Green protocol for conjugate addition of thiols to α,β -unsaturated ketones using a [Bmim] PF6/H2O system

Article abstract of DOI:10.1021/jo034335l

α,β-Unsaturated ketones undergo conjugate addition rapidly with thiols in a hydrophobic ionic liquid [bmim] PF₆/H₂O solvent system (2:1) in the absence of any acid catalyst to afford the corresponding Michael adducts in high to quant

Full text of DOI:10.1021/jo034335l

SCHEME 1
Gr een P r otocol for Con ju ga te Ad d ition of
Th iols to r,â-Un sa tu r a ted Keton es Usin g a
[Bm im ]P F 6/H2O System
J . S. Yadav,* B. V. S. Reddy, and Gakul Baishya
Division of Organic Chemistry, Indian Institute of Chemical
Technology, Hyderabad-500 007, India
SCHEME 2
yadav@iict.ap.nic.in
Received March 13, 2003
Abstr a ct: R,â-Unsaturated ketones undergo conjugate ad-
dition rapidly with thiols in a hydrophobic ionic liquid
[bmim]PF6/H2O solvent system (2:1) in the absence of any
acid catalyst to afford the corresponding Michael adducts
in high to quantitative yields with excellent 1,4-selectivity
under mild and neutral conditions. The enones show en-
hanced reactivity in ionic liquids, thereby reducing reaction
times and improving the yields significantly. The use of ionic
liquids helps to avoid the use of either acid or base catalysts
for this conversion. The recovered ionic liquid was reused
four to five times with consistent activity.
aqueous workup for the catalyst separation, recycling and
disposal. Furthermore, some of them involve the use of
harsh conditions and expensive reagents. In many cases,
the yields and selectivities are far from satisfactory due
to the occurrence of several side reactions. Since orga-
nosulfur compounds have become increasingly useful and
important in the synthesis of biologically active com-
pounds such as the calcium antagonist diltiazem,8 the
development of simple, convenient, and environmentally
benign approaches are desirable.
In recent times, ionic liquids have emerged as an
alternative reaction media for the immobilization of
transition-metal catalysts, Lewis acids, and enzymes.9
They are being used as green solvents with unique
properties such as a wide liquid range, good solvating
ability, tunable polarity, high thermal stability, negligible
vapor pressure, and ease of recyclability. They are
referred to as “designer solvents” as their properties such
as hydrophilicity, hydrophobicity, Lewis acidity, viscosity,
and density can be altered by the fine-tuning of param-
eters such as the choice of organic cation, inorganic anion,
and the length of alkyl chain attached to an organic
cation. These structural variations offer flexibility to the
chemist to devise the most idealized solvent, catering to
the needs of any particular process.10
The conjugate addition of thiols to R,â-unsaturated
ketones to form carbon-sulfur bond constitutes a key
reaction in biosynthetic processes as well as in organic
synthesis.1,2 Consequently, a large number of methods
have been reported for the 1,4-addition of thiols to
electron-deficient olefins through the activation of thiols
by bases.3,4 In contrast, there are only a few reports of
thiol addition to enones activated by Lewis acids.5 Asym-
metric versions of Michael addition of thiols to R,â-
unsaturated ketones have also been reported using
cinchona alkaloids and proline-derived chiral amines to
produce enantiomerically enriched organosulfur com-
pounds.6 More recently, tetrabutylammonium bromide
has been reported as an efficient catalyst for this conver-
sion.7 However, many of these methods often involve the
use of an acid or a base catalyst which always demand
* To whom correspondence should be address. Fax: 91-40-27160512.
(1) (a) Fluharty, A. L. In The Chemistry of the Thiol Group; Patai,
S., Ed.; Wiely: New York, 1974; Part 2, p 589. (b) Clark, J . H. Chem.
Rev. 1980, 80, 429. (c) Fujita, E.; Nagao, Y. J . Bioorg. Chem. 1977, 6
287.
(2) (a) Trost, B. M.; Keeley, D. E. J . Org. Chem. 1975, 40, 2013. (b)
Shono, T.; Matsumura, Y.; Kashimura, S.; Hatanaka, K. J . Am. Chem.
Soc. 1979, 101, 4752. (c) Nishimura, K.; Ono, M.; Nagaoka, Y.;
Tomioka, K. J . Am. Chem. Soc. 1997, 119, 12974.
(3) (a) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M. J . Am. Chem.
Soc. 1998, 120, 4043. (b) Suzuki, K.; Ikekawa, A.; Mukaiyama, T. Bull.
Soc. Chem. J pn. 1982, 55, 3277. (c) Yamashita, H.; Mukaiyama, T.
Chem. Lett. 1985, 363.
(4) (a) Zahouily, M.; Abrouki, Y.; Rayadh, A. Tetrahedron Lett. 2002,
43, 7729. (b) Abrouki, Y.; Zahouily, M.; Rayadh, A.; Bahlaouan, B.;
Sebti, S. Tetrahedron Lett. 2002, 43, 8951.
(5) (a) Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J . Am. Chem. Soc.
1999, 121, 8675. (b) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Mel-
chiorre, P.; Selva, S.; Umani-Ronchi, A. J . Org. Chem. 2002, 67, 3700.
(c) Subbareddy, K.; Sudalai, A.; Benicewicz, B. C. Tetrahedron Lett.
2001, 42, 3791.
(6) (a) McDaid, P.; Chen, Y.; Deng, Li. Angew. Chem., Int. Ed. 2002,
41, 338. (b) Helder, R.; Arends, R.; Bolt, W.; Hiemstra, H.; Wynberg,
H. Tetrahedron Lett. 1977, 2181. (c) Hiemstra, H.; Wynberg, H. J . Am.
Chem. Soc. 1981, 103, 417.
Their high polarity and ability to solubilize both
organic and inorganic compounds can result in enhanced
rates of chemical processes and can provide higher
selectivities compared to conventional solvents. As a
result of their green credentials and potential to enhance
rates and selectivities, ionic liquids are finding increasing
applications in organic synthesis.11
With an ever-increasing quest for exploration of newer
reactions in ionic liquids, we report herein the use of ionic
liquids as green solvents for the conjugate addition of
thiols to R,â-unsaturated ketones to afford Michael
(8) Sheldon, R. A. Chirotechnologies, Industrial Synthesis of Opti-
cally Active Compounds; Dekker Publishing: New York, 1993.
(9) Sheldon, R. J . Chem. Soc., Chem. Commun. 2001, 2399.
(10) (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Wasserscheid, P.;
Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772.
(7) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2003, 59, 2417.
(11) Gordon, C. M. Applied Catalysis A: General 2001, 222, 101.
10.1021/jo034335l CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/01/2003
7098
J . Org. Chem. 2003, 68, 7098-7100

