of reaction time under solvent-free conditions.
Furthermore, the catalyst could be recycled up to three times
without loss of activity. The authors also reported that 2 mol% of
cerium ammonium nitrate (CAN) could be employed as catalyst
for the same reaction under similar conditions.110 The thermal
yields of the two reactions were reported to be non-existent. It
should be noted that the two protocols have been reported to be
difficult to reproduce.83
amide product was obtained in 25% yield. However, no
experimental details were given for this control experiment or for
the microwave method.
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70
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O
R
50
55
This journal is © The Royal Society of Chemistry [year]
OH
R
116 °C, 5-24 h
H
N
O
NHAc
NHAc
NHAc
Cl
99%, 5 h
99%, 6 h
99%, 6 h
85
NHAc
NHAc
N
10%, 8 h
98%, 8 h
105
110
98%, 8 h
CO2Me
NHAc
95
NHAc
CN
85%, 24 h
90
5.2.2 Secondary and tertiary amides
Zeolites, a heterogeneous aluminosilicate-based material with a
microporous structure, have been employed as catalysts in the
direct amidation of non-activated carboxylic acids. In 1998,
Gadhwal et al. published the first catalytic protocol based on the
protonated form of zeolite Y (zeolite-HY) as heterogeneous
catalyst for direct amidation reaction.111 The reactions were
performed in a domestic microwave oven under solvent free
conditions for 30-60 min to obtain the secondary amide products
in 80-97% yield. The loading of the zeolite-HY catalyst was 50
mg/mmol substrate with an equimolar amount of the carboxylic
acid and amine substrates. When the reaction of aniline and acetic
acid was performed in the absence of microwave irradiation, the
Zeolite-HY
NH2
80
100
45
The catalytic activity of zeolite-HY in the acylation of amines
was further investigated by Kulkarni and co-workers.112 The
reaction was performed in refluxing acetic acid with a catalyst
loading of 150 mg/mmol substrate for the synthesis of aromatic
as well as aliphatic acetamides (Scheme 29). The
chemoselectivity of the catalytic amidation was demonstrated in
the reaction of 4-hydroxyaniline where only N-acetylation was
observed. Furthermore, the ester functionality in phenylalanine
methyl ester remained untouched under the reaction conditions,
which is in contrast to many other amidation catalysts which are
also active catalysts for aminolysis of esters. The thermal reaction
was found to be slow in the control experiment with
benzylamine, and the zeolite-HY catalyst could be recycled three
times without any loss of activity.
9
NHAc
40%, 8 h
Scheme 29. Zeolite-HY -catalysed acylation of aromatic and
aliphatic amines (Kulkarni, 2000).
The catalytic acetylation of amines was further investigated by
employing metal doped zeolites under microwave irradiation. It
was found that an iron doped zeolite (Feß-zeolite) was the most
efficient catalyst in comparison to zeolites containing La, Cu, Cr,
Co, Zn, Ni, Pb, and W. The iron doped catalyst could be recycled
at least three times without any loss in activity.113
Recently, Bahari et al. published a protocol for the direct Nformylation of amines using a natural HEU zeolite as a recyclable
catalyst.114 The reaction could be performed under very mild
conditions (ambient temperature) in short reaction times and the
catalyst could be recycled five times with a minimal loss in yield.
In order to expand the substrate scope for zeolite catalysts to
include bulkier substrates, Sugi and co-workers developed a
material with a larger pore size.115 A calcium-containing
mesoporous aluminosilicate molecular sieves (AlMMSH) catalyst
was employed for the condensation of fatty acids and long-chain
Journal Name, [year], [vol], 00–00 | 17
aliphatic amines. The reaction of palmitic acid and Nhexadecylamine furnished the aliphatic amide in 69% conversion
at elevated temperatures (150 ºC).
5
10
The first catalytic protocol employing formic acid as
formylating reagent was developed by Hosseini-Sarvari and coworkers in 2006.116 It was demonstrated that the N-formylation of
both aromatic and aliphatic amines could be performed at 70°C
under solvent-free conditions using ZnO as catalyst. The
formamide products were obtained in good to excellent yields in
reaction times of 10-720 minutes (Figure 11).
60
65
70
15
75
20
80
25
30
35
40
45
Figure 11. Selected examples from the first N-formylation of
amines with formic acid using ZnO as catalyst (Hosseini-Sarvari,
2006).
During the optimization studies, it was noted that the amount of
formic acid was crucial; a large excess of formic acid gave only
trace amounts of the desired product. The optimal ratio (formic
acid:amine) was found to be 3:1, furnishing a 99 % yield of the
model product formanilide using a catalyst loading of 50 mol%.
If the catalyst loading was either increased or decreased from the
optimal 50 mol %, this also resulted in a lower yield. The catalyst
could be recovered and reused, although with a small loss of the
catalyst for each run (4-10%). Furthermore, the catalytic protocol
was suitable for a large-scale synthesis, demonstrated by the
formylation of aniline on a 100 mmol scale with a yield of 99%
after 40 min.
In 2007, Thakuria et al. performed a comparative study,117
using macroporous ZnO and other macroporous metal oxides
(CuO, NiO, CoO, Mn2O3 and Cr2O3) as catalysts in the Nformylation under conditions similar to those present in the
Hosseini-Sarvari protocol. It was shown that the recyclable
macroporous metal-oxide catalysts could be used in significantly
lower loadings (0.05%-0.25%) compared to the amorphous
compounds, still giving rise to comparable yields. The authors
suggested that this improvement was due to the larger internal
surface area and pore volume of the macroporous material.
