A new method for the preparation of alkyl aryl sulfides from alcohols via alkoxydiphenylphosphines by oxidation-reduction condensation

Article abstract of DOI:10.1246/cl.2004.1522

A new method for the preparation of alkyl aryl sulfides from alcohols via alkoxydiphenylphosphines by oxidation-reduction condensation was established. Various primary, secondary, and tertiary alcohols were successfully converted into the corresponding su

Full text of DOI:10.1246/cl.2004.1522

1522
Chemistry Letters Vol.33, No.11 (2004)
A New Method for the Preparation of Alkyl Aryl Sulfides from Alcohols via
Alkoxydiphenylphosphines by Oxidation–Reduction Condensation
Teruaki Mukaiyamaꢀy;yy and Kazuhiro Ikegaiy;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 August 3, 2004; CL-040918)
A new method for the preparation of alkyl aryl sulfides from
Table 1. Thioetherification of 3-phenyl-1-propanol via 1a
using various disulfides
alcohols via alkoxydiphenylphosphines by oxidation–reduction
condensation was established. Various primary, secondary, and
tertiary alcohols were successfully converted into the corre-
sponding sulfides in moderate to high yields.
RSSR
(1.0 equiv.)
ClPPh2
nBuLi
R'OH
R'OPPh2
1a
(1.1 equiv.)
R' SR
CHCl3 (0.2 M)
r.t.
R' = Ph(CH2)3
RSSR
R
RSSR
R
Entry
Time /h Yield /% Entry
Time /h Yield /%
To prepare alkyl aryl sulfides is one of the important syn-
thetic problem in organic1 and medicinal chemistry,2 and there-
fore many trials have been made to develop its synthetic meth-
ods. Of the methods, conversion of alcohols into alkyl aryl sul-
fides by oxidation–reduction condensation using phosphorus re-
agent systems3 such as Ph3P–DEAD–RSH3a or n-Bu3P–
RSSR3b,c is considered useful. Though the phosphorus reagents
showed powerfulness and broad substrate generality, thioetheri-
fication of tertiary alcohols still remained a difficult problem
even when tert-butyl alcohol was used.3b–e
Recently, a new type of oxidation–reduction condensation
using alkoxydiphenylphosphines, 2,6-dimethyl-1,4-benzoqui-
none (DMBQ), and carboxylic acids was reported from our lab-
oratory and various alkyl carboxylates were prepared from alco-
hols including chiral tertiary ones in good to high yields with in-
version of configurations in high levels (up to >99.9% inver-
sion).4 This method was further applied to the synthesis of
symmetrical/unsymmetrical dialkyl ethers by using tetra-
fluoro-1,4-benzoquinone as an oxidant.5 As a constitution to
our investigation on this novel oxidation–reduction condensa-
tion, we would like to describe here a new synthetic method of
alkyl aryl sulfides from primary, secondary, and tertiary alcohols
via alkoxydiphenylphosphines. As shown in Scheme 1, it was as-
sumed that the alkoxydiphenylphosphines 1 derived from lithiat-
ed alcohols and chlorodiphenylphosphine (ClPPh2)6 were read-
ily transformed into the inverted sulfides 2 on treatment with di-
aryl disulfides or with arylthiols and DMBQ via the phosphoni-
um salt intermediates.
1
2
3
4
Ph
20
55
68
74
72
5
6
7
8
4-NO2-Ph 20
78
77
89
90
4-Me-Ph 20
4-Cl-Ph 20
2-NO2-Ph 20
Py
Bt
Box
3
0.5
0.5
N
N
N
O
Py =
Bt =
Box =
S
Table 2. Thioetherification of (l)-menthol via 1b
BtSSBt
ClPPh2
nBuLi
iPr
iPr
(or BtSH, DMBQ)
(l)-menthol
CHCl3
r.t., 15 h
OPPh2
SBt
1b
Entry
1
Reagents /equiv.
1b /equiv. Conc. /M Yield /%
BtSSBt (1.0)
1.1
1.1
1.5
1.5
2.0
0.2
0.2
0.2
1.5
1.5
48
44
66
77
96
2
3
4
5
BtSH (1.0), DMBQ (1.1)
BtSH (1.0), DMBQ (1.5)
BtSH (1.0), DMBQ (1.5)
BtSH (1.0), DMBQ (2.0)
diaryl disulfides was tried (Table 1). Substituted diphenyl disul-
fide derivatives reacted in chloroform smoothly with 1a at room
temperature to give the corresponding sulfides in good yields
within 24 h (Entries 1–5), as expected. It is interesting to note
that 2,20-dibenzothiazolyl disulfide and its bezoxazolyl deriva-
tive were much more reactive than diphenyl disulfide and that
the desired sulfides were provided in high yields within 30 min
or less whereas the reaction proceeded relatively slower with
2,20-dipyridyl disulfide (Entries 6–8).
