An unprecedented and highly chemoselective esterification method

Article abstract of DOI:10.1016/S0040-4039(00)01954-7

A series of carboxylic acids was transformed to their corresponding methyl esters under CBr₄/CH₃OH (0.05 eq., 5 ml) reaction conditions. The rate of esterification is decreased with increasing bulkiness of the alcohol. Chemoselectivity can be achieved between phenylacetic and benzoic acids, sp³-C and sp²-C acids as well as between sp³-C and sp-C tethered carboxylic acids.

Full text of DOI:10.1016/S0040-4039(00)01954-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 301–303
An unprecedented and highly chemoselective esterification method
Adam Shih-Yuan Lee,* Hui-Chun Yang and Feng-Yih Su
Department of Chemistry, Tamkang University, Tamsui, Taiwan 251
Received 18 August 2000; revised 9 October 2000; accepted 2 November 2000
Abstract—A series of carboxylic acids was transformed to their corresponding methyl esters under CBr /CH OH (0.05 eq., 5 ml)
4
3
reaction conditions. The rate of esterification is decreased with increasing bulkiness of the alcohol. Chemoselectivity can be
3
2
3
achieved between phenylacetic and benzoic acids, sp -C and sp -C acids as well as between sp -C and sp-C tethered carboxylic
acids. © 2000 Elsevier Science Ltd. All rights reserved.
The transformation of a carboxylic acid to an ester is a
common and useful method for protecting carboxyl
Primary and secondary tethered carboxylic acids were
converted into their esters with high yields (Entries
1–6). Benzoic acid, sp -C tethered and a-amino acids
1
–6
2
groups.
The selective esterification of a carboxyl
group is an important tool in organic synthesis. Al-
though many effective and reliable reactions for the
preparation of esters have been reported, there is still a
need for simple and selective esterification methods.
Several selective esterification procedures have been
undergo esterification slowly even after a prolonged
reaction time (Entries 7, 8 and 10). It is interesting to
note that the rate of esterification becomes much slower
when the methanol is replaced with a more sterically
hindered alcohol, such as ethanol or isopropanol. A
mixture of phenylacetic and benzoic acids were investi-
gated for selective esterification. The results showed
that phenylacetic acid was selectively transformed to its
methyl or ethyl ester whereas benzoic acid was stable
under the reaction conditions (Scheme 2).
7
–14
reported in the literature.
Recently, our laboratory
reported effective and selective methods for hydrolysis
1
5,16
17
of trialkylsilyl ethers,
acetals/ketals and tetra-
18
hydropyranyl ethers. Under the reaction conditions
for desilylation of silyl esters, we found that a-unsubsti-
tuted carboxylic acids were esterified to their corre-
sponding esters. Therefore, we investigated ester-
ification of different carboxylic acids under these reac-
tion conditions. Herewith, we wish to report a mild,
highly efficient and selective esterification method for
1
9
The results led us to investigate further this highly
chemoselective esterification process which distin-
3
2
guishes between sp -C and sp -C tethered carboxylic
acids. A mixture of 8-bromo-1-octanoic acid and 2,4-
carboxylic acids under CBr /MeOH (or EtOH) reaction
4
hexadienoic acid in CBr /MeOH (10%/10 ml) was in-
conditions (Scheme 1).
4
vestigated under the reaction conditions (Scheme 3).
3
A typical procedure for esterification of a carboxylic
acid is as follows: A solution of the carboxylic acid (1.0
mmol), CBr (0.05 mmol) and anhydrous CH OH (5
The sp -C tethered primary acid was converted into its
2
methyl ester in 98% yield, whereas the sp -C tethered
carboxylic acid was stable under the reaction conditions
for 24 hours and a 96% recovery was obtained after
4
3
ml) in a Pyrex culture tube is irradiated directly by a
TLC lamp at room temperature (UVltec Limited, 8
watt, 254 nm) for 30 minutes and then stirred without
irradiation at room temperature. After the reaction is
complete (by TLC), the organic solvent is removed
directly under reduced pressure. Further purification is
achieved by flash chromatography with ethyl acetate/
hexane as eluant. A series of carboxylic acids were
esterified under these reaction conditions and the results
are shown in Table 1.
3
chromatography. The sp -C tethered secondary car-
boxylic acid was also converted into its methyl ester in
2
9
7% yield, whereas the sp -C tethered carboxylic acid
was resistant under the reaction conditions for 50 hours
and a 99% recovery was obtained after chromato-
graphy.
CBr / MeOH (5%/5mL)
4
R-CO H
R-CO Me
2
2
hv (30 min); stir at rt
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
Scheme 1.
PII: S0040-4039(00)01954-7

