A versatile, practical, and inexpensive reagent, pyridine-3-carboxylic anhydride (3-PCA), for condensation reactions

Article abstract of DOI:10.1246/bcsj.81.148

A highly useful method for the preparation of carboxylic esters and carboxamides from various carboxylic acids was established by using a novel condensing reagent, pyridine-3-carboxylic anhydride (3-PCA), in the presence of 4-(dimethylamino)pyridine as an activator. The reactions of various carboxylic acids with nucleophiles, such as alcohols or amines, afforded the corresponding carboxylic acids or carboxamides in good to high yields under mild conditions by using simple experimental procedure. In addition, it was confirmed that this protocol was applicable to a gram-scale synthesis and the by-products, including pyridine-3-carboxylic acid and pyridine-3-carboxylate (or pyridine-3- carboxamide) produced in situ, were easily removed by using a simple aqueous workup.

Full text of DOI:10.1246/bcsj.81.148

148 Bull. Chem. Soc. Jpn. Vol. 81, No. 1, 148–159 (2008)
Ó 2008 The Chemical Society of Japan
A Versatile, Practical, and Inexpensive Reagent, Pyridine-3-carboxylic
Anhydride (3-PCA), for Condensation Reactions
ꢀ1;2
Setsuo Funasaka1 and Teruaki Mukaiyama
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 July 17, 2007; E-mail: mukaiyam@abeam.ocn.ne.jp
A highly useful method for the preparation of carboxylic esters and carboxamides from various carboxylic acids
was established by using a novel condensing reagent, pyridine-3-carboxylic anhydride (3-PCA), in the presence of 4-
(dimethylamino)pyridine as an activator. The reactions of various carboxylic acids with nucleophiles, such as alcohols
or amines, afforded the corresponding carboxylic acids or carboxamides in good to high yields under mild conditions by
using simple experimental procedure. In addition, it was confirmed that this protocol was applicable to a gram-scale syn-
thesis and the by-products, including pyridine-3-carboxylic acid and pyridine-3-carboxylate (or pyridine-3-carboxamide)
produced in situ, were easily removed by using a simple aqueous workup.
Since the synthesis of carboxylic esters and carboxamides
from carboxylic acid and nucleophile, such as alcohol or
amine, is considered to be one of the most important reactions
in the field of synthetic organic chemistry, medicinal chemis-
try, and so forth, various condensation methods have been re-
ported and are widely employed in the syntheses of natural and
unnatural molecules that have carboxylic ester or carboxamide
moieties.1–12
O
Cl3CO OCCl3
(1.0 mol. amt.)
O
O
O
iPr2EtN (6.0 mol. amt.)
OH
O
N
N
N
THF, 0 °C to rt, 2 h
(6.0 mol. amt.)
1
97%
Scheme 1. Synthesis of pyridine-3-carboxylic anhydride (3-
PCA).
Benzoic acid derivatives, such as 2,4,6-trichlorobenzoyl
chloride reported by Yamaguchi et al.3 and 2-methyl-6-nitro-
benzoic anhydride reported by Shiina et al.,7 are used as effec-
tive condensing reagents in order to synthesize carboxylic
esters under mild conditions, whereas an excess amount of
bases, such as DMAP or triethylamine, is generally required
to enhance the electrophilicity of the carboxylic acids in these
reactions. In addition, these methods require purification by
using silica-gel column chromatography to remove by-prod-
ucts, namely, the corresponding benzoic acid and benzoate
produced from dehydrating agent and alcohol. Thus, it is still
desired to develop more efficient reagent from the viewpoints
of reactivity and purification. Then, pyridine carboxylic an-
hydride was chosen with the expectation that it would be reac-
tive, because of the electron-withdrawing nature of pyridine
ring.13 In addition, the condensation reaction was expected
to proceed without using any bases since the basicity was al-
ready inherent in the condensing reagent. Further, the hydro-
philic pyridine carboxylic acid formed via this reaction would
be readily removed by using a simple aqueous workup. We
would like to report herein a convenient condensation reaction
using pyridine-3-carboxylic anhydride (3-PCA, 1), which is
easily prepared from inexpensive pyridine-3-carboxylic acid
(nicotinic acid) (Scheme 1).14,15
condensing agents, including pyridine carboxylic anhydride
derivartives, such as pyridine-2-carboxylic anhydride (2)
(quant.) and pyridine-4-carboxylic anhydride (3) (55%), furan
carboxylic anhydride derivatives, such as furan-2-carboxylic
anhydride (4) (98%) and furan-3-carboxylic anhydride (5)
(98%), and thiophene carboxylic anhydride derivatives, such
as thiophene-2-carboxylic anhydride (6) (99%) and thio-
phene-3-carboxylic anhydride (7) (99%), in good to excellent
yields, as in the case of 3-PCA. Next, to evaluate the potential
ability of hetero aryl carboxylic anhydrides as condensation
reagent, the condensation reaction of 3-phenylpropionic acid
(8) with 3-phenylpropan-1-ol (9) was initially examined in
the presence of triethylamine, DMAP, and various dehydrating
agents similar to the method using benzoic anhydride deriva-
tives3,7 (Table 1). When nicotinic anhydride (1) (pyridine-3-
carboxylic anhydride, 3-PCA) was used, the reaction proceed-
ed smoothly within 1 h, and the desired ester 10, 3-phenylpro-
pyl 3-phenylpropanoate, was afforded in 97% yield (Entry 1).
However, the yield of 10 was smaller (72% or 87%) in the
presence of a 3-PCA derivative, such as 2 or 3 (Entry 2 or 3).
On the other hand, it was observed that the desired product was
obtained in high yield when other carboxylic anhydrides, such
as furoic anhydrides 4 and 5 or thenoic anhydrides 6 and 7,
were used (Entries 4–7). In regards to the reactivity and the
ease of crystallization, 3-PCA (1) was chosen as a promising
agent.
Results and Discussion
Condensation Reaction between Carboxylic Acids and
Alcohols with 3-PCA. First, we tried the synthesized various
Published on the web January 10, 2008; doi:10.1246/bcsj.81.148

S. Funasaka et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
149
Table 1. Screening of Dehydrating Agents
O
O
R3
O
R3
Dehydrating agent
(1.3 mol. amt.)
Et3N (2.6 mol. amt.),
DMAP (0.1 mol. amt.)
O
O
O
R2OH
+
+
R1 OH
R1 OR2
R3
OR2
CH2Cl2, rt, 1 h
8 (1.3 mol. amt.) 9 (1.0 mol. amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
By-product
10
YieldaÞ/%
By-product
Entry
1
R3
Anhydride
10
1
97
3
N
2
3
2
3
72
87
28
5
N
N
O
4
5
6
7
4
5
6
7
98
1
O
quant.
93
trace
trace
trace
S
quant.
S
a) Isolated yield.
Table 2. Effect of Activators
O
O
O
N
N
1 (1.3 mol. amt.)
O
O
O
OR2
Et3N (2.6 mol. amt.),
Activator (0.1 mol. amt.)
R2OH
+
+
R1 OH
R1 OR2
N
CH2Cl2, rt, 1 h
8 (1.3 mol. amt.) 9 (1.0 mol. amt.)
10
By-product
R1 = Ph(CH2)2 R2 = Ph(CH2)3
YieldaÞ/%
By-product
Entry
Activator
10
1
2
3
4
5
DMAP
PPYbÞ
97
95
80
93
94
3
4
2
5
6
HOBtbÞ
N-Methylimidazole
N-Butylimidazole
a) Isolated yield. b) PPY = 4-(1-pyrrolidinyl)pyridine, HOBt = 1-hydroxy-
benzotriazole.
Next, the effect of activators was examined (Table 2). When
4-(1-pyrrolidinyl)pyridine (PPY) was used, the desired ester
10 was obtained in high yield, just as in the case of DMAP
(Entry 2). In the case of benzotriazole derivatives, such as 1-
hydroxybenzotriazole (HOBt), the coupling reaction proceed-
ed smoothly to afford 10 in good yield (Entry 3). Imidazole
derivatives, such as N-methylimidazole or N-butylimidazole,
which are known to be good nucleophilic bases,16 also worked
as activators for this coupling reaction (Entries 4 and 5).
Then, the reaction was further examined in order to reduce
the amounts of the reagents, namely, carboxylic acid, triethyl-
amine, DMAP, and 3-PCA (Table 3). It was observed that
the corresponding ester formed in high yield even when the
amounts of carboxylic acid, dehydrating reagent and triethyl-
amine were all reduced to 1.1 molar amount (Entries 1–4). It
is noteworthy that the desired carboxylic ester was obtained
in high yield in the absence of triethylamine (Entry 5). This
clearly indicates that the pyridine moiety of 3-PCA works as
the base to capture pyridine-3-carboxylic acid formed in situ.
In addition, it was found that the reaction proceeded smoothly

