Convenient N-acetylation of amines in N,N-dimethylacetamide with N,N-carbonyldiimidazole

Article abstract of DOI:10.1016/j.tetlet.2015.04.077

Dimethylacetamide (DMAc) acts as an efficient source of acetyl and dimethylamine gas in the presence of N,N-carbonyldiimidazole (CDI). Addition of amines to the reaction mixture delivers the corresponding amides in good to excellent yields. The acetylation of amines reported herein, which relies on the in situ generation of N-acetylimidazole on warming of DMAc with CDI at 120-125 °C, serves as a convenient alternative to other acetylation methods.

Full text of DOI:10.1016/j.tetlet.2015.04.077

Accepted Manuscript
Convenient N-acetylation of amines in N,N-dimethylacetamide with N,N-car-
bonyldiimidazole
Anil Chikkulapalli, Sanjeev Kumar Aavula, Rifahath Mona, C. Karthikeyan,
C.H. Vinodh Kumar, G. Manjunatha Sulur, Sumathi Shanmugam
PII:
S0040-4039(15)00723-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.04.077
TETL 46216
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 January 2015
19 April 2015
20 April 2015
Please cite this article as: Chikkulapalli, A., Aavula, S.K., Mona, R., Karthikeyan, C., Vinodh Kumar, C.H.,
Manjunatha Sulur, G., Shanmugam, S., Convenient N-acetylation of amines in N,N-dimethylacetamide with N,N-
carbonyldiimidazole, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.077
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Convenient N-acetylation of amines in N,N-
dimethylacetamide with N,N-
carbonyldiimidazole
Leave this area blank for abstract info.
a
a
a
Anil Chikkulapalli a,b, Sanjeev Kumar Aavula , Rifahath Mona , Karthikeyan C , Vinodh Kumar CHa ,
Manjunatha Sulur G a and Sumathi Shanmugam b,*
CDI
DMAc
H
N
NH2
120-125 oC
O
FG
FG
FG = Br, Me, CH(CH3)2, OMe, CN, CONH2, N(CH3)2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Convenient N-acetylation of amines in N,N-dimethylacetamide with N,N-
carbonyldiimidazole
a
a
Anil Chikkulapalli a,b, Sanjeev Kumar Aavula , Rifahath Mona a, Karthikeyan C , Vinodh Kumar CHa ,
Manjunatha Sulur G a & Sumathi Shanmugam b,*
a Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Off Bellary Road, Hebbal, Bangalore 560 024, India
b Department of Chemistry, VIT University, Vellore, 574199, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Dimethylacetamide (DMAc) acts as an efficient source of acetyl and dimethylamine gas in
presence of N,N-carbonyldiimidazole (CDI). Addition of amines to the reaction mixture delivers
the corresponding amides in good to excellent yields. The acetylation of amines reported herein,
which relies on the in situ generation of N-acetylimidazole on warming of DMAc with CDI at
120-125oC, serves as a convenient alternative to other acetylation methods.
Available online
Keywords: Acetylation, amines, carbonyldiimidazole, N,N-dimethylacetamide, imidazole
2009 Elsevier Ltd. All rights reserved.
N-Acetylation of amines is a common and routinely utilized
method as a protecting group in organic synthesis.1 These amides
have wide industrial applications, for example, the amides are
important chemical compounds for various pharmaceutical,
polymers and agrochemicals.2 Traditionally N-acetylation is
carried out by the reaction of amines with carboxylic acid
derivatives such as acetic anhydride, lachrymatory acetyl
chloride or esters or acids.3 However, there are a number of
problems associated with the use of acyl chlorides and acid
anhydrides in N-acetylation reactions.4 For example, many acid
chlorides and acid anhydrides are moisture sensitive and due to
its high reactivity, the acid chloride has the disadvantage of being
liable to decomposition and give side reactions, thereby
producing a product of low purity. Hence, a new method for the
acetylation of amines without use of these two reagents would be
useful.
by-products, and (iv) excellent chemical yields for wide variety
of substrates.
We started our studies on N-acetylation of aniline as a model
reaction. First, CDI was added to dimethylacetamide solvent and
heated to 150-155°C for 1 h, minor foaming was observed. The
reaction mass was then cooled to 60-65oC and aniline 1 was
added. After 60 minutes, HPLC analysis of the reaction mixture
showed that the reaction had proceeded in 100% conversion to 2.
After diluting the reaction mixture with water the product was
extracted with isopropyl acetate. The solvent was concentrated
to give the N-phenylacetamide 2 (Table 1, entry 1) in 85% yield
with >98% (hplc area by percentage) pure sample. Reaction with
less mole equivalents of CDI with decreased temperature had
also resulted >80% of N-acetylated product (Table 1, entries 2
and 3), but the reaction was slower and taken longer time for
completion. A similar reaction performed without using CDI
reagent did not render the product (Table 1, entry 4). Upon
varying the temperature of the reaction between 60-95oC, a
complete lack of reactivity was observed (Table 1, entries 5 and
6).
Recently, we reported a novel method for the conversion of
carboxylic acids into N,N-dimethylamides using N,N-dimethyl-
acetamide as a dimethylamine source in the presence of CDI at
160–165°C.5 Along with N,N-dimethylamide products, 1-acetyl
imidazole was observed as a by-product and this observation
prompted us to further explore the DMAc solvent as an efficient
N-acetylating agent in presence of CDI. Replacing the carboxylic
acid with amines one could easily expect the acylation of amine.
To the best of our knowledge, this is the first convenient
procedure developed for the efficient N-acetylation of amines
using DMAc in combination with CDI. This protocol is
convenient for N-acetylation as it has several advantages over the
previous methods reported in the literature which includes (i)
inexpensive reagents, shorter reaction times and easy workup
procedure, (ii) operational simplicity, (iii) highly water soluble
CDI
DMAc
2
1
Scheme 1. N-Acetylation of aniline
b, Corresponding author. Tel.: +91 9789685252
e-mail: sumathishanmugam2003@gmail.com

