A convenient method for the preparation of alkyl aryl sulfides from alcohols and (chloromethylene)dimethylammonium chloride

Article abstract of DOI:10.1246/cl.2005.1612

(Chloromethylene)dimethylammonium chloride (Vilsmeier reagent), prepared easily from DMF and oxalyl chloride, works as an efficient condensation reagent for the thioetherification of alcohols in one-pot under mild conditions. Various alcohols are successively converted into the corresponding sulfides with inversion of configurations in moderate to high yields. Copyright

Full text of DOI:10.1246/cl.2005.1612

1612
Chemistry Letters Vol.34, No.12 (2005)
A Convenient Method for the Preparation of Alkyl Aryl Sulfides from Alcohols
and (Chloromethylene)dimethylammonium Chloride
Yoshikazu Kawano,y;yy Nobuya Kaneko,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received September 21, 2005; CL-051206)
Table 1. Effect of bases
ClHC N+Me2 Cl−
(1.5 equiv.)
(Chloromethylene)dimethylammonium chloride (Vilsmeier
reagent), prepared easily from DMF and oxalyl chloride, works
as an efficient condensation reagent for the thioetherification of
alcohols in one-pot under mild conditions. Various alcohols are
successively converted into the corresponding sulfides with
inversion of configurations in moderate to high yields.
N
N
OH
Me
(1.5 equiv.)
99 %ee
SH
+
S
S
Base (3.0 equiv.)
THF, rt, 4 h
S
Ph
(1.0 equiv.)
Ph
Me
Yield/%a
Yield/%a
(% ee)b
Base
NEt3
Entry
1
Entry
4
Base
CsF
(% ee)b
87
(99)
N.D.
Preparation of alkyl aryl sulfides from alcohols is a versatile
synthetic method in organic chemistry and several useful prepa-
rative methods have been reported. Among them, oxidation–
reduction condensation using trivalent phosphorus compounds
such as Ph3P-DEAD-RSH (Mitsunobu reaction) is considered
one of the most important and fundamental reaction because it
is so useful in constructing chiral centers via the inversion of
configuration by SN2 displacement. Many examples for the prep-
aration of various sulfides from alcohols have accordingly been
reported thereafter.1 However, these conventional methods leave
following synthetic problems: (i) isolation of the desired product
from co-products such as triphenylphosphine oxide or diethyl
hydrazinedicarboxylate is often difficult. (ii) Azodicarboxylate
such as diethyl azodicarboxylate is a hazardous compound.
Therefore, it is still an important topic to develop more efficient
and convenient procedure for the preparation of various sulfides.
(Chloromethylene)dimethylammonium chloride, prepared
easily by the chlorination of an amide, has frequently been used
as a formylating reagent or a reagent to activate carboxylic acid
for the formation of esters and amides. In spite of their powerful
ability to dehydrate carboxylic acids, however, only a few exam-
ples have been reported on the methods to dehydrate from an al-
coholic moiety.2 Of few examples, Barrett et al. reported that
secondary alcohols could be converted into the corresponding
esters by an inverted fashion with Vilsmeier reagents and potas-
sium benzoate.2a Also, Fujisawa et al. reported on the synthesis
of alkyl chlorides from alcohols by using the iminium salts.2c
In this communication, we would like to describe a conven-
ient method for the preparation of alkyl aryl sulfides from
various primary, secondary, and tertiary alcohols via (alkoxy-
methylene)dimethylammonium chloride under mild conditions
(Scheme 1).
DBU
5
6
K2CO3
57
(11)
2
3
51
(96)
Pyridine
Cs2CO3
52
(35)
32
(84)
aIsolated yields. bDetermined by HPLC using Daicel CHIRAL-
CEL OD-H (See Ref. 4).
In the first place, effects of bases were examined by taking a
thioetherification of (R)-(þ)-1-phenylethyl alcohol that used 1.5
equivalents of Vilsmeier reagent in THF at room temperature
(Table 1).3 Then, triethylamine was found to be a suitable base
and the corresponding sulfide was obtained in good yields while
DBU or pyridine was not effective. Next, insoluble solid bases
were tried as the scavenger of hydrogen chloride because they
trap the liberated hydrogen chloride. However, neither potassi-
um nor cesium carbonate was effective under these conditions.
