Catalysis by an ionic liquid: Efficient conjugate addition of thiols to electron deficient alkenes catalyzed by molten tetrabutylammonium bromide under solvent-free conditions

Article abstract of DOI:10.1016/S0040-4020(03)00289-8

An inexpensive and readily available ionic liquid, tetrabutylammonium bromide in the molten state, efficiently catalyzes the conjugate addition of thiols to α,β-unsaturated nitriles, carboxylic ester, ketones and aldehydes as well as nitro olefins.

Full text of DOI:10.1016/S0040-4020(03)00289-8

Tetrahedron 59 (2003) 2417–2421
Catalysis by an ionic liquid: efficient conjugate addition of thiols to
electron deficient alkenes catalyzed by molten
tetrabutylammonium bromide under solvent-free conditions
*
Brindaban C. Ranu, Suvendu S. Dey and Alakananda Hajra
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta 700032, India
Received 16 November 2002; revised 28 January 2003; accepted 21 February 2003
Abstract—An inexpensive and readily available ionic liquid, tetrabutylammonium bromide in the molten state, efficiently catalyzes the
conjugate addition of thiols to a,b-unsaturated nitriles, carboxylic ester, ketones and aldehydes as well as nitro olefins. q 2003 Elsevier
Science Ltd. All rights reserved.
1. Introduction
efficient catalyst in a number of useful synthetic transform-
ations by us6a and other groups.6b–d
The conjugate addition of nucleophiles to electron deficient
alkenes is one of the most effective methods for carbon–
carbon bond formation and has many applications in organic
synthesis.1 Among various nucleophilic additions, the
reaction of thiols is of much importance as it leads to the
synthesis of compounds with promising biological
activities.2 Usually, this conjugate addition is based either
on the activation of thiols by a base3 or activation of the
acceptor olefins with Lewis acids.4 We report here an
efficient conjugate addition of a thiol to an activated alkene
catalyzed by molten tetrabutylammonium bromide without
any solvent (Scheme 1). Recently, the use of ionic liquids as
solvent and catalyst has attracted much attention in the
context of green synthesis.5
2. Results and discussion
The experimental procedure for the reaction is very simple:
A mixture of alkene and thiol was added to molten
tetrabutylammonium bromide (15 mol%) at 100–1058C
and was stirred at that temperature for 1–2 h as required to
complete the reaction. The reaction mixture was extracted
with ether and the crude product was purified by column
chromatography to furnish the pure adduct. The tetrabutyl-
ammonium bromide remaining in the reaction flask was
washed with hexane, dried under vacuum and was recycled
for subsequent uses without any loss of efficiency.
However, high cost of most of the conventional room
temperature ionic liquids and apprehension regarding the
toxicity of some of them has led to the use of more benign
salts in the molten state as practical alternatives. Recently,
molten tetrabutylammonium bromide was used as an
Both aromatic and aliphatic thiols react with a variety of
conjugated alkenes by this procedure to produce the
corresponding adducts in high yields. The results are
summarized in Table 1. The conjugated alkenes include
a,b-unsaturated nitriles, carboxylic esters, ketones and
aldehydes as well as nitro olefins. These reactions catalyzed
by molten tetrabutylammonium bromide are in general,
very fast and clean. The crude products obtained are
virtually pure and a ‘short’ column chromatography gave
analytically pure sample. No addition was observed using
solid tetrabutylammonium bromide at room temperature.
Also, reaction in the absence of tetrabutylammonium
bromide at 100–1058C leads to a mixture of unidentified
products. Thus, the presence of molten tetrabutylammonium
bromide is essential for an efficient and clean reaction. The
amount of tetrabutylammonium bromide may be reduced to
as little as 15 mol%; however, a higher amount may be used.
Presumably, molten tetrabutylammonium bromide acts as a
Scheme 1.
Keywords: thiol; alkene; tetrabutylammonium bromide; conjugate addition;
solvent-free reaction.