2
Tetrahedron
peak corresponding to N-acetyl imidazole D was seen in LCMS
Table 1. N-Acetylation of aniline 1 under different reaction
conditions.a
suggesting that N-acetyl imidazole might be hydrolysed to
imidazole under these conditions. When warmed CDI and DMAc
mixture was treated with N-methylaniline, N-methyl-N-phenyl
acetanilide (Table 2, entry 22) was observed as a product along
with N,N-dimethylimidazole-1-carboxamide C and imidazole as
by-products. Surprisingly N-methylaniline has not reacted with C
to yield N,N-dimethylurea G and can be easily washed out by
aqueous acidic workup from reaction mixture.
CDI
Imidazole
Temp
(oC)
Time Conversion (%)b
Entry
(mol equiv) (mol equiv)
(h)
1
2
1
2
3
4
5
6
7
2.0
1.0
1.0
--
--
--
155-160
155-160
120-125
155-160
60-65
85
2
84
--
4
80
--
24
6
No reaction
No reaction
No reaction
No reaction
2.0
2.0
--
--
--
90-95
6
Pathway 1
Pathway 2
2.0
120-125
6
aReaction was carried out by warming DMAc (2 mL) and CDI/Imidazole
mixture, and the resultant solution was cooled to 60-65 oC followed by
addition of aniline 1 (1.0 g, 0.01 mol) with vigorous stirring.
-CO2
bDetermined by HPLC
A
A
According to Hudson and et al.,6 the formation of acetanilide 2
presumed to be a nucleophilic attack of imidazole on DMAc that
might have generated the reactive species of N-acetyl imidazole,
so it is possible that the liberated N-acetyl imidazole reacts with
the amine to yield the corresponding N-acetylated product
(Scheme 2). Further we thought that the CDI completely
decomposed to imidazole because of prolonged storage might
have triggered this reaction path and decided to employ
imidazole as an external base source to consider whether the N-
acetylation is accessible (Scheme 2). To our surprise, a complete
lack of reactivity was observed (Table 1, entry 7).
B
B
C
D
G
C
-H+
N-Acetylimidazole
F
D
R-NH2
E
Scheme 3: A proposed mechanism of N-acetylation of N-methyl-
R
aniline with CDI and DMAc solvent
This successful N-acetylation protocol was then applied to a
range of amines and the results are summarized in Table 2. The
acetylation reactions of aniline, o/m/p-anisidine, m/p- toluidine
and p-isopropyl aniline proceeded well, allowing the amide
products to be isolated in around 85-92% yield, (Table 2, entries
1-7).7 Even the reactions with disubstituted amines like 3-bromo-
5-methyl-aniline (Table 2, entry 8)7 and 4-methoxy-2-methyl-
aniline (Table 2, entry 9)7 were successfully produced N-(3-
bromo-5-methyl-phenyl)acetamide and N-(4-methoxy-2-methyl-
phenyl) acetamide in good yields. The acetylation reaction was
equally worked well for even the presence of electron
withdrawing group like 2-aminobenzonitrile, 4-aminobenzo-
nitrile, and 2-aminobenzamide to give N-(2-cyanophenyl)-
acetamide, N-(p-cyanophenyl)acetamide, and 2-acetamido-
benzamide (Table 2, entries 10-12)7 in moderate to good yields.
This methodology was also investigated on the heterocyclic
systems like 5-chloropyridin-2-amine (Table 2, entry 13), and 5-
methoxypyridin-2-amine (Table 2, entry 14) were successfully
produced N-(5-chloro-2-pyridyl)acetamide and N-(5-methoxy-2-
pyridyl)acetamide in good yields. The reaction also explored on
electron poor systems like 5-nitro-pyridin-2-amine to give N-(5-
nitro-2-pyridyl)acetamide with 70% (Table 2, entry 15). Next, the
acetylation protocol was explored on primary amines like
benzylamine (Table 2, entry 16), N,N-dimethylamino benzyl-
amine (Table 2, entry 17)7 and 1-phenyl- ethanamine (Table 2,
entry 18)7 examined under the similar conditions. Acetylation
was proceeded smoothly to give the corresponding amides above
Scheme 2: A proposed mechanism of N-acetylation of amines from
DMAc and imidazole
Regarding the mechanism, there are two possibilities as shown
in Scheme 3. According to pathway 1, the N,N-dimethyl-
acetamide with CDI at 120-125oC could produce an electrophilic
1-imidozol-1-ylethylidene(dimethyl)-ammonium
salt
A.
Nucleophilic attack of the amine with reactive species of A lead
to a tetrahedral intermediate B, which collapse to form the
reactive species C, followed by hydrolysis to get desired N-
acetylated product of amine F. Alternatively N,N-
dimethylacetamide with CDI at 120-125oC could produce a [1-
(dimethylamino)-1-imidazol-1-yl-ethyl]imidazole-1-carboxylate
A (Scheme 3, pathway 2), followed by an intramolecular
rearrangement leading to intermediate B. Collapse of B lead to
formation of N,N-dimethylimidazole-1-carboxamide
C and
reactive species N-acetyl- imidazole D. Nucleophilic attack of the
amine on N-acetyl imidazole give a tetrahedral intermediate E,
followed by elimination of imidazole to get desired N-acetylated
product of amine F.
To understand the reaction mechanism, a sample of warmed
CDI and DMAc reaction mixture was subjected to liquid
chromatography mass spectrometry (LCMS) after quenching
with water. A peak corresponding to mass 140 (M+H)+ was
observed along with DMAc and imidazole, which corresponds to
the structure of N,N-dimethylimidazole-1-carboxamide C and no

