An efficient chemoselective etherification of phenols in polyfunctional aromatic compounds

Article abstract of DOI:10.1016/j.tetlet.2007.11.129

A simple and efficient chemoselective alkylation of phenols in polyfunctional aromatic compounds with different alkyl halides in the presence of K₂CO₃/TBAB is reported. The method is successful with various hydroxy aromatic acids or oximes possessing other functional groups.

Full text of DOI:10.1016/j.tetlet.2007.11.129

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 695–698
An efficient chemoselective etherification of phenols
in polyfunctional aromatic compounds
Jyoti Pandey, Mridul Mishra, Surendra Singh Bisht, Anindra Sharma,
Rama P. Tripathi *
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 6 September 2007; revised 14 November 2007; accepted 21 November 2007
Abstract
A simple and efficient chemoselective alkylation of phenols in polyfunctional aromatic compounds with different alkyl halides in the
presence of K2CO3/TBAB is reported. The method is successful with various hydroxy aromatic acids or oximes possessing other func-
tional groups.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Etherification; Phenol; Naphthoic acid; Tetrabutylammonium bromide; Chemoselective alkylation
1. Introduction
from hydroxy benzoic acids is known,17–19 a method for
chemoselective alkylation of phenols over carboxylic acids
was only reported recently by Liu et al.20 during the course
of our studies and involves chemoselective alkylation of
hydroxy benzoic acids with alkyl halides in the presence
of tetrabutylphosphonium hydroxide as a phase transfer
catalyst. Herein, we report an alternative, efficient, eco-
nomical, high yielding, simple, and practical method for
chemoselective alkylation of phenolic groups in hydroxy
aromatic acids and hydroxy aromatic compounds possess-
ing other potentially reactive functionalities.
Tetrabutylammonium bromide has been used as phase
transfer catalyst in a variety of organic reactions and is
known to enhance nucleophilicity.21,22 A combination of
tetrabutylammonium bromide and inorganic bases under
microwave irradiation has also been used for alkylation
of phenols.23 The basis of a chemoselective alkylation of
phenolic groups relies on substantial pKa differences rela-
tive to other functionalities.
Naphthoic acid derivatives and phenolic ethers are con-
stituents of some well-known pharmaceutical com-
pounds.1,2 Naphthoic acid derivatives play a crucial role
in the development of new drugs against several human ail-
ments and infectious diseases.3–6 In our continuing effort to
develop new antitubercular agents we were interested in
preparing naphthoic acid derivatives, because several mole-
cules with a naphthyl moiety are potent antitubercular
agents (Fig. 1).7,8 One such naphthyl derivative, a diaryl
quinoline, is at an advanced stage in clinical trials.9
We required alkyl ethers of hydroxy naphthoic acids
which could be later modified via carboxyl group manipu-
lations. This led us to seek a chemoselective method for
etherificaton of phenolic groups in hydroxy naphthoic
acids. Earlier methods include Fischer ester formation then
phenol alkylation, followed by saponification10–12 or
dialkylation of both the phenol and carboxylic acid groups
followed by ester saponification.13–16 Although the
chemoselective preparation of hydroxy benzoic acid esters
2. Results and discussion
*
1-Hydroxy-2-naphthoic acid on treatment with allyl
bromide in the presence of anhydrous K2CO3 (10 mol %)
Corresponding author. Tel.: +91 522 2612412; fax: +91 522 2623405.
E-mail address: rpt.cdri@gmail.com (R.P. Tripathi).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.129

