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Chemistry Letters Vol.36, No.12 (2007)
Highly Efficient Method for the Synthesis of Carboxamides from Carboxylic Acids
and Amines Using Benzenesulfonic Anhydride (BSA)
Setsuo Funasaka,1 Koji Kato,1 and Teruaki Mukaiyamaꢀ1;2
1Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
2Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received September 25, 2007; CL-071055; E-mail: mukaiyam@abeam.ocn.ne.jp)
Table 1. Synthesis of carboxamide using DMAP as an activator
A highly efficient method by using benzenesulfonic anhy-
dride (BSA) in the presence of 4-(dimethylamino)pyridine
(DMAP) to synthesize carboxamides from various carboxylic
acids and amines including sterically hindered ones is establish-
ed. This reaction proceeds smoothly to provide the desired prod-
uct in high yield.
O OO O
S
S
O
O
O
R2NH2
1
+
R1 OH
2 (1.1 mol amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
R1
NHR2
DMAP
3 (1.0 mol amt.)
4
CH2Cl2, rt, 1 h
Entry
BSA/mol amt.
DMAP/mol amt.
Yielda/%
89
68
82
quant.
Preparation of carboxamides from carboxylic acids and
amines is one of the most fundamental and important steps for
the syntheses of various natural and unnatural compounds,
and, therefore, various dehydrating methods for it have been re-
ported to date.1–11
1
2
3
4
1.1
1.1
1.1
1.2
2.2
1.2
2.4
2.4
aIsolated yield.
Among them, carboxylic anhydride derivatives such as aro-
matic carboxylic anhydrides are known to be powerful reagents
in the dehydration reaction.3,7 It was previously reported from
our laboratory that an effective method for the synthesis of car-
boxylic esters or carboxamides using pyridine-3-carboxylic an-
hydride (3-PCA) in the presence of 4-(dimethylamino)pyridine
(DMAP) as the activator.12 However, it was observed that the
yield of carboxylic esters or carboxamides decreased since the
yield of by-product increased in the cases of carboxylic acids
such as benzoic acid and cinnamic acid due to the factor of steric
and leaving-group ability.
On the basis of the above background, we focused on a link-
er moiety of the carboxylic anhydride, and sulfonic anhydride
derivatives such as benzenesulfonic anhydride were chosen. To
the best of our knowledge, no general procedures for the prepa-
ration of carboxamides from carboxylic acids and amines by us-
ing sulfonic anhydrides as a dehydrating agent have been report-
ed. Sulfonic anhydrides are known as good sulfonylation re-
agents owing to their leaving ability. Thus, the mixed anhydride
intermediates are expected to be easily formed at the first step in
this condensation reaction.
Table 2. Effect of activators
O OO O
S
S
O
O
O
R2NH2
1 (1.2 mol amt.)
activator (2.4 mol amt.)
+
R1 OH
R1
NHR2
CH2Cl2, rt, 1 h
2 (1.1 mol amt.) 3 (1.0 mol amt.)
4
R1 = Ph(CH2)2 R2 = Ph(CH2)3
Entry
1
2
Activator
DMAP
PPY
Yielda/%
quant.
87
93
93
33
3
N-Methylimidazole
N-Butylimidazole
HOBt
N-Methylmorpholine
TEA/cat. DMAPc
4
5b
6
64
77
7
aIsolated yield. bThe reaction was carried out in the presence
of N-methylmorpholine (2.4 mol amt.). c2.4 mol amt. of TEA
and 0.1 mol amt. of DMAP were used.
the yield was not improved (Entry 3). On the other hand, the re-
action of 1.2 molar amount of BSA with 2.4 molar amount of
DMAP gave quantitative yield of the carboxamide.13
Herein, we would like to describe a simple and efficient
method for the synthesis of carboxamides by using commercial-
ly available benzenesulfonic anhydride (BSA) as a dehydrating
agent.
The effect of activators was further examined (Table 2).
Then, 4-(1-pyrrolidinyl)pyridine (PPY) as DMAP derivative
was also successfully employed in this reaction and the desired
carboxamide was afforded in good yield (Entry 2). It was con-
firmed that imidazole derivatives such as N-methylimidazole
and N-butylimidazole gave good results similar to the case of us-
ing DMAP (Entries 3 and 4). In contrast, the yield decreased
markably down to 33% when 1-hydroxybenzotriazole (HOBt)
was used (Entry 5). In the case of using excess amount of trieth-
ylamine (TEA) and catalytic amount of DMAP the yield de-
creased to 77% (Entry 7).
In the first place, the reaction of 3-phenylpropionic acid and
3-phenylpropylamine as a model substrate in the presence of
DMAP and BSA was examined in CH2Cl2 at room temparature
(Table 1). As a result, in the case when 1.1 molar amount of BSA
with 2.2 molar amount of DMAP were used, the reaction pro-
ceeded smoothly within 1 h to provide 3-phenyl-N-(3-phenyl-
propyl)propanamide as the desired carboxamide in 89% yield
(Entry 1). Then, the reaction was further investigated about the
amount of reagents, namely BSA and DMAP. It was found that
the yield of carboxamide decreased to 68% when the amount of
DMAP was reduced to 1.2 molar amount (Entry 2). Further, even
when the amount of DMAP was increased to 2.4 molar amount,
In the next place, the effect of solvents was examined
(Table 3). The results obtained by the reactions in CH2Cl2,
MeCN, and DMF were also excellent (Entries 1, 3, and 4).
Whereas, in the case of using THF or toluene, the yield of de-
Copyright Ó 2007 The Chemical Society of Japan
Funasaka, Setsuo