150 Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
3-PCA as Effective Condensation Reagent
Table 3. Synthesis of Carboxylic Esters Using 3-PCA
O
O
O
N
N
1 (X mol. amt.)
O
O
O
OR2
Et3N (Y mol. amt.),
R2OH
+
+
R1 OH
DMAP (Z mol. amt.) R1
OR2
N
CH2Cl2, rt, 1 h
8 (X mol. amt.) 9 (1.0 mol. amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
By-product
10
YieldaÞ/%
Entry
X
Y
Z
10
97
96
96
96
97
96
96
By-product
1
2
3
4
5
6
7
8bÞ
1.3
1.2
1.1
1.1
1.1
1.1
1.1
1.1
2.6
2.4
2.2
1.1
0
0
0
0
0.1
0.1
0.1
0.1
0.1
0.05
0.02
0
3
4
3
3
3
3
3
3
cÞ
49 ð47Þ
a) Isolated yield. b) The reaction mixture was stirred for 24 h. c) The unreact-
ed starting material was recovered.
Table 4. Effect of Solvents
O
O
O
N
N
O
1 (1.1 mol. amt.)
DMAP (0.1 mol. amt.)
O
O
OR2
R2OH
+
+
R1
OR2
R1 OH
N
rt, 1 h
8 (1.1 mol. amt.)
By-product
9 (1.0 mol. amt.)
10
R1 = Ph(CH2)2 R2 = Ph(CH2)3
YieldaÞ/%
By-product
Entry
Solvent
10
1
CH2Cl2
CH2Cl2
CH2Cl2
THF
Et2O
DMF
DMSO
Toluene
MeCN
97
97
82
94
93
95
76
91
96
3
3
2
3
4
4
4
4
4
2bÞ
3cÞ
4
5
6
7
8
9
a) Isolated yield. b) The reaction was carried out at 0 ꢂC. c) The reaction was
carried out at ꢁ78 ꢂC.
even when 0.02 molar amount of DMAP was used (Entry 7).
Interestingly, the desired ester was obtained in 49% yield in
the absence of DMAP (Entry 8).
of the primary and secondary aliphatic alcohols gave the de-
sired carboxylic esters in high yields (Entries 1–6). On the
other hand, in the case of tertiary alcohols, such as t-butyl
alcohol, the corresponding ester was not detected (Entry 9).
This reaction was applicable also to aromatic alcohols, which
afforded ester 16 in high yield (Entry 7), and was effective
even when a substrate possessing an acid-sensitive moiety in
the same molecule (Entry 8). The corresponding products
were likewise obtained rapidly in good to high yields when
hindered ꢀ,ꢀ-disubstituted carboxylic acids or ꢀ,ꢁ-unsaturat-
ed carboxylic acids were used (Entries 10–17). In addition, it
was observed that the yields of carboxylic esters increased
Effect of solvents was examined (Table 4). It was shown
that the reaction proceeded not only in a non-polar solvent,
such as CH2Cl2 or toluene (Entries 1 and 8), but also in a polar
solvent, such as THF, Et2O, DMF, DMSO, or MeCN, and
afforded ester 10 in good to excellent yields (Entries 1 and
4–9). In addition, it should be noted that the reaction well
proceeded even at ꢁ78 ꢂC (Entry 3).
Results of the condensation reactions between various car-
boxylic acids and alcohols are shown in Table 5. Reactions

S. Funasaka et al.
Table 5. Synthesis of Various Carboxylic Esters with 3-PCA
Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
151
O
O
O
N
N
O
1 (1.1 mol. amt.)
DMAP (Z mol. amt.)
O
O
OR2
R2OH
+
+
R1
OR2
R1 OH
CH2Cl2, rt, 1 h
N
(1.1 mol. amt.) (1.0 mol. amt.)
Ester
By-product
YieldaÞ/%
Entry
Carboxylic acid
Alcohol
Ester
Z
Ester
By-product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)3OH
PhCH2OH
CH2=CHCH2OH
PhCH(CH3)OH
Ph(CH2)2CH(CH3)OH
c-C6H11OH
PhOH
10
11
12
13
14
15
16
17
—
18
19
20
21
22
23
24
25
26
27
0.02 97
0.02 96
0.02 93
0.02 95
0.05 94
0.10 89
0.02 91
0.02 95
0.10 NDbÞ
0.05 90
0.05 85
0.05 97
0.05 95
0.05 97
0.05 93
3
4
3
3
5
5
8
5
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
c-C6H11CO2H
c-C6H11CO2H
PhCH(CH3)CO2H
PhCH(CH3)CO2H
Ph2CHCO2H
THPO(CH2)5OH
t-BuOH
NDbÞ
10
8
3
3
Ph(CH2)3OH
PhCH(CH3)OH
Ph(CH2)3OH
PhCH(CH3)OH
Ph(CH2)3OH
PhCH(CH3)OH
Ph(CH2)3OH
PhCH(CH3)OH
Ph(CH2)3OH
Ph(CH2)3OH
3
6
Ph2CHCO2H
(E)-PhCH=CHCO2H
(E)-PhCH=CHCO2H
PhCO2H
0.05 70 (76)cÞ 28 (23)cÞ
0.05 60 (80)cÞ 35 (14)cÞ
0.10 26 (33)cÞ 72 (62)cÞ
0.10 10 (11)cÞ 67 (57)cÞ
t-BuCO2H
a) Isolated yield. b) Not detected. c) The reaction was carried out at 0 ꢂC.
O
O
O
CH3
O
CH3
O
N
N
CH3
OH
O
Ph
CH3
+
1 (1.1 mol. amt.)
DMAP (0.05 mol. amt.)
Ph
Ph
HO Ph
28 (1.1 mol. amt.) 29 (1.0 mol. amt.)
21
10 g
diastereomeric ratio = ca. 1/1
Scheme 2. Large-scale synthesis of 1-phenylethyl 2-phenylpropanecarboxylate with 3-PCA.
CH2Cl2, rt, 1 h
5.0 g
96%
when the reactions were carried out at 0 ꢂC (Entries 16 and
17). On the other hand, the reaction of benzoic acid with 3-
phenylpropan-1-ol (9) gave the corresponding ester 26 (26%)
along with a large amount of pyridine-3-carboxylate as a by-
product (72%) (Entry 18). 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. Further, when highly sterically hindered pivalic
acid was used, corresponding ester 27 was afforded in low
yield along with the undesirable by-product (67%) (Entry 19).
This method was also applicable to a gram-scale synthesis,
from which ester 21 was obtained in 96% yield by using 3-
PCA and a catalytic amount of DMAP (Scheme 2).17 Impor-
tantly, the by-products, such as pyridine-3-carboxylic acid and
1-phenylethyl pyridine-3-carboxylate which were produced
from 3-PCA and 29, were easily removed by using an aqueous
workup.18
Synthesis of Carboxamides from Nearly Molar Amounts
of Carboxylic Acids and Amines Using 3-PCA. A conden-
sation reaction for the synthesis of carboxamides from 3-
phenylpropionic acid (8) and 3-phenylpropylamine (30) using
various dehydrating agents in the presence of 2.2 molar
amounts of DMAP at room temperature was tried to evaluate
the potential ability of hetero aryl carboxylic anhydrides
(Table 6). The reaction using 3-PCA proceeded smoothly
within 1 h to provide the desired carboxamide 31, 3-phenyl-
N-(3-phenylpropyl)propanamide, in 91% yield along with
9% of N-(3-phenylpropyl)pyridine-3-carboxamide (Entry 1).
In the case of using pyridine-4-carboxylic anhydride (3) the

152 Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
Table 6. Screening of Dehydrating Agents
3-PCA as Effective Condensation Reagent
O
O
R3
O
R3
Dehydrating agent
(1.1 mol. amt.)
DMAP (2.2 mol. amt.)
O
O
O
+
R2NH2
+
R1 OH
R1
NHR2 R3
NHR2
CH2Cl2, rt, 1 h
8 (1.1 mol. amt.) 30 (1.0 mol. amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
31
By-product
YieldaÞ/%
Entry
1
R3
Anhydride
31
By-product
1
91
8
N
2
3
2
3
90
69
4
N
20
N
O
4
5
6
7
4
5
6
7
91
88
92
89
9
11
7
O
S
10
S
a) Isolated yield.
Table 7. Effect of Activators
O
O
O
N
N
O
1 (1.1 mol. amt.)
Activator (2.2 mol. amt.)
NHR2
O
O
R2NH2
+
+
R1
CH2Cl2, rt, 1 h
R1
NHR2
OH
N
2 (1.1 mol. amt.) 30 (1.0 mol. amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
By-product
31
YieldaÞ/%
By-product
Entry
Activator
31
1
2
3bÞ
4
5
6
7
DMAP
PPYdÞ
91
78
81
79
80
67
9
8
3
19
HOBtdÞ
N-Methylimidazole
N-Butylimidazole
N-Methylmorpholine
none
20
NDcÞ
32
91
a) Isolated yield. b) The reaction was carried out in the presence of N-methyl-
morpholine (2.2 equiv). c) Not detected. d) PPY = 4-(1-pyrrolidinyl)pyri-
dine, HOBt = 1-hydroxybenzotriazole.
yield of 32 decreased to 69%, and the corresponding by-prod-
(1) was chosen, as described in the section on esterification.
Next, the effect of the activators was further examined
(Table 7). In the case of using 4-(1-pyrrolidinyl)pyridine
(PPY) or 1-hydroxybenzotriazole (HOBt), these activators
worked effectively to afford the desired carboxamides 31 in
good yields (Entries 2 and 3). Imidazole derivatives, such as
N-methylimidazole and N-butylimidazole, also gave good
results (Entries 4 and 5), whereas the yield decreased to 67%
uct was obtained in 20% yield (Entry 3). Pyridine-2-carboxyl-
ic anhydride (2) gave the desired product in 90% yield, but
this reagent was liable to decomposition (Entry 2). Further, it
was observed that other carboxylic anhydrides, such as furoic
anhydrides 4 and 5 or thenoic anhydrides 6 and 7, also provid-
ed the desired carboxamide in high yield (Entries 4–7). In re-
gards to the reactivity and the ease of crystallization, 3-PCA

