Indium(I) iodide promoted cleavage of dialkyl/diaryl disulfides and subsequent anti-Markovnikov addition to styrenes: a new route to linear thioethers

Article abstract of DOI:10.1016/j.tetlet.2006.07.017

The reaction of thiolate anions, generated in situ by indium(I) iodide promoted cleavage of dialkyl/diaryl disulfides, with styrenes has been investigated. Thiolate anions add to a variety of styrenes in an anti-Markovnikov manner producing linear thioethers in high yields. This method provides a new route to the synthesis of thioethers.

Full text of DOI:10.1016/j.tetlet.2006.07.017

Tetrahedron Letters 47 (2006) 6911–6914
Indium(I) iodide promoted cleavage of dialkyl/diaryl disulfides
and subsequent anti-Markovnikov addition to styrenes: a new
route to linear thioethers
Brindaban C. Ranu* and Tanmay Mandal
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 6 May 2006; revised 26 June 2006; accepted 6 July 2006
Available online 4 August 2006
Abstract—The reaction of thiolate anions, generated in situ by indium(I) iodide promoted cleavage of dialkyl/diaryl disulfides, with
styrenes has been investigated. Thiolate anions add to a variety of styrenes in an anti-Markovnikov manner producing linear thio-
ethers in high yields. This method provides a new route to the synthesis of thioethers.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The synthesis of thioethers by the addition of thiolate
anions to olefins is of much importance. The reaction
is usually carried out using thiols and is catalyzed by
protic1 as well as Lewis acids.2 Although the addition
of thiols to carbon–carbon double bonds has been well
studied, reactions with styrenes have not been ade-
quately addressed, probably due to their facile polymer-
ization under acidic conditions.2 Thus, addition of thiols
to styrenic substrates has been investigated with a vari-
ety of mild catalysts.3 Although Markovnikov additions
to styrenes are common,1,2,3a only a few reagents such as
H-rho-zeolite3b and benzene-reflux3a lead to anti-Mark-
ovnikov products. Several of these procedures are asso-
ciated with disadvantages such as unsatisfactory yields,
long reaction times and they also lack systematic study.
This prompted us to find a more convenient and general
method for this transformation.
We report here a new strategy for the synthesis of thio-
ethers via the anti-Markovnikov addition of thiolate
anions, generated in situ by InI-promoted cleavage of
dialkyl/diaryl disulfides to styrenes in the presence of
zinc chloride (Scheme 1). We are not aware of any other
method using the reaction of dialkyl/diaryl disulfides
with styrenes for the synthesis of thioethers.
The experimental procedure is very simple.5 Several
substituted styrenes underwent reactions with a variety
of dialkyl or diaryl disulfides to produce the correspond-
ing linear thioethers via regioselective anti-Markov-
nikov addition. The results are summarized in Table 1.
Several sensitive functional groups such as Cl, Br,
OMe and methylenedioxy remained unaffected under
the reaction conditions. Sensitive molecules such as
dihydropyran and dihydrofuran (entries 14 and 15) also
underwent addition at the more electrophilic C-2 centres
giving good yields (60–70%) of products. All the addi-
tions were regioselective and anti-Markovnikov in nat-
ure. The other regioisomer (Markovnikov addition
product) was not isolated from any of the reactions.
We have been actively engaged in exploring new deriva-
tives of indium for organic reactions and as a part of this
program we have already disclosed several applications4
of indium(I) iodide, which include cleavage of diaryl
diselenides and disulfides and subsequent reactions with
alkyl halides,4a acyl halides,4b vinyl halides,4c conjugated
carbonyl compounds4d and more recently, the use of InI
as a radical initiator.4e
In general, the reactions were fast, clean and high yield-
ing. Diaryl disulfides react faster than dialkyl disulfides.
It was also observed that diselenides did not react at all
InI, RSSR
SR
Keywords: Thioether; Anti-Markovnikov addition; Styrene; Dialkyl
disulfide; Indium(I) iodide; Zinc chloride.
Ar
Ar
ZnCl2 (cat.)
THF, reflux
*
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473
2805; e-mail: ocbcr@iacs.res.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.017