3
85% respectively. We also explored the reaction on non benzylic
volatile primary amines like butylamine (Table 2, entry 19) and
isobutylamine (Table 2, entry 20). GC analysis of the reaction
mixture showed that the reaction had proceeded in 100%
conversion, but the isolated yields of products were very low.
Low yield presumed to be high volatile nature of amines or
amide products. Next, we were interested to see the acetylation
on secondary amines; therefore 1-phenylpiperzine was subjected
to the optimised procedure. The acetylation proceeded smoothly,
yielding the desired product in good yield (Table 2, entry 21).7 N-
methylaniline also reacted to give tertiary amide in 86% yield
(Table 2, entry 22). However, the acetylation of the more
sterically hindered N-phenylaniline was unsuccessful, with no
amide product even on prolonged time of 10 h (Table 2, entry
23).7
16
17
2
2
86
89
18
19
20
21
22
2
2
2
2
2
86
46
52
87
86
Table 2: N- Acetylation of anilines and benzyl amines using
DMAc and CDIa
Entry
Substrate
Product
Time (h)
Yield(%)b
23
10
0
1
2
2
2
90
85
a
Reaction conditions: Amine (1.0 equiv), CDI (1.0 equiv), DMAc (1 mL),
temperature 120-125oC and time 2-6 h.
b Isolated yields
After successful N-acetylation protocol by conventional
method we then carried out reactions by microwave irradiation
method. In the conventional method, the total time for the N-
acetylation reaction was found to vary from 2 to 6 h. When the
same reactions were carried out by microwave irradiation, the
total reaction found to be in the range of 0.5 to 1 h and yield of
the products were marginally improved by 2-5% as compared to
that in the conventional method. The reaction time and yield of
the selected products by conventional and microwave irradiation
methods are tabulated in Table 3.
3
4
2
88
2
2
91
86
5
6
7
2
86
Table 3: Reaction time and yield of the products by
conventional and microwave irradiation methods.
Conventional
method
Microwave
Method
2
2
92
82
Entry
Substrate
Product
Reaction Yield Reaction Yield
8
time (h)
(%)
time (h)
(%)
9
2
6
6
85
60
73
1
2
2
2
90
85
0.5
0.5
92
86
10
11
3
4
5
6
6
2
60
73
80
1.0
1.0
1.0
65
75
82
12
13
14
2
2
2
6
83
80
84
70
In summary, we have developed a highly efficient and
convenient protocol for N-acetylation of amines using N,N-
dimethylacetamide with carbonyldiimidazole. This protocol is
convenient for acetylation as it has several advantages over the
previous methods reported in the literature and the process was
15

