Rhodium-catalyzed alkyne hydrothiolation with aromatic and aliphatic thiols

Article abstract of DOI:10.1021/ja055096h

Alkyne hydrothiolation is a potentially attractive method for the formation of vinyl sulfides, which are valuable synthetic intermediates. Known methods for hydrothiolation using alkyl thiols are quite limited. We report herein that Tp*Rh(PPh₃)

Full text of DOI:10.1021/ja055096h

Published on Web 11/23/2005
Rhodium-Catalyzed Alkyne Hydrothiolation with Aromatic and Aliphatic
Thiols
Changsheng Cao, Lauren R. Fraser, and Jennifer A. Love*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia,
VancouVer, British Columbia V6T 1Z1, Canada
Received July 27, 2005; E-mail: jenlove@chem.ubc.ca
The presence of sulfur in naturally occurring compounds and
synthetic materials, coupled with the utility of sulfur-based reagents
in synthetic methodology, illustrates the need for efficient and
versatile strategies for the construction of molecules containing
sulfur.1 However, because sulfur compounds are often considered
to be incompatible with metal-catalyzed reactions, the catalytic
Figure 1. Complex I, Tp*Rh(PPh3)2.
reactivity of thiols has been explored to a much lesser extent than
that of amines, alcohols, and phosphines. Nevertheless, some
reactivity of complex I. Notably, these reactions are conducted on
10 mmol scale of limiting reagent, suggesting that even larger scale
catalytic reactions involving thiols have been developed.2 One such
process, alkyne hydrothiolation (eq 1), is an attractive method for
reactions are feasible. A variety of alkyl thiols underwent hydro-
the formation of vinyl sulfides, which are valuable as synthetic
thiolation with both aromatic and aliphatic alkynes (entries 1-8).
The lower yield with tert-butylacetylene is presumably due to steric
hindrance of the alkyne, as well as product volatility. With n-octyne,
intermediates in total synthesis3 and as precursors to a wide range
of functionalized molecules.1,4
selectivity for the branched product is somewhat diminished
(branched:linear ratio ) 12:1), and the branched product is
susceptible to isomerization (entry 8). Internal alkynes also react
and require heat for the reactions to proceed efficiently. For
example, diphenylacetylene provided a single isomer in 94% yield
(entry 9). An unsymmetrical internal alkyne proceeded with modest
regioselectivity in favor of the less-hindered isomer (entry 10); Pd
catalysts also give poor regioselectivity for hydrothiolation of similar
unsymmetrical internal alkynes using aryl thiols.7a,8a
Given the high activity of I for alkyl thiols, we sought to explore
the use of I for hydrothiolation reactions involving aryl thiols. The
reaction of phenylacetylene with thiophenol was selected for initial
study (Table 2, entry 1). A mixture of linear and branched
regioisomers was obtained, although the predominant regioisomer
using I is opposite of that obtained with other Rh complexes.8
Consequently, I generates the same regioisomer that is produced
using Pd catalysts. Hydrothiolation with complex I, however, occurs
much faster and under considerably milder conditions than with
the Pd complexes; the reaction using I proceeds at room temper-
ature, while the Pd-catalyzed reactions require prolonged times at
80 °C.7
Intrigued by the regioselectivity change using Tp* as a ligand
for Rh, we examined a series of arylacetylene and aryl thiol
substrates (Table 2). Isolated yields were excellent (83-90%), but
regioselectivities were modest (6:1 to 1.4:1). In all cases, the major
isomer was the branched isomer, which is separable from the minor
isomer using column chromatography. The presence of any
substituent on the aromatic ring of the alkyne or thiol substrates
was detrimental to the regioselectivity of the reaction. This lowered
regioselectivity could be indicative of a reversible reaction or change
in mechanism. Mechanistic studies are underway to address these
possibilities. Monitoring the reactions indicated in entries 1 and 4
revealed that the product ratio remained constant over the course
of both reactions. In addition, exposure of the major (branched)
product of entry 5 to the catalyst resulted in minimal equilibration
