An iron-catalysed synthesis of amides from nitriles and amines

Article abstract of DOI:10.1016/j.tetlet.2009.05.021

The cheap, commercially available iron complex, Fe(NO₃)₃·9H₂O, has been used to catalyse the formation of amides by the addition of amines to nitriles.

Full text of DOI:10.1016/j.tetlet.2009.05.021

Tetrahedron Letters 50 (2009) 4262–4264
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Tetrahedron Letters
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An iron-catalysed synthesis of amides from nitriles and amines
C. Liana Allen a, Alexei A. Lapkin b, Jonathan M. J. Williams a,
*
a Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
b Department of Chemical Engineering, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The cheap, commercially available iron complex, Fe(NO3)3Á9H2O, has been used to catalyse the formation
of amides by the addition of amines to nitriles.
Received 24 March 2009
Revised 29 April 2009
Accepted 8 May 2009
Available online 13 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
O
Amides are an important functional group in a wide range of
biologically relevant molecules. Current popular syntheses of
amides include the coupling reaction of an acid chloride1 or a car-
boxylic acid1,2 and an amine, the rearrangement of an oxime3 and
the recently reported ruthenium-catalysed reaction between an
alcohol and an amine known as dehydrogenative acylation.4
A less frequently reported amide synthesis is the coupling of a
nitrile and an amine (Scheme 1).5
R
R
R''CN
HN
R'
+
R''
N
R'
Scheme 1. Formation of amides from nitriles and amines.
amide formation (entries 2–4), although a relatively high catalyst
loading was required in order to obtain a good conversion into
product. The addition of water did not lead to higher conversions,
and we believe that there is sufficient adventitious water present
in the undried nitrile to allow full conversion into product.
The use of the ferric salt, FeCl3Á6H2O was less successful, even
though it presumably has a more Lewis acidic character. Iron(II)
bromide (entry 6) and iron(II) iodide (entry 7) afforded similar lev-
els of catalytic activity to iron(II) chloride, although iron(III) acetyl-
acetonate (entry 8) gave none of the desired amide, even with a
high catalyst loading.
However, iron(III) nitrate nonahydrate (entries 9–11) was found
to be an effective catalyst when used at 10 mol % loading.
Formation of imine 4 was observed as a by-product in this reac-
tion, especially for catalysts other than iron(III) nitrate. This trans-
formation has previously been reported using photochemical16 or
electrochemical17 conditions, and using ruthenium or iron cata-
lysts [pentacyanonitrosyl ferrate(II)].18 Indeed, in the absence of
the nitrile substrate, the imine was formed in 88% conversion with
10 mol % FeCl2Á4H2O, and in 90% conversion with 10 mol %
Fe(NO3)3Á9H2O (Scheme 3), even in the absence of an additional
oxidant.
This reaction has been performed using a ruthenium6 or a plat-
inum7 catalyst. With concerns regarding the toxicity, expense and
diminishing availability of precious metals such as ruthenium and
platinum,8 we wanted to identify economical and readily available
catalysts which would perform the same reactions with compara-
ble yields.
With its environmentally friendly character, considerable natu-
ral abundance and low price (FeCl3 is over 500 times cheaper than
RuCl3 and over 2000 times cheaper than PtCl2 per mol),9 iron was
an obvious choice to investigate. Iron complexes are already
known to catalyse reactions such as hydroxylations,10 conjugate
additions,11 epoxidations of alkenes12 and even Grignard reac-
tions.13 Recently, work has been published describing the iron-cat-
alysed coupling of phenyl iodides with amides,14 and a Ritter
reaction of alcohols with nitriles to form amides.15 However, to
our knowledge, this is the first example of an iron-catalysed cou-
pling of nitriles and amines to form amides.
Initially, we chose to compare the performance of various iron
complexes in the reaction of benzylamine 1 and propionitrile 2,
which leads to the formation of amide 3 after 24 h at 125 °C
(Scheme 2).
The results of this initial catalyst screening are summarised in
Table 1. In the absence of any catalyst there was no conversion
to amide 3 (entry 1). FeCl2Á4H2O was identified as a catalyst for
O
Fe catalyst
+
Ph
NH2
Ph
N
H
3
CN
125 ºC, 24 h
1
2
8 equiv.
* Corresponding author.
E-mail address: j.m.j.williams@bath.ac.uk (J.M.J. Williams).
Scheme 2. Formation of amide 3 by the reaction of benzylamine 1 and propionitrile
2 in the presence of an iron catalyst.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.021