55
18 | Journal Name, [year], [vol], 00–00
Other metal oxides have also attracted attention in recent
years. Reddy et al. prepared a porous nanocrystalline-MgO
material by calcination of a mixture of Mg(NO3)2•6H2O and
glycine.119 The nano-MgO was utilized as catalyst for the Nformylation of anilines under microwave irradiation (320W) to
obtain the corresponding formanilides in 90-98% yield after 1-2
minutes (Scheme 30). The background reaction showed only
traces of the formylated amine and a comparative study with
commercially available bulk-MgO showed that the catalytic
power of nano-MgO was superior.
85
90
95
100
105
50
Recently, other research groups have continued to explore zinc
oxide as catalyst for direct amidation of carboxylic acids.
Tamaddon et al. prepared a ZnO-nanofluid by dispersing ZnO
nanoparticles in glycerol.118 The authors reported that the ZnOnanofluid was a more efficient catalyst than the zinc
nanoparticles itself, suggesting better diffusion and dispersion
abilities of the nanofluid catalyst in the reaction mixture. A series
of amides were prepared under neat conditions at 110 °C, with a
catalyst loading of 160 mg ZnO nanofluid to 1 mmol substrate
(50 wt% ZnO in the catalyst). A representative example of the
efficiency of the protocol was illustrated by the reaction of stearic
acid and aniline, which furnished N-phenylstearamide in 91 %
yield after 4 hours. However, the thermal reaction was found to
contribute substantially to the yield (56%) under the applied
reaction conditions. The reaction was found to be accelerated
under microwave irradiation, yielding the amide products in short
reaction times (60-180 seconds). The ZnO-nanofluid in itself was
not recovered after the reaction, although the ZnO nanoparticles
could be recovered and dispersed again in glycerol without any
loss in catalytic activity after three consecutive cycles.
110
Scheme 30. Microwave-assisted formylation of anilines with a
nano-MgO catalyst (Reddy, 2010).
The group of Hosseini-Sarvari recently reported on a nanosulfated TiO2 catalyst for the direct amidation of fatty acids.120 It
was found that a 98 % yield could be obtained in the reaction of
stearic acid and aniline after 3 h using 0.011 mol% of the catalyst
at 115 °C. The procedure worked well for variety of aromatic,
heteroaromatic, aliphatic and long chain amines in the
condensation with stearic acid under solvent free conditions
(Scheme 31). Additionally, a few benzoic acid derivatives were
shown to form the secondary amides with aniline in excellent
yields, employing the same titania catalyst. Performing the
reaction in absence of the titania catalyst did not show any trace
of the amide, even after 48 hours. Although this direct amidation
protocol was based on a heterogeneous catalyst, no recycling
study was reported.
115
This journal is © The Royal Society of Chemistry [year]
60
5
65
10
70
15
75
20
Scheme 31. Direct amidation of stearic acid using a nano sulfated
titania catalyst (Hosseini-Sarvari, 2011).
80
25
The nano-sulfated titania catalyst was also demonstrated to be
efficient in the formylation of amino substituted β-lactams at
room temperature.121 It was found that the previously developed
ZnO-catalysed N-formylation protocol failed in the case of βlactam substrates.116 However, the nano-sulfated TiO2 (0.015
mol%) displayed a high catalytic activity using equimolar
amounts of the β-lactams and formic acid (Scheme 32).
85
30
90
35
95
40
100
A similar sulfated titania catalyst was discovered by
Swaminathan to be efficient in the N-formylation at room
temperature.122 Most N-formylation protocols with formic acid
report on solvent-free procedures and that the addition of solvent
reduces the efficiency of the catalysis. However, Swaminathan
and co-workers found that excellent yields of formanilide could
be obtained in the presence of acetonitrile, chloroform,
dichloromethane and ethanol. The titania catalyst could be
filtered off at the end of the reaction and re-used five times with
negligible loss in activity.
Nagarajan et al. reported on the synthesis and catalytic activity
of sulfated titania nanotubes.123 The nanotubes had a length of
several hundred nm with diameters of around 3-6 nm, and the
authors showed that if the nanotubes were prepared from
calcination of the titania nanoparticles at 400, 600 or 800 °C, the
tubes would bundle together and therefore display a smaller
surface area. The authors observed that the calcinated catalysts
were less active in the amidation reaction, which was attributed to
the larger particle size, and hence smaller surface area. In the
amidation of phenylacetic acid with aniline, the product was
formed in 98% yield at 110 ºC under solvent free conditions with
a catalyst loading of 24 wt%. The thermal yield was found to be
45% under the same reaction conditions. Moreover, a correlation
between the catalyst activity and the sulfur content in the
nanostructure was observed. Calcinated nanoparticles, which
were found to have a lower sulfur content, were less active as
catalysts and the recyclability study revealed that sulfur was
leaching, leading to a steady decrease of the catalytic activity in
subsequent cycles.
An efficient and recyclable aluminium oxide catalyst was
developed by Thakur and co-workers for the N-formylation of
amines.124 With 5 mol% of a nano rod-shaped basic Al2O3
catalyst, formanilide was obtained in 98% yield after only 5 min
at 40 ºC (TON 78 / TOF 945 h-1) from aniline and formic acid.
