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TUTORIAL REVIEW
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Metal-catalysed approaches to amide bond formation
C. Liana Allen and Jonathan M. J. Williams*
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Published on 17 March 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00196A
Received 30th November 2010
DOI: 10.1039/c0cs00196a
Amongst the many ways of constructing the amide bond, there has been a growing interest in the
use of metal-catalysed methods for preparing this important functional group. In this tutorial
review, highlights of the recent literature have been presented covering the key areas where metal
catalysts have been used in amide bond formation. Acids and esters have been used in coupling
reactions with amines, but aldehydes and alcohols have also been used in oxidative couplings. The
use of nitriles and oximes as starting materials for amide formation are also emerging areas of
interest. The use of carbon monoxide in the transition metal catalysed coupling of amines has led
to a powerful methodology for amide bond formation and this is complemented by the addition
of an aryl or alkenyl group to an amide typically using palladium or copper catalysts.
1. Introduction
The amide bond is one of the most important functional
groups in contemporary chemistry. It is essential to sustain
life, making up the peptide bonds in proteins such as enzymes.
It is found in numerous natural products and it is also one of
the most prolific moieties in modern pharmaceutical molecules.1
Despite their obvious importance, the majority of amide bond
syntheses involve the use of stoichiometric amounts of
coupling reagents, making them generally expensive and wasteful
procedures.2 This discrepancy has encouraged efforts towards
the identification and development of more atom-efficient,
catalytic methods for amide bond formation, as evidenced
Department of Chemistry, University of Bath, Claverton Down, Bath,
BA2 7AY, UK. E-mail: [email protected];
Fax: +44 (0)1225 386231; Tel: +44 (0)1225 383942
C. Liana Allen
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Liana Allen was born near
Manchester, UK. She received
her Masters in Chemistry
for Drug Discovery at the
University of Bath and is
currently a PhD candidate at
the same university under the
supervision of Prof. Jonathan
Williams. Liana’s current
research
interests
are
developing novel, efficient,
Lewis acid catalysed syntheses
of amide bonds and applying
them to the synthesis of
pharmaceutical molecules.
The Royal Society of Chemistry 2011
by the increasing number of publications in the area in
recent years.
Currently, the most popular industrial methods of amide
synthesis rely on activation of a carboxylic acid (using a
coupling reagent such as a carbodiimide) and subsequent
coupling of the activated species with an amine (Scheme 1).
Although a huge amount of development has been devoted to
fine tuning these coupling reagents for more efficient amide
synthesis, this methodology still suffers from the inherent
drawback of producing a stoichiometric amount of waste
product along with the desired amide.3 With this come the
Scheme 1 Activation of a carboxylic acid.
Jonathan Williams was born
in Stourbridge, England in
1964. He received a BSc from
University of York, a DPhil.
from University of Oxford
(with Prof. S G Davies), and
was then a post-doctoral
fellow at Harvard with Prof.
D. A. Evans (1989–1991). He
was appointed to a Lectureship
in Organic Chemistry at
Loughborough University in
1991, and was then appointed
as a Professor of Organic
Chemistry at the University
Jonathan M. J. Williams
of Bath in 1996, where his
research has mainly involved the use of transition metals for
the catalysis of organic reactions.
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further problems of increased costs and significant waste
by-products which need to be removed from the reaction
mixture and cannot be recycled. Enzymatic methods are also
available, although high isolation costs and somewhat limited
substrate ranges can be problematic.4
In the search for an alternative to coupling reagents and
enzymes in amide bond synthesis, non-metal catalysts such as
organocatalysts and boron reagents5 have been reported,
although these still often suffer from low atom efficiency and
difficult isolations. A possible solution to these drawbacks lies
with metal catalysis. Increasing attention is now being devoted
to developing such amide bond syntheses which are not only
atom-economical but also low cost and more environmentally
friendly. Employing metal catalysis in amide syntheses also
creates the possibility to start from substrates other than
carboxylic acids, opening up previously unavailable synthetic
routes to target molecules.
2. Amides from carboxylic acids
With the abundance of coupling reagents available for the
formation of amide bonds from carboxylic acids and amines,
there has been little development in the area of metal catalysts
for this reaction. The natural equilibrium of a carboxylic acid
and an amine is heavily towards the salt formation (except at
high temperatures), making a catalytic reaction between them
challenging.
