A Simple, efficient, green, cost effective and chemoselective process for the esterification of carboxylic acids

Article abstract of DOI:10.1021/op900096y

Carboxylic acids have been esterified under mild and solvent-free conditions in high yield and purity using the green reagents, dimethyl carbonate and diethyl carbonate, under acid catalysis. The present methodology is free of the disadvantages of base catalysis described earlier, such as high temperatures, use of autoclaves, use of the expensive DBU as base in stoichiometric amounts and the carbonate as solvent. High chemoselectivity is observed in the case of hydroxybenzoic acids.

Full text of DOI:10.1021/op900096y

Organic Process Research & Development 2009, 13, 769–773
A Simple, Efficient, Green, Cost Effective and Chemoselective Process for the
Esterification of Carboxylic Acids
Vamsi V. Rekha, Modukuri V. Ramani, A. Ratnamala, Vempati Rupakalpana, Gottumukkala V. Subbaraju,
Chava Satyanarayana, and C. Someswara Rao*
Aptuit Laurus PriVate Limited, ICICI Knowledge Park, Turkapally, Shameerpet, Hyderabad-500078, India
,3k
H
BO
,3l Bronsted acidic ionic liquids,
3m
Abstract:
Ti(O)(acac)
2
3
3
3
n
3o
·6H
2
O.3p
Carboxylic acids have been esterified under mild and solvent-free
conditions in high yield and purity using the green reagents,
dimethyl carbonate and diethyl carbonate, under acid catalysis.
The present methodology is free of the disadvantages of base
catalysis described earlier, such as high temperatures, use of
autoclaves, use of the expensive DBU as base in stoichiometric
amounts and the carbonate as solvent. High chemoselectivity is
observed in the case of hydroxybenzoic acids.
5
K CoW12O14 ·3H
2
O, (Mes)
2
NH
2
C
6
F
5
SO
3
, and FeCl
3
While yields are generally high, there are limitations to this
3e,k
strategy: need to use a solvent, need to azeotrope,
high
3e,h
3g
temperatures, long reaction times, lack of general ap-
plicability except in two cases, difficulty in using MeOH or
3k,n
3a,c
EtOH, use of a dehydrative agent,
recovered ionic liquids, etc.
extensive drying of
3m
4
In the last two decades, dimethyl carbonate (DMC) has
gained prominence as a green reagent in base-catalyzed me-
thylation or methoxycarbonylation of anilines, phenols, active
methylene compounds and carboxylic acids. The uniqueness
of DMC lies in the fact that it is nontoxic and gives rise only
Introduction
1
Esters are encountered in various roles in all areas of
synthetic organic chemistry, and making them efficiently is of
paramount importance. General methods available start from
carboxylic acids which are directly condensed with alcohol
under acid catalysis (Fischer esterification), activated and then
used for acylation of alcohols or converted to salts and the
carboxylates treated with alkylating agents. These methods, in
spite of their exceptional utility, suffer from a severe environ-
mental burden. Fischer esterification is an equilibrium process
catalyzed by strong, corrosive, mineral acids. The water
generated in the reaction has to be continuously removed (not
very effective) by azeotroping or by use of a dehydrative agent
or its role countered by use of a large excess of the alcohol.
Methanol and ethanol can generate genotoxic alkyl sulphuric
acids. Acylation and alkylation are inherently polluting because
of salt generation, use of toxic catalysts and reagents and use
of chlorinated solvents.
to CO
2
(nontoxic) and MeOH (recoverable). However, it is
SO or MeX as an alkylating
inherently not as reactive as Me
agent in a BAL2-type mechanism. As a consequence, higher
temperatures (160-300 °C) under base catalysis are essential.
The Novartis group has made a significant contribution to this
area by the use of 1 equiv of DBU as a base in alkylation of
carboxylic acids with DMC used as a solvent at reflux. DBU
was found to activate DMC, resulting in a lower temperature
2
4
5
6
(3) (a) Bertin, J.; Kagan, H. B.; Luche, J. L.; Setton, R. J. Am. Chem.
Soc. 1992, 114, 9327. (b) Carlson, C. G.; Hall, J. E.; Huang, Y. Y.;
Kotila, S.; Rauk, A.; Tavares, D. F. Can. J. Chem. 1987, 65, 2461.
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(
d) Li, Y.-Q. Synth. Commun. 1999, 29, 3901. (e) Ishihara, K.; Ohara,
S.; Yamamoto, H. Science 2000, 290, 1140. Ishihara, K.; Nakayama,
M.; Ohara, S.; Yamamoto, H. Tetrahedron 2002, 58, 8179. Nakayama,
M.; Sato, A.; Ishihara, K.; Yamamoto, H. AdV. Synth. Catal. 2004,
3
46, 1275. (f) Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y.