*
Corresponding author. Tel.: þ91-33-24734971; fax: þ91-33-24732805;
e-mail: ocbcr@iacs.res.in
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00289-8

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B. C. Ranu et al. / Tetrahedron 59 (2003) 2417–2421
Table 1. Addition of thiol to alkenes catalyzed by molten tetrabutylammonium bromide
Entry
1
Thiol
Alkene
Time (h)
1.0
Product
Yield (%)a
92
PhSH
2
3
4
5
6
7
8
n-BuSH
o-(NH2)–C6H4SH
PhSH
1.5
0.5
1.0
1.5
2.0
2.0
0.75
88
90
92
90
85
87
90
n-BuSH
PhSH
n-BuSH
PhSH
9
n-BuSH
1.5
2.0
87
91
10
PhSH
11
12
n-BuSH
2.0
0.5
88
92
PhSH

B. C. Ranu et al. / Tetrahedron 59 (2003) 2417–2421
2419
Table 1 (continued)
Entry
Thiol
Alkene
Time (h)
0.75
Product
Yield (%)a
90
13
14
15
EtSH
PhSH
2.0
2.5
78
81
n-BuSH
16
17
PhSH
2.0
2.0
72
70
n-BuSH
18
19
PhSH
1.0
1.5
90
89
n-BuSH
a
Yields refer to those of pure isolated products characterized by IR, 1H NMR and 13C NMR spectroscopy.
ready source of bromide ion, which is hydrogen-bonding to
the thiol increasing the nucleophilicity of sulfur atom. This
4. Experimental
makes the thiolate anion a better nucleophile leading to
efficient addition to conjugated alkenes.
4.1. General
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
run in CDCl3 solutions. IR spectra were taken as neat.
Elemental analyses were done by a Perkin–Elmer auto-
analyzer. Column chromatography was performed on silica
gel (60–120 mesh, SRL, India). Thiols and conjugated
alkenes are mostly commercial materials and were distilled
before use. Tetrabutylammonium bromide (Lancaster, UK)
was also recrystallized before use.
3. Conclusion
In conclusion, the reported procedure of the conjugate
addition of thiols to electron-deficient alkenes under
solvent-free conditions demonstrates the potential of molten
tetrabutylammonium bromide, a benign readily available
ionic liquid as an efficient and recyclable catalyst and has
much promise for further applications. Moreover, this
methodology offers significant improvements with regard
to yield of products, simplicity in operation, cost efficiency
and green aspects avoiding toxic catalysts and solvents.
4.1.1. General procedure for conjugate addition of thiols
to alkenes: representative procedure for the synthesis of
1-cyano-2-thiophenylethane (entry 1). A mixture of
thiophenol (242 mg, 2.2 mmol) and acrylonitrile (106 mg,

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B. C. Ranu et al. / Tetrahedron 59 (2003) 2417–2421
1
2 mmol) was added to molten tetrabutylammonium bromide
(97 mg, 0.30 mmol, 15 mol%) and the whole mixture was
stirred at 1058C (oil bath) for 1 h as indicated by TLC for a
complete reaction. The reaction mixture was then allowed to
cool to room temperature and extracted with ether
(3£25 mL). The ether extract was washed with water and
dried over Na2SO4. Evaporation of solvent followed by
column chromatography of the crude product over silica gel
(hexane/ether 97:3) furnished the pure 1-cyano-2-thio-
phenyl ethane as a colorless oil (300 mg, 92%), whose
spectroscopic data (IR and NMR) are identical to those
reported.7
oil;13 IR 2954, 1738 cm21; H NMR (300 MHz, CDCl3) d
4.02–3.86 (m, 4H), 3.39 (dd, J¼9.9, 5.6 Hz, 1H), 2.73 (dd,
J¼9.9, 16.9 Hz, 1H), 2.49–2.36 (m, 3H), 1.36–1.27 (m,
2H), 1.21–0.98 (m, 8H), 0.66 (t, J¼7.3 Hz, 3H); 13C NMR d
172.2, 171.1, 61.7, 61.3, 41.91, 36.9, 31.6, 31.5, 22.3, 14.5
(2C), 13.9.
