Nucleophilic catalysis with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) for the esterification of carboxylic acids with dimethyl carbonate

Article abstract of DOI:10.1021/jo011036s

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is an effective nucleophilic catalyst for carboxylic acid esterification with dimethyl carbonate (DMC). The reaction pathway of this new class of nucleophilic catalysis has been studied. A plausible, multistep mech

Full text of DOI:10.1021/jo011036s

2
188
J . Org. Chem. 2002, 67, 2188-2191
Nu cleop h ilic Ca ta lysis w ith 1,8-Dia za bicyclo[5.4.0]u n d ec-7-en e
(
DBU) for th e Ester ifica tion of Ca r boxylic Acid s w ith Dim eth yl
Ca r bon a te
Wen-Chung Shieh,* Steven Dell, and Oljan Repicˇ
Chemical and Analytical Development, Novartis Institute for Biomedical Research,
East Hanover, New J ersey 07936
wen.shieh@pharma.novartis.com
Received October 29, 2001
1
,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is an effective nucleophilic catalyst for carboxylic acid
esterification with dimethyl carbonate (DMC). The reaction pathway of this new class of nucleophilic
catalysis has been studied. A plausible, multistep mechanism is proposed, which involves an initial
N-acylation of DBU with DMC to form a carbamate intermediate. Subsequent O-alkylation of the
carboxylate with this intermediate generates the corresponding methyl ester in excellent yield. In
the absence of DBU or in the presence of other bases, such as ammonium hydroxide or
N-methylmorpholine, the same reaction affords no desired product. This method is particularly
valuable for the synthesis of methyl esters that contain acid-sensitive functionality.
In tr od u ction
Methylation of alcohols, amines, carboxylic acids, and
Sch em e 1
activated methylenes is an important process in chem-
istry. However, because of the environmental and human
impact of using toxic and unsafe methylating reagents
1
2
such as methyl iodide or dimethyl sulfate, the investi-
gation of safer, generally applicable alternatives is
imperative. As an alternative to these toxic methylating
agents, dimethyl carbonate (DMC) has attracted consid-
erable attention (Scheme 1) for the methylation of
phosgene but from methanol and carbon dioxide cata-
lyzed by transition metals.6 However, the use of this
3
4
5
phenols, anilines, and activated methylenes. DMC is
nontoxic and generates CO and methanol as byproducts
“green reagent” (DMC) as a methylating regent requires
2
temperatures above the boiling point of DMC. Therefore,
during methylations. DMC is also a volatile liquid with
a boiling point of 90 °C. Hence, the unreacted DMC can
be easily recovered by distillation from the reaction
mixture and reused. Furthermore, DMC has been shown
to be quite selective in monomethylation of primary
autoclaves4
,5,7
or the use of asymmetrical carbonates
8
with a higher boiling point than DMC have to be
employed. These restrictions lower the popularity of DMC
as a widely used methylating reagent. The search for
either a chemical or a physical means to accelerate the
rate of methylation using DMC is a practical and chal-
lenging task.
4
aromatic amines and C-methylation of arylacetonitriles
5
and arylacetoesters. DMC is no longer synthesized from
(
1) For examples using MeI with ROH, RNH
2
, RCOOH, and RCH
2
-
The methylation of phenols under autoclave conditions
CN, see: (a) J ohnstone, R. A. W.; Rose, M. E. Tetrahedron 1979, 35,
(
120-200 °C) are believed to proceed through a BAL
2
2
4
1
169. (b) Ahmad, A. R.; Mehta, L. K.; Parrick, J . Tetrahedron 1995,
7, 12899. (c) Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org. Lett. 1999, 1,
835. (d) Abbotto, A.; Bradamante, S.; Facchetti, A.; Pagani, G. A. J .
3
f,9
mechanism
in which the O-nucleophile attacks the
methyl group of DMC.3b However, aromatic amines such
as aniline are thought to proceed in a stepwise mech-
anism.4 Since arylacetonitriles and arylacetoesters yield
only monomethylated compounds, they are also believed
to go through several steps in which DMC acts as both a
Org. Chem. 1997, 62, 5755.
2) For examples using Me
RCH CN, see: (a) Merz, A. Angew. Chem., Int. Ed. Engl. 1973, 12,
(
2 4 2
SO with ROH, RNH , RCOOH, and
a
2
8
3
6
46. (b) Voskresensky, S.; Makosza, M. Synth. Commun. 2000, 30,
523. (c) Chakraborti, A. K.; Basak, A.; Grover, V. J . Org. Chem. 1999,
4, 8014. (d) Ngooi, T. K.; So, R.; McGolrick, J . D.; Oudenes, J . Can.
