Naphthyl ester synthesis using 1,3-dicyclohexylcarbodiimide

Article abstract of DOI:10.1055/s-2004-829158

Dicyclohexylcarbodiimide (DCC) has been used in the past as a condensing agent in ester synthesis. Yields of ester using this route have been reported as unsatisfactory due to the formation of the by-product, an N-acylurea compound. A catalytic amount of p-toluenesulfonic acid in addition to DCC was used for the synthesis of naphthyl esters. Several other attempts to achieve esterification were also tried but were found to be unsuccessful. One method involved the in situ generation of the carboxylate anion in DMF by the use of a base followed by subsequent alkylation with an alkyl halide. Another method attempted for esterification was acylation of a carboxylic acid. The preferred method for the synthesis of a naphthyl ester was that using DCC as the condensing agent with catalytic amounts of a strong acid.

Full text of DOI:10.1055/s-2004-829158

1
932
SHORT PAPER
Naphthyl Ester Synthesis Using 1,3-Dicyclohexylcarbodiimide
N
G
aphthyl Este
r
Sy
u
nthesis
U
sing
l
1,3-D
a
icyclohexyl
y
carbodiimide Zengin,* John W. Huffman
Howard L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA
Fax +90(342)3601170; E-mail: zengin@gantep.edu.tr
Received 11 March 2004
was accomplished to give the desired ester 2 with a yield
of 90% (Scheme 1). Any traces of dicyclohexyl urea by-
product were removed by flushing through a plug of silica
gel.
Abstract: Dicyclohexylcarbodiimide (DCC) has been used in the
past as a condensing agent in ester synthesis. Yields of ester using
this route have been reported as unsatisfactory due to the formation
of the by-product, an N-acylurea compound. A catalytic amount of
p-toluenesulfonic acid in addition to DCC was used for the synthe-
sis of naphthyl esters. Several other attempts to achieve esterifica-
tion were also tried but were found to be unsuccessful. One method
involved the in situ generation of the carboxylate anion in DMF by
the use of a base followed by subsequent alkylation with an alkyl
halide. Another method attempted for esterification was acylation
of a carboxylic acid. The preferred method for the synthesis of a
naphthyl ester was that using DCC as the condensing agent with cat-
alytic amounts of a strong acid.
HO
O
MeO
O
OH
OH
MeOH/ Py
DCC, HOTs, 90%
1
2
Key words: 1,3-dicyclohexylcarbodiimide, esterification, p-tolu-
enesulfonic acid, naphthyl ester, dicyclohexyl urea
Scheme 1 Esterification of 1 using DCC
A number of other attempts to achieve esterification of 1
were also tried but were found to be unsuccessful. First
the method of Bocchi and co-workers was employed.18
This method involved the in situ generation of the carbox-
ylate anion in DMF by the use of sodium bicarbonate and
subsequent alkylation with methyl iodide (Scheme 2).
The NMR data showed no evidence of the desired ester 2.
Spectral data revealed the presence of starting material 1.
Many useful processes for the esterification of carboxylic
1
–11
acids have been reported in the literature.
Some of
these procedures utilize alkyl halides, but none have
achieved a high yield esterification with an alkyl halide.
Carbodiimides, especially dicyclohexylcarbodiimide
(
DCC), have attracted attention over the years as condens-
1
2,13
ing agents in ester synthesis.
have been prepared by this method,
Esters of carboxylic acids
9
,14,15
but the simulta-
HO
O
MeO
O
neous formation of an N-acylurea derivative as by-prod-
uct decreased the yields of the ester. It was noted that the
use of pyridine as a solvent promoted the formation of es-
OH
OH
MeI/ DMF
1
2,16
ters,
although the by-product, the N-acylurea deriva-
NaHCO3, 18 h
tive, was still apparent in large quantities. However, the
addition of a catalytic amount of a strong acid, such as p-
toluenesulfonic acid (TsOH), to the pyridine solution en-
hances the yield of the ester and decreases the formation
1
2
Scheme 2 Attempted esterification of 1 by MeI using sodium bicar-
bonate in DMF
1
7
of the N-acylurea compound.
This paper presents an excellent route to a naphthyl ester
by the reaction of a naphthoic acid with an alcohol in py-
ridine using DCC as the condensing agent, in the presence
The method of Huffman and co-workers was also unsuc-
cessful. This reaction was similar to the Bocchi method
19
of a catalytic amount of p-toluenesulfonic acid. Esterifica- except that the base used was cesium carbonate and the
tion was accomplished to give the desired ester in excel- solvent was again DMF (Scheme 3). The reaction was
1
7
lent yields. This is the preferred method for the synthesis stirred for 17 hours but the desired product was not ob-
of naphthyl esters.
tained. The NMR spectra indicated the formation of the
dimethylated compound 3 (Scheme 3). It appeared that
the cesium carbonate deprotonated both the carboxylic
acid and phenolic protons. This reaction was attempted
again with a reaction time of only two hours but with no
improvement because the starting material 1 was still ev-
ident (Scheme 3).
Esterification of commercially available 2-hydroxy-1-
naphthoic acid (1) was achieved by reaction with metha-
nol in pyridine using DCC, in the presence of a catalytic
1
7
amount of p-toluenesulfonic acid (HOTs). Esterification
SYNTHESIS 2004, No. 12, pp 1932–1934
x
x.
x
x
.
2
0
0
4
Esterification of 1 was attempted using the method of
Stevens and co-workers. In this reaction, methanol and
acetyl chloride were mixed together at 0 °C and then 1
Advanced online publication: 21.07.2004
DOI: 10.1055/s-2004-829158; Art ID: M01704SS
Georg Thieme Verlag Stuttgart · New York
20
©

