Mild and useful method for n-acylation of amines

Article abstract of DOI:10.1080/00397910802663428

Iodine is found to promote quantitative N-acylation of primary and secondary amines (aliphatic and aromatic) in a very short time with an equimolar amount of acetyl chloride and benzoyl chloride under solvent-free conditions at room temperature. This catalytic acylation of amines offers an additional useful method for the acetylation using acetyl chloride instead of acetic anhydride and other acetylating agents. This method is also useful in the N-acylation of heterocycles. Mild reaction condition, high selectivity, efficiency, and good yields are some of the major advantages of the procedure.

Full text of DOI:10.1080/00397910802663428

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Mild and Useful Method for N-
Acylation of Amines
a
a
Kandarpa Phukan , Mausumi Ganguly & Nirada
a
Devi
a
Department of Chemistry, Cotton College,
Guwahati, Assam, India
Version of record first published: 26 Jun 2009
To cite this article: Kandarpa Phukan, Mausumi Ganguly & Nirada Devi (2009):
Mild and Useful Method for N-Acylation of Amines, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:15,
2694-2701
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1
Synthetic Communications , 39: 2694–2701, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802663428
Mild and Useful Method for N-Acylation
of Amines
Kandarpa Phukan, Mausumi Ganguly, and Nirada Devi
Department of Chemistry, Cotton College, Guwahati, Assam, India
Abstract: Iodine is found to promote quantitative N-acylation of primary and
secondary amines (aliphatic and aromatic) in a very short time with an equimolar
amount of acetyl chloride and benzoyl chloride under solvent-free conditions at
room temperature. This catalytic acylation of amines offers an additional useful
method for the acetylation using acetyl chloride instead of acetic anhydride and
other acetylating agents. This method is also useful in the N-acylation of hetero-
cycles. Mild reaction condition, high selectivity, efficiency, and good yields are
some of the major advantages of the procedure.
Keywords: Acetamide, acetyl chloride, N-acylation, benzamides, benzoyl
chloride, iodine
The acetylation and benzoylation of primary and secondary amines are
among the most widely used transformations in organic synthesis.
N-Acyl derivatives of amines are used widely in the synthesis of amides
and their derivatives, as starting materials for various organic transfor-
[
1,2]
mations, and in protection of –NH and OH- groups.
In practical
terms, acylation involves the following categories: (a) direct reaction of
an amine and an acid, (b) reaction of a readily available acid derivative
(e.g., simple methyl ester) with an amine, (c) formation of an activated
carbonyl compound (e.g., acid chloride, anhydride, or active ester) fol-
lowed by condensation with an amine, and (d) one-pot reaction of a car-
boxylic acid with an amine in which a coupling reagent activates the acid
[3]
component in situ. Acid halides and acid anhydrides are commonly
Received October 10, 2008.
Address correspondence to Nirada Devi, Department of Chemistry, Cotton
College, Guwahati 781001, Assam, India. E-mail: niradadevi@rediffmail.com
2
694

N-Acylation of Amines
2695
used as acylating agents in various solvent systems in the presence of a
[1]
protic or Lewis acid catalyst. Novel catalysts used are a basic, aqueous
alkali like sodium hydroxide (Schotten–Bauman condition) or a tertiary
[
4]
[5]
amine (py or Et N). Cp Sn(THF) , tetrabutyl ammonium salts, and
3
2
2
[
6]
cyanide anion have been reportedly used as catalysts in the acetylation
of amines with esters. 18-Crown-6 has also been reportedly used in the
[7]
selective acylation of secondary amines. All these existing procedures
have some drawbacks, such as the rquirement of more expensive
reagents, relatively harsh reaction conditions, and long reaction times.
The widely used Schotten–Baumann condition suffers from the drawback
that hydrolysis of acetyl chloride and benzoyl chloride is a significant
competing side reaction, so a strict maintenance of pH is required. Other-
wise, acetic anhydride is recommended. However, this is highly expensive
and creates technical problem so. Thus, there is still a great need to find
better alternatives to make use of the high reactivity of acyl chlorides
toward the acylation of amines, which might proceed under mild, envir-
onmentally benign, efficient, clean, and economically much cheaper reac-
tion conditions. In recent years, iodine has been used as a Lewis acid
[8]
catalyst for various organic transformations. Use of iodine in catalyz-
[9]
ing the Mukaiyana aldol condensation reaction and in acetylation of
[
10]
alcohols
has been reported. Herein we report a general, rapid, and
one-pot convenient procedure for N-acetylation and N-benzoylation of
amines using acetyl chloride and benzoyl chloride respectively under
solvent-free conditions catalyzed by iodine (Scheme 1).
The general efficiency of this reaction is evident from the variety of
amino compounds including aliphatic, aromatic, and heterocyclic amines
(
primary and secondary), which react in excellent yields within a very
short time; simple primary amines are acylated within 1 min. First, we
have tried to optimize the reaction conditions for acetylation of aniline.
At room temperature, use of 0.1 mmol of I with 1 mmol of aniline and
2
1
.05 mmol of acetyl chloride gave 95% of acetanilide. Similarly, we have
converted various primary and secondary amines to respective amides in
relatively good yields under identical reaction conditions (Table 1). The
Scheme 1. (i) R
iv) R ¼ imidazolyl, R ¼ ꢀ; and (v) R ¼ indole residue, R ¼ ꢀ.
1
¼ H, R
2
¼ alkyl, aryl; (ii) R
1
¼ R
2
¼ alkyl; (iii) R
1
¼ R ¼ aryl;
2
(
1
2
1
2