There have been attempts to make Fischer esterification
highly atom economical and practically very convenient. An
Tetrahedron Lett. 2000, 41, 5249. (g) Manabe, K.; Sun, X.-M.;
Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 10101. (h) Xiang, J.;
Orita, A.; Otera, J. Angew. Chem., Int. Ed. 2002, 41, 4117. (i)
Kawabata, T.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Tetrahedron Lett.
2
ideal esterification has been defined as one with a 1:1 acid/
alcohol stoichiometry, a neutral catalyst, no dehydrative agent
2
003, 44, 9205. (j) Liu, X.-G.; Hu, W.-X. J. Chem. Res. 2004, 564.
3
and yields and conversions being 100%. Several catalysts have
(k) Chen, C.-T.; Munot, Y. S. J. Org. Chem. 2005, 70, 8625. (l) Maki,
T.; Ishihara, K.; Yamamoto, H. Org. Lett. 2005, 7, 5047. only for
R-hydroxycarboxylic acids. (m) Ganeshpure, P. A.; George, G.; Das,
J. ArkiVoc 2007, 273. Joseph, T.; Sahoo, S.; Halligudi, S. B. J. Mol.
Catal. A: Chem. 2005, 234, 107. Zhang, H.; Xu, F.; Zhou, X.; Zhang,
G.; Wang, C. Green Chem. 2007, 9, 1208. (n) Bose, D. S.; Satyender,
A.; RudraDas, A. P.; Mereyala, H. B. Synthesis 2006, 2392. (o)
Ishihara, K.; Sakakura, A.; Hatano, M. Synlett 2007, 686. (p) Komura,
K.; Ozaki, A.; Ieda, A.; Sugi, Y. Synthesis 2008, 3407.
been evolved to achieve high yields with equimolar acid and
3
a
alcohol, for example, graphite bisulphate C24HSO
4
2 4
·2H SO ,
3b
3c
3d
B O
2 3
/PTS, TiCl(OTf)
THF or ZrCl ·2THF, HfOCl
TfO, p-dodecylbenzenesulphonic acid, fluorous
3
/(Me
2
SiO)
4
, NaHSO
4
·H
2 4
O, HfCl ·
3e
2
Ph
4
2
·8H
2
O or ZrOCl
2
2
·8H O,
3
f
3g
2 2
NH
3
h
IV
3i
3j
distannoxane, Ti on K-10, 4-NO
2 6 4 2 6 5
C H NH C H TfO,
(
4) (a) Tundo, P.; Selva, M. Acc. Chem. Res. 2002, 35, 706. (b) Mauri,
M. M.; Romano, U.; Rivetti, F. Q. Ing. Chim. Ital. 1985, 21, 6. (c)
Shaikh, A.-A. G.; Sivaram, S. Chem. ReV. 1996, 96, 951. (d) Ono, Y.
Pure. Appl. Chem. 1996, 68, 367. (e) Collier, S. J. Sci. Synth. 2006,
20.5, 1. (f) Lissel, M.; Dezfuli, A. R. R. Kontakte (Darmstadt) 1990,
20. (g) Shieh, W.-C.; Dell, S.; Bach, A.; Repi cˇ , O.; Blacklock, T. J.
J. Org. Chem. 2003, 68, 1954. (h) Parrish, J. P.; Salvatore, R. N.;
Jung, K. W. Tetrahedron 2001, 56, 8207.
*
To whom correspondence should be addressed. E-mail: someswara.c@
aptuitlaurus.com.
(
1) (a) Otera, J. Chem. ReV. 1993, 93, 1449. (b) Franklin, A. S. J. Chem.
Soc., Perkin Trans. 1 1998, 2451. (c) Otera, J. Esterification Methods,
Reactions and Applications; Wiley VCH: Weinheim, 2003. (d) Greene,
T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis; John
Wiley & Sons: New York, 1999. (e) Newman, M. S. J. Am. Chem.
Soc. 1941, 63, 2431.
(5) (a) PGG Industries, Pittsburg, PA, U.S.A. U. S. Patent 4,513,146. 1985.
(b) Anonymous Research Disclosure, U.S.A.; 241210, 1984. (c) Lee,
Y.; Shimizu, I. Synlett 1998, 1063.
(
2) Otera, J. Angew. Chem., Int. Ed. 2001, 40, 2044.