4.1.10. 3-(4-Chlorophenyl)-2-nitro-2-thiophenylpropane
(entry 10). Colorless oil (1:1 mixture of diastreoisomers);
;
IR 2958, 1552, 1490, 1091 cm21 1H NMR (300 MHz,
CDCl3) d 7.36–7.25 (m, 14H), 7.16–7.08 (m, 4H), 5.03–
4.91 (m, 2H), 4.61 (d, J¼12.2 Hz, 1H), 4.58 (d, J¼12.2 Hz,
1H), 1.89 (d, J¼6.7 Hz, 3H), 1.46 (d, J¼6.7 Hz, 3H); 13C
NMR (2 sets of peaks) d 136.5, 135.5, 134.6, 134.5 (2C),
134.4 (2C), 134.3 (2C), 132.1 (2C), 130.1 (2C), 129.7 (2C),
129.6 (2C), 129.4 (2C), 129.2 (3C), 129.1 (2C), 87.0, 86.4,
57.1, 56.5, 18.6, 17.8. Anal. calcd for C15H14ClSNO2: C,
58.53; H, 4.58; N, 4.55. Found: C, 58.36; H, 4.39; N, 4.41.
This procedure was followed for all the reactions listed in
Table 1. The compounds that are known are identified by
comparison of their spectroscopic data with those reported
in the literature (however, a few known compounds reported
in entries 2,5,8,9 whose spectroscopic data are not available
for comparison are also properly characterized by their
spectroscopic data). The IR, 1H and 13C NMR spectral data
and elemental analysis, confirms the identities of new
compounds. All these data are furnished below in order of
their entries in Table 1.
4.1.11. 4-(4-Chlorophenyl)-3-nitro-4-thiobutylbutane
(entry 11). Colorless oil (1:1 mixture of diastreoisomers);
;
IR 2958, 1556, 1490, 1091 cm21 1H NMR (300 MHz,
CDCl3) d 7.54–7.41 (m, 8H), 4.90–4.77 (m, 2H), 4.36 (d,
J¼10.6 Hz, 1H), 4.34 (d, J¼10.6 Hz, 1H), 2.56–2.38 (m,
5H), 2.38–2.21 (m, 1H), 2.13–1.88 (m, 1H), 1.68–1.61 (m,
4H), 1.52–1.46 (m, 4H), 1.19 (t, J¼7.4 Hz, 3H), 1.07–0.99
(m, 9H); 13C NMR (2 sets of peaks) d 136.9 (2C), 134.4,
134.3, 130.0 (2C), 129.9 (2C), 129.6 (2C), 129.3 (2C), 94.5,
94.2, 52.0, 51.7, 31.9, 31.5, 31.4, 31.3, 26.4, 26.3, 22.2,
22.1, 13.9 (2C), 10.7, 10.6. Anal. calcd for C14H20ClSNO2:
C, 55.71; H, 6.68; N, 4.64. Found: C, 55.59; H, 6.51; N,
4.48.
4.1.2. 1-Cyano-2-thiobutylethane (entry 2). Colorless oil;8
IR 2929, 2250 cm21; 1H NMR (300 MHz, CDCl3) d 2.79 (t,
J¼7.1 Hz, 2H), 2.66–2.57 (m, 4H), 1.63–1.54 (m, 2H),
1.48–1.36 (m, 2H), 0.93 (t, J¼7.2 Hz, 3H); 13C NMR d
118.8, 32.4, 31.9, 28.1, 22.3, 19.3, 14.0.
4.1.3. 1-Cyano-2-(2-aminothiophenyl)ethane (entry 3).