S. Funasaka et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
153
Table 8. Synthesis of Carboxamide Using DMAP as an Activator
O
O
O
N
N
O
1 (1.1 mol. amt.)
NHR2
O
O
R2NH2
DMAP
+
+
R1
NHR2
R1 OH
N
CH2Cl2, rt, 1 h
2 (1.1 mol. amt.) 30 (1.0 mol. amt.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
By-product
31
YieldaÞ/%
By-product
Entry
DMAP/mol amt.
31
1
2
3
4
5
3.3
2.2
1.1
0.55
0.05
75
91
92
84
79
8
8
8
15
20
a) Isolated yield.
Table 9. Effect of Solvents
O
O
O
N
N
O
1 (1.1 mol. amt.)
NHR2
O
O
R2NH2
+
+
DMAP (1.1 mol. amt.)
NHR2
R1 OH
R1
N
rt, 1 h
2 (1.1 mol. amt.)
By-product
30 (1.0 mol. amt.)
31
R1 = Ph(CH2)2 R2 = Ph(CH2)3
YieldaÞ/%
By-product
Entry
Solvent
31
1
CH2Cl2
CH2Cl2
CH2Cl2
THF
Et2O
DMF
DMSO
Toluene
MeCN
92
95
97
75
85
86
88
90
92
8
5
3
13
15
7
10
9
2bÞ
3cÞ
4
5
6
7
8
9
8
a) Isolated yield. b) The reaction was carried out at 0 ꢂC. c) The reaction was
carried out at ꢁ78 ꢂC.
when N-methylmorpholine was used (Entry 6). In addition, the
carboxamide was obtained in only 9%, and the remaining 91%
was a by-product, N-(3-phenylpropyl)pyridine-3-carboxamide,
in the absence of an activator (Entry 7). These results indicate
the necessity of an effective activator in this reaction.
Next, the effect of DMAP was examined (Table 8). 3.3 mo-
lar amount of DMAP gave the desired product 31 in 75% yield
and N-(3-phenylpropyl)pyridine-3-carboxamide 8% yield ac-
companied by a mixute of unknown compounds (Entry 1).
In addition, the yield of carboxamide decreased to 79% when
a catalytic amount of DMAP was used (Entry 5). On the other
hand, it was observed that the desired product was obtained
in high yield even when the amount of DMAP was reduced
to 1.1 molar amount (Entries 1–3).
Not only in a non-polar solvent, such as CH2Cl2 or toluene
but also in a polar solvent such as THF, Et2O, DMF, DMSO,
or MeCN, the reaction was successfully carried out as similar
to the section on esterification (Entries 1 and 4–9), and CH2Cl2
was found to be the best solvent, as shown in Entry 1. It is
noteworthy that the reaction rapidly proceeded even at ꢁ78
ꢂC, and the yield of desired carboxamide increased at lower
temperatures (Entries 2 and 3).
The results obtained by using various carboxylic acids
and amines under optimized conditions are summarized in
Table 10. Even when nearly molar amounts of primary or
secondary aliphatic amines were used, reactions of 3-phenyl-
propionic acid 8 with the respective amines proceeded smooth-
ly to afford the corresponding carboxamides 31–36 in good to
high yields (Entries 1–6). In the case of a tertiary amine, such
Finally, the effect of the solvents was examined (Table 9).

154 Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
3-PCA as Effective Condensation Reagent
Table 10. Synthesis of Various Carboxamides with 3-PCA
O
O
O
N
N
1 (1.1 mol. amt.)
O
O
O
R2R3NH
+
NR2R3
DMAP (1.1 mol. amt.)
R1
NR2R3
R1 OH
+
CH2Cl2, 0 °C, 1 h
N
(1.1 mol. amt.)
(1.0 mol. amt.)
Carboxamide
By-product
YieldaÞ/%
Entry
Carboxylic acid
Amine
Carboxamide
31
Carboxamide
By-product
1
2
3
4
5
6
7
8
9bÞ
10cÞ
11dÞ
12eÞ
13
14
15
16
17
18
19
20
21
22
23
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
Ph(CH2)2CO2H
c-C6H11CO2H
c-C6H11CO2H
PhCH(CH3)CO2H
PhCH(CH3)CO2H
Ph2CHCO2H
Ph(CH2)3NH2
PhCH2NHCH3
PhCH(NH2)CH3
PhCH2NH2
Ph2CHNH2
Piperidine
95
92
98
94
97
88
67
98
85
97
95
98
90
90
92
98
5
8
2
6
2
11
2
2
2
2
3
2
10
10
8
2
5
2
15 (6)fÞ
16 (8)fÞ
57 (44)fÞ
56 (35)fÞ
32
33
34
35
36
37
38
39
38
40
41
42
43
44
45
46
47
48
49
50
51
—
t-BuNH2
PhNH2
o-Cl-C6H4NH2
PhNH2 HCl
ꢃ
EtNH2 HCl
CH3ONHCH3 HCl
ꢃ
ꢃ
Ph(CH2)3NH2
PhCH(NH2)CH3
Ph(CH2)3NH2
PhCH(NH2)CH3
Ph(CH2)3NH2
PhCH(NH2)CH3
Ph(CH2)3NH2
PhCH(NH2)CH3
Ph(CH2)3NH2
PhNH2
94
98
85 (93)fÞ
80 (91)fÞ
43 (55)fÞ
35 (50)fÞ
Ph2CHCO2H
(E)-PhCH=CHCO2H
(E)-PhCH=CHCO2H
PhCO2H
PhCO2H
t-BuCO2H
Ph(CH2)3NH2
trace (trace)fÞ NDgÞ (ND)f),g)
a) Isolated yield. b) The reaction was carried out for 24 h. c) The reaction was carried out for 12 h.
d) The reaction was carried out for 6 h. e) The reaction was carried out for 3 h. f) The reaction was
carried out at ꢁ78 ꢂC. g) Not detected.
as t-butyl amine, the corresponding carboxamide was obtained
(Entries 21–23).
in moderate yield (Entry 7). Aromatic amines including steri-
cally hindered o-chloroaniline were successfully employed,
and the corresponding carboxamides 38 and 39 were obtained
in good to excellent yields (Entries 8 and 9). Importantly, this
method was applicable to the reaction with amine hydrochlo-
ride, from which the desired carboxamides 38 and 40 were ob-
tained in high yields (Entries 10 and 11). Further, N,O-dimeth-
ylhydroxylamine hydrochloride was also effectively converted
to carboxamide 41, as shown in Entry 12. This result indicates
that the present procedure is a convenient method for the direct
synthesis of N-methoxy-N-methylamides (Weinreb amides19)
from free carboxylic acid under mild conditions. It was then
confirmed that carboxamides 42–49 were also obtained in
good yields in the cases of using hindered ꢀ,ꢀ-disubstituted
and ꢀ,ꢁ-unsaturated carboxylic acids (Entries 13–20). In addi-
tion, the yields of carboxamides 48 and 49 increased when
the reactions were carried out at ꢁ78 ꢂC (Entries 19 and 20).
On the other hand, the reaction with benzoic acid resulted
in a low yield similar to that of the esterification reaction,
and the reactions with pivalic acid also gave poor results
The present protocol with 3-PCA was successfully em-
ployed for a gram-scale synthesis, and 45 was obtained in
98% yield (Scheme 3).17 It is noteworthy that DMAP and
by-products, such as pyridine-3-carboxylic acid and N-(1-
phenylethyl)pyridine-3-carboxamide produced from 3-PCA
and 53, were easily removed by using an aqueous workup.18
Conclusion
A convenient and effective method for the synthesis of var-
ious carboxylic esters or carboxamides was successfully estab-
lished. The reaction of various carboxylic acids and nucleo-
philes, such as alcohols or amines, with 3-PCA (1) and DMAP
gave the corresponding products in good to high yields by
using the simple experimental procedure. In addition, it is not-
ed that the by-products produced in situ were easily removed
by using an aqueous workup. Thus, pyridine-3-carboxylic an-
hydride is one of the most efficient and convenient reagents
for the condensation reaction. Further study on the application
and improvement of the present dehydrating reagent is now
in progress.

