Water-promoted highly selective anti-Markovnikov addition of thiols to unactivated alkenes

Article abstract of DOI:10.1055/s-2007-973877

The highly selective anti-Markovnikov addition of thiols to unactivated alkenes is demonstrated in water at room temperature without any additive. This is a very simple and efficient method for the synthesis of linear thioethers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973877

LETTER
925
Water-Promoted Highly Selective Anti-Markovnikov Addition of Thiols to
Unactivated Alkenes
A
nti-Markovniko
r
v
A
dditi
i
on of
T
n
hiols to Una
d
ctivated Alk
a
enes ban C. Ranu,* Tanmay Mandal
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Fax +91(33)24732805; E-mail: ocbcr@iacs.res.in
Received 3 October 2006
R1
R1
R2SH
Abstract: The highly selective anti-Markovnikov addition of thiols
to unactivated alkenes is demonstrated in water at room temperature
without any additive. This is a very simple and efficient method for
the synthesis of linear thioethers.
SR2
R
R
H2O, r.t.
Scheme 1
Key words: water, anti-Markovnikov addition, thiol, thioether,
unactivated alkene
The experimental procedure is very simple.10 A mixture of
thiol (1 mmol) and alkene (1 mmol) in water was stirred
at room temperature for a certain period of time (moni-
tored by TLC). Usual work-up and extraction with diethyl
ether followed by column chromatography provided the
pure product.
The serious environmental impact associated with the use
of volatile organic solvents in chemical transformations
has led to the quest for safer green solvents. Thus, over the
last decade investigations into the use of several alterna-
tive solvents such as room temperature ionic liquids
(RTIL),1 supercritical fluids2 and water3 as viable reaction
media have been the focus of increasing attention. Al-
though water is gifted with several advantages over other
solvents when environmental acceptability is considered,
including cost and safety, until recently the potential of
water in organic synthesis has not been thoroughly ex-
plored. Several recent reports revealed that water exhibits
unique reactivity and selectivity that cannot be attained by
conventional organic solvents or ionic liquids.4
A variety of terminal, internal, cyclic, acyclic and
branched unactivated olefins underwent facile anti-Mark-
ovnikov additions with thiophenol, substituted thio-
phenols, ethanethiol and n-butanethiol by this procedure
to provide the corresponding thioethers. The results are
summarized in Table 1. Styrenes and substituted styrenes
also reacted smoothly with thiols to afford the anti-Mark-
ovnikov products without any polymerization as observed
under acidic conditions.7 Sensitive molecules such as di-
hydropyran (Table 1, entries 4–6) and dihydrofuran
(Table 1, entry 7) underwent addition at the more electro-
philic C-2 centres without any difficulty. Various acid-
sensitive functionalities such as OMe, OEt, OAc and me-
thylenedioxy remained unaffected under the reaction con-
ditions. The reaction of thiophenols and olefin has been
reported to give the Friedel Crafts product;9c however, no
such side-reaction was observed in any reaction with
thiophenols by this procedure.
Diorganyl sulfides or thioethers are very useful building
blocks in the synthesis of various organosulfur
compounds5 and they also play important roles in biolog-
ical and chemical processes.6 Thus, the synthesis of thio-
ethers is of much importance. One of the simplest routes
is the addition of thiols to alkenes. This reaction may pro-
ceed via an electrophilic pathway involving an ionic pro-
cess or a free radical pathway.7 Usually, the free radical
course promotes anti-Markovnikov addition, whereas the
ionic process leads to Markovnikov adducts.8 Of all the
catalysts reported (H2SO4, HClO4, p-TSOH, AlCl3, BF3,
TiCl4, SnCl4, ZnCl2) for electrophilic addition of thiols,
only H-Rho zeolite in n-hexane9f and neat benzene9g are
found to induce anti-Markovnikov addition. The latter
procedure using benzene is obviously not welcome in any
laboratory as benzene is highly carcinogenic and hazard-
ous to health. We demonstrate here a very simple and
green procedure for anti-Markovnikov addition of thiols
to unactivated alkenes in water at room temperature with-
out the use of any additive (Scheme 1).
In general, the reactions were clean, high-yielding and
considerably fast (1.5–4.5 h). The additions were always
through anti-Markovnikov mode and no Markovnikov ad-
dition product was obtained in any reaction. The products
were obtained in high purity after simple column chroma-
tography. All the compounds were characterized from
their spectroscopic data and elemental analysis. These
data are in good agreement with what has been previously
reported for the known compounds.
Water has a very specific role in this reaction. The anti-
Markovnikov addition of thiophenol to styrene in benzene
was reported to be complete at room temperature in 24
hours and under reflux at 10 hours,9g whereas in water this
reaction took only 1.5 hours at room temperature
(Table 1, entry 14). The neat reactions without water are
very slow and even after 24 hours the reactions had not
proceeded more than 50%. Possibly, water promotes
the reaction through hydrogen bond formation with the
SYNLETT 2007, No. 6, pp 0925–0928
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973877; Art ID: D28606ST
© Georg Thieme Verlag Stuttgart · New York