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B. C. Ranu, T. Mandal / Tetrahedron Letters 47 (2006) 6911–6914
Table 1. Synthesis of linear thioethers via anti-Markovnikov addition of dialkyl/diaryl disulfides to styrenes
InI, RSSR
SR
Ar
Ar
ZnCl2 (cat.)
THF, reflux
Entry
1
Styrene
R
Product
Time (h)
4.5
Yielda (%)
90
Ref.
3a
SC6H5
C6H5
SC6H5
2
3
4
5
C6H5
4.5
6.0
5.0
5.0
80
65
70
69
3b
S-n-C4H9
n-C4H9
C6H5
Cl
Cl
Cl
Cl
Cl
Cl
SC6H5
7
SC6H4(p-Cl)
(p-Cl)C6H4
C6H5
SC6H5
6
7
6.0
5.5
5.5
5.5
6.0
65
71
72
70
69
Br
Br
SC6H5
C6H5
OMe
OMe
SC6H4(p-Cl)
8
(p-Cl)C6H4
C6H5
MeO
O
MeO
O
SC6H5
9
O
O
S-n-C4H9
10
n-C4H9
MeO
MeO
MeO
MeO
OMe
OMe
OMe
OMe
SC6H5
11
C6H5
5.75
71
8
SC6H5
12
13
C6H5
5.5
6.0
70
73
SC6H4(p-Cl)
(p-Cl)C6H4
14
15
C6H5
C6H5
5.0
5.5
70
60
3d
3d
O
O
O
O
SC6H5
SC6H5
a Yields refer to those of pure isolated products characterized by IR and 1H and 13C NMR spectroscopic data.
using this procedure. The products were obtained in
high purity after simple column chromatography. All
the compounds were characterized from spectroscopic
data and elemental analysis. THF was found to be the
solvent of choice as other solvents including CH3CN
and CH2Cl2 did not give the desired products. It was