S. Funasaka et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
155
O
O
O
N
N
1 (1.1 mol. amt.)
CH3
O
CH
3 H
N
CH3
DMAP (1.1 mol. amt.)
OH
Ph
CH3
+
Ph
Ph
H2N Ph
O
CH2Cl2, 0 °C, 1 h
52 (1.1 mol. amt.) 53 (1.0 mol. amt.)
45
5.0 g
10 g
98%
diastereomeric ratio = ca. 1/1
Scheme 3. Large-scale synthesis of 2-phenyl-N-(1-phenylethyl)propanamide with 3-PCA.
1782, 1736 cmꢁ1 1H NMR (270 MHz, acetone-d6) ꢂ 8.80–8.50
;
Experimental
(m, 2H), 8.40–8.20 (m, 2H), 8.20–7.90 (m, 2H), 7.75–7.50 (m,
2H). 13C NMR (68 MHz, acetone-d6) ꢂ 206.0, 163.0, 150.2, 146.7,
138.3, 128.7, 126.7. HRMS (EI positive) Calcd for C12H8N2O3
Mþ: 228.0535. Found: m=z 228.0530.
Pyridine-4-carboxylic Anhydride (3): White solid; mp 102–
104 ꢂC; IR (ATR) 1799, 1735 cmꢁ1; 1H NMR (270 MHz, acetone-
d6) ꢂ 8.93 (dd, J ¼ 1:6, 4.6 Hz, 4H), 8.09 (dd, J ¼ 1:6, 4.6 Hz,
4H). 13C NMR (68 MHz, acetone-d6) ꢂ 205.8, 161.2, 151.8, 136.2,
123.8. Anal. Calcd for C12H8N2O3: C, 63.16; H, 3.53; N, 12.28%.
Found: C, 63.00; H, 3.64; N, 12.09%.
General. All melting points were determined on a Yanagimoto
micro melting apparatus (Yanaco MP-S3) and are uncorrected.
Infrared (IR) spectra were recorded by using an attenuated total
reflection (ATR) method on a SensIR Technologies Travel IRÔ
spectrometer. 1H NMR spectra were recorded on a JEOL JNM
EX270L (270 MHz) or a Varian Mercury Plus 400 (400 MHz)
spectrometer; chemical shifts (ꢂ) are reported in parts per million
relative to tetramethylsilane. Splitting patterns are designated as s,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broad
singlet. 13C NMR spectra were recorded on a JEOL EX270L
(68 MHz) or a Varian Mercury Plus 400 (100 MHz) spectrometer
with complete proton decoupling. Chemical shifts are reported in
parts per million relative to tetramethylsilane, with the solvent
resonance as the internal standard (CDCl3; ꢂ 77.0, acetone-d6; ꢂ
30.3). High-resolution mass spectra (HRMS) were recorded on a
JMS-700V (JEOL) or Q-Tof-2-(micromass) mass spectrometer.
Elemental analyses were conducted using a Yanaco MT-5 CHN
corder. Analytical TLC was performed on Merck preparative
TLC plates (silica gel 60 GF254, 0.25 mm). Preparative thin-layer
chromatography (PTLC) was carried out on silica gel Wakogel
B-5F. Dry solvents were purchased from Kanto Chemical. All
reagents were purchased from Tokyo Kasei Kogyo, Kanto Chemi-
cal, Kokusan Chemical, or Aldrich Chemical. Carboxylic acids
were used without further purification. Alcohols and amines were
used after purification by distillation.
Experimental Procedure for the Preparation of 3-PCA (1).
A solution of pyridine-3-carboxylic acid (1.00 g, 8.12 mmol) and
diisopropylethylamine (1.41 mL, 8.12 mol) in THF (18 mL) was
stirred for 10 min at 0 ꢂC. To the reaction mixture, a solution of
triphosgene (402 mg, 1.35 mmol) in THF (2 mL) was added at
0 ꢂC, then stirred for 1 h. After addition of the solution, the reac-
tion mixture was additionally stirred for 1 h at room temperature.
After filtration of the reaction mixture to remove diisopropylethyl-
ammonium chloride formed, the filtrate was concentrated under
reduced pressure. After EtOAc was added to the residue, the
mixture was washed with water. The organic layer was washed
with water and brine, dried over anhydrous sodium sulfate. The
solvent was evaporated to afford pyridine-3-carboxylic anhydride
(898 mg, 97%).
Furan-2-carboxylic Anhydride (4): White solid; mp 62–64
ꢂC; IR (ATR) 1780, 1733 cmꢁ1 1H NMR (270 MHz, acetone-
;
d6) ꢂ 8.03 (dd, J ¼ 0:8, 1.6 Hz, 2H), 7.63 (dd, J ¼ 0:8, 3.8 Hz,
2H), 6.79 (dd, J ¼ 1:6, 3.8 Hz, 2H). 13C NMR (68 MHz, acetone-
d6) ꢂ 206.2, 153.4, 150.2, 143.4, 122.7, 113.5. Anal. Calcd for
C10H6O5: C, 58.26; H, 2.93%. Found: C, 58.12; H, 2.98%.
Furan-3-carboxylic Anhydride (5): White solid; mp 56–58
ꢂC; IR (ATR) 1771, 1719 cmꢁ1 1H NMR (270 MHz, acetone-
;
d6) ꢂ 8.65–8.45 (m, 2H), 7.77 (t, J ¼ 1:6 Hz, 2H), 6.92 (dd, J ¼
0:5, 1.6 Hz, 2H). 13C NMR (68 MHz, acetone-d6) ꢂ 206.3, 158.2,
151.1, 145.9, 119.0, 110.2. Anal. Calcd for C10H6O5: C, 58.26;
H, 2.93%. Found: C, 58.05; H, 3.02%.
Thiophene-2-carboxylic Anhydride (6): Brown solid; mp
57–59 ꢂC; IR (ATR) 1757, 1700 cmꢁ1
;
1H NMR (270 MHz,
acetone-d6) ꢂ 8.15–7.95 (m, 4H), 7.31 (dd, J ¼ 3:8, 4.9 Hz, 2H).
13C NMR (68 MHz, acetone-d6) ꢂ 205.9, 157.2, 136.9, 136.8,
132.2, 129.4. Anal. Calcd for C10H6O3S2: C, 50.41; H, 2.54%.
Found: C, 50.51; H, 2.49%.
Thiophene-3-carboxylic Anhydride (7): Brown solid; mp
1
50–52 ꢂC; IR (ATR) 1765, 1707 cmꢁ1; H NMR (270 MHz, ace-
tone-d6) ꢂ 8.57 (m, 2H), 7.70–7.55 (m, 4H). 13C NMR (68 MHz,
acetone-d6) ꢂ 206.1, 158.0, 136.9, 132.5, 128.4, 128.4. Anal.
Calcd for C10H6O3S2: C, 50.41; H, 2.54%. Found: C, 50.51; H,
2.55%.
Preparation of Carboxylic Esters. To a stirred solution of
3-phenylpropionic acid (49.6 mg, 0.33 mmol) in CH2Cl2 (1.5 mL)
were successively added pyridine-3-carboxylic anhydride (75.4
mg, 0.30 mmol) and DMAP (0.7 mg, 0.006 mmol) at room temper-
ature. After stirring for 10 min, a solution of 3-phenylpropan-1-ol
(40.9 mg, 0.30 mmol) in dichloromethane (1.5 mL) was added.
After the reaction mixture was stirred for 1 h, it was quenched
with saturated aqueous sodium hydrogen carbonate. The mixture
was extracted with tert-butyl methyl ether. The organic layer
was washed with 1 mol dmꢁ3 hydrochloric acid (3 times), brine
and dried over anhydrous Na2SO4, and the solvent was evaporat-
ed. The crude product was purified by preparative TLC (hexane/
EtOAc = 9/1) to afford 3-phenylpropyl 3-phenylpropanoate
(77.3 mg, 96%) as a colorless oil.
Pyridine-3-carboxylic Anhydride (3-PCA, 1): White solid;
mp 121–123 ꢂC; IR (ATR) 1797, 1723 cmꢁ1; 1H NMR (400 MHz,
acetone-d6) ꢂ 9.34 (dd, J ¼ 0:8, 1.8 Hz, 2H), 8.92 (dd, J ¼ 1:8,
4.8 Hz, 2H), 8.55 (ddd, J ¼ 1:8, 1.8, 8.0 Hz, 2H), 7.66 (ddd, J ¼
0:8, 4.8, 8.0 Hz, 2H). 13C NMR (100 MHz, acetone-d6) ꢂ 161.2,
155.3, 151.6, 138.1, 125.0, 124.2. Anal. Calcd for C12H8N2O3: C,
63.16; H, 3.53; N, 12.28%. Found: C, 62.94; H, 3.49; N, 12.21%.
Pyridine-2-carboxylic Anhydride (2): Brown oil; IR (ATR)