696
J. Pandey et al. / Tetrahedron Letters 49 (2008) 695–698
OH
O
OH OH
NMe2
O
Br
COOH
HO
N
OMe
C12H25
MeO
2-(4-methoxy benzoyl)-1
-naphthoic acid (antimalarial)
Natural product antitubercular
R207910 antiTB molecule in clinical trial
O
Me
O
O
Me
OH
Me
H
N
H
O
O
O
O
Me
N
MeO
MeO
O
N
N
H
H
O
AcO
O
AcO
O
O
N
N
Me
HO
Azinomycin B2
HO
Me
Azinomycin A1
Fig. 1. Biologically important compounds with a naphthyl moiety.
OH
oximes was also possible with benzyl bromide (Table 2,
entries 12 and 13).
OR
COOH
COOH
RX/K2CO3/TBAB
THF/30 oC
3. Conclusion
1
2
Scheme 1. Synthesis of alkyl ethers of 1-hydroxy-2-naphthoic acid.
In summary, we have demonstrated that chemoselective
alkylation of phenols in aromatic compounds having other
reactive functionalities can be carried out successfully with
a variety of alkyl halides using tetrabutylammonium bro-
mide/K2CO3 in an organic solvent. The method is simple,
economical, of high yield and useful in the preparation of
alkoxy benzoic acid and alkoxy benzaldehyde oximes.
and a catalytic amount of TBAB in anhydrous THF at
ambient temperature for 10 min leads to 1-allyloxy-2-naph-
thoic acid (Scheme 1) as the only product in 90% yield. The
use of tetrabutylammonium hydroxide on the other hand
produced a mixture of the above desired compound along
with allyl 1-allyloxy-2-naphthoate as a minor product.
Similarly, benzyl bromide, ethyl bromoacetate, ethyl
chloroacetate, 1-(2-chloroethyl)-piperidine, benzyl chlo-
ride, and N,N-di-isopropylaminoethyl chloride all reacted
to form the respective 1-O-alkyl derivatives in good yields
(Scheme 1, Table 1, entries 2–7).
4. Typical experimental procedure and selected data
A mixture of the hydroxy aromatic compound (1 equiv),
anhydrous K2CO3 (10 mol %), TBAB (10 mol %) and alkyl
halide (1 equiv), in anhydrous THF was stirred at ambient
temperature until TLC analysis showed the disappearance
of the starting materials. The reaction mixture was filtered
and the organic solvent was evaporated to give the desired
ether. If needed, purification of the crude product was car-
ried out over a short column of silica gel using a gradient of
hexane: ethyl acetate as eluent.
Encouraged by these findings we carried out phenol
alkylations on a variety of substrates with different alkyl
halides and the results are depicted in Table 2. Chemoselec-
tive alkylation of the phenol in a hydroxy benzaldehyde
Table 1
4.1. 1-Allyloxy-2-naphthoic acid
Preparation of alkyl ethers of 1-hydroxy-2-naphthoic acid (Scheme 1)
White solid, mp 65–66 °C; FT-IR (KBr, cmÀ1): 3745,
Entry RX
Time
(min)
% Yield of 2
(isolated)
1
3116, 2641, 2231, 1744, 1699, 1516; H NMR (200 MHz,
1
2
3
4
5
6
7
Allyl bromide
Benzyl bromide
10
10
10
90
30
20
60
90
91
90
60
65
85
65
CDCl3–CCl4): d 8.42 (d, J = 8.05 Hz, 1H, ArH), 7.79–
7.22 (m, 4H, ArH), 7.24 (d, J = 8.80 Hz, 1H, ArH), 6.2–
5.9 (m, 1H, CH2@CH), 5.49–5.30 (m, 2H, CH2@CH),
4.87 (dd, 2H, J1 = 2.63 Hz, J2 = 2.64 Hz, –OCH2); 13C
NMR (50 MHz, CDCl3–CCl4): d 171.0, 161.61, 137.64,
132.17, 129.75, 127.79, 126.07, 125.24, 124.61, 124.40,
119.24, 118.92, 105.91, 66.13; MS(ESI): 229 (M+H+);
Ethyl bromoacetate
Ethyl chloroacetate
1-(2-Chloroethyl)-piperidine
Benzyl chloride
N,N-Di-isopropylaminoethyl
chloride

