Chemoselective etherification of benzyl alcohols using 2,4,6-trichloro-1,3, 5-triazine and methanol or ethanol catalyzed by dimethyl sulfoxide

Article abstract of DOI:10.1055/s-0028-1083184

An efficient method for the transformation of benzyl alcohols into their methyl or ethyl ethers has been established using 2,4,6-trichloro-1,3,5-triazine (TCT) and dimethyl sulfoxide in methanol or ethanol. This procedure chemoselectively converts benzylic hydroxys into their methyl or ethyl ethers in the presence of aliphatic or phenolic hydroxys. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083184

PAPER
3487
Chemoselective Etherification of Benzyl Alcohols Using 2,4,6-Trichloro-1,3,5-
triazine and Methanol or Ethanol Catalyzed by Dimethyl Sulfoxide
Etherification
o
i
f
Benzy
l
l
A
lc
o
i
hols Using T
C
S
T
C
atalyzed
uby DMSO n, Yuping Guo, Guisheng Peng, Chunbao Li*
Department of Chemistry, College of Science, Tianjin University, 300072 Tianjin, P. R. of China
Fax +86(22)27403475; E-mail: lichunbao@tju.edu.cn
Received 4 June 2008; revised 22 July 2008
ethanol (5 mL) to a solution of benzyl alcohol (1 equiv)
and TCT (1.2 equiv) in dry methanol or ethanol (5 mL).
Abstract: An efficient method for the transformation of benzyl al-
cohols into their methyl or ethyl ethers has been established using
2,4,6-trichloro-1,3,5-triazine (TCT) and dimethyl sulfoxide in
methanol or ethanol. This procedure chemoselectively converts
benzylic hydroxys into their methyl or ethyl ethers in the presence
of aliphatic or phenolic hydroxys.
It is apparent from Table 1 that ether formation coincides
quite favorably with what would be expected from the
structures of the benzyl alcohols in terms of the ease of
carbocation formation. Most of the alcohols in Table 1
were converted into their methyl or ethyl ethers in moder-
ate to high yields under our conditions. For cinnamyl al-
cohol (Table 1, entry 8), the formation of the carbocation
is not as easy as the other benzyl alcohols bearing elec-
tron-donating groups, which results in a prolonged reac-
tion time (18 h) and a small amount of chloride byproduct.
A definite trend towards decreased yields and prolonged
times was observed from the formation of methyl and eth-
yl ethers (Table 1, entries 1 and 4 vs entries 10 and 11).
This effect could well be a manifestation of the progres-
sive decrease in the dielectric constant (32.63 and 24.3 for
MeOH and EtOH, respectively)10 and consistent with the
carbocation mechanism (Scheme 2). When the elimina-
tion reaction competed with etherification, the yield of the
desired ether could be increased by performing the reac-
tion at lower temperature (Table 1, entry 9). Under our re-
action conditions, the desired ethers could be prepared
starting from acid-labile substrates (Table 1, entries 2 and
6) although in moderate yield for Table 1, entry 6.
Key words: benzyl alcohols, chemoselectivity, ethers, sulfoxide,
2,4,6-trichloro-1,3,5-triazine
Ethers are of great importance as intermediates and prod-
ucts in organic synthesis, and the conversion of alcohols
into ethers is one of the most important synthetic proce-
dures.1 Frequently used methods for the transformation of
alcohols to ethers are the reactions of alcohols or their
salts with different alkylating reagents, such as alkyl
halides,2 diazomethane,3 and methyl trifluoromethane-
sulfonate.4 The dehydration of alcohols using protonic
acids5 (H3PO4 and H2SO4), Lewis acids6 [ZnCl2,
Mg(ClO4)2, FeCl3, and Fe(ClO4)3], iodine,7 and dimethyl
sulfoxide at high temperature8 has also been reported.
