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Phenolic acid esters motifs have been found in bioactive natural products, for
example, the NF-^B inhibitors CAPE.'"' the honeybee propolis contact
allergen prenyl cafleate,'"' and the EGCG mimic and HIV-1 reverse transcriptase inhibitor hydroxytyrosol gallate.'^^' In many cases, phenolic acid esters are
also used as important intermediates for the medicine synthesis.'"^"^^ Although
these compounds are structurally unsophisticated, their reported synthesis
typically suffer from a heavy burden of protecting groups for the purpose of
improved chemoselectivity.''"''' In the presence of strong protic acids
(Fisher esterification), phenolic acids could be esterified with good
Received in Poland August 20, 2004
Address corre.'ipondence lo Wei Guo. School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, China. E-mail: guow@sxu.edu.cn or shxgw@
eyou.com
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W. Guo et al.
chemoselectivity,"^' but the harsh reaction conditions and the excess of alcohol
made this strategy of limited applicability. The cesium salts of phenolic acids
have been reported to react with alkyl halides in a highly chemoselective
way.'"' but the yield is modest along with an excess of halides. Recently.
Appentino et al. reported the preparation of phenolic acid esters with g(K>d
chemoseleclivity by Mitsunobu reaction,'^' but the modest yields and costly
reagents limited it for practical applications. Herein, we hope to report
a practical and effective reaction system. KHCO3/alkyl halide/DMF, for
chemoselective esterafication of phenolic acids.
Firstly, with 4-hydroxybenzoic acid (l.Oeq.) and CH3I (L.'ieq.') as
reaction substrates we screened a series of bases and solvents at room temperature to find optimal reaction conditions (Scheme 1 and Table I). It is interesting to note that with KHCO3 as base and DMF as solvent, the desired
product was obtained in almost quantitative yield, and no side product 2
was observed (Table I, entry 1). Witb DMSO as solvent, the yield was
slightly decreased (Table I. entry 2). However, acetone and THF failed to
provide .significant amounts of 1 even in lengthening time (Table 1, entries
3 and 4). With DMF as solvent, other bases were also investigated. When
using K2C0-1 (I.Oeq.). tbe reaction partly lost selectivity, and 9% of dialkylated product 2 was separated (Table I. entry 5). However. NaHCO, and
Na2C0:, gave good results comparable to KHCO3 (Table I. entries 6 and 7)
in spite of the longer reaction time. When using stronger base NaOH
(I eq.). the reaction lost .selectivity (Table 1, entry 8).
With DMF as optimal solvent and KHCO3 as optimal base, we next
studied the effect of reaction temperature and concentration of CHiI to
yield and selectivity of the reaction. Using 1.5 eq. of CH3I. we found that
when the temperature was 40"C, the reaction was completed after 1.5 hr
without the loss of yield and selectivity. In addition, the reaction still
worked well even if excessive CH3I (4eq.) was used at 40 C.
With DMF as optimal solvent and KHCO3 as optimal base, we further
investigated the chemoselective esteralication of various pbenolic acids at
40 C (Table 2). For mcthylation, almost all reactions showed excellent
OOH
OOCH3
CH3I. base
solvent, R. T.
Scheme I.
OOCH3
147
Table I. Base and solvent effect at room temperature in the chemoselective estcrification of 4-hydroxyben/.oic acid"
Entry
1
2
4
5
6
7
8
Base (eq.)
Solvent
KHCO3(I.2)
KHCO3(I.2)
KHCO, (1.2)
DMF
DMSO
Acetone
THF
DMF
DMF
DMF
DMF
KHCO3 (1.2)
K2CO1 (1.0)
NaHC0,(1.2)
Na^CO, (1.0)
NaOH (1.0)
Time(h)
5
24
24
3
5
5
5
Yield (1)%''
Yield (2)%
98
n. d.
n. d.
n. d.
n. d.
9%'
85
20
8
85''
88
91
5W'
n. d.
n. d.
148
W. Guo et al.
Substrate
COOH
COOH
,COOH
HgC
HO
HO
^ ^
^-^
Type of
esters
Product
XOOR
COOR
COOR
OH
Yield
{%f
R = CH, 1
99
R = CHiPh 3
94
R = CH, 4
98
R = CH.Ph 5
95
R = CH, 6
96
R = CHjPh 7
96
R = CH, 8
98
R = CH.Ph 9
95
OH
COOH
cooR
R = CH, 10
99
OH
OH
R = CHjPh I I
91
COOH
COOR
R = CH, 12
94
OH
R = CH.Ph 13
92
R = CH, 14
92
R = CH,Ph 15
90
R = CH, 16
93
R = CH^Ph 17
94
R = CH, 18
n.d
R = CHjPh 19
n.d
COOH
COOH
{continued)
Substrate
10
149
Continued
Type of
esters
Product
COOH
COOR
Yield
(%)''
R ^ CH, 20
95
R - CH^Ph 21
92
R = CH, 22
96
R = CH,Ph 23
95
R - CH3 24
98
R = CHjPh 25
95
R = CH3 26
R-CH.Ph27
91
COOR
12
COOH
COOR
13
COOH
COOR
EXPERIMENTAL SECTION
General. The carboxylic acids, KHCO3, CH3I and benzyl bromide are
available cotnmercially without further purification. Solvents were dried
according to standard procedures. All reactions were magnetically stirred
and monitored by thin-layer chromatography (TLC) using Huanghai GF254
silica gel-coated plates.
General Procedures for the Preparation of Phenolic acid ester:
2 mmol phenolic acid was dissolved in 3.0 mL dry DMF, 2.4 mmol KHCO3
was added and stirred for several minutes at room temperature. Then,
3 mmol CH3I were added. The reaction mixture was allowed to 40 C with a
water bath and monitored by TLC. Upon completion, the reaction mixture
was added to lOmI water and extracted with ethyl acetate. The organic
layer was subsequently washed with 5% NaHCO, and 5% NaCI, and dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure to
give the desired products. Benzyl e.sters of phenolic acid may be prepared
according to the similar method, and the excess benzyl bromide can he
easily removed by column chrotnatography (EtOAc/hexane).
150
W. Guo et al.
151
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of
China (No. 20272034), and the Natural Science Foundation of Shanxi
Province. China (No. 20041006).
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