Environmentally friendly esterification of carboxylic acids with triethyl orthoacetate in ionic liquid

Article abstract of DOI:10.1055/s-2004-829058

An operationally simple, inexpensive, efficient, and environmentally friendly esterification of carboxylic acids with triethyl orthoacetate under neutral conditions in a typical room temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate, was carried out to provide the corresponding ethyl esters in high yields.

Full text of DOI:10.1055/s-2004-829058

1604
LETTER
Environmentally Friendly Esterification of Carboxylic Acids with Triethyl
Orthoacetate in Ionic Liquid
E
nvironmentall
o
y Friendly
E
m
sterification of Carb
o
oxylic
A
cidsnori Yoshino,a Hideo Togo*a,b
a
Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33, Inage-ku 263-8522, Chiba, Japan
b
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho 1-33, Inage-ku 263-8522, Chiba, Japan
E-mail: togo@faculty.chiba-u.jp
Received 19 March 2004
the esterification of sulfonic acids16 and carboxylic ac-
ids.16b However, generally, esterification of carboxylic ac-
ids with triethyl orthoacetate requires high temperatures
and long reaction times. For example, 1-naphthoic acid
Abstract: An operationally simple, inexpensive, efficient, and
environmentally friendly esterification of carboxylic acids with tri-
ethyl orthoacetate under neutral conditions in a typical room
temperature ionic liquid, 1-butyl-3-methylimidazolium hexafluoro-
phosphate, was carried out to provide the corresponding ethyl esters was converted to the desired ethyl ester in 89% yield with
in high yields.
triethyl orthoacetate (3 equiv) under refluxing conditions
in toluene for 24 hours. In our present study, when a mix-
ture of 1-naphthoic acid with triethyl orthoacetate (2.0
equiv) in [bmim]PF6 (2 mL) was heated at 80 °C for 100
minutes without any additive, the desired ethyl ester was
smoothly obtained in 98% yield, this reaction gave rise to
low yields under the same conditions in toluene, DMF,
DMSO, and even in solvent-free conditions. Several ex-
amples of esterification by use of our protocol are shown
in Table 1, and the formation of the corresponding ethyl
esters was much accelerated except for more acidic car-
boxylic acid such as 3,5-dinitrobenzoic acid. Thus, the
present system is highly effective, especially for less acid-
ic carboxylic acids. Here, room temperature ionic liquid
[bmim]PF6 can be recycled and reused without loss of
chemical yield of ester.
Key words: carboxylic acid, ethyl ester, triethyl orthoacetate, ionic
liquid, environmentally friendly
Esterification of carboxylic acids is one of the most im-
portant functional group conversions in organic synthesis.
Therefore, since the first esterification method with the
Fischer ester synthesis,1 a number of useful esterification
methods catalyzed by Brønsted acids, Lewis acids, ion ex-
change regins, zeolite, etc., have been reported.2 Today,
environmentally friendly organic synthesis has become
much more important and popular, aiming toward green
chemistry. Especially, room temperature ionic liquids at-
tracts great interest as environmentally friendly reaction
media and reaction promotion media for organic synthe-
sis.3 Thus, these solvents possesses interesting and useful
advantages such as negligible vapor pressure, nonflam-
mability, high thermal stability at a wide range of temper-
ature, and easy reusability. Therefore, these solvents have
been successfully used in Friedel–Crafts reaction,4 hydro-
genation,5 Diels–Alder reactions,6 Heck, Suzuki, Sono-
gashira, and olefin metathesis reactions,7 Michael
addition,8 oxidation,9 condensation such as Knoevenagel
and Robinson annulation reactions,10 1,2-rearrange-
