One-pot catalyst-free synthesis of β-and γ-hydroxy sulfides using diaryliodonium salts and microwave irradiation

Article abstract of DOI:10.1002/ejoc.201201313

A simple and rapid one-pot protocol is described for the preparation of α- and β-hydroxy sulfides. The direct solvent-free microwave irradiation of diaryliodonium salts, potassium thiocyanate, and ethylene glycol/β-propylene glycol without any catalyst or base affords the final compounds in good yields (65-95 %) in around 10-25 min. Copyright

Full text of DOI:10.1002/ejoc.201201313

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201313
One-Pot Catalyst-Free Synthesis of β- and γ-Hydroxy Sulfides Using
Diaryliodonium Salts and Microwave Irradiation
Buchi Reddy Vaddula,[a] Rajender S. Varma,*[a] and John Leazer*[a]
Keywords: Iodine / Cross-coupling / Sulfur / Microwave chemistry / Thionation
A simple and rapid one-pot protocol is described for the
preparation of α- and β-hydroxy sulfides. The direct solvent-
free microwave irradiation of diaryliodonium salts, potassium
thiocyanate, and ethylene glycol/β-propylene glycol without
any catalyst or base affords the final compounds in good
yields (65–95%) in around 10–25 min.
hydroxy sulfides.[20] This protocol requires a stoichiometric
amount of triphenylphosphane (1 equiv.) and generates tri-
phenylphosphane oxide as a byproduct. However, a simple
and sustainable method that avoids additional reagents
such as triphenylphosphane and the isolation of aryl thiocy-
anate intermediates from inexpensive starting materials is
therefore highly desirable. In our continued quest to explore
the application of hypervalent iodine reagents[21] and keep-
ing in view the uses associated with hydroxy sulfides, the
synthesis of β- and γ-hydroxy sulfides by using readily avail-
able potassium thiocyanate and ethylene glycol/propylene
glycol with diaryliodonium salts has been attempted. The
idea of the intermediacy of this protocol for various appli-
cations from simple starting materials is represented in
Scheme 1.
Introduction
C–S coupling is an important tool in the organic chem-
ist’s toolbox especially when its application in organic, me-
dicinal, and materials chemistry is kept in view.[1] β- and γ-
Hydroxy sulfides are important organic intermediates that
possess various applications; they have been used in the
synthesis of biologically active compounds that show anti-
cancer, anti-HIV, and 5-HT binding properties;[2] they have
been used in the synthesis of crown ether ring-fused uridine
analogs[3] and aryl vinyl sulfones;[4] they can be used as base
protecting groups for thymidine analogs[5] and in the con-
struction of natural products,[6] metallophthalocyanines,[7]
organolithium complexes,[8] and α,β-unsaturated lactones.[9]
The development of an efficient and simple protocol for
the synthesis of hydroxy sulfides is therefore important. Ge-
neral routes for their preparation involve nucleophilic ring
opening of epoxides. Reported methods include ring open-
ing of epoxides with thiols catalyzed by alumina,[10] Lewis
[4,11]
[12]
or Brønsted acids,
polyethylene glycol (PEG) 4000,
[13]
zinc chloride,
DABCO or triethylamine,[14] and ionic li-
quids.[15] They are also prepared by the reaction of aryl
bromides with thiols catalyzed by PEG-400 and nickel in
the presence of base,[16] reaction of thiols with cyclic car-
bonates catalyzed by large-pore zeolites,[17] heating thiols
with ethyl potassium xanthogenate in the presence of
CuO,[18] and alkoxide-directed iodine–magnesium exchange
at sp3 centers.[19] Heating aryl thiocyanates with ethylene
glycol in the presence of triphenylphosphane also affords
[a] Sustainable Technology Division, National Risk Management
Research Laboratory, U.S. Environmental Protection Agency,
26 West Martin Luther King Drive, MS 443,
Cincinnati, OH 45268, USA
Scheme 1. General representation of the synthesis and uses of hy-
droxy sulfides.
Fax: +1-513-569-7677
Diaryliodonium salts are trivalent iodine compounds
that belong to the class of hypervalent iodine reagents with
two carbon ligands. They are nontoxic, thermally stable,
and nonexplosive. These intermediates find applications in
medicinal chemistry, organic chemistry, and photochemis-
try.[22] Recently, there has been a significant improvement
E-mail: Leazer.John@epa.gov
Varma.Rajender@epa.gov
Homepage: http://www.epa.gov/nrmrl/std/
organic_reactions.html
http://www.epa.gov/nrmrl/std/green_chem_nano.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201313.
6852
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 6852–6855