156 Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
3-PCA as Effective Condensation Reagent
3-Phenylpropyl 3-Phenylpropanoate (10):7c Colorless oil;
C15H20O2: C, 77.55; H, 8.68%. Found: C, 77.23; H, 8.28%.
3-Phenylpropyl 2-Phenylpropanoate (20):10b Colorless oil;
IR (ATR) 1731 cmꢁ1
;
1H NMR (270 MHz, CDCl3) ꢂ 7.36–7.15
(m, 10H), 4.12 (t, J ¼ 6:5 Hz, 2H), 2.99 (t, J ¼ 7:9 Hz, 2H), 2.67
(t, J ¼ 7:9 Hz, 4H), 1.96 (m, 2H); 13C NMR (68 MHz, CDCl3) ꢂ
172.7, 141.0, 140.3, 128.4, 128.3, 128.2, 128.1, 126.1, 125.8, 63.8,
35.9, 32.2, 31.0, 30.2.
Benzyl 3-Phenylpropanoate (11):7c Colorless oil; IR (ATR)
1732 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.31–7.11 (m, 10H),
;
5.08 (s, 2H), 2.94 (t, J ¼ 7:7 Hz, 2H), 2.65 (t, J ¼ 7:7 Hz, 2H);
13C NMR (68 MHz, CDCl3) ꢂ 172.4, 140.2, 135.7, 128.3, 128.3,
128.2, 128.1, 128.0, 128.0, 126.1, 66.1, 35.8, 30.9.
Allyl 3-Phenylpropanoate (12):7c Colorless oil; IR (ATR)
;
1734 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.45–7.05 (m, 5H),
IR (ATR) 1730 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.45–7.12
;
(m, 8H), 7.04 (m, 2H), 4.05 (t, J ¼ 6:4 Hz, 2H), 3.72 (q, J ¼
6:9 Hz, 1H), 2.54 (t, J ¼ 7:2 Hz, 2H), 1.87 (t, J ¼ 7:2 Hz, 2H),
1.50 (d, J ¼ 6:9 Hz, 3H); 13C NMR (68 MHz, CDCl3) ꢂ 174.3,
140.9, 140.5, 128.5, 128.2, 128.2, 127.4, 127.0, 125.8, 63.8, 45.6,
32.0, 30.2, 18.4.
1-(RS)-Phenylethyl 2-(RS)-Phenylpropanoate (21):17 Color-
less oil; IR (ATR) 1730 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ
;
7.35–7.00 (m, 10H), 5.84 (q, J ¼ 6:6 Hz, 1H), 3.74 (q, J ¼ 7:2
Hz, 1H), 1.49 (d, J ¼ 7:2 Hz, 3H), 1.48 (d, J ¼ 6:6 Hz, 3H);
13C NMR (68 MHz, CDCl3) ꢂ 173.3, 141.5, 141.4, 140.2, 128.3,
128.1, 127.4, 126.9, 125.5, 72.4, 45.7, 22.4, 18.4. Anal. Calcd
for C17H18O2: C, 80.28; H, 7.13%. Found: C, 80.35; H, 7.11%.
1-(RS)-Phenylethyl 2-(SR)-Phenylpropanoate (21):17 White
5.87 (m, 1H), 5.45–5.10 (m, 2H), 4.56 (d, J ¼ 5:6 Hz, 2H), 2.95
(t, J ¼ 7:8 Hz, 2H), 2.65 (t, J ¼ 7:8 Hz, 2H); 13C NMR (68 MHz,
CDCl3) ꢂ 172.2, 140.2, 132.0, 128.3, 128.1, 126.1, 118.0, 65.0,
35.8, 30.9.
solid; mp 88–91 ꢂC; IR (ATR) 1723 cmꢁ1 1H NMR (270 MHz,
;
1-Phenylethyl 3-Phenylpropanoate (13): Colorless oil; IR
1
CDCl3) ꢂ 7.35–7.05 (m, 10H), 5.85 (q, J ¼ 6:6 Hz, 1H), 3.73 (q,
J ¼ 7:2 Hz, 1H), 1.47 (d, J ¼ 7:2 Hz, 3H), 1.40 (d, J ¼ 6:6 Hz,
3H); 13C NMR (68 MHz, CDCl3) ꢂ 173.4, 141.4, 141.4, 140.3,
128.4, 128.3, 127.6, 127.3, 125.8, 72.5, 45.6, 22.0, 18.4. Anal.
Calcd for C17H18O2: C, 80.28; H, 7.13%. Found: C, 80.21; H,
6.76%.
(ATR) 1730 cmꢁ1; H NMR (270 MHz, CDCl3) ꢂ 7.34–7.10 (m,
10H), 5.92–5.82 (m, 1H), 2.92 (t, J ¼ 7:7 Hz, 2H), 2.62 (t, J ¼
7:7 Hz, 2H), 1.47 (d, J ¼ 6:6 Hz, 3H); 13C NMR (68 MHz, CDCl3)
ꢂ 171.8, 141.4, 140.2, 128.3, 128.2, 128.1, 127.6, 126.0, 125.8,
72.2, 36.1, 30.9, 22.1. Anal. Calcd for C17H18O2: C, 80.28; H,
7.13%. Found: C, 80.27; H, 7.09%.
1-Methyl-3-phenylpropyl 3-Phenylpropanoate (14):7c Col-
orless oil; IR (ATR) 1727 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ
;
3-Phenylpropyl Diphenylacetate (22):
Colorless oil; IR
(ATR) 1731 cmꢁ1; H NMR (270 MHz, CDCl3) ꢂ 7.45–7.00 (m,
15H), 5.03 (s, 1H), 4.14 (t, J ¼ 6:5 Hz, 2H), 2.56 (t, J ¼ 7:3 Hz,
2H), 1.92 (dt, J ¼ 6:5, 7.3 Hz, 2H); 13C NMR (68 MHz, CDCl3)
ꢂ 172.2, 140.8, 138.5, 128.5, 128.4, 128.2, 127.1, 125.8, 64.3,
57.2, 32.0, 30.2. Anal. Calcd for C23H22O2: C, 83.60; H, 6.71%.
Found: C, 83.47; H, 6.64%.
1
7.35–7.00 (m, 10H), 4.93 (m, 1H), 2.93 (t, J ¼ 7:6 Hz, 2H), 2.58
(t, J ¼ 7:6 Hz, 2H), 2.70–2.40 (m, 2H), 2.00–1.60 (m, 2H), 1.19
(d, J ¼ 6:3 Hz, 3H); 13C NMR (68 MHz, CDCl3) ꢂ 172.2, 141.3,
140.3, 128.3, 128.2, 128.1, 126.0, 125.7, 70.4, 37.5, 36.1, 31.7,
31.0, 20.0.
1-Phenyethyl Diphenylacetate (23): Colorless oil; IR (ATR)
1731 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.35–7.10 (m, 15H),
;
5.94 (q, J ¼ 6:5 Hz, 1H), 5.05 (s, 1H), 1.50 (d, J ¼ 6:5 Hz, 3H);
13C NMR (68 MHz, CDCl3) ꢂ 171.4, 141.1, 138.6, 138.4, 128.5,
128.4, 128.3, 128.2, 127.7, 127.1, 127.0, 125.9, 73.1, 57.2, 22.1.
Anal. Calcd for C22H20O2: C, 83.51; H, 6.37%. Found: C, 83.40;
H, 6.49%.
3-Phenylpropyl (E)-3-Phenyl-2-propenoate (24):7c Color-
less oil; IR (ATR) 1708 cmꢁ1; 1H NMR (270 MHz, CDCl3) ꢂ 7.67
(d, J ¼ 16:0 Hz, 1H), 7.60–7.45 (m, 2H), 7.45–7.10 (m, 8H), 6.44
(d, J ¼ 16:0 Hz, 1H), 4.21 (t, J ¼ 6:6 Hz, 2H), 2.73 (t, J ¼ 7:6 Hz,
2H), 2.02 (tt, J ¼ 6:6, 7.6 Hz, 2H); 13C NMR (68 MHz, CDCl3) ꢂ
166.7, 144.5, 141.0, 134.2, 130.1, 128.7, 128.2, 128.2, 127.9,
125.8, 117.9, 63.8, 32.2, 30.3.
Cyclohexyl 3-Phenylpropanoate (15):7c Colorless oil; IR
1
(ATR) 1727 cmꢁ1; H NMR (270 MHz, CDCl3) ꢂ 7.35–7.05 (m,
5H), 4.74 (m, 1H), 2.92 (t, J ¼ 7:8 Hz, 2H), 2.58 (t, J ¼ 7:8 Hz,
2H), 1.85–1.05 (m, 10H); 13C NMR (68 MHz, CDCl3) ꢂ 171.9,
140.3, 128.1, 128.0, 128.0, 125.9, 72.4, 36.1, 31.5, 31.0, 25.3,
23.6.
Phenyl 3-Phenylpropanoate (16):10b Colorless oil; IR (ATR)
1755 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.45–6.94 (m, 10H),
;
3.03 (t, J ¼ 7:4 Hz, 2H), 2.84 (t, J ¼ 7:4 Hz, 2H); 13C NMR
(68 MHz, CDCl3) ꢂ 171.0, 150.4, 139.9, 129.2, 128.4, 128.2,
126.2, 125.6, 121.3, 35.9, 30.9.
5-(Tetrahydropyranyloxy)pentyl 3-Phenylpropanoate (17):7c
1
Colorless oil; IR (ATR) 1732 cmꢁ1; H NMR (270 MHz, CDCl3)
ꢂ 7.40–7.10 (m, 5H), 4.65–4.50 (m, 1H), 4.07 (t, J ¼ 6:5 Hz, 2H),
3.95–3.80 (m, 1H), 3.80–3.65 (m, 1H), 3.60–3.45 (m, 1H), 3.45–
3.30 (m, 1H), 2.94 (t, J ¼ 7:6 Hz, 2H), 2.62 (t, J ¼ 7:6 Hz, 2H),
2.00–1.25 (m, 12H); 13C NMR (68 MHz, CDCl3) ꢂ 172.7, 140.3,
128.2, 128.0, 126.0, 98.7, 67.2, 64.3, 62.2, 35.8, 30.9, 30.7, 29.3,
28.4, 25.4, 22.7, 19.6.
1-Phenylethyl (E)-3-Phenyl-2-propenoate (25): Colorless
1
oil; IR (ATR) 1706 cmꢁ1; H NMR (270 MHz, CDCl3) ꢂ 7.70 (d,
J ¼ 16:0 Hz, 1H), 7.60–7.45 (m, 2H), 7.45–7.20 (m, 8H), 6.47 (d,
J ¼ 16:0 Hz, 1H), 6.02 (q, J ¼ 6:6 Hz, 1H), 1.61 (d, J ¼ 6:6 Hz,
3H); 13C NMR (68 MHz, CDCl3) ꢂ 166.0, 144.7, 141.6, 134.2,
130.1, 128.7, 128.4, 127.9, 127.7, 126.0, 118.2, 72.4, 22.3. Anal.
Calcd for C17H16O2: C, 80.93; H, 6.39%. Found: C, 80.54, H,
6.32%.
3-Phenylpropyl Benzoate (26):7c Colorless oil; IR (ATR)
1715 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 8.25–7.90 (m, 2H),
;
7.80–7.12 (m, 8H), 4.32 (t, J ¼ 6:5 Hz, 2H), 2.77 (t, J ¼ 8:1 Hz,
2H), 2.08 (tt, J ¼ 6:5, 8.1 Hz, 2H); 13C NMR (68 MHz, CDCl3)
ꢂ 166.3, 141.0, 132.7, 130.2, 129.4, 128.4, 128.3, 128.2, 128.1,
125.8, 64.2, 32.3, 30.3.
3-Phenylpropyl Cyclohexanecarboxylate (18):7c Colorless
oil; IR (ATR) 1728 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.40–
;
7.10 (m, 5H), 4.07 (t, J ¼ 6:4 Hz, 2H), 2.68 (t, J ¼ 7:3 Hz, 2H),
1.94 (m, 1H), 2.10–1.80 (m, 4H), 1.80–1.40 (m, 2H), 1.55–1.10
(m, 6H); 13C NMR (68 MHz, CDCl3) ꢂ 175.9, 141.1, 128.2, 125.8,
63.3, 43.2, 32.2, 30.3, 29.1, 25.8, 25.5.
1-Phenylethyl Cyclohexanecarboxylate (19): Colorless oil;
;
IR (ATR) 1729 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.35–7.15
(m, 5H), 5.87 (q, J ¼ 6:6 Hz, 1H), 2.31 (m, 1H), 1.90 (m, 2H),
1.72 (m, 2H), 1.51 (d, J ¼ 6:6 Hz, 3H), 1.60–1.10 (m, 6H);
13C NMR (68 MHz, CDCl3) ꢂ 175.0, 141.9, 128.3, 127.5, 125.8,
71.7, 43.3, 29.0, 29.0, 25.8, 25.5, 25.5, 22.4. Anal. Calcd for
3-Phenylpropyl 2,2-Dimethylpropanoate (27):7c Colorless
;
oil; IR (ATR) 1727 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ 7.45–
7.14 (m, 5H), 4.07 (t, J ¼ 6:5 Hz, 2H), 2.69 (t, J ¼ 8:1 Hz, 2H),
1.95 (tt, J ¼ 6:5, 8.1 Hz, 2H), 1.21 (s, 9H); 13C NMR (68 MHz,

