Conjugate addition of unactivated thiols to α,β-unsaturated ketones catalyzed by a bifunctional rhenium(V)-oxo complex

Article abstract of DOI:10.1016/j.tetlet.2012.03.075

ReOCl₃(OPPh₃)(S(CH₃)₂) has been found to be an efficient bifunctional catalyst for the 1,4-addition of thiols to α,β-unsaturated ketones. The addition of thiophenol derivatives and alkyl thiols proceeds under mi

Full text of DOI:10.1016/j.tetlet.2012.03.075

Tetrahedron Letters 53 (2012) 2712–2714
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Conjugate addition of unactivated thiols to
a,b-unsaturated ketones
catalyzed by a bifunctional rhenium(V)–oxo complex
⇑
Allan Peng, Ross Rosenblatt, Kristine Nolin
Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
ReOCl3(OPPh3)(S(CH3)2) has been found to be an efficient bifunctional catalyst for the 1,4-addition of thi-
Received 16 February 2012
Revised 8 March 2012
Accepted 20 March 2012
Available online 26 March 2012
ols to
a,b-unsaturated ketones. The addition of thiophenol derivatives and alkyl thiols proceeds under
mild reaction conditions without pre-activation of the thiol or exogenous base. Reactions of aryl, alkyl,
and cyclic enones produce the corresponding b-sulfanyl ketones in good to excellent yield.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Rhenium
Conjugate addition
Thiols
Bifunctional
Catalytic
Conjugate addition reactions are one of the most important syn-
thetic tools for strategic bond formation. The conjugate addition of
thiols to a,b-unsaturated ketones provides access to b-sulfanyl ke-
air- and moisture-tolerant Re(V)–oxo complex 1 was identified as
a catalyst for the reaction. Complex 1 displays several convenient
properties that increase its practical value. The complex requires
no special handling and no efforts need to be made to exclude oxy-
gen or water from the reaction. Upon completion of the reaction,
the catalyst can be triturated and removed by filtration, thus elim-
inating the need for aqueous extraction, which is typically required
for reactions facilitated by Brønsted acids and bases.
tones. The synthetic utility and medicinal properties of these com-
pounds have been the subject of numerous reports. Recently, b-
aryl-b-sulfanyl ketone analogs were found to have antiproliferative
activity in a number of breast cancer cell lines.1 In addition, these
functional scaffolds have been reported to have antiviral activity.2
The synthetic utility of b-sulfanyl ketones has been demonstrated
in their application as alkene protecting groups.3,4 They have also
been used as b-acylvinyl cation precursors5 and homoenolate
equivalents.6 Pioneering efforts to synthesize b-sulfanyl ketones
through the conjugate addition of thiols to enones include the
use of catalytic Brønsted acids and bases7–13 and Lewis acids such
as Bi3+ and In3+ salts.14–16 In pursuit of a general method for the
conjugate addition of thiols to
a,b-unsaturated ketones, we envi-
sioned the use of a bench-top stable, bifunctional rhenium(V)–
oxo complex as a catalyst for the transformation. It is proposed
that the Lewis acidic metal center will activate the enone while
the Brønsted basic oxo ligand will facilitate proton transfer. The
application of these complexes to this transformation also provides
an opportunity to tune reactivity and selectivity of the catalyst
through modifications of the associated ligands.
We first investigated the addition of 4-methylbenzenethiol
(1.2 equiv) to 4-phenyl-3-buten-2-one (2) in the presence of
2 mol % of 1 under ambient conditions (Eq. 1). The reaction pro-
ceeded at room temperature, in ethyl acetate (2.0 M) without
pre-activation of the thiol or addition of exogenous base. Gratify-
ingly, b-phenyl-b-sulfanyl ketone 3 was isolated in 85% yield. The
reaction also proceeded with similar yields in diethyl ether and
dichloromethane but was less efficient in aromatic solvents, such
as toluene. Only modest product yields were observed when the
reaction was run in hexanes. Because of its industrial and environ-
mental advantages,18 ethyl acetate was utilized as the solvent for
this method.
The development of a highly efficient and practical method for
the conjugate addition of thiols to
a,b-unsaturated ketones is de-
scribed. After a brief catalyst screen,17 commercially available,
⇑
Corresponding author. Fax: +1 804 287 1897.
E-mail address: knolin@richmond.edu (K. Nolin).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.075

