Solvent-free Williamson synthesis: An efficient, simple, and convenient method for chemoselective etherification of phenols and bisphenols

Article abstract of DOI:10.1080/00397910701316268

Etherification of phenols with dimethyl- and diethylsulfates and benzyl chloride was performed efficiently in the presence of a suitable solid base, NaHCO3 or K2CO3, under solvent-free conditions. The reaction proceeded rapidly at low temperature, and the corresponding ethers were obtained with high purity and excellent yield. Selective etherification of electron-poor phenols in the presence of electron-rich ones and also selective mono-etherification of bisphenols are the noteworthy advantages of this method. This method is environmentally friendly. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701316268

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Solvent‐Free Williamson Synthesis: An
Efficient, Simple, and Convenient Method for
Chemoselective Etherification of Phenols and
Bisphenols
a
a
a
Ahmad R. Massah , Masumeh Mosharafian , Ahamad R. Momeni , Hamid
a
a
b
Aliyan , H. Javaherian Naghash & Mohamad Adibnejad
a
Department of Chemistry, Islamic Azad University, Shahreza Branch,
Shahreza, Isfahan, Iran
b
Department of Chemistry, Islamic Azad University, Falavarjan Branch,
Falavarjan, Isfahan, Iran
Available online: 30 Jun 2007
To cite this article: Ahmad R. Massah, Masumeh Mosharafian, Ahamad R. Momeni, Hamid Aliyan, H.
Javaherian Naghash & Mohamad Adibnejad (2007): Solvent‐Free Williamson Synthesis: An Efficient,
Simple, and Convenient Method for Chemoselective Etherification of Phenols and Bisphenols, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:11,
1807-1815
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Synthetic Communications , 37: 1807–1815, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701316268
Solvent-Free Williamson Synthesis: An
Efficient, Simple, and Convenient Method
for Chemoselective Etherification of Phenols
and Bisphenols
Ahmad R. Massah, Masumeh Mosharafian,
Ahamad R. Momeni, Hamid Aliyan, and
H. Javaherian Naghash
Department of Chemistry, Islamic Azad University, Shahreza Branch,
Shahreza, Isfahan, Iran
Mohamad Adibnejad
Department of Chemistry, Islamic Azad University, Falavarjan Branch,
Falavarjan, Isfahan, Iran
Abstract: Etherification of phenols with dimethyl- and diethylsulfates and benzyl
chloride was performed efficiently in the presence of a suitable solid base,
3 2 3
NaHCO or K CO , under solvent-free conditions. The reaction proceeded rapidly
at low temperature, and the corresponding ethers were obtained with high purity
and excellent yield. Selective etherification of electron-poor phenols in the
presence of electron-rich ones and also selective mono-etherification of bisphenols
are the noteworthy advantages of this method. This method is environmentally
friendly.
Keywords: chemoselective, bisphenols, etherification, phenols, solvent-free
Aromatic ethers are ubiquitous structural units in biologically important
[2]
molecules such as cyclooxygenase inhibitors, b-galactosidase inhibitors,
[1]
Received in the U.K. August 4, 2006
Address correspondence to Ahmad R. Massah, Department of Chemistry, Islamic
Azad University, Shahreza Branch, P. O. Box 86145-311, Shahreza, Isfahan, Iran.
E-mail: massah@iuash.ac.ir
1
807

1
808
A. R. Massah et al.
[
3,4]
and anticancer porphyrines
[
and thus are very important for synthetic
5]
organic chemistry.
Direct nucleophilic substitution of an alkyl halide or other alkylating
agent with phenols and a base in an aprotic solvent are the most useful
[6–12]
[13,14]
[15–17]
methods for the synthesis of aryl ethers.
[
Several Ni-,
substitutions of aryl halide with an alcohol
Cu-,
18–20]
[21]
pd-,
or Fe-catalyzed
were reported. However, these methodologies suffer from one or more disad-
vantages, such as long reaction times, elevated temperatures, and low yields.
Furthermore, selective monoetherification of bisphenols is not easy in the
reactions with solvents and is always inevitably accompanied by bietherified
products. Recently, Fu and coworkers reported the highly selective
vapor-phase O-methylation of catechol with methanol over ZnCl -modified
2
g-Al O catalysts. The reaction was carried out in a fixed-bed reactor at
2
3
5
cathechol and the selectivity for o-methoxy phenol were up to 82 and 91%
53 K and under the optimum reaction conditions; the conversion of
[
22]
respectively.
Solvent-free organic synthesis for the preparation of small molecule
libraries is now routinely applied in pharmaceutical research for the
[
23–26]
discovery and optimization of lead compounds.
tion of phenols that were catalyzed by solid–liquid phase-transfer PEG has
Solvent-free etherifica-
4
00
[
27]
been reported.
In this method, the hydroxyl groups of PEG were alkylated,
and it is more difficult to remove the ethers of PEG. Also, the long reaction
time and high temperature of the reaction are other limitations of this
method. Therefore, introduction of an efficient and selective method for ether-
ification of phenols and bisphenols is of practical importance and is still in
demand. In this article, we report the results that successfully led to the devel-
opment of a novel, simple, and convenient method for the transformation of
phenols, naphthols, and bisphenols to their corresponding ethers.
A variety of aromatic ethers were synthesized from phenols and naphthols
in a solid base at 608C. Dimethylsulfate, diethylsulfate, and benzyl chloride
were used as alkylating agent (Scheme 1). The process in its entirety
involves a simple mixing of phenols with solid base under vigorous stirring
at 608C. Then, an alkylating agent was added, and the progress of the
reaction was monitored by thin-layer chromatography (TLC). The product
was purified by short column chromatography, but in most cases the ethers
were obtained very pure.
Scheme 1.

