Study of the Michael addition of β-cyclodextrin-thiol complexes to conjugated alkenes in water

Article abstract of DOI:10.1039/b411736k

An environmentally benign and highly efficient supramolecular Michael addition of thiols from the secondary side of β-cyclodextrin to α,β-unsaturated compounds at the primary side in water is described in quantitative yields; products of undesirable side

Full text of DOI:10.1039/b411736k

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Study of the Michael addition of b-cyclodextrin–thiol complexes to
conjugated alkenes in water{
N. Srilakshmi Krishnaveni, K. Surendra and K. Rama Rao*
Received (in Cambridge, UK) 2nd August 2004, Accepted 7th October 2004
First published as an Advance Article on the web 14th December 2004
DOI: 10.1039/b411736k
Cyclodextrins (CDs) are cyclic oligosaccharides possessing
hydrophobic cavities, which bind substrates selectively and
catalyze chemical reactions with high selectivity. They catalyze
reactions by supramolecular catalysis involving reversible forma-
tion of host–guest complexes by non-covalent bonding as seen in
enzymes.14 Complexation depends on the size, shape and
hydrophobicity of the guest molecule. Thus mimicking of
biochemical selectivity, which is due to orientation of the substrate
by complex formation positioning only a certain region for
favorable attack, will be superior to chemical selectivity, which
involves random attack due to intrinsic reactivity of the substrate
at different regions. Our earlier expertise in the field of biomimetic
modelling of organic chemical reactions involving cyclodextrins15
prompted us to attempt the Michael addition of various thiols to
conjugated alkenes under biomimetic conditions using cyclodex-
trins with water as a solvent at room temperature (Scheme 1). Such
reactions also do not generate any toxic waste products.
An environmentally benign and highly efficient supramolecular
Michael addition of thiols from the secondary side of
b-cyclodextrin to a,b-unsaturated compounds at the primary
side in water is described in quantitative yields; products of
undesirable side reactions resulting from polymerization are not
observed; the use of cyclodextrin precludes the use of either acid
or base and the catalyst can be recovered and reused.
The Michael reaction since its discovery in 1889 is one of the most
important reactions in organic chemistry.1 The conjugate addition
of thiols to electron deficient olefins to form a carbon–sulfur bond
constitutes a key reaction in biosynthesis as well as in organic
synthesis.2 The organosulfur compounds are also useful in the
synthesis of biologically active compounds such as the calcium
antagonist diltiazem.3 Consequently, a large number of reagents
have been reported in the literature for the addition of mercaptans
to conjugated alkenes.4 However, to avoid side reactions, several
inorganic salts have been introduced in the presence of strong acid
or base.5 A number of procedures either based on activation of
thiol by a base or activation of the acceptor olefins with Lewis
acids are used.6 More recently tetrabutylammonium halides have
been used as phase transfer catalysts.7 The use of strong acids
(polymerization of vinyl ketones) and bases in the medium, toxic
catalysts, harsh conditions, far from satisfactory yields and
selectivities due to the occurrence of side reactions make these
methods lack any practical application in industry. Recently, there
is also a report of carrying out these reactions in ionic liquids8 and
a mixture of ionic liquids and water (2:1).9 These ionic liquids have
been shown to have serious drawbacks, especially imidazolium
ones with PF6 and BF4 anions, as they are as toxic as benzene in
certain aquatic ecosystems and also liberate hazardous HF during
recycling.10 Apart from this, the high cost11 and disposability of
these solvents also limit their utility. Moreover, these reactions
were unsuccessful in water alone.
The reaction was carried out as follows: b-CD (1 mmol) was
dissolved in water (15 ml) by warming to 60 uC until a clear
solution was formed, then thiophenol (1 mmol) dissolved in
acetone (1 ml) was added dropwise and allowed to cool to room
temperature. The alkene (1.1 mmol) was then added and stirred at
room temperature until the reaction was complete (Table 1). The
organic material was extracted with ethyl acetate, dried and
concentrated under reduced pressure and the resulting product
though seen as a single compound by TLC, was further purified by
passing over a column of silica gel. CD was recovered by filtration
and reused. The yields were almost quantitative.