This should be compared to the thermal amidation which resulted
in 28 and 42 % yield at 40 and 70 ºC, respectively, after 7-10 h. A
range of substrates including both electron-rich and electron-poor
aromatic amines, unprotected amino acids (glycine and valine),
phenylhydrazine, diamines, and N-heterocycles were formylated
in high to excellent yields (Scheme 33). The recycling of the
catalyst proved to be successful and no decrease in product yield
was observed after 5 cycles.
45
105
50
Scheme 32. N-formylation of ß-lactams catalysed by nanosulfated titania (Hosseini-Sarvari, 2012).
110
55
The authors suggested that the difference in activity could be
explained in terms of larger catalyst surface area and the amount
of sulfuric acid suspended on the titania. The catalyst showed
excellent recyclability with a negligible decrease in yields after
six cycles.
This journal is © The Royal Society of Chemistry [year]
115
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60
5
65
10
70
15
75
Figure 12. Selected examples for the catalytic amidation with a
recyclable alumina catalyst (Mukhopadhyay, 2012).
20
80
25
Scheme 33. N-formylation of amines with a recyclable
aluminium oxide catalyst (Thakur, 2012).
85
30
35
40
45
50
Alumina beads (3-5 mm in size) were demonstrated to be an
easily available, clean and reusable heterogeneous catalyst for the
carboxylic acid/amine condensation.125 In contrast to the sulfated
titania nanoparticles which were deactivated upon calcination, the
alumina beads displayed a higher catalytic activity with
increasing calcination temperatures. The highest activity was
observed after calcination at 700 ºC upon which the morphology
of the material changed from spherical to rhombohedral. The
authors noted that even though the aggregation of the particles
increased after calcination, hence decreasing the surface area, the
pore volume and pore width increased. The authors suggested
that the increase in pore volume gave a favourable diffusion of
the substrates and products, which could explain the observed
higher activity. The activated alumina catalyst was compared to a
non-activated catalyst in the reaction between heptanoic acid and
p-chloroaniline at 140 ºC without any solvent, using a 10 wt%
catalyst loading. The non-activated catalyst led to 65 %
conversion after 3 hours: considerably lower than the 98 % which
was obtained for the calcinated catalyst. Despite the high reaction
temperature, no product formation was observed in the absence of
catalyst. The catalytic protocol was effective for a variety of
amines and carboxylic acids, and the catalyst could easily be
filtered off and re-used up to three times with a minor decrease in
activity (Figure 12).
Akamanchi and co-workers reported on an efficient process for
the direct amidation of various carboxylic acids, employing
sulfated tungstate as a heterogeneous acid catalyst.126 The catalyst
was evaluated against other acid catalysts such as ptoluenesulfonic acid, camphorsulfonic acid and silica in the
formation of N-benzylbenzamide, and sulfated tungstate was
found to be a superior catalyst (Scheme 34).
90
95
100
105
110
Scheme 34. Catalytic performance of sulfated tungstate in
comparison with other acid catalyst (Akamanchi, 2010).
55
115
20 | Journal Name, [year], [vol], 00–00
The substrate scope included 12 examples of amides formed
within 12-24 h, and the thermal amidation reaction did not exceed
26% for any of the substrates. Furthermore, the catalytic
This journal is © The Royal Society of Chemistry [year]
5
10
performance of the sulfated tungstate material was evaluated in
the N-formylation of amines.127 It was demonstrated that pchloroaniline was formylated in 98% yield at 55 ºC with 10 wt%
of the catalyst and 2.5 hours reaction time. However, the reaction
was considerably faster at 70 ºC, and the p-chloro formanilide
was obtained in the same yield after only 10 minutes, using a
slight excess of the formic acid. A range of amines were
efficiently formylated in short reaction times, and full
chemoselectivity in favour of N-formylation was obtained when
hydroxy-substituted substrates were employed. Moreover, full
retention of the stereochemistry of enantiopure starting
compounds was observed with this protocol (Scheme 35).
NH2
H
N
Sulfated tungstate (10 wt %)
15
Cl
Furthermore, it was also demonstrated that propionic and butyric
acid could be used as acylating agents using the Fe(III)montmorillonite catalyst.
65
N
98%, 60 min.
H
N
H
N
70
O
O
OH
25
O
99%, 10 min
HN
H
30
O
35
40
45
50
55
80
NH
S
Ph
N
N
H
97%, 150 min.
72%, 240 min.
O
85
84%, 30 min
90
Scheme 35. N-formylation of amines with a sulfated tungstate
catalyst (Akamanchi, 2012).
Clays such as montmorillonite and chamosite have been used
as catalysts for the direct amidation. In 2001, Choudary and
Kantam performed a study of different metal ion-exchanged
montmorillonites, as catalysts for the direct acylation of amines
with acetic acid.128 A Fe3+ exchanged K-10-montmorillonite was
found to be the most efficient catalyst in the model reaction of
benzylamine with acetic acid under solvent free conditions at 116
ºC. The amide was obtained in 99% yield after 5 minutes using a
catalyst loading of 20 mg/mmol substrate. The non-catalysed
reaction gave rise to less than 5% yield after the same reaction
time. Montmorillonites doped with Cu2+, Al3+, Zn2+, as well as
the non-doped version, also resulted in high yields (>98%),
although they all required longer reaction times (20-40 minutes).
The scope of the Fe(III)-montmorillonite catalysed N-acetylation
was found to be quite broad, furnishing the acetamides in yields
of 72-99% after 5-360 minutes (Figure 13). No racemisation
occurred when (R)-(+)-α-methylbenzylamine was acylated, and a
98% yield of the optically pure amide was obtained in 45 min.
