Pyridine-3-carboxylic anhydride (3-PCA): A versatile, practical, and inexpensive reagent for condensation reaction between carboxylic acids and alcohols

Article abstract of DOI:10.1246/cl.2007.326

A synthesis of carboxylic esters from various carboxylic acids and alcohols is successfully carried out by using a condensation reagent, pyridine-3-carboxylic anhydride (3-PCA). This reaction materialized synthesis of various carboxylic esters to be carried out under mild conditions by simple experimental procedure. Copyright

Full text of DOI:10.1246/cl.2007.326

326
Chemistry Letters Vol.36, No.2 (2007)
Pyridine-3-carboxylic Anhydride (3-PCA):
A Versatile, Practical, and Inexpensive Reagent for Condensation Reaction
between Carboxylic Acids and Alcohols
Teruaki Mukaiyamaꢀ1;2 and Setsuo Funasaka1
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 December 14, 2006; CL-061467; E-mail: mukaiyam@abeam.ocn.ne.jp)
A synthesis of carboxylic esters from various carboxylic
would readily be removed by a simple aqueous workup. We
would like to report herein a convenient condensation reaction
using pyridine-3-carboxylic anhydride (3-PCA) that is readily
prepared quantitatively from inexpensive pyridine-3-carboxylic
acid (nicotinic acid).12,13
acids and alcohols is successfully carried out by using a conden-
sation reagent, pyridine-3-carboxylic anhydride (3-PCA). This
reaction materialized synthesis of various carboxylic esters to
be carried out under mild conditions by simple experimental
procedure.
In the first place, a condensation reaction of 3-phenylpropa-
noic acid with 3-phenylpropan-1-ol was examined in dichloro-
methane at room temperature in the coexistence of triethylamine,
3-PCA, and DMAP (Table 1). When 1.3 molar amounts of the
dehydrating reagent and 2.6 molar amounts of triethylamine
were used, the reaction proceeded smoothly within 1 h under
the above conditions, and the desired ester, 3-phenylpropyl 3-
phenylpropanoate, was afforded in 97% yield (Entry 1). Next,
the reactions were further examined in order to reduce the
amounts of the reagents, namely carboxylic acid, triethylamine,
and the dehydrating reagent. It was then observed that the corre-
sponding ester was formed in high yield even when the amounts
of carboxylic acid, dehydrating reagent and trietylamine were all
reduced to 1.1 equivalents (Entries 2–4). It is noteworthy that the
desired carboxylic ester was obtained in high yield also in the ab-
sence of triethylamine (Entry 5). This clearly indicates that the
pyridine moiety of 3-PCA worked as the base to capture pyri-
dine-3-carboxylic acid formed in situ. In addition, it was found
that the reaction proceeded smoothly even when 2 mol % of
DMAP was used (Entries 6 and 7). Interestingly, the desired ester
was obtained in 49% yield also in the absence of a base (Entry 8).
In the next place, effect of solvents was examined (Table 2).
It was revealed then that the reaction proceeded not only in
a non-polar solvent such as CH2Cl2 or toluene but also in a
polar solvent such as THF, Et2O, DMF, or MeCN and afford
the desired ester 4 in excellent yields (Entries 1–6).
The condensation reaction between a carboxylic acid and
an alcohol is considered one of the most important reactions in
organic synthesis. Although various esterification methods have
been developed to date,1–10 most of them require strong acids or
bases, high reaction temperature, troublesome procedure, or high
cost. Therefore, it was strongly desired to find more convenient
and effective esterification reaction that proceeds under simple
and mild conditions.
Benzoic acid derivatives have been known as effective con-
densation reagent for synthesizing carboxylic esters under mild
condition, whereas an excess amount of a base such as triethyl-
amine is generally required in order to enhance the nucleophilic-
ity of carboxylic acids. Thus, it was needed to develop a new and
effective reagent that allows the reaction to proceed smoothly
just by mixing carboxylic acids and alcohols. Then, pyridine-
3-carboxylic anhydride was chosen with the expectation that it
would be reactive because of the electron-withdrawing nature
of pyridine ring.11 In addition, this condensation reaction is
assumed to proceed without using any base since the basicity
is already inherent in the condensing reagent, and further, the
hydrophilic pyridine-3-carboxylic acid formed via this reaction
Table 1. Synthesis of carboxylic esters using 3-PCA
O
O
Table 2. Effect of solvents
O
O
O
N
N
1 (X equiv.)
O
O
O
Et3N (Y equiv.), DMAP (Z equiv.)