This is the first practically feasible Michael addition reaction of
thiols with a variety of conjugated alkenes in water. The reaction
proceeds efficiently at room temperature without the need of any
acid or base catalyst. The reaction goes to completion in a short
time (5–45 min). This methodology is compatible with various
a,b-unsaturated ketones, aldehydes, esters, nitriles and amides and
different substituted aromatic thiols and cyclohexanethiol under
mild reaction conditions. No byproduct formation was observed.
Moreover, these reactions are clean with nearly quantitative yields
compared to conventional methods, shorter reaction times, higher
selectivities and recyclable catalyst. While these reactions do take
place with a-CD, b-CD was chosen as the catalyst since it is
With green chemistry becoming a central issue in both academic
and industrial research in the 21st century,12 the development of
environmentally benign and clean synthetic procedures has
become the goal of present day organic synthesis. Thus, there is
need for developing Michael addition in water with a recyclable
catalyst and without the use of any harmful organic solvents since
water is a safe, economical and environmentally benign solvent.13
To achieve these ideal conditions, the best choice appeared to be
through supramolecular catalysis involving cyclodextrins using
water as solvent.
{ IICT communication no. 040936.
*drkrrao@yahoo.com
Scheme 1
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 669–671 | 669

View Article Online
Table 1 Michael addition of thiols to conjugated alkenes using b-CD
in water
Entry
R
R1
Time/min
Yielda,b (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
CHO
5
5
5
10
10
15
5
95
98
98c
97
96
96
95
98
96
95
94
92
97
95
94
92
90
96
95
94
92
95
92
90
COMe
COMe
CN
CO2Me
CONH2
CHO
COMe
CN
CO2Me
CONH2
CHO
COMe
CN
CO2Me
CONH2
CHO
COMe
CN
CO2Me
CONH2
COMe
CN
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
o-MeC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
C6H12
5
10
10
15
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
a
5
10
10
15
5
5
10
10
15
25
30
45
Fig. 1 1H NMR spectra (D2O) of (A) b-CD, (B) b-CD–thiophenol
complex (C) and a freeze-dried reaction mixture of the thiophenol–CD
complex with MVK at 3 min (D).
C6H12
C6H12
CONH2
All the products were characterized by mass, 1H NMR, IR
spectroscopy and compared with known compounds.8 Isolated
yields. Catalyst was recovered and reused for three consecutive
runs in this reaction without change in the yield and purity.
b
c
inexpensive and easily accessible. In an earlier report by Sakuraba
et al, Michael addition of thiols to 2-cyclohexenone and maleic
acid esters in the presence of cyclodextrin had been shown to take
unusually long reaction times of over seven days.16
The catalytic activity of cyclodextrins for these Michael
additions is established by the fact that no reaction was observed
in the absence of cyclodextrin. The mechanism of addition of thiols
as b-cyclodextrin complexes to conjugated alkenes was postulated
via convincing evidence from 1H NMR spectroscopy. The
hydrogen bonding of thiols with the CD hydroxyl makes the
S–H bond weaker enhancing the nucleophilicity of sulfur and
making it a better nucleophile towards addition to electron
deficient alkenes. Using thiophenol and methyl vinyl ketone
(MVK) as a representative example, a comparison of the 1H NMR
spectra (D2O) of b-CD, b-CD–thiophenol complex and a freeze-
dried reaction mixture of the thiophenol–CD complex with MVK
at 3 min were studied. It could be observed from Fig. 1 that there is
an upfield shift of H3 (0.018 ppm) and H5 (0.015 ppm) protons of
cyclodextrin in the b-CD–thiophenol complex as compared to
b-CD, indicating the formation of an inclusion complex of
thiophenol with b-CD.17 It is further observed from the spectra of
the reaction mixture of b-CD–thiophenol complex and MVK at
3 min that there is also an upfield shift of the H6 proton by
0.028 ppm. This indicates the complexation of MVK from the
primary side of the cyclodextrin. Thus, it is deduced from these
1H NMR studies that while the thiophenol is still being retained in
the hydrophobic cavity of b-CD, MVK complexes from the
primary side of b-cyclodextrin for the reaction to proceed (Fig. 2).