One-Pot Catalyst-Free Synthesis of β- and γ-Hydroxy Sulfides
in the synthesis of these versatile precursors, as one-pot pro- Table 1. Synthesis of β- and γ-hydroxy sulfides 3a–j.[a]
tocols have been developed from the corresponding arenes
Entry
Ar
Iodonium n[b] Product Time
Yield[c]
[%]
and elemental iodine or arenes and aryl iodides.[23]
salt
[min]
1
2
3
4
5
6
7
8
9
10
C6H5
4-tBuC6H4
4-BrC6H4
4-OMeC6H4
2,4,6-(Me)3C6H2
C6H5
4-tBuC6H4
4-BrC6H4
4-OMeC6H4
2,4,6-(Me)3C6H2
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
2
2
2
2
2
3
3
3
3
3
3a
3b
3c
3d
3e
3f
3g
3h
3i
10
25
10
20
10
15
20
10
20
15
85
80
82
95
75
92
85
80
90
65
Results and Discussion
When diphenyliodonium triflate (1a), potassium thiocya-
nate, and ethylene glycol (2a) were allowed to react over-
night at 120 °C under a N2 atmosphere, product 3a was
obtained in high yield, along with the formation of iodo-
benzene as a byproduct (Scheme 2).
3j
[a] Reaction conditions:
A
mixture of diaryliodonium salt
(1.0 mmol), KSCN (2.0 mmol), and ethylene glycol (1 mL) was ir-
radiated in a microwave oven for 10–25 min at 120 °C. [b] n = 2 for
ethylene glycol (2a) and n = 3 for β-propylene glycol (2b). [c] Iso-
lated yield.
Scheme 2. Synthesis of 3a under conventional heating.
In an attempt to expedite the reaction, the same compo-
nents were irradiated under microwave (MW) conditions in
the absence of any catalyst or reaction solvent to afford
product 3a in 20 min at 100 °C (CEM Discover microwave
system). The reaction conditions were optimized for time
and temperature (MW, 120 °C, 10 min) to finally provide
product 3a in 85% isolated yield. The synthesis of com-
pound 3a was also attempted by using diphenyliodonium
salts with counterions such as triflate, tosylate, hexafluoro-
phosphate, and bromide. The reaction afforded high yields
of the product in all cases. However, the bromide counter-
ion competed with thiocyanate as a nucleophile, which re-
sulted in the formation of a small amount of phenyl brom-
ide.
The protocol was subsequently extended to diaryliodon-
ium salts 1b–e and β-propylene glycol (2b) to synthesize
products 3b–j in good yields (Scheme 3, Table 1). However,
the scope of the reaction is limited to diols. Primary
alcohols, such as ethanol and methanol, failed to afford the
desired products under similar conditions.
The protocol was studied for the reaction of 1a with glyc-
erol (Scheme 4). Diol 3k was obtained regioselectively along
with diphenyl disulfide after only 20 min under MW heat-
ing.
Scheme 4. Reaction of diphenyliodonium triflate with glycerol.
Similarly, when 1a was allowed to react with 1,3-butane-
diol under MW heating (Scheme 5), it regioselectively af-
forded 3m in 75% yield along with small amounts of di-
phenyl sulfide and diphenyl disulfide.
Scheme 5. Reaction of diphenyliodonium triflate with 1,3-butane-
diol.
Scheme 3. General route for the synthesis of hydroxy sulfides 3.
To study the course of this one-pot transformation, the
Triflate 1a was allowed to react with glycol 2b for 15 min reaction of 1a with potassium thiocyanate was carried out
to provide product 3f in 92% yield. The reaction of triflate under MW irradiation in DMF to generate phenyl thiocya-
1b with 2a and 2b yielded products 3b and 3g in 80 and nate (4a) in situ.[22d] Addition of ethylene glycol to this in-
85% yield, respectively, in 20 min. Similarly, tosylate 1d re- termediate and further heating resulted in the formation of
acted efficiently with glycols 2a and 2b to afford products product 3a in 75% yield (Scheme 6). At this stage, the
3d and 3i in high yields (95 and 90%, respectively). The mechanism for the one-pot formation of hydroxy sulfides
relatively fast reaction of triflate 1c with 2a and 2b (reaction and the regioselective reaction with primary alcohols is not
time: 10 min) also afforded products 3c and 3h in 82 and clearly understood. However, it is inferred from the above
80% yield, respectively. Sterically bulky tosylate 1e, how- experiment that the reaction proceeds via the in situ forma-
ever, afforded products 3e and 3j in relatively moderate tion of the aryl thiocyanate intermediate, followed by thion-
yields (75 and 65%, respectively).
ation of glycol (Scheme 6).
Eur. J. Org. Chem. 2012, 6852–6855
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www.eurjoc.org
6853

B. R. Vaddula, R. S. Varma, J. Leazer
SHORT COMMUNICATION
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Scheme 6. Probable reaction sequence for the three-component re-
action.
Conclusions
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In conclusion, an efficient and facile multicomponent C–
S cross-coupling protocol has been developed for the prepa-
ration of β- and γ-hydroxy sulfides under microwave irradi-
ation conditions. The reaction of diaryliodonium salts, po-
tassium thiocyanate, and 1,2-ethanediol/1,3-propanediol in
the absence of any other catalyst or reaction solvent gener-
ates the desired products in high yields. This protocol as-
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ates and eliminates the need for additional reagents such as
triphenylphosphane that generates triphenylphosphane ox-
ide as a byproduct. The highlights of the protocol include
readily available starting materials, short reaction times, and
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Experimental Section
Representative Procedure for the Preparation of 2-(Phenylthio)eth-
anol: A tube containing diphenyliodonium triflate (1.0 mmol), po-
tassium thiocyanate (2.0 mmol), and ethylene glycol (1 mL) was
heated at 120 °C for 20 min in a CEM Discover microwave system
in the standard mode. Upon completion of the reaction, the mix-
ture was diluted with water and extracted into ethyl acetate. The
organic layer was dried with anhydrous sodium sulfate and evapo-
rated under reduced pressure. The crude residue was purified by
flash chromatography over silica gel column (20% EtOAc/hexane)
to afford the pure product in 85% yield. 1H NMR (300 MHz,
CDCl3): δ = 7.39–7.35 (m, 2 H), 7.30–7.24 (m, 2 H), 7.22–7.16 (m,
1 H), 3.12 (t, J = 6.0 Hz, 2 H), 3.08 (t, J = 6.0 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 134.99, 130.09, 129.05, 126.61, 60.40,
37.14 ppm. MS (EI): m/z = 154.0 [M]+.
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Acknowledgments
B. R. V. is supported by the Postgraduate Research Program at the
National Risk Management Research Laboratory administered by
the Oak Ridge Institute for Science and Education through an in-
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Received: October 4, 2012
Published Online: November 2, 2012
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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6855