A. Peng et al. / Tetrahedron Letters 53 (2012) 2712–2714
2713
Table 2
Addition of thiophenol derivatives to 4-phenyl-3-buten-2-one
ð1Þ
The addition of 4-methylbenzenethiol to aryl and alkyl substi-
tuted a
,b-unsaturated ketones is summarized in Table 1.19
Electron rich and electron deficient 4-aryl-3-buten-2-one deriv-
atives reacted very well (Table 1, entries 1 and 2) providing the
corresponding thioethers in high yield (83–89%). Substrates bear-
ing heteroaromatic substitution at the b-position performed com-
parably well (entry 3, 88% yield). Aromatic substitution was not
required for reactivity as evidenced by alkyl substituted enone
4d (entry 4, 85%). Of particular note, the conjugate addition to
mesityl oxide (4e) readily provided the corresponding tertiary thi-
oether 5e in excellent yield (97%). In addition to the substrates
listed in Table 1, this catalytic conjugate addition reaction was able
to be extended to cyclic enones. The addition of 4-methybenze-
nethiol to cyclohexenone readily provided thioether 6 in 75% yield
(Eq. 2).
Entry
R
Yield (%)
1
2
3
4
5
OCH3
H
Cl
Br
NO2
7a
7b
7c
7d
7e
97
91
85
91
75
8a
8b
8c
8d
8e
Table 3
Addition of thiophenol derivatives to mesityl oxide
ð2Þ
The tolerance of the reaction to changes in the electronic struc-
ture of the thiophenol derivative was examined using 4-phenyl-3-
butene-2-one (2) as the model substrate. Electron-rich thiophenol
7a was (Table 2, entry 1) readily added to enone 2 to give the cor-
responding thioether in 97% yield. Electron-deficient thiophenols
were only slightly less reactive leading to the formation of thio-
ethers 8c–e in very good yield (75–91%, entries 3–5). Notable is
the tolerance of the reaction to the presence of halide substitution
on the aromatic ring, thus providing thioethers with a handle for
additional synthetic manipulation.
Aryl substituted enones, as represented by enone 2, are toler-
ated by a number of thioconjugate addition methods.16,20 There-
fore, when addressing the generality of conjugate addition
reactions involving thiophenol derivatives, mesityl oxide (4e)
was also examined. A similar trend in reactivity to those described
above was observed for the addition of electron-rich (Table 3, entry
1) and electron-deficient (entries 3–5) thiophenol derivatives to
mesityl oxide. The corresponding tertiary thioethers were isolated
in good to excellent yield (78–93%).
Entry
R
Yield (%)
1
2
3
4
5
OCH3
H
Cl
Br
NO2
7a
7b
7c
7d
7e
78
82
93
88
78
9a
9b
9c
9d
9e
tion conditions. Thioethers 10 and 11 were isolated in good yield,
80% and 78%, respectively (Eqs. 3 and 4). This is a notable improve-
ment on a previously reported yield for 11 of 52%, which was ob-
tained under acid catalyzed conditions.21 To date, we have
encountered no structural limitation with regard to the thiol.
ð3Þ
ð4Þ
The reactivity of alkyl thiols in the conjugate addition was
examined using dodecanethiol. The addition to 4-phenyl-3-bu-
tene-2-one and mesityl oxide proceeded under the standard reac-
A reaction mechanism is proposed for the conjugate addition of
unactivated thiols to a,b-unsaturated ketones catalyzed by Re(V)–
oxo complex 1, illustrating how this bifunctional Re–oxo complex
is especially suited for this reaction (Scheme 1). We hypothesize
that catalytic reaction proceeds through Lewis acid activation of
the enone by the metal center following ligand dissociation. Addi-
tion of the thiol and proton transfer leads to the generation of a
putative rhenium–enolate. Tautomerization regenerates the oxo li-
gand and facilitates the release of the product closing the catalytic
cycle. The generation of rhenium–enolate creates the possibility
that this proposed intermediate may add to another equivalent
of enone; no such products were observed.22
Table 1
Addition of 4-methylbenzene thiol to differentially substituted enones
Entry
R1
R2
R3
Yield (%)
In conclusion, Re(V)–oxo complex 1 has been shown to be a ver-
satile catalyst for the conjugate addition of unactivated thiols to
1
2
3
4
5
6
4-OCH3-Ph
4-ClPh
Thiophene
Pentyl
CH3
H
H
H
H
CH3
H
CH3
CH3
CH3
CH3
CH3
Ph
4a
4b
4c
4d
4e
4f
83
89
88
85
97
69
5a
5b
5c
5d
5e
5f
a,b-unsaturated ketones. A wide range of enones and thiols were
found to be reactive under the mild reaction conditions. Elabora-
tion of this reaction, including the pursuit of enantioselective addi-
tions, is currently underway in our laboratories and will be
reported in due time.
Ph