5
a-c
carboxymethylating agent and a methylating reagent.
Pat. Appl. 2049274, 1993.
3) (a) Lissel, M.; Schmidt, S.; Neumann, B. Synthesis 1986, 382.
b) Shimizu, I.; Lee, Y. Synlett 1998, 1063. (c) Bomben, A.; Selva, M.;
(
In the carboxymethylation step, it is postulated that the
carbanion attacks the carbonyl of DMC (BAC2 mecha-
(
Tundo, P.; Valli, L. Ind. Eng. Chem. Res. 1999, 38, 2075. (d) Tundo,
P.; Trotta, F.; Moraglio, G.; Ligorati, F. Ind. Eng. Chem. Res. 1988,
2
7, 1565. (e) Barcelo, G.; Grenouillat, D.; Senet, J .-P.; Sennyey, G.
(6) (a) Delledonne, D.; Rivetti, F.; Romano, U. J . Organomet. Chem.
1995, 488, C15-C19. (b) Ikeda, Y.; Sakaihori, T.; Tomishige, K.;
Fujimoto, K. Catal. Lett. 2000, 66, 59. (c) Tomishige, K.; Ikeda, Y.;
Sakaihori, T.; Fujimoto, K. J . Catat. 2000, 192, 355. (d) Sato, Y.;
Yamamoto, T.; Souma, Y. Catal. Lett. 2000, 65, 123.
(7) (a) Thompson, R. B. U.S. Patent 4,513,146, 1985. (b) Loosen, P.
C.; Tundo, P.; Selva, M. U.S. Patent 5,278,333, 1994.
Tetrahedron 1991, 46, 1839. (f) Selva, M.; Trotta, F.; Tundo, P. J . Chem.
Soc., Perkin Trans. 2 1992, 519.
(4) (a) Selva, M.; Bomben, A.; Tundo, P. J . Chem. Soc., Perkin Trans.
1
6
1997, 1041. (b) Selva, M.; Tundo, P.; Perosa, A. J . Org. Chem. 2001,
6, 677.
(5) (a) Bomben, A.; Marques, C. A.; Selva, M.; Tundo, P. Tetrahedron
1
995, 51, 11573. (b) Tundo, P. Pure Appl. Chem. 2000, 72, 1793. (c)
(8) Perosa, A.; Selva, M.; Tundo, P.; Zordan, F. Synlett 2000, 272.
(9) For classification of mechanisms for ester hydrolysis and forma-
tion, see: March, J . Advanced Organic Chemistry; J ohn Wiley &
Sons: New York, 1985; Chapter 10, pp 334-338.
Selva, M.; Marques, C.; Tundo, P. J . Chem. Soc., Perkin Trans. 1 1994,
323. (d) Tundo, P.; Trotta, F.; Moraglio, G. J . Chem. Soc., Perkin
Trans. 1 1989, 1070.
1
1
0.1021/jo011036s CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/01/2002

Esterification of Carboxylic Acids
J . Org. Chem., Vol. 67, No. 7, 2002 2189
Ta ble 1. Rea ction of Ben zoic Acid w ith DMC in th e
P r esen ce of Differ en t Am in e Ba ses
Sch em e 2
entry
amine base
none
NMM
tributylamine
NH4OH
DBU
DABCO
DMAP
time [h]
PhCO2Me [% yield]a
1
2
3
4
5
6
7
8
9
16
16
48
24
2.5
2.5
2.5
7.5
22
0
0
1
b
0
97
14
2.5
99
99
DABCO
DMAP
a
HPLC yield. b N-Methylmorpholine.
nism). In the methylation step, the anion of the corre-
sponding intermediate attacks the methyl group of
another molecule of DMC (BAL2 mechanism).
The exploration of DMC for the esterification of car-
boxylic acids is quite limited. To the best of our knowl-
edge, this type of esterification has been described only
in a few instances employing elevated temperature (175
7
°
C) in autoclaves. Furthermore, a review of the current
literature illustrates a need for an in-depth study of the
methylating power of DMC so that the proposed mech-
anisms can move from the realm of mere speculation to
concrete confidence. As a result of the great potential for
DMC as a environmentally friendly methylating reagent,
a study was initiated to obtain a thorough understanding
of the methylating process of DMC and to develop
procedures for methylating without the use of autoclaves
and elevated temperatures.
methyl benzoate formation is still not complete after 24
h. The results could imply an unfavorable equilibrium
caused by the addition of methanol (path C). However,
it is also possible that the rate of the reaction is slowed
by lowering the nucleophilicity of the carboxylate anion
in the presence of additional methanol.10 As previously
mentioned, the reaction does not proceed when N-
methylmorpholine is used as the base, and the use of
DMAP requires a longer reaction time (22 h) for comple-
tion compared to DBU (3 h). This suggests that DMC is
a poor electrophile under certain conditions. To initiate
the esterification, DMC needs to be activated by a
suitable catalyst to form a more reactive methylating
species.
