Efficient synthesis of primary amides from carboxylic acids using n,n'-carbonyldiimidazole and ammonium acetate in ionic liquid

Article abstract of DOI:10.1080/00397911.2010.518331

A novel and efficient method for the conversion of carboxylic acids to primary amides using N,N'-carbonyldiimidazole in combination with ammonium acetate/triethyl amine system in [BMIM]BF₄ is developed.

Full text of DOI:10.1080/00397911.2010.518331

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Efficient Synthesis of Primary Amides
from Carboxylic Acids Using N,N′-
Carbonyldiimidazole and Ammonium
Acetate in Ionic Liquid
Kwan Soo Lee a & Kee D. Kim b
a Department of Chemistry, KAIST, Daejeon, South Korea
b Department of Fine Chemical and Advanced Materials, Sangji
University, Wonju, South Korea
Accepted author version posted online: 30 Jun 2011.Version of
record first published: 27 May 2011.
To cite this article: Kwan Soo Lee & Kee D. Kim (2011): Efficient Synthesis of Primary Amides from
Carboxylic Acids Using N,N′-Carbonyldiimidazole and Ammonium Acetate in Ionic Liquid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:23, 3497-3500
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Synthetic Communications1, 41: 3497–3500, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518331
EFFICIENT SYNTHESIS OF PRIMARY AMIDES
FROM CARBOXYLIC ACIDS USING
N,N’-CARBONYLDIIMIDAZOLE AND AMMONIUM
ACETATE IN IONIC LIQUID
Kwan Soo Lee1 and Kee D. Kim2
1Department of Chemistry, KAIST, Daejeon, South Korea
2Department of Fine Chemical and Advanced Materials, Sangji University,
Wonju, South Korea
GRAPHICAL ABSTRACT
Abstract A novel and efficient method for the conversion of carboxylic acids to primary
amides using N,N0-carbonyldiimidazole in combination with ammonium acetate/triethyl
amine system in [BMIM]BF4 is developed.
Keywords Amide; ammonia; carboxylic acid; ionic liquid
INTRODUCTION
The conversion of carboxylic acids to the corresponding primary amides is a
fundamental and important transformation in organic synthesis.[1,2] Direct prep-
aration of primary amides via the reaction of carboxylic acids with ammonia required
very high reaction temperature, elevated pressure, and long reaction times.[3] Prep-
aration of primary amides has been generally achieved by the activation of carboxylic
acids to the more reactive carboxylic acid derivatives prior to the reaction with
ammonia. The activation of carboxylic acids can be commonly achieved by use of
the various reactive coupling reagents such as N,N-dicyclohexylcarbodiimide
(DCC),[4] N-halosuccinimide=triphenyl phophine,[5] ArB(OH)2,[6] di-tert-butyl pyro-
carbonate,[7] chlorosulfonyl isocyanate,[8] Sn[N(TMS)2]2,[9] 2-mercaptopyridone-1-
oxide-based uronium salts,[10] and silica-supported ammonium salts=tosyl chloride.[11]
Although all of these methods have some degree of general utility, most of them have
several disadvantages such as use of exotic reagents, difficult operation, drastic reac-
tion conditions, and long reaction times. In recent years, N,N0-carbonyldiimidazole
(CDI) has been successfully used for the activation of carboxylic acids to form an acyl
Received June 21, 2010.
Address correspondence to Kee D. Kim, Department of Fine Chemical and Advanced Materials,
Sangji University, Wonju, South Korea. E-mail: kdkim@sangji.ac.kr
3497