However, the N-formylation of amines using formic acid as
the formylating agent has recently been reported to proceed
under catalytic conditions. Hosseini-Sarvari and Sharghi
published the first example of this in their highly efficient
reaction using ZnO as a catalyst under solvent-free conditions
at 70 1C, achieving some excellent yields in short reaction
times (Scheme 2).6 They also demonstrated the reusability of
the ZnO catalyst, incurring only a small decrease in yield of
amide after the third use.
Rao and co-workers later published their investigation into
a range of Lewis acid catalysts for the same reaction, reporting
dichloride complexes of zinc, tin, lanthanum, iron, aluminium
and nickel to give yields in the range of 80–100%.7 They found
the best results were obtained when using ZnCl2 as a catalyst
under the same solvent-free, 70 1C conditions that HosseiniSarvari and Sharghi had used. Although the catalyst loading
could now be reduced from 50 mol% (ZnO) to just 10 mol%
(ZnCl2), there was no report of possible recovery and reuse of
Rao’s catalyst.
Kim and Jang have reported the use of indium metal as a
catalyst for the N-formylation of amines with formic acid,
again under solvent-free conditions at 70 1C.8 They found the
reaction to be efficiently catalysed by 10 mol% of the indium
metal, which they presume reacts with the formic acid to form
In(O2CH)3 and acts as a Lewis acid in the reaction.
Scheme 2 N-Formylation of an amine with formic acid.
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3. Amides from esters
As the preparation of amides from carboxylic acids is difficult
to achieve in a catalytic manner, their derivatives, particularly
esters, have been explored as an alternative in catalytic amide
forming reactions.
In 2003, a simple procedure was published by Ranu and
Dutta, using a catalytic amount of indium triiodide and an
excess of the amine.9 The elimination of toxic reagents and
operational simplicity made this reaction a good alternative to
the methods known at that time. Several excellent yields were
reported for a range of amides containing functional groups
using their conditions, but the reaction was not successful with
secondary amines, making it unsuitable for the synthesis of
tertiary amides.
The same transformation was reported in 2005 by Gupta
et al., using zinc dust as a reusable catalyst under either
microwave or conventional heating.10 A modest range of
amides was synthesised, using only aromatic esters and amines
and again no demonstration of a tertiary amide synthesis.
Despite the reported substrate range being limited, their
procedure had the advantages of the zinc dust being able to
be reused up to six times (after washing with dilute HCl) with
only slight decreases in yield and a very short reaction time
(2–8 minutes) when microwave heating was used.
The same year, Porco and co-workers reported their
findings of group (IV) metal alkoxide complexes which, in
conjunction with an activator, could be used for the formation
of amides from esters and amines (Scheme 3).11 They demonstrated an impressively varied substrate range, including
the formation of amides 1–3 along with an intramolecular
example giving 4.
The wide range of structurally diverse amines and esters
successfully coupled and the excellent yields attained under
their reaction conditions make this a valuable methodology.
A detailed mechanistic study was also carried out by the
group. Using X-ray crystallography and NMR studies, they
were able to determine the structures of key intermediates
Scheme 3 Zirconium catalysed coupling of esters and amines with
selected examples (HOAt = 1-hydroxy-7-azabenzotriazole, HOBt =
1-hydroxy-1H-benzotriazole, HYP = L-hydroxyproline).
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Scheme 6
Scheme 4 Formation of key intermediate dimeric zirconium
complexes.
along the reaction pathway and deduce the active catalyst to
be a dimeric zirconium complex (Scheme 4).
Dimeric species 5 in which both zirconium centres are
hexacoordinate is formed in the presence of amines. Coordination of an ester to one of the zirconium centres results in
formation of either 6 or 7 by breaking of one bridging Zr–O
bonds. Nucleophilic attack of the amine onto the ester then
proceeds via a six-membered (path A) or four-membered (path B)
transition state.
4. Amides from aldehydes or alcohols
Aldehydes and alcohols are desirable starting materials in
amide synthesis due to their ready availability and non-toxic
nature. In the last ten years, catalytic systems to effect this
transformation have been substantially developed into useful
organic reactions.
