One-pot preparation of esters from carboxylic acids using the PPh3-CCl3CN system

Article abstract of DOI:10.1081/SCC-120022178

A convenient one-pot process for preparing various esters from carboxylic acids using the Ph₃P-CCl₃CN has been developed. Racemic α-tocopherol, clofibrate and flavoxate were prepared in high yields using this method.

Full text of DOI:10.1081/SCC-120022178

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One-Pot Preparation of Esters from Carboxylic Acids
Using the PPh -CCl CN System
3
3
a
a
b
Doo Ok Jang , Dae Hyan Cho & Joong-Gon Kim
a
Department of Chemistry , Yonsei University , Wonju, Korea
b
Biotechnology Division , Hanwha Chemical R & D Center , Taejon, Korea
Published online: 19 Aug 2006.
To cite this article: Doo Ok Jang , Dae Hyan Cho & Joong-Gon Kim (2003) One-Pot Preparation of Esters from Carboxylic Acids
Using the PPh -CCl CN System, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
3
3
Organic Chemistry, 33:16, 2885-2890, DOI: 10.1081/SCC-120022178
To link to this article: http://dx.doi.org/10.1081/SCC-120022178
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 16, pp. 2885–2890, 2003
One-Pot Preparation of Esters from Carboxylic
Acids Using the PPh -CCl CN System
3
3
1,
1
2
Doo Ok Jang, * Dae Hyan Cho, and Joong-Gon Kim
1
Department of Chemistry, Yonsei University,
Wonju, Korea
2
Biotechnology Division, Hanwha Chemical
R & D Center, Taejon, Korea
ABSTRACT
A convenient one-pot process for preparing various esters from
carboxylic acids using the Ph P-CCl CN has been developed.
3
3
Racemic a-tocopherol, clofibrate and flavoxate were prepared in
high yields using this method.
Key Words: Ester; Acyl chloride; Carboxylic acid; Trichloronitrile.
Acyl halides are very useful preparative intermediates for preparing
[
1]
othersubstances such as amides and este sr . Although many coupling
reagents for preparing esters directly from carboxylic acids have been
*Correspondence: Doo Ok Jang, Department of Chemistry, Yonsei University,
Wonju 220-710, Korea; E-mail: dojang@dragon.yonsei.ac.kr.
2
885
DOI: 10.1081/SCC-120022178
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2
886
Jang, Cho, and Kim
[2]
developed, the method for the preparation of esters through acyl chlor-
ides is still demanded. The traditional methods to prepare acyl chlorides
[
from carboxylic acids used thionyl chloride, phosphorous chlorides,
3]
[1]
[4]
oroxalyl chlo ri de.
However, the methods cannot be employed for acid-
sensitive molecules due to their strong acidic conditions. When acid-free
conditions are required, acyl chlorides can be obtained by treatment of
carboxylic acids with an adduct of triphenylphosphine with carbon tetra-
[
5]
[6]
[7]
chloride, cyanuric chloride, tetramethyl-a-chloroenamine, orhexa-
[8]
chloroacetone. However, the methods have their own disadvantages
such as long reaction times, or using toxic materials to prepare. We
have recently reported work on the preparation of acyl chlorides using
triphenylphosphine and trichloroacetonitrile. The efficiency of the
process prompted us to apply the reaction to preparation of a variety
of esters.
[
9]
First, the reaction was examined with various alcohols. The results
are summarized in Table 1. Treatment of benzoic acid with Ph P and
3
CCl CN in CH CN at room temperature, followed by cyclododecanol in
3
3
the presence of 4-(dimethylamino)pyridine (DMAP) at reflux resulted in
the formation of the corresponding ester in 93% yield (Entry 1). The yield
of ester decreased as the amount of DMAP decreased (Entries 2–3).
[
10]
Use of zinc as a promoter gave a poor yield of ester (Entry 4).
Compared with acyclic alcohols, the reaction proceeded efficiently with
cyclic secondary alcohols affording excellent yields of the corresponding
esters (Entries 5 and 6). A primary alcohol afforded a high yield of the

