Convenient, cost-effective, and mild method for the N-acetylation of anilines and secondary amines

Article abstract of DOI:10.1081/SCC-200054764

An efficient, cost-effective, and mild method for the N-acetylation of anilines and secondary amines with ammonium acetate in acetic acid media at reflux temperature in good yield is described. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054764

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Convenient, Cost‐Effective,
and Mild Method for the
N‐Acetylation of Anilines and
Secondary Amines
H. S. Prasad a , G. R. Srinivasa a & D. Channe Gowda
a
a Department of Studies in Chemistry, University of
Mysore, Manasagangotri, Mysore, Karnataka, India
Published online: 16 Aug 2006.
To cite this article: H. S. Prasad , G. R. Srinivasa & D. Channe Gowda (2005)
Convenient, Cost‐Effective, and Mild Method for the N‐Acetylation of Anilines and
Secondary Amines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:9, 1189-1195, DOI: 10.1081/
SCC-200054764
To link to this article: http://dx.doi.org/10.1081/SCC-200054764
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Synthetic Communicationsw, 35: 1189–1195, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054764
Convenient, Cost-Effective, and Mild
Method for the N-Acetylation of Anilines
and Secondary Amines
H. S. Prasad, G. R. Srinivasa, and D. Channe Gowda
Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore, Karnataka, India
Abstract: An efficient, cost-effective, and mild method for the N-acetylation of
anilines and secondary amines with ammonium acetate in acetic acid media at reflux
temperature in good yield is described.
Keywords: N-Acetylation, ammonium acetate, anilines, secondary amines
INTRODUCTION
The N-acetylation of amino groups is an important fundamental transform-
ation in organic chemistry.[1,2] The most common reagents employed for
N-acetylation of amines are acetic anhydride and acetyl chloride. Acetic
anhydride is used as a N-acetylating agent in the presence of basic catalysts,
such as pyridine, 4-pyrrolidinopyridine, and 4-dialkylaminopyridine.[3]
A
variety of other catalysts such as Cu(OTf)2,[4] basic alumina,[5] In(OTf)3,[6]
montmorillonite K-10 and KSF,[7] ruthenium(III)chloride,[8] and zeolite
H-FER[9] in -the presence of acetic anhydride and with various reagents
under microwave irradiation,[10] were also used for N-acetylation of amines.
Further, the N-acetylation of primary and secondary amines can be achieved
by the methods such as ethyl trifluoroacetate,[11] pentafluorophenylacetate,[12]
Received in India December 20, 2004
Address correspondence to D. Channe Gowda, Department of Studies in Chemistry,
University of Mysore, Manasagangotri, , Mysore, Karnataka 570 006, India. Fax: 091-
0821-2421263/2518835; E-mail: dcgowda@yahoo.com

1190
H. S. Prasad G. R. Srinivasa, and D. C. Gowda
N-methoxydiacetamide,[13] poly(3-acyl-2-oxazolone),[14] N-acyl-N-(2,3,4,5,6-
pentafluorophenyl)methanesulfonamides,[15] ortho-substituted N,N-diacetyla-
niline,[16] and N-acetyl-N-acyl-3-aminoquinazolinones.[17] At the same time,
selective N-acetylation of the primary amine moiety in the presence of
secondary amine moiety can also be achieved by these methods. However,
many of the earlier methods suffer from certain drawbacks. The catalysts are
rather expensive and toxic, and require not-readily-available reagents. Thus,
an efficient, convenient, and mild method is still desirable. To this end, we
developed a convenient and mild method (Scheme 1) for the N-acetylation
of anilines and secondary amines in good yields using ammonium acetate,
which is a very useful reagent in the synthesis of many organic
compounds,[18–21] including b-amino acids.[22]
As shown in Table 1, a number of substituted anilines and secondary
amines underwent N-acetylation smoothly with ammonium acetate in
presence of acetic acid at reflux temperature in good yields. The course of
the reaction was monitored by thin layer chromatography (TLC) and IR
spectra. The workup and isolation of the products were easy. All the acetylated
products were characterized by comparison of their TLC, IR spectra, 1H-NMR
spectra, and melting points with authentic samples.
With this present method, only N-acetylated products were observed. The
generality of this methodology was examined using other functionally and
sterically hindered amines. The presence of electron-withdrawing groups
such as nitro and chloro groups in anilines slow down the acetylation (entries
4–9 in Table 1), whereas the electron-releasing group facilitates the process
(entries 10, 11, 13–16). The operation of both the electron-withdrawing
effect and the steric effect completely stop the process of acetylation (entries
4, 7). It was also observed that the acetylation reaction is fast in acetic acid,
but it was very slow in acetonitrile or methanol. A control experiment was
carried out using an amino compound with acetic acid, in the absence of
ammonium acetate, and conversion of amino to N-acetylated product was
observed to be less than 5%.
In conclusion, this new method does not require any expensive catalysts
or reagents such as Cu(OTf)2,[4] basic alumina,[5] In(OTf)3,[6] montmorillonite
K-10 and KSF,[7] ruthenium(III)chloride,[8] or zeolite H-FER.[9] The ease of
product separation, safe reaction medium, high selectivity, and low cost of
the reagents promote this method as a promising alternative to the other
existing methods.
Scheme 1. For anilines, R1 ¼ aryl, R2 ¼ H; for secondary amines, R1, R2 ¼ alkyl.