Solvent-Free Williamson Synthesis
1809
To optimize the best reaction conditions, 4-hydroxy benzaldehyde was
treated with diethylsulfate in the presence of various solid bases in the
absence of any solvent. Complete conversion took place in 20 min when
K CO was used as base. One of the other important factors is the rate of
2
3
mixing of the reaction mixture. However, if the rate of mixing is not high
enough, the yield of product decreases and the reaction time increases.
A series of aromatic ethers were synthesized in the presence of K CO as
2
3
base to study the steric and electronic effects of substituent on phenols and
naphthols during the reaction. The results are summarized in Table 1.
Several points from this table are worth comment. Under the optimized con-
ditions, the etherification reaction was found to be uniformly successful, and
expected ethers were furnished in good yields and purity. The reaction
proceeds well for both electron-rich and electron-poor phenols. However,
quantitative yields of ethers were obtained at lower time during the reaction
of phenols with electron-withdrawing substituents such as 2-bromophenol,
3
-nitrophenol, and 4-hydroxy benzaldehyde (Table 1, entries 13–20). It
must be noted that the competing alkylation of the ring did not occur, and
no ring-alkylated by-product in these reactions was seen.
Based on this observation, we conducted a set of competitive etherification
reactions between electron-rich and electron-poor phenols, the results of which
are shown in Scheme 2. These results show that the presented method is poten-
tially applicable for chemoselective etherification of electron-withdrawing
substituted phenols in the presence of electron-donating substituted ones. To
show the chemoselectivity of the method for the etherification of different
hydroxyl groups, in multifunctional molecules, a number of competitive
reactions were performed on some bisphenols (Table 2). According to the
obtained results, the hydroxyl with stronger acidity was alkylated better,
when the two hydroxyl groups of a bisphenol differ in acidity. For example,
0
the pKa of 2,2 -bisphenol is 8.0 and with a base such as NaHCO , the
1
3
corresponding phenoxide was produced (entry 6). For the conversion of the
second hydroxyl group (pKa ¼ 11.32) to anion, we used K CO as a
2
2
3
stronger base. In this case, the reaction time of the second step was higher
than the first step (entries 7, 8). This is further supported by the fact that we
0
observed a small amount of 2,2 -dimethoxy biphenyl when we used K CO
2
3
as base (Scheme 3). Methylation of 4-hydroxybenzylalcohol showed that
only phenolic hydroxyl group was etherified, and the benzyl hydroxyl group
did not react even in the presence of extra dimethylsulfate, in agreement
with acidity power of hydroxyl groups (entry 5).
In conclusion, a facile route to the etherification of phenols has been
demonstrated. This methodology offers significant advantages over other
current procedures with regard to yields, mild reaction conditions, excellent
chemoselectivity, and easy work-up. The low cost of reagent and the
solvent-free reaction conditions are consistent with increasing environmental
concerns and will make the present method potentially useful for industrial
applications.

a
Table 1. Etherification results of some phenols in K CO at 608C
2
3
Mp (bp)8C
b
[27–29]
Entry
ArOH
ArOR
Time (h)
Yield (%)
Obs.
(156)
Lit.
1
2
3
4
5
6
7
8
9
Phenol
Phenol
1-Naphthol
Methoxy benzene
Ethoxy benzene
3.5
5.0
1.5
2.0
1.0
1.5
5.0
4.5
1.0
1.5
2.0
1.5
0.3
0.5
0.5
0.75
8.0
0.3
0.5
6.0
90
87
88
83
90
86
87
88
82
95
92
80
94
92
90
87
78
98
96
82
(156)
(172–174)
(264–266)
118–119
73–74
(171–173)
(265–266)
118–119
72
1-Methoxy naphthalene
1-Ethoxy naphthalene
2-Methoxy naphthalene
2-Ethoxy naphthalene
1-Naphthol
2-Naphthol
2-Naphthol
37–38
37–38
(188–189)
192
4-Methyl phenol
3-Methyl phenol
1,2-Dihydroxy benzene
1-Ethoxy-4-methyl benzene
1-Ethoxy-3-methyl benzene
1,2-Dimethoxy benzene
(188–190)
(190–192)
(206–207)
153–155
190–192
54–56
(206–207)
155
190
0
0
0
0
10
11
12
13
14
15
16
17
18
19
20
1,1 -Dihydroxy biphenyl
1,1 -Dihydroxy binaphthyl
1,1 -Dimethoxy biphenyl
1,1 -Dimethoxy binaphthyl
1,4-Dimethoxy benzene
1,4-Dihydroxy benzene
2-Bromro phenol
2-Bromo phenol
55–56
(210)
1-Bromo 2-methoxy benzene
1-Bromo 2-ethoxy benzene
1-Methoxy-3-nitro benzene
1-Ethoxy-3-nitro benzene
1-Benzyloxy-3-nitro benzene
4-methoxy benzaldehyde
4-Ethoxy benzaldehyde
(210–211)
(221–223)
37–38
(221–223)
38–39
34
3-Nitro phenol
3-Nitro phenol
3-Nitro phenol
34–36
150–151
(247–248)
(249)
150
(248)
4-Hydroxy benzaldehyde
4-Hydroxy benzaldehyde
4-Hydroxy benzaldehyde
(249)
72–74
4-Benzyloxy benzaldehyde
71–73
a
b
The molar ratio of alkylating agent to phenols, naphthols, or bisphenols was 1.5 for entries 1–8, 2.5 for entries 9–12, and 1.0 for entries 13–20.
Isolated yield.