This can be compared to the thermal non-catalysed reaction,
which gave rise to 52% yield after 6 hours. The catalyst could be
recycled and reused five times for the formation of the
enantiomerically pure acetamide without any loss of activity.
This journal is © The Royal Society of Chemistry [year]
HN
O
96%, 120 min.
H
Ph
87%, 45 min
98%, 210 min.
OMe
O
N
O
N
10 H
N
H
87%, 10 min
H
97%, 180 min.
O
H
O
CO2Me
O
98%, 180 min.
O
96%, 10 min
95%, 10 min
N
H
O
O
70°C, 10 min, 98%
N
H
H
N
HO
98%, 180 min.
95%, 210 min.
75
20
H
N
H
99%, 5 min.
55°C, 2.5h, 98%
O
O
2N
H
N
H
H
r.t., 6h, 80%
H
N
O
O
O
Cl
Formic acid (1.2 eq)
60
95
100
105
110
Figure 13. Selected substrates from Fe(III)-montmorillonitecatalysed protocol of Choudary and Kantam (2001).
The catalytic activity of the Fe3+-K-10-montmorillonite clay
was further investigated by Srinivas and Das.129 While the
previous amidation method was performed under solvent-free
conditions at 116-120 ºC and mainly utilized acetic acid as
acylating agent, the group of Das performed the reaction at lower
reaction temperature in refluxing chloroform (b.p. 61 ºC). It was
shown that both aromatic and aliphatic carboxylic acids could be
coupled with aliphatic and aromatic amines in yields of 78-97%
of the corresponding amides. Compared to the neat reaction, a
higher catalyst loading (100 mg/1 mmol) and longer reaction
times (7-9 hours) had to be employed.
The most recent example of the Fe3+-K-10-montmorillonite
catalyst for direct amidation of carboxylic acids was presented by
the group of Handique.130 It was reported that different aromatic
carboxylic acids (caffeic, ferulic and p-coumaric acid) could be
condensed with diamines and triamines to form polyphenolic
amides in yields of 47-79%, after 4-5 hours of reaction time. A
screening of the catalytic properties of different Mn+montmorillonites came to the same conclusion as earlier reports,
namely that the Fe3+ exchanged clay was the most active species
(Scheme 36).
115
Journal Name, [year], [vol], 00–00 | 21
60
5
65
Scheme 37. Preparation of hydroxyapatite-γ-Fe2O3 supported
sulfonic acid catalyst (Yamini, 2010).
10
70
15
75
20
80
25
85
30
Scheme 36. Direct catalytic condensation of caffeic acid with diand triamines. (Handique, 2011).
35
40
A naturally occurring iron-containing chamosite clay was used
by Arundhathi et al. in the catalytic acetylation of amines with
acetic acid.131 The catalysis was performed with 10 mg clay to 1
mmol amine, and a molar ratio of 1:2 amine:glacial acetic acid at
100 ºC. The reaction times were around 0.5-4 h, giving rise to
yields of <90% of 17 acetamides, where the bulkiest and most
electron-poor substrates were the hardest to react. The authors
noted a tremendous acceleration of the reaction rate when the
reaction was subjected to ultra-sonic irradiation and demonstrated
the recyclability of the clay material.
90
95
100
45
50
The Yamini group reported on a sulfonic acid-functionalized
hydroxyapatite-encapsulated-γ-Fe2O3 nanocatalyst
(Scheme
37).132 The catalyst displayed magnetic properties and could
easily be separated from the reaction mixture by an external
magnet and reused four times with negligible loss in activity.
Excellent activity of the catalyst was reported and the formylation
of 15 different amines was completed within 15-60 min with
yields >90% with a catalyst loading of 0.9 mol% at room
temperature.
105
Elemental zinc was demonstrated to be an active Nformylation catalyst by the group of Jang.134 Various amines were
reacted with formic acid (3 eq) for 0.5-12 h at 70 ºC in the
presence of 10 mol% activated zinc dust (pre-treated with HCl).
Primary and secondary amines, both aromatic and aliphatic, were
successfully transformed into the corresponding formamides in
yields of 71-96%. The catalytic protocol was found to be
selective for N- vs. O-acylation, and neither phenol nor benzyl
alcohol were formylated even after 72 h. The chemoselectivity
was also illustrated by selective formylation of the amino group
of 2-aminoethanol. The N-formylation of α-amino acid esters was
successfully performed without any racemisation of the
stereocenter. A similar protocol has also been reported based on
elemental indium as catalyst for the N-formylation.135
Recently, Xiao et al. found that a hafnium(IV) complex
supported on fluorous silica gel was able to catalyse the Nformylation of amines using aqueous formic acid.136 Hafnium(IV)
chloride was reacted with perfluorooctanesulfonylamide to form
the water-tolerant Lewis acid complex which then was suspended
onto the fluorous silica (Figure 14). Anilines, benzylamine and
butylamine were transformed into the corresponding formamides
in yields of 60-87% with the aid of 1 mol% catalyst and reaction
times between 1-3 h at 70 ºC.
110
Figure 14. Water tolerant Hafnium(IV)-complex suspended on
fluorous silica gel reported by Xiao et al. (2013).
55
115
22 | Journal Name, [year], [vol], 00–00
Kumar et al. reported on an acylation protocol of alcohols and
amines using a zirconium/yttrium-based heterogeneous
catalyst.133 The Lewis acidic material was synthesised from
yttrium nitrate and zirconyl nitrate and the chemical composition
of the solid material was determined to be 82.6 mol% zirconium
and 15.6 mol% yttrium. Aniline and benzylamine were reacted
with acetic acid and converted into the corresponding amides in
93% and 92% yield, respectively. 2-aminoethanol was turned into
the corresponding acetamide in 94% yield with full
chemoselectivity in favour of N-acylation.