Dep en d en ce of Ra te of Ester ifica tion on th e
Am ou n t of DBU. If there is no direct BAL2 displacement
and the reaction rate is dependent on the amine base
used, then the transition state most likely involves DBU
itself (Scheme 2, path B or C). As mentioned before,
esterification of benzoic acid with DMC can be completed
within 3 h in the presence of 1 equiv of DBU. However,
when only 0.2 equiv of DBU was used in a reaction of
benzoic acid with DMC, the reaction rate dramatically
decreased. After 17 h, only 2% of methyl benzoate (2) was
formed. When 0.5 equiv of DBU was used, a total
conversion of methyl benzoate was observed in 17 h as
indicated by HPLC analysis. It is postulated that with 1
equiv of DBU, the initial diffusion-controlled deprotona-
tion of carboxylic acid consumes all of the DBU, and only
a slight amount of DBU is available via equilibrium to
react with DMC to form an active intermediate. As more
benzoic acid is converted to the ester, more DBU becomes
available, and the rate of esterification accelerates.
Consequently, the rate of reaction should be much slower
in the initial stages, which is consistent with the kinetic
Resu lts a n d Discu ssion
R ea ct ion of Ben zoic Acid w it h DMC in t h e
P r esen ce of Va r iou s Ba ses. Esterification of benzoic
acid with DMC at 90 °C in the presence of a variety
of amine bases (1 equiv) to form methyl benzoate (2)
was first investigated (Table 1). In comparison with all
other explored bases, 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) dramatically shortened the reaction time. The
conversion time to 2 using DBU is much shorter than
the widely used acylation catalyst 4-(dimethylamino)-
pyridine (DMAP). In 2.5 h, methyl benzoate formation
is 97% complete using DBU but is only 2.5% complete
using DMAP. Thus DBU leads to a shorter completion
time. N-Methylmorpholine gave no product after 16 h.
The use of tributylamine produced no methyl benzoate
(2) after 3 h, and only 1% is produced after 48 h. With
these experimental results, a fundamental question
arises: Why is the reaction so fast with DBU? We began
to speculate that the role of DBU is more than just as a
proton scavenger and that perhaps it functions as a
catalyst in the reaction.
Exclu sion of BAL2 Disp la cem en t by Kin etic Dif-
fer en ce. Several reasonable mechanisms can be postu-
lated (Scheme 2) for benzoate formation employing a
combination of DMC and DBU. The first possible mech-
anism (path A) is a direct BAL2 displacement, which is
described for the reaction of phenols with DMC under
different conditions.3b This mechanism is ruled out for
two reasons. First, with a BAL2 mechanism, the presence
of 1 equiv of methanol should not dramatically reduce
the conversion rate. However, when benzoic acid, DBU,
and DMC are heated to reflux with 1 equiv of methanol,
the reaction is much slower. We observed that without
the added methanol, methyl benzoate (2) formation is
complete (99%) within 3 h, but with extra methanol,
(10) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry;
VCH: New York, 1988; p 210.

2
190 J . Org. Chem., Vol. 67, No. 7, 2002
Shieh et al.
Sch em e 4
Sch em e 5
F igu r e 1. Rate of methyl benzoate formation with 1 equiv of
DBU.
Sch em e 3
rium. As previously stated, adding 1 equiv of methanol
dramatically slows down the conversion rate. To support
carbamate (4) as the likely intermediate during the
esterification, an analogous carbamate (4a ) was inde-
pendently synthesized in situ from methyl chloroformate
1
13
and an excess of DBU (Scheme 4). H and C NMR and
MS spectra support the identity of the carbamate inter-
mediate. When benzoate (1) was added to this mixture,
a voluminous evolution of gas started within a few
minutes and methyl benzoate (2) formed. As benzoate
data acquired in our experiment (Figure 1). The depen-
dence of the reaction rate on the amount of DBU used
strongly suggests that the esterification pathway involves
a DBU-catalyzed step.
