Y. Kacem, B. Ben Hassine / Tetrahedron Letters 53 (2012) 5608–5610
5609
Table 2
SO2Cl
O
O
+
Synthesis of imidazo[1,2-b][1,2]benzothiazin-2-one 4,4-dioxides 4a–j
R
S
Et3N
R
O
O
R0
Mp (°C)
Yield (%)
+
Product
R
NH
0 °C, CH2Cl2
Cl-
NH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
Bn
Ph
Ph
Ph
Ph
Ph
Pr
Pr
Pr
Pr
Pr
99–101
60–62
Oil
73–75
120–122
88–90
53–55
Oil
58
65
60
57
51
50
44
46
52
48
O
O
1
i-Pr
Me
i-Bu
Ph
2
O
R
R'
N
1) NaH, THF, 0 °C
N
Bn
2) R'
C
N
O
S
O
O
O
i-Pr
Me
i-Bu
Ph
3
82–84
115–117
4j
Scheme 1.
Acknowledgments
Table 1
Synthesis of N-mesitylenesulfonyl hydantoins 3a–j
The authors thank the DGRST (Direction Générale de la Recher-
che Scientifique et de la Rénovation Technologique) of the Tunisian
Ministry of Higher Education and Scientific Research for financial
support of this research.
Product
R
R0
Mp (°C)
[
a
]
D
(c 1, CHCl3)
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
Bn
Ph
Ph
Ph
Ph
Ph
Pr
Pr
Pr
Pr
Pr
121–123
175–177
112–114
144–146
192–194
96–98
113–115
83–85
165–167
180–182
+161
+103
+91
+133
+75
+165
+111
+61
95
91
94
89
71
75
79
83
90
68
i-Pr
Me
i-Bu
Ph
References and notes
Bn
i-Pr
Me
i-Bu
Ph
1. Lombardino, J. G.; Kuhla, D. E. Adv. Heterocycl. Chem. 1981, 28, 73.
2. Aran, V. J.; Goya, P.; Ochoa, C. Adv. Heterocycl. Chem. 1988, 44, 81.
3. Chamber, M. S.; Hobbs, S. C.; Graham, M. I.; Watt, A. P.; Fletcher, S. R.; Baker, R.;
Freedman, S. B.; Patel, S.; Smith, A. J.; Matassa, V. G. Bioorg. Med. Chem. Lett.
1995, 5, 2303.
+88
+49
3j
4. Rice, W. G.; Supko, J. G.; Malspeis, L.; Buckheit, R. W.; Clanton, D.; Bu, M.;
Graham, L.; Schaeffer, C. A.; Turpin, J. A.; Domagala, J.; Gogliotti, R.; Bader, J. P.;
Halliday, S. M.; Coren, L.; Sowder, R. C.; Arthur, L. O.; Henderson, L. E. Science
1995, 270, 1194.
5. Lazer, E. S.; Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H. C.; Meng, Z.; Potocki,
I.; Hoermann, M.; Snow, R. J.; Tschantz, M. A.; Kelly, T. A.; McNeil, D. W.; Coutts,
S. J.; Churchill, L.; Graham, A. G.; David, E.; Grob, P. M.; Engel, W.; Meier, H.;
Trummlitz, G. J. Med. Chem. 1997, 40, 980.
6. Hasegawa, T. M.; Furuta, T.; Tsuda, T. Japanese Patent 71/22,027, 1971; Chem.
Abstr. 1971, 75, 76815.
7. Lombardino, J. G.; Wiseman, E. H. U.S. Patent 3,862,319, 1975; Chem. Abstr.
1975, 83, 72175.
R
R
O
S
O
N
O
O
N
*
OH
S
1) LDA, TMEDA
*
O
THF, -20 °C
O
2) NH4Cl
O
5
6
Scheme 2.
8. Sircar, J. C.; Zinnes, H.; Shavel, J. U.S. Patent 3,878,198, 1975; Chem. Abstr. 1975,
83, 97274.
9. Lombardino, J. G. Antiinflammatory Agents: Chemistry and Pharmacology;
Academic Press: New York, 1974. p. 129.
The scope and limitation of this process were examined using
N-mesitylenesulfonyl hydantoins 3a–j (Table 2). Attempts to en-
hance the yield through the use of an alternative base (LHMDS)
and additive (HMPA), and higher reaction temperatures provided
no significant benefit. Increasing the equivalents of LDA–TMEDA
also afforded the desired product 4a along with a complex mixture
of by-products. However, the excess LDA led to racemized products
4a–j.