4.1
Amides from aldehydes [not via an oxime]
Oxidative amidation of aldehydes into amides has been known
since the early 1980s. The general mechanism of this process is
based on the reaction of an aldehyde with an amine to form a
hemiaminal intermediate and subsequent oxidation to the
amide product (Scheme 5). Loss of water from the hemiaminal
to form the imine, then hydrogenation of the imine to form an
amine is a potential side reaction in this process, one which has
been exploited in the ‘borrowing hydrogen’ reaction where
alcohols are used as alkylating agents for amines.12
The first catalyst system to be used for this transformation
was Pd(OAc)2 (5 mol%), triphenylphosphine (15 mol%),
potassium carbonate and an aryl bromide as the oxidant.13
Several aldehydes were successfully coupled with morpholine
to form the corresponding amides under these conditions.
Scheme 5 General mechanism of amide formation from aldehydes
and amines.
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Copper catalysed oxidative amidation.
Improved reaction conditions using another palladium catalyst
were reported by Torisawa and co-workers in 2008.14 Their
use of H2O2 in urea as the oxidant combined with PdCl2
(2.5 mol%) and xantphos (2.5 mol%) allowed the reaction
temperature and required time to be reduced, as well as greatly
expanding the range of amides that could be synthesised in this
reaction.
A copper catalysed oxidative amidation has been reported
(Scheme 6).13 tert-Butyl hydroperoxide solution in water
serves as the oxidising agent and the use of amine hydrochloride salts minimises the competing reaction, oxidation of
the amine. Their yields decreased when an aliphatic or
electron-poor arylaldehyde was used, but when the reaction
was applied to an enantiomerically pure amine, no racemisation
occurred.
Recently, several lanthanide catalysts have been reported to
catalyse the oxidative coupling of aldehydes and amines. These
catalysts are generally capable of facilitating the reaction at
room temperature, which is a useful advantage. Additionally,
no external oxidant is required, as the aldehyde is presumed to
act as a hydrogen acceptor in the proposed catalytic cycle.
Marks and Seos’ lanthanide-amido complex La[N(TMS)2]3
achieved varied yields of amides at room temperature in
deuterated benzene.13 Due to the aldehyde substrate also
acting as a hydrogen acceptor, a threefold excess was required.
Shen and co-workers have reported several bimetallic lanthanide
complexes used to catalyse this reaction. Their 2010 paper15
details the first structurally characterised complex of lanthanide
and lithium metals with dianionic guanidinate ligands,
with the Nd demonstrating its effectiveness for amidation of
aldehydes with amines at just 1 mol% catalyst loading at room
temperature.
4.2 Amides from alcohols [via an aldehyde]
The direct catalytic conversion of alcohols and amines into
amides and dihydrogen is a particularly desirable reaction due
to its high atom efficiency and widely available starting
materials. Murahasi and Naota reported the synthesis of
lactams from an intramolecular reaction of amino alcohols
in 1991,16 but the intermolecular reaction was realised by
Milstein and co-workers in their breakthrough report from
2007.17 Catalysed by a ruthenium pincer complex with molecular
hydrogen being the only by-product, this exceptionally clean
and simple reaction has been emulated by several other groups
since Milstein’s original publication (Scheme 8).
The general mechanism of this reaction is the same as that
of oxidative amidation involving aldehydes and amine, but
with an additional oxidation step at the start to convert the
alcohol into the aldehyde (Scheme 7).
Milstein’s PNN pincer complex 8 undergoes an aromatisation/
dearomatisation catalytic cycle, where initial addition of the
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Scheme 7 General mechanism of amide formation from alcohols and
amines.
An example of primary amide formation in this reaction was
demonstrated by the group of Grützmacher.21 Using a
rhodium catalyst and ammonia as the nitrogen source,
primary amides were obtained in excellent yields in just four
hours and at a temperature of 30 1C to 25 1C.
These catalysts, though efficient and highly chemoselective
in favour of amide formation, can be expensive, difficult to
handle and do not tolerate secondary amines well. Some of
these issues were addressed by Satsuma and co-workers in
their reported g-alumina supported silver cluster.22 This
re-usable, heterogeneous, easily prepared catalyst is a more
economic alternative to the homogenous ruthenium and
rhodium catalysts reported. In addition to this, secondary
amines could be used in the reaction, giving tertiary amides
in very good yields.
