Chemoselective esterification of phenolic acids in the presence of sodium bicarbonate in ionic liquids

Article abstract of DOI:10.1080/00397910701845480

Chemoselective esterification of phenolic acids with dialkyl sulphates or alkyl halides in the presence of sodium bicarbonate in 1,3-dialkylimidazolium ionic liquids is reported in excellent yields and less reaction time as compared to organic solvents. Copyright Taylor & Francis Group, LLC.

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Chemoselective Esterification of Phenolic
Acids in the Presence of Sodium Bicarbonate
in Ionic Liquids
Ambika a , Pradeep Pratap Singh a & S. M. S. Chauhan a
a Department of Chemistry, University of Delhi, Delhi, India
Available online: 22 Feb 2008
To cite this article: Ambika, Pradeep Pratap Singh & S. M. S. Chauhan (2008): Chemoselective Esterification
of Phenolic Acids in the Presence of Sodium Bicarbonate in Ionic Liquids, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:6, 928-936
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Synthetic Communicationsw, 38: 928–936, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701845480
Chemoselective Esterification of Phenolic
Acids in the Presence of Sodium
Bicarbonate in Ionic Liquids
Ambika, Pradeep Pratap Singh, and S. M. S. Chauhan
Department of Chemistry, University of Delhi, Delhi, India
Abstract: Chemoselective esterification of phenolic acids with dialkyl sulphates or
alkyl halides in the presence of sodium bicarbonate in 1,3-dialkylimidazolium ionic
liquids is reported in excellent yields and less reaction time as compared to organic
solvents.
Keywords: chemoselective esterification, ionic liquid, phenolic esters, sodium
bicarbonate
INTRODUCTION
Natural phenolic acids and their esters are common plant constituents that
possess antioxidant, anti-inflammatory, antimicrobial, antiallergic, antiviral,
anti-carcinogenic and other biological activities.[1–5] Synthetic esters of
phenolic acids are important intermediates for the synthesis of biologically
active products.[6,7] Specific protection and deprotection methods have been
employed for the synthesis of the phenolic esters.[5–7] Selected reagents
such as diisopropyl azodicarboxylate/triphenylphosphine (DIAD/PPh3),[3]
cesium fluoride–celite,[8] lithium hydroxide monohydrate–dimethyl
[9]
.
sulphate (LiOH H2O–Me2SO4), cesium fluoride–methyl iodide (CsF-
MeI),[10] potassium bicarbonate in dimethyl formamide,[11] and trialkyl
orthoacetates[12] have been used in chemoselective esterification of phenolic
acids. The use of expensive reagents and catalysts, harsh reaction conditions,
Received in India September 25, 2007
Address correspondence to S. M. S. Chauhan, Department of Chemistry, University
of Delhi, Delhi 110007, India. E-mail: smschauhan@chemistry.du.ac.in
928

Chemoselective Esterification of Phenolic Acids
929
long reaction times, and relatively low yields are some of the limitations of
these chemoselective methods.
Room-temperature ionic liquids (RTILs) are potential environmentally
benign solvents for various organic and biochemical transformations.[13]
The hydrophilicity, hydrophobicity, Lewis acidity, viscosity, and density
have been altered by the fine-tuning of parameters such as the choice of
organic cation, inorganic anion, and the length of the alkyl chain attached
to the imidazolium ionic liquids.[13,14] The ionic liquids have been used in
oxidation, reduction, hydrolysis, alkylation, protection, and deprotection and
other reactions becasue of their reusability, potential to enhance reaction
rates and selectivity, and easy separation of the products from the reaction
mixture.[15] We report the chemoselective synthesis of phenolic esters from
the corresponding phenolic acids with dialkyl sulphates or alkyl halides in
the presence of NaHCO3 in 1,3-dialkylimidazolium ionic liquids.
The reaction of salicylic acid (1a) with dimethyl sulphate in the
presence of NaHCO3 in 1-butyl-3-methyl-imidazoliumhexafluorophosphate,
[bmim][PF6], gave methyl salicylate (2a) in 94% yield (Scheme 1, Table 1).
The reaction of 1a in the absence of sodium bicarbonate in different ionic
liquids gave 2a in 5–10% yield (Table 1). The esterification of 1a in the
presence of NaHCO3 proceeded much faster and more efficiently in different
ionic liquids as compared to the conventional solvents such as dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF)
(Table 1). The reaction of other phenolic acids (1b–h) with dimethyl sulphate
in the presence of NaHCO3 in [bmim][PF6] gave the corresponding phenolic
esters (2b–h) in good yields (Table 2). Further reaction of the phenolic acids
(1a–h) with (CH3CH2)2SO4 and C6H5CH2Br in the presence of NaHCO3 in
ionic liquid gave the chemoselective products 2a0 –h0 and 2a00 –h00 respectively
(Table 2). The nature and position of the groups in the aromatic ring have
minor effect on the yields of esters of phenolic acids (Table 2).
Further, the recovery of the product is relatively simple in ionic liquids as
compared to organic solvents. The esters are easily separated from the reaction
mixture by simple extraction with ethyl acetate and purification by distillation
and recrystallization with suitable solvents. The reaction of 1a with dimethyl
sulphate in the presence of NaHCO3 in [bmim][PF6] afforded 2a in 94, 92, 87,
and 83% yields by reuse of recovered ionic liquid in four cycles. Thus, the
ionic liquids can be reused for several cycles without appreciable change in
Scheme 1.