We speculate that the reaction, possibly driven by the complex
induced proximity effect33,34 (CIPE), proceeds via initial lateral lith-
iation of the mesitylene sulfonamide. The resulting carbanion then
attacks the hydantoin carbonyl group which is itself activated by
the coordination with TMSCl.
10. Lombardino, J. G.; Wiseman, E. H. Med. Res. Rev. 1982, 2, 127.
11. Brooks, P. M.; Day, R. O. N. Eng. J. Med. 1991, 324, 1716.
12. Panara, M. R.; Renda, G.; Sciulli, M. G. J. Pharmacol. Exp. Ther. 1999, 290, 276.
13. Perillo, I. A.; Schapira, C. B.; Lamdan, S. J. Heterocycl. Chem. 1983, 20, 155.
14. Bakker, W. M.; Familoni, O. B.; Padfield, J.; Snieckus, V. Synlett 1997, 1079.
15. Fraga, C. A. M.; Barreiro, E. J. J. Heterocycl. Chem. 1992, 29, 1667.
16. Fravolini, A.; Schiaffella, F.; Strappaghetti, G. J. Heterocycl. Chem. 1979, 16, 29.
17. Steiner, G. Justus Liebigs Ann. Chem. 1978, 643.
18. Rasmussen, C. R.; Shaw, D. L. J. Org. Chem. 1974, 39, 1560.
19. Kubo, K.; Ito, N.; Soto, I.; Isomura, Y.; Honma, H. Japanese Patent 79/22,399
1979; Chem. Abstr. 1979, 91, 5235.
20. Kacem, Y.; Kraiem, J.; Kerkani, E.; Bouraoui, A.; Ben Hassine, B. Eur. J. Pharmacol.
Sci. 2002, 16, 221.
21. Kacem, Y.; Bouraoui, A.; Vidal, R. V.; Genêt, J. P.; Ben Hassine, B. C. R. Chimie
2002, 5, 611.
22. Ould Aliyenne, A.; Khiari, J. E.; Kraiem, J.; Kacem, Y.; Ben Hassine, B. Tetrahedron
Lett. 2006, 47, 6405.
23. Ould Aliyenne, A.; Kraiem, J.; Kacem, Y.; Ben Hassine, B. Tetrahedron Lett. 2008,
49, 1473.
24. Snieckus, V. Chem. Rev. 1990, 90, 879.
In summary, the efficient three-step process described in this
letter has enabled us to prepare imidazo[1,2-b][1,2]benzothiazin-
2-one 4,4-dioxides from inexpensive and readily available a-amino
acid methyl esters. The potential anti-inflammatory activity of
these new products is under investigation in our laboratory.
25. Green, L.; Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999, 36, 1453.
26. Clark, R. D.; Jahangir, A. In Organic Reactions; Paquette, L. A., Ed.; John Wiley
and Sons: New York, 1995; p 1.
27. Watanabe, H.; Mao, C. L.; Barnish, I. T.; Hauser, C. R. J. Org. Chem. 1969, 34,
1786.
28. Lohse, O.; Beutler, U.; Fünfschilling, P.; Furet, P.; France, J.; Kaufmann, D.; Penn,
G.; Zaugg, W. Tetrahedron Lett. 2001, 42, 385.
29. Beak, P.; Brown, R. A. J. Org. Chem. 1982, 47, 1.
30. Alo, B. I.; Familoni, O. B.; Marsais, F.; Quequiner, G. J. J. Chem. Soc., Perkin Trans.
1990, 1, 1611.
31. MacNeil, S. L.; Familoni, O. B.; Snieckus, V. J. Org. Chem. 2001, 66, 3662.
32. Typical cyclization procedure: A flame-dried, argon-flushed, round-bottomed
O
O
O
R
1) LDA, TMEDA
R
R'
N
S
THF, -20 °C, 30 min
N
N
O
S
O
O
2) TMSCl, 2 h
3) NH4Cl
N
O
R'
flask
containing
a
solution
of
5-benzyl-1-mesitylenesulfonyl-3-
4
3
phenylimidazolidin-2,4-dione (3a) (320 mg, 0.71 mmol) and TMEDA
(0.21 mL, 1.42 mmol) in THF (10 mL) was cooled to ꢀ20 °C and treated
Scheme 3.