1
0.1021/op900096y CCC: $40.75  2009 American Chemical Society
Vol. 13, No. 4, 2009 / Organic Process Research & Development
•
769
Published on Web 07/02/2009

Scheme 1. Esterification of carboxylic acids using DMC
2 4
1. Concentrated H SO (96%) at 0.1 equiv level and PTSA
(anhydrous or hydrate) at 0.2 equiv level are catalysts of choice.
Higher loadings of the catalysts reduced reaction times, while
lower amounts of acid catalysts increased the reaction time but
not to a great extent (entry 3,4), thus permitting use of 2.5 mol
for reaction (90 °C). But the use of 1 equiv of an expensive
base, such as DBU, and DMC as a solvent is to be regarded as
drawbacks.
Only two examples could be found in the literature for acid-
2
catalyzed esterifications using DMC. In one case, PTSA ·H O
%
2 4
H SO . Small amounts of acetic acid (0.1-0.2 equiv) helped
increase mobility of the reaction mixture without affecting yields
or purity.
2 4
Surprisingly, aq H SO (72%) was quite effective but at the
expense of reaction time (entry 8). The most effective catalyst
was triflic acid (entry 15). Even the Lewis acid TfOSiMe3, was
was used at 170 °C, and in the other, acidic zeolites (Hꢀ and
8
HZSM-5) at 160 °C were used, with yields dependent on the
14
15
quite efficient (not shown). Silica-sulfuric acid was as
effective as H SO but not quite efficient after recovery and
pore size of zeolites. An amphoteric zeolite (NaY Faujasite)
9
2
4
has also been used. Expensive dialkyl dicarbonates (pyrocar-
10
11
one recycle. Highly inactive catalysts were: NH
2
SO
3
H,
bonates) in the presence of catalytic (Mg(ClO
)
4 2
or DMAP
+
-
NaHSO
anhydrous H
NaHCO and extracting the product into ethyl acetate. Part of
4
·H
2
O, Zn(OTf)
2
, BiCl
3
, BF
3
·Et
2
O, PyH TfO and
(
esp. for tert-butyl esters) were also found to be quite effective
12
3 4
PO . Workup is by quenching into aqueous
for esterification. Catalytic MgCl
2
2
·6H O permitted the prepa-
3
ration of tert-butyl esters as well as methyl and ethyl esters
excess DMC along with MeOH can be recovered by direct
distillation from the reaction mixture before or after workup.
The present method has general applicability for aromatic,
aliphatic, cinnamic, nicotinic and aminobenzoic acids (Table
from the corresponding dicarbonates.
Results and Discussion
It seemed reasonable to expect DMC to get protonated by a
2 4
strong acid such as H SO and thereby initiate the esterification
2). Reactivity differences between aromatic and aliphatic acids
process at moderate temperatures. In such a process a carboxylic
acid functions as a nucleophile unlike in the Fischer esterifi-
cation, where it functions as an electrophile after protonation.
At the time we started this study we were unaware of the acid-
catalyzed study on DMC which might, in fact, have discouraged
us from further investigation.
We now report the first mild (80-90°), efficient and
solvent-free esterification of carboxylic acids under acid catalysis
by the green reagent, DMC. The preferred catalyst is conc.
are negligible, and the longer times with nitrogen-containing
acids are, to a considerable degree, due to a solubility problem.
Method A is for monocarboxylic acids reacting with 1.8 equiv
2 4
of DMC in the presence of 0.1 equiv of H SO or 0.2 equiv of
PTSA (anhydrous or hydrate) with or without 0.1 equiv of
added AcOH at 80-85° or at reflux (100°, bath). Method B is
for dicarboxylic acids reacting with 3.6 equiv of DMC in the
presence of 0.2 equiv of H SO (for a faster reaction) to give
13
2
4
diesters. Method C is for nitrogen-containing acids reacting with
3.6 equiv of DMC and 1.4 equiv of H SO .
H
2
SO
at a 0.2 equiv level. A remarkable outcome of the present work
Scheme 1) is the high yield of product (up to 99%) in most
4
(0.025-0.1 equiv). PTSA is an efficient alternative but
2
4
Terephthalic acid, thiosalicyclic acid, phenylglycine, and
phenylalanine did not react at all because of high insolubility.
Sterically hindered benzoic acid (entry 10) gave a 74.5% yield
while pivalic acid (entry 24) did not react at all. It is interesting
to note that for sterically hindered carboxylic acids the recom-
mended procedure consists in dissolution of the acid in 100%
(
cases with very high purity (95->99%) after a simple workup
without any purification step involved.