Colorless oil.9
4.1.4. Methyl 3-thiophenylpropionate (entry 4). Colorless
oil.10
4.1.12. 3-Thiophenylcyclohexanone (entry 12). Colorless
oil.3a
4.1.5. Methyl 3-thiobutylpropionate (entry 5). Colorless
1
4.1.13. 3-Thioethylcyclohexanone (entry 13). Colorless
oil.14
oil;11 IR 2956, 1741 cm21; H NMR (300 MHz, CDCl3) d
3.7 (s, 3H), 2.78 (t, J¼7.2 Hz, 2H), 2.61 (t, J¼7.2 Hz, 2H),
2.53 (t, J¼7.4 Hz, 2H), 1.62–1.52 (m, 2H), 1.47–1.37 (m,
2H), 0.92 (t, J¼7.3 Hz, 3H); 13C NMR d 172.8, 52.1, 35.1,
32.2, 31.9, 27.3, 22.3, 14.0.
4.1.14. 4-Methyl-4-thiophenylpentan-2-one (entry 14).
Colorless oil.15
4.1.15. 4-Methyl-4-thiobutylpentan-2-one (entry 15).
1
4.1.6. Methyl 2-methyl-3-thiophenylpropionate (entry
6). Colorless oil.7b
Colorless oil; IR 2958, 1714 cm21; H NMR (300 MHz,
CDCl3) d 2.68 (s, 2H), 2.53 (t, J¼7.2 Hz, 2H), 1.57–1.38
(m, 4H), 1.41 (s, 6H), 0.92 (t, J¼7.3 Hz, 3H); 13C NMR d
206.9, 55.0, 43.6, 32.6, 31.9, 28.9 (2C), 28.1, 22.7, 14.1.
Anal. calcd for C10H20SO: C, 63.78; H, 10.70. Found: C,
63.59; H, 10.61.
4.1.7. Methyl 2-methyl-3-thiobutylpropionate (entry 7).
1
Colorless oil; IR 2956, 1739 cm21; H NMR (300 MHz,
CDCl3) d 3.61 (s, 3H), 2.75 (dd, J¼12.2, 6.2 Hz, 1H), 2.60–
2.40 (m, 4H), 1.49–1.42 (m, 2H), 1.35–1.25 (m, 2H), 1.17
(d, J¼6.8 Hz, 3H), 0.83 (t, J¼7.2 Hz, 3H); 13C NMR d
176.0, 52.1, 40.6, 35.9, 32.7, 32.1, 22.3, 17.2, 14.0. Anal.
calcd for C9H18SO2: C, 56.80; H, 9.53. Found: C, 56.63; H,
9.39.
4.1.16. 4-Thiophenylbutan-2-one (entry 16). Colorless
oil.15
4.1.17. 4-Thiobutylbutan-2-one (entry 17). Colorless
oil.16
4.1.8. Diethyl 2-thiophenylsuccinate (entry 8). Colorless
1
oil;12 IR 2976, 1735 cm21; H NMR (300 MHz, CDCl3) d
4.1.18. 3-Thiophenylbutanal (entry 18). Colorless oil.17
7.49–7.28 (m, 5H), 4.15–4.06 (m, 4H), 4.00–3.96 (m, 1H),
2.97–2.87 (m, 1H), 2.74–2.66 (m, 1H), 1.26–1.15 (m, 6H);
13C NMR d 171.5, 170.9, 134.5 (2C), 132.2, 129.4 (2C),
129.1, 61.8, 61.3, 46.1, 36.9, 14.5, 14.4.
4.1.19. 3-Thiobutylbutanal (entry 19). Colorless oil; IR
1
2958, 1726 cm21; H NMR (300 MHz, CDCl3) d 9.66 (t,
J¼1.7 Hz, 1H), 3.23–3.14 (m, 1H), 2.61–2.43 (m, 4H),
1.52–1.42 (m, 2H), 1.37–1.24 (m, 2H), 1.21 (d, J¼6.9 Hz,
3H), 0.82 (t, J¼7.2 Hz, 3H); 13C NMR d 200.9, 50.8, 34.4,
4.1.9. Diethyl 2-thiobutylsuccinate (entry 9). Colorless

B. C. Ranu et al. / Tetrahedron 59 (2003) 2417–2421
2421
Chem. Commun. 2002, 342. (c) Sheldon, R. Chem. Commun.
