A simple and greener approach for the amide bond formation employing FeCl3 as a catalyst

Article abstract of DOI:10.1039/c5nj01047k

Catalytic use of FeCl₃ in the presence of glacial AcOH for the direct amidation of acid with amine in toluene has been described in this paper. The protocol worked well for the less nucleophilic aniline and its variants which gave the best results under the present reaction conditions. Amidation of bromoacetic acid and sterically hindered amino acid also proceed effectively to yield the corresponding amides. The protocol is catalytic and circumvents the use of stoichiometric amounts of reagents. The reaction led to water soluble by-products and thus makes the product isolation easier.

Full text of DOI:10.1039/c5nj01047k

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A simple and greener approach for the amide bond formation
employing FeCl3 as a catalyst
Received 00th June 2015,
Accepted 00th June 2015
Basavaprabhu, Muniyappa Krishnamurthy, Nageswara Rao Panguluri, Veladi Panduranga and
Vommina V. Sureshbabu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
of wasteful by-products that complicate the isolation of the
desired amide product.
Catalytic use of FeCl3 in presence of glacial AcOH for the direct
amidation of acid with amine in toluene has been described in this
paper. The protocol worked well for the less nucleophilic aniline
and its variants which gave best results under present reaction
conditions. Amidation of bromoacetic acid and sterically hindered
amino acid also proceed effectively to yield corresponding amides.
The protocol is catalytic and circumvents the use of stoichiometric
amount of reagent. The reaction led to water soluble by-products
and thus makes the product isolation easier.
A general strategy for amide bond formation is the activation
of carboxylic acid as acyl halide, acylimidazole, acyl azide,
anhydride or active ester followed by aminolysis.6 Although,
these methods have been developed to facilitate amide
formation, they all have inherent advantages as well as
limitations due to the structural diversity of substrates
participating in amide formation. The direct amidation of
carboxylic acid is highly attractive for industrial perspective as
it would lead to be cost-effective and atom economy
processes.
The amide bond is ubiquitous in nature. It constitutes the
backbone of biologically significant peptides as well as in
proteins.1 It is present in many natural products and
pharmaceutically interesting compounds.2 Consequently,
development of an efficient amidation method continues to be
an important scientific pursuit. Despite the favourable
thermodynamic stability of the resulting amide bond, the
simple thermal dehydration reaction between a carboxylic acid
and an amine is plagued by a large activation energy.3 The
initial formation of a stable ammonium carboxylate salt deters
the dehydration step, and the intermediate salt collapses to
provide the amide product only at very high temperatures (>
200 oC)4 that are not compatible with most functionalized
molecules. Consequently, there are still no general methods to
access amides directly from free carboxylic acids and amines in
a simple, green, and atom-economical fashion at ambient
temperature. Common protocols for forming amide bonds
involve the use of stoichiometric amount of expensive
coupling reagents such as carbodiimides or phosphonium or
uronium salts to activate and condense the carboxylic acid
with amine.5 These reagents and their associated co-reagents,
including bases, and other additives, generate large amounts
To overcome some of these problems associated with the
above said approaches, different catalytic methods have also
been designed. Amide bond formation using starting materials
such as nitriles, isonitriles, oximes, aldehydes and alcohols,
esters7 as well as aminocarbonylation8 methods employing
metal catalysts are also well documented in the literature.
However, ideal situation is the direct coupling of carboxylic
acids with amines producing water as the only by-product. Up
to now, only a few catalytic systems for the direct amide
coupling of carboxylic acids and amines have been developed.9
Organocatalytic methods employing enzymes have been used
to some extent,10 albeit with a limited substrate scope. Due to
the significance of the amide bond in a vast array of
applications, we were intrigued by the challenge and started to
investigate the possibility of generating a direct catalytic
amidation method starting from carboxylic acid.