4
Tetrahedron
efficiently applied to variety of amines to produce the
(4) (a) Murakami, Y.; Kondo, K.; Miki, K.; Akiyama, Y.; Watanabe, T.;
corresponding amide products in good to excellent yields.
Yokoyama, Y. Tetrahedron Lett. 1997, 38, 3751. (b) Kondo, K.;
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Wakasugi, K.; Nakamura, A.; Tanabe, Y. Tetrahedron Lett. 2001, 42,
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Acknowledgments
We thank Sudhir Nambiar, R. Sridharan, Ramachandra
Puranik, and Bill Moss for useful discussions in the manuscript
preparation.
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Conventional Method: CDI (1.74 g, 0.01 mol) was added to
dimethylacetamide solvent (1.0 mL) and were heated to 120-125°C for 0.5 h.
Cooled the solution to 60-65oC and aniline (1.0 g, 0.01 mol) was added. After
1.5 h, HPLC analysis of the crude product showed that the reaction had
proceeded to 100% conversion. The reaction solution was cooled to 20-25oC
and quenched with water (15 mL). The reaction mixture was extracted with
isopropyl acetate (2 x 10 mL). The combined organic layer was washed with
1% aqueous HCl solution (2 x 10 mL), dried over anhydrous Na2SO4 and
filtered. The filtrate was evaporated under vacuum to give 1.3 g (90 %) of N-
phenylacetamide (Table 1, entry 1).
Microwave Method: CDI (1.74 g, 0.01mol) was added to DMAc solvent
(1.0 mL) and heated to 120-125°C for 0.5 h. The reaction mass was then
cooled to 60-65oC and aniline (1.0 g, 0.01 mol) was added. Reaction contents
were then irradiated with microwave radiation at 490 W till the reaction was
complete. The reaction mixture was processed in the similar way as that in
the conventional method.
All experiments were run on a 1.0 g scale. The yields refer to isolated
yields. All products gave satisfactory analytical data. Identification of the
products was carried out by 1HNMR, and mass spectroscopic analytical
techniques. All the products are known compounds and are easily identified
by comparison of their physical properties with those of authentic samples.