930
Ambika, P. P. Singh, and S. M. S. Chauhan
Table 1. Effect of base and solvent on chemoselective esterification of
salicylic acid (1a)
Solvents
Bases
Time (min)
(%) Yielda
[bmim][Br]
[bmim][BF4]
[bmim][PF6]
DMF
—
—
120
120
120
240
240
180
40
5
8
—
10
35
40
50
88
94
90
45
50
48
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaOH
NaOH
NaOH
DMSO
THF
[bmim][Br]
[bmim][PF6]
[bmim][BF4]
[bmim][Br]
[bmim][PF6]
[bmim][BF4]
20
20
20
20
20
Notes: All reactions were carried out using salicylic acid (1a,
1.0 mmol) and dimethyl sulphate (1.0 mmol).
aHPLC yields; [bmim][Br] ¼ 1-butyl-3-methyl-imidazolium bromide,
[bmim][BF4] ¼ 1-butyl-3-methylimidazolium tetrafluoroborate, and
[bmim][PF6] ¼ 1-butyl-3-methyl-imidazolium hexafluoro-phosphate.
its reactivity. Similar yields and selectivity were obtained using the ionic
liquids [bmim][BF4] and [bmim][Br] (Table 1).
In summary, the chemoselective esterification of phenolic acids with
dialkyl sulphates or alkyl halides in the presence of sodium bicarbonate in
different ionic liquids is a simple and efficient method with shorter reaction
times than other organic solvents.
EXPERIMENTAL
All melting points were determined on a Thomas Hoover Unimelt melting-point
apparatus and are uncorrected. IR spectra were recorded on a Shimadzu IR 435
1
spectrometer. H NMR spectra were recorded on a Bruker Avance 300 spec-
trometer using TMS as internal standard (chemical shift in parts per million).
The symbols s, d, t, q, and m stand for singlet, doublet, triplet, quartet, and
multiplet respectively. The electron spray ionization mass spectra (ESI-MS)
were recorded on a Waters, LCT micromass instrument. High performance
liquid chromatography (HPLC) analyses were performed on a Schimadzu LC
4A UV detector spectrophotometer.
General Procedure
Ionic liquids based on 1-butyl-3-methyl-imidazolium (bmim) salts such as
1-butyl-3-methyl-imidazolium bromide [bmim][Br], 1-butyl-3-methylimidazolium