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PPh -CCl CN System
3
2887
3
Table 1. Synthesis of esters from benzoic acid using the PPh -CCl CN system.
3
3
Entry
ROH
DMAP (equiv.)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Cyclododecanol
Cyclododecanol
Cyclododecanol
Cyclododecanol
Cyclohexanol
(þ)-Menthol
3
2
1.5
1.5
2.0
2.0
1.5
1.5
1.5
1.5
1.5
3.0
93
73
a
1
—
81
35
b
3
3
3
3
3
3
88
92
2-Dodecanol
72
82
1-Dodecanol
t-Butanol
1-Ethylcyclododecanol
c
26 (70)
0
1
0
a
Et
3
N (3 equiv.) was added.
b
Zn (1 equiv.) was used instead of DMAP.
Recovered starting material.
c
ester than a secondary alcohol (Entries 7 and 8). The method reaches a
t
limit with sterically hindered alcohols such as BuOH and 1-ethylcyclo-
t
dodecanol. The reaction gave a poor yield of the ester with BuOH
(
Entry 9), and did not proceed at all with a bulkier tertiary alcohol,
1-ethylcyclododecanol (Entry 10).
The preparation of esters has been performed on a variety of struc-
turally different carboxylic acids to determine the scope and limitations of
this method. The results are presented in Table 2. Aromatic carboxylic
acids afforded excellent yields while aliphatic acids gave moderate to high
yields of the corresponding esters (Entries 1–5).
Next, we applied our method to preparing important medicines
[
11]
such as the hyperkinemic agent, DL-a-tocopherol nicotinate (1c),
the
and the hypolipid-
The reaction of nicotinic acid (1a) with
[
12]
anticholinergic-spasmolytic agent, flavoxate (2c)
[
13]
emic agent, clofibrate (3c).
DL-a-tocopherol (1b) under reaction conditions produced the desired
ester, DL-a-tocopherol nicotinate (1c) in 84% yield (Entry 6). Similarly,
flavoxate (2c) and clofibrate (3c) were prepared in 73% and 78% yields,
respectively (Entries 7 and 8).
In conclusion, the Ph P/CCl CN system provides an efficient one-pot
3
3
process for preparing various esters from aromatic and aliphatic

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Jang, Cho, and Kim
Table 2. Synthesis of various esters from carboxylic acids using the
PPh -CCl CN system.
3
3
0
Entry
RCO
2
H
R OH
Time (h)
Yield (%)
1
2
3
4
5
p-Nitrobenzoic
t
p- Butylbenzoic
Cyclododecanol
Cyclododecanol
Cyclododecanol
Cyclododecanol
Cyclohexanol
1b
1.0
1.0
3.5
3.5
3.5
2.0
2.0
2.0
94
94
85
62
64
84
73
78
Heptanoic
6-Bromohexanoic
2-Bromoisovaleric
a
6
1a
2a
3a
a
7
b
2b
Ethanol
8
a
The reaction was carried out in THF.
The reaction was carried out with 2 equiv. of ethanol in THF.
b
carboxylic acids. The reaction conditions are mild, and as a result,
functionalities such as double bond, nitro, chloro, bromo, ether, and
carbonyl groups remain unaffected. Furthermore, the reagents employed
are inexpensive and are readily available.
EXPERIMENTAL
Melting points were determined with a Fisher-Jones melting point
1
13
apparatus and are uncorrected. H and C NMR spectra were deter-
mined forsolutions in CDCl 3 with TMS internal reference on a Varian
Gemini 300 NMR spectrometer. Thin-layer chromatography (TLC) was
performed on 0.25 mm silica gel plates (Merck, Kieselgel 60F-254).
Column chromatography was performed on silica gel (Merck, Kieselgel
60, 230–400 mesh). All commercially available reagents were used as
received from the suppliers. Solvents were used either as purchased or
dried and purified by standard methodology under argon. All yields refer
to isolated products.
Synthesis of DL-a-tocopherol nicotinate (1c). To a mixture of nicotinic
acid (1a) (246 mg, 2.0 mmol) and CCl CN (0.4 mL, 4.0 mmol) in anhy-
3
drous THF (10 mL) under argon was added Ph P (1.05 g, 4.0 mmol)
3
at room temperature. The reaction mixture was stirred for 3 h. The