Table 1. N-Acetylation of anilines and secondary amines with CH3COONH4/CH3COOH
Melting point (8C)
Entry
1
Substrate
Producta
Time (h)
0.75
Yield (%)b
75
Found
Lit.
113–115
114[23]
2
2.5
86
57–59
60[24]
3
4
2.0
88
77–79
—
79–80[15]
24.0
100c
—
5
4.5
60
153–155
155[23]
6
7
6.0
36
214–215
—
216[23]
24.0
100c
—
(continued)

Table 1. Continued
Melting point (8C)
Entry
8
Substrate
Producta
Time (h)
16.0
Yield (%)b
40
Found
Lit.
77–79
79[23]
9
8.0
2.0
48
82
177–178
147–149
179[23]
10
149[23]
11
12
1.5
2.0
88
89
167–168
115–117
168[23]
118–119[13]
13
2.0
67
123–124
125[23]

14
15
16
17
1.5
5.0
82
89
91
34
144–146
86–87
146[23]
88[23]
0.5
129–131
161–162
130[23]
15.0
163[23]
18
19
20
13.0
11.0
1.5
52
82
85
168–170
224–226d
Oil
171[23]
226–227[5]
14[5]
aAll products were identified by their H-NMR, IR spectra, mp, or bp with authentic samples.
bIsolated yields are based on single experiment and the yields were not optimized.
cBased on recovery of the starting material, no acetylation was observed even after 24 reflections.
dBoiling point.
1

1194
H. S. Prasad G. R. Srinivasa, and D. C. Gowda
EXPERIMENTAL
Materials
All the anilines and secondary amines were purchased from Aldrich Chemical
Company (USA). Ammonium acetate and acetic acid were purchased from
SISCO Research Laboratories Pvt. Ltd., Bombay (India). All of the solvents
used were analytical grade or were purified according to standard procedures.
Thin layer chromatography was carried out on silica-gel plates obtained from
Whatman Inc. The melting points were determined by using a Thomas-
Hoover melting point apparatus and are uncorrected. IR spectra were
1
recorded on a Shimadzu FTIR-8300 spectrometer. H-NMR spectra were
recorded on an AMX-400 MHz spectrometer using CDCl3 as the solvent
and TMS as internal standard.
General Procedure for the N-Acetylation of Anilines and
Secondary Amines
To a mixture of ammonium acetate (15 mmol) and acetic acid (5 ml), the
substrate (amine, 5 mmol) was added and the reaction mixture stirred at
95 8C for a length of time indicated in Table 1. After completion of the
reaction (monitored by TLC), the reaction mixture was neutralized with
saturated NaHCO3 solution. The obtained product was extracted with chloro-
form (3 Â 15 ml) and the combined organic extracts were washed with cold
water and dried over Na2SO4. The product obtained, after removal of the
solvent under reduced pressure, was crystallized from a suitable solvent.
ACKNOWLEDGMENTS
The authors thank the University Grants Commission, New Delhi, India, for
financial assistance.
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