A simple and effective method for chemoselective esterification of phenolic acids

Article abstract of DOI:10.1081/SCC-200046532

A new method for efficient and chemoselective esterification of phenolic acids in KHCO₃/alkyl halide/DMF reaction system is described, by which a series of phenoic acid esters were obtained in excellent yields.

Full text of DOI:10.1081/SCC-200046532

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A Simple and Effective
Method for Chemoselective
Esterification of Phenolic Acids
Wei Guo a , Junfei Li a , Ningjuan Fan a , Weiwei Wu
a , Peiwen Zhou a & Chizhong Xia a
a School of Chemistry and Chemical Engineering,
Shanxi University, Taiyuan, 030006, China
Version of record first published: 05 Aug 2006.
To cite this article: Wei Guo, Junfei Li, Ningjuan Fan, Weiwei Wu, Peiwen Zhou &
Chizhong Xia (2005): A Simple and Effective Method for Chemoselective Esterification
of Phenolic Acids, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:1, 145-152
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Synthetic Communicationsw, 35: 145–152, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200046532
A Simple and Effective Method
for Chemoselective Esterification of
Phenolic Acids
Wei Guo, Junfei Li, Ningjuan Fan, Weiwei Wu,
Peiwen Zhou, and Chizhong Xia
School of Chemistry and Chemical Engineering, Shanxi University,
Taiyuan, China
Abstract: A new method for efficient and chemoselective esterification of phenolic
acids in KHCO3/alkyl halide/DMF reaction system is described, by which a series
of phenoic acid esters were obtained in excellent yields.
Keywords: Phenolic acids, chemoselective esterification, alkyl halide
Phenolic acid esters motifs have been found in bioactive natural products, for
example, the NF-kB inhibitors CAPE,[1] the honeybee propolis contact
allergen prenyl caffeate,[2] and the EGCG mimic and HIV-1 reverse transcrip-
tase inhibitor hydroxytyrosol gallate.[3] In many cases, phenolic acid esters are
also used as important intermediates for the medicine synthesis.[4,5] Although
these compounds are structurally unsophisticated, their reported synthesis
typically suffer from a heavy burden of protecting groups for the purpose of
improved chemoselectivity.[1–5] In the presence of strong protic acids
(Fisher esterification), phenolic acids could be esterified with good
Received in Poland August 20, 2004
Address correspondence to Wei Guo, School of Chemistry and Chemical Engineer-
ing, Shanxi University, Taiyuan 030006, China. E-mail: guow@sxu.edu.cn or shxgw@
eyou.com

146
W. Guo et al.
chemoselectivity,[6] 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,[2] but the yield is modest along with an excess of halides. Recently,
Appentino et al. reported the preparation of phenolic acid esters with good
chemoselectivity by Mitsunobu reaction,[7] 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 (1.0 eq.) and CH3I (1.5 eq.) as
reaction substrates we screened a series of bases and solvents at room temp-
erature to find optimal reaction conditions (Scheme 1 and Table 1). It is inter-
esting 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 1, entry 1). With DMSO as solvent, the yield was
slightly decreased (Table 1, 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 K2CO3 (1.0 eq.), the reaction partly lost selectivity, and 9% of dialky-
lated product 2 was separated (Table 1, entry 5). However, NaHCO3 and
Na2CO3 gave good results comparable to KHCO3 (Table 1, entries 6 and 7)
in spite of the longer reaction time. When using stronger base NaOH
(1 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 CH3I to
yield and selectivity of the reaction. Using 1.5 eq. of CH3I, we found that
when the temperature was 408C, 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 (4 eq.) was used at 408C.
With DMF as optimal solvent and KHCO3 as optimal base, we further
investigated the chemoselective esterafication of various phenolic acids at
408C (Table 2). For methylation, almost all reactions showed excellent
Scheme 1.