Microwave irradiation was used by Talukdar et al. in the
formation of N-methylamides from carboxylic acids and N,N’This journal is © The Royal Society of Chemistry [year]
5
dimethylurea with catalytic amounts of ZrOCl•8H2O.137 Under
solvent free conditions and 10 mol% catalyst, a variety of amides
were formed in 45-98% yield in short reaction times (Scheme
38). The catalyst could be reused up to four times without any
loss of activity, but no other ureas were demonstrated to work as
amine source.
O
O
R
OH
NHMe
MeHN
R
MWI 600W
10
O
15
98% 3 min
HO
H2N
25
75% 8 min
35
R1
N
R2
R1
R2
IL-MCM
ScIL-MCM
n-Butyl
H
18.3
100
n-Pentyl
H
6.6
100
n-Hexyl
H
6.7
100
Cyclohexyl
Me
20.3
97.3
In 2009, a catalytic system utilizing FeCl3 was reported for
amide synthesis. The group of Kantam made use of nanofibers of
polyaniline (PANI) as a support for iron(III) chloride (Figure
15).139
N
H
65% 30 min
85
Scheme 38. Selected methylamides formed by Zr-catalysed
amidation (Talukdar, 2011).
30
80°C, 24 h
80
O
O
Acetic acid (10 eq.)
75
90% 10 min
H
N
R2
Scheme 40. The importance of scandium in the acylation of
aliphatic amines (Coman, 2007).
N
H
50% 15 min
N
H
O
70
O
O
H
N
N
H
55% 10 min
N
H
O
Catalyst
65
N
H
O
20
R1
H
N
Conversion (%)
O
N
H
was performed with aliphatic amines and acetic acid, as ScILMCM proved to be superior over the IL-MCM (Scheme 40).
O
ZrOCl2 8H2O 10 mol%
+
60
Coman et al. combined the features of ionic liquids and Lewis
acids in a heterogeneous catalyst by immobilization onto a
mesoporous MCM-41 support (Scheme 39).138 The material was
used as a catalyst for direct amidation of acetic, propionic and
butyric acid. In their synthesis of the solid support material, ionic
liquids (IL) based on butyl-substituted imidazolium salts were
grafted onto the MCM-41 (IL-MCM), after which a metal-triflate
(scandium triflate or zinc triflate) was anchored onto the material
(ScIL-MCM and ZnIL-MCM).
Figure 15. Iron doped nanofibers of polyaniline (Kantam, 2009).
90
95
The nanofiber material was employed as catalyst with a loading
of 17 mg/mmol substrate in the acetylation of amines using acetic
acid in a 1:26 molar ratio at 100 ºC. A few substrates were
efficiently transformed into the corresponding amides, including
aniline (90%), 4-fluoroaniline (96%) and benzylamine (87%),
whereas other substrates, for instance cyclohexylamine (35 %), 2nitroaniline (36%) and 2-methylaniline (21%) were found to be
less reactive. The catalyst was also suitable for the acetylation of
alcohols and could be recycled up to five times without loss of
activity. No corresponding study of recyclability in the amidation
reaction was however presented.
40
100
45
105
50
Scheme 39. Immobilized ionic liquid for the preparation of
ScIL-MCM and ZnIL-MCM (Coman, 2007).
110
55
In the reaction between aniline and acetic, propionic and butyric
acid, it was found that the support without any Lewis acid (ILMCM) was slightly more active as catalyst and no synergistic
effects were found between the IL and the metal-triflates. The
amidation was performed in a 1:10 ratio of the amine:acid at 80
ºC for 21 h. However, a strong synergistic effect between the
ionic liquid and scandium-triflate could be seen when the reaction
This journal is © The Royal Society of Chemistry [year]
115
5.3 Summary and conclusions on metal catalysis
The literature on homogeneous metal catalysis for direct
amidation of non-activated carboxylic acids is fairly limited, and
it becomes clear that most of the catalytic complexes are based on
early transition metals. Metal catalysis has a large potential in the
direct amidation due to the ease of tuning the metal centre by
addition of ligands, and this area is at present underexplored.
Generally, the metal catalysts that are presented in the literature
require high to fairly high reaction temperatures in order to work,
which can be a drawback for sensitive substrates. The majority of
the catalytic systems are inhibited by coordinating groups in the
substrates. Removal of the formed water is also required in order
to reach high conversions. However more successful than boronbased catalysis, very few methods for the formation of primary
amines with homogeneous metal-catalysis are known. In this
respect, enzyme catalysis is superior despite the limited substrate
scope of biocatalysts.
Journal Name, [year], [vol], 00–00 | 23
5
10
15
The environmental benefits of catalytic direct amidation of
carboxylic acids with amines can further be improved by the use
of heterogeneous catalysts. The increasing number of catalytic
protocols employing heterogeneous metal-containing materials
with good recyclability indicates that this pathway is indeed
viable. However, these protocols are often limited to either Nformylation or N-acetylation with formic or acetic acid,
respectively. There are a few heterogeneous catalysts that have
been reported to have a larger scope. For instance, the sulfated
tungstate catalyst developed by Akamanchi and co-workers and
the nano-sulfated TiO2 catalyst prepared by the group of
Hosseini-Sarvari, have proved to be efficient for both Nformylation as well as for N-acylation of other carboxylic
acids.117,118,123,124 The fields of homogeneous and heterogeneous
metal-based catalysis for direct amidation remain underdeveloped
areas and future improvements is likely to be seen.
