Selective N-acetylation of aromatic amines using acetonitrile as acylating agent

Article abstract of DOI:10.1016/j.tetlet.2016.01.108

A method for N-acetylation of amines has been developed using acetonitrile as an acylating agent and in situ generated trimethylsilyl iodide as the catalyst under microwave heating condition. The reaction is selective toward aromatic amines while aliphatic amines remain intact. The process eliminates the requirement of toxic acylating reagents like acetic anhydride and acetyl chloride.

Full text of DOI:10.1016/j.tetlet.2016.01.108

Tetrahedron Letters 57 (2016) 1158–1160
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective N-acetylation of aromatic amines using acetonitrile as
acylating agent
⇑
Ujwal Pratim Saikia, Farhaz L. Hussain, Mrinaly Suri, Pallab Pahari
Chemical Science and Technology Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for N-acetylation of amines has been developed using acetonitrile as an acylating agent and
in situ generated trimethylsilyl iodide as the catalyst under microwave heating condition. The reaction
is selective toward aromatic amines while aliphatic amines remain intact. The process eliminates the
requirement of toxic acylating reagents like acetic anhydride and acetyl chloride.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 9 January 2016
Revised 29 January 2016
Accepted 30 January 2016
Available online 1 February 2016
Keywords:
Acetylation
Trimethylsilyl iodide
Microwave assisted synthesis
N-acetylation of amine is one of the widely used reactions in
organic chemistry.1 While acetyl is commonly used as a fundamen-
tal protecting group for the amine functionalities, its products find
a broad range of applications in pharmaceutical, polymer, and
agrochemical industries.2 Usually, acetic anhydride and acetyl
chlorides are the most commonly used reagents for the acetylation
of amines (Scheme 1).3 These reagents are cheap, but suffer from
drawbacks like, toxicity, hygroscopicity, etc. Usually, pyridine or
imidazole bases are required to carry out the reaction. Theses bases
are well known for their toxic effects to the humans and environ-
ment. Acid chlorides and anhydrides are highly reactive and thus
maintaining selectivity in the presence of other functional groups
is difficult. They also easily react with moisture and alcohols to
produce acetic acid and esters, respectively, leading to the products
with low purity. The basic reaction medium creates problem for
sensitive functional groups. Moreover, both the chemicals are
restricted in many countries due to their use in the preparation
of narcotics. Alternatively, acetylation can be carried out using free
acids, thioacids, and other amides via transamidification
(Scheme 1).4 Although these methods often give good yields, either
they use costly/toxic reagents or they need to be synthesized start-
ing from acid chlorides/anhydrides. Moreover, most of these reac-
tions are not selective toward N-acetylation. Thus, development of
a new reagent system for selective N-acetylation of amines under
neutral condition and without use of the acetyl chloride or acetic
anhydride would be highly useful.
process of synthesis of aryl/heteroaryl ketones through the
transition metal catalyzed insertion of nitriles into arenes/
heteroarenes was reported by many different groups like
Larock,5b–e Lu,5f Wang,5l etc. In these reactions, an aryl metal
complex reacts with a nitrile to give a nitrile addition product.
The ketimine, thus formed, undergoes subsequent hydrolysis to
produce the ketone. The nucleophilic attack of aryl metal
complex to comparatively inert nitrile is facilitated by the co-
ordination of transition metal with the nitrogen. A few examples
of similar reactions using amine nucleophile to produce amides
have also been reported.6 But, these reported processes suffer from
many drawbacks like, use of expensive catalysts (e.g., Ru,6a Pt,6b),
requirement of expensive ligands,6c long reaction time,6d etc. In
Previous works
NH2
O
NH
CH3COCl/(CH3CO)2O, base (Ref. 3)
OR
R
R
CH3COOH, metal catalyst (Ref. 3)
OR
(Ref. 4)
N
O
This work
O
NH2
NH
There are quite a few examples of nitriles being used as acyl
equivalents.5 Starting from the pioneering work by Garves,5a the
CH3CN
TMSI
R
R
⇑
Corresponding author.
E-mail address: ppahari@gmail.com (P. Pahari).
Scheme 1. Different strategies for the N-acetylation of amines.
http://dx.doi.org/10.1016/j.tetlet.2016.01.108
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