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PPh -CCl CN System
3
2889
3
reaction mixture was then treated with DL-a-tocopherol (1b) (862 mg,
2
.0 mmol) followed by DMAP (733 mg, 6.0 mmol). The reaction mixture
ꢀ
was allowed to react for 2 h at 75 C. The reaction mixture was then con-
centrated under vacuum. The reaction mixture was washed with water.
The organic layer was dried over anhydrous MgSO . Afterfilt ar tion,
4
the solvent was removed and the residue was purified with column chro-
matography on silica gel (n-hexane:EtOAc, 2:1) to give DL-a-tocopherol
ꢀ
[13]
ꢀ
nicotinate (1c) (900 mg, 84%): M.p. 37–38 C (Lit.
1
32 C);
H NMR ꢀ (CDCl , 300 MHz) ꢀ 0.83–0.88 (m, 15H), 2.02 (s, 3H), 2.06
3
(
1
1
s, 3H), 2.12 (s, 3H), 2.63 (t, J ¼ 6.6 Hz), 7.48 (dd, J ¼ 5.1 Hz, J ¼ 8.0 Hz,
H), 8.49 (d, J ¼ 8.1 Hz, 1H), 8.86 (d, J ¼ 5.1 Hz, 1H), 9.45 (s, 1H);
3
C NMR (CDCl , 75 MHz) ꢀ 11.9, 12.1, 13.9, 19.8, 19.9, 21.3, 21.6,
3
2
4
1
2.7, 24.8, 25.2, 25.2, 28.6, 32.6, 33.0, 33.1, 37.5, 37.7, 37.8, 37.9, 39.7,
1.5, 75.1, 120.2, 123.1, 123.5, 124.4, 125.4, 130.6, 136.8, 144.8, 146.3,
51.4, 152.5, 167.7.
Synthesis of flavoxate (2c). Flavoxate (2c) was prepared according to
the typical procedure with 3-methylflavone-8-carboxylic acid (2a)
560 mg, 2.0 mmol) and 1-(2-hydroxyethyl)piperidine (2b) (0.27 mL,
.0 mmol). The product was purified with column chromatography on
silica gel (n-hexane:EtOAc, 2:1) to give 572 mg (73%) of flavoxate (2c):
(
2
ꢀ
[12]
ꢀ
1
M.p. 87–88 C (Lit. 85–86 C); H NMR (CDCl , 300 MHz) ꢀ 1.37–1.57
3
(
m, 6H), 2.10 (s, 3H), 2.38 (m, 4H), 2.43 (t, J ¼ 5.4 Hz, 2H), 3.55 (t,
J ¼ 5.4 Hz, 2H), 7.56 (m, 4H), 7.81 (m, 2H), 8.19 (d, J ¼ 7.8 Hz, 1H),
1
3
8
5
1
.26 (d, J ¼ 8.2 Hz, 1H); C NMR (CDCl , 75 MHz) ꢀ 8.9, 25.1, 26.4,
3
5.5, 57.9, 62.3, 112.2, 114.4, 121.5, 125.4, 128.8, 128.8, 129.0, 129.3,
23.0, 135.3, 158.7, 162.1, 165.4, 176.6.
Synthesis of clofibrate (3c). Clofibrate (3c) was prepared according to
the typical procedure with clofibric acid (3a) (860 mg, 4.0 mmol) and
ethanol (0.47 mL, 8.0 mmol). The product was purified with column chro-
matography on silica gel (n-hexane:EtOAc, 2:1) to give 752 mg (78%) of
ꢀ
[11]
ꢀ
clofibrate (3c): b.p. 148–150 C/20 mmHg (Lit.
1
80–84 C/0.1 mmHg);
H NMR (CDCl , 300 MHz) ꢀ 1.34 (t, J ¼ 7.1 Hz, 3H), 1.59 (s, 6H),
3
4
2
.23 (q, J ¼ 6.6 Hz, 2H), 6.79 (d, J ¼ 8.9 Hz, 2H), 7.19 (d, J ¼ 8.9 Hz,
1
3
H); C NMR (CDCl , 75 MHz) ꢀ 14.4, 24.9, 61.5, 78.7, 115.9, 128.3,
3
136.6, 155.6, 170.3.
ACKNOWLEDGMENTS
This work was supported by Maeji Institute of Academic Research,
Yonsei University.

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Jang, Cho, and Kim
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Received in Japan November20, 2002