2001, 2399. (d) Wasserscheid, P.; Keim, W. Angew. Chem. Int.
Ed. 2000, 39, 3773. (e) Welton, T. Chem. Rev. 1999, 99, 2071.
6. (a) Ranu, B. C.; Das, A.; Samanta, S. J. Chem. Soc., Perkin
Trans. 1 2002, 1520. (b) Smietana, M.; Mioskowski, C. Org.
Lett. 2001, 3, 1037. (c) Amantini, C.; Fringuelli, F.; Pizzo, F.;
Vaccaro, L. J. Org. Chem. 2001, 66, 6734. (d) Selvakumar, K.;
Zapt, A.; Beller, M. Org. Lett. 2002, 4, 3031.
32.0, 30.5, 22.4, 22.2, 13.9. Anal. calcd for C8H16SO: C,
59.95; H, 10.06. Found: C, 59.79; H, 9.89.
Acknowledgements
We are pleased to acknowledge the financial support from
CSIR, New Delhi [Grant No. 01(1739)/02]. S. S. D and A. H.
are also thankful to CSIR for their fellowships.
7. (a) Adams, H.; Anderson, J. C.; Bell, R.; Jones, D. N.; Peel,
M. R.; Tomkinson, N. C. O. J. Chem. Soc., Perkin Trans. 1
1998, 3967. (b) Bakuzis, P.; Bakuzis, M. L. F. J. Org. Chem.
1981, 46, 235.
References
8. Hurd, C. D.; Gershbein, L. L. J. Am. Chem. Soc. 1947, 69,
2328.
1. Perlmutter, P. Conjugated Addition Reactions in Organic
Synthesis; Pergamon: Oxford, 1992; p 114.
9. Lankin, D. C.; Petterson, R. C.; Velazquez, R. A. J. Org.
Chem. 1974, 39, 2801.
2. Sheldon, R. A. Chirotechnologies, Industrial Synthesis of
Optically Active Compounds; Dekker: New York, 1993.
3. (a) McDaid, P.; Chen, Y.; Deng, A. Angew. Chem. Int. Ed.
2002, 41, 338. (b) Emori, E.; Arai, T.; Sasai, H.; Shibasaki, M.
J. Am. Chem. Soc. 1998, 120, 4043. (c) Colonna, S.; Re, A.;
Wynberg, H. J. Chem. Soc., Perkin Trans. 1 1981, 547.
4. (a) Bandini, M.; Cozzi, P. G.; Giacomini, M.; Melchiorre, P.;
Selva, S.; Ronchi, A. U. J. Org. Chem. 2002, 67, 3700.
(b) Kanagasabapathy, S.; Sudalai, A.; Benicewicz, B. C.
Tetrahedron Lett. 2001, 42, 3791. (c) Kanemasa, S.;
Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675.
5. (a) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M. Tetrahedron
Lett. 2002, 43, 1127. (b) Namboodiri, V. V.; Varma, R. S.
10. Iqbal, J.; Sukla, A. Tetrahedron 1991, 47, 8753.
11. Fehnel, E. A.; Carmack, M. J. Am. Chem. Soc. 1949, 71, 85.
12. Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363.
13. Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Shimizu, T.
J. Org. Chem. 1968, 33, 544.
14. Gorthey, L. N.; Vairamani, M.; Djerassi, C. J. Org. Chem.
1985, 50, 4173.
15. Cherkquaskas, J. P.; Cohen, T. J. Org. Chem. 1992, 57, 6.
16. Ogawa, A.; Nishiyama, Y.; Kumbe, N.; Murai, S.; Sonoda, N.
Tetrahedron Lett. 1987, 28, 3271.
17. Mudryk, B.; Cohen, T. J. Am. Chem. Soc. 1993, 115, 3855.