Chemoselective Esterification of Phenolic Acids
147
Table 1. Base and solvent effect at room temperature in the chemoselective esterifica-
tion of 4-hydroxybenzoic acida
Entry
Base (eq.)
Solvent
Time (h)
Yield (1)%b
Yield (2)%
1
2
3
4
5
6
7
8
KHCO3 (1.2)
KHCO3 (1.2)
KHCO3 (1.2)
KHCO3 (1.2)
K2CO3 (1.0)
NaHCO3 (1.2)
Na2CO3 (1.0)
NaOH (1.0)
DMF
DMSO
Acetone
THF
3
5
98
85
20
8
85c
88
91
58c
n. d.
n. d.
n. d.
n. d.
9%c
n. d.
n. d.
35c
24
24
3
DMF
DMF
DMF
DMF
5
5
5
aMole ratio of 4-hydroxybenzoic acid : CH3I ¼ 1 : 1.5.
bIsolated yields by simple work up described in Experimental section.
cPurified by column chromatography.
yield and chemoselectivity in 1–3 h. One noteworthy point is that the numbers
and position of phenolic hydroxyls or carboxyls involved in the aromatic ring
did not affect the good yield and selectivity. For phenolic acids bearing
electron-withdrawing groups, such as Br and I, the reaction was also good
(Table 2, entries 7 and 8). However, when 3, 5-dinitrosalicyclic acid was
used, no any product was detected either in lengthening time or at elevated
temperature (Table 2, entry 9). Obviously, it is due to the weak nucleophilic
activation of the carboxylate anion, resulting from strong electron-withdrawing
nitro groups.
In addition to methyl ester of phenolic acid, we also applied this method
to prepare benzyl ester of phenolic acids considering its clean and convenient
deprotection by Pd/C hydrogenation. Initially, we tested the reaction of
4-hydroxybenzoic acid with benzyl chloride in the above condition.
However, the reaction was very slow, and after 56 h, 20% desired product
was only separated. Once temperature was evaluated to 608C, after 24 h the
desired product was obtained in 34% yield along with 23% dialkylated
product. When more active benzyl bromide was used, most of the reactions
were finished after 3 h at 408C with excellent selectivity and yields
(Table 2). Furthermore, we also checked up 4-hydroxycinnamic acid and its
derivative in view of their versatility in medicine synthesis and relation to
the NF-kB inhibitors CAPE.[1] The results obtained also showed excellent
selectivity and yields (Table 2, entries 12 and 13).
In summary, KHCO3/alkyl halide/DMF reaction system provides a
clean, practical method for chemoselective esterification of phenolic acids
in high yields. We hope this method could provide some application in
medicine synthesis.

148
W. Guo et al.
Table 2. Chemoselective Esterification of Phenolic acids Using KHCO3/alkyl
halide/DMF reaction systema
Type of
esters
Yield
(%)b
Entry
Substrate
Product
R ¼ CH3 1
99
94
98
95
1
2
R ¼ CH2Ph 3
R ¼ CH3 4
R ¼ CH2Ph 5
3
4
R ¼ CH3 6
96
96
R ¼ CH2Ph 7
R ¼ CH3 8
98
95
R ¼ CH2Ph 9
5
6
R ¼ CH3 10
99
91
R ¼ CH2Ph 11
R ¼ CH3 12
94
92
R ¼ CH2Ph 13
7
R ¼ CH3 14
92
90
R ¼ CH2Ph 15
8
9
R ¼ CH3 16
93
94
R ¼ CH2Ph 17
R ¼ CH3 18
n.d
n.d
R ¼ CH2Ph 19
(continued)

Chemoselective Esterification of Phenolic Acids
149
Table 2. Continued
Type of
esters
Yield
(%)b
Entry
10
Substrate
Product
R ¼ CH3 20
95
92
R ¼ CH2Ph 21
11
12
13
R ¼ CH3 22
96
95
R ¼ CH2Ph 23
R ¼ CH3 24
98
95
R ¼ CH2Ph 25
R ¼ CH3 26
96
91
R ¼ CH2Ph 27
aAll reactions were performed at 408C. Mole ratio of phenolic acid : alkyl
halides ¼ 1 : 1.5.
bIsolated yields by simple workup described in the Experimental section.
EXPERIMENTAL SECTION
General. The carboxylic acids, KHCO3, CH3I and benzyl bromide are
available commercially 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 408C with a
water bath and monitored by TLC. Upon completion, the reaction mixture
was added to 10 ml water and extracted with ethyl acetate. The organic
layer was subsequently washed with 5% NaHCO3 and 5% NaCl, and dried
over anhydrous Na2SO4, filtered and concentrated under reduced pressure to
give the desired products. Benzyl esters of phenolic acid may be prepared
according to the similar method, and the excess benzyl bromide can be
easily removed by column chromatography (EtOAc/hexane).