Table 2. Chemoselective esterification of phenolic acids (1a–h) using NaHCO3/alkylating agent in [bmim][PF6]a
lit. Bp/mp (8C)
Entry
Substrate
Product
Alkylating agent
Time (min)
Yield (%)b
Obs.
Rep.
1a
2a
2a0
2a00
(CH3)2SO4
(CH2CH3)2SO4
C6H5CH2Br
20
35
40
94 (74)c (77)e
221–222d
232d
296–297d
223[17]
231[17]
—
90
88
1b
1c
2b
2b0
2b00
(CH3)2SO4
(CH2CH3)2SO4
C6H5CH2Br
20
40
25
87
86
88
279–281d
70–71
69–70
280[17]
72–73[17]
68–69[21]
2c
2c0
2c00
(CH3)2SO4
(CH2 CH3)2SO4
C6H5CH2Br
20
40
25
90
88
86
126–128
113–114
118–119
127–129[17]
116[17]
119–121[19]
1d
1e
2d
2d0
2d00
(CH3)2SO4
(CH2 CH3)2SO4
C6H5CH2Br
25
40
35
87
85
84
163–165
117–119
130–132
163–164[17]
115–122[17]
132–133[19]
2e
2e0
2e00
(CH3)2SO4
(CH2 CH3)2SO4
C6H5CH2Br
25
35
35
84
82
80
155–156
163–164
148–149
157[17]
162[17]
145–149[19]
(continued)

Table 2. Continued
lit. Bp/mp (8C)
Entry
Substrate
Product
Alkylating agent
Time (min)
Yield (%)b
Obs.
Rep.
1f
2f
2f0
2f00
(CH3)2SO4
(CH2CH3)2SO4
C6H5CH2Br
20
35
35
88
85
86
140–141
49–50
92–93
139.5–141[18]
50–52[20]
92–93[12]
1g
1h
2g
2g0
2g00
(CH3)2SO4
(CH2 H3)2SO4
C6H5CH2Br
20
30
35
92
90
87
86–87
75–77
102–103
88[16]
77[16]
—
2h
2h0
2h00
(CH3)2SO4
(CH2CH3)2SO4
C6H5CH2Br
15
25
35
80
78
84
74–77
86–87
86–87
75–76[16]
85[16]
—
aAll reactions were carried out using phenolic acids (1.0 mmol), NaHCO3 (1.2 mmol), dialkyl sulphate (1.0 mmol), or alkyl halide (1.5 mmol) in
[bmim][PF6].
bHPLC yields (m-bond pack C-18 reverse phase column, acetonitrile, flow rate ¼ 1 ml/min monitored at 232 nm).
cYields using 0.5 eq. of DMS.
dBoiling point.
eReaction was performed at room temperature.

Chemoselective Esterification of Phenolic Acids
933
tetrafluoroborate bmim][BF4], and 1-butyl-3-methyl-imidazolium hexafluoropho-
sphate [bmim][PF6] were synthesized according to the modified literature
procedure.[13] Phenolic acid (1.0 mmol) was dissolved in ionic liquid
[bmim][PF6] (2 ml), and NaHCO3 (1.2 mmol) was added. The reaction mixture
was stirred for 10–15 min. The dialkyl sulphate (1.0 mmol) or alkyl halide
(1.5 mmol) was added dropwise to the suspension of the reaction mixture and
stirred for 15–20 min at 408C. The progress of the reaction was monitored by
thin-layer chromatography (TLC), and after the completion of the reaction, the
product was extracted with ethyl acetate (3 ꢀ 3 ml), and the organic layer was sub-
sequently washed with 5% NaHCO3 and 5% NaCl and dried (anhy. Na2SO4). The
ethyl acetate layer was concentrated under reduced pressure to give the desired
product. The remaining ionic liquid was dissolved in CHCl3 and filtered to
remove insoluble NaHCO3 and precipitated sodium halides.
The spectroscopic data including IR, NMR, and mass spectra of the
products were identical to those of authentic samples. The physical data are
given in Table 2, and the spectroscopic data of selected phenolic esters
(2a00 –h00) are given as follows.
Data
Benzyl 2-hydroxybenzoate (2a00): IR (nujol, cm21): 3392, 1670, 1639, 1580,
1
1325, 1232, 1110; H NMR (300 MHz, d ppm, CDCl3): 5.50 (s, 2H, -CH2),
7.05–7.30 (m, 3H, H-3 to H-5), 7.34–7.59 (m, 6H, H-6, H-2a0 to H-6a0),
9.80 (s, 1H, OH); ESI-MS: 229.2479 (M þ 1).
Benzyl 3-hydroxybenzoate (2b00): IR (nujol, cm21): 3395, 1696, 1612, 1350;
1H NMR (300 MHz, d ppm, CDCl3): 5.39 (s, 2H, -CH2), 5.82 (s, 1H, OH),
7.08 (m, 1H, H-4), 7.28–7.48 (m, 5H, H-2a0 to H-6a0), 7.30 (t, 1H,
J ¼ 8.2 Hz, H-5), 7.62 (m, 1H, H-2), 7.68 (m, 1H, H-6); ESI-MS: 252.2378
(M þ Na).
Benzyl 4-hydroxybenzoate (2c00): IR (nujol, cm21): 3425, 1712, 1270, 1160;
1H NMR (300 MHz, d ppm, CDCl3): 5.40 (s, 2H, -CH2), 6.96 (d, J ¼ 8.6 Hz,
2H, H-3 & H-5), 7.34–7.45 (m, 5H, H-2a0 to H-6a0), 8.15 (d, J ¼ 8.6 Hz, 2H,
H-2 & H-6); ESI-MS: 229.2482 (M þ 1).
Benzyl 3,5-dihydroxybenzoate (2d00): IR (nujol, cm21): 3392, 1696, 1611,
1
1337; H NMR (300 MHz, d ppm, CDCl3): 5.34 (s, 2H, -CH2), 6.60 (d, 1H,
J ¼ 2.5 Hz, H-4), 7.05 (d, 2H, J ¼ 2.5 Hz, H-2 & H-6), 7.31–7.53 (m, 5H,
H-2a0 to H-6a0), 8.58 (s, 2H, OH); ESI-MS: 267.0632 (M þ Na).
Benzyl 3,4,5-trihydroxybenzoate (2e00): IR (nujol, cm21): 3369, 1690, 1605,
1
1339 1235; H NMR (300 MHz, d ppm, CDCl3): 5.32 (s, 1H, -CH2), 7.20