5. Amides from nitriles
Scheme 8 Milstein’s catalyst for conversion of alcohols into amides.
alcohol leads to aromatisation giving the pyridine complex 9.
Subsequent loss of an aldehyde generates the known trans
ruthenium dihydride complex 10. Elimination of dihydrogen
regenerates the catalyst 8 and enables the catalytic cycle to
continue (Scheme 9). The aldehyde forms an aminol by
reaction with the amine and a similar cycle oxidises this to
the amide product.
Alternative ruthenium catalyst systems employing ruthenium
precursors in combination with N-heterocyclic carbenes have
been found to give exclusively the amide product (as opposed
to the amine) as have been reported by the groups of Madsen18
and Hong.19 Although this was the first step towards the use of
a simple, commercially available catalyst in this reaction, there
was no real improvement in terms of yields or scope of
reagents on those reported by Milstein. The first commercially
available catalyst system for formation of amides from alcohols
and amines was reported by our own group (although
Milstein’s catalyst is now commercially available).20 The use
of [Ru(p-cymene)Cl2]2 in combination with dppb, a base and a
hydrogen acceptor produced the amide products in reasonable
to good yields, however required increased reaction times
compared with alternative catalysts.
Scheme 9 Catalytic cycle for Milstein’s catalyst.
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Nitriles are well recognised as important substrates in organic
chemistry due to their chemical versatility, allowing addition
to the CRN triple bond by nucleophiles or electrophiles to
lead to new C–N, C–C and C–O bonds. Their use in the
synthesis of amides has, however, been somewhat limited to
the three reactions discussed below.
5.1 Hydration of nitriles into primary amides
A simple and efficient method of synthesising primary amides
is the hydration of nitriles. Many metal catalysts have
been reported to facilitate this transformation efficiently, an
excellent and in depth review of which was pub lished by
Kukushkin and Pombeiro in 2005.23 More recently, catalysts
which allow the hydration of organonitriles under ambient
conditions24 or in reaction times as short as 2 hours using
microwave radiation25 have been published (Scheme 10).
5.2 Coupling of nitriles with amines
A little known reaction which yields amides is the hydrolytic
amidation of nitriles with amines. This was first published in
1986 by Murahashi and co-workers using the ruthenium
catalyst RuH2(PPh3)4 (Scheme 11).26 They demonstrated the
wide scope of this reaction with the efficient synthesis of
several drug precursors (including 11) as well as lactams from
the intramolecular reaction and diamide 12 from cinnamonitrile
and a triamine.
Development of this reaction has been sporadic; in 2000 a
platinum catalyst was found by de Vries and co-workers to
Scheme 10 Rhodium and gold catalysed nitrile hydration.
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Scheme 13 Iron-catalysed Ritter reaction.
previously reported, but the reaction conditions are less
desirable (Scheme 13).30
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6. Amides from oximes
Scheme 11 Murahashi’s ruthenium-catalysed hydrolytic coupling of
nitriles with amines.
perform the coupling,27 then in 2009 an iron catalysed version
was published by our group.28 The former decreased the
catalyst loading from 3 mol% with the ruthenium catalyst to
levels as low as 0.1 mol% with the platinum(II) complex, but
the reaction temperature remained high at 160 1C and the
yields were moderate. Our own iron catalysed reaction allowed
the reaction to be performed at 125 1C under solvent-free
conditions, but a higher catalyst loading (10 mol%) was
required as well as an excess of one of the reagents.
Brief mechanistic investigations suggest that the involvement
of an amidine intermediate formed from nucleophilic attack of
the amine on the nitrile seems likely, as opposed to initial
hydration of the nitrile to the primary amide then N-alkylation
(Scheme 12).
De Vries and co-workers found that when the reaction is
run in the absence of water, the major product isolated is the
amidine. The possibility of the reaction proceeding through
initial hydration of the nitrile to the primary amide then
subsequent N-acylation of the amine was ruled out after we
found only a 21% conversion into secondary amide in the
reaction between butyramide and benzylamine.
5.3
Coupling of nitriles with alcohols
Nitriles can also be coupled with alcohols to form amides in
the Ritter reaction. As an alternative to sulfuric acid, the
Ritter reaction can be catalysed by metal complexes. One of
the first examples of this was the use of bismuth triflate by
Barrett and co-workers who published a wide range of amides
synthesised from coupling various nitriles and tertiary alcohols.29
A later example by Cossy’s group described an iron-catalysed
Ritter reaction with a wider substrate range than those
Scheme 12 Proposed mechanism pathways for the addition of amines
to nitriles.