J. Pandey et al. / Tetrahedron Letters 49 (2008) 695–698
697
Table 2
Chemoselective alkylation of phenolic substrates with various alkyl halides
Entry
Substrate
RX
Time (min)
Product
% Yielda
1
2
3
2-Hydroxy naphthoic acid
2-Hydroxy naphthoic acid
2-Hydroxy naphthoic acid
Allyl bromide
Benzyl bromide
Ethyl bromoacetate
10
10
15
2-Allyloxynaphthoic acid
2-Benzyloxynaphthoic acid
2-O-(Ethoxycarbonyl methyl)naphthoic
acid
95
90
90
4
5
6
Salicylic acid
Salicylic acid
Salicylic acid
Allyl bromide
Benzyl bromide
Ethyl bromoacetate
10
10
20
2-Allyloxybenzoic acid
2-Benzyloxybenzoic acid
2-O-(Ethoxycarbonylmethyl)benzoic
acid
95
90
80
7
8
Salicylic acid
2-Hydroxynaphthoic acid
1-(2-Chloroethyl)piperidine
1-(2-Chloroethyl)piperidine 240
60
2-O-(2-Piperidin-1-yl-ethyl)benzoic acid
2-O-(2-Piperidin-1-yl-ethyl)naphthoic
acid
65
90
9
10
11
12
4-Hydroxyphenylacetic acid
4-Nitrophenol
4-Hydroxyacetophenone
4-Hydroxy-3-methoxybenzaldehyde
oxime
Benzyl bromide
Benzyl bromide
Benzyl bromide
Benzyl bromide
30
450
450
400
4-Benzyloxyphenylacetic acid
4-Benzyloxynitrobenzene
4-Benzyloxyacetophenone
4-Benzyloxy-3-methoxybenzaldehyde
oxime
93
95
90
85
13
14
a
4-Hydroxybenzaldehyde oxime
4-Cyanophenol
Benzyl bromide
Benzyl bromide
400
10
4-Benzyloxybenzaldehyde oxime
4-Benzyloxybenzonitrile
65
90
Yields refer to isolated yield.
Anal. Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C,
73.65; H, 5.33.
C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C, 70.01;
H, 5.86; N, 5.41.
4.5. 1-Benzyloxy-4-nitrobenzene
4.2. 2-Benzyloxy-1-naphthoic acid
White solid, mp 90–93 °C; FT-IR (KBr, cmÀ1): 3429,
3082, 1764, 1592, 1511, 1H NMR (200 MHz, CDCl3–
CCl4): d 8.21–6.96 (m, 9H, ArH), 5.14 (s, 2H, –OCH2);
13C NMR (50 MHz, CDCl3–CCl4): d 164.00, 142.15,
135.90, 129.19, 128.89, 127.83, 126.28, 115.21, 71.04;
MS(ESI): 230 (M+H+); Anal. Calcd for C13H11NO3: C,
68.11; H, 4.84; N, 6.11. Found: C, 68.10; H, 4.86; N, 6.09.
White solid, mp 77–80 °C; FT-IR (KBr, cmÀ1): 3745,
3395, 2714, 2092, 1647, 1518; 1H NMR (200 MHz,
CDCl3–CCl4): d 8.76 (d, J = 8.7 Hz,1H, ArH), 7.89–7.32
(m, 9H, ArH), 7.14 (d, J = 9.0 Hz, 1H, ArH), 5.55 (s,
2H, –OCH2); 13C NMR (50 MHz, CDCl3–CCl4): d 172.5,
165.09, 137.31, 135.69, 132.31, 129.46, 129.17, 129.06,
128.96, 128.88, 128.82, 125.77, 123.97, 119.75, 104.99,
67.85; MS(ESI): 279 (M+H+); Anal. Calcd for C18H14O3:
C, 77.68; H, 5.07. Found: C, 77.65; H, 5.09.
4.6. Benzyloxyacetophenone
Colorless oil, FT-IR (neat) cmÀ1: 3745, 3034, 1742,
1684, 1517; H NMR (200 MHz, CDCl3–CCl4): d 7.55–
1
4.3. 4-Benzyloxyphenylacetic acid
7.17 (m, 9H, ArH), 5.09 (s, 2H, –OCH2), 2.57 (s, 3H,
–COCH3); 13C NMR (50 MHz, CDCl3–CCl4): d 197.76,
159.39, 138.95, 136.91, 129.96, 129.02, 128.50, 127.91,
121.68, 120.68, 113.8, 70.54, 27.01; MS(ESI): 227
(M+H+); Anal. Calcd for C15H14O2: C, 79.62; H, 6.24.
Found: C, 79.60; H, 6.27.
White solid, mp 110 °C; FT-IR (KBr, cmÀ1): 3376, 3042,
2373, 1712, 1615, 1519; 1H NMR (200 MHz, CDCl3–
CCl4): d 7.31–6.08 (m, 9H, ArH), 5.11 (s, 2H, –OCH2),
3.56 (s, 2H, –COCH2); 13C NMR (50 MHz, CDCl3–
CCl4): d = 172.84, 155.50, 136.07, 130.84, 128.97, 128.69,
128.58, 125.81, 116.01, 67.22, 40.89; MS(ESI): 243
(M+H+); Anal. Calcd for C15H14O3: C, 74.36; H, 5.82.
Found: C, 74.34; H, 5.85.
4.7. 2-O-(2-Piperidin-1-yl-ethyl)-benzoic acid
1
Yellow oil, IR (neat) cmÀ1: 2936, 1676, 1300; H NMR
4.4. 4-Benzyloxy-3-methoxybenzaldehyde oxime
(200 MHz, CDCl3–CCl4): 7.79 (dd, 1H, J = 7.9 Hz, 1.5Hz,
1H, ArH), 7.47–6.82 (m, 3H, ArH), 4.46 (t, 2H, J = 6.0 Hz,
2H, OCH2), 2.74 (t, 2H, J = 6.0 Hz, NCH2), 2.52–2.47 (m,
4H, 2 Â CH2), 1.65–1.55 (m, 4H, 2 Â CH2), 1.49–1.45 (m,
2H, CH2); 13C NMR (50 MHz, CDCl3–CCl4): 170.1,
162.0, 135.9, 130.3, 119.4, 118.0, 63.2, 57.5, 55.1, 26.3,
24.5; MS (ESI): 250 (M+H+); Anal. Calcd for
C18H21NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.25;
H, 7.72; N, 5.65.
White solid, mp 97–102 °C; FT-IR (KBr, cmÀ1): 3763,
3296, 2931, 1810, 1590, 1515; 1H NMR (200 MHz,
CDCl3–CCl4): d 8.03 (s, 1H, –CH), 8.43–6.84 (m, 8H,
ArH), 5.15 (s, 2H, –OCH2), 3.92 (s, 3H, –OCH3); 13C
NMR (50 MHz, CDCl3–CCl4): d = 150.36, 137.08,
128.99, 128.36, 127.61, 125.71, 121.89, 113.72, 109.03,
71.24, 56.2; MS(ESI): 258 (M+H+); Anal. Calcd for