It is noteworthy to point out that the reaction proceeded with
clean inversion of configuration in spite of the easily epimeriza-
ble substrate.
Next, the reaction of (R)-(þ)-1-phenylethyl alcohol with
several thiols was tried (Table 2). In the case of sufficiently acid-
ic aryl thiols such as heteroaryl thiols or electron-withdrawing
Table 2. Thioetherification of (R)-(þ)-1-phenylethyl alcohol
using various thiols
OH
Me
ClHC N+Me2 Cl−
(1.5 equiv.)
SAr
Me
ArSH
+
Ph
Ph
Et3N (3.0 equiv.)
THF, rt, 4 h
1 (1.5 equiv.)
2 (1.0 equiv.)
Yield/%a
(% ee)
3
Yield/%a
(% ee)
Entry
ArSH
Entry
ArSH
N
51b
(81)
75b
(98)
87
(99)
Cl−
H
5
6
1
3a
3e
3f
SH
SH
SH
S
N
O
ClHC N+Me2 Cl−
Base
Me
OH
R'
SAr
R'
+
N
ArSH
88
(99)
O
2
3b
Cl
SH
R
R
Me
R
R'
78
(97)
81
(99)
O2N
SH
SH
7
8
COSH
3
4
3c
3g
3h
DMF
+
91
(98)
83
(99)
3d
AcSH
Inversion
N
aIsolated yields. bThe reaction time was 20 h.
Scheme 1. Preparation of alkyl aryl sulfides from alcohol.
Copyright ꢀ 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.12 (2005)
1613
Table 3. Thioetherification of various alcohols
ArS−
path A
Cl−
path B
Me
H
ClHC N+Me2 Cl−
N
Ar
S
Cl Cl−
+
OH
R'
N
path A
(1.5 equiv.)
SH
Ph
O
Cl−
+
S
S
Me
R
Ph
Me
S
+
N
Et3N (3.0 equiv.)
THF, rt, 4 h
H
N
Me
(1.5 equiv.)
(1.0 equiv.)
R
R'
Me
inversion
Me
Yield/%a
(% ee)
Yield/%a
(% ee)
4
Entry
RR'OH
Entry
7
RR'OH
path B
Ar
ArS−
Me
S
OH
1
2
91
87
86b
Cl
Ph
O
OH
Ph
Me
Ph
Me
retention
OH
8
87
Ph
OH
Scheme 2.
(99)
Me
path B gives the corresponding sulfide with partial inversion
of configuration.
3
9
81b
(99)
90b
94
Ph
OH
OH
PhCH2CH2
OH
Thus, a convenient method for the preparation of inverted
alkyl aryl sulfides from various chiral alcohols was established
by using readily available Vilsmeier reagent under mild condi-
tions. Further investigations on the preparation of the iminium
salts and their application to various dehydration reactions are
now in progress.
Me
Ph
Me
4
10
82
(97)
EtO2C
OH
Me
O
Me
Me
OH
81c
70b
84b
5
6
11
12
EtO2C
O
OH
Me
Et
N.D.
TBSO
OH
BnO2C
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
OH
aIsolated yields. bThe reaction time was 16 h. cReaction was
carried out in toluene at 60 ꢁC.
References and Notes
thiophenols were used, the reaction proceeded to afford the cor-
responding sulfides at room temperature in good yields with al-
most complete inversion of stereochemistries (Entries 2–6).4,5
When benzenethiol was used, however, the desired thioether
was obtained in 51% yield with 81% ee (Entry 1). Further, the
reactions proceeded smoothly and gave the corresponding thio-
esters in good yields with complete inversions when thiocarbox-
ylic acids were used as a substrate (Entries 7 and 8).