However, each method has certain limitations with regard
to scope and reaction conditions.5a,9
In our research into the chlorination of benzyl alcohols, it
was found that 4-methoxybenzyl alcohol could be con-
verted into its methyl ether in excellent yield by treatment
of the alcohol with 2,4,6-trichloro-1,3,5-triazine (TCT)
and dimethyl sulfoxide in dry methanol. Therefore, it be-
came of interest to study this ether-forming reaction with
other benzyl alcohols.
Most interestingly, the method is clearly inefficient for
aliphatic alcohols, in which the carbocation can not be
formed as easily as in benzyl alcohols. This provides a
chemoselective etherification of benzylic hydroxys in the
presence of aliphatic or phenolic hydroxys (Table 2 and
Scheme 1). For the substrates in Table 2 and Scheme 1,
all the benzylic hydroxys were converted into methyl or
ethyl ethers while the aliphatic or phenolic hydroxys were
left intact.
Table 1 summarizes some mixed ethers synthesized by
this procedure. Although dimethyl sulfoxide was shown
to be a catalyst by the conversion of 4-methoxybenzyl al-
cohol (Table 1, entry 1) into its methyl ether using 0.1
equiv of dimethyl sulfoxide, the best results were obtained
when it was used in an approximately equimolar amount.
A decreased amount of TCT caused longer reaction times
and lower yields. Portionwise addition of dimethyl sulf-
oxide in methanol to the mixture of benzyl alcohol and
TCT in methanol gave better results than addition as one
portion. Thus, the procedure was based on portionwise ad-
dition of dimethyl sulfoxide (1 equiv) in dry methanol or
Using the above procedure, we converted 2-(hydroxy-
methyl)estradiol
into
2-(methoxymethyl)estradiol
(Scheme 1), which was previously synthesized from es-
tradiol through a five-step procedure with protection and
deprotection steps in the research of its effect as an inhib-
itor of tubulin polymerization and for cytotoxicity.11 The
five-step synthetic route to 2-(methoxymethyl)estradiol
was shortened to a three-step route using our procedure
without protection and deprotection steps (Scheme 1).12,13
This makes it much easier to prepare the target compound
for biological tests.
SYNTHESIS 2008, No. 21, pp 3487–3491
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Advanced online publication: 16.10.2008
DOI: 10.1055/s-0028-1083184; Art ID: F12508SS
© Georg Thieme Verlag Stuttgart · New York
In order to verify our assumption that the reaction pro-
ceeds with the formation of a carbocation intermediate,

3488
L. Sun et al.
PAPER
Table 1 Preparation of Methyl or Ethyl Ethers from Benzyl Alcohols Using TCT and Dimethyl Sulfoxidea
Entry
1
Substrate
Product
Timeb
Yield (%)
OH
OMe
3 h (9 hc)
91 (79c)
MeO
MeO
OMe
OH
2
5 h (12 hc)
94 (75c)
O
O
O
O
OH
OMe
3d
5 h
62
OBn
OBn
OH
OMe
OMe
4
5
6
15 min
25 min
30 min
77
91
40
MeO
MeO
OH
BuO
BuO
OH
OMe
TBDMSO
TBDMSO
OH
OMe
7
1.5 h
69
8e
9f
18 h
4 h
55
OH
OMe
OH
OMe
80 (7g)
OH
OH
OEt
OEt
10
11
7.5 h
75
69
MeO
MeO
MeO
MeO
20 min
a To a mixture of alcohol (1 equiv) and TCT (1.2 equiv) in anhyd MeOH or EtOH was added DMSO (1 equiv) in anhyd MeOH or EtOH por-
tionwise.
b Time for complete disappearance of alcohols. The reactions were worked up 4 hours later for an easier separation of products.
c Catalyzed by 0.1 equiv of DMSO.
d The reaction was performed at the reflux temperature of MeOH.
e Plus 5% of cinnamyl chloride and 27% recovered cinnamyl alcohol.
f The reaction was performed at 0 °C.
g Yield of elimination product.