SHORT PAPER
Naphthyl Ester Synthesis Using 1,3-Dicyclohexylcarbodiimide
1933
HO
O
MeO
O
O
OMe
OMe
OH
OH
MeI/ DMF
Cs2CO3, r.t., 2–17 h
97%
1
2
3
Scheme 3 Attempted esterification of 1 by MeI using cesium carbonate in DMF
was added (Table 1). The reaction mixture was stirred at Methyl 2-Hydroxy-1-naphthoate (2)
A mixture of 2-hydroxy-1-naphthoic acid (1; 10.00 g, 53.1 mmol),
MeOH (2.40 mL, 58.4 mmol) and p-toluenesulfonic acid monohy-
drate (0.48 g, 2.51 mmol) was dissolved in pyridine (48.0 mL).
Then DCC (13.16 g, 63.8 mmol) was added and the resulting solu-
tion was stirred at r.t. for 24 h after which glacial AcOH (5.3 mL)
was added. The mixture was kept overnight at 4 °C and then fil-
room temperature for 12 hours, however NMR and mass
spectral data revealed only starting material. This reaction
was repeated several times, varying the reaction tempera-
ture and reaction times, but did not yield the desired ester
2
(Table 1). At best, under reflux, only 37% of the desired
ester 2 was obtained.
tered. The crystals were washed with cold pyridine and CHCl (53
3
mL), and then ice (53 g) was added to the filtrate. The filtrate was
acidified with 5 M HCl, the phases were separated and the organic
phase was washed with H O, aq NaHCO and H O, dried (MgSO )
Table 1 Attempted Esterification of 1 by MeOH Using AcCl
2
3
2
4
HO
O
MeO
O
and evaporated in vacuo to give the crude product. Column chroma-
tography [petroleum ether (bp 35–60 °C)–EtOAc, 19:1] and recrys-
OH
OH
1. MeOH/ AcCl, 0 °C
tallization (EtOH–H O) afforded 7.60 g (90%) of the product as a
2
2
1
cream-colored solid; mp 80–82 °C (Lit. mp 81–82 °C),
2. Reaction temperature,
–
1
reaction time
IR (Nujol): 2938, 1758, 1025 cm .
1
H NMR (300 MHz, CDCl ): d = 4.10 (s, 3 H), 7.15 (d, J = 2.7 Hz,
1
2
3
1
H), 7.35–7.90 (m, 4 H), 8.74 (d, J = 8.8 Hz, 1 H), 12.30 (s, 1 H).
Entry
2-Hydroxy-1-
naphthoic Acid (1) (°C)
Temp
Time
(h)
Product
13
C NMR (75.5 MHz, CDCl ): d = 52.3, 104.6, 119.2, 123.6, 125.2,
3
1
28.4, 128.6, 129.0, 131.7, 136.8, 164.3, 172.8.
1
2
3
1
1
1
25
12
21
21
no reaction
2 (34%)
GC/MS (EI): m/z (%) = 202 (34), 170 (100), 142 (29), 114 (46).
80
Acknowledgment
reflux
2 (37%)
The authors wish to thank NIDA and Clemson University Chem-
istry Department for the financial support.
Melting points were determined using a Fisher-Johns melting point
1
13
apparatus and are uncorrected. The H NMR (300 MHz) and
NMR (75.5 MHz) data were recorded on a Bruker 300 AC or JEOL
00 MHz spectrometer, using CDCl as the solvent. The NMR
C
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1
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(
(
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1
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Synthesis 2004, No. 12, 1932–1934 © Thieme Stuttgart · New York

1
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G. Zengin, J. W. Huffman
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Synthesis 2004, No. 12, 1932–1934 © Thieme Stuttgart · New York