InCl3-catalyzed highly regioselective ring opening of epoxides with thiols

Article abstract of DOI:10.1246/cl.2002.906

Epoxides react smoothly with thiols in the presence of 10 mol% InCl₃ under very mild conditions to afford the corresponding β-hydroxy sulfides in high yields with high regioselectivity. Similar yields and selectivity are also obtained with cata

Full text of DOI:10.1246/cl.2002.906

906
Chemistry Letters 2002
InCl3-Catalyzed Highly Regioselective Ring Opening of Epoxides with Thiols
J. S. Yadav,ꢀ B. V. S. Reddy, and Gakul Baishya
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
(Received May 9, 2002; CL-020401)
Table 1. InCl3-Catalyzed regioselective opening of epoxides
with thiols
Epoxides react smoothly with thiols in the presence of
10 mol% InCl3 under very mild conditions to afford the
corresponding ꢀ-hydroxy sulfides in high yields with high
regioselectivity. Similar yields and selectivity are also obtained
with catalytic amount of indium triflate under these reaction
conditions.
Thiol
Product a
Yield/%b
90
Time/h
3.0
Entry
Epoxide
O
2a
2b
Phenyl
a
b
c
d
Ph
n-Decyl
2-Naphthyl
Phenyl
87
82
75
4.5
3.5
3.0
"
2c
"
The ring opening process of epoxides with thiols to yield ꢀ-
hydroxy sulfides is of great importance in the field of
pharmaceuticals1 and natural products,2 particularly for the
synthesis of leukotrienes such as LTC4 and LTD4. Epoxides are
well known carbon electrophiles capable of reacting with various
nucleophiles and their ability to undergo regioselective ring
opening reactions contribute largely to their synthetic value.3;4
One of the most straightforward synthetic procedures for the
preparation of ꢀ-hydroxy sulfides is the ring opening of epoxides
with thiols in the presence of base in a protic solvent.5
Subsequently, several methods have been developed using Lewis
acid catalysis to perform these epoxide ring-opening reactions
under mild conditions.6;7 However, many of these methods often
involve the use of stoichiometric amounts of the reagents,7a
drastic reaction conditions, poor regioselectivity, extended
reaction times,6a unsatisfactory yields and entail undesirable side
reactions6b due to oxidation of thiol or rearrangement of oxiranes.
Since organic sulfur compounds have become increasingly useful
and important in organic synthesis, the development of
convenient and efficient methods for the preparation of appro-
priate sulfides, especially those, which carry other functional
groups, are well appreciated. In recent years, indium reagents
have emerged as mild and water-tolerant Lewis acids imparting
high regio- and chemoselectivity in various chemical trans-
formations.8 In addition, they can be conveniently used either in
aqueous or in non-aqueous medium and can be recovered via
aqueous work-up.
O
2dc
2ec
e
4-MeC6H4
Phenyl
3.5
"
80
90
87
4f
O
f
4.5
6.0
g
h
4g
"
"
n-Decyl
2-Naphthyl
4h
4i
80
88
5.0
4.5
i
j
O
Phenyl
2-Naphthyl
n-Decyl
4j
5.5
6.0
"
"
81
85
k
4k
OH
SPh
O
l
Phenyl
3l
75
70
4.0
4.5
OH
SR
m
R = n-Decyl
3m
"
O
n
o
87
85
3n
3.0
4.5
Phenyl
O
O
3o
3p
Cl
4-BrC6H4
Phenyl
O
p
q
89
3.5
O
O
4-MeOC6H4
3q
87
4.5
In continuation of our interest on the use of indium halides as
mild and efficient Lewis acids in promoting various trans-
formations,9 we herein describe another remarkable catalytic
activity of indium chloride in the regioselective ring opening of
oxiranes with thiols. Thus treatment of styrene oxide with
thiophenol in the presence of 10 mol% InCl3 under mild
conditions afforded the corresponding 2-phenylthio-2-pheny-
lethanol 2 in 90% yield (Scheme 1).
aAll products were characterized by 1H NMR, IR and mass spectroscopy. bisolated
and unoptimized yields. cIsomer 3 was also obtained in 15-20% yield.