ment,11 esterification of carboxylic acids and carboxy-
lates,12 nucleophilic substitution such as the Williamson
ether synthesis,13 etc. Here, as a part of our study on envi-
ronmentally friendly organic synthesis with ionic liquid,14
we would like to report an operationally simple, inexpen-
sive, efficient, and environmental friendly esterification
of carboxylic acids with triethyl orthoacetate under neu-
tral conditions in 1-butyl-3-methylimidazolium hexafluo-
rophosphate ([bmim]PF6), which is a typical room
temperature ionic liquid. It is well known that generally
triethyl orthoformate and triethyl orthoacetate are used for
the conversion of carbonyl groups to their acetals and ket-
als.15 Additionally, triethyl orthoacetate can be used for
Another interesting advantage of this esterification is the
use for sterically hindered carboxylic acids such as 2,4,6-
triisopropylbenzoic acid, and for amino acid without any
racemization as shown in Table 2. Here, ethyl 2,4,6-triiso-
propylbenzoate cannot be obtained by typical esterifica-
tion processes such as the Fischer method or the DCC
method. Moreover, when competitive esterification reac-
tions of 3,5-dinitrobenzoic and palmitic acids, and 3,5-
dinitrobenzoic and 3,4,5-trimethoxybenzoic acids were
carried out, the corresponding ethyl 3,5-dinitrobenzoate
together with recovered palmitic acid, and ethyl 3,5-dini-
trobenzoate together with recovered 3,4,5-trimethoxyben-
zoic acid were selectively obtained, respectively
(Scheme 1). When 1-butyl-3-methylimidazolium tetra-
fluoroborate ([bmim]BF4), instead of [bmim]PF6, was
used as an ionic liquid, the same results were obtained.
Trimethyl orthoacetate can be also used for the same es-
terification reaction, methylation of carboxylic acids, and
shows the same reactivity as with triethyl orthoacetate.
SYNLETT 2004, No. 9, pp 1604–1606
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Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829058; Art ID: U08004ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Environmentally Friendly Esterification of Carboxylic Acids
1605
Table 1 Solvent Effects in the Esterification of Carboxylic Acids with Triethyl Orthoacetate
CH3C(OC2H5)3 (2.0 equiv)
RCO2H
RCO2C2H5m
Solvent, 80 °C
Time
Carboxylic Acid
Yields (%)
[bmim]PF6
97
Toluene
90
Solvent-free
98
DMF
88
DMSO
30 min
62 (27)a
CO2H
O2N
NO2
2.5 h
94
19 (78)a
39 (47)a
5 (94)a
15 (82)a
23 (64)a
23 (68)a
19 (75)a
CO2H
OCH3
H3CO
100 min
98
66 (28)a
CO2H
95c
92d
97e
94f
CH3(CH2)14CO2H
3.5 hb
5 hb
95
94
66 (32)a
79 (20)a
70 (30)a
73 (14)a
30 (70)a
39 (54)a
28 (72)a
47 (53)a
CO2H
5 hb
91
42 (48)a
22 (74)a
21 (76)a
18 (80)a
CO2H
a Yields in parentheses refer to recovered carboxylic acid.
b Reaction temperature was 100 ºC.
c With the first regenerated [bmim]PF6.
d With the second regenerated [bmim]PF6.
e With the third regenerated [bmim]PF6.
f With the fourth regenerated [bmim]PF6.
CO2H
CO2C2H5
Table 2 Esterification of Carboxylic Acids in [bmim]PF6
CH3C(OC2H5)3 (2.0 equiv)
97%
NO2
CH3C(OC2H5)3
RCO2H
RCO2C2H5m
O2N
NO2
O2N
[bmim]PF6, 80 °C
(1.1 equiv)
+
+
[bmim]PF6, 80 °C
Carboxylic Acid
Time (h)
Yield (%)
97
79%
CH3(CH2)14CO2H
CH3(CH2)14CO2H
CO2H
(ethyl ester 11%)
3
CO2H
CO2C2H5
91%
NO2
CH3C(OC2H5)3
(1.1 equiv)
O2N
O2N
NO2
3
96
+
+
[bmim]PF6, 80 °C
CO2H
CO2H
CO2H
66%
H3CO
OCH3
OCH3
(ethyl ester 17%)
H3CO
OCH3
OCH3
12
96a
Cbz NH
H
Scheme 1
CO2H
N
H
Thus, the present method is an operationally simple, inex-
pensive, efficient, and environmentally friendly esterifi-
cation of carboxylic acids with triethyl orthoacetate under
neutral conditions in [bmim]PF6, and it can be used for
various kinds of carboxylic acids, even those that are ster-
ically hindered.17
a Optically pure (Daicel Chiralcel OD-H; eluent: hexane–i-PrOH,
4:1).