Fig. 2
This shows in a very elegant way how the olefin is set for the
addition reaction with the thiol nucleophile in the hydrophobic
cavity of b-cyclodextrin.
These CD mediated water solvent reactions are very useful both
from economical and environmental points of view.
b-Cyclodextrin, apart from being non-toxic is also considered as
metabolically safe.18 In contrast with the existing methods using
many acidic catalysts, this method is very simple, high yielding and
environfriendly. Significant improvements offered by this proce-
dure are: (i) fast reaction (time), (ii) simple operational and mild
conditions (room temperature), (iii) excellent yields, (iv) cost
efficiency providing recyclability of the catalyst and (v) green
aspect avoiding hazardous organic solvents, toxic and expensive
reagents. Further potential applications of this reaction are under
study.
K. S. thanks CSIR, New Delhi, India, for the award of a
research fellowship.
N. Srilakshmi Krishnaveni, K. Surendra and K. Rama Rao*
Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad-500 007, India. E-mail: drkrrao@yahoo.com
670 | Chem. Commun., 2005, 669–671
This journal is ß The Royal Society of Chemistry 2005

View Article Online
7 B. C. Ranu, S. S. Dey and A. Hajra, Tetrahedron, 2003, 59, 2417.
Notes and references
8 B. C. Ranu and S. S. Dey, Tetrahedron, 2004, 60, 4183.
9 J. S. Yadav, B. V. S. Reddy and G. Baishya, J. Org. Chem., 2003, 68,
7098.
10 (a) E. J. Maginn, www.nd.edu/yed/IL_toxicology.htm; (b) J. S. Yadav,
B. V. S. Reddy, Ch. Srinivas Reddy and K. Rajasekhar, J. Org. Chem.,
2003, 68, 2525.
11 Ionic liquids cost 60-400 USD/50 g as against b-CD which costs 105
USD/100 g.
12 (a) P. T. Anastas and J. C. Warner, Green Chemistry, Theory and
Practice, Oxford University Press, Oxford, 1998; (b) Green Chemistry,
Frontiers in Benign Chemical Synthesis and Processes, ed. P. T. Anastas
and T. C. Williamson, Oxford University Press, Oxford, 1998; (c)
1 A. J. Michael, J. Prakt. Chem., 1889, 35, 349.
2 (a) A. L. Fluharty, In The Chemistry of the Thiol Group, ed. S. Patai,
Wiley, New York, 1974, Part 2, p. 589; (b) J. H. Clark, Chem. Rev.,
1980, 80, 429; (c) E. Fujita and Y. J. Nagao, Bioorg. Chem., 1977, 6, 287;
(d) B. M. Trost and D. E. Keeley, J. Org. Chem., 1975, 40, 2013; (e)
T. Shono, Y. Matsumura, S. Kashimura and K. Hatanaka, J. Am.
Chem. Soc., 1979, 101, 4752; (f) K. Nishimura, M. Ono, Y. Nagaoka
and K. Tomioka, J. Am. Chem. Soc., 1997, 119, 12974.
3 R. A. Sheldon, Chirotechnologies Industrial Synthesis of Optically Active
Compounds, Dekker Publishing, New York, 1993.
4 P. Perlmutter, Conjugated Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992, p. 114.
Handbook of Green Chemistry
& Technology, ed. J. Clark,
D. Macquarrie and M. A. Blackwell, 2002; (d) M. Eissen,
J. O. Metzger, E. Schmidt and U. Schneidewind, Angew. Chem., Int.
Ed., 2002, 41, 414.
5 (a) B. C. Ranu, S. Bhar and D. C. Sarkar, Tetrahedron Lett., 1991, 32,
2811; (b) N. Srivastava and B. K. Banik, J. Org. Chem., 2003, 68, 2109;
(c) R. Sreekumar, P. Rugmimi and R. Padmakumar, Tetrahedron Lett.,
1997, 38, 6557; (d) S. Sebati and A. Saber, Tetrahedron Lett., 1994, 35,
9399; (e) P. Laszole, P. M.-T. Montaufier and S. L. Randriamahefa,
Tetrahedron Lett., 1990, 31, 4867.
