Indium(iii) catalysed substrate selective hydrothiolation of terminal alkynes

Article abstract of DOI:10.1039/c2cc30350g

In(OTf)₃ is reported as the first catalyst having the ability to selectively catalyse both Markovnikov and anti-Markovnikov hydrothiolation of terminal alkynes under identical reaction conditions depending upon the nature of the thiol employed.

Full text of DOI:10.1039/c2cc30350g

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COMMUNICATION
Indium(III) catalysed substrate selective hydrothiolation of terminal
alkynesw
Rupam Sarma, Nimmakuri Rajesh and Dipak Prajapati*
Received 16th January 2012, Accepted 2nd March 2012
DOI: 10.1039/c2cc30350g
In(OTf)3 is reported as the first catalyst having the ability to
selectively catalyse both Markovnikov and anti-Markovnikov
hydrothiolation of terminal alkynes under identical reaction
conditions depending upon the nature of the thiol employed.
of these methods,7–9 to the best of our knowledge, there is no
report of any catalytic process that selectively mediates both
the pathways under identical reaction conditions. Previously,
we have demonstrated that indium(III) effectively activates
terminal alkynes in various reactions such as coupling reaction,
nucleophilic addition, hydroamination and hydroalkylation
reaction.10 Indium(III) is also known to catalyse intra- and
intermolecular addition of thiols to non-activated olefins in a
Markovnikov fashion.11 Herein we report the first example of
indium(III) triflate as a single catalyst that can selectively catalyse
both Markovnikov and anti-Markovnikov hydrothiolation of
terminal alkynes to generate vinyl sulfides. Vinyl sulfides are an
important class of organic compounds as they are versatile
building blocks12 for functionalised molecules and serve as
synthetic intermediates13 in natural product synthesis.
Designing efficient and selective catalyst systems has always
been the primary focus in performing organic reactions.1 In
this regard, development of multi-functional catalysts2 that
can promote alternative reaction pathways depending on the
nature of the substrate is an interesting and intriguing area of
research that remains to be explored fully. The addition of
^
S–H bonds across C–C d systems, also known as hydrothiolation,
is a powerful and straightforward method for the construction of
vinyl sulfides.3 The addition reaction is believed to proceed via
either the radical,4 nucleophilic,5 or metal-catalysed6 pathway.
Although metal-catalysed anti-Markovnikov hydrothiolation
of terminal alkynes5b,7 is well-known, Markovnikov addition8
presents a significant synthetic challenge. Several catalytic
protocols containing Pd,8a Ni,8b,c Rh,8d–f Th,8g U8g and Zr8h
have been developed for Markovnikov addition of thiols to
terminal alkynes. Despite having drawbacks such as formation
of byproducts, requirement of an inert atmosphere, additives
and/or co-catalysts and pre-requisite for synthesis of the
catalyst system, these methodologies serve the purpose of accessing
the Markovnikov product in moderate to excellent yield. For
example, Weiss and Marks developed an organozirconium
catalysed process for Markovnikov hydrothiolation of alkynes
in good to excellent yield, but required an excess of the alkyne
for the transformation to take place.8h Beletskaya and
co-workers reported a Ni(II)-catalysed method but suffered
from the limitation of competing side reactions.8b Love and
co-workers developed and extended a Rh-catalysed Markovnikov
hydrothiolation of aromatic, aliphatic and benzylic thiols but
failed to obtain the desired product in the case of heteroaromatic
thiols.8d,e While hydrothiolation reactions of aryl, benzyl and
aliphatic thiols with terminal alkynes have been achieved via the
Markovnikov or the anti-Markovnikov pathway by one or more
In the present study, we demonstrate that indium(III) acts as
a selective catalyst for hydrothiolation reaction of terminal
alkynes with different thiols. These studies have revealed that
heteroaromatic thiols selectively add in a Markovnikov fashion,
while aromatic and aliphatic thiols add via an anti-Markovnikov
way under identical reaction conditions.
Preliminary studies were directed to investigate the catalytic
action of indium trifluoromethanesulfonate on the reaction of
terminal alkynes with heteroaromatic thiols as addition of
heteroaromatic thiols across alkynes has so far been an unmet
goal. Initially, reaction of 2-mercaptobenzothiazole 1a with
one equivalent of phenylacetylene 2a was carried out
(Scheme 1). Formation of the Markovnikov addition product
3a was observed in 50% yield when the reactants were refluxed
in toluene for 2 h by employing 5 mol% of In(OTf)3 as catalyst.
This result was quite exciting as Markovnikov hydrothiolation
is a difficult proposition under conventional conditions and
encouraged us to undertake a detailed study of the reaction. We
began by examining the reaction of 2-mercaptobenzothiazole
with phenylacetylene in the presence of catalytic amount of
In(OTf)3. Optimisation of the reaction conditions revealed that
the yield could be increased to 90% under reduced time (1 h)
Medicinal Chemistry Division, CSIR-North-East Institute of Science
& Technology, Jorhat 785006, Assam, India.
E-mail: dr_dprajapati2003@yahoo.co.uk; Fax: +91 376 2370011
w Electronic supplementary information (ESI) available: Detailed
experimental procedure, compound characterization data and NMR
spectra. See DOI: 10.1039/c2cc30350g
Scheme 1 Reaction of 2-mercaptobenzothiazole with phenylacetylene.
c
4014 Chem. Commun., 2012, 48, 4014–4016
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Table 2 Anti-Markovnikov hydrothiolation of phenylacetylenea
Table 1 Markovnikov hydrothiolation of terminal alkynesa
Time/ %
h
Yieldb
Entry Thiol 1
Acetylene 2 Product 3
1
1
90
Time/
h
Entry Thiol 1
Product 4
% Yieldb
85 (10 : 1)
2
3
4
5
6
7
1
88
85
86
85
85
88
1
2
2
2
3
4
5
6
1.5
1.5
1.5
1.5
1.7
85 (5 : 1)
80 (9 : 1)
78 (4 : 1)
85 (10 : 1)
82 (10 : 1)
2
3
1.5
3
7
8
2
80 (10 : 1)
8
3
85
80
82
75
(trace : 499)
1.5
2
9
2
9
90 (1 : 4)
10
1.5
a
Reaction conditions: thiol (5 mmol), phenylacetylene (6 mmol) and
In(OTf)3 (0.5 mmol) were refluxed in toluene (10 mL) till reaction
b
is complete. Yield of isolated products; figures in parentheses show
E/Z ratios; the E/Z ratio was determined by 1H NMR spectrum of the
crude product.
11
12
2
85
1
2
84
86
The effect of the indium catalyst on the hydrothiolation
reaction of phenylacetylene was further explored by reacting it
with an aliphatic thiol under identical reaction conditions. So,
when cyclohexyl mercaptan was reacted with 1.2 equivalents
of phenylacetylene in refluxing toluene by employing 10 mol%
In(OTf)3 as catalyst, an anti-Markovnikov hydrothiolation
product was obtained in excellent yield within a short time.
This unprecedented catalytic activity of indium to switch from
the Markovnikov to the anti-Markovnikov pathway upon
changing the substrate is quite significant and hence a study
was undertaken to examine this phenomenon.14 Various aliphatic
and aromatic thiols were investigated and the results obtained are
summarised in Table 2. It was observed that cyclic as well as
acyclic aliphatic thiols (Table 2, entries 1–4) and aromatic thiols
with both electron-donating and withdrawing substituents
(Table 2, entries 5–9) participated in the reaction to generate a
mixture of E and Z-vinyl sulfides in excellent yield. In all cases,
exclusive anti-Markovnikov hydrothiolation was observed and
formation of side products could not be detected. The thermo-
dynamically stable E-isomer was favoured over the Z-isomer in
13
a
Reaction conditions: thiol (5 mmol), terminal alkyne (6 mmol) and
In(OTf)3 (0.5 mmol) were refluxed in toluene (10 mL) till reaction is
b
complete. Yield of isolated products.
when 10 mol% of the catalyst and 1.2 equivalents of the
alkyne were employed (see Table S1, ESIw). Using these
optimised conditions, the scope of the reaction was then
investigated with a number of different terminal alkynes as
well as heteroaromatic thiols and the results obtained are
summarised in Table 1. Alkynes with an electron donating
or a halogen substituent on the aromatic ring (entries 1–4,
Table 1) and various heteroaromatic thiols (entries 1, 6 and 7,
11 and 12, Table 1) were examined. We were pleased to find
that smooth reaction occurred in all cases with excellent yield
within a very short time period of 1–3 h. It is important to note
here that exclusive Markovnikov addition took place and
formation of side-products could not be detected.
c
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Chem. Commun., 2012, 48, 4014–4016 4015