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Oximes have been used in organic synthesis since the 19th
century in a diverse range of reactions. Their applications
in metal catalysed amide bond synthesis have been well
documented in the areas of aldoxime rearrangement into a
primary amide and the Beckmann rearrangement of ketoximes.
Recently, aldoximes have also been shown to react with
amines to form secondary and tertiary amides.
6.1 Rearrangement of aldoximes into primary amides
The rearrangement of aldoximes into primary amides has been
shown to be catalysed by several metal complexes. This highly
atom-efficient reaction also offers the option to start from an
aldehyde and hydroxylamine (which forms the aldoxime
in situ) (Scheme 14), or even the alcohol oxidation state.
The examples of catalysts suitable for this rearrangement
are largely based on precious metals. Chang31 and Mizuno32
have independently published reports of rhodium complexes,
the latter being an example of a supported, reusable catalyst.
Ruthenium catalysts have also been reported by both
Crabtree33 and our group to perform this rearrangement.34
Another report by our group demonstrates the potential to
start from the alcohol with the first step of the mechanism then
being oxidation of the alcohol to the aldehyde, then condensation
with hydroxylamine and subsequent rearrangement to the
primary amide (Scheme 15).35 The oxidation step was
conveniently catalysed by the same iridium catalyst used for
the rearrangement and use of styrene as a sacrificial hydrogen
acceptor. These current conditions are not particularly desirable,
Scheme 14 Rearrangement of aldoximes into primary amides starting
from an aldehyde.
Scheme 15 Formation of primary amides from alcohols via
aldoximes.
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but the novel concept of transformation of an alcohol into a
primary amide via an oxime is clearly demonstrated.
The most recent advances on this reaction have introduced
more catalysts; a gold/silver co-catalysed system (Nolan et al.),36
a palladium acetate complex (Ali and Punniyamurthy)37 and
most recently the use of simple metal salts InCl3 or Zn(NO3)2
at low catalyst loadings (0.1 mol% and 10 mol% respectively)
have been published by our own group, representing the most
cost-efficient catalysts reported so far.38
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6.2 Beckmann rearrangement of ketoximes into secondary
amides
The Beckmann rearrangement of ketoximes into amides is a
powerful methodology in organic synthesis. Traditionally this
reaction requires harsh conditions such as high temperatures
and strong acids, although recently, metal catalysed Beckmann
rearrangements have been published, including conditions
such as using an ionic liquid medium, or performing the
reaction in the vapour phase. A notable metal catalysed
varient has been reported by Ramalingan and Park and details
a mercury(II) chloride catalysed reaction, run in acetonitrile at
80 1C (Scheme 16).39 A wide range of ketoximes was transformed
into the corresponding secondary amides under their conditions,
including several halogen substituted amides including 13 and a
cyclic ketoxime yielding caprolactam 14 as the product.
A further example of a metal catalysed Beckmann
rearrangement uses a novel heterobimetallic catalyst with a
cobalt centre and Lewis acidic zinc site on the periphery.40
Reasonable yields were achieved in a reaction time of 2 hours
at 5 mol% catalyst loading.
6.3
Scheme 17 Nickel-catalysed formation of amides from aldehydes via
aldoximes.
Coupling of aldoximes and amines
Our own recent paper on amide bond syntheses from aldoximes
and amines describes the novel synthesis of amides from the
coupling of aldoximes and amines.41 This reaction can also be
run with the aldehyde and hydroxylamine forming the oxime
in situ, catalysed by the simple metal salt NiCl2, present
at 5 mol% in the reaction mixture (Scheme 17). As an additional
oxidising agent is not required, this method of coupling
aldehydes and amines is a more atom-efficient method
compared with other conditions reported for this coupling.
Based on the knowledge that a nitrile is an intermediate in
the rearrangement of aldoximes into primary amides and
amines and nitriles can couple to form secondary and tertiary
amides, we proposed a reaction mechanism whereby the nitrile
intermediate was intercepted by an amine.
Scheme 18 Proposed mechanism of aldoxime rearrangement into
primary amide.