S. Funasaka et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
157
CDCl3) ꢂ 178.3, 141.1, 128.3, 128.3, 125.9, 63.5, 38.8, 32.2,
30.4, 27.3.
J ¼ 7:3 Hz, 2H), 2.37 (t, J ¼ 7:3 Hz, 2H), 1.28 (s, 9H); 13C NMR
(68 MHz, CDCl3) ꢂ 171.1, 140.8, 128.2, 125.9, 50.9, 39.3, 31.8,
28.7.
Typical Experimental Procedure for the Preparation of
Carboxamides. To a stirred solution of 3-phenylpropionic acid
(49.6 mg, 0.33 mmol) in CH2Cl2 (1.5 mL) were successively
added pyridine-3-carboxylic anhydride (75.4 mg) and DMAP
(40.4 mg) at 0 ꢂC. After stirring for 10 min, a solution of 3-phenyl-
propylamine (40.6 mg, 0.30 mmol) in dichloromethane (1.5 mL)
was added. After the reaction mixture was stirred for 1 h, it was
quenched with saturated aqueous sodium hydrogencarbonate.
The mixture was extracted with EtOAc. The organic layer was
washed with 1 mol dmꢁ3 hydrochloric acid (3 times), brine and
dried over anhydrous Na2SO4, and the solvent was evaporated.
The crude product was purified by preparative TLC (hexane/
EtOAc = 1/9) to afford 3-phenyl-N-(3-phenylpropyl)propanamide
(75.9 mg, 95%) as a white solid.
N-Phenyl-3-phenylpropanamide (38):7d
White solid; mp
96–98 ꢂC; IR (ATR) 3324, 1654, 1525 cmꢁ1; 1H NMR (270 MHz,
CDCl3) ꢂ 8.66 (brs, 1H), 7.54 (d, J ¼ 7:6 Hz, 2H), 7.50–7.45 (m,
8H), 3.00 (t, J ¼ 7:6 Hz, 2H), 2.65 (t, J ¼ 7:6 Hz, 2H); 13C NMR
(68 MHz, CDCl3) ꢂ 171.1, 140.3, 137.7, 128.5, 128.2, 128.1,
128.0, 125.9, 124.0, 120.2, 38.7, 31.5.
N-(2-Chlorophenyl)-3-phenylpropanamide (39):21
White
solid; mp 110–112 ꢂC; IR (ATR) 3274, 1655, 1526 cmꢁ1; 1H NMR
(270 MHz, CDCl3) ꢂ 8.33 (d, J ¼ 7:9 Hz, 1H), 7.57 (brs, 1H),
7.45–7.10 (m, 7H), 6.99 (t, J ¼ 7:6 Hz, 1H), 3.05 (t, J ¼ 7:6 Hz,
2H), 2.72 (t, J ¼ 7:6 Hz, 2H); 13C NMR (68 MHz, CDCl3) ꢂ
170.1, 140.1, 134.3, 128.8, 128.5, 128.2, 127.5, 126.2, 124.4,
122.5, 121.6, 39.4, 31.3.
3-Phenyl-N-(3-phenylpropyl)propanamide (31):7d
White
N-Ethyl-3-phenylpropanamide (40):11
White solid; mp
solid; mp 54–56 ꢂC; IR (ATR) 3305, 1627, 1538 cmꢁ1; H NMR
(270 MHz, CDCl3) ꢂ 7.35–6.85 (m, 10H), 6.57 (dr, 1H), 3.17 (dt,
J ¼ 6:4, 7.1 Hz, 2H), 2.88 (t, J ¼ 7:6 Hz, 2H), 2.49 (t, J ¼ 7:6 Hz,
2H), 2.41 (t, J ¼ 7:6 Hz, 2H), 1.70 (tt, J ¼ 7:1, 7.6 Hz, 2H);
13C NMR (68 MHz, CDCl3) ꢂ 171.9, 141.0, 140.3, 128.3, 128.0,
127.9, 127.9, 127.8, 125.8, 125.7, 125.5, 38.8, 37.9, 32.9, 31.5,
30.8.
52–54 ꢂC; IR (ATR) 3292, 1629, 1549 cmꢁ1; 1H NMR (270 MHz,
CDCl3) ꢂ 7.50–7.00 (m, 5H), 6.19 (brs, 1H), 3.20 (t, J ¼ 6:5 Hz,
2H), 2.93 (t, J ¼ 7:6 Hz, 2H), 2.44 (t, J ¼ 7:6 Hz, 2H), 1.05 (t,
J ¼ 6:5 Hz, 3H); 13C NMR (68 MHz, CDCl3) ꢂ 171.8, 140.6,
128.1, 128.0, 125.8, 38.2, 34.2, 31.7, 14.6.
1
N-Methoxy-N-methyl-3-phenylpropanamide (41):
Color-
less oil; IR (ATR) 2937, 1658 cmꢁ1; 1H NMR (270 MHz, CDCl3)
ꢂ 7.35–7.10 (m, 5H), 3.58 (s, 3H), 3.16 (s, 3H), 2.96 (t, J ¼ 8:4
Hz, 2H), 2.73 (t, J ¼ 8:4 Hz, 2H); 13C NMR (68 MHz, CDCl3) ꢂ
141.0, 128.2, 128.2, 125.8, 61.0, 33.7, 30.6. Anal. Calcd for
C11H15NO2: C, 68.37; H, 7.82; N, 7.25%. Found: C, 68.33; H,
7.49; N, 6.95%.
N-Benzyl-N-methyl-3-phenylpropanamide (32):7d Mixture
of two conformational isomers A and B. Colorless oil; IR
1
(ATR) 1641 cmꢁ1; H NMR (270 MHz, CDCl3) ꢂ 7.50–7.01 (m,
10H, A þ B), 4.57 (s, 2aH, A), 4.40 (s, 2bH, B), 3.30–2.94 (m,
2H, A þ B), 2.92 (s, 3bH, B), 2.78 (s, 3aH, A), 2.70–2.59 (m,
2H, A þ B); 13C NMR (68 MHz, CDCl3) ꢂ 172.0 (B), 171.7 (A),
140.9, 140.9, 136.9, 136.1, 128.5, 128.1, 128.1, 128.0, 127.6,
127.1, 126.9, 125.8, 125.7, 125.7, 52.9 (B), 50.5 (A), 35.1 (A),
34.7 (B), 34.5 (A), 33.7 (B), 31.3 (B), 31.1 (A).