we treated an optically active alcohol, (S,E)-4-phenylbut- of neutral nucleophiles such as methanol and ethanol in
20
3-en-2-ol, [a]D –32.1 (c 0.018, CHCl3) with TCT and higher concentration can exceed that of negatively
dimethyl sulfoxide in methanol. It was observed that race- charged nucleophiles such as chloride in lower concentra-
mization occurred under our reaction conditions. This is tion.
also in agreement with the results reported by Salehi et
In conclusion, a new method for the transformation of
al.6c On the basis of the above experiments, a plausible
benzyl alcohols into their methyl or ethyl ethers has been
mechanism is proposed (Scheme 2). The adduct I of TCT
developed using 2,4,6-trichloro-1,3,5-triazine (TCT) and
and dimethyl sulfoxide reacts with the benzyl alcohol to
dimethyl sulfoxide. The procedure reported herein is op-
form a dimethyl alkoxysulfonium salt II, which decom-
erationally simple, and requires inexpensive and commer-
cial available reagents. This procedure has been proven to
poses to form carbocation III and regenerate dimethyl
sulfoxide. Nucleophilic attack of methanol or ethanol on
be chemoselective for benzylic hydroxys in the presence
III produces the methyl or ethyl ether, respectively. This
of aliphatic or phenolic hydroxys, which constitutes a use-
reaction also demonstrates that the substitution capability
ful tool for medicinal and organic chemistry.
Synthesis 2008, No. 21, 3487–3491 © Thieme Stuttgart · New York

PAPER
Etherification of Benzyl Alcohols Using TCT Catalyzed by DMSO
3489
Table 2 Chemoselective Etherification of Benzylic Hydroxys in the Presence of Aliphatic or Phenolic Hydroxysa
Entry
1
Substrate
Product
Timeb
6.5 h
Yield (%)
65
HO
MeO
OH
OH
O
O
OH
OMe
2c
3
5.5 h
5 h
62
71
76
OH
OH
O
O
OMe
OMe
HO
HO
OH
OH
MeO
MeO
OH
OH
O
O
OMe
OMe
4
5 h
O
O
5
6
35 min
45 min
84
84
HO
MeO
OH
OH
O
O
MeO
HO
MeO
HO
OH
OMe
a To a mixture of alcohol (1 equiv) and TCT (1.2 equiv) in anhyd MeOH was added DMSO (1 equiv) in anhyd MeOH portionwise.
b Time for complete disappearance of alcohols. The reactions were worked up 4 hours later for a easier separation of products
c The reaction was performed at the reflux temperature of MeOH.
Cl
N
OH
OH
N
N
O
Ref. 12
Cl
Cl
H
HO
HO
S
N
O
Cl
O
N
S
I
N
Ref. 13
Cl
Cl
OH
OH
TCT,
OH
R1
DMSO
MeOH,
r.t. 1.5 h
Ar
OH
OR2
R1
Cl
H
MeO
HO
HO
II
R2OH
HCl
C
Cl
S
61%
R1
Ar
Ar
O
HO
III
N
N
Ref. 11
Ar
R1
Cl
N
Cl
Scheme 1
Scheme 2
All of the chemicals were obtained from commercial sources or pre-
pared according to standard methods. All the chemicals and sol-
vents used in reactions were dried by standard procedures prior to
use. IR spectra were recorded on a Bio-Rad Exalibur FTS3000
1-Methoxy-4-(methoxymethyl)benzene (Table 1, Entry 1); Typ-
ical Procedure
To a soln of 4-methoxybenzyl alcohol (189 mg, 1.37 mmol) and
TCT (101 mg, 1.64 mmol) in anhyd MeOH (5 mL) was added
DMSO (107 mg, 1.37 mmol) in anhyd MeOH (5 mL) portionwise.