B. C. Ranu, T. Mandal / Tetrahedron Letters 47 (2006) 6911–6914
6913
(121 mg, 0.5 mmol) was added to a solution of diphenyl
disulfide (109 mg, 0.5 mmol) in freshly distilled THF
(2.5 mL) under argon followed by the addition of a-methyl
styrene (118 mg, 1 mmol) and ZnCl2 (20.7 mg, 15 mol %).
The reaction mixture was heated under reflux for 4.5 h
(TLC). THF was then evaporated and the residue was
quenched with saturated ammonium chloride solution and
extracted with Et2O (3 · 20 mL). The Et2O extract was
successively washed with water, 2% NaOH solution and
brine and then dried (Na2SO4). Evaporation of the solvent
gave a crude product, which was purified by column
chromatography over silica gel (hexane–Et2O, 95:5) to
provide 1-(1-methyl-2-phenylsulfanyl-ethyl)-benzene (182.4
mg, 80%) as a colourless liquid, IR (neat): 1438, 1479,
InI
RSSR
IIn(SR)2
RS
A
Ar
ZnCl2
δ−
δ+
Cl
Ar
ZnCl
sat.
ΝΗ4Cl
SR
SR
Ar
Scheme 2.
observed that the reaction did not proceed at all in the
absence of either InI or ZnCl2. It is speculated6 that
the reaction proceeds through the intermediacy of
bis(thioalkyl)-iodo-indium(III) species (A) formed read-
ily by the reaction of equimolar quantities of InI and the
dialkyl/diaryl disulfide, which then releases a thiolate
anion, which adds to the styrene (Scheme 2). The pres-
ence of ZnCl2 facilitates the addition through polariza-
tion of the double bond. Zinc chloride was used in a
catalytic amount and is probably regenerated by trans-
metallation to indium during the reaction.
1581 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d 1.55 (d,
J = 6.5 Hz, 3H), 3.10–3.24 (m, 2H), 3.35–3.40 (m, 1H),
7.27–7.48 (m, 10H); 13C NMR (CDCl3, 75 MHz): d 21.2,
39.6, 42.1, 125.9, 126.7, 127.1 (2C), 128.6 (2C), 129.0 (2C),
129.1 (2C), 137.0, 145.6. These data are in good agreement
with those reported.3b This procedure was followed for the
reactions of all the substrates listed in Table 1.
The products from entries 1, 2, 4, 11, 14 and 15, which are
known, were identified by comparison of their spectro-
scopic data (IR, 1H NMR and 13C NMR) with those
reported. New compounds (entries 3, 5, 6, 7, 8, 9, 10, 12 and
13) were characterized from their spectroscopic data and
elemental analysis. These data are presented below:
In conclusion, the present procedure using the indium(I)
iodide–ZnCl2 system provides a new route to linear thio-
ethers via a highly regioselective anti-Markovnikov
addition of dialkyl/diaryl disulfides to styrenes. The sig-
nificant features of this methodology are the use of more
stable disulfides in place of thiols, good isolated yields of
products (60–90%), fast reactions and atom economy.
1-(2-Butylsulfanylethyl)-4-chlorobenzene (entry 3): Colour-
less liquid; IR (neat): 1438, 1478, 1583 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d 0.87–0.94 (m, 3H), 1.36–1.45 (m, 2H),
1.51–1.59 (m, 2H), 2.48–2.54 (m, 2H), 2.71–2.76 (m, 2H),
2.82–2.88 (m, 2H), 7.11–7.14 (m, 2H), 7.23–7.27 (m, 2H);
13C NMR (CDCl3, 75 MHz): d 13.6, 21.9, 31.7, 31.9, 33.5,
35.6, 128.5 (2C), 129.8 (2C), 132.0, 139.0. Anal. Calcd for
C12H17ClS: C, 63.00; H, 7.49. Found: C, 62.78; H, 7.32.
1-[2-(4-Chlorophenyl)sulfanylethyl]-4-chlorobenzene (entry
1
5): Colourless liquid; IR (neat): 1438, 1478, 1581 cmÀ1; H
Acknowledgements
NMR (CDCl3, 300 MHz): d 2.78–2.85 (m, 2H), 3.03–3.09
(m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 7.20–7.23 (m, 6H); 13C
NMR (CDCl3, 75 MHz): d 34.8, 35.4, 128.7 (2C), 129.1
(2C), 129.9 (2C), 130.7 (2C), 132.2, 132.3, 134.7, 138.3.
Anal. Calcd for C14H12Cl2S: C, 59.37; H, 4.27. Found: C,
59.20; H, 4.13.
We are pleased to acknowledge the financial support
from CSIR, New Delhi [Grant No. 01(1936)/04], for this
investigation. T.M. is also thankful to CSIR for his
fellowship.
1-(2-Phenylsulfanylethyl)-3-bromobenzene (entry 6): Col-
ourless viscous oil; IR (neat): 1438, 1478, 1582 cmÀ1 1H
;
References and notes
NMR (CDCl3, 300 MHz): d 2.84–2.90 (m, 2H), 3.11–3.16
(m, 2H), 7.11–7.37 (m, 9H); 13C NMR (CDCl3, 75 MHz): d
34.9, 35.3, 126.2, 127.2, 129.0 (2C), 129.5 (2C), 129.6, 130.0,
131.1, 131.6, 135.9, 142.4. Anal. Calcd for C14H13BrS: C,
57.35; H, 4.47. Found: C, 57.13; H, 4.33.
1. Screttas, C. G.; Micha-Screttas, M. J. Org. Chem. 1979, 44,
713–719, and references cited therein.
2. (a) Mukaiyama, T.; Izawa, T.; Saigo, K.; Takai, H. Chem.
Lett. 1973, 355–356; (b) Belley, M.; Zamboni, R. J. Org.
Chem. 1989, 54, 1230–1232.
1-(2-Phenylsulfanylethyl)-2-methoxybenzene (entry 7):
Colourless liquid; IR (neat): 1438, 1475, 1580 cmÀ1 1H
;
3. (a) Kanagasabapathy, S.; Sudalai, A.; Benicewicz, B. C.
Tetrahedron Lett. 2001, 42, 3791–3794, and references cited
therein; (b) Kumar, P.; Pandey, R. K.; Hegde, V. R. Synlett
1999, 1921–1922; (c) Converso, A.; Saaidi, P.-L.; Sharpless,
K. B.; Finn, M. G. J. Org. Chem. 2004, 69, 7336–7339; (d)
Braga, A. L.; Silveira, C. C.; Dornelles, L.; Zeni, G.;
Galarza, F. A. D.; Wessjohann, L. A. Synth. Commun.
1995, 25, 3155–3162.
4. (a) Ranu, B. C.; Mandal, T.; Samanta, S. Org. Lett. 2003, 5,
1439–1441; (b) Ranu, B. C.; Mandal, T. J. Org. Chem.
2004, 69, 5793–5795; (c) Ranu, B. C.; Mandal, T. Synlett
2004, 1239–1242; (d) Ranu, B. C.; Chattopadhyay, K.;
Banerjee, S. J. Org. Chem. 2006, 71, 423–425; (e) Ranu, B.
C.; Mandal, T. Tetrahedron Lett. 2006, 47, 2859–2861.
5. Representative experimental procedure for the cleavage of
diphenyl disulfide and subsequent anti-Markovnikov addi-
tion to a-methyl styrene (Table 1, entry 2). Indium(I) iodide
NMR (CDCl3, 300 MHz): d 3.05–3.10 (m, 2H), 3.25–3.30
(m, 2H), 3.88 (s, 3H), 6.92–7.02 (m, 2H), 7.22–7.50 (m, 7H);
13C NMR (CDCl3, 75 MHz): d 31.5, 33.5, 55.7, 110.9,
121.0, 126.0, 128.4, 129.1 (2C), 129.3 (2C), 129.6, 130.8,
137.5, 158.0. Anal. Calcd for C15H16OS: C, 73.73; H, 6.60.
Found: C, 73.51; H, 6.45.
1-[2-(4-Chlorophenyl)sulfanylethyl]-4-methoxybenzene
(entry 8): Colourless oil; IR (neat): 1439, 1478, 1582 cmÀ1
;
1H NMR (CDCl3, 300 MHz): d 2.81–2.86 (m, 2H), 3.06–
3.12 (m, 2H), 3.76 (s, 3H), 6.81–6.84 (m, 2H), 7.07–7.24 (m,
6H); 13C NMR (CDCl3, 75 MHz): d 34.6, 35.6, 55.2, 113.9
(2C), 127.8, 128.9 (2C), 129.4 (2C), 130.6 (2C), 132.0, 133.9,
158.2. Anal. Calcd for C15H15ClOS: C, 64.62; H, 5.42.
Found: C, 64.40; H, 5.25.
1-(2-Phenylsulfanylethyl)-3,4-methylenedioxybenzene (entry
9): Colourless liquid; IR (neat): 1246, 1439, 1488,
1
1583 cmÀ1; H NMR (CDCl3, 300 MHz): d 2.86–2.91 (m,