Synlett 2004, No. 9, 1604–1606 © Thieme Stuttgart · New York

1606
T. Yoshino, H. Togo
LETTER
(7) (a) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.;
Typical Experimental Procedure
A flask containing 1-butyl-3-methyl imidazolium hexafluorophos-
phate ([bmim]PF6, 2.0 mL) as a solvent was dried under reduced
pressure with a vacuum pump for 2 h at 80 °C. Then, 1-naphthoic
acid (1.0 mmol) and triethyl orthoacetate (2.0 mmol) were added in
the ionic liquid and the obtained mixture was heated at 80 °C under
an argon atmosphere. The reaction was monitored by TLC until the
starting 1-naphthoic acid disappeared. After 100 min., the mixture
was extracted with Et2O (5 × 5 mL). The combined Et2O extract was
purified by short column chromatography on silica gel (eluent: hex-
ane–EtOAc, 9:1) to give pure ethyl 1-naphthalenecarboxylate in
98% yield (bp 120 °C/1 mmHg, lit.15b 100 °C/0.45 mmHg).
McCormac, P. B.; Seddon, K. R. Org. Lett. 1999, 1, 997.
(b) Calo, V.; Nacci, A.; Lopez, L.; Mannarini, N.
Tetrahedron Lett. 2000, 41, 8973. (c) Mathews, C. J.;
Smith, P. J.; Welton, T. Chem. Commun. 2000, 1249.
(d) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.;
Ryu, I. Org. Lett. 2002, 4, 1691. (e) Mayo, K. G.; Nearhoof,
E. H.; Kiddle, J. J. Org. Lett. 2002, 4, 1567.
(8) Calo, V.; Nacci, A.; Lopez, L.; Lerario, V. L. Tetrahedron
Lett. 2000, 41, 8977.
(9) (a) Owens, G. S.; Abu-Omar, M. M. Chem. Commun. 2000,
1165. (b) Howarth, J. Tetrahedron Lett. 2000, 41, 6627.
(c) Ansari, I. A.; Gree, R. Org. Lett. 2002, 4, 1507.
(d) Yanada, R.; Takemoto, Y. Tetrahedron Lett. 2002, 43,
6849. (e) Liu, Z.; Chen, Z.-C.; Zheng, Q.-G. Org. Lett. 2003,
5, 3321.
(10) (a) Morrison, D. W.; Forbes, D. C.; Davis, J. H. Jr.
Tetrahedron Lett. 2001, 42, 6053. (b) Xie, Y.-Y.; Chen,
Z.-C.; Zheng, Q.-G. Synthesis 2002, 1505. (c) Su, C.; Chen,
Z.-C.; Zheng, Q.-G. Synthesis 2003, 555.
The recovered ionic liquid was washed with distilled water (5 mL)
once and then dried under reduced pressure with a vacuum pump at
80 °C for 2 h, and the ionic liquid was repeatedly used for the same
reaction.
Acknowledgment
Financial support from a Grant-in-Aid for Scientific Research (No.
13554028) from the Ministry of Education, Science, Sports and
Culture of Japan is gratefully acknowledged.
(11) Ren, R. X.; Zueva, L. D.; Ou, W. Tetrahedron Lett. 2001, 42,
8441.
(12) (a) Deng, Y.; Shi, F.; Beng, J.; Quio, K. J. Mol. Cat. A.:
Chem. 2001, 165, 33. (b) Fraga-Dubreuil, J.; Bourahla, K.;
Rahmouni, M.; Bazureau, J. P.; Hamelin, J. Cat. Commun.
2002, 3, 185. (c) Brinchi, L.; Germani, R.; Savelli, G.
Tetrahedron Lett. 2003, 44, 2027.