Thioetherification of various alcohols under the optimized
conditions are summarized in Table 3. The reactions of primary
and secondary alcohols proceeded smoothly and afforded the de-
sired sulfides even when ethyl ester and tert-butyldimethylsilyl
groups coexisted in the same molecule (Entries 1–10). Next,
the stereo-course of the present reaction was studied by using
chiral secondary alcohols and the desired 2-benzothiazolyl sul-
fides were then obtained with virtually complete inversion of
configurations (Entries 8–10). Further, an alcohol having an es-
ter group at the quaternary centers was smoothly transformed in-
to the sulfide in good yield (Entry 11). On the other hand, no
similar reaction proceeded when a more hindered chiral tertiary
alcohol was used as a substrate (Entry 12).
A proposed reaction mechanism is illustrated in Scheme 2.
In the first place, (chloromethylene)dimethylammonium chlo-
ride reacts with (R)-(þ)-1-phenylethyl alcohol to form the ad-
ducts 4 through addition and elimination processes. In the next
step, two different pathways may possibly be considered: that
is, i) when sufficiently acidic aryl thiols were used as substrates,
the nucleophilic attack of the thiolate anions takes place at the
benzylic carbon of the salt 4 and forms the corresponding sul-
fides with inversion of configurations via path A, or ii) when
the nucleophilicity of the thiol was not sufficient, rate of the re-
action is slow. Therefore, the salt 4 competitively reacts with the
chloride ion and the following thioetherification with thiol via
1
a) K. Ikegai, W. Pluempanupat, and T. Mukaiyama, Chem. Lett.,
34, 638 (2005). b) T. Mukaiyama and K. Ikegai, Chem. Lett., 33,
1522 (2004). c) J. R. Falck, J.-Y. Lai, S.-D. Cho, and J. Yu,
Tetrahedron Lett., 40, 2903 (1999). d) D. L. Hughes, Org. Prep.
Proced. Int., 28, 127 (1996). e) H. Kotsuki, K. Matsumoto,
and H. Nishizawa, Tetrahedron Lett., 32, 4155 (1991). f) I.
Nakagawa, K. Aki, and T. Hata, J. Chem. Soc., Perkin Trans.
1, 1983, 1315. g) T. Mukaiyama, S. Ikeda, and S. Kobayashi,
Chem. Lett., 1975, 1159.
2
3
For the reactions using iminium salts: a) A. G. M. Barrett, N.
Koike, and P. A. Procopiou, J. Chem. Soc., Chem. Commun.,
1995, 1403. b) P. A. Procopiou, A. C. Brodie, M. J. Deal, and
D. F. Hayman, Tetrahedron Lett., 1993, 7483. c) T. Fujisawa,
T. Mori, K. Fukumoto, and T. Sato, Chem. Lett., 1982, 1891.
Typical experimental procedure is as follows (Table 1, Entry 1):
to a stirred solution of DMF (117 mL, 1.37 mmol) in dry CH2Cl2
(3.0 mL) were added dropwise oxalyl chloride (108 mL, 1.24
mmol) at 0 ꢁC under argon atmosphere. The mixture was stirred
for 5 min at the same temperature and solvent was evaporated.
The obtained white solid was cooled down to 0 ꢁC and suspend-
ed in dry THF. (R)-(þ)-Phenylethyl alcohol (151.2 mg, 1.24
mmol) and triethylamine (346.7 mL, 2.49 mmol) and 2-mercap-
tobenzothiazole (138.7 mg, 0.83 mmol) were added sequential-
ly. The reaction mixture was stirred for 4 h at room temperature.
After completion of the reaction, it was quenched with water.
The mixture was extracted with AcOEt and the organic layer
was washed with brine and dried over anhydrous Na2SO4,
filtrated and concentrated. The crude product was purified by
preparative TLC to afford the desired product (196.2 mg,
87%) as colorless prisms.
4
5
Enantiomeric purity for thioether 3e was determined by HPLC
(CHIRALCEL OD-H, hexane/iPrOH = 50:1, flow rate = 1.0
mL/min): tR = 7.7 min.
The absolute configurations of 3b–3g were determined by
comparing with configuration of products, which were prepared
via our procedure.1a,1b
Published on the web (Advance View) October 29, 2005; DOI 10.1246/cl.2005.1612