A new method for the esterification of carboxylic acids with various alcohols by using di-2-thienyl carbonate, a new coupling reagent

Article abstract of DOI:10.1246/cl.2004.552

Esterification of carboxylic acids with alcohols by using di-2-thienyl carbonate in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) proceeded smoothly under mild conditions to afford the corresponding esters and 2(5H)-thiophenone in good to high yields.

Full text of DOI:10.1246/cl.2004.552

552
Chemistry Letters Vol.33, No.5 (2004)
A New Method for the Esterification of Carboxylic Acids with Various Alcohols
by Using Di-2-thienyl Carbonate, a New Coupling Reagent
Teruaki Mukaiyama,ꢀy;yy Yoshiaki Oohashi,y and Kentarou Fukumotoy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received February 2, 2004; CL-040124)
Esterification of carboxylic acids with alcohols by using di-
Table 1. Esterification using various alcohols.
2-thienyl carbonate in the presence of a catalytic amount of 4-
(dimethylamino)pyridine (DMAP) proceeded smoothly under
mild conditions to afford the corresponding esters and 2(5H)-thi-
ophenone in good to high yields.
O
O
2-DTC (1.0 equiv.)
+
R'OH
Ph
OH
Ph
OR'
DMAP
CH2Cl2, rt
(1.0 equiv.)
(1.0 equiv.)
Entry
R0OH
Time / h
Yield /%
1
2
3
4
5
6
7
Ph(CH2)3OH
CH3(CH2)3OH
BnOH
6
8
4
8
11
8
94
91
96
82a
81a
87
95
Esterification of carboxylic acids with alcohols is one of the
most important and fundamental reactions in synthetic organic
chemistry. There have been reported several useful coupling re-
agents such as N,N0-dicyclohexylcarbodiimide/DMAP,1 2,4,6-
trichlorobenzoyl chloride/Et3N/DMAP,2 di(2-pyridyl) carbo-
nate/DMAP,3 O,O0-di(2-pyridyl) thiocarbonate/DMAP,4 2-Me-
6-NO2-benzoic anhydride/DMAP,5 or 4-(trifluoromethyl)ben-
zoic anhydride/TiCl4/2AgClO4, Me3SiCl,6 4-NO2-benzoic an-
hydride/Sc(OTf)3,7 and several other coupling reagents which
activated carboxylic acids in the coexistence of a base or a Lewis
acid, respectively.8
Ph(CH2)2CH(OH)CH3
c-C6H11OH
Ph2CHOH
PhOH
2
a1.2 equivalent of alcohol was used.
Condensation of 3-phenylpropionic acid with various alco-
hols afforded the corresponding esters in high yields by using
equimolar amounts of primary alcohols (Table 1, Entries 1–3).
In the case when secondary alcohols and phenol were used (En-
tries 4–7), the esters were also obtained in good to high yields.
Experimental results by using various carboxylic acids are
listed in Table 2. The corresponding esters were obtained in
good to high yields by using equimolar amounts of primary car-
boxylic acids (Entries 1–2) or a 3-pyridine propionic acid pos-
sessing a basic part in the molecule (Entry 3). The corresponding
esters were obtained in good yields even when ꢀ,ꢀ-disubstituted
carboxylic acids and secondary alcohols were used (Entries 5, 7
and 9).
In order to study the mechanism of this reaction, isolation of
thienyl ester 4,11 an active ester intermediate, was tried by treat-
ing carboxylic acid 3 with 2-DTC in the presence of DMAP
(10 mol%). The reaction completed immediately to afford the
desired thienyl ester 4 in high yield along with the evolution
of carbon dioxide while nothing was obtained in the absence
of base. In regard to reaction time with other bases such as Et3N
or DBU, it became longer i.e. 10 and 4 h, respectively. Actually,
the corresponding ester 5 was not detected when acylation of 1-
phenylpropanol with isolated thienyl ester 4 was tried in the ab-
sence of bases. In the presence of DMAP (10 mol%), on the other
hand, the above reaction proceeded smoothly within 4 hours to
afford the corresponding ester 5 in high yield while the yield
was 20% even after 22 hours if Et3N was used instead of DMAP.
These concludes that a catalytic amount of DMAP was quite ef-
fective in the above two steps in forming thienyl ester 4 and the
acylated product of alcohol. The acylpyridinium salts are thus
key intermediates in the above steps.
Esterification that uses these coupling reagents is widely
employed in the synthesis of natural or unnatural molecules with
carboxylic ester moieties. It is still necessary to develop various
type of coupling reagents that effectively afford the desired es-
ters. Therefore, it is important to design and to prepare the active
esters that possess a new efficient leaving group. Then, carbox-
ylic acid esters derived from five-membered hetero lactones such
as 2(5H)-thiophenone were considered useful since the reaction
proceeded effectively by utilizing the transformation of 2-oxy-
thiophene to more stable 2(5H)-thiophenone. Thus formed