(13) (a) Kim, D. W.; Song, C. E.; Chi, D. Y. J. Am. Chem. Soc.
2002, 124, 10278. (b) Chiappe, C.; Pieraccini, D.; Saullo, P.
J. Org. Chem. 2003, 68, 6710. (c) Brinchi, L.; Germani, R.;
Savelli, G. Tetrahedron Lett. 2003, 44, 6583. (d) Brinchi,
L.; Germani, R.; Savelli, G. Tetrahedron Lett. 2003, 44,
2027. (e) Mohile, S. S.; Potdar, M. K.; Salunkhe, M. M.
Tetrahedron Lett. 2003, 44, 1255. (f) Yadav, J. S.; Reddy,
B. V. S.; Basak, A. K.; Venkat Narsaiah, A. Tetrahedron
Lett. 2003, 44, 2217. (g) Kotti, S. R. S. S.; Xu, X.; Li, G.;
Headley, A. D. Tetrahedron Lett. 2004, 45, 1427.
(14) Togo, H.; Hirai, T. Synlett 2003, 702.
(15) (a) Hurd, C. D.; Pollack, M. A. J. Am. Chem. Soc. 1938, 60,
1905. (b) MacKenzie, C. A.; Stocker, J. H. J. Org. Chem.
1955, 20, 1695. (c) Wohl, R. A. Synthesis 1974, 38.
(d) Patwardhan, S. A.; Dev, S. Synthesis 1974, 348.
(e) Taylor, E. C.; Chiang, C.-S. Synthesis 1977, 467.
(16) (a) Padmapriya, A. A.; Just, G.; Lewis, N. G. Synth.
Commun. 1985, 15, 1057. (b) Trujillo, J. I.; Gopalan, A. S.
Tetrahedron Lett. 1993, 34, 7355.
References
(1) Fischer, E.; Speier, A. Ber. 1895, 28, 3252.
(2) (a) Beaz, G. Comprehensive Organic Synthesis, Vol. 6;
Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991.
(b) Protective Groups in Organic Synthesis, 3rd ed.; Greene,
T. M.; Wutz, P. G., Eds.; Wiley: New York, 1999.
(c) Otera, J. Chem. Rev. 1993, 93, 1449.
(3) Reviews: (a) Welton, T. Chem. Rev. 1999, 99, 2071.
(b) Wasserscheid, P.; Keim, W. Angew. Chem. Int. Ed. 2000,
39, 3772. (c) Sheldon, R. Chem. Commun. 2001, 2399.
(d) Sheldon, R. A. Pure Appl. Chem. 2000, 72, 1233.
(e) Earle, M. J.; Seddon, K. R. Pure Appl. Chem. 2000, 72,
1391. (f) Zhao, H.; Malhotra, S. V. Aldrichim. Acta 2002,
35, 75.
(4) (a) Surette, J. K. D.; Green, L.; Singer, R. D. Chem.
Commun. 1996, 2753. (b) Adams, C. J.; Earle, M. J.;
Roberts, G.; Seddon, K. R. Chem. Commun. 1998, 2097.
(5) (a) Monteiro, A. L.; Zinn, F. K.; De Souza, R. F.; Dupont, J.
Tetrahedron: Asymmetry 1997, 8, 177. (b) Dyson, P. J.;
Ellis, D. J.; Parker, D. G.; Welton, T. Chem. Commun. 1999,
25. (c) Adams, C. J.; Earle, M. J.; Seddon, K. R. Chem.
Commun. 1999, 1043.
(6) (a) Howarth, J.; Hanlon, K.; Fayne, D.; McCormac, P.
Tetrahedron Lett. 1997, 38, 3097. (b) Huddleston, J. G.;
Rogers, R. D. Chem. Commun. 1998, 1765. (c) Lee, C. W.
Tetrahedron Lett. 1999, 40, 2461.
(17) Most ethyl esters were identified by comparison with
authentic commercially available materials, or with
spectroscopic and microanalytical data.
Synlett 2004, No. 9, 1604–1606 © Thieme Stuttgart · New York