150
W. Guo et al.
The NMR and IR spectra of the following esters were in complete
agreement with those of the authentic samples: methyl 4-hydroxybenzoate,
methyl 4-methoxybenzoate, benzyl 4-hydroxybenzoate, methyl salicylate,
methyl 2,6-dihydroxybenzoate, methyl 2,5-dihydroxybenzoate, methyl
2,4-dihydroxybenzoate, dimethyl 5-hydroxyisophthalate, Methyl 3-(4-hydro-
xyphenyl)propionate (Aldrich), benzyl salicylate (Acros), methyl 4-methyl-
salicylate,[8] benzyl 2,5-dihydroxybenzoate,[9] methyl 2-hydroxy-1-
naphthoate,[10] methyl 4-hydroxycinnamate.[11] For others, spectral data are
given below, which are consistent with the assigned structures.
Benzyl 4-methylsalicylate (7): Oil; 1H-NMR (300 MHz, dppm, CDCl3):
2.36 (s, 3H), 5.39 (s, 2H), 6.71 (d, J ¼ 7.5, 1H), 6.82 (s, 1H), 7.42 (m, 6H),
7.77 (d, J ¼ 7.8, 1H); IR (KBr) cm21: 3180, 3035, 2360, 1670, 1624, 1502,
1388; MS m/z: 242 (M); Anal. Calcd for C15H14O3: C, 74.36; H, 5.82.
Found C, 74.33; H, 5.80.
Benzyl 2,6-dihydroxybenzoate (9): M.p. 66–688C; 1H-NMR (300 MHz,
dppm, CDCl3): 5.50 (s, 2H), 6.47 (d, J ¼ 8.4, 2H), 7.30 (m, 1H), 7.44 (s, 5H),
9.71 (b, 2H); IR (KBr) cm21: 3388, 1668, 1637, 1575, 1319, 1228, 1195,
1161, 1103; MS m/z: 244 (M); Anal. Calcd for C14H12O4: C, 68.85; H,
4.95. Found C, 68.81; H, 4.94.
Benzyl 2,4-dihydroxybenzoate (13): M.p. 94–968C; 1H-NMR
(300 MHz, dppm, CDCl3): 5.35 (s, 3H), 5.52 (s, 1H), 6.35 (d, J ¼ 9, 1H),
6.40 (s, 1H), 7.40 (m, 5H), 7.78 (d, J ¼ 8.7, 1H), 10.99 (s, 1H); IR (KBr)
cm21: 3375, 1662, 1624, 1377, 1261; MS m/z: 244 (M); Anal. Calcd for
C14H12O4: C, 68.85; H, 4.95. Found C, 68.83; H, 4.93.
Methyl 5-bromo-4-methylsalicylate (14): M.p. 46–478C; 1H-NMR
(300 MHz, dppm, CDCl3): 2.37 (s, 3H), 3.93 (s, 3H), 6.87 (s, 1H), 7.96
(s, 1H), 10.57 (s, 1H); IR (KBr) cm21: 1678, 1616, 1442, 1334, 1253,
1207; MS m/z: 244 (M), 246 (M þ 2); Anal. Calcd for C9H9BrO3: C, 44.11;
H, 3.70. Found C, 44.23; H, 3.73.
Benzyl 5-bromo-4-methylsalicylate (15): M.p. 61–628C; 1H-NMR
(300 MHz, dppm, CDCl3): 2.37 (s, 3H), 5.37 (s, 2H), 6.88 (s, 1H), 7.42
(s, 5H), 7.98 (s, 1H), 10.60 (s, 1H); IR (KBr) cm21: 1666, 1616, 1477,
1396, 1245; MS m/z: 320 (M), 322 (M þ 2); Anal. Calcd for C15H13BrO3:
C, 56.10; H, 4.08. Found C, 56.09; H, 4.07.
Methyl 5-iodo-4-methylsalicylate (16): M.p. 62–648C; 1H-NMR
(300 MHz, dppm, CDCl3): 2.42 (s, 3H), 3.95 (s, 3H), 6.92 (s, 1H), 8.23
(s, 1H), 10.61 (s, 1H); IR (KBr) cm21: 3155, 2952, 1674, 1610, 1469, 1440,
1338, 1255; MS m/z: 292 (M); Anal. Calcd for C9H9IO3: C, 37.01; H, 3.11.
Found C, 37.08; H, 3.09.
Benzyl 5-iodo-4-methylsalicylate (17): M.p. 64–658C; 1H-NMR
(300 MHz, dppm, CDCl3): 2.42 (s, 3H), 5.39 (s, 2H), 6.93 (s, 1H), 7.44
(m, 5H), 8.25 (s, 1H), 10.64 (s, 1H); IR (KBr) cm21: 1672, 1610, 1463,
1392, 1255, 1213; MS m/z: 368 (M); Anal. Calcd for C15H13IO3: C, 48.94;
H, 3.56. Found C, 48.90; H, 3.51.