N
N
R1 OH
R2OH
R1 OR2
+
CH2Cl2,, rt, 1 h
1 (1.1 equiv.)
DMAP (0.1 equiv.)
O
O
2 (X equiv.) 3 (1.0 equiv.)
1 = Ph(CH2)2 R2 = Ph(CH2)3
4
R1 OH
2 (1.1 equiv.)
R1 = Ph(CH2)2 R2 = Ph(CH2)3
R1 OR2
R2OH
+
R
CH2Cl2,, rt, 1 h
3 (1.0 equiv.)
4
Entry
X
Y
Z
Yielda/%
1
2
3
4
5
6
7
8b
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
0.1
0.1
0.1
0.1
0.1
0.05
0.02
0
97
96
96
96
97
96
96
49
Entry
Solvent
CH2Cl2
Toluene
Et2O
DMF
Yielda/%
1
2
3
4
5
6
97
91
93
95
94
96
0
0
0
THF
MeCN
aIsolated yield. bThe reaction mixture was stirred for 24 h.
aIsolated yield.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.2 (2007)
327
References and Notes
Table 3. Synthesis of various carboxylic esters with 3-PCA
1
2
3
4
5
6
DCC see: a) B. Neises, W. Steglich, Angew. Chem., Int. Ed. Engl. 1978, 17,
522. b) A. Hassner, V. Alexanian, Tetrahedron Lett. 1978, 19, 4475.
2,4,6-Trichlorobenzoyl chloride see: J. Inanaga, K. Hirata, H. Saeki, T.
Katsuki, M. Yamaguchi, Bull. Chem. Soc. Jpn. 1979, 52, 1989.
2,20-Dipyridyl disulfide/Ph3P see: E. J. Corey, K. C. Nicolaou, J. Am. Chem.
Soc. 1974, 96, 5614.
O
O
O
N
N
1 (1.1 equiv.)
DMAP (Z equiv.)
O,O0-Di(2-pyridyl) thiocarbonate (DPTC) see: K. Saitoh, I. Shiina, T.
Mukaiyama, Chem. Lett. 1998, 679.
O
O
R1 OH
2 (1.1 equiv.)
R2OH
R1 OR2
+
CH2Cl2,, rt, 1 h
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, R. Ibuka, M.
Kubota, Chem. Lett. 2002, 286. b) I. Shiina, M. Kubota, R. Ibuka, Tetra-
hedron Lett. 2002, 43, 7535.
4-(Trifluoromethyl)benzoic anhydride see: I. Shiina, S. Miyoshi, M.
Miyashita, T. Mukaiyama, Chem. Lett. 1994, 515; I. Shiina, T. Mukaiyama,
Chem. Lett. 1994, 677; I. Shiina, Tetrahedron 2004, 60, 1587.
4-Nitrobenzoic anhydride/Sc(OTf)3 see: K. Ishihara, M. Kubota, H.
Kurihara, H. Yamamoto, J. Org. Chem. 1996, 61, 4560.
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.
3 (1.0 equiv.)
4
Entry
R1
R2
Z
Yielda/%
1
2
3
4
5
6
7
8
9
Ph(CH2)2
Ph(CH2)3
PhCH(CH3)
PhCH2
Ph
c-C6H11
0.02
0.02
0.02
0.02
0.10
0.05
0.02
0.05
0.05
0.05
0.05
97
95
96
91
89
94
93
90
85
97
95
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
c-C6H11
c-C6H11
PhCH(CH3)
PhCH(CH3)
7
8
9
Ph(CH2)2CH(CH3)
CH2=CHCH2
Ph(CH2)3
PhCH(CH3)
Ph(CH2)3
PhCH(CH3)
10 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.
10
11
´
Palomo-Coll, J. R. Fernandez-Lizarbe, A. Zugaza-Bilbao, Synthesis 1980,
aIsolated yield.
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, Heterocycles 2000, 52,
O
O
O
Me
Me
N
N
OH
Ph
Me
Ph
O
Ph
Me
Ph
1 (1.1 equiv.)
DMAP (0.05 equiv.)
+
1105; L. Gooßen, A. Dohring, Adv. Synth. Catal. 2003, 345, 943.
¨
11 J. A. Mackay, E. Vedejs, J. Org. Chem. 2004, 69, 6934.
O
O
HO
5 (1.0 equiv.) 6 (1.0 equiv.)