2
attacks the methyl group of carbamate (4a ), CO should
evolve and DBU should be regenerated.
1
8
DBU-Con tain in g In ter m ediate: DMC as a Meth yl-
a tin g Agen t. Since DMC can act as either a methylating
or a carboxymethylating reagent toward DBU, two pos-
sible intermediates, 3 and 4, are proposed (Scheme 2).
The first intermediate (path B) involves the reaction of
DBU with a methyl group of DMC to form an N-
methylated-DBU salt (3), analogous to a known com-
pound from the reaction of DBU and methyl iodide.11 To
discover if 3 is the active intermediate, labeled 3 was
O-La belin g Stu d y. Another question arises about
carbamate (4) as the intermediate. Mixed anhydrides
are known intermediates in the synthesis of methylcar-
bamates from amines and DMC.13 Does the carboxylate
react with 4 in a direct BAL2 methylation (path E) or does
it form an unsymmetrical anhydride, 5, which is attacked
by methanol to form ester 2 (path D)? The answer to this
question was found in a labeling experiment. Labeled
benzoic acid (with only one 18O) was reacted with DBU
and DMC (Scheme 5) at 90 °C. If the reaction proceeded
through 5 (path D), then isotopomer 2 and 2b will be the
products in approximately a 1:1 ratio. The ratios of
different isomers can be determined from GC-MS and
IR analyses. However, the labeling study concluded that
90.6% of the methyl benzoate contains one oxygen-18
(isotopomers 2b and 2c). This result supported the
postulate that a direct O-alkylation of benzoate with
carbamate (4) is the preferred mechanism for the forma-
tion of methyl benzoate (2) (Figure 2). The small quantity
of 2 and 2d is most likely due to transesterification
because prolonged heating of the reaction mixture could
increase the amount of 2 and 2d .
independently synthesized from 13CH
, 6). A solution of benzoic acid, DBU, and salt-6 in
I and DBU (Scheme
3
3
acetonitrile was heated to reflux overnight but failed to
produce any labeled methyl benzoate (2a ). 13C NMR
indicated a total recovery of salt-6. These outcomes
clearly suggest that salt-6 is not the active intermediate
responsible for the formation of the methyl ester.
DBU-Con ta in in g In ter m ed ia te: DMC a s a Ca r -
boxym eth yla tin g Agen t. Attention now turned to DMC
acting as a carboxymethylating reagent with DBU
(Scheme 2, path C). It has been reported that reaction of
carboxylic acids with alkyl chloroformate in the presence
of a stoichiometric amount of triethylamine and a cata-
lytic amount of DMAP affords the corresponding esters.
This methodology is convenient; however, it utilizes a
highly hazardous chloroformate that could generate a
significant amount of symmetrical anhydride as the
byproduct.12 If DBU reacts with DMC to form carbamate
Syn th etic Utility. To investigate the synthetic utility
of this reaction, a variety of carboxylic acids were
methylated using DMC as both a solvent and a reactant
with 1 equiv of DBU (Table 2). All of the reactions were
complete within 24 h. Since quantitative conversions
were achieved in many cases, clean products can be
isolated after simple aqueous acid and base washes
(4), the presence of excess methanol should slow the
formation of 4 since methanol can reverse the equilib-
(
11) Heidelberger, v. C.; Guggisberg, A.; Stephanou, E.; Hesse, M.
(12) Kim, S.; Kim, Y. C.; Lee, J . I. Tetrahedron Lett. 1983, 24, 3365.
(13) Aresta, M.; Quaranta, E.; Tetrahedron 1991, 47, 9489.
Helv. Chim. Acta. 1981, 64, 399.

Esterification of Carboxylic Acids
J . Org. Chem., Vol. 67, No. 7, 2002 2191
Con clu sion s
1
,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is generally
used as a hindered base for enolate formation or as a
proton scavenger. We discovered that DBU can function
as an effective catalyst for carboxylic acid esterification
with dimethyl carbonate (DMC) without autoclave condi-
tions. The mechanism of this new class of nucleophilic
catalysis15 involves the reaction of DBU with DMC to
form an unstable carbamate (4), which behaves as a
highly activated methylating reagent. This carbamate
then reacts with carboxylates to afford the respective
methyl esters. Synthetic applications to a variety of
carboxylic acids, including sterically hindered unacti-
vated aromatic acids, an acid-sensitive amino acid, and
a carbohydrate acid, were demonstrated with excellent
yields. Investigation of DBU as a nucleophilic catalyst
for other reactions is currently being conducted in our
laboratory.