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A. Peng et al. / Tetrahedron Letters 53 (2012) 2712–2714
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17. Re(O)Cl3(PPh3)2, Re(O)I2(OCH2Ph)(PPh3)2 and Re(O)I2(OCH3)(PPh3)2 were
catalytically active but resulted in yields that were typically 20–43% lower
than those obtained with 1.
Scheme 1. Proposed catalytic cycle.
Acknowledgments
18. US Department of Health and Human Services; Food and Drug Administration;
Center for Drug Evaluation and Research, Center for Biologics Evaluation and
Research. Guidance for Industry. Q3C—Tables and List: International Conference
on Harmonisation, November 2003.
We gratefully acknowledge the University of Richmond and the
Thomas F. and Kate Miller Jeffress Memorial Trust for financial sup-
port. We thank Dr. Wade Downey for many helpful discussions.
19. General procedure for addition of thiol to enones: At room temperature under an
ambient atmosphere, EtOAc (2.0 mL, 2.0 M) was added to a scintillation vial
containing thiol (1.2 mmol, 1.2 equiv). Enone (1 mmol, 1 equiv) then
Re(O)Cl3(SMe2)(OPPh3) (13.0 mg, 0.02 mmol, 0.02 equiv) were added to the
solution. The reaction solution was stirred at room temperature and monitored
by TLC. Upon completion, the reaction was quenched by diluting with hexanes
and filtering the solution through a plug of celite to remove the catalyst. The
solvents were evaporated and the residue was purified by column
chromatography yielding the corresponding b-sulfanyl ketone. (silica gel
chromatography, eluent 10–20% EtOAc in hexanes).
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/j.tet-
let.2012.03.075. These data include MOL files and InChiKeys of
the most important compounds described in this article.
20. Yadav, J. S.; Reddy, B. V. S.; Baishya, G. J. Org. Chem. 2003, 68, 7098–7100. and
references therein..
21. Stephens, J.; Hydock, J.; Kleinholz, M. P. J. Am. Chem. Soc. 1951, 73, 4050.
22. Re(V)–oxo complexes have been reported to facilitate oxidation and oxygen
transfer reactions; it should be noted that no oxidation was observed. Arias, J.;
Newlands, C. R.; Abu-Omar, M. M. Inorg. Chem. 2001, 40, 2185–2192.
References and notes
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Nayak, V. L.; Siddiqui, J. A.; Chakravarti, B.; Saxena, R.; Dwivedi, A.; Siddiquee,