Optimized experiments using m-toluic acid (MTA) and
o-toluic acid (OTA) and 1.8 equiv of DMC are shown in Table
1e
H
2
SO
high chemoselectivity was observed with hydroxybenzoic acids
entries 11, 12). Methyl paraben (entry 12) was thus prepared
4
and adding the solution into a desired alcohol. Very
(
6) (a) Shieh, W.-C.; Dell, S. J.; Bach, A.; Repi cˇ , O. J. Org. Chem. 2002,
7, 2188. (b) Shieh, W.-C.; Dell, S. J. U.S. Patent 6,515,167 B1, 2003.
c) Shieh, W.-C.; Lozanov, M.; Loo, M.; Repi cˇ , O.; Blacklock, T. J.
6
(
(
Tetrahedron Lett. 2003, 44, 4563; 135 °C reaction temperature with
in high yield and purity. A similar high selectivity was observed
with diethyl carbonate (DEC) even at 120 °C to give ethyl
paraben (Table 3). Such a selectivity was also observed
benzylcarbonate and Dabco.
(
(
7) Heuer, L.; Joentgen, W.; Klausener, A. DE 4311424, 1994.
8) Kirumakki, S. R.; Nagaraju, N.; Chary, K. V. R.; Narayanan, S. Appl.
Catal., A 2003, 248, 161. (b) Kirumakki, S. R.; Nagaraju, N.; Murthy,
K. V. V. S. B. S. R.; Narayanan, S. Appl. Catal., A 2002, 226, 175.
16
17
frequently under acidic and basic conditions. The phenolic
group in 4-chlorophenol and hydroquinone were untouched
under the present conditions using DMC or DEC. The naph-
(
c) Reddy, B. M.; Sreekanth, P. M.; Reddy, V. R. J. Mol. Catal. A:
Chem. 2005, 225, 71.
(
9) Selva, M.; Tundo, P. J. Org. Chem. 2006, 71, 1464.
(
10) (a) Tarbell, D. S.; Leister, N. A. J. Org. Chem. 1958, 23, 1149. Leister,
N. A.; Tarbell, D. S. J. Org. Chem. 1958, 23, 1152 (for a discussion
of the stability and reactivity). (b) Goossen, L.; Dohring, A. AdV. Synth.
Catal. 2003, 345, 943. (c) For a similar selective activation of a
18
thols, however, gave excellent yields of methyl ethers (see
Experimental Section). An interesting case of chemoselective
methoxycabonylation of aliphatic OH in hydroxyalkyl-substi-
4 2
dicarbonate with Mg(ClO ) in the synthesis of aryl ethyl carbonates,
2 4
tuted phenols in the presence of a catalytic amount of H SO
see: Bartoli, G.; Bosco, M.; Carlone, A.; Locatelli, M.; Marcantoni,
E.; Melchiorre, P.; Palazzi, P.; Sambri, L. Eur. J. Org. Chem. 2006,
19
in DMC as solvent has been reported recently.
4
429.
(
11) Mandal, A. B.; Bhat, S. N.; Sambasivan, G., Kodange, G.; Sridharan,
M. American Chemical Society National Meeting, Chicago, IL, U.S.A.,
August 26-30, 2001.
(14) Reaction of m-toluic acid with 1.8 equiv of DMC at 80-85 °C/10
h using 0.1 equiv of CF SO SiMe gave rise to the ester product
3
3
3
(
12) Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo, R.; Marcantoni, E.;
Melchiorre, P.; Sambri, L. Synthesis 2007, 3489.
in 92% yield and 98% purity. It may be noted in this connection
that trimethylsilyl carboxylates are totally unreactive in the present
work.
(
13) Someswara Rao, C.; Subbaraju, G. V.; Satyanarayana, C. Aptuit
Laurus, Hyderabad. Indian Patent Appl. No. 296/CHE/2009, 2009.
(15) Zolfigol, M. A. Tetrahedron 2001, 57, 9509.