6. Miscellaneous catalysts
20
25
30
35
65
70
Figure 16. Condensing agent used in catalytic amounts under
micellar conditions for amide formation of fatty acid sodium salts
with n-butylamine (Kunishima, 2012).
75
Apart from enzymes, boric and boronic acids and metal-based
catalysts, there are a handful of reports which report on direct
amide formation with other types of catalysts.
Shteinberg et al. studied various phosphorous-based catalysts
in the amidation of benzoic acid with aniline.140 Several trivalent
phosphorous compounds and one phosphorous(V) compound
were reported to show a catalytic activity. The reaction required
elevated reaction temperatures in order to work, and was
performed either in refluxing o-xylene (bp 145 ºC) or in decane
(bp 174 ºC). Despite the high reaction temperatures, the uncatalysed thermal reaction was reported to be only 5% and 9%,
respectively. With 2 mol% of the catalyst, the best results were
obtained with PCl3, PBr3, H3PO3 and (EtO)2P(O)H in refluxing
decane with 7 hours of reaction time (Scheme 41). Since not only
phosphorous halides were reported to display a catalytic activity,
it was suggested that a benzoyl halide is not an intermediate in
the reaction mechanism. Rather, the formation of benzanilide was
proposed to take place via a reactive acyl phosphite intermediate.
CO2H
+
40
60
NH2 Catalyst
(2 mol%)
decane
174 °C, 7h
that the reaction could take place in micelles formed by common
surfactants.142 At room temperature using 30 mol% catalyst in a
phosphate buffer (pH 8), the amide of n-butylamine and sodium
octanoate was obtained in 8% yield without a surfactant present.
However, the yield was increased to 50% when sodium 1decanesulfonate (DSA) was used in a concentration of five times
the critical micelle concentration.
80
85
A similar catalyst was studied by Lei et al. for the formylation
of amines with formic acid.143 The catalytic activity of a thiamine
hydrochloride salt (2 mol%) was demonstrated with 18 examples
to obtain the corresponding formamides in 87-96% yield at 80 ºC
(Figure 17). No thermal amidation was observed with aniline,
even at 100 ºC in the absence of the thiamine catalyst. The
reaction was found to be selective for N- versus O-acylation, and
the scope of the acylating agent could be extended to include
acetic, propionic and butyric acid for the acylation of aniline.
However, cinnamic and benzoic acid, as well as amines
containing a carboxylic acid functionality, were not suitable as
substrates for the reaction. The latter was explained to most likely
be due to an intramolecular salt formation, which reduces the
amine nucleophilicity.
90
95
O
N
H
Figure 17. Thiamine catalyst developed by Lei et al. (2010).
100
45
Catalyst:
none
PCl3
PBr3
H3PO3
(EtO)2P(O)H
Product yield:
9%
83%
82%
95%
95%
Scheme 41. Phosphorous-catalysed formation of benzanilide
(Shteinberg, 1992).
50
55
The use of quaternary nitrogen compounds as catalysts in the
amidation reaction was first demonstrated by Kunishima et al.
With 10 mol% of 1,3,5-triazine reagents (Figure 16) in a micellar
phase, fatty acid sodium salts were coupled with n-butylamine in
an aqueous solution.141 In the reaction between the fatty acid and
the catalyst, a marked rate enhancement was observed when the
carbon chain of both substrate and catalyst were long enough to
efficiently form a micellar aggregate. Moreover, it was shown
24 | Journal Name, [year], [vol], 00–00
105
110
115
Brahmachari et al. showed that sodium formate was an
efficient catalyst for the formylation of a range of different
amines under solvent free conditions at room temperature.144 By
employing 20 mol% of sodium formate and a four-fold molar
excess of formic acid, 27 examples of formamides (80-99%
yield) were reported. The sodium formate could be recovered and
reused four times in the formylation of 4-bromoaniline without
any loss of activity. The authors also reported that the reaction
conditions were selective for N-acylation with respect to Oacylation for both aromatic and aliphatic substrates. Majumdar et
al. recently reported that different imidazolium-based protic ionic
liquids were active catalysts for the same transformation.145 The
formylation of several nitrogen- and oxygen-based nucleophiles
was effective with 5 mol% catalyst under solvent-free conditions
at 70 oC. The optimal ratio of formic acid to amine was found to
This journal is © The Royal Society of Chemistry [year]
5
10
15
20
be 1.4:1, and acetic acid could as well be used as acylating agent
under similar conditions. Another method for the N-formylation
of amines was reported by Kim and Jang, employing 5 mol% of
molecular iodine as catalyst.146 High to excellent yields (69-96%)
of the corresponding formamides were obtained from anilines,
and primary and secondary amines using two equivalents of
formic acid. The reaction performed optimally under solvent free
conditions at 70 ºC, and with reaction times of 2-8 hours.
The use of metal-free mesoporous materials as recyclable
catalysts has recently gained some interest. Luque and coworkers found that a sulfonated mesoporous material, derived
from acidic polysaccharides (Starbon®-400-SO3H), was efficient
as amidation catalysts under microwave irradiation.147 A catalyst
loading of 50 mg per 1 mmol amine was used in the acetylation
of amines with acetic acid at a maximum temperature of 130 ºC.