13 (a) Organic Synthesis in Water, ed. P. A. Grieco, Blackie Academic and
Professional, London, 1998; (b) C.-J. Li and T.-H. Chan, Organic
Reactions in Aqueous Media, John Wiley & Sons, New York, 1997.
14 (a) R. Breslowang and S. D. Dong, Chem. Rev., 1998, 98, 1997; (b)
J. M. Desper and R. Breslow, J. Am. Chem. Soc., 1994, 116, 12081.
15 (a) K. Surendra, N. S. Krishnaveni, M. A. Reddy, Y. V. D. Nageswar
and K. R. Rao, J. Org. Chem., 2003, 68, 9119; (b) K. Surendra,
N. S. Krishnaveni, Y. V. D. Nageswar and K. R. Rao, J. Org. Chem.,
2003, 68, 4994; (c) K. Surendra, N. S. Krishnaveni, M. A. Reddy,
Y. V. D. Nageswar and K. R. Rao, J. Org. Chem., 2003, 68, 2058; (d)
N. S. Krishnaveni, K. Surendra, M. A. Reddy, Y. V. D. Nageswar and
K. R. Rao, J. Org. Chem., 2003, 68, 2018; (e) M. A. Reddy,
N. Bhanumathi and K. R. Rao, Chem. Commun., 2001, 1974; (f)
L. R. Reddy, N. Bhanumathi and K. R. Rao, Chem. Commun., 2000,
2321.
6 (a) F. M. Silva, A. K. Gomes and J. Jones, Jr., Can. J. Chem., 1999, 77,
624; (b) M. M. Alam, R. V. Varala and S. R. Adapa, Tetrahedron Lett.,
2003, 44, 5115; (c) T. C. Wabnitz, J.-Q. Yu and J. B. Spencer, Synlett,
2003, 1070; (d) S. Cheng and D. D. Comer, Tetrahedron Lett., 2002, 43,
1179; (e) M. Jahouily, Y. Abrouki, A. Rayadh, S. Sebti, H. Dhimane
and M. David, Tetrahedron Lett., 2003, 44, 2463; (f) M. Bandini,
P. G. Cozzi, M. Giacomini, P. Melchiorre, S. Selva and A. U. Ronchi,
J. Org. Chem., 2002, 67, 3700; (g) M. Zahouily, Y. Abrouki and
A. Rayadh, Tetrahedron Lett., 2002, 43, 7729; (h) Y. Abrouki,
M. Zahouily, A. Rayadh, B. Bahlaouan and S. Sebti, Tetrahedron
Lett., 2002, 43, 8951, and references cited therein; (i) A. Kamimura,
N. Murakami, K. Yokota, M. Shirai and H. Okamoto, Tetrahedron
Lett., 2002, 43, 7521; (j) S. Kangasabapathi, A. Sudalai and
B. C. Benicewicz, Tetrahedron Lett., 2001, 42, 3791; (k) E. Emori,
T. Arai, H. Sasai and M. Shibasaki, J. Am. Chem. Soc., 1998, 120, 4043,
and references cited therein; (l) P. R. Ahuja, A. A. Natu and V. N. Gogte,
Tetrahedron Lett., 1980, 21, 4743.
16 H. Sakuraba, Y. Tanaka and F. Toda, J. Inclusion Phenom., 1991, 11,
195.
17 (a) P. V. Demarco and A. L. Thakkar, Chem. Commun., 1970, 2; (b)
H.-J. Schneir, F. Hacket and V. Rudiger, Chem. Rev., 1998, 98, 1755.
18 K. Uekama, F. Hirayama and T. Irie, Chem. Rev., 1998, 98, 2045.
This journal is ß The Royal Society of Chemistry 2005
Chem. Commun., 2005, 669–671 | 671