U. P. Saikia et al. / Tetrahedron Letters 57 (2016) 1158–1160
1159
Table 1
Table 2
Optimization of the catalyst
N-acetylation of different amines
Entry
Substrates
NH2
Products
Yielda (%)
O
H
NH2
NH
N
CH3CN
1
79
NO2
NH2
O
NO2
Catalyst, Condition
H
N
1
2
2
3
4
81
78
76
O
Entry
Reagentsa
Condition
Catalyst
Time
Yieldb (%)
NO2
1
2
3
4
5
6
7
8
TMSCl
110 °C
110 °C
110 °C
110 °C
110 °C
110 °C
110 °C
110 °C
110 °C
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
100 mol %
20 mol %
48 h
36 h
24 h
48 h
36 h
48 h
36 h
36 h
0
NO2
Cu(OAc)2
TMSCl-KI
FeCl3
20
80
10
5
0
10
0
0
80
80
NH2
H
N
Cl
InCl3
O
Cl
BF3ÁEt2O
Mn(OAc)2
Bi(NO3)3
AlCl3
TMSCl-KI
TMSCl-KI
NH2
H
N
9
10
11
36 h
15 min
15 min
O
O
l
l
W, 110 °C
W, 110 °C
F
F
a
NH2
Br
H
N
1 mmol of aniline was refluxed in CH3CN in the presence of 0.2 mmol catalyst.
Yields refer to isolated yield of the products.
b
5
6
75
77
Br
NH2
NH2
H
N
continuation of our work on trimethylsilyl iodide catalyzed
reactions of amides,7 herein, we wish to report a process for selec-
tive acetylation of aromatic amines using acetonitrile as acylating
agent.
Br
O
O
Br
H
N
To start with, reaction of aniline (1) was studied using acetoni-
trile both as reagent and solvent. A number of different Lewis acids
were employed for the study (Table 1). While most of the Lewis
acids were unable to carry out any reaction, Cu(OAc)2, FeCl3, and
Mn(OAc)2 produced a small amount of acylation product (entries
2, 4, 7, Table 1). A very good yield of the product acetanilide could
be obtained when trimethylsilyl iodide (TMSI), prepared in situ
from trimethylsilyl chloride and potassium iodide, was used as
the catalyst (entry 3, Table 1). The reaction required 12 h of reflux
under normal heating condition. Inspired by the earlier report of
dramatic rate enhancement of different reactions by microwave
irradiation,8 the reaction was repeated under microwave heating
condition. This time the reaction completed within 15 min. The
requirement of the amount of catalyst was also standardized using
different amounts of TMSI. It was observed that 20 mol % of
catalyst was enough for the complete conversion of the starting
material. At the optimal condition, a solution of aniline in acetoni-
trile was heated under microwave irradiation at 110 °C for 15 min
in the presence of catalytic amount of TMSI.9
Using the optimized reaction condition a number of different
aniline derivatives were acetylated (Table 2). It was observed that
the reaction was equally applicable to the substrates having both
electron withdrawing (entries 1–7, Table 2) and donating (entries
8–10, Table 2) groups. Sensitive functional group like alkynes
remains intact under the reaction condition (entry 12, Table 2).
An interesting result was obtained when reaction of 3-aminophe-
nol was studied (entry 11, Table 2). The reaction provided a
monoacetylated product. Careful observation of the 13C NMR spec-
tra of the product showed that there was a peak at d 157.3 corre-
sponding to an aromatic carbon attached to free –OH. No peak at
d 151 corresponding to C-NH2 and a peak at d 138.5 corresponding
to C-NHAc, proved the selective acetylation of amine group in the
presence of phenolic OH. All the prepared compounds were well
characterized by the help of regular spectroscopic methods like
IR, 1H NMR, and 13C NMR. Also the physical properties of a few
products were compared to that obtained via conventional pro-
cesses. To expand the scope of the reaction, aliphatic amines like
phenylethyl amine and 2-(cyclohex-1-en-1-yl)ethan-1-amine
7
8
9
Me
75
73
70
Me
NO2
NO2
NH2
Me
H
N
Me
O
Me
Me
NH2
H
N
MeO
O
MeO
OMe
OMe
O
NH2
NH2
NH
10
75
NH
O
NH2
NH2
H
N
11
12
63
68
O
OH
OH
H
N
O
NH2
NH2
H
N
13
14
0
0
O
H
N
O
a
Yields refer to isolated yield of the products.
were studied (entries 13 and 14, Table 2). Surprisingly, no product
was formed even after 30 min of microwave heating.

1160
U. P. Saikia et al. / Tetrahedron Letters 57 (2016) 1158–1160
References and notes
I
Si
Si
N
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9. General Procedure for acetylation: TMSCl (0.1 mL, 0.8 mmol) and KI (132 mg,
0.8 mmol) was dissolved in CH3CN (2 mL) in a 10 mL microwave reaction vial.
The mixture was allowed to stir for 15 min when a deep yellow color generated.
The amine (4 mmol) dissolved in CH3CN (4 mL) was added. Sealed with a Teflon
septum, the mixture was heated under microwave for 15 min at 110 °C. After
cooling, CH3CN was removed in vacuum. The mixture was extracted with ethyl
acetate (2 Â 20 mL) and the combined organic layer was washed with water,
sodium thiosulfate, sodium bicarbonate, and brine. Drying over Na2SO4 and
removal of the solvent under reduced pressure, produced the crude mixture
which was purified by column chromatography.
NH
O
H2O
N
N
H
H
Scheme 2. A plausible mechanism for the N-acetylation.
Mechanistically, it may be proposed that electron rich nitriles
get activated by the co-ordination with TMSI (Scheme 2).
Nucleophilic attack of amine to the activated nitrile produces an
amidine which is then hydrolyzed to amide. Aromatic amines,
being poor base, do not form strong complex with TMSI and thus
easily react with nitrile. On the other hand, aliphatic amines react
with TMSI and form an insoluble complex which prevents further
reaction.
In conclusion, we have developed a mild and efficient process
for N-acetylation of aromatic amines without the use of toxic/
prohibited reagents like acetic anhydride or acetyl chloride. The
reaction is selective toward aromatic amines. Milder reaction
conditions, short reaction time, no requirement of any extra
chlorinated solvents are among the few important features of the
reaction. Works on the application of the process toward more
complex system are going on.
Acknowledgments
The work is financially supported by DST-SERB, New Delhi,
India (GPP0299) and CSIR, New Delhi, India (MLP3000/03 and
CSC0131). The authors thank analytical facility CSIR-NEIST for
recording the spectral data. The authors are also thankful to Ms.
Sampurna Bordoloi for carrying out some initial experiments.
Supplementary data
Supplementary data (experimental procedure and the charac-
terization data of all the synthesized compounds) associated with
this article can be found, in the online version, at http://dx.doi.
org/10.1016/j.tetlet.2016.01.108.