Further mechanistic investigations using 18O labelled
oximes suggested that a bimolecular mechanism was operating
(Scheme 18). A nickel metallocycle has been suggested to be a
key intermediate in the mechanism, susceptible to nucleophilic
attack in the presence of an amine.
7. Aminocarbonylation
Scheme 16 Mercury
ketoximes.
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Beckmann
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rearrangement
of
The combination of amines with carbon monoxide has been
used in the catalytic aminocarbonylation of a variety of
substrates to give amide products.42 Schoenberg and Heck
published the first examples of the palladium-catalysed
aminocarbonylation of aryl halides and vinyl halides over
35 years ago.43 Murahashi and co-workers later reported a
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palladium catalysed carbonylation of allylamines to give
b,g-unsaturated amides, avoiding the use of a halide species
in the reaction. They proposed a p-allylpalladium complex,
formed from oxidative addition of allylamines to a coordinatively unsaturated palladium–phosphine species, as a
key intermediate in the mechanism of their reaction.44
More recent reports include the use of a Pd(OAc)2/xantphos
catalyst developed by Buchwald and co-workers.45 For
example, aryl bromides such as 1-bromonaphthalene 15 and
3-bromothiophene 16 were converted into the corresponding
amide 17 or Weinreb amide 18 using the Pd(OAc)2/xantphos
catalyst (Scheme 19). These coupling reactions involve the
oxidative addition of the active Pd(0) catalyst into the aryl
halide, ligand combination with CO to give an acylated
palladium species which is then converted into amide by the
addition of amine either directly or by prior co-ordination to
the metal.
Amongst the many other reports of aminocarbonylation of
aryl halides, Beller and co-workers have prepared CNS active
amphetamine derivatives 19 by the three component coupling
of unprotected 5-bromoindole, carbon monoxide and a
piperazine (Scheme 20).46 Aminocarbonylation reactions
have also been performed in water using Pd(OAc)2 under
ligand-free conditions.47
The direct synthesis of primary amides by aminocarbonylation
can be problematic due to the handling difficulties of ammonia,
its low nucleophilicity and ability to complex strongly with
palladium. Several indirect approaches for the formation of
primary amides have been developed, including the use of
tert-butylamine as an ammonia equivalent followed by
deprotection.48 Using this procedure, iodobenzene was
converted into benzamide after removal of the t-Bu group
with TBDMSOTf (tert-butyldimethylsilyl triflate) as shown in
Scheme 21. Formamide has also been used as an ammonia
equivalent for the formation of primary aromatic amides
from aryl halides.49 However, Beller and co-workers have
demonstrated that careful selection of a phosphine ligand does
provide a catalytic system capable of converting aryl bromides
with ammonia and CO directly into the corresponding
primary amides.50 The use of Pd(OAc)2 in combination with
dppf was effective for a range of aryl bromides and, under
more forcing conditions, aryl chlorides. For example,
4-bromotoluene was converted into toluamide in good yield
(Scheme 21).
Aryl chlorides are usually cheaper alternatives to other aryl
halides although they require more forcing conditions to
undergo aminocarbonylation. Milstein and co-workers
reported the first examples of the use of aryl chlorides in
aminocarbonylation reactions where electron-rich bidentate
phosphines were found to improve the reactivity of the
palladium catalyst.51 Buchwald and co-workers have
developed an interesting and practical approach to the aminocarbonylation of aryl chlorides which proceeds via an intermediate phenyl ester.52 The intermediate palladium acyl
complex 20 reacts with sodium phenoxide which is a better
nucleophile than the amine. The so-formed phenyl ester 21
then reacts with the amine in a subsequent step which does not
involve the palladium catalyst. This approach was used for the
conversion of a range of aryl chlorides into secondary and
tertiary amines. In one example, the reaction of aryl chloride
22 with morpholine gave the tertiary amide 23 (Scheme 22).
Mo(CO)6 has been used as a solid source of CO for the
aminocarbonylation reactions of aryl triflates using a palladium catalyst, with DMAP (N,N-dimethylaminopyridine) as a
co-catalyst which is believed to catalyse acyl transfer from the
intermediate acylpalladium species.53 N,N-Dimethylformamide
has also been used as a substrate to allow aminoformylation
reactions to take place without the need for CO.54 The
N,N-dimethylformamide is activated by the addition of POCl3
and then used to convert aryl iodides into the N,N-dimethylamide products (Scheme 23).