1
this reaction the structure of which was confirmed by H-NMR
spectrum of the crude product. The method is highly regioselec-
tive affording exclusively the ring-opened product 2. In a similar
fashion, glycidyl aryl ethers reacted smoothly with thiols to afford
the corresponding ꢀ-hydroxy sulfides 3 in high yields (entries p,
q). Alkyl oxiranes such as limonene oxide, epichlorohydrin and
pentene oxide underwent cleavage with thiols to produce
respective thioethers in high yields (Scheme 2).
SR
O
10 mol%, InCl3
CH2Cl2, r.t
R-SH
OH
+
Ar
Ar
1(a-e)
2 (a-e)
OH
Scheme 1.
O
10 mol%, InCl3
CH2Cl2, r.t
R
SR'
R
+
R'-SH
Aryl oxiranes underwent cleavage by a variety of thiols in a
regioselective manner with preferential attack at benzylic
position (see Table 1). Only a single product was obtained in
3 (l-q)
1(l-q)
R = aryloxy; alkyl
Scheme 2.
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
907
Alkyl oxiranes (entries l–q) underwent cleavage by a range of
thiols in a regioselective manner with preferential attack at the
terminal position (see Table 1). In all cases the reactions
proceeded efficiently at ambient temperature with high regios-
electivity. Furthermore, cycloalkyl epoxides such as cyclohexene
oxide and cyclopentene oxides reacted smoothly with thiols to
afford the corresponding ꢀ-hydroxy sulfides 4 in high yields
(Scheme 3).
C. Bonini and G. Righi, Synthesis, 1994, 225.
4a) S. K. Paknikar and J. G. Kirtane, Tetrahedron, 39, 2323
(1983). b) J. G. Smith, Synthesis, 1984, 629.
5
a) M. E. Peach, ‘‘The Chemistry of the Thiol Group’’ ed. by S.
Patai, John Wiley, New York (1974), Part 3, p 771.
a) A. E. Vougioukas and H. B. Kagan, Tetrahedron Lett., 28,
6065 (1987). b) J. Iqbal, A. Pandey, A. Shukla, R. R.
Srivastava, and S. Tripathi, Tetrahedron, 46, 6423 (1990). c)
A. K. Maiti and P. Battacharyya, Tetrahedron, 50, 10483
(1994).
6
OH
SR
10 mol%, InCl3
CH2Cl2, r.t
+
O
R-SH
7
a) M. Chini, P. Crotti, E. Giovani, F. Macchia, and M.
Pineschi, Synlett, 1992, 303. b) P. Raubo and J. Wicha,
Synlett, 1993, 25. c) D. Albanese, D. Landini, and M. Penso,
Synthesis, 1993, 34. d) T. Iida, N. Yamamoto, H. Sasai, and M.
Shibasaki, J. Am. Chem. Soc., 119, 4783 (1997).
1(f-k)
4 (f-k)
Scheme 3.
In the case of cycloalkyl epoxides (entries f–k), the
stereochemistry of the ring product 4f was found to be trans
from the coupling constants of the ring protons at ꢁ 2.78 (ddd,
J ¼ 4:5, 9.8, 11.6 Hz, 1H), for (SCH) in 1H NMR spectrum
similarly the peak at ꢁ 3.30 ppm for (OCH) showed the similar
splitting pattern (ddd, J ¼ 4:5, 9.8, 9.8 Hz, 1H). A variety of
epoxides underwent cleavage with thiols to afford the corre-
sponding ꢀ-hydroxy thioethers in high yields. All products were
characterized by 1H NMR, IR and mass spectroscopic data. This
method does not require anhydrous solvents or any stringent
reaction conditions. No precautions need to be taken to exclude
moisture from the reaction medium. The reactions are clean and
highly regioselective affording high yields of products in a short
period. The scope and generality of this process is illustrated with
respect to various epoxides and thiols. Among the various Lewis
acids such as InCl3, YCl3, YbCl3 and CeCl3 studied for this
transformation, InCl3 was found to be more effective in terms of
yields and selectivity. Thus, this method is superior to acid
catalyzed or base catalyzed epoxide ring opening reactions with
thiols. Furthermore, 10 mol% indium triflate was also found to be
equally effective for the ring opening reactions of epoxides with
thiols.