3498
K. S. LEE AND K. D. KIM
Scheme 1.
imidazole intermediate, which undergoes subsequent reaction with amines to afford
carboxamides.[12,13] However, this method has been applicable only for the prep-
aration of secondary and tertiary amides under organic solvents such as chloroform,
tetrahydrofuran (THF), and 2-methyltetrahydrofuran. To the best of our knowledge,
CDI-mediated conversion of carboxylic acids to the corresponding primary amide has
been unprecedented, probably because of the low solubility of ammonium salts as
source of ammonia in organic solvents. Therefore, we envisioned the highly polar ionic
liquid medium could promote the reaction of acyl imidazole intermediate with
ammonium acetate to provide primary amides.
Herein, we report a new procedure for the efficient preparation of primary
amides by the reaction of carboxylic acids with CDI and ammonium acetate in ionic
liquid medium. We found the sequential treatment of carboxylic acids with CDI and
ammonium acetate=triethylamine in 1-butyl-3-methylimidazolium tetrafluoroborate,
[BMIM]BF4,. ionic liquid successfully afforded primary amides. Treatment of acyl
imidazole intermediate, performed via the reaction of carboxylic acid with CDI in
[bmim]BF4 with ammonium acetate and triethylamine at 80 ꢀC in the same reaction
vessel gave the corresponding primary amides in good yield (Scheme 1). We have
examined the effect of various reagents as the source of nonvolatile ammonia, which
include ammonium acetate, ammonium carbamate, ammonium formate, and
urea. The best experimental results were obtained with ammonium acetate in terms
of yields and reaction times at the present reaction conditions. To demonstrate
Table 1. Preparation of primary carboxamides from carboxylic acids
Entry
Substrate
Product
Yield (%)a
1
2
PhCO2H
PhCONH2
92
90
88
90
92
86
84
85
88
87
88
90
90
88
2-Cl-C6H4CO2H
4-Br-C6H4CO2H
4-Me-C6H4CO2H
4-MeO-C6H4CO2H
2-NO2-C6H4CO2H
4-NO2-C6H4CO2H
4-CN-C6H4CO2H
PhCH2CO2H
2-Cl-C6H4CONH2
4-Br-C6H4CONH2
4-Me-C6H4CONH2
4-MeO-C6H4CONH2
2-NO2-C6H4CONH2
4-NO2-C6H4CONH2
4-CN-C6H4CONH2
PhCH2CONH2
3
4
5
6
7
8
9
10
11
12
13
14
CH3(CH2)3CH2CO2H
BrCH2(CH2)4CO2H
PhCH¼CHCO2H
PhOCH2CO2H
CH3(CH2)3CH2CONH2
BrCH2(CH2)4CONH2
PhCH¼CHCONH2
PhOCH2CONH2
Nicotinic acid
Nicotinamide
aPure isolated yields.

EFFICIENT SYNTHESIS OF PRIMARY AMIDES
3499
the scope and generality of the present protocol, the amidation reactions were
applied to a variety of carboxylic acids. The results of preparation of a variety of
carboxamides are summarized in Table 1. As shown in the Table 1, both
electron-donating and electron-withdrawing substituents in the aromatic rings had
relatively minor influence on the efficiency of reactions. Aliphatic carboxylic acids
can be also smoothly converted to the corresponding primary amides (entries 10
and 11). Amidation reactions can be successfully carried out in the presence
of various sensitive functionalities such as alkyl halide, alkene, and phenyl ether
(entries 11–13).
In summary, we have developed a highly efficient, practical method for the
conversion of carboxylic acids into the corresponding primary amides by use of
readily available CDI and ammonium acetate in [BMIM]BF4. Good yields, short
reaction times, and clean reactions make this method an attractive and useful
contribution to the other existing methodologies.
EXPERIMENTAL
All the carboxylic acids were obtained commercially. The 1-butyl-3-methylimi-
dazolium tetrafluoroborate was obtained from Fluka. The NH4OAc was obtained
from Aldrich. Merck silica gel 60 (230–400 mesh) was used for flash column chroma-
tography. The isolated products were characterized by infrared (IR), NMR, and mass
spectroscopy and compared with the reported literature data of authentic samples.
N,N0-carbonyldiimidazole (0.195 g, 1.2 mmol) was added to a solution of car-
boxylic acid (1.0 mmol) in [bmim]BF4 (2 mL). The resulting mixture was stirred at
80 ꢀC for 2 h. Ammonium acetate (0.308 g, 4.0 mmol) and triethylamine (0.304 g,
3.0 mmol) were added to the reaction mixture. The reaction was heated at 80 ꢀC
for 3 h. After completion of the reaction, the product was extracted with ethyl
acetate (2 ꢁ 30 mL), washed with 0.01 N solution of HCl (30 mL), and dried over
anhydrous MgSO4. The solvent was evaporated in vacuo, and the crude product
was purified by silica-gel column chromatography using EtOAc=n-hexane (1:2) to
give the pure caboxamide.
ACKNOWLEDGMENT
This research was supported by Sangji University Research Fund, 2010.
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