3
02
A. Shih-Yuan Lee et al. / Tetrahedron Letters 42 (2001) 301–303
Table 1. Esterification of carboxylic acids
Yielda
Entry
Substrate
Product
R' Time (h)
Me
Et
iPr
13
48
48
90%
b
b
85%(10%)
( )6
1
2
(
)6
)5
CO H
2
CO R'
2
N.R.(95%)
Me
Et
iPr
24
67
48
98%
98%
Trace(90%)
(
( )5
Br
CO H Br
CO R'
2
2
b
CO H
CO R'
2
2
Me
Et
7
48
96%
90%
3
4
5
CO H
CO R'
40%c
N.R.(95%)
2
2
Me
Et
72
189
b
CO H
CO2R'
Me
Et
2
68
96%
99%
2
CH3
CO H
CH3
CO2R'
Me
Et
25
79
95%
84%(13%)
b
6
7
2
CO H
CO R'
2
2
14%(80%)b
Me
72
b
Me
Et
48
390
N.R.(99%)
N.R.(95%)
CO H
CO2R'
2
b
8
9
Me
Et
140
330
93%
64%(34%)b
CO H
CO2R'
2
10
AcNH-CH2-CO2H
AcNH-CH2-CO2R'
Me
240
60%(32%)b
(a) The yields were determined after chromatographic purification.
(b) The yield of recovered starting material after chromatography.
(c) Th yield is low because the product is highly volatile.
CO H
CO H
2
2
CBr /ROH (5%/5 mL),
CO H
4
CO R
2
2
+
+
hv (30 min); stir at r.t.
MeOH
EtOH
8h
99% (R=Me) + 95%
99% (R=Et) + 90%
65h
Scheme 2.
Br
( )5 CO H
2
Br
( )5 CO2Me 98%
+
CBr / MeOH (10%/10mL),
4
+
hv (30 min); stir 24h at r.t.
CO H
CO H
2
2
96%
CH3
CO H
CH3
CO Me
97%
2
2
CBr / MeOH (10%/10mL),
4
+
+
hv (30 min); stir 50h at r.t.
CO H
CO H
2
2
99%
Scheme 3.

A. Shih-Yuan Lee et al. / Tetrahedron Letters 42 (2001) 301–303
CO H
CO Et
303
2
2
87%
CBr / EtOH (5%/5mL),
4
+
+
hv (30 min); stir 40h at r.t.
CO H
CO2H 91%
2
Scheme 4.
We further investigated this highly chemoselective ester-
ification process between phenylacetic and phenylpropi-
olic acids (Scheme 4). The sp -C tethered primary
carboxylic acid was converted into its ethyl ester in 87%
yield, whereas the sp-C tethered carboxylic acid was
resistant under the reaction conditions for 40 hours and
a 91% recovery was obtained after chromatography.
2. Kocienski, P. J. Protecting Group; Georg Thieme Verlag:
New York, 1994.
3
3. Ogliaruso, M. A.; Wolfe, J. F. In Synthesis of Carboxylic
Acids, Esters and Their Derivatives; Patai, S.; Rappoport,
Z., Eds.; John Wiley & Sons: New York, 1991.
4. Ladduwahettu, T. Contemp. Org. Synth. 1997, 4, 326.
5. Haslam, E. Tetrahedron 1980, 36, 2409.
6
. Sutherland, I. O. In Comprehensive Organic Chemistry;
Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon: Oxford,
1979; Vol. 6, p. 871.
In conclusion: these reaction conditions provide a
highly chemoselective method for the esterification of a
carboxylic acid. This method enables the esterification
7. Rodriguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1998, 39, 8563.
8. Ram, R. N.; Charles, I. Tetrahedron 1997, 53, 7335.
9. Saitoh, M.; Fujisaki, S.; Ishii, Y.; Nishiguchi, T. Tetra-
hedron Lett. 1996, 37, 6733.
3
2
of an sp -C tethered carboxylic acid, whereas sp -C and
sp-C tethered carboxylic acids were stable under the
reaction conditions. Our previous investigations have
shown that numerous functionalities are hydrolyzed by
this reaction system (e.g. acetals/ketals, silyl ethers,
tetrahydropyranyl ethers, etc.). These results lead us to
investigate the mechanism of this highly chemoselective
method and studies are underway.
10. Albert, R.; Danklmaier, J.; Honig, H.; Kandolf, H. Syn-
thesis 1987, 635.
11. Ogawa, T.; Hikasa, T.; Ikegami, T.; Ono, N.; Suzuki, H.
J. Chem. Soc., Perkin Trans. 1 1994, 23, 3473.
12. Banerjee, A.; Adak, M. M.; Das, S.; Banerjee, S.; Sen-
gupta, S. J. Indian Chem. Soc. 1987, 64, 34.
Acknowledgements
13. Blossey, E. C.; Turner, L. M.; Neekers, D. C. Tetra-
hedron Lett. 1973, 15, 1823.
14. Chakraborti, A. K.; Basak, A.; Grover, V. J. Org. Chem.
We thank the National Science Council in Taiwan
1999, 64, 8014.
(
NSC 89-2113-M-032-004) and Tamkang University for
15. Lee, A. S.-Y.; Yeh, H.-C.; Shie, J.-J. Tetrahedron Lett.
1998, 39, 5249.
financial support.
1
6. Lee, A. S.-Y.; Yeh, H.-C.; Tsai, M.-H. Tetrahedron Lett.
995, 36, 6891.
17. Lee, A. S.-Y.; Cheng, C.-L. Tetrahedron 1997, 42, 14255.
1
References
1
8. Lee, A. S.-Y.; Su, F.-Y.; Liao, Y.-C. Tetrahedron Lett.
1
. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis; John Wiley & Sons, Inc.: New York,
991.
1999, 40, 1323.
19. The results for selective desilylation of silyl esters will be
submitted for publication soon.
1
CBr / MeOH (5%/5mL)
4
RCH -CO SitBuMe
RCH -CO Me
2 2
2
2
2
hv (30 min); stir at rt, 2-3.5h
CBr / MeOH (5%/5mL)
4
R CH-CO SitBuMe
R CH-CO H
2 2
2
2
2
hv (30 min); stir at rt, 2.5-5h
.