8
9
a) C. J. Li and T. H. Chan, Tetrahedron, 55, 11149 (1999). b)
G. Babu and P. T. Perumal, Aldrichimica Acta, 33, 16 (2000).
c) R. Ghosh, Indian J. Chem., Sect. B, 40, 550 (2001).
a) J. S. Yadav, B. V. S. Reddy, and G. M. Kumar, Synlett,
2001, 1417. b) J. S. Yadav, A. Sunny, B. V. S. Reddy, and G.
Sabitha, Synthesis, 2001, 2165. c) J. S. Yadav, A. Sunny, B. V.
S. Reddy, and G. Sabitha, Tetrahedron Lett., 42, 8063 (2001).
10 Experimental Procedure: A mixture of epoxide (5 mmol),
thiol (5 mmol) and InCl3 (10 mol%) in dichloromethane
(10 mL) was stirred at ambient temperature for an appropriate
time (Table 1). After completion of the reaction, as indicated
by TLC, the reaction mixture was diluted with water
(2 Â 10 mL) and extracted with dichloromethane (2Â
15 mL). The combined organic layers were dried over
anhydrous Na2SO4, concentrated in vacuo and purified by
column chromatography on silica gel (Merck, 100–200 mesh,
ethyl acetate-hexane 2 : 8) to afford pure product. The
aqueous layer was concentrated in vacuo to recover the
catalyst. Compared to indium trichloride, indium triflate was
recovered inquantitatively and reused in subsequentreactions
without loss of activity. Spectroscopic data for compounds:
2a: 2-phenylthio-2-phenylethanol: Oil, 1H NMR (200 MHz,
CDCl3) ꢁ: 7.55–7.15 (m, 10H), 4.70 (t, 1H, J ¼ 6:8 Hz), 3.65
(d, 2H, J ¼ 6:8 Hz). EIMS: m=z: 230[Mþ]; IR (neat) ꢂ: 3340,
1620, 1508 1243, 1048, 710 cm.ꢁ1 Anal. Calcd for C14H14OS
(230.324): C, 73.01; H, 6.13; S, 13.92%. Found: C, 73.1; H,
6.15; S, 13.95%. 4f: 2-phenylthiocyclohexanol: Oil, 1H NMR
(200 MHz, CDCl3) ꢁ: 7.20–7.30 (m, 5H), 3.30 (ddd, 1H,
J ¼ 9:8, 9.8, 4.5 Hz), 3.0 (brs, 1H, OH), 2.78 (ddd, 1H,
J ¼ 11:6; 9:8; 4:5 Hz), 2.43–2.14 (m, 2H), 1.80–1.65 (m, 1H),
1.40–1.20 (m, 4H). EIMS: m=z: 208 [Mþ]; IR (neat) ꢂ: 3345,
3347, 1620, 1515 1243, 1053, 715 cm.ꢁ1 Anal. Calcd for
C12H16OS (208.317): C, 69.19; H, 7.74; S, 15.39%. Found: C,
69.23; H, 7.75; S, 15.42%. 3p: 3-phenoxy-1-phenylthio-
In summary, this paper describes a simple, convenient and
efficient method for the regioselective ring opening of epoxides
with thiols using a novel catalyst InCl3. The notable features of
this procedure are mild reaction conditions, greater regioselec-
tivity, cleaner reaction profiles, improved yields, enhanced rates
and simplicity in operation which make it a useful and attractive
process for the synthesis of ꢀ-hydroxy thioethers of biological
importance.
BVS thanks CSIR New Delhi for the award of fellowship.
References and Notes
J. R. Luly, N. Yi, J. Soderquist, H. Stein, J. Cohen, T. J. Perun,
and J. J. Plattner, J. Med. Chem., 30, 1609 (1987).
1
1
propan-2-ol: Oil, H NMR (200 MHz, CDCl3) ꢁ: 7.80–6.77
(m, 10H), 4.20 (m, 1H), 3.80 (d, 2H, J ¼ 7:0 Hz), 3.10 (d, 2H,
J ¼ 6:8 Hz). EIMS: m=z: 260[Mþ]; IR (neat) ꢂ: 3420, 1620,
1517 1245, 1058, 721 cm.ꢁ1 Anal. Calcd for C15H16O2S
(260.349): C, 69.20; H, 6.19; S, 12.31%. Found: C, 69.28; H,
6.21; S, 12.35%.
2
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3
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