C. L. Allen et al. / Tetrahedron Letters 50 (2009) 4262–4264
4263
Table 1
Table 2
Effect of different iron catalysts and loading on amide formation
Reactions of a range of amines with propionitrile to give the corresponding amides 6
Entry
Catalyst
Mol %
Conversion into amide 3a
Entry
Amine
Conversion to amidea (%)
1
2
3
4
5
6
7
8
9
None
—
5
0
47
55
80
36
50
60
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Benzylamine
87 (65)
88 (79)
90 (82)
8
15
100
100
89
78
86
31
0
10
88
FeCl2Á4H2O
FeCl2Á4H2O
FeCl2Á4H2O
FeCl3Á6H2O
FeBr2ÁxH2O
FeI2ÁxH2O
p-Methoxybenzylamine
p-Methylbenzylamine
Aniline
p-Fluoroaniline
n-Butylamine
10
25
15
10
10
25
2.5
10
20
Allylamine
Fe(acac)3
2-Phenylethylamine
(N-2-Aminoethyl)morpholine
Isopropylamine
1-Phenylethylamine
t-Butylamine
N-Methylbenzylamine
Morpholine
1,3-Diaminopropane
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
Fe(NO3)3Á9H2O
42
87
88
10
11
a
Conversion was determined by analysis of the 1H NMR spectra.
50 (diamide), 42 (monoamide)
a
Conversion was determined by analysis of the 1H NMR spectra. Figures in
10 mol% [Fe]
brackets indicate isolated yields (%).
Ph
NH2
Ph
N
Ph
125 ºC, 24 h
DCE
1
4
88% [Fe] = FeCl2·4H2O
90% [Fe] = Fe(NO3)3·9H2O
O
10 mol% Fe(NO3)3·9H2O
Scheme 3. Reaction of benzylamine in the absence of nitrile. DCE = 1,2-
dichloroethane.
CN
NH2
125 ºC, 24 h
70% conversion
7
8
Fortunately, minimal imine side product was observed when
the reaction was performed in the presence of nitrile, using
10 mol % Fe(NO3)3Á9H2O as catalyst. The use of additional ligands
was examined briefly for the conversion of nitrile 2 into amide 3.
When iron(II) chloride was used as the catalyst, the addition of
DPEphos [bis(2-diphenylphosphinophenyl)ether] or ethylenedia-
mine led to no product formation. When 2,2-bipyridyl was used
in conjunction with either the iron(II) chloride catalyst or iron(III)
nitrate catalyst, the reactions were successful, but afforded no ben-
eficial effect.
When the reaction using 10 mol % iron(III) nitrate (Table 1, en-
try 10) was repeated in the presence of solvent, the conversion was
somewhat reduced using polar solvents (THF, 60%; EtOAc, 66%; and
DCE, 77%), and usage of non-polar solvents led to a more significant
reduction (toluene, 18%; pentane, 30%).
Scheme 5. Reaction in the absence of amine.
13), although when the less sterically demanding cyclic secondary
amine, morpholine (entry 14), was used, the reaction was
successful.
In the cases where the amine was unreactive, for either steric or
electronic reasons, significant amounts of the primary amide,
CH3CH2CONH2, were formed by hydrolysis. The reaction was re-
peated on butyronitrile 7 in the absence of an amine substrate
and this led to the formation of butyramide 8 in 70% conversion
(Scheme 5). Although many reactions in which a nitrile is hydroly-
sed to a primary amide already exist,19 to our knowledge, this is
the first example of an iron-catalysed synthesis of a primary amide
via hydrolysis of a nitrile.
We also wanted to explore a range of nitriles as substrates for
amide formation. We chose to use allylamine 9 with a range of ni-
triles 10, which led to the formation of allylamides 11 (Scheme 6
and Table 3). Aliphatic (entries 1–3) and aromatic nitriles were
successfully converted into amides, except for p-aminobenzonitrile
(entry 8), which afforded none of the expected amide, presumably
due to electronic deactivation.
The amide product from entry 6, Table 3 is a precursor to a drug
molecule which has diuretic and anti-inflammatory properties.20
In order to demonstrate further the use of this reaction in the syn-
thesis of another biologically active molecule, a simple preparation
of the anti-depressant Moclobemide 14 (marketed as ManerixÒ)21
from commercially available starting materials 12 and 13 was per-
formed (Scheme 7) in a moderate 54% isolated yield.
Having concluded from these results that the optimal catalyst
system was 10 mol % Fe(NO3)3Á9H2O, we then turned our attention
to expanding the scope of this reaction, initially investigating the
reaction of propionitrile 2 with a range of amines 5 to form amides
6 (Scheme 4 and Table 2).
In general, unbranched primary amines were successful for the
formation of secondary amines from nitriles. Benzylamine (entry
1) and substituted variants (entries 2 and 3) were suitable,
although anilines (entries 4 and 5) afforded low conversion into
product, presumably due to their low nucleophilicity. The simple
amines, n-butylamine (entry 6) and allylamine (entry 7), afforded
the corresponding amides with quantitative conversion. The pres-
ence of a-substituents on the amine can have a detrimental effect
on reactivity; whilst isopropylamine (entry 10) could be converted
into amides efficiently, the more hindered 1-phenylethylamine
(entry 11) gave a lower conversion and t-butylamine was suffi-
ciently bulky that no secondary amide product was formed. The
use of a secondary amine also led to a lower conversion (entry
We assume that the iron catalyst acts as a Lewis acid making
the nitrile more susceptible to nucleophilic addition. Two possible
routes to the amide product can be considered, either proceeding
NH2
O
O
6 equiv.
10 mol% Fe(NO3)3·9H2O
125 ºC, 24 h
10 mol% Fe(NO3)3·9H2O
N
H
11
R
9
CN
+
HNR2
NR2
+
125 ºC, 24 h
2
5
NC
10
R
6
8 equiv.
Scheme 4. Optimised reaction with a range of amines.
Scheme 6. Optimised reaction with a range of nitriles.