Next, thioetherification of more hindered alkoxydiphenyl-
phosphine 1b6 derived from (ꢁ)-(l)-menthol was tried (see
Table 2). When 1.1 equiv. of 1b and 1.0 equiv. of 2,20-dibenzo-
thiazolyl disulfide were used, the desired sulfide was obtained
only in 48% yield with complete inversion at the reaction center
(Entry 1). The combined use of 2-mercaptobenzothiazole
(BtSH) and DMBQ4 gave the corresponding sulfide in nearly
the same yield (Entry 2). When 2 equiv. of 1b and DMBQ were
used under highly concentrated condition, on the other hand, the
yield was improved up to 96% (Entries 3–5).
In the first place, condensation reaction of alkoxydiphenyl-
phosphine 1a prepared from 3-phenyl-1-propanol with several
SAr
Ph2P
ClPPh2
nBuLi
Ph2P
ArS SAr
R3
R2
HO
R1
R3
R2
O
O
R3
R2
R1
ArSH
R1
1
R3
O
SAr
R2
"SN2 displacement"
+
Ph2PSAr
R1
2
Thioetherification of various primary, secondary, and terti-
ary alcohols were further examined by employing the disulfide
and DMBQ systems (methods A and B represent the respective
systems.; Table 3). Condensation reactions of less hindered pri-
"Inversion"
Scheme 1. Preparation of alkyl aryl sulfides from alcohols
via 1.
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.11 (2004)
1523
Table 3. Thioetherification of various alcohols via 1
is established. This method is applicable to the thioetherification
of primary and chiral secondary alcohols as well as that of terti-
ary ones. Further studies on the scope and limitation of the pres-
ent reaction are currently in progress.
RSSR
(or HSR, DMBQ)
ClPPh
BuLi
2
n
R' SR
R' OPPh
R' OH
2
CHCl
r.t.
3
1
a
This study was supported in part by the Grant of the 21st
Century COE Program from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
RSSR/HSR Method
Time
/ h
Yield
/ %
Entry
R'OPPh
2
R
A or B
1
2
4-ClPh
Bt
A
A
0.5
0.5
98
91
1c
Ph
OPPh2
OPPh2
b
References and Notes
3
4-ClPh
Bt
A
A
20
84
90
1d
BocHN
1
For recent reviews, see: a) D. J. Procter, J. Chem. Soc., Perkin
Trans. 1, 2000, 835. b) D. J. Procter, J. Chem. Soc., Perkin
Trans. 1, 1999, 641. c) D. J. Procter, J. Chem. Soc., Perkin
Trans. 1, 1998, 1973.
b
4
0.5
b
b
5
6
4-ClPh
Bt
A
A
20
83
89
MeO2C
OPPh2
1e
1f
0.5
7
4-ClPh
Bt
A
A
48
0.5
40
61
82
2
a) A. K. Pathak, V. Pathak, L. E. Seitz, W. J. Suling, and
R. C. Reimonds, J. Med. Chem., 47, 273 (2004). b) A. Gangjee,
W. Lin, and S. F. Queener, J. Med. Chem., 47, 3689 (2004).
Ph
OPPh2
OPPh2
8
c
9
Ph
Bt
A
A
70
1g
´
c
d
c) N. Pelloux-Leon, A. Fkyerat, A. Piripitsi, W. Tertiuk, W.
Ph
10
0.5 58 (17 )
e
Schunack, H. Stark, M. Garbarg, W. Lingneau, J.-M. Arrang,
J.-C. Schwartz, and C. R. Ganellin, J. Med. Chem., 47, 3264
(2004).
11
12
1b
Box
Py
B
B
15
24
96
41
13
14
1h
Bt
Box
B
B
15
20
64
61
3
a) D. L. Hughes, Org. Prep. Proced. Int., 28, 127 (1996).
b) I. Nakagawa, K. Aki, and T. Hata, J. Chem. Soc., Perkin
Trans. 1, 1983, 1315. c) H. Kotsuki, K. Matsumoto, and H.
Nishizawa, Tetrahedron Lett., 32, 4155 (1991). d) K. A. M.
Walker, Tetrahedron Lett., 18, 4475 (1977). e) W. T. Flowers,
G. Holt, F. Omogbai, and C. P. Poulos, J. Chem. Soc., Perkin
Trans. 1, 1976, 2394. f) Y. Tanigawa, H. Kanamaru, and S.