Scheme 19 Pd-catalysed aminocarbonylation of aryl bromides.
Scheme 20 Aminocarbonylation of an unprotected indole.
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Scheme 21 Synthesis of primary amides.
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Scheme 26 Cobalt and rhodium catalysed aminocarbonylation.
Scheme 22 Aminocarbonylation of aryl chlorides.
Scheme 27 Aminocarbonylation using an isocyanate, IPr = 1,3bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Scheme 23 Use of DMF in aminocarbonylation.
Aryl substrates which do not contain a halide or other
suitable leaving group are able to undergo palladiumcatalysed coupling reactions by C–H insertion, but usually
require the presence of an oxidant in order to allow for
catalyst recycling. Orito and co-workers have demonstrated
that substrates such as the amine-containing arene 24 can
undergo direct aromatic carbonylation to give the benzolactam
product 25.55 The reaction is catalysed by Pd(OAc)2 in the
presence of Cu(OAc)2 and air which re-oxidises the catalyst
(Scheme 24).
Alkynes can also undergo aminocarbonylation reactions
and this methodology is completely atom-efficient. In one
example, Matteoli and co-workers have coupled phenylacetylene
with aniline and CO to give the acrylamide product 26 with
almost complete regioselectivity for the branched product
(Scheme 25).56 Lu and Alper have reported a related example
using a supported palladium catalyst to cyclise an aniline onto
a pendant alkyne.57
The aminocarbonylation of alkenes has been less widely
explored, although the three component coupling of an alkene,
an amine and CO has considerable potential as an atom
efficient synthesis of saturated amides. Chung and co-workers
have used a heterogeneous cobalt catalyst for the aminocarbonylation of 1-pentene with aniline to give the amide 27
(Scheme 26).58 However, high temperatures and long
reaction times were required and some alkenes led to lower
conversions. An interesting double aminocarbonylation of
alkynes using a rhodium catalyst has been reported by Huang
and Hua.59 Using phenylacetylene as the substrate, the
reaction was believed to occur by initial aminocarbonylation
of the alkyne with pyrrolidine to give a branched acrylamide
followed by a second aminocarbonylation leading to the
1,4-diamide 28 shown in Scheme 26. The reaction was also
successful for aliphatic alkynes.
Using isocyanates in place of the amine and CO, Schleicher
and Jamison used a nickel catalyst complexed to the
N-heterocyclic carbene ligand IPr to convert simple alkenes
into the corresponding acrylamides.60 Although some alkene/
isocyanate combinations led to mixtures of branched and
unbranched products, the use of vinylcyclohexane with
tert-butylisocyanate gave the branched acrylamide 29 with
complete selectivity and good isolated yield (Scheme 27).
8. N-Arylation and N-alkenylation of amides
Scheme 24 Direct aromatic carbonylation.
The cross coupling of amides with aryl and alkenyl halides is
an important process that has been widely used for the
preparation of amides of pharmaceutical interest.61 These
reactions have mainly been achieved using palladium or
copper catalysts, although other metals have been shown to
be effective, including simple iron salts.62
8.1 Palladium-catalysed reactions
Scheme 25 Aminocarbonylation of an alkyne.
3412
Chem. Soc. Rev., 2011, 40, 3405–3415
Buchwald and co-workers have developed a palladium
catalyst that has shown broad scope for the N-arylation of
amides wth aryl chlorides, aryl tosylates and aryl nonaflates
(ArONf = ArOSO2CF2CF2CF2CF3).63 Typical examples
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Scheme 30 Synthesis of potential anti-bacterial agents.
Scheme 31 Amide formation by amination/hydrolysis.
Scheme 28 Palladium-catalysed N-arylation reactions.
include the use of [Pd(allyl)Cl]2 with JackiePhos for the
coupling of aryl nonaflate 30 with amide 31 and the aryl
chloride 33 with amide 34 (Scheme 28). The electron-withdrawing nature of the trifluoromethyl groups in JackiePhos
was important for achieving full conversion under the reaction
conditions.
The more readily available ligand, xantphos (see
Scheme 19), has also been shown to be useful for other
palladium-catalysed cross coupling reactions of amides.