TABLE 1. Con ju ga te Ad d ition of Th iols to En on es in 1-Bu tyl-3-m eth ylim id a zoliu m Ion ic Liqu id s/H 2O
a
b
All the products were reported previously in the literature.12 Conversions (obtained by [bmim]PF6/H2O) were determined by GC
analysis. c Yield refers to the isolated pure products after column chromatography. Monoadduct was obtained (when 1 equiv of thiocresol
d
was used). e The product was filtered by diluting the ionic liquid with water.
adducts in high to quantitative yields under mild and
neutral conditions (Scheme 1).
estingly, numerous cyclic and acyclic enones including
chalcones underwent 1,4-addition with a range of thiols
under mild reaction conditions to afford the correspond-
ing Michael adducts (Scheme 2).
Accordingly, treatment of 2-cyclohexen-1-one with
thiophenol in 1-butyl-3-methylimidazolium hexafluoro-
phosphate/water (2:1) solvent system in the absence of
catalyst gave the corresponding 1,4-adduct in 97% yield.
The reaction proceeded efficiently at room temperature
without the need of any acid or base catalyst. The
reaction went to completion in a short time (10-15 min).
The product thus obtained was isolated by simple extrac-
tion with diethyl ether. The ionic liquid was further
washed with ether and reused several times without
further purification. Encouraged by the results obtained
with cyclohexenone and thiophenol, we turned our at-
tention to various thiols and substituted enones. Inter-
It is noteworthy to mention that readily available
thiosalicylic acid afforded the 1,4-adduct in 90% yield
after crystallization (entry m , Table 1). Sterically hin-
dered 2-thionaphthol also gave the desired 1,4-adducts
in excellent yields (entries e and g, Table 1). No byprod-
ucts resulting from 1,2-addition or bis-addition were
observed. Moreover, the reactions are clean, high yield-
ing, and sometimes quantitative. Compared to conven-
tional methods, enhanced reaction rates, improved yields,
and high 1,4-selectivity are the features observed in ionic
liquids. For instance, treatment of 1,3-diphenyl-(E)-2-
J . Org. Chem, Vol. 68, No. 18, 2003 7099