N-(3-Phenylpropyl)cyclohexanecarboxamide (42):11 White
1
solid; mp 81–83 ꢂC; IR (ATR) 3295, 1639, 1549 cmꢁ1; H NMR
(270 MHz, CDCl3) ꢂ 7.35–7.05 (m, 5H), 6.15 (brs, 1H), 3.24 (dt,
J ¼ 6:4, 6.6 Hz, 2H), 2.61 (t, J ¼ 7:6 Hz, 2H), 2.05 (m, 1H), 1.95–
1.55 (m, 6H), 1.50–1.05 (m, 6H); 13C NMR (68 MHz, CDCl3) ꢂ
175.9, 141.3, 128.1, 128.0, 125.6, 45.3, 38.8, 33.2, 31.2, 29.6,
25.6. Anal. Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71%.
Found: C, 78.31; H, 9.38; N, 5.71%.
3-Phenyl-N-(1-phenylethyl)propanamide (33):7d
White
solid; mp 52–54 ꢂC; IR (ATR) 3307, 1636, 1534 cmꢁ1; H NMR
(270 MHz, CDCl3) ꢂ 7.70–7.35 (m, 10H), 6.51 (m, 1H), 5.03 (q,
J ¼ 7:2 Hz, 1H), 2.87 (t, J ¼ 7:6 Hz, 2H), 2.40 (t, J ¼ 7:6 Hz,
2H), 1.29 (d, J ¼ 7:2 Hz, 3H); 13C NMR (68 MHz, CDCl3) ꢂ
171.0, 143.0, 140.5, 128.2, 128.1, 128.0, 126.7, 125.8, 125.8, 48.3,
38.0, 31.6, 21.6.
1
N-(1-Phenylethyl)cyclohexanecarboxamide (43):
White
solid; mp 113–115 ꢂC; IR (ATR) 3328, 1636, 1528 cmꢁ1; 1H NMR
(270 MHz, CDCl3) ꢂ 7.40–7.15 (m, 5H), 6.05 (brs, 1H), 5.11 (q,
J ¼ 7:1 Hz, 1H), 2.08 (m, 1H), 1.90–1.55 (m, 4H), 1.45 (d, J ¼
7:1 Hz, 3H), 1.55–1.10 (m, 6H); 13C NMR (68 MHz, CDCl3) ꢂ
174.9, 143.3, 128.3, 126.9, 125.9, 48.1, 45.4, 29.6, 29.5, 25.7,
25.7, 21.8. Anal. Calcd for C15H21NO: C, 77.88; H, 9.16; N,
6.05%. Found: C, 77.89; H, 9.22; N, 6.03%.
N-Benzyl-3-phenylpropanamide (34):7d
White solid; mp
81–83 ꢂC; IR (ATR) 3290, 1638, 1542 cmꢁ1; 1H NMR (270 MHz,
CDCl3) ꢂ 7.35–6.95 (m, 10H), 6.52 (brs, 1H), 4.25 (d, J ¼ 5:8 Hz,
2H), 2.88 (t, J ¼ 7:7 Hz, 2H), 2.42 (t, J ¼ 7:7 Hz, 2H); 13C NMR
(68 MHz, CDCl3) ꢂ 171.9, 140.5, 138.0, 128.2, 128.2, 128.1,
127.2, 126.9, 125.9, 43.2, 38.0, 31.6.
2-Phenyl-N-(3-phenylpropyl)propanamide (44):7d
White
N-(Diphenylmethyl)-3-phenylpropanamide (35):7d
White
solid; mp 91–93 ꢂC; IR (ATR) 3240, 1640, 1560 cmꢁ1; H NMR
(270 MHz, CDCl3) ꢂ 7.40–7.10 (m, 8H), 7.10–6.95 (m, 2H), 5.84
(brs, 1H), 3.52 (q, J ¼ 7:1 Hz, 1H), 3.17 (dt, J ¼ 6:4, 6.6 Hz, 2H),
2.49 (t, J ¼ 7:6 Hz, 2H), 1.70 (tt, J ¼ 7:1, 7.6 Hz, 2H), 1.48 (d,
J ¼ 7:1 Hz, 3H); 13C NMR (68 MHz, CDCl3) ꢂ 173.8, 141.3,
141.1, 128.5, 128.1, 128.0, 127.3, 126.9, 125.6, 46.8, 39.0, 33.0,
31.0, 18.4.
1
solid; mp 147–149 ꢂC; IR (ATR) 3307, 1644, 1534 cmꢁ1; 1H NMR
(270 MHz, CDCl3) ꢂ 7.50–7.20 (m, 9H), 7.25–7.00 (m, 6H), 6.94
(d, J ¼ 8:1 Hz, 1H), 6.21 (d, J ¼ 8:1 Hz, 1H), 2.90 (t, J ¼ 7:4 Hz,
2H), 2.47 (t, J ¼ 7:4 Hz, 2H); 13C NMR (68 MHz, CDCl3) ꢂ
171.0, 141.2, 140.4, 128.2, 128.1, 127.2, 126.9, 125.9, 56.5, 37.9,
31.5.
1-(3-Phenylpropanoyl)piperidine (36):7d Colorless oil; IR
(2RS)-2-Phenyl-N-((1RS)-1-phenylethyl)propanamide (45):7d
White solid; mp 116–118 ꢂC; IR (ATR) 3244, 1639, 1543 cmꢁ1
;
1
(ATR) 1635 cmꢁ1; H NMR (270 MHz, CDCl3) ꢂ 7.55–7.10 (m,
5H), 3.54 (t, J ¼ 5:4 Hz, 2H), 3.31 (t, J ¼ 5:4 Hz, 2H), 2.96 (t,
J ¼ 7:6 Hz, 2H), 2.60 (t, J ¼ 7:6 Hz, 2H), 1.90–1.35 (m, 6H);
13C NMR (68 MHz, CDCl3) ꢂ 169.9, 141.1, 128.1, 128.1, 125.7,
46.4, 42.5, 35.0, 31.4, 26.2, 25.4, 24.3.
1H NMR (270 MHz, CDCl3) ꢂ 7.45–7.00 (m, 10H), 5.76 (m, 1H),
5.08 (q, J ¼ 6:9 Hz, 1H), 3.57 (q, J ¼ 7:1 Hz, 1H), 1.49 (d, J ¼
7:1 Hz, 3H), 1.37 (d, J ¼ 6:9 Hz, 3H); 13C NMR (68 MHz, CDCl3)
ꢂ 172.9, 143.1, 141.2, 128.7, 128.3, 127.4, 127.0, 126.9, 125.6,
48.6, 47.0, 21.9, 18.5. Anal. Calcd for C17H19NO: C, 80.60; H,
7.56; N, 5.53%. Found: C, 80.51; H, 7.61; N, 5.43%.
N-(1,1-Dimethylethyl)-3-phenylpropanamide (37):20 White
1
solid; mp 81–83 ꢂC; IR (ATR) 3283, 1640, 1552 cmꢁ1; H NMR
(270 MHz, CDCl3) ꢂ 7.38–7.14 (m, 5H), 5.20 (brs, 1H), 2.93 (t,
(2RS)-2-Phenyl-N-((1SR)-1-phenylethyl)propanamide (45):7d