698
J. Pandey et al. / Tetrahedron Letters 49 (2008) 695–698
4.8. 2-O-(2-Piperidin-1-yl-ethyl)-naphthoic acid
respectively. Financial assistance from DRDO, New Delhi
as a Project ERIP/ER/0502127/M/01/857 and ICMR,
New Delhi, is gratefully acknowledged.
Yellow oil, IR (neat) cmÀ1: 2934, 1660, 1257; H NMR
(200 MHz, CDCl3–CCl4): 8.39 (d, 1H, J = 7.8 Hz, 1.5 Hz,
ArH), 7.76–7.72 (m, 2H, ArH), 7.62–7.47 (m, 2H, ArH),
7.24 (d, J = 7.8 Hz, 1H, ArH), 4.51 (t, J = 6.0 Hz, 2H,
OCH2), 2.78 (t, J = 6.0 Hz, 2H, NCH2), 2.56–2.51 (m,
4H, 2 Â CH2), 1.67–1.46 (m, 6H, 3 Â CH2), 13C NMR
(50 MHz, CDCl3–CCl4): 171.1, 161.3, 137.58, 129.71,
126.07, 125.25, 124.71, 124.37, 118.92, 106.51, 63.30,
57.58, 55.21, 26.31, 24.55; MS (ESI): 300 (M+H+); Anal.
Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found:
C, 72.00; H, 7.12; N, 4.65.
1
References and notes
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4.9. 1-Pentyloxynaphthalene-2-carboxylic acid
Solid, mp 50–52 °C; IR (KBr) cmÀ1: 2935, 1659, 1339;
1H NMR (200 MHz, CDCl3–CCl4): 8.41 (d, 1H,
J = 8.0 Hz, ArH), 7.76–7.71 (m, 2H, ArH), 7.60–7.44 (m,
2H, ArH), 4.36 (t, 2H, J = 6.6 Hz, OCH2), 1.87–1.74 (m,
2H, CH2), 1.45–1.30 (m, 4H, 2 Â CH2), 0.94 (t, J =
6.9 Hz, CH3); 13C NMR (50 MHz, CDCl3 + CCl4): 171.4,
161.4, 137.5, 129.6, 127.7, 126.0, 125.2, 124.6, 124.3,
118.8, 106.1, 65.7, 28.7, 28.5, 22.7, 14.4; MS (ESI): 258
(M+H+); Anal. Calcd for C16H17O3: C, 74.39; H, 7.02.
Found: C, 74.37; H, 7.09.
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4.10. 1-Ethoxycarbonylmethoxynaphthalene-2-carboxylic
acid
Solid, mp 69–70 °C; IR (KBr) cmÀ1: 3449, 1736; 1H
NMR (200 MHz, CDCl3–CCl4): 8.40 (d, 1H, J = 8.0 Hz,
ArH), 7.84–7.72 (m, 2H, ArH), 7.63–7.50 (m, 2H, ArH),
7.26 (d, 1H, J = 10.6 Hz), 4.88 (s, 2H, OCH2CO), 4.29
(q, 2H, J = 7.2 Hz, OCH2), 1.31 (t, J = 7.2 Hz, CH3); 13C
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129.9, 127.8, 127.8, 126.1, 125.1, 124.6, 124.4, 119.1,
105.3, 61.9, 61.5, 14.5. MS (ESI): 259 (M+H+); Anal.
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Acknowledgments
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