Solvent-Free Williamson Synthesis
1811
Scheme 2.
EXPERIMENTAL
All chemicals were purchased from Merck and Fluka chemical companies.
Infrared spectra were recorded on Nicolet (impact 400D model) spec-
1
13
trometer. H NMR and C NMR spectra were recorded on Bruker DRX
00 Avance spectrometer. MS analysis was performed using Saturn 2200
specterometer. Column chromatography was performed using silica gel 60
230–400 mesh).
5
(
General Procedure
A phenol or naphthol (2 mmol) and anhydrous base (1 g) were ground
altogether into fine powder and heated at 608C under vigorous stirring.
Alkylating agent (2 mmol) was added and heated under vigorous stirring,
and the progress of reaction was monitored by thin-layer chromatography
(TLC) (by dissolving the sample in ethyl acetate) until the conversion of
phenol was completed. Then, water was added to the mixture, and the
solid ether was filtrated and washed with additional water. In the case of
liquid ethers, the products were extracted with diethyl ether. The solvent
(diethyl ether) was evaporated, and the crude product was purified by
short-column chromatography using petroleum ether–ethylacetate as
eluent or by recrystallization in ethylacetate-n-hexan (in the case of solid
ethers).
The products were characterized by comparison of their melting point,
1 [27–30]
boiling point, IR, and H NMR spectra with those of known compounds,
0
except 2-ethoxy 2 -methoxy biphenyl (Table 2, entry 8), which is a new
compound. Its spectral analytical data is the following.

Table 2. Chemoselective etherification results of some bisphenols
Mp (bp)8C
Lit.
a
[27–30]
Entry
1
ArOH
ArOR
Time (h)
2.0
Yield (%)
82
Condition
Obs.
NaHCO
3
, 508C
32–34
32
2
3
4
1.0
1.0
1.0
78
78
80
K
2
2
CO
CO
3
, 508C
(206–207)
(207–208)
(244)
(206–207)
(207–209)
(244)
K
3
, 508C
NaHCO , 508C
3
5
1.0
88
K CO , 508C
(259)
(259)
2
3

6
7
8
9
1.0
2.5
4.5
5.0
92
90
85
75
NaHCO
3
, rt
74–75
74–75
155
K CO , rt
2
154–155
258–260
152–153
3
K
2
CO
3
, rt
—
b
K
2
CO
3
c
,/
152–153
NaHCO , 108C
3
a
b
c
Isolated yield.
Dimethylsulfate was added slowly over 5.0 h.
0.1gr K
2
CO
3
þ 0.8gr Na HCO
3
.

1
814
A. R. Massah et al.
Scheme 3.
0
2
-Ethoxy 2 -methoxy Biphenyl
White crystals; mp 258–2608C. IR (KBr): 1592, 1482, 1445, 1378, 1253, 1225,
2
1 1
7
58 cm . H NMR (500 MHz, CDCl ): d ¼ 1.31 (t, 3H, J ¼ 7.0 Hz), 3.82
3
(
s, 3H), 4.07 (q, 2H, J ¼ 7.0 Hz), 7.01 (dd, 2H, J ¼ 8.4, J ¼ 1.4 Hz), 7.05
1
2
(
1
t, 2H, J ¼ 7.5 Hz), 7.3 (dd, 2H, J ¼ 7.5, J ¼ 1.7 Hz), 7.33–7.39 (m, 2H).
1 2
3
C NMR(125 MHz, CDCl ): d ¼ 14.84, 55.53, 64.03, 110.83, 112.59,
3
1
1
20.26, 120.39, 128.09, 128.36, 128.45, 128.55, 131.38, 131.56, 156.48,
57.11. MS (m/e): 228 [M ], 213, 200, 185, 169, 77. Anal. calcd. for
þ
C H O : C, 78.92; H, 7.06; O, 14.02. Found: C, 79.04; H, 7.12; O, 14.06.
15 16 2
ACKNOWLEDGMENT
We appreciate partial support from the Islamic Azad University of Shahreza
Research Council.
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