926
B. C. Ranu, T. Mandal
LETTER
sulfhydryl hydrogen of the thiol and thus increases the Although the conjugate addition of thiols to activated
nucleophilicity of the thiolate ion. It may be further alkenes has been well explored,26 addition to unactivated
speculated that addition of the thiolate anion to the C=C alkenes in a regioselective manner is rather difficult and
bond takes place in a concerted manner with steric factors less explored.8,9 Thus, this reaction in water alone is of
controlling the regioselectivity leading to the anti- much significance.
Markovnikov product (Scheme 2).
To conclude, we have developed a very simple and effi-
cient methodology for addition of thiols to unactivated
alkenes in water without any additive producing linear
R1
R1
R1
R2SH
H2O, r.t.
R
thioethers. The significant advantages offered by this
method are simple operation, mild (room temperature)
and environmentally friendly experimental conditions
acceptable to several sensitive functionalities, excellent
regioselectivity, high yields of isolated products and cost
effectiveness. This methodology thus provides a very con-
venient procedure and further studies on broadening the
scope of water as an effective promoter for organic reac-
tions are under way and will be reported in due course.
R2
R
R
R2
H
S
δ–
δ+
O
H
S
δ–
H
δ+
H
O
H
H
– H2O
R1
SR2
R
Scheme 2
Table 1 Anti-Markovnikov Addition of Thiols to Alkenes
Entry
1
Alkene
Thiol
PhSH
Product
Time (h)
2.5
Yield (%)a
8.5
Ref.b
9f
S
11
12
2
3
EtSH
4.5
2.5
71
85
S
Cl
4-ClC6H4SH
S
S
S
13
9f
4
5
n-BuSH
4.5
2.5
71
80
O
O
O
O
O
PhSH
Cl
14
6
7
8
n-BuSH
2.5
3.0
3.5
78
76
77
O
S
S
15
16
4-ClC6H4SH
4-ClC6H4SH
Cl
O
O
O
S
S
O
17
18
O
9
PhSH
3.5
3.0
78
72
O
Cl
Cl
Cl
O
O
O
O
S
S
10
4-ClC6H4SH
O
O
O
O
19
9f
11
12
4-ClC6H4SH
4-ClC6H4SH
3.5
4.0
71
72
S
Synlett 2007, No. 6, 925–928 © Thieme Stuttgart · New York

LETTER
Anti-Markovnikov Addition of Thiols to Unactivated Alkenes
927
Table 1 Anti-Markovnikov Addition of Thiols to Alkenes (continued)
Entry
13
Alkene
Thiol
Product
Time (h)
4.5
Yield (%)a
45
Ref.b
20
HS(CH2)3SH
S
S
( )2
( )2
( )3
9f
14
15
PhSH
1.5
1.5
90
88
S
Cl
21
4-ClC6H4SH
S
S
9f
16
PhSH
1.5
80
Cl
Cl
Cl
Cl
22
23
23
23
17
18
19
20
PhSH
3.0
3.0
3.0
3.5
75
72
72
73
S
Cl
4-ClC6H4SH
PhSH
S
S
Br
Br
OMe
OMe
PhSH
S
MeO
O
Cl
MeO
O
23
23
24
21
22
23
24
4-ClC6H4SH
PhSH
3.5
4.0
3.5
3.5
72
74
73
75
S
O
O
O
O
S
Cl
4-ClC6H4SH
PhSH
O
O
S
MeO
MeO
25
23
MeO
MeO
S
25
PhSH
3.0
76
S
a Yields refer to those of pure isolated products characterized by spectroscopic data (IR, 1H and 13C NMR).
b Known compounds were confirmed by comparison of IR, 1H and 13C NMR spectra with reported data. Unknown compounds were character-
ized by their spectroscopic and analytical data.
Acknowledgment
References and Notes
This work has enjoyed support from CSIR, New Delhi [Grant no.
01(1936)/04]. T.M. thanks CSIR for a fellowship.
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Synlett 2007, No. 6, 925–928 © Thieme Stuttgart · New York