Chemoselective Esterification of Phenolic Acids
151
Dibenzyl 5-hydroxyisophthalate (21): M.p. 116–1188C; 1H-NMR
(300 MHz, dppm, CDCl3): 5.36 (s, 4H), 6.48 (b, 1H), 7.41 (m, 10H), 7.79
(s, 2H), 8.30 (s, 1H); IR (KBr) cm21: 3436, 1720, 1697, 1388, 1334; MS
m/z: 362 (M); Anal. Calcd for C22H18O5: C, 72.92; H, 5.01. Found C,
74.91; H, 4.97.
Benzyl 2-hydroxy-1-naphthoate (23): M.p. 81–828C; 1H-NMR
(300 MHz, dppm, CDCl3): 5.59 (s, 2H), 7.18 (d, J ¼ 8.7, 1H), 7.35–7.54
(m, 8H), 7.76 (d, J ¼ 7.5, 1H), 7.91 (d, J ¼ 8.7, 1H), 8.82 (d, J ¼ 8.4, 1H);
IR (KBr) cm21: 1691, 1633, 1598, 1518, 1170; MS m/z: 278 (M); Anal.
Calcd for C18H14O3: C,77.68; H, 5.07. Found C, 77.72; H, 5.04.
Benzyl 4-hydroxycinnamate (25): M.p. 90–928C; 1H-NMR (300 MHz,
dppm, CDCl3): 5.25 (s, 2H), 6.01 (b, 1H), 6.34 (d, J ¼ 15.9, 1H), 6.85
(d, J ¼ 8.1, 2H), 7.34–7.42 (m, 7H), 7.67 (d, J ¼ 15.9, 1H); IR (KBr)
cm21: 1641, 1465, 1377, 1244, 1203; MS m/z: 254 (M); Anal. Calcd for
C16H14O3: C, 75.58; H, 5.55. Found C, 75.36; H, 5.59.
Benzyl 3-(4-hydroxyphenyl)propionate (27): Oil; 1H-NMR (300 MHz,
dppm, CDCl3): 2.64 (t, 2H), 2.89 (t, 2H), 4.95 (b, 1H), 5.10 (s, 2H), 6.72
(d, J ¼ 7.8, 2H), 7.04 (d, J ¼ 7.8, 2H), 7.32 (m, 5H); IR (KBr) cm21: 3396,
3031, 2927, 2358, 1699, 1614,1456; MS m/z: 256 (M); Anal. Calcd for
C16H16O3: C, 74.98; H, 6.29. Found C, 74.92; H, 6.24.
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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