F igu r e 2. Proposed mechanism.
Ta ble 2. DBU-Ca ta lyzed Ester ifica tion w ith DMC:
RCOOH f RCOOCH3
Exp er im en ta l Section
All reagents were purchased from commercial suppliers and
1
6
17
18
used without further purification. Methyl esters 2, 7, 8,
1
9
16
20
21
9
,
10, 11, and 12 are known compounds. The identity
1
13
of the methylated products was confirmed by H and C NMR
and MS spectra. Solvents used were of technical grade. H and
C NMR spectra were recorded with Bruker FT-NMR spec-
1
1
3
trometer at 300 and 75 MHz, respectively. GC-MS analysis
was performed on a ThermoFinnigan Trace MS with a Restek
RTX-5 (15 mm × 0.25 mm) column. High-resolution mass
spectroscopy (HRMS) was carried out on a ThermoFinnigan
MAT-900 in electrospray mode. Other mass spectroscopy was
performed on a Micromass LCT in electrospray mode. IR data
were collected on a Nicolet Magna 550.
Gen er a l P r oced u r e for Ester ifica tion w ith DMC. DBU
(1 equiv) was added to a 10% solution of carboxylic acid in
DMC, and the resulting mixture was heated to reflux. Upon
completion, the reaction mixture was cooled to room temper-
ature and diluted with either CH
aqueous layer was removed, and the organic layer was washed
with H O, twice with 2 M HCl or 10% aqueous citric acid, twice
with saturated aqueous NaHCO , and twice with H O. The
organic layer was dried over Na SO , filtered, and concentrated
under vacuum to afford the ester.
2 2 2
Cl or EtOAc and H O. The
2
3
2
2
4
Ack n ow led gm en t. We thank Prof. Dieter Seebach
for stimulating discussions on mechanistic interpreta-
tions. We appreciate Dr. J uergen Brokatzky and Dr.
Thomas Blacklock for their encouragement in pursuing
this study. We are in debt to Dr. Song Xue for helpful
suggestions. We thank Dr. Grazyna Ciszewski for
1
8
preparing O-labeled benzoic acid. We are grateful to
Ms. Noela Reel, Mr. Leonard Hargiss and Mr. Richard
Beveridge for their assistance in obtaining chiral HPLC,
MS, and NMR spectra, respectively.
a
HPLC yield. b The identity of the methylated products was
confirmed by 1H and 13C NMR and MS spectra.
J O011036S
without further purification. Not only can simple aro-
matic esters be synthesized, but also a sterically hindered
ester (7, entry 1) and an unactivated ester (8, entry 2)
can be as well. For a protected amino acid, N-R-t-Boc-L-
proline (entry 5), the esterification yield was excellent.
However, partial racemization (3.5%) for the isolated
N-R-t-Boc-L-proline methyl ester (11) was detected by
chiral HPLC. The ability to esterify N-R-t-Boc-L-proline
and 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid (en-
try 6) to form 11 and 12, respectively, demonstrates
another niche for this methodology. These esters, con-
taining acid-sensitive functionalities, would not survive
acid-catalyzed esterification conditions.14
(
14) For an example of acid-catalyzed esterification, see: Nakao, R.;
Oka, K.; Fukomoto, T. Bull. Chem. Soc. J pn. 1981, 54, 126.
15) There is one other instance in which DBU was reported as
(
a nucleophilic catalyst for the Baylis-Hillman-type reaction. See:
Aggarwal, V. K.; Mereeu, A. Chem. Commun. 1999, 2311.
(16) Commercially available from Aldrich.
(
17) Tsuchida, E.; Hasegawa, E.; Komatsu, T. Chem. Lett. 1990,
89-392.
18) Walther, H.; Schlunegger, U. P.; Friedli, F. Org. Mass. Spec-
trom. 1983, 18, 572-575.
19) De Luca, C.; Inesi, A.; Rampazzo, L. J . Chem. Soc., Perkin
3
(
(
Trans. 2 1982, 1403-1407.
(20) (a) Harris, B. D.; Bhat, K. L.; J oullie, M. M. Heterocyles 1986,
2
1
4, 1045-1060. (b) Becker, Y.; Eisenstadt, A.; Stille, J . K. J . Org. Chem.
980, 45, 2145-2151.
(21) Heathcock, C. H.; White, C. T.; Morrison, J . J .; VanDerveer,
D. J . Org. Chem. 1981, 46, 1296-1309.