2696
K. Phukan, M. Ganguly, and N. Devi
a
Table 1. Acetylation of primary and secondary amines using iodine as a catalyst
b
c
Yield =%
Entry
A
Substrate 1
Time (min)
1
Product 2
94.5
d
b
5
60.3
d
c
8
68.5
64.6
d
d
10
d
e
7
74.7
d
f
10
77.09
d
g
5
97.58
(
Continued )

N-Acylation of Amines
2697
Table 1. Continued
b
c
Yield =%
Entry
H
Substrate 1
C–NH
Time (min)
1
Product 2
H
3
2
70.87
I
1
86.3
84.9
d
j
15
K
2
75.0
L
5
2
78.00
75.5
M
a
Reaction condition: substrate ¼ 1 mmol, AcCl ¼ 1.05 mmol, iodine ¼ 0.1 mmol,
ꢁ
5 C.
2
b
Products have been characterized by melting points, chemical tests, IR, and
H NMR data.
1
c
Isolated yield.
AcCl (3.5 eq) was used.
d
1
products are fully characterized by H NMR, infrared (IR), and melting
points.
Encouraged by the results of acetylation, we have extended the
process to benzoylation of the same substrates using benzoyl chloride
in place of acetyl chloride, keeping all other conditions identical
(
Scheme 2). Both aromatic and aliphatic primary and secondary amines

2698
K. Phukan, M. Ganguly, and N. Devi
Scheme 2. (i) R
(
1
¼ H, R
2
¼ alkyl, aryl; (ii) R
1
¼ R
2
¼ alkyl; (iii) R
¼ ꢀ.
1
¼ R ¼ aryl;
2
iv) R
1
¼ imidazolyl, R
2
¼ ꢀ; and (v) R
1
¼ indole residue, R
2
as well as the heterocycles were found to be N-benzoylated in good yields.
Table 2 shows representative results of the benzoylation of various
amines with benzoyl chloride using iodine as catalyst.
In conclusion, iodine shows a very strong catalytic activity toward
general acylation of primary and secondary amines including N-
containing heterocycles with actyl and benzoyl chloride. The merits of
this method are that (a) it is a very simple, one-pot, rapid, high-yielding
process, (b) iodine is cheap and easily available as compared to other cat-
alysts, (c) the method is environmentally benign because it does not
require any solvent, and (d) iodine is not moisture sensitive, and reactions
are carried out in air at room temperature. Near equimolar acyl chlorides
are typically used, avoiding waste and providing very simple experimental
and workup procedure. It is significant to note that neither the substi-
tuted groups like the nitro group nor the aromatic ring is acylated under
the experimental conditions. Because of its simplicity, generality, efficacy,
and cost-effectiveness, this method is expected to have wide applicability
for N-acylation of primary and secondary amines. This method is also
useful in the N-acylation of heterocycles.
EXPERIMENTAL
General Procedure for N-Acylation
Acyl chloride (acetyl or benzoyl chloride) (1.05 mmol) was added to a
stirred mixture of the amine 1 or 2 (1 mmol) and iodine (1 mmol), and
stirring continued between two additions at room temperature for the
appropriate time as monitored by thin-layer chromatography (TLC). In
case of solid substrate, 3.5 eqv of the acyl chloride were used to solubilize
the substrate. After completion of the reaction, iodine was destroyed by
adding saturated Na S O solution (5 ml). Diethyl ether (10 ml) was
2
2
3
added, and the two phases were separated. The organic phase was washed
with saturated NaHCO3 solution (2.5 ml) and brine (2.5 ml), dried
(Na SO ), and concentrated to give the pure product.
2 4

N-Acylation of Amines
2699
Table 2. Benzoylation of primary and secondary amines using iodine as a
a
catalyst
Time
(min)
b
c
Yield =%
Entry
A
Substrate 3
Product 4
1
95.66
d
b
10
65.32
d
c
12
90.05
62.12
d
d
8
d
e
14
10
97.32
62.72
d
f
d
g
5
99.19
(
Continued )

2700
K. Phukan, M. Ganguly, and N. Devi
Table 2. Continued
Time
(min)
b
c
Yield =%
Entry
h
Substrate 3
C–NH
Product 4
H
3
2
1
54.29
i
1
88.34
92.03
d
j
13
k
l
2
5
82.5
78.0
m
2
75.5
a
Reaction condition: substrate ¼ 1 mmol, PhCOCl ¼ 1.05 mmol, iodine ¼
ꢁ
0
.1 mmol, 25 C.
b
Products have been characterized by melting points, chemical tests, IR, and
H NMR data.
1
c
Isolated yield.
AcCl (3.5 eq) was used.
d
1
H NMR spectroscopic data of compound (2h): (liquid) 2.0 and 2.1
1
2s, 3H), 2.8 (d, 3H), 4.7 (s, 1H). H NMR spectroscopic data of
(
compound (4e): (melting point 100 C) 7.25 (s, 1H), 7.5 (m, 1H), 7.65
ꢁ
1
m, 1H), 8.1 (m, 5H). H NMR spectroscopic data of compound (4i):
semisolid) 1.1 (t, 6H), 3.5 (q, 4H), 7.1 (s, 1H), 7.3 (m, 4H).
(
(

N-Acylation of Amines
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