158 Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
3-PCA as Effective Condensation Reagent
White solid; mp 116–118 ꢂC; IR (ATR) 3244, 1639, 1543 cmꢁ1
;
52, 1989.
2,20-Dipyridyl disulfide/Ph3P see: a) T. Mukaiyama, R.
1H NMR (270 MHz, CDCl3) ꢂ 7.45–7.10 (m, 10H), 5.82 (m, 1H),
5.07 (q, J ¼ 6:5 Hz, 1H), 3.53 (q, J ¼ 7:0 Hz, 1H), 1.49 (d, J ¼
7:0 Hz, 3H), 1.33 (d, J ¼ 6:5 Hz, 3H); 13C NMR (68 MHz, CDCl3)
ꢂ 173.0, 143.0, 141.3, 128.7, 128.4, 127.4, 127.0, 127.0, 125.8,
48.6, 46.9, 21.6, 18.6. Anal. Calcd for C17H19NO: C, 80.60; H,
7.56; N, 5.53%. Found: C, 80.27; H, 7.55; N, 5.42%.
4
Matsueda, M. Suzuki, Tetrahedron Lett. 1970, 11, 1901. b) E. J.
Corey, K. C. Nicolaou, J. Am. Chem. Soc. 1974, 96, 5614.
5
O,O0-Di(2-pyridyl)thiocarbonate (DPTC) see: K. Saitoh,
I. Shiina, T. Mukaiyama, Chem. Lett. 1998, 679.
Di(2-pyridyl)carbonate (DPC) see: S. Kim, J. I. Lee, Y. K.
Ko, Tetrahedron Lett. 1984, 25, 4943.
2-Me-6-NO2-benzoic anhydride (MNBA) see: a) I. Shiina,
6
N-(3-Phenylpropyl)diphenylacetamide (46): White solid; IR
(ATR) 3287, 1636, 1539 cmꢁ1; mp 139–141 ꢂC; 1H NMR (270
MHz, CDCl3) ꢂ 7.45–7.00 (m, 15H), 5.72 (m, 1H), 4.89 (s, 1H),
3.27 (dt, J ¼ 6:2, 7.0 Hz, 2H), 2.55 (t, J ¼ 7:3 Hz, 2H), 1.78 (tt,
J ¼ 7:0, 7.3 Hz, 2H); 13C NMR (68 MHz, CDCl3) ꢂ 171.6, 141.1,
139.3, 128.7, 128.6, 128.3, 128.2, 127.1, 125.8, 59.1, 39.4, 33.2,
31.1. Anal. Calcd for C23H23NO: C, 83.85; H, 7.04; N, 4.25%.
Found: C, 83.43; H, 7.06; N, 4.15%.
7
R. Ibuka, M. Kubota, Chem. Lett. 2002, 286. b) I. Shiina, M.
Kubota, R. Ibuka, Tetrahedron Lett. 2002, 43, 7535. c) I. Shiina,
M. Kubota, H. Oshiumi, M. Hashizume, J. Org. Chem. 2004, 69,
1822. d) I. Shiina, Y. Kawakita, Tetrahedron 2004, 60, 4729. e) I.
Shiina, Chem. Rev. 2007, 107, 239.
8
4-(Trifluoromethyl)benzoic anhydride see: a) I. Shiina, S.
N-(1-Phenylethyl)diphenylacetamide (47): White solid; IR
(ATR) 3270, 1637, 1545 cmꢁ1; mp 119–121 ꢂC; 1H NMR (270
MHz, CDCl3) ꢂ 7.40–7.05 (m, 15H), 6.14 (m, 1H), 5.13 (q, J ¼
7:0 Hz, 1H), 4.89 (s, 1H), 1.37 (d, J ¼ 7:0 Hz, 3H); 13C NMR
(68 MHz, CDCl3) ꢂ 170.7, 142.9, 139.3, 139.3, 128.7, 128.7,
128.5, 128.4, 127.0, 127.0, 127.0, 125.8, 58.8, 48.9, 21.8. HRMS
(ESI positive) Calcd for C22H22NO Mþ: 316.1701. Found: m=z
316.1703.
Miyoshi, M. Miyashita, T. Mukaiyama, Chem. Lett. 1994, 515.
b) I. Shiina, T. Mukaiyama, Chem. Lett. 1994, 677. c) I. Shiina,
Tetrahedron 2004, 60, 1587.
9
4-Nitrobenzoic anhydride/Sc(OTf)3 see: K. Ishihara, M.
Kubota, H. Kurihara, H. Yamamoto, J. Org. Chem. 1996, 61,
4560.
10 Di-2-thienyl carbonate (2-DTC) see: a) Y. Oohashi, K.
Fukumoto, T. Mukaiyama, Chem. Lett. 2004, 33, 968. b) Y.
Oohashi, K. Fukumoto, T. Mukaiyama, Bull. Chem. Soc. Jpn.
2005, 78, 1508.
(E)-3-Phenyl-N-(3-phenylpropyl)-2-propenamide
(48):
White solid; mp 115–118 ꢂC; IR (ATR) 3244, 1639, 1543 cmꢁ1
;
1H NMR (270 MHz, CDCl3) ꢂ 7.62 (d, J ¼ 15:7 Hz, 1H), 7.50–
7.30 (m, 2H), 7.30–7.05 (m, 8H), 7.01 (m, 1H), 6.57 (d, J ¼
15:7 Hz, 1H), 3.39 (dt, J ¼ 6:4, 6.6 Hz, 2H), 2.62 (t, J ¼ 7:6 Hz,
2H), 1.87 (tt, J ¼ 7:2, 7.6 Hz, 2H); 13C NMR (68 MHz, CDCl3)
ꢂ 166.0, 141.1, 140.2, 134.6, 129.2, 128.5, 128.1, 128.1, 127.4,
125.6, 121.0, 39.3, 33.2, 31.1. Anal. Calcd for C18H19NO: C,
81.47; H, 7.22; N, 5.28%. Found: C, 81.53; H, 7.30; N, 5.25%.
(E)-3-Phenyl-N-(1-phenylethyl)-2-propenamide (49): White
solid; mp 136–138 ꢂC; IR (ATR) 3305, 1615, 1550 cmꢁ1; 1H NMR
(270 MHz, CDCl3) ꢂ 7.61 (d, J ¼ 15:7 Hz, 1H), 7.50–7.05 (m,
11H), 6.59 (d, J ¼ 15:7 Hz, 1H), 5.23 (q, J ¼ 6:9 Hz, 1H), 1.48
(d, J ¼ 6:9 Hz, 3H); 13C NMR (68 MHz, CDCl3) ꢂ 165.1, 143.1,
140.6, 134.6, 129.2, 128.5, 128.3, 127.5, 126.9, 126.0, 120.9, 48.8,
21.8. Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57%.
Found: C, 81.07; H, 7.06; N, 5.52%.
11 Tetrakis(2-methylimidazol-1-yl)silane see: T. Tozawa, Y.
Yamane, T. Mukaiyama, Heterocycles 2006, 67, 629.
12 Another condensation reagents see: K. Saigo, M. Usui, K.
Kikuchi, E. Shimada, T. Mukaiyama, Bull. Chem. Soc. Jpn. 1977,
50, 1863; H. A. Staab, A. Mannschreck, Chem. Ber. 1962, 95,
´
1284; J. Diago-Meseguer, A. L. Palomo-Coll, J. R. Fernandez-
Lizarbe, A. Zugaza-Bilbao, Synthesis 1980, 547; K. Takeda, A.
Akiyama, H. Nakamura, S. Takizawa, Y. Mizuno, H. Takayanagi,
Y. Harigaya, Synthesis 1994, 1063; K. Wakasugi, A. Nakamura,
Y. Tanabe, Tetrahedron Lett. 2001, 42, 7427; K. Wakasugi, A.
Nakamura, A. Iida, Y. Nishii, N. Nakatani, S. Fukushima, Y.
Tanabe, Tetrahedron 2003, 59, 5337; K. Wakasugi, A. Iida, T.
Misaki, Y. Nishii, Y. Tanabe, Adv. Synth. Catal. 2003, 345,
1209; I. Shiina, Y. Kawakita, Tetrahedron Lett. 2003, 44, 1951;
I. Shiina, Y. Fukuda, T. Ishii, H. Fujisawa, T. Mukaiyama,
Chem. Lett. 1998, 831; I. Shiina, H. Fujisawa, T. Ishii, Y. Fukuda,
N-(3-Phenylpropyl)benzamide (50):11 White solid; mp 40–
42 ꢂC; IR (ATR) 3309, 1634, 1536 cmꢁ1
;
1H NMR (270 MHz,
Heterocycles 2000, 52, 1105; L. Gooßen, A. Dohring, Adv. Synth.
Catal. 2003, 345, 943.
¨
CDCl3) ꢂ 8.00–7.65 (m, 2H), 7.60–7.50 (m, 9H), 3.44 (dt, J ¼
6:5, 7.1 Hz, 2H), 2.66 (t, J ¼ 7:6 Hz, 2H), 1.95 (tt, J ¼ 7:1, 7.6
Hz, 2H); 13C NMR (68 MHz, CDCl3) ꢂ 167.4, 141.2, 134.3, 130.9,
128.1, 128.1, 128.0, 126.7, 125.6, 39.7, 33.3, 30.9.
N-Phenylbenzamide (51): White solid; mp 166–167 ꢂC; IR
(ATR) 3343, 1654, 1598 cmꢁ1 1H NMR (270 MHz, CDCl3) ꢂ
;
8.20–7.76 (m, 3H), 7.75–7.30 (m, 7H), 7.25–7.10 (m, 1H);
13C NMR (68 MHz, CDCl3) ꢂ 165.6, 137.8, 134.9, 131.7, 129.0,
128.7, 126.9, 124.5, 120.1. Anal. Calcd for C13H11NO: C, 79.16;
H, 5.62; N, 7.10%. Found: C, 78.99; H, 5.62; N, 6.86%.
13 J. A. Mackay, E. Vedejs, J. Org. Chem. 2004, 69, 6934.
14 R. Kocz, J. Roestamadji, S. Mobashery, J. Org. Chem.
1994, 59, 2913.
15 Preliminary communications: a) T. Mukaiyama, S.
Funasaka, Chem. Lett. 2007, 36, 326. b) S. Funasaka, T.
Mukaiyama, Chem. Lett. 2007, 36, 658.
16 A. Sakakura, M. Katsukawa, K. Ishihara, Org. Lett. 2005,
7, 1999.
17 The diastereomeric ratios of 21 and 45 were ca. 1:1 respec-
tively. These results were based on the 1H NMR chemical shift
of the characteristic methyl group, which resonates at a lower
magnetic field in the syn-isomer than anti-isomer. see: H. Yang,
E. Henke, U. T. Bornscheuer, Tetrahedron: Asymmetry 1999,
10, 957.
18 After aqueous workup these by-products were not observed
by using 1H NMR using a crude mixture. It indicates that by-
products, such as 1-phenylethyl pyridine-3-carboxylate and N-
(1-phenylethyl)pyridine-3-carboxamide, are transferred to the
aqueous layer by aqueous workup.
References
1
For reviews of dehydration reaction, see: C. A. G. N.
Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827.
DCC see: a) B. Neises, W. Steglich, Angew. Chem., Int.
2
Ed. Engl. 1978, 17, 522. b) A. Hassner, V. Alexanian, Tetra-
hedron Lett. 1978, 19, 4475.
3 2,4,6-Trichlorobenzoyl chloride see: J. Inanaga, K. Hirata,
H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 1979,

S. Funasaka et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 1 (2008)
159
19 a) M. P. Sibi, C. C. Stessman, J. A. Schutz, J. W.
Christensen, J. Lu, M. Marvin, Synth. Commun. 1995, 25, 1255.
b) A. R. Tunoori, J. M. White, G. I. Georg, Org. Lett. 2000, 2,
4091. c) L. D. Luca, G. Giacomelli, M. Taddei, J. Org. Chem.
Kobayashi, R. Ohkihara, S. Tani, M. Kunishima, Chem. Pharm.
Bull. 2004, 52, 470.
20 F. Matsuda, S. Itoh, N. Hattori, M. Yanagiya, T.
Matsumoto, Tetrahedron 1985, 41, 3625.
´
2001, 66, 2534. d) M. A. Bailen, R. Chinchilla, D. J. Dodsworth,
C. Najera, Tetrahedron Lett. 2001, 42, 5013. e) K. Hioki, H.
21 X. Wan, Z. Ma, B. Li, K. Zhang, S. Cao, S. Zhang, Z. Shi,
J. Am. Chem. Soc. 2006, 128, 7416.
´