7
70
•
Vol. 13, No. 4, 2009 / Organic Process Research & Development

Table 1. Optimization of the acid catalyst in DMC-mediated esterification
s. no.
substratea
catalyst (equiv)
temp (°C)b
time (h)c
yield (%)d
purity (%)e
1
2
3
4
5
6
7
8
9
OTA
OTA
OTA
OTA
OTA
OTA
OTA
OTA
MTA
MTA
MTA
MTA
MTA
MTA
MTA
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
SO
SO
SO
SO
SO
SO
SO
SO
4
4
4
4
4
4
4
4
(0.1)
80-85
100
8.5
6.5
10
13
3
92.5
97.0
92.5
87.0
94.7
99.95
94.3
97.0
97.0
98.5
98.0
71.0
98.3
98.0
95.11
99.59
99.74
99.93
96.20
99.94
97.80
99.14
98.75
98.83
97.0
(0.1)
(0.05)
(0.025)
(0.2)
100
100
100
(1)
100
1
(0.1)/AcOH
80-85
80-85
80-85
80-85
80-85
80-85
100
9.5
24
6
(0.1)/H
2
O(0.2)
silica-OSO
3
H (0.1)
10
11
12
13
14
15
PTSA anhyd. (0.1)
PTSA anhyd. (0.2)
PTSA H
PTSA H
CH
CF
14
6
97.0
O (0.1)
O (0.2)
12f
5
97.8
2
2
98.0
3
SO
SO
3
H (0.1)
H (0.1)
80-85
80-85
16
3.5
99.5
3
3
99.2
a
g batch size. b Bath temp. c Time for completion (TLC). d After workup with aq NaHCO and EtOAc. e By HPLC area %. f Incomplete reaction.
3
5
+
-
Table 2. Reaction of RCO
2
H with DMC under catalysis by
to note a temperature effect on catalytic activity of PyH TfO .
This catalyst was quite effective with DEC at 110-120°/6 h in
the case of phenylpropionic acid giving rise to the ethyl ester
in 97% yield and 98% purity. It was, however, totally ineffective
towards DMC at 80-85 °C.
2 4
conc. H SO
time
(h)
isolated
yield (%)
%
purityb
a
s. no.
substrate , R)
method
1
2
3
4
5
6
7
8
9
Ph
A
A
A
A
A
A
A
8
8.5
9
10
9.5
16
6
22
10
8
22
7.5
13
11
7.5
20
12
22
17
5.5
3.5
2
93.89
92.55
99.4
95.7
94.2
95.2
99.8
99.59
99.5
2-CH
3-CH
4-CH
4-NO
4-MeO C
3,5-(MeO)
4-PhC
2-(4-CH
2,6-Me
2-OH-C
4-OH-C
Ph CHdCH
2-CO HC
2-furyl
2-NH
4-NH
3-pyridyl
4-pyridyl
PhCH
Ph CH
CH
CH
t-Bu
3
3
3
C
C
C
6
6
6
H
H
H
4
4
4
Cost Effectiveness. The process reported in this com-
munication is more cost-effective for methyl and ethyl esters
and practically more convenient than the normal Fischer
esterifcation process using MeOH or EtOH as solvent. The
recovered solvent in the Fischer process accumulates water
progressively on recycling and becomes increasingly ineffective.
Genreation of genotoxic alkyl sulphuric acid is of serious
concern in the Fischer process. The present process is also
superior to the equimolar acid and alcohol strategy discussed
in the introduction particularly because of the absence of a
solvent, absence of water as a by product and the general
applicability to many structural types of carboxylic acid. More
importantly, it is so easy to scale up, and the productivity factor
will be very high since there is no solvent and the reaction times
are reasonably short. (See Experimental Section.)
98.62
97.02
98.31
99.56
99.49
98.2
99.95
99.72
99.77
97.65
99.59
96.9
99.86
97.39
99.86
99.89
97.33
98.46
95.46
99.2
2
C
6
H
4
6
H
4
c
2
C
6
H
3
99.9
84.5
d
d
6
H
4
CH
2
A (reflux)
A (reflux)
3
C
6
H
3
4
)C
6
H
4
75.23
74.50
92.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2
C
6
H
A
A
A
A
B
A
C
C
6
H
H
4
e
6
4
97.6
91.4
99.8
92.4
2
6 4
H
2
C
C
6
H
H
4
64.6
87.9f
2
6
4
C (reflux)
C (reflux)
54.7
67.5
97.09
97.5
2
A
A
C
A
A
A
2
g
2
CO
2
H
99.8
3
(CH
2
)
3
CHEt
10
9
5
99.2
h
-
-
99.22
PhCH
2
CH
2
99.8
(16) (a) Chem. Abstr 1984, 100, 174379. (b) Chem. Abstr. 1979, 90, 186616,
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17) (a) Rama Rao, A. V.; Deshmukh, M. N.; Sivadasan, L. Chem. Ind.
981, 164. (b) Ambika; Singh, P. P.; Chauhan, S.M. S. Synth.
a
g batches. By HPLC or GC. c Pale yellow solid; mp 35-38 °C (rep
b
5
d
e
3
(
1-33 °C). 0.1 equiv of AcOH added to facilitate stirring. Mp 125-127 °C
f
g
rep 126-128 °C). Off-white solid; mp 109-110 °C (rep 110-111 °C). Diester,
h
even with 1.8 equiv of DMC. No reaction.