Murahashi, Tetrahedron Lett., 16, 4655 (1975).
a) T. Shintou, K. Fukumoto, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 77, 1569 (2004). b) T. Shintou, W. Kikuchi, and
T. Mukaiyama, Bull. Chem. Soc. Jpn., 76, 1645 (2003). c) T.
Mukaiyama, T. Shintou, and K. Fukumoto, J. Am. Chem.
Soc., 125, 10538 (2003). d) T. Mukaiyama, T. Shintou, and
W. Kikuchi, Chem. Lett., 2002, 1126. e) T. Mukaiyama, W.
Kikuchi, and T. Shintou, Chem. Lett., 32, 300 (2003). f) T.
Shintou and T. Mukaiyama, Chem. Lett., 32, 1100 (2003).
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(2004). b) T. Shintou and T. Mukaiyama, Chem. Lett., 32, 984
(2003).
For the preparation of alkoxydiphenylphosphines, see Ref. 4;
to a stirred solution of (l)-menthol (10 mmol) in fleshly distill-
ed THF (20 mL) was dropped-nBuLi/hexane (10 mmol) at 0 ꢂC
under argon atmosphere. After stirring for 30 min at 0 ꢂC,
ClPPh2 (10 mmol) was added dropwise. The reaction mixture
was further stirred at 0 ꢂC for 1 h, then concentrated in vacuo
(the white precipitate of LiCl was observed). The residue
was diluted with hexane and filtered through a pad of basic alu-
mina and Celite. After concentration in vacuo, 1b was obtained
as a colorless oil (3.19 g, 94%).
A typical experimental procedure is as follows; to a stirred so-
lution of 1b (1.2 mmol) in chloroform (0.4 mL) under argon at-
mosphere were added BtSH (0.6 mmol) followed by DMBQ
(1.2 mmol) at room temperature. The color of the solution
gradually changed from dark red to orange. After 15 h, the
crude product was purified by preparative TLC on silica gel
to afford the corresponding sulfide as a colorless oil (175 mg,
96%).
Ph
OPPh2
OPPh2
15
16
Bt
Box
B
B
18
18
36
40
1i
1j
17
18
Bt
Box
B
B
18
18
35
42
Ph
OPPh2
19
20
Bt
Box
B
B
6
6
48
48
1k
1l
OPPh2
4
f
Me
Ph
Et
OPPh2
21
22
Bt
Box
B
B
6
6
74
77
g
aMethod A: RSSR (1.0 equiv.), R0OPPh2 (1.1 equiv.), CHCl3
(0.2 M); B: RSH (1.0 equiv.), DMBQ (2.0 equiv.), R0OPPh2
(2.0 equiv.), CHCl3 (1.5 M). bThe alkoxyphosphines were prepared
using alcohol (1.0 equiv.), ClPPh2 (1.0 equiv.) and Et3N (1.0 equiv.)
in THF at r.t. c97% Ee. dYield of N-alkylated product. eComplete
inversion. f65% Ee. 63% Ee.
g
5
6
mary and secondary alcohols via alkoxyphosphines 1c–1f with
diaryl disulfides proceeded smoothly at room temperature even
when methyl ester and tert-butyl carbamate (Boc) groups coex-
isted in the molecule and the desired sulfides were obtained in
good to high yields (Entries 1–8). Next, the stereo course of
the present reaction was studied by using 1g and 1b derived from
chiral secondary alcohols (Entries 9–11). When 1g derived from
(R)-(þ)-1-phenylethanol (>99% ee) which has a chiral center at
benzylic position was allowed to react with diphenyl- or 2,20-di-
benzothiazolyl- disulfides, the corresponding (S)-sulfides were
obtained with virtually complete inversion of stereochemistry
(97% ee, respectively). In the case of 1b, the desired 2-benzox-
azolyl sulfide was obtained in 96% yield with complete inver-
sion of configuration. tert-Alkyl aryl sulfides were also obtained
according to the DMBQ method (Entries 12–22). Condensation
reactions of 1h–1k with heteroaromatic thiols afforded the cor-
responding sulfides in modelate to good yields (35–64%). The
chiral tert-alkyl sulfides were formed in good yields (74–77%)
with moderate stereo-inversion (63–65% ee), when 1l prepared
from (S)-2-phenyl-2-butanol (96% ee)8 was used.
7
Thus, a novel condensation reaction for the preparation of
alkyl aryl sulfides from alcohols via alkoxydiphenylphosphines
8
C. Garcia, L. K. LaRochelle, and P. J. Walsh, J. Am. Chem.
Soc., 124, 10970 (2002).
Published on the web (Advance View) October 23, 2004; DOI 10.1246/cl.2004.1522