The corresponding acetamides were obtained in 68-99% yields in
short reaction times (<15 minutes). Additionally, six other
carboxylic acids were also employed in the reaction with
benzylamine (Figure 18). The solid catalyst could be recovered
and reused at least three times without any loss of activity
60
mesoporous SBA-15 catalyst and the amorphous K60 silica were
used in a flow reactor, the SBA-15 silica displayed a higher
activity based on weight.
65
70
75
80
25
85
Scheme 42. K60 Silica and SBA-15 catalysis by Comerford et al.
(2009 and 2012).
30
90
35
95
40
Figure 18. Selection of the substrate evaluation in the protocol by
Luque and Clark (2009).
100
45
50
55
A catalytic protocol based on activated amorphous K60 silica
was developed by Comerford et al.148 In refluxing toluene, 12
different amides were synthesized in isolated yields of 20-81%,
using 20 mol% catalyst. Higher yields were often observed with
an increased catalyst loading, and the thermal reaction was
generally low (0-10%). A notable exception was the amidation of
propionic acid with butylamine which gave rise to 89% product
yield after 24 hours without any catalyst present. The system
proved to be tolerant towards water formed in the reaction, and
reactivation of the solid catalyst at 700 ºC made it possible to
recycle the material at least five times without loss of activity.
An improved silica catalyst (SBA-15) with a well-defined
mesoporous structure was shown to be more catalytically active
than the K60 silica.149 Similar yields were obtained with the
SBA-15 catalyst, however a lower catalyst loading (5 mol% vs.
20 mol%) could be utilized (Scheme 42). In addition, when the
This journal is © The Royal Society of Chemistry [year]
105
110
Another mesoporous silica, MCM-41, was shown by Komura
et al. to be an efficient catalyst for the amidation of fatty acids
and long-chain aliphatic amines.150 In the coupling of palmitic
acid and n-hexylamine in refluxing toluene, 20 mol% of the
MCM-41 catalyst furnished the product in 94% yield after 6
hours using a Dean-Stark apparatus. Seventeen additional
examples of amide products were presented with yields of 85 >99% for primary unhindered amines, whereas more sterically
hindered amines (tert-butylamide, N,N-dihexylamine and
cyclohexylamine) gave rise to considerably lower yields with
palmitic acid (0, 3 and 59%, respectively). Filtration and
calcination of the catalyst, allowed for recycling in 3 additional
cycles.
Malakooti et al. published a protocol for the formylation of
amines using 20 mol% of an aminopropylated SBA-15 (APMS)
catalyst under solvent-free conditions.151 A range of aromatic and
aliphatic amines, including diamines, cyclic amines, imidazole,
aminoalcohols and the amino acid isoleucine were converted into
the corresponding amides at 40-70 oC using a 2-10 molar excess
of the amine. Furthermore, full chemoselectivity in favor of Nacylation was reported for substrates containing both hydroxyl
and amine groups. The catalyst could be filtered off and recycled
at least five times without loss of activity in the formylation of
aniline.
115
There are some recent examples in the literature of NJournal Name, [year], [vol], 00–00 | 25
5
10
15
20
formylation of amines catalysed by supported Brønstedt acids.
Bhojegowd et al. reported on the heterogeneous acid Amberlite
IR-120 as a formylation catalyst under microwave irradiation.152
A catalyst loading of 50 mg per 1 mmol substrate was employed
for the formylation of 17 anilines and 2 aliphatic amines with a
three-fold excess of the formic acid. The formamides were
obtained in 90-97% yield after 1-2 minutes when the mixture was
irradiated at 320W with 20 second intervals. Substrates
containing free hydroxyl-groups were reported to display a full
chemoselectivity in favour of N-formylation, and the catalyst
could be recycled at least five times with a difference in yield of
5% between the first and the fifth run. In addition, Ansari et al.
screened the catalytic activity of various acid-functionalized silica
species in the direct N-formylation reaction of amines.153 Among
the screened species (HClO4-SiO2, H2SO4-SiO2, HBF4-SiO2 and
TFA-SiO2), the supported perchloric acid was the most
catalytically active species. The amidation could be performed at
ambient temperature employing 2.5 mol% of HClO4-SiO2 giving
rise to yields in the range of 70-96%. The catalyst could be
filtered off after the reaction and reused three times. However, a
significant drop in product yield was observed in the third cycle.
7. Conclusions/discussion
25
30
Alternatives to the traditional approaches to amide formation,
which employs coupling reagents with low cost- and wasteefficiency, are starting to find their way into the tool-box of the
organic chemist. Although catalysis for direct amidation is still in
its infancy, the emerging methodologies for the transformation
mirror the need for new environmentally conscious chemistry. To
date, the number of published catalytic protocols is still limited.
As can be seen in this review, there are two main types of
catalysts that have been used: enzymes and Lewis acids, where
the latter type can be divided into two sub-groups of boron-based
and metal-based catalysts. In addition, there is a handful of other
catalyst types.
evolution.