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most cases. Quite interestingly though, the reaction with
p-nitrothiophenol and o-aminothiophenol yielded the Z-isomer
as the major product. When a competing amine functionality is
present in the aromatic ring, such as in o-aminothiophenol
(Table 2, entry 9), exclusive hydrothiolation was observed. This
is an important fact considering that indium is known to catalyse
hydroamination of terminal alkynes with aromatic amines.10d
Although mechanistic studies were not performed, the observed
switch in selectivity might arise because of difference in the
nucleophilic character of the reacting thiols. It is believed that in
the case of alkyl and phenyl thiols, an initial indium alkynylide is
formed from indium(III) triflate and the terminal alkyne15 which
then reacts with the thiol to give the anti-Markovnikov addition
product. However, in the case of heteroaromatic thiols, an indium
sulfide complex is formed in the first step followed by regioselective
addition of the thiol to the alkynes to give the corresponding
Markovnikov-type vinylic sulfide.9e Further studies are underway
to understand the mechanism and role of the substrate in selecting
the preferred pathway for the reaction.
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In summary, we have reported indium(III) triflate as the
first catalyst for substrate selective Markovnikov and anti-
Markovnikov hydrothiolation of terminal alkynes in the
absence of any other additive and/or co-catalyst. The nature
of the substrate is found to be the key factor in determining the
selectivity of the transformation. Heteroaromatic thiols have
been found to undergo selective Markovnikov hydrothiolation,
whereas aromatic and aliphatic thiols show anti-Markovnikov
selectivity under identical reaction conditions. Excellent yield,
regioselectivity, short reaction time and no additional require-
ment of additives make it an attractive protocol for obtaining
vinyl sulfides.
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We thank DST, New Delhi, for financial support to this
work. RS and NR thank CSIR, New Delhi, and UGC,
New Delhi, respectively, for the award of research fellowships.
We also thank the Director, NEIST, Jorhat, for his keen
interest and constant encouragement.
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c
4016 Chem. Commun., 2012, 48, 4014–4016
This journal is The Royal Society of Chemistry 2012