506
Chemistry Letters Vol.37, No.5 (2008)
Highly Efficient Method for the Synthesis of Carboxamides from Carboxylic Acids
and Amines Using Pyridine-3-sulfonyl Chloride (3-PSC)
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 February 27, 2008; CL-080223; E-mail: mukaiyam@abeam.ocn.ne.jp)
The use of pyridine-3-sulfonyl chloride (3-PSC) in dehy-
reaction was found to proceed smoothly within 1 h to provide
the desired carboxamide in 99% yield (Table 1, Entry 1), and
the by-products such as pyridine-3-sulfonic acid and pyridine-
3-sulfoxamide formed in this reaction were found to be easily
removed by aqueous workup.13 Further, the effect of activators
was investigated. As the result, in the cases where a DMAP
derivative such as 4-(1-pyrrolidinyl)pyridine (PPY) and an imi-
dazole derivative such as N-methylimidazole or N-butylimida-
zole were used the carboxamides were obtained in high yield
respectively (Entries 2–4). Among them, DMAP was found to
give the best result (Entry 1).
The effect of solvent was further examined as shown in
Table 2. The results obtained by using CH2Cl2 or MeCN were
also excellent (Entries 1 and 2). On the other hand, in the case
of using DMF, THF, or toluene, the carboxamide was obtained
in moderate yields (Entries 3–5).
Several examples of carboxamides obtained by using 3-PSC
as a dehydrating reagent are listed in Table 3.14 In most cases, the
reactions of 3-phenylpropionic acid proceeded smoothly at room
temperature within 1 h to form the corresponding carboxamides
in good to high yields even when hindered amine such as tert-
butylamine was used (Entry 6). Even in the cases of hindered
ꢀ,ꢀ-disubstituted carboxylic acids such as diphenylacetic acid,
the desired products were afforded in high yields (Entries 7
and 8). It was noteworthy that this protocol is applicable to
the carboxylic acids such as benzoic acid, cinnamic acid, and
drating condensation was investigated. This novel reagent was
successfully employed as a mild dehydrating reagent for prepar-
ing various carboxamides in good to excellent yields from the
corresponding carboxylic acids and amines.
To prepare carboxamide is one of the most important and
fundamental reactions in synthetic chemistry since there exist
numerous natural or unnatural bioactive compounds having
carboxamide moieties. Thus, mild and efficient condensation
methods for synthesizing carboxamides have been developed
and widely employed in the syntheses of many natural products
to date.1–11
In our previous communication, an efficient method for
the syntheses of carboxamides by using pyridine-3-carboxylic
anhydride (3-PCA) with 4-(dimethylamino)pyridine (DMAP)
as the activator was reported.12a–12c One of the features in this
reaction is that the by-products such as pyridine-3-carboxylic
acid and pyridine-3-carboxamide formed are easily removed
by aqueous workup. This method, however, has some drawbacks
that the yield of carboxamide decreased in the case of carboxylic
acid such as benzoic acid or cinnamic acid. The reason of low
yield may be due to the steric factor of the substrate, that is, there
is not such a steric bulk difference between a phenyl ring and a
pyridine ring in the mixed anhydride formed from 3-PCA and
benzoic acid in situ.
Then, in order to improve the yield we focused on the linker
moiety of carboxylic anhydride, and benzenesulfonic anhydride
(BSA) was found to show high reactivity even in the case of
benzoic acid or cinnamic acid to provide the corresponding
carboxamides in excellent yields.12d On the other hand, since
by-product such as sulfoxamide derived from the condensing
reagent was obtained in some cases this method requires purifi-
cation by using silica gel column chromatography to remove by-
products. Then, as our continuous investigation for the purpose
of extending the utility of BSA in the point of the purification
pyridine-3-sulfonyl chloride (3-PSC; 1) was designed. Since
this reagent has a basic pyridine moiety, the by-products such
as pyridine-3-sulfonic acid and pyridine-3-sulfoxamide formed
in the reaction are assumed to be removed by aqueous workup
as in the case of 3-PCA.
In this communication, we would like to report a convenient
synthetic method for carboxamides from the corresponding
carboxylic acids and amines by using commercially available
3-PSC as a dehydrating reagent.
In the first place, the reaction of 3-phenylpropionic acid (2)
and 3-phenylpropylamine (3) as a model substrate in the pres-
ence of 3-PSC with DMAP was examined in CH2Cl2 under
the conditions similar to those applied to 3-PCA or BSA. The
Table 1. Effect of activators
O O
S
Cl
N
1 (1.1 mol amt.)
Activator
(2.2 mol amt.)
O
O
O
O
S
R2NH2
NHR2
+
+
R1 OH
R1 NHR2
CH2Cl2, rt, 1 h
N
2 (1.1 mol amt.) 3 (1.0 mol amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
By-product
4
Isolated yield/%
By-product
Entry
Activator
4
1
DMAP
PPYb
99
96
97
96
78
66
1
1
2
3
N-Methylimidazole
N-Butylimidazole
HOBtb
2
4
5a
2
14
9
6
N-Methylmorpholine
aThe reaction was carried out in the presence of N-methylmorpho-
line (2.2 mol amt.). bPPY = 4-(1-pyrrolidinyl)pyridine, HOBt =
1-hydroxybenzotriazole.
Copyright Ó 2008 The Chemical Society of Japan
Funasaka, Setsuo