The mixture was stirred at r.t. for 3 h (completion, TLC monitor-
ing). The mixture was added to EtOAc (50 mL) and the organic
phase was washed with H2O (30 mL), sat. NaHCO3 (30 mL), and
brine (30 mL), dried (anhyd Na2SO4), and concentrated in vacuo to
give the crude product which was then purified by chromatography
(silica gel, petroleum ether–Et2O, 8:1) to afford 1-methoxy-4-
(methoxymethyl)benzene (190 mg, 91%).
1
spectrophotometer. The H NMR (500 MHz) and 13C NMR (125
MHz) were recorded on a Varian Oxford 500 spectrometer relative
to TMS (1H) or CDCl3 (13C). MS (EI) were obtained on a Thermo
Finnigan TRACE-DSQ spectrometer. Elemental analyses for C, H
and N were performed on a Yanaco CHNCORNER MF-3 elemental
analyzer, and the analytical results were within 0.4% of the theo-
retical values. All novel compounds were fully characterized, all
known compounds (Table 1, entries 1–5, 7–11;14–20 Table 2, entry
621) were characterized and the data compared to the literature.
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L. Sun et al.
PAPER
2-[2-Methoxy-4-(methoxymethyl)phenoxy]ethanol (Table 2,
tert-Butyl[4-(1-methoxyethyl)phenoxy]dimethylsilane (Table 1,
Entry 6)
Entry 4)
Yield: 99 mg (40%); colorless oil.
Yield: 163 mg (76%); colorless oil.
IR (KBr): 3425, 2957, 2830, 2859, 1609, 1510, 1256, 1117, 1103,
916, 839, 780 cm–1.
IR (KBr): 3448, 2935, 2867, 1593, 1515, 1458, 1420, 1364, 1262,
1235, 1140, 1087, 1033, 905, 810 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.16 (d, J = 8.5 Hz, 2 H), 6.81 (d,
J = 8.5 Hz, 2 H), 4.23 (q, J = 6.4 Hz, 1 H), 3.19 (s, 3 H), 1.41 (d,
J = 6.4 Hz, 3 H), 0.98 (s, 9 H), 0.20 (s, 6 H).
13C NMR (125 MHz, CDCl3): d = 154.9, 136.0, 127.3, 119.8, 79.1,
55.2, 25.6, 23.6, 18.1, –4.4.
MS: m/z (%) = 266 (10, M+), 251 (60), 234 (26), 209 (32), 196 (9),
177 (100), 151 (20).
1H NMR (500 MHz, CDCl3): d = 6.90 (m, 1 H), 6.87 (s, 1 H), 6.84
(dd, J = 1.4 Hz, J = 8.1 Hz, 1 H), 4.39 (s, 2 H), 4.11 (t, J = 4.5 Hz,
2 H), 3.92 (t, J = 4.5 Hz, 2 H), 3.87 (s, 3 H), 3.37 (s, 3 H), 2.77 (br
s, 1 H).
13C NMR (125 MHz, CDCl3): d = 149.6, 147.5, 131.7, 120.3, 114.0,
111.2, 74.4, 71.1, 61.0, 57.8, 55.7.
MS: m/z (%) = 212 (47, M+), 181 (11), 167 (25), 137 (100).
Anal. Calcd for C15H26O2Si: C, 67.61; H, 9.84. Found: C, 67.57; H,
9.86.
Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.11; H,
7.59.
2-[4-(Methoxymethyl)phenoxy]ethanol (Table 2, Entry 1)
Yield: 140 mg (65%); colorless oil.
2-[4-(1-Methoxyethyl)phenoxy]ethanol (Table 2, Entry 5)
Yield: 180 mg (84%); colorless oil.
IR (KBr): 3398, 2924, 2860, 2818, 1611, 1512, 1458, 1364, 1245,
1174, 1083, 1057, 918, 822 cm–1.
IR (KBr): 3419, 2925, 2873, 1608, 1583, 1512, 1461, 1366, 1246,
1096, 1076, 1052, 922, 834 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.26 (d, J = 8.6 Hz, 2 H), 6.90 (d,
J = 8.6 Hz, 2 H), 4.39 (s, 2 H), 4.08 (t, J = 4.5 Hz, 2 H), 3.95 (t,
J = 4.5 Hz, 2 H), 3.36 (s, 3 H), 2.81 (br s, 1 H).