Wallace and co-workers have used the Pd(0)/xantphos
combination for the coupling of vinyl triflates with amides.64
Vinyl triflate 36 was coupled with acetamide to give the
product 37 with good isolated yield (Scheme 29). An interesting
tandem process involving N-alkenylation and N-arylation was
designed by Willis and co-workers for the synthesis of
indoles.65 When substrate 38 was reacted with benzamide, a
double cross coupling led to the formation of the N-benzoylindole 39 (Scheme 29).
The functional group tolerance of the palladium-catalysed
arylation of amides is apparent from the work of a team of
chemists from GlaxoSmithKline who reported the coupling of
Scheme 29 Use of palladium/xantphos for N-arylation.
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amide 40 with a range of heterocyclic triflates and bromides
including triflate 41 to give the arylated product 42
(Scheme 30).66
An alternative approach to the formation of amides by
palladium-catalysed cross coupling involving the use of
anilines was developed by Xu and co-workers.67 The gemdibromoalkene 43 underwent palladium-catalysed amination
where the initially-formed bromoenamine is readily hydrolysed
to liberate the amide 44 which was isolated in good yield
(Scheme 31).
8.2 Copper-catalysed reactions
The copper-catalysed arylation of amides offers a cheaper
alternative to the palladium-catalysed reactions. Typically, a
copper(I) salt is used in combination with a diamine, such as 45
or 46, or a related ligand.68 Buchwald and co-workers have
reported several related CuI/diamine catalysts which are effective
for the N-arylation of amides with aryl halides. Representative
examples for the formation of amides 47 and 48 are given in
Scheme 32 Copper-catalysed N-arylation of aryl halides.
Chem. Soc. Rev., 2011, 40, 3405–3415
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Scheme 33 Copper-catalysed N-arylation of aryl halides.
Scheme 36 Oxidative coupling of an amide and alkene.
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52. The selective formation of the (Z)-enamide was attributed
to hydrogen bonding between the ester carbonyl oxygen and
the amide NH in the intermediate (Scheme 36).
10.
Scheme 34 Copper-catalysed N-arylation of aryl halides.
Scheme 32. The N-arylation of amides could also be achieved
using aryl chlorides, although a four-fold excess of the chloride
was required under solvent-free conditions.
The copper-catalysed coupling of vinyl halides with amides
is also known,69,70 which has been exploited in an interesting
example reported by the group of Li.71 N-Arylpyrroles were
formed by the tandem coupling of an amide with dienyldiiodide 49. Using pentanamide, the acylpyrrole 50 was
isolated in 95% yield (Scheme 33), although yields were lower
in other reported examples.
Potassium alkenyltrifluoroborate salts have also been used
for the N-alkenylation of amides, as reported by Bolshan and
Batey.72 These reactions occur under oxidative conditions with
lower temperatures than those needed by vinyl halides. For
example, various amides undergo copper-catalysed coupling
with potassium hexenyltrifluoroborate at 40 1C (Scheme 34).
9. Enamide formation by addition reactions
The transition metal catalysed addition of amides to alkynes
provides a useful approach to the preparation of enamides.
Gooßen and co-workers identified Ru(methallyl)(cod) with
n-Bu3P and DMAP as an efficient catalyst for the selective
formation of the (E)-enamide 51 from the coupling partners
1-hexyne and N-methylformamide.73 None of the branched
product arising from Markovnikov addition to the alkyne was
observed. The reaction was mainly used for the addition of
lactams to alkynes. RuCl3 could be used as an alternative
ruthenium source under otherwise similar reaction conditions,74
while the use of the rhenium catalyst Re2(CO)10 was also
found to be highly regio- and stereoselective (Scheme 35).75
The oxidative coupling of amides with conjugated alkenes
under Wacker-type conditions has been found to lead to the
selective formation of (Z)-enamides.76 Using a palladium
catalyst which required a copper co-catalyst for re-oxidation,
benzamide reacted with ethyl acrylate to give the (Z)-enamide
Scheme 35 Ru-catalysed addition of an amide to an alkyne.
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Conclusions
In conclusion, there has been impressive progress in the use of
metal catalysts for the formation of amides. The range of
available methods allows the synthetic chemist to choose from
a variety of starting materials for the construction of the
amide bond.
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council for financial support (for C. L. A.) through the
Doctoral Training Account.
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