934
Ambika, P. P. Singh, and S. M. S. Chauhan
(s, 2H, H-2 & H-6), 7.32–7.47 (m, 5H, H-2a0 to H-6a0), 9.09 (s, 3H, OH); ESI-
MS: 261.2471 (M þ 1).
Benzyl 4-hydroxycinnamate (2f00): IR (KBr, cm21): 3470, 2950, 1717, 1630,
1
1220, 1170, 1080, 1027; H NMR (300 MHz, d ppm, CDCl3): 5.27 (s, 2H, -
CH2), 6.13 (s, 1H, OH), 6.44 (d, J ¼ 16.0 Hz, 1H, ¼CHAr), 6.92
(d, J ¼ 8.1 Hz, 2H, H-3 & H-5), 7.31–7.44 (m, 7H, H-2 & H-6, H-2a0 to
H-6a0), 7.62 (d, J ¼ 16.0 Hz, 1H, ¼CHCO); ESI-MS: 277.3080 (M þ Na).
Benzyl 2,5-dihydroxybenzoate (2g00): IR (KBr, cm21): 3388, 1668, 1637,
1
1575, 1319, 1228, 1103; H NMR (300 MHz, d ppm, CDCl3): 4.80 (s, 1H,
OH), 5.54 (s, 2H, -CH2), 6.95 (d, J ¼ 8.4 Hz, 1H, H-3), 7.08 (dd, J ¼ 2.5,
8.2 Hz, 1H, H-4), 7.20 (d, J ¼ 2.5 Hz, 1H, H-6), 7.44–7.53 (m, 5H, H-2a0
to H-6a0), 10.40 (s, 1H, OH); ESI-MS: 245.2496 (M þ 1).
Benzyl-3-hydroxy-2-naphthoate (2h00): IR (KBr, cm21): 3418, 1651, 1517,
1
1404, 1317, 1210, 1022; H NMR (300 MHz, d ppm, CDCl3): 5.52 (s, 2H, -
CH2), 7.43 (s, 1H, H-4), 7.49–7.53 (m, 5H, H-2a0 to H-6a0), 7.65–7.72
(m, 4H, H-5 to H-8), 7.90 (s, 1H, H-1), 11.80 (s, 1H, OH); ESI-MS:
279.3080 (M þ 1).
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