Catalysis is a key technology, since approximately 80% of all
chemical and pharmaceutical products on an industrial scale
are made in presence of catalysts. During the last decades,
manifold transition-metal catalysts especially based on
precious metals such as palladium, rhodium, iridium, and
ruthenium have been proven to be efficient for a large number
of applications in organic synthesis. However, their high price
as well as toxicity makes it desirable to search for more
economical and environmentally benign protocol. A possible
solution of this problem could be the increased use of catalysts
a.# 109, Peptide Research Laboratory, Department of Studies in Chemistry, Central
College Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore-560
001, India Email: hariccb@hotmail.com; hariccb@gmail.com;
sureshbabuvommina@rediffmail.com
† Electronic Supporting Information (ESI) available: [1H NMR, 13C NMR and HRMS
spectra of all the compounds are available in the supporting information]. See
DOI: 10.1039/x0xx00000x
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based on first row transition metals, such as iron, copper, zinc,
and manganese. Especially iron offers significant advantages
compared with precious metals, since it is the second most
abundant metal in the earth crust. The facile change of
oxidation state and the distinct Lewis acid character, iron
Fig. 1 Possible mechanism of amide bond formation.
catalysts allow in principle
a broad range of synthetic
proceeds via FeCl3 catalysed activation of the carbonyl group
of the acid. Therefore, iron-coordinated carbonyl increases its
electrophilicity to trigger the nucleophilic attack by an amine
component and AcOH serve as source of H+ ions (Fig. 1). In
addition, according to the literature preceding as in case of
triflic acid,15 FeCl3 may combine with AcOH to form
Fe(OCOCH3)3 which may behave as active catalyst species and
may involve in the reaction and meanwhile the H+ ion
liberated will assist in the protonation of the –OH group of an
acid. Hence in the above case no coupling product of AcOH
was observed, since the AcOH employed was only 0.5 eq.
However, in the absence of an acid component, usage of 1.0
and 1.5 eq. AcOH led to the corresponding coupling product
with benzylamine in 6 and 16 % yields respectively.
transformations, for example, addition reactions, substitution
reactions, cycloaddition, hydrogenation, reduction, oxidation,
coupling reactions, isomerizations, rearrangements, and
polymerizations.11
Das
et
al.,
reported
Fe+3-K10
montmorillonite clay catalysed preparation of esters and
amides.12 Rao and co-workers described a facile N-formylation
of amines using Lewis acid catalysts including AlCl3, FeCl3,
NiCl2, ZnCl2.13 Williams et al., also reported an iron catalysed
coupling of nitriles and amines to form amides.14
In a typical experiment, phenylacetic acid and aniline were
chosen as model substrates. Our catalytic system consisted on
commercially available iron salt, FeCl3. A synthetic study was
first undertaken to define the best reaction conditions. The
table lists the representative data obtained for the synthesis of
amide in presence of iron salts including FeCl2, FeCl3,
FeCl3.6H2O. Among the catalysts used FeCl2 afforded 38%
yield, where as the use of FeCl3 and FeCl3.6H2O lead to 76 and
65% yields of product respectively. When the similar reaction
was carried out using FeCl3 in presence of 0.5 eq of glacial
AcOH afforded the product in 89% yield. Increase in the yield
of product is possibly due to the increased leaving group ability
of hydroxy group of an acid in presence of AcOH.
H
R
FeCl3
0.5 eq AcOH
toluene, reflux
R
N
COOH
n
n
n
H2N
n
+
O
R
1
2
3
Scheme 1 Synthesis of amides 3.
To check the feasibility of this optimized process, amidation of
variety of acids with various amines was carried out (Scheme
1). To our delight, the corresponding amides were obtained in
good to excellent yields (Table 1). The products were
characterized by mass, 1H and 13C NMR analyses.
A solvent screening was carried out and among the solvents
screened such as, CH2Cl2, THF, CH3CN, toluene, DMF and
EtOAc, toluene yielded satisfactory result. As illustrated in the
earlier reports, formation of charged species is disfavoured in
non polar solvent i.e., toluene and thus avoids the formation
of salt during the amidation. A 20 mol% of the catalyst proved
Bromoacetic acid whose coupling is troublesome via acid
chloride method also gave the corresponding amide with
aniline in fairly good yields (Table 1, entry 12). It is also
enough for the desired transformation.
o
Since quantitative conversions can be obtained at 160 C with interesting to see if racemisation could occur when a chiral
simple substrates and to make sure that the system would be
sufficiently catalytic, a control experiment was conducted. In
which, an amide formed by the treatment of acid with an
amine in toluene at reflux temperature can be assumed to be
the result of a background reaction (i.e., amide formation due
to the thermal treatment of acid and amine). To verify that the
amidation reaction is indeed catalysed by the FeCl3,
experiments were performed without the catalyst. These
reactions resulted in 10-13% yields of the amide depending on
the stoichiometry between the amine and acid components.