60
65
70
75
110
It is likely that catalytic protocols for direct amidation will
have its first and perhaps largest impact on small molecules
containg the amide functionality. However, future extension of
the methods to include the formation of peptides would be highly
valuable. To date, the enzyme-catalysed solid-supported protocol
by Ulijn et al. is the only example of catalytic protocols for the
formation of protected dipeptides.31 In addition, the
stoichiometric boronic acid-mediated protocol by Whiting and
co-workers is suggesting that this catalyst type might be a
promising future alternative.71 An advantage of using a nonbiological catalyst could be the possibility of introducing
unnatural amino acids which a biocatalyst would exclude. A
catalytic protocol combining such a strategy with the kinetic
resolution of a racemic amino acid, could very well serve as a
valuable new route to novel chiral peptides with a well-defined
stereochemistry. There is to date one example of a boronic acidbased chiral catalyst for kinetic resolution of amines, however
resulting in considerably lower ee’s in the amide product
compared to enzyme-mediated protocols.77 No chiral metal-based
catalysts are yet known for this transformation. The strategy of
adding a chiral ligand to a metal center to render an
enantioselective version of a racemic catalytic reaction is
however well-established in the field of metal catalysis, and it is
not unlikely that such a strategy will prove viable in the field of
direct amidation as well. Further development of ligands to Lewis
acid catalysts could also help to solve the problems with
reactivity, which coordinating functional groups in the substrate
or product often give rise to. The possibility of using starting
materials without hydrophobic protecting groups in catalytic
direct amidation would indeed be valuable for future application
in peptide synthesis.
115
Despite the wide range of applications for polyamide
materials, there is only one catalytic example for direct amidation
of a linear polyamide, developed by Yamamoto and co-workers.62
Even though this protocol is the only successful catalytic method
80
85
90
35
40
45
The advantage of Lewis acid-based catalysts over biocatalysts
is generally that the substrate scope is considerably wider, the
reaction times are shorter and the catalysts are usually easier to
access. However, most of these catalysts need elevated reaction
temperatures which limit their applicability, although there are a
few exceptions. In addition, water removal is often needed in
order for the catalysts to work efficiently. Metal-based
homogeneous catalysts are also often sensitive towards
coordinating groups in the substrates, which can lead to inhibition
of the catalytic cycle. To address these problems, the use of
different ligands in order to tune the central atom of the Lewis
acid catalysts is promising. This possibility makes these catalyst
types interesting for future development of selective protocols
functioning under mild conditions.
95
100
105
50
55
The main advantage of enzymatic protocols is that they are
usually milder than Lewis acid-based methods and work at lower
temperatures. As long as the starting materials to the target amide
is compatible with the biocatalyst, enzymatic protocols might
well be the best choice for sensitive substrates to date. The
substrate scope of the biocatalyst, which is often limited, can be
expanded by changing the structure of the enzyme by directed
26 | Journal Name, [year], [vol], 00–00
The field of heterogeneous metal-based catalysis is rapidly
growing, especially in the field of metal nanoparticle catalysts.
Recent improvements in their preparation and characterization
make it possible to modify the size and shape of the nanoparticles
on a molecular level, which has been shown to have a strong
influence of efficiency and selectivity in catalytic reactions.154
However, the protocols using heterogeneous metal-based
catalysts for direct amidation are mainly focused on Nformylation or N-acetylation of amines, with a few exceptions.
Solid-supported boronic acids usually display a wider substrate
scope while offering high stability and efficient recyclability. The
reported protocols for direct amidation with biocatalysis have
most often employed immobilized enzymes as catalyst, due to
their high stability and easy handling, however they also suffer
from a low substrate scope. In general, hetereogeneous catalysed
direct amidation of carboxylic acids remain an underdeveloped
topic. A stable, efficient and selective recyclable catalyst would
be a valuable contribution to green catalysis in this field of
chemistry.
This journal is © The Royal Society of Chemistry [year]
5
10
15
20
for the formation of polyamides via direct amidation, it also
suffers from problems such as a high polydispersity in the
product. In a review from 2011, Bode notes that commercially
produced polyamides usually lack unprotected functionalities and
complex stereochemistry, which could give rise to unique and
powerful properties.9e To incorporate such elements in a
controlled way into the polymers remains a considerable
synthetic challenge. Clever catalysis might very well be the tool
needed in order to enable the formation of new functional
materials with novel properties.
Today, a number of green catalytic protocols for amide bond
formation between carboxylic acids and amines have been
developed. However, there are still several problems that need to
be solved before catalysis can compete with the waste-intensive
but efficient use of coupling reagents. Before catalysis can
become a real alternative for large-scale production of e.g.
pharmaceuticals, peptides and polyamide materials, further
advancements in the field is needed. Below, some of the
remaining challenges for direct amidation catalysts are listed:
-
25
30
-
35
40
High yielding at low temperatures and high
concentrations
High functional group tolerance and large substrate
scope: allowing sterical hindrance and coordinating
groups in the substrates
Mild reaction conditions, allowing for a minimal
epimerization of stereocenters
High chemoselectivity for N-acylation over e.g. O- or
S-acylation
Efficient without removal of the formed water
Detailed mechanistic understanding of known catalytic direct
amidation reactions will likely be important in order to address
these challenges. Catalytic protocols which allow for the efficient
synthesis of oligo- and polypeptides as well as novel polyamide
materials would indeed become very valuable. The generation of
water as the only byproduct makes the amide bond formation an
ideal reaction in the environmentally and financially conscious
future in both academia and industry. The opportunities these
challenges represent should serve as an inspiration for today’s
chemists to develop the chemistry of tomorrow.
3
4
5
6
7
8
9
10
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12
13
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16
17
18
19
20
21
22
23
24
Acknowledgements
45
We are grateful for financial support from the Swedish Research
Council and the K & A Wallenberg foundation.
Notes and references
50
a
Stockholm University, Department of Organic Chemistry, Arrhenius
Laboratory, 106 91, Stockholm, Sweden Fax: +46 8 154908; Email:[email protected] (HA) [email protected] (NS)
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