1
(
Table 3. Reaction of RCO
equiv) at 110-120° C (bath) in presence of H
2
H with diethyl carbonate (1.8
SO (0.1 equiv)
2
4
1
s. no.
R
time (h) isolated yield (%) purity (%)
(
1
1
2
3
4
5
2-CH
2-CH
PhCH
4-OHC
3,5-(OH)
3
3
C
6
CH
2 2
6
C
H
H
4
13
10
6
2.5
3
99
99.8
96.7
98.75
97.9
a
Commun. 2008, 38, 928. (c) Biondini, D.; Brinchi, L.; Germani, R.;
Savelli, G. Lett. Org. Chem. 2006, 3, 207. (d) Chem. Abstr. 1986,
04, 88298; East German Patent. (e) Barry, J.; Bram, G.; Decodts,
G.; Loupy, A.; Orange, C.; Petit, A.; Sansoulet, J. Synthesis 1985, 40.
f) Artus, J. J. Chem. Abstr. 1979, 90, 186616s; Spanish Patent. (g)
Guo, W.; Li, J.; Fan, N.; Wu, W.; Zhou, P.; Xia, C. Synth. Commun.
4
94.5
98.6
9.0
89
1
6
H
4
CH
2
b
2
C
6
H
3
99.4
(
a
2 4
h using 1.3 equiv of DEC and 0.5 equiv of conc. H SO
. b White solid; mp
5
2
005, 35, 145.
1
27-129 °C (rep 127-130 °C); 5.47 equiv of DEC was used along with 0.1 equiv
(
(
18) (a) Someswara Rao, C. The Chemistry of Process DeVelopment in
Fine Chemical and Pharmaceutical Industry, 2nd ed.; John Wiley &
Sons Ltd.: U.K., and Asian Books Pvt. Ltd.: New Delhi, 2006; p 511.
of AcOH.
(
b) For a recent use of DMC in methylation of ꢀ-naphthol using a
Diethyl carbonate (DEC) was much less reactive than DMC
phosphonium ionic liquid (IL 103 of Cytec, Canada), see: Yadav,
G. D.; Pavankumar, A. 11th Annual Green Chemistry Engineering
Conference, Washington, DC, June 26-29, 2007.
at 80-85 °C but proved to be as effective at 110-120 °C. Using
2 4
1.8 equiv of DEC and 0.1 equiv of H SO high yields of ethyl
19) Bernini, R.; Mincione, E.; Crisante, F.; Barontini, M.; Fabrizi, G.;
Gentili, P. Tetrahedron Lett. 2007, 48, 7000.
esters could be obtained in high purity (Table 3). It is interesting
Vol. 13, No. 4, 2009 / Organic Process Research & Development
•
771

2
Table 4. Reaction of RCO H with reduced amounts of carbonate in the presence of added methanol or ethanol
s. no.
substrate
carbonate (equiv)
MeOH/ EtOH (equiv)
time (h)
temp (° C)
yield (%)
purity (%)
1
2
3
4-OHC
4-OHC
6
6
H
H
4
4
CO
CO
2
2
H
H
DMC (0.66)
DEC (0.66)
DMC (0.66)
3.3/-
-/2.3
0.33/-
24
24
9
90
100
90
88
97.22
92.3
99.93
99.41
99.62
PhCH
2
CH
2
CO
2
H
Scheme 2. Possible mechanism for DMC-mediated esterification (under acid catalysis)
To reduce the costs even further a new strategy was evolved
Method D). It consists of using a synergistic combination of
DMC-MeOH or DEC-EtOH in a 0.66-0.33 to 3.3 equiv ratio
Table 4). Consumption of the carbonate is thereby drastically
reduced. The well-known Fischer esterification mechanism may
be operating here along with the mechanism for carbonate-
mediated esterification (Scheme 2).
A likely reaction mechanism for carbonate-mediated esteri-
fication based on earlier studies (refs 8b and 10) is shown in
disadvantages of DMC-mediated esterifications under base
catalysis, the regular Fischer esterification process using metha-
nol or ethanol in large excess and also the recent modification
of the Fischer process using equimolar acid and alcohol in
presence of various catalysts. It is very easily scalable to any
level without any effect on yield and purity.
(
(
Experimental Section
All products are characterized by IR and NMR spectra and
purities checked by HPLC or GC (area % values). Reaction
monitoring was done by TLC on silica gel plates or by GC.