928
B. C. Ranu, T. Mandal
LETTER
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(15) Table 1, entry 7: Yellow oil. IR (neat): 1590, 2957 cm–1. 1H
NMR (300 MHz, CDCl3): d = 1.79–1.83 (m, 2 H), 1.95–2.02
(m, 2 H), 3.53–3.60 (m, 1 H), 4.10–4.17 (m, 1 H), 5.14–5.17
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(18) Table 1, entry 10: Yellow viscous liquid. IR (neat): 1741,
1477, 1382 cm–1. 1H NMR (300 MHz, CDCl3): d = 2.00 (s,
3 H), 3.09 (t, J = 6.9 Hz, 2 H), 4.20 (t, J = 6.9 Hz, 2 H), 7.23–
7.32 (m, 4 H). 13C NMR (75 MHz, CDCl3): d = 20.8, 32.6,
62.7, 129.3 (2 C), 131.2 (2 C), 132.7, 133.7, 170.8. Anal.
Calcd for C10H11ClO2S: C, 52.06; H, 4.81. Found: C, 51.78;
H, 4.72.
(19) Table 1, entry 11: Yellow viscous liquid. IR (neat): 1735,
2933, 2979 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.30 (d,
J = 2.4 Hz, 3 H), 1.95 (s, 3 H), 2.88–2.95 (m, 1 H), 3.07–3.14
(m, 1 H), 4.96–5.02 (m, 1 H), 7.21–7.31 (m, 4 H). 13C NMR
(75 MHz, CDCl3): d = 19.2, 21.1, 39.3, 69.5, 129.1 (2 C),
131.0 (2 C), 132.4, 134.4, 170.4. Anal. Calcd for
C11H13ClO2S: C, 53.98; H, 5.35. Found: C, 53.76; H, 5.23.
(20) Table 1, entry 13: Colorless liquid. IR (neat): 1479, 1585,
2925 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.76–1.94 (m,
2 H), 2.48–2.67 (t, J = 7.12 Hz, 4 H), 2.76–2.86 (m, 4 H),
2.88–2.94 (m, 4 H), 7.14–7.38 (m, 10 H). 13C NMR (75
MHz, CDCl3): d = 29.3, 31.1 (2 C), 33.7 (2 C), 36.9 (2 C),
126.4 (4 C), 128.4 (4 C), 130.6 (2 C), 140.6 (2 C). Anal.
Calcd for C19H24S2: C, 72.10; H, 7.64. Found: C, 72.29; H,
7.58.
(21) Table 1, entry 15: Colorless liquid. IR (neat): 1580, 2934
cm–1. 1H NMR (300 MHz, CDCl3): d = 2.93 (t, J = 6.9 Hz, 2
H), 3.16 (t, J = 6.9 Hz, 2 H), 7.20–7.35 (m, 9 H). 13C NMR
(75 MHz, CDCl3): d = 35.2, 35.6, 126.6 (2 C), 127.8 (2 C),
128.5 (2 C), 129.0 (2 C), 130.6, 132.0, 135.0, 140.0. Anal.
Calcd for C14H13ClS: C, 67.59; H, 5.27. Found: C, 67.86; H,
5.16.
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(25) Table 1, entry 23: Yellow oil. IR (neat): 1246, 1489, 1588
cm–1. 1H NMR (300 MHz, CDCl3): d = 2.83 (t, J = 7.2 Hz, 2
H), 3.10 (t, J = 7.2 Hz, 2 H), 5.95 (s, 2 H), 6.61–6.75 (m, 4
H), 7.12–7.26 (m, 3 H). 13C NMR (75 MHz, CDCl3): d =
35.3, 35.7, 101.3, 108.3, 109.0, 121.6, 129.1, 129.4 (2 C),
130.7 (2 C), 133.8, 134.9, 146.2, 147.8. Anal. Calcd for
C15H13O2SCl: C, 61.53; H, 4.48. Found: C, 61.49; H, 4.34.
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(10) Typical Experimental Procedure (Table 1, entry 14): A
mixture of styrene (1 mmol, 104 mg) and thiophenol (1.1
mmol, 121 mg) was stirred in H2O (0.5 mL) at r.t. for 1.5 h
until completion of the reaction (monitored by TLC). The
reaction mixture was extracted with Et2O (3 × 10 mL). The
Et2O extract was washed with H2O, NaOH solution (2%)
and then brine and dried over Na2SO4. Evaporation of the
solvent gave a crude product which was purified by column
chromatography over silica gel (hexane–Et2O, 95:5) to
provide 2-phenylsulfanylethylbenzene (192.6 mg, 90%) as a
colorless liquid. This procedure was followed for all the
reactions listed in Table 1.
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Synlett 2007, No. 6, 925–928 © Thieme Stuttgart · New York