1H NMR (500 MHz, CDCl3): d = 7.23 (d, J = 8.6 Hz, 2 H), 6.91 (d,
J = 8.6 Hz, 2 H), 4.25 (q, J = 6.4 Hz, 1 H), 4.09 (t, J = 4.5 Hz, 2 H),
3.96 (t, J = 4.5 Hz, 2 H), 3.20 (s, 3 H), 1.42 (d, J = 6.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): d = 158.2, 130.6, 129.3, 114.4, 74.2,
69.2, 61.3, 57.7.
13C NMR (125 MHz, CDCl3): d = 158.0, 135.8, 127.3, 114.3, 79.0,
69.1, 61.2, 56.1, 55.2.
MS: m/z (%) = 182 (82, M+), 167 (5), 151 (50), 137 (49), 121 (24),
MS: m/z (%) = 196 (15, M+), 181 (100), 164 (20), 137 (70), 120
107 (100), 89 (18).
(52), 91 (20).
Anal. Calcd for C10H14O3: C, 65.91; H, 7.74. Found: C, 65.96; H,
7.77.
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.44; H,
8.25.
2-[2-(Methoxymethyl)phenoxy]ethanol (Table 2, Entry 2)
Yield: 165 mg (62%); colorless oil.
Acknowledgment
IR (KBr): 3428, 2927, 2877, 1601, 1490, 1450, 1240, 1080, 1050,
915, 750 cm–1.
We thank NSFC (20572078) for financial support.
1H NMR (500 MHz, CDCl3): d = 7.30 (m, 2 H), 6.97 (t, J = 7.3 Hz,
1 H), 6.92 (d, J = 8.2 Hz, 1 H), 4.52 (s, 2 H), 4.18 (t, J = 4.5 Hz, 2
H), 3.88 (t, J = 4.5 Hz, 2 H), 3.38 (s, 3 H).
13C NMR (125 MHz, CDCl3): d = 157.1, 130.2, 129.4, 126.6, 120.9,
113.1, 70.7, 70.5, 61.1, 57.8.
MS: m/z (%) = 182 (78, M+), 167 (35), 137 (100), 133 (35), 121
(60), 107 (60), 106 (72), 91 (45), 78 (56), 77 (28), 45 (30).
References
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Anal. Calcd for C10H14O3: C, 65.91; H, 7.74. Found: C, 65.93; H,
7.71.
2-[2-Methoxy-5-(methoxymethyl)phenoxy]ethanol (Table 2,
Entry 3)
Yield: 153 mg (71%); colorless oil.
IR (KBr): 3423, 2935, 1586, 1517, 1427, 1262, 1236, 1164, 1139,
1086, 1027, 905, 810, 765 cm–1.
1H NMR (500 MHz, CDCl3): d = 6.93 (d, J = 1.8 Hz, 1 H), 6.90 (dd,
J = 1.8 Hz, J = 8.1 Hz, 1 H), 6.84 (d, J = 8.1 Hz, 1 H), 4.37 (s, 2 H),
4.13 (t, J = 4.5 Hz, 2 H), 3.93 (t, J = 4.5 Hz, 2 H), 3.85 (s, 3 H), 3.36
(s, 3 H), 2.65 (br s, 1 H).
13C NMR (125 MHz, CDCl3): d = 149.0, 147.9, 130.8, 121.1, 113.8,
111.2, 74.3, 70.9, 61.0, 57.8, 55.8.
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7.57.
Synthesis 2008, No. 21, 3487–3491 © Thieme Stuttgart · New York

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Etherification of Benzyl Alcohols Using TCT Catalyzed by DMSO
3491
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Synthesis 2008, No. 21, 3487–3491 © Thieme Stuttgart · New York