propen-1-one with thiophenol in a [bmim]PF6/H2O solvent
system (2:1) afforded the corresponding Michael adduct
3i in 95% yield within 15 min, whereas the same reaction
in commonly used organic solvents such as acetonitrile
and methanol after 8 h gave the desired product in 52%
and 67% yield, respectively. However, in the absence of
ionic liquid, the product 3i was obtained in 60% yield in
water after 8 h at room temperature. The addition of
phase transfer catalyst, i.e., benzyltriethylammonium
bromide, the product 3i was isolated in 85% yield after
6 h. Thus, the combination of ionic liquid and water was
found to be the most effective solvent system for this
conversion. In this reaction, the efficiency of ionic liquid
was strongly influenced by the nature of the anion. The
reactivity of various thiols and enones was studied in
both hydrophobic [bimim]PF6 and hydrophilic [bmim]BF4
ionic liquids and the results are presented in the Table
1. Among them, [bmim]PF6 was found to be superior in
terms of conversion. The yields are generally high to
quatitative in a few minutes. The recovered ionic liquid
was reused several times without loss of activity, even
after fourth cycle the product 3a was obtained with the
similar yield and purity of those obtained in the first
cycle. In further reactions, the efficacy of various qua-
ternary ammonium salts was tested. The reactions,
however, did not proceed at room-temperature either in
n-tetrabutylammonium chloride/water (2:1) or in 1-n-
butyl-3-methylimidazolium chloride/water (2:1) solvent
system, but the reactions were successful at 65 °C with
moderate yields (45-69%). The commercially available
ionic liquids were used in this study. They have also been
prepared in our laboratory from the readily available and
inexpensive N-methylimidazole, 1-chlorobutane, and
hexafluorophosphoric acid or sodium tetrafluroborate,12
heavy metal Lewis acids or solid acids or bases as
promoters, thereby minimizing the production of toxic
waste during workup.
In summary, we describe a simple, convenient, and
efficient protocol for the 1,4-conjugate addition of thiols
to R,â-unsaturated ketones using ionic liquids as green
solvents under mild and neutral conditions. The ionic
liquids play the dual role of solvent and the promoter.
The enones exhibit enhanced reactivity in ionic liquids
thereby reducing the reaction times and improving the
yield significantly. The simple experimental procedure
combined with ease of recovery and reuse of this novel
reaction media is expected to contributes to the develop-
ment of a green strategy for the conjugate addition of
thiols to enones.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. TLC was
performed using precoated silica gel 60 F254 (0.25 mm) glass
plates. Chromatography was performed using silica gel (100-
200 mesh). IR spectra were recorded neat on refractive spectro-
photometer. 1H NMR spectra were recorded in CDCl3 at 200
MHz. Chemical shifts are given in ppm with respect to internal
TMS, and J values are quoted in Hz. Mass spectra were recorded
at 70 eV.
Gen er a l P r oced u r e for th e Con ju ga te Ad d ition of Th iols
to r,â-Un sa tu r a ted Keton es. A mixture of the enone (1 mmol)
and aryl- or alkanethiol (1 mmol) in 1-butyl-3-methylimidazo-
lium hexafluorophosphate/water (2:1, 3 mL) was stirred at room
temperature for the appropriate time (Table 1). After completion
of the reaction, as indicated by TLC, the reaction mixture was
washed with diethyl ether (3 × 10 mL). The combined ether
extracts were concentrated in vacuo, and the resulting product
was directly charged on a small silica gel column and eluted
with a mixture of ethyl acetate/n-hexane to afford the pure 1,4-
adduct. The products thus obtained were characterized by
comparison of their NMR, IR, mass, TLC, and mixed TLC
analysis and physical data with those of authentic samples. The
spectral data of all the products were identical with those of
authentic samples.5,6
1
and their purity was determined by comparing their H
NMR spectra with commercial samples. The purity of
[bmim]PF6 ionic liquid is g97.0% (NMR). The use of ionic
liquids as the reaction media for this transformation
helps to avoid the use of moisture sensitive reagents or
Ack n ow led gm en t. B.V.S.R. thanks CSIR New Del-
(12) Preparation of ionic liquids: (a) Park, S.; Kazlauskas, R. J . J .
Org. Chem. 2001, 66, 8395. (b) Suarez, P. A. Z.; Dullius, J . E. L.; Einloft,
S.; De Souza, R. F.; Dupont, J . Polyhedron 1996, 15, 1217.
hi for the award of a fellowship.
J O034335L
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