4264
C. L. Allen et al. / Tetrahedron Letters 50 (2009) 4262–4264
Table 3
O
Reactions of a range of nitriles with allylamine to give the corresponding amides 11
NH2
O
Entry
Nitrile 10
Conversion to amidea (%)
8
+
10 mol% Fe(NO3)3·9H2O
125 ºC, 24 h
N
H
Ph
1
2
3
4
5b
6
7
8
Acetonitrile
Butyronitrile
Octonitrile
Benzonitrile
p-Chlorobenzonitrile
p-(Trifluoromethyl)benzonitrile
3-Cyanopyridine
p-Aminobenzonitrile
100
100
87
50
100 (69)
100 (72)
100 (98)
0
16
Ph
NH2
21% conversion
15
Scheme 9. Low conversion for the reaction of a primary amide with an amine
suggests that this is not the major reaction pathway.
a
Conversion was determined by analysis of the 1H NMR spectra. Figures in
The fact that t-butylamine is not an effective substrate for ami-
dation indicates that a Ritter-type pathway involving the forma-
tion of a carbocation is unlikely to be operating.
brackets indicate isolated yields (%).
b
In this example, n-butylamine was used in the place of allylamine.
In summary, Fe(NO3)3Á9H2O acts as a cost-efficient catalyst for
the experimentally straightforward synthesis of amides from ni-
triles and amines.23 The reaction is most favourable for primary
unbranched amines reacting with nitriles which are not too elec-
tron rich. Efforts to improve the catalyst, confirm the scope and
limitations of these reactions and further mechanistic studies are
currently underway in our laboratory.
CN
Cl
10 mol% Fe(NO3)3·9H2O
12
125 ºC, 24 h
+
O
O
O
Acknowledgement
N
N
N
H
H2N
13
We thank the EPSRC for the award of a studentship (to C.L.A.)
administered through the Doctoral Training Account.
Cl
8 equiv.
Moclobemide (14)
71% conversion
References and notes
54% isolated yield
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of Amides; Wiley: New York, 1970.
Scheme 7. Synthesis of the anti-depressant Moclobemide using iron catalysis.
2. Srinivas, K. V. N. S.; Das, B. J. Org. Chem. 2003, 68, 1165.
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O
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R'R''NH
O
R
R
NH2
R'
R'
RCN
R'R''NH
R
N
R''
NH
H2O
N
R''
11. Kawatsura, M.; Komatsu, Y.; Yamamoto, M.; Hayase, S.; Itoh, T. Tetrahedron
2008, 64, 3488.
Scheme 8. Proposed pathways for amide formation.
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19. Mauger, J.; Nagasawa, T.; Yamada, H. Tetrahedron 1989, 45, 1347; Kim, J. H.;
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via the primary amide which then reacts with the amine, or alter-
natively via an amidine intermediate which is then hydrolysed to
the amide (Scheme 8).
The metal-catalysed formation of amidines from nitriles and
amines has previously been reported.22 Evidence specifically sup-
porting the amidine mechanism, at least for the Pt-catalysed reac-
tion, has been put forward by de Vries and co-workers7 who found
that when n-propylamine was reacted with acetonitrile in the ab-
sence of water, the major products formed were mono- and bis-
amidines. In addition, for the reaction between propionitrile and
2-aminoethanol, the first product formed is an amidine, which
then reacts further, forming the final product, 2-ethyl-2-oxazoline.
We treated primary amide 8 with amine 15 (Scheme 9), which
led to a low conversion into secondary amide 16 after 24 h when
exposed to the iron catalyst under the same reaction conditions
as previously used. Since the conversion is lower than that ob-
served in the overall transformation of nitrile into amide, this sug-
gests that initial primary amide formation is a minor pathway. We,
therefore, propose that the amine adds to the iron-complexed ni-
trile to give an amidine, and that this is then hydrolysed to the
amide.
21. Burkard, W.;Wyss, P.-C. (Hoffman-La Roche Inc.), USPTO, 1980, 4,210,754;
Chem. Abstr. 1981, 94, 65702.
22. Rousselet, G.; Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 6395.
23. Representative experimental procedure: Fe(NO3)3Á9H2O (80 mg, 0.2 mmol,
10 mol %) was added to an oven-dried Schlenk tube. Propionitrile (1.14 mL,
16 mmol) and benzylamine (0.21 mL, 2 mmol) were added dropwise to the
Schlenk tube, which was then sealed and the reaction mixture was allowed to
stir at room temperature for 10 min before being heated (125 °C) for 24 h. The
resulting reaction mixture was filtered through a short plug of silica, eluting
with CH2Cl2–MeOH (98:2), and then concentrated in vacuo to give a brown oil.
The product was recrystallised from CH2Cl2–hexane and allowed to stand in a
freezer overnight before being filtered. The resulting amides were analysed by
1H NMR spectroscopy and mass spectrometry and their data were compared
with the literature values.