6914
B. C. Ranu, T. Mandal / Tetrahedron Letters 47 (2006) 6911–6914
2H), 3.14–3.19 (m, 2H), 5.96 (m, 2H), 6.67–6.80 (m, 3H),
75 MHz): d 32.9, 34.5, 123.2, 125.4, 125.5, 126.0, 126.1,
126.3, 127.2, 128.8, 128.9 (2C), 129.0, 129.5 (2C), 131.5,
133.8, 136.1. Anal. Calcd for C18H16S: C, 81.77; H, 6.10.
Found: C, 81.57; H, 5.95.
7.20–7.42 (m, 5H); 13C NMR (CDCl3, 75 MHz): d 35.2
(2C), 100.7, 108.1, 108.8, 121.3, 125.8, 128.8 (2C), 129.1
(2C), 133.9, 136.2, 146.0, 147.5. Anal. Calcd for C15H14O2S:
C, 69.74; H, 5.46. Found: C, 69.51; H, 5.33.
1-[2-(4-Chloro-phenylsulfanyl)ethyl]-naphthalene
(entry
1-(2-Butylsulfanylethyl)-3,4-dimethoxybenzene (entry 10):
13): Colourless liquid; IR (neat): 1437, 1475, 1596 cmÀ1
;
Colourless liquid; IR (neat): 1437, 1477, 1583 cmÀ1
;
1H
1H NMR (CDCl3, 300 MHz): d 3.07–3.13 (m, 2H), 3.16–
3.22 (m, 2H), 7.15–7.42 (m, 8H), 7.68–7.88 (m, 3H); 13C
NMR (CDCl3, 75 MHz): d 31.9, 33.8, 122.2, 124.5, 124.6,
125.2, 125.5, 126.4, 127.0, 127.7, 127.9, 128.2 (2C), 129.8
(2C), 129.9, 132.7, 134.9. Anal. Calcd for C18H15ClS: C,
72.35; H, 5.06. Found: C, 72.11; H, 4.94.
NMR (CDCl3, 300 MHz): d 0.92 (t, J = 7.20 Hz, 3H), 1.35–
1.45 (m, 2H), 1.51–1.63 (m, 2H), 2.54 (t, J = 7.20 Hz, 2H),
2.72–2.86 (m, 4H), 3.86 (s, 3H), 3.88 (s, 3H), 6.70–6.82 (m,
3H); 13C NMR (CDCl3, 75 MHz): d 13.5, 21.8, 31.6, 31.9,
33.7, 35.8, 55.6, 55.7, 111.1, 111.7, 120.2, 133.2, 147.4,
148.7. Anal. Calcd for C14H22O2S: C, 66.10; H, 8.72.
Found: C, 65.90; H, 8.59.
6. Nobrega, J. A.; Goncalves, S. M. C.; Peppe, C. Tetrahedron
Lett. 2000, 41, 5779–5782.
1-(2-Phenylsulfanylethyl)-naphthalene (entry 12): Colour-
7. Lewis, E. S.; Butler, M. M. J. Am. Chem. Soc. 1976, 98,
2257–2260.
less liquid; IR (neat): 1439, 1477, 1579 cmÀ1 1H NMR
;
(CDCl3, 300 MHz): d 3.20–3.28 (m, 2H), 3.33–3.39 (m, 2H),
8. Baciocchi, E.; Lanzalunga, O.; Pirozzi, B. Tetrahedron
1997, 53, 12287–12298.
7.18–7.49 (m, 9H), 7.70–7.90 (m, 3H); 13C NMR (CDCl3,