The poor outcome of the uncatalyzed reactions clearly
confirms catalytic efficiency of iron (III).
amino acid is used under present reaction conditions. Thus we
carried out the amidation of Fmoc-Val-OH with benzyl amine
and the product
5 was obtained in 74% yield, but with
noticeable racemisation as observed through HPLC analysis
(method: ACN:H2O-70:30, run time = 30 min). However, we
undertook the coupling of sterically hindered Aib amino acid,
which doesn’t possess the chiral centre as well. Satisfactorily,
corresponding Fmoc-protected Aib-Aib dipeptide
obtained in 67% yield (Scheme 2).
4 was
Although the mechanism of the present reaction has not been
studied in detail and if any mechanistic discussion is
speculative, we believe that the catalyzed transformation
Scheme 2 Synthesis of amino acid derived amides 4 and 5.
2 | J. Name., 2015, 00, 1-3
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Overall, the protocol employing FeCl3 in presence of glacial
AcOH worked well for the less nucleophilic aniline and its
variants, bromoacetic acid and sterically hindered amino acid
which gave best results when subjected to amidation under
present reaction conditions. The protocol discussed in the
present work is catalytic and thus circumvents the use of
stoichiometric amount of reagents for the amide formation.
The reaction led to water soluble by-products and thus makes
the product isolation simple as well as easier.
Experimental Section
To a solution of acid (1.0 mmol) in toluene (6 mL) was added
20 mol% FeCl3 [98% purity, procured from Merck] and an
additional 0.5 eq of AcOH and the reaction mixture was
allowed stir at 50 oC for 10-15 min. Then an amine (1.0 mmol)
in toluene (4 mL) was added to the above reaction mixture.
o
The reaction mixture was refluxed at 70-75 C temperature till
the completion of the reaction as monitored by TLC. Upon
complete consumption of the starting materials, the reaction
mixture was filtered and the filtrate was evaporated under
reduced pressure. The crude product was extracted into EtOAc
(15 mL). The EtOAc layer was then washed with 5% Na2CO3
(5 mL), dil. HCl (5 mL), water (2 x 5 mL) and brine (5 mL). The
organic layer was dried over anhydrous Na2SO4 and the
solvent was evaporated in vacuo to afford the crude which
was then purified through silica gel column chromatography
(EtOAc/hexane).
Table 1. List of amides prepared employing FeCl3.
entry
1
Acid (1)
Amine (2)
Amide (3)
(6 h) 3a
Yield
(%)
89
80
2
3
4
5
The NMR spectra provided in the ESI† are of the as-isolated
products.
(5.5 h) 3b
(5 h) 3c
84
81
74
Acknowledgements
We thank Department of Science and Technology (DST) and
Council of Scientific and Industrial Research (CSIR) for
financial assistance. Authors Basavaprabhu, NP and VP thank
CSIR for SRF fellowship.
(6 h) 3d
(5.5 h) 3e
(4.5 h) 3f
Notes and references
COOH
6
7
8
1
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Graphical abstract:
A simple and greener approach for the amide bond formation employing
FeCl3 as a catalyst
Basavaprabhu, Muniyappa Krishnamurthy, Nageswara Rao Panguluri, Veladi Panduranga and
Vommina V. Sureshbabu*
# 109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College
Campus, Bangalore University, Dr. B. R. Ambedkar Veedhi, Bangalore-560 001, India
Email: hariccb@hotmail.com; hariccb@gmail.com; sureshbabuvommina@rediffmail.com
Protocol employing FeCl3 in presence of glacial AcOH is described for the less nucleophilic
aniline and its variants, bromoacetic acid and sterically hindered amino acids.
H
R
FeCl3
0.5 eq AcOH
toluene, reflux
R
N
COOH
n
n
n
H2N
n
+
O
R
1
2
3a-l
yield = 68-89 %
O
H
12 examples
N
FmocHN
OMe
O
yield = 67 %