7
12 3-PCA was prepared from pyridine-3-carboxylic acid. 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 ꢁC. To the reaction mix-
ture, a solution of triphosgene (402 mg, 1.35 mmol) in THF (2 mL) was added
at 0 ꢁC, then stirred for 1 h. The reaction mixture was additionally stirred for
1 h at room temperature. After filtration of the reaction mixture to remove di-
isopropylethylammonium chloride formed, the filtrate was condensed 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 898 mg
(97%) of pyridine-3-carboxylic anhydride as a white solid. mp 121–123 ꢁC.
IR (neat, cmꢂ1) 1797, 1723. 1H NMR (400 MHz, Acetone-d6) ꢁ 7.66 (ddd,
2H, J ¼ 0:8, 4.8, 8.0 Hz), 8.55 (ddd, 2H, J ¼ 1:8, 1.8, 8.0 Hz), 8.92 (dd,
2H, J ¼ 1:8, 4.8 Hz), 9.34 (dd, 2H, J ¼ 0:8, 1.8 Hz). 13C NMR (100 MHz,
Acetone-d6) ꢁ 124.2, 125.0, 138.1, 151.6, 155.3, 161.2. Anal: calcd for
C12H8N2O3: C, 63.16; H, 3.53; N, 12.28%. Found: C, 62.94; H, 3.49; N,
12.21%.
CH2Cl2, rt, 1 h
96 %
10 g
5.0 g
Scheme 1. Large-scale synthesis of ꢀ-phenylethyl 2-phenyl-
propanoate with 3-PCA.
The results obtained by using various carboxylic acids and
alcohols were summarized in Table 3.14 When nearly equimolar
amounts of primary or secondary alcohols were used, the con-
densation reaction of 3-phenylpropanoic acid with respective
alcohols afforded the corresponding esters in high yields (Entries
1–7). The desired esters were also obtained in good yields when
hindered ꢀ,ꢀ-disubstituted carboxylic acids were used (Entries
8–11).
This method is applicable also to gram-scale synthesis in
which the desired ester 7 was given in 96% yield by using 3-
PCA and catalytic amount of DMAP (Scheme 1). Importantly,
by-products, pyridine-3-carboxylic acid and 1-phenylethyl pyri-
dine-3-carboxylate that were produced from 3-PCA and 6, were
easily removed by aqueous workup.15,16
It is noted that a convenient and effective method for the
synthesis of various carboxylic esters from carboxylic acids
and alcohols is established. The reaction of various alcohols
and carboxylic acids with 3-PCA and a catalytic amount of
DMAP gave the corresponding esters in high to excellent yields.
Thus, pyridine-3-carboxylic anhydride is one of the most
efficient and convenient reagents for the condensation reaction
between various carboxylic acids and alcohols. Further study
on the usefulness of the present dehydrating reagent is now in
progress.
13 For the preparation of carboxylic anhydrides using triphosgene, see: R. Kocz,
J. Roestamadji, S. Mobashery, J. Org. Chem. 1994, 59, 2913.
14 Typical experimental procedure for the preparation of 3-phenylpropyl 3-
phenylpropanoate is shown in the following: To a stirred solution of 3-
phenylpropanoic acid (49.6 mg, 0.33 mmol) in CH2Cl2 (1.5 mL) were succes-
sively added pyridine-3-carboxylic anhydride (75.4 mg) and DMAP (0.7 mg)
at room temperature. After having been stirred 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 hydrogencarbonate. The mixture was extracted
with EtOAc. The organic layer was washed with brine, dried over anhydrous
Na2SO4, and evaporated. 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.
15 After the reaction of ꢀ-phenylethyl alcohol (5.00 g) with 2-phenylpropanoic
acid (6.76 g) in dichloromethane (100 mL) at room temperature in the pres-
ence of 3-PCA (10.23 g) and DMAP (250 mg) according to the typical proce-
dure,13 it was quenched with saturated aqueous sodium hydrogencarbonate.
The mixture was extracted with tert-butyl methyl ether. The organic layer
was washed with saturated aqueous sodium hydrogencarbonate (2 times),
1 M hydrogenchloride (3 times), brine, dried over anhydrous Na2SO4, and
evaporated. The crude product was purified by silica-gel column chromatog-
raphy (hexane/EtOAc = 10/1) to afford ꢀ-phenylethyl 2-phenylpropanoate
(9.96 g, 96%) as colorless oil.
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
16 After aqueous workup, these by-products were not observed in a crude mix-
ture by 1H NMR. It indicates that 1-phenylethyl pyridine-3-carboxylate is
transferred to aqueous layer by acidic workup.
Published on the web (Advance View) January 27, 2007; doi:10.1246/cl.2007.326