Reaction temperatures refer to oil bath temperatures.
Method A: Methyl o-Toluate (Representative Procedure
for Monocarboxylic Acids). A mixture of o-toluic acid (50 g,
0.367 mol), dimethyl carbonate (55.6 mL, 0.661 mol) and conc.
Scheme 2. Protonated DMC reacts with RCO
giving rise to the reactive acyloxy methyl carbonate intermediate
mixed carbonic acid anhydrides)10a which can give rise to the
2
H (a nucleophile),
(
ester by an intramolecular route or intermolecularly by reaction
with MeOH. An attempt to distinguish between these two
10b
pathways was inconclusive. Such intermediates are known
to be involved in the reaction of carboxylic acids with alkyl
2 4
H SO (96%) (1.9 mL, 0.0342 mol, 9.32 mol %) was heated
2
0-22
10b,c
chloroformates,
with dialkyl dicarbonates
with dimethyl
under magnetic stirring at 80-85 °C for 8.5 h. TLC (20%
EtOAc in hexane) showed only traces of unreacted acid. On
cooling the homogeneous reaction mixture to room temperature
a small volume of a brown layer separated out. The reaction
8,9
23
carbonate and with activated carbamates such as EEDQ and
24
BBDI.
Conclusion
A green, solvent-free, highly efficient and very cost-effective
esterification method under mild conditions using dimethyl and
diethyl carbonates has been developed using H SO and PTSA
mixture was poured into 10% aq NaHCO
water) under stirring. The product was extracted into EtOAc
or CH Cl , and the extract was washed with brine, dried
(Na SO ) and stripped of solvent in a rotary evaporator under
3
(30.8 g in 300 mL
2
2
2
4
2
4
as catalysts. The crude isolated yields and purities of ester
products are remarkably high. This method is free of the
vacuum at 60-70 °C to give methyl o-toluate as a pale-yellow
liquid. The yield was 52 g (94.3%, purity: 99.14%).
Method A: Ethyl 3,5-dihydroxybenzoate (Chemoselec-
tivity). A mixture of 3,5-dihydroxybenzoic acid (5 g, 0.032
mol), diethyl carbonate (20.69 g, 0.175 mol) and conc. H SO
2 4
(0.95 g, 0.0097 mol) and acetic acid (0.58 g, 0.0093 mol) was
heated under stirring at 120 °C for 3 h. Workup as above gave
ethyl 3,5-dihydroxybenzoate as an off-white solid after slurrying
in hexane. The yield was 5.26 g (89%, purity: 99.46%).
Method B: Dimethyl Phthalate. A mixture of phthalic acid
(
(
(
20) (a) Kim, S.; Kim, Y. C.; Lee, J. I. Tetrahedron Lett. 1983, 24, 3365.
b) Kim, S.; Lee, J. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560. (c)
Kanth, J. V. B.; Periasamy, M. Tetrahedron 1993, 49, 5127.
21) (a) Albertson, N. F. Org. React. 1962, 12, 157. (b) Chandrasekhar,
B.; Kumar, G. B.; Mallela, S.; Bhirud, S. B. Org. Prep. Proced. Int.
(
2
004, 36, 469.
22) (a) Rodriguez, M.; Llinares, M.; Doulut, S.; Heitz, A.; Martinez, J.
Tetrahedron Lett. 1991, 32, 923. (b) Kokotos, G. Synthesis 1990, 299.
(
c) Sugimoto, A.; Tanaka, H.; Eguchi, Y.; Ito, S.; Takashima, Y.;
Ishikawa, M. J. Med. Chem. 1984, 27, 1300.
(
(
23) Belleau, B.; Malek, G. J. Am. Chem. Soc. 1968, 90, 1651. (a) Kiso,
Y.; Kai, Y.; Yajima, H. Chem. Pharm. Bull. 1973, 21, 2507.
24) Saito, Y.; Ouchi, H.; Takahata, H. Tetrahedron 2008, 64, 11129. in
the absence of a base.
(
5 g, 0.03 mol), dimethyl carbonate (9.76 g, 0.108 mol, 3.6
equiv) and conc. H SO (0.32 mL, 0.0058 mol) was heated
under stirring at 80-85 °C for 6 h. After workup, dimethyl
2
4
7
72
•
Vol. 13, No. 4, 2009 / Organic Process Research & Development

phthalate was obtained as a very pale-yellow liquid. The yield
was 5.7 g (97.6% purity: 98.87%).