(<5%) over 48 h, suggesting that the low regioselectivity is not
due to reversibility.
Radical, nucleophilic, and metal-catalyzed hydrothiolation using
aryl thiols is well-precedented,5-8 but reactions using alkyl thiols
are less common. With alkyl thiols, linear products B and C are
accessible under radical9 and nucleophilic10 conditions. The branched
product A can be obtained by Michael addition when the alkyne
isomerizes to an allene or internal alkyne;11 these procedures are
consequently limited to certain aliphatic alkynes. Other methods
to prepare isomer A involve the use of Hg salts or elevated reaction
temperatures (>120 °C), which often results in poor regioselec-
tivity.12 Overall, synthetic approaches to branched alkyl vinyl
sulfides (A, R ) alkyl), which have significant potential for use in
synthesis, are very limited.
Although metal catalysts are reportedly ineffective for hydro-
thiolation using alkyl thiols,8,9,13,14 we postulated that highly
electron-rich metal complexes, such as rhodium pyrazolylborates,
would be sufficiently reactive to catalyze these reactions. Despite
the efficacy of rhodium pyrazolylborate complexes in stoichiometric
transformations involving bond activation,15 catalytic reactions are
comparatively rare.16 Even so, we reasoned that rhodium pyrazolyl-
borates offer significant promise for catalytic reactions involving
bond activation (i.e., S-H activation) as a fundamental step.
17
Tp*Rh(PPh3)2 (I, Tp* ) hydrotris(3,5-dimethylpyrazolyl)-
borate, Figure 1) was selected for initial study, as this complex is
noted for its ability to activate C-H,15a Sn-H,17b Si-H,17b and
S-H15c bonds. To our delight, a test reaction between benzylthiol
and phenylacetylene revealed that I is a highly active catalyst,
providing the branched isomer as the exclusive product within 20
min and in 90% isolated yield (Table 1, entry 1).
On the basis of this encouraging result, we selected a range of
alkyl thiols to probe the influence of steric and electronic perturba-
tions on the efficiency of hydrothiolation catalyzed by I. Most
reactions proceeded with excellent regioselectivity and good to
excellent isolated yields (63-94%), illustrating the outstanding
9
17614
J. AM. CHEM. SOC. 2005, 127, 17614-17615
10.1021/ja055096h CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Alkyne Hydrothiolation with Alkyl Thiols Using I
apparent with aryl thiols, we anticipate that mechanistic studies
will provide insight into the regioselectivity of this process. In
addition, we are currently exploring the origin of the typically high
selectivity with alkyl thiols relative to aryl thiols. We are also
exploring the use of I in other catalytic processes involving X-H
activation.
Acknowledgment. We thank the following for support of this
research: University of British Columbia (start-up funds), NSERC
(Discovery Grant, Research Tools and Instrumentation Grant), the
Canada Foundation for Innovation (New Opportunities Grant), and
the British Columbia Knowledge Development Fund.
Supporting Information Available: Complete experimental details
for all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1
DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst, unless otherwise noted.
b Conditions: A ) rt; B ) 20 min at 0 °C, warmed to 20 °C over 1 h; C
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Entrya
RSH
R1
Time (h)
Yield (%)b
A:Bc
1
2
3
4
5
Ph
Ph
Ph
Ph
2
10
2
1.5
23
84
89
90
83
85
6:1
p-CH3OC6H4
o,p-F2C6H3
3.2:1
2.6:1
1.4:1
1.7:1
p-CH3C6H4
p-BrC6H4
Ph
Ph
a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1
DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst. b Isolated yields. c Trace
amounts of C observed.
In summary, we have found that Tp*Rh(PPh3)2 (I) catalyzes the
hydrothiolation of a range of alkynes with both aryl and alkyl thiols.
The reactions with alkyl thiols proceeded with excellent regio-
selectivity, providing convenient access to branched alkyl vinyl
sulfides, which are difficult to synthesize by other means. Hydro-
thiolation reactions with aryl thiols were less selective, providing
a mixture of branched and linear products. Although no trend is
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