2(5H)-thiophenone were no longer involved in further reactions.
In this communication, we would like to report on di-2-thienyl
carbonate (2-DTC), a new and effective coupling reagent, for
the esterification of carboxylic acids with alcohols in the pres-
ence of a catalytic amount of DMAP under mild conditions.
Di-2-thienyl carbonate was prepared easily in good yield by
the reaction of triphosgene with 2(5H)-thiophenone in the pres-
i
ence of Pr2NEt in CH3CN (Scheme 1).9
Esterification of carboxylic acids with alcohols was then
tried by using 2-DTC and the reaction proceeded smoothly in
the presence of a catalytic amount of DMAP in CH2Cl2 to afford
the corresponding esters in high yields.10 Similarly, the desired
ester was afforded also in other solvents such as Et2O, CH3CN,
toluene.
O
Cl3C
CCl3
O
O
O
iPr2NEt, CH3CN
O
S
O
O
S
S
It is noted that various esters could be obtained in good to
high yields by the coupling reaction between free carboxylic
acids and alcohols including hindered ones with the use of 2-
73%
1
2
Scheme 1. Synthesis of di-2- thienyl carbonate.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.5 (2004)
Table 2. Esterification using various carboxylic acids.
553
O
O
2-DTC (1.0 equiv.)
+
R'OH
R
OH
R
OR'
DMAP
CH2Cl2, rt
(1.0 equiv.)
(1.0 equiv.)
Entry
RCO2H
R0OH
Time /h
Yield /%
1
2
3
4
5
6
7
8
9
PhCH2CH2COOH
CH3(CH2)3COOH
m-PyCH2CH2COOHb
PhMeCHCOOH
PhMeCHCOOH
c-C6H11COOH
Ph(CH2)3OH
Ph(CH2)3OH
Ph(CH2)3OH
Ph(CH2)3OH
c-C6H11OH
Ph(CH2)3OH
Ph2CHOH
6
8
6
94
91a
84
6
79
83
87
90a
95a
86a
11
11
22
11
22
c-C6H11COOH
Ph2CHCOOH
Ph2CHCOOH
Ph(CH2)3OH
Ph(CH2)2CH(OH)CH3
a1.2 equivalent of alcohol was used. b3-pyridinepropionic acid.
5337 (2003); K. Wakasugi, A. Iida, T. Misaki, Y. Nishii,
and Y. Tanabe, Adv. Synth. Catal., 345, 1209 (2003); I.
Shiina and Y. Kawakita, Tetrahedron Lett., 44, 1951
(2003); I. Shiina, Y. Fukuda, T. Ishii, H. Fujisawa, and T.
Mukaiyama, Chem. Lett., 1998, 831; I. Shiina, H. Fujisawa,
T. Ishii, and Y. Fukuda, Heterocycles, 52, 1105 (2000); L.
Gooßen and A. Dohring, Adv. Synth. Catal., 345, 943 (2003).
Di-2-thienyl carbonate was synthesized as follows: After a
mixture of 2(5H)-thiophenone (100 mg, 1.0 mmol) and
iPr2NEt (0.174 mL, 1.0 mmol) in CH3CN (3 mL) had been
stirred for 10 minutes at room temperature under argon at-
mosphere, triphosgene (49.6 mg, 0.167 mmol) in CH3CN
(1 mL) was added at ꢁ50 ꢂC, and the reaction mixture was
stirred for 2 h at ꢁ50 ꢂC. After evaporation of the solvent,
the residue was dissolved in ether and filtered. After evapo-
ration of the solvent, the residue was separated by short silica
gel column chromatography (eluent : hexane/AcOEt = 12/
1) and recrystallized from 2-propanol to afford 2-DTC
(82.4 mg, 73%) as a colorless solid. Thus prepared 2-DTC
was stable crystalline and showed no sign of decomposition
when kept standing under argon at room temperature for one
month. 1H NMR (270 MHz, C6D6): ꢁ 6.47 (dd, J ¼ 3:2,
1.8 Hz, 2H), 6.35 (dd, J ¼ 6:0, 3.2 Hz, 2H), 6.29 (dd, J ¼
6:0, 1.8 Hz, 2H); 13C NMR (67.8 MHz, C6D6): ꢁ 152.6,
150.2, 123.8, 118.5, 114.5; MS (EIþ) m=z 226 [M]þ; HRMS
(EIþ) calcd for C9H6O3S2 [M]þ 225.9758, found m=z
225.9784; mp 53–54 ꢂC.
O
O
2-DTC
CO2
(1)
(2)
+1
+
Ph
O
Ph
OH
S
DMAP (0.1 equiv.)
Et2O, rt
3
4
4
99%
(fast)
O
Ph(CH2)3OH
+
1
DMAP (0.1 equiv.)
CH2Cl2, rt
9
Ph
O
5
93%
Ph
(slow)
Scheme 2. Esterification of 3-phenylpropanol with 3-phenyl-
propionic acid using di-2- thienyl carbonate.
DTC in the presence of a catalytic amount of DMAP.
References and Notes
1
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2
3
4
5
10 A typical experimental procedure was as follows: to a mix-
ture of 3-phenylpropionic acid (26.5 mg, 0.176 mmol) and
2-DTC (40.0 mg, 0.176 mmol) in CH2Cl2 (0.2 mL) was add-
ed DMAP (2.2 mg, 0.0176 mmol). After stirring for 10 mi-
nutes at room temperature, 3-phenylpropanol (24.1 mg,
0.176 mmol) was added and the mixture was stirred for 6 h
at room temperature. After evaporation of the solvent, crude
product was purified by preparative thin layer chromatogra-
phy to afford the corresponding ester (44.6 mg, 94%).
11 2-Thienyl 3-phenylpropionate: 1H NMR (270 MHz, CDCl3):
ꢁ 7:34 ꢁ 7:19 (m, 5H), 6.87 (dd, J ¼ 5:8, 1.9 Hz, 1H), 6.81
(dd, J ¼ 5:8, 3.9 Hz, 1H), 6.65 (dd, J ¼ 3:9, 1.9 Hz, 1H),
3.06 (t, J ¼ 7:4 Hz, 2H), 2:91 ꢁ 2:83 (m, 2H); 13C NMR
(67.8 MHz, CDCl3): ꢁ 169.3, 152.0, 140.0, 128.5, 128.2,
126.4, 123.2, 117.9, 113.2, 35.7, 30.7; HRMS (EIþ) calcd
for C13H12O2S [M]þ 232.0558, found m=z 232.0573.
6
7
8
Published on the web (Advance View) April 12, 2004; DOI 10.1246/cl.2004.552