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Chemistry Letters Vol.36, No.5 (2007)
Efficient Method for Dehydration Condensation
Using Pyridine-3-carboxylic Anhydride (3-PCA):
Synthesis of Carboxamides from Nearly Equimolar Amounts
of Carboxylic Acids and Amines
Setsuo Funasaka1 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 20, 2007; CL-070193; E-mail: mukaiyam@abeam.ocn.ne.jp)
A highly useful method for the preparation of carboxamides
to the procedure reported previously for the preparation of car-
boxylic esters: that is, the reaction was carried out in dichloro-
methane in the presence of 3-PCA and an activator at room tem-
perature shown in Table 1. When 2.2 molar amounts of DMAP
were used, the reaction proceeded smoothly within 1 h to afford
the carboxamide, 3-phenyl-N-(3-phenylpropyl)propanamide, in
91% yield (Entry 1). Then, the effect of the activators was
further examined: in the case of using 4-pyrrolidinopyridine
(PPY) as DMAP derivative and benzotriazole derivative such
as 1-hydroxybenzotriazole (HOBt), the coupling reactions pro-
ceeded smoothly to afford the desired carboxamide in good yield
(Entries 2 and 3). Imidazole derivatives such as N-methylimida-
zole or N-butylimidazole that are known to be good nucleophilic
bases14 also worked as the activator for this coupling reaction
(Entries 4 and 5). On the other hand, the yield decreased to
67% when N-methylmorpholine was used (Entry 6).
Next, the amount of DMAP was examined (Table 2). The
yield of the desired carboxamide 4 decreased to 79% when a
catalytic amount of DMAP was used (Entries 4 and 5). However,
it was observed that the carboxamide 4 was obtained in high
yields even when the amount of DMAP was reduced to 1.1
equiv. (Entries 1–3).
In the next place, the effect of solvents was examined: it
was observed then that the reaction proceeded smoothly in each
solvent (Table 3). As shown in Entry 1, CH2Cl2 was found to be
most suitable solvent. It is also noted that the yield increased
when the reaction was carried out at 0 ꢁC (Entry 2).
from various carboxylic acids and amines is established by
using pyridine-3-carboxylic anhydride (3-PCA) in the presence
of 4-(dimethylamino)pyridine (DMAP). This reaction proceeds
smoothly under mild conditions by simple experimental proce-
dure.
Since amide bond formation is one of the most fundamental
and important reactions in synthetic organic chemistry, medici-
nal chemistry, and so forth, various efficient coupling methods
for the synthesis of carboxamides have been reported.1–11 In
the point of process chemistry, however, the further develop-
ment of mild, efficient, and inexpensive reagents is still desired
toward large-scale synthesis.12
Recently, a novel condensation reaction between various
carboxylic acids and alcohols using pyridine-3-carboxylic anhy-
dride (3-PCA), which can be readily prepared from inexpensive
pyridine-3-carboxylic acid (nicotinic acid), was reported from
our laboratory.13 This anhydride is considered one of the most
practical and useful reagents because the by-product, pyridine-
3-carboxylic acid, can be removed just by biphasic separation.
Now, we would like to report on a mild and convenient method
using a novel-dehydrating reagent, 3-PCA, for the synthesis of
carboxamides from the corresponding carboxylic acids and
amines including sterically hindered ones.
In the first place, a condensation reaction of 3-phenylpro-
pionic acid with 3-phenylpropylamine was examined according
The results obtained by using various carboxylic acids and
amines under the optimized conditions are summarized in
Table 4. The reactions of 3-phenylpropionic acid with respective
amines proceeded smoothly to afford the corresponding carbox-
Table 1. Effect of activators
O
O
O
Table 2. Synthesis of carboxamide using DMAP as an activator
N
N
O
O
1 (1.1 equiv.)
activator (2.2 equiv.)
CH2Cl2, rt, 1 h
O
O
O
R2NH2
+
R1 OH
2 (1.1 equiv.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
R1
NHR2
4
N
N
3 (1.0 equiv.)
1 (1.1 equiv.)
O
O
R2NH2
DMAP
+
R1 OH
2 (1.1 equiv.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
R1
NHR2
Entry
Activator
Yielda/%
CH2Cl2, rt, 1 h
3 (1.0 equiv.)
4
1
DMAP
PPYc
HOBtc
N-Methylimidazole
91
78
81
79
80
67
2
3b
Entry
DMAP/equiv.
Yielda/%
4
1
2
3
4
5
3.3
2.2
75
91
92
84
79
5
N-Butylimidazole
N-Methylmorpholine
aIsolated yield. bThe reaction was carried out in the presence of
N-methylmorpholine (2.2 equiv.). cPPY = 4-pyrrolidinopyridine,
HOBt = 1-hydroxybenzotriazole.
6
1.1
0.55
0.05
aIsolated yield.
Copyright Ó 2007 The Chemical Society of Japan
Funasaka, Setsuo