Method C: Methyl 4-aminobenzoate. A mixture of 4-ami-
nobenzoic acid (5 g, 0.036 mol), dimethyl carbonate (10.95 mL,
showed m-toluic acid content to be <3% w/w. The reaction mass
was cooled to 25-30 °C and 10% aq NaHCO (200 L) was
3
added over 30 min. The aqueous mixture was stirred for 15-30
min and allowed to settle, and the aqueous and organic layers
were separated. The aqueous layer was extracted once with
dichloromethane (200 L) or ethyl acetate (200 L). The ethyl
acetate/dichloromethane layer was separated and combined with
the organic layer. The combined organic layer was washed with
DM water (200 L) and then distilled in a 1.5 KL SSR first at
atmospheric pressure and then under a low vacuum at ∼50 °C.
Methyl m-toluate was obtained as a pale-yellow liquid. The yield
was 107.7 kg (97.65%, purity: 98.30%).
2 4
0.131 mol, 3.64 equiv) and conc. H SO (2.72 mL, 0.049 mol,
1
.39 equiv) was refluxed for 16 h. Workup using aq NaHCO
3
solution (8.6 g in 86 mL water) gave solid methyl 4-aminoben-
zoate, mp 109-110 °C (rep 110-111 °C). The yield was 4.94 g
(89.64%, purity: 99.09%).
ꢀ
-Naphthol to 2-Methoxynaphthalane. A mixture of
-naphthol (100 g, 0.694 mol), DMC (112.47 g, 1.249 mol),
SO (6.79 g, 0.0665 mol) and acetic acid (4.162 g,
.0694 mol) was heated at 90 °C for 20 h. Excess DMC was
distilled off at ∼50 °C under vacuum. Aqueous NaOH (15%,
50 mL) was added to the residue, and the mixture was stirred
ꢀ
conc. H
2
4
0
Similarly, 260 kg of o-toluic acid (3.0 KL GLR) gave methyl
o-toluate as a pale-yellow liquid. The yield was 282 kg (98.34%,
purity: 99.63%).
2
for 15 min; the very white solid 2-methoxynaphthalene was
filtered, washed with water, and dried. The yield was 86.6 g
Method A: Large-Scale Preparation of Methyl 3,5-
Dimethoxybenzoate. Dimethyl carbonate (128.4 kg, 1.427 ×
(78.9%, purity: 99.79%), mp 69-71 °C (rep 70-73 °C).
3
3
1
0 mol), 3,5-dimethoxybenzoic acid (130 kg, 0.714 × 10 mol)
Similarly R-naphthol gave the corresponding methy ether
in 85.7% yield and 97.95% purity (2% unreacted R-naphthol).
Method D: Ethyl p-Hydroxybenzoate (Ethyl Paraben)
3
and conc. H
SO
2 4
(14.3 kg, 0.14 × 10 mol) were charged into
a 630 L GLR, and the mixture was heated to 85-90 °C with
steam under stirring. The temperature was maintained for 6 h.
TLC showed not more than 1% of the starting acid. The reaction
mass was cooled to 25-30 °C, DM water (390 L) was added,
and the mixture was stirred for 1 h at 10-15 °C. The solid
obtained was centrifuged and washed with DM water (260 L).
The solid was dried under vacuum at 25-30 °C until moisture
content by Karl Fischer was less than 3%. The yield of methyl
3,5-dimethoxy benzoate was 138 kg (98.5%, purity: 99.54%),
mp 35-39 °C (rep 31-33 °C) with a moisture content of 2.9%.
(Using a Synergistic Combination of EtOH and DEC. A
mixture of p-hydroxybenzoic acid (3 g, 0.0217 mol), diethyl
carbonate (1.71 g, 0.0144 mol), EtOH (3 mL, 0.051 mol) and
conc. H SO (0.071 g, 0.000717 mol) was heated at 100 °C
2 4
for 20-24 h. Usual workup gave ethyl p-hydroxybenzoate as
a white solid, mp 113.7-115.1 °C (rep. 114-117 °C). The yield
was 3.6 g (97.22%, purity: 99.46%).
Method A: Large-Scale Preparation of Methyl m-Tolu-
3
ate. Dimethyl carbonate (119.2 kg, 1.323 × 10 mol), m-toluic
3
acid (100 kg, 0.7353 × 10 mol), conc. H
2 4
SO (7.2 kg, 70.5
mol) and acetic acid (4.4 kg, 73.3 mol) were charged into a 3.0
KL GLR, and the temperature was raised to 85-90 °C with
steam and maintained at 85-90 °C for 12 h under stirring. TLC
Received for review April 20, 2009.
OP900096Y
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