Efficient synthesis of new imidazo[1,2-b][1,2]benzothiazine 4,4-dioxide derivatives via lateral lithiation of N-mesitylenesulfonyl hydantoins

Article abstract of DOI:10.1016/j.tetlet.2012.08.008

N-Mesitylenesulfonyl hydantoins, readily available from commercial α-amino acids, undergo lateral lithiation with an excess of lithium diisopropylamide and tetramethylethylenediamine in the presence of trimethylsilyl chloride to provide new imidazo[1,2-b]

Full text of DOI:10.1016/j.tetlet.2012.08.008

Tetrahedron Letters 53 (2012) 5608–5610
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Tetrahedron Letters
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Efficient synthesis of new imidazo[1,2-b][1,2]benzothiazine 4,4-dioxide
derivatives via lateral lithiation of N-mesitylenesulfonyl hydantoins
⇑
Yakdhane Kacem, Béchir Ben Hassine
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, Faculté des Sciences, Université de Monastir, Avenue de l’environnement, 5019 Monastir, Tunisia
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Mesitylenesulfonyl hydantoins, readily available from commercial a-amino acids, undergo lateral lith-
Received 24 April 2012
Revised 23 July 2012
Accepted 2 August 2012
Available online 9 August 2012
iation with an excess of lithium diisopropylamide and tetramethylethylenediamine in the presence of tri-
methylsilyl chloride to provide new imidazo[1,2-b][1,2]benzothiazin-2-one 4,4-dioxide derivatives in
yields ranging from 44–65%.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Hydantoins
Mesitylenesulfonyl
Lateral lithiation
Imidazo[1,2-b][1,2]benzothiazin-2-one 4,4-
dioxides
Heterocycles incorporating a sulfonamide moiety have been
viewed with considerable interest, especially in the pharmaceutical
industry.1–5 For example, 1,2-benzothiazines with basic side chains
are claimed to be diuretic agents.6 Antithrombotic and lipid-regu-
lating properties are observed for 1,2-benzothiazine-3-carboxam-
ides.7 Anti-bacterial activity was found for several penicillin
derivatives containing the 1,2-benzothiazinyl fragment.8 The
discovery of the anti-inflammatory properties of the 4-hydroxy-
2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (oxicam) ring
system, further stimulated synthetic approaches in this area.9–11
Owing to these important pharmacological activities of 1,2-ben-
zothiazinones and 1,2-benzothiazines, several publications have ap-
peared describing interesting methods for their preparation.12–15 In
addition, a few reports have been published concerning the synthe-
sis of heterocyclic ring fused 1,2-benzothiazines.16–19 Almost all of
these methods use a preformed 1,2-benzothiazine as the starting
material. As part of our continued efforts to develop synthetically
useful anionic aromatic reactions for the synthesis of biologically ac-
tive compounds,20–23 we report in this communication the success-
ful transformation of readily prepared N-mesitylenesulfonyl
hydantoins into new imidazo[1,2-b][1,2]benzothiazin-2-one 4,4-
dioxide derivatives via an in situ sequence involving lateral lithia-
tion—cyclization—elimination reactions. These heterocycles are
analogues of 1,2-benzothiazine derivatives that were required for
biological activity evaluations and as starting materials to prepare
new drugs.
The starting N-mesitylenesulfonyl hydantoins were prepared in
two steps from the corresponding -amino acid methyl esters
(Scheme 1). Treatment of -amino acid methyl esters 1 with mes-
itylsulfonyl chloride and triethylamine at 0 °C gave N-mesitylsulfo-
nylamino acid methyl esters 2 in high yields. Deprotonation of
compounds 2 with NaH in THF followed by the addition of an eas-
ily accessible isocyanate, afforded the corresponding N-mes-
itylenesulfonyl hydantoins 3 in good yields (Table 1).
The utility of directed lateral metalation (DLM) cyclization reac-
tions in organic synthesis has been widely demonstrated by
Snieckus and others.24–26 Also, DLM has been reported for o-tolyl-
sulfonamide,27 o-tolylanthranilamide,28 p-tolylcarbamide,29 p-tol-
ylsulfonate,30 and p-tolylsulfonamide31 which undergo benzylic
deprotonation.
a
a
Previously, we reported the LDA–TMEDA-mediated conversion
of 3-N-mesitylenesulfonyl-1,3-oxazolidin-2-ones
5 into chiral
1,2-benzothiazin-3-one 1,1-dioxide derivatives 623 (Scheme 2).
Inspired by these results, we undertook studies to test the gen-
erality of this type of process for other heterocycle-bridged mes-
itylenesulfonyl groups. However, subjecting N-mesitylenesulfonyl
hydantoin 3a to these conditions failed to provide any products
and only the recovered starting sulfonamide 3a was obtained. Sur-
prisingly, treatment of 3a with two equivalents of LDA–TMEDA, fol-
lowed by the addition of TMSCl (2 equiv) afforded a new product
(58%) accompanied by the formation of silylated by-products. Anal-
yses of 1H NMR spectra indicated only two methyl groups
[d(ppm) = 2.24, s and 2.66, s] together with a new olefinic signal
at d = 5.82. Combined with the molecular ion (MH+) at m/
z = 431.0986, this suggested that the product was the unusual fused
benzothiazine32 4a (Scheme 3).
⇑
Corresponding author. Tel.: +216 73500279; fax: +216 73500278.
E-mail address: bechirbenhassine@yahoo.fr (B. Ben Hassine).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.008

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.

5610
Y. Kacem, B. Ben Hassine / Tetrahedron Letters 53 (2012) 5608–5610
dropwise with a freshly prepared solution of LDA (1.42 mmol, in 5 mL of THF).
101 °C; IR (cmꢀ1): 1664, 1620, 1340, 1163. 1H NMR (300 MHz, CDCl3): d
224(s, 3H, Ar–CH3), 2.66 (s, 3H, Ar–CH3), 3.43 (dd, 1H, J = 3.9, 14.1 Hz, CH–Ph),
3.70 (dd, 1H, J = 3.9, 14.1 Hz, CH–Ph), 5.10 (t, 1H, J = 3.9 Hz, CH–N), 5.82 (s, 1H,
CH'C), 6.74–7.31 (m, 12H, ArH). 13C NMR (75 MHz, CDCl3): d = 21.19, 23.13,
37.58, 63.13, 110.05, 115.12, 118.50, 126.36, 127.89, 128.74, 129.00, 129.15,
129.31, 129.85, 130.72, 132.04, 132.44, 132.66, 141.21, 144.77, 168.70. HRMS
(ES) found MH+ 431.0986, C25H23N2O3S requires 431.0981.
The resulting yellow solution was allowed to stir for 30 min after which time a
cold THF solution of TMSCl (0.18 mL, 1.42 mmol, 2 mL) was added via cannula.
The reaction mixture was stirred at ꢀ20 °C for 2 h and then warmed to room
temperature and quenched with saturated aqueous NH4Cl (10 mL). The
mixture was concentrated in vacuo and the aqueous phase extracted with
ethyl acetate (3 ꢁ 20 mL). The organic phase was washed with brine
(3 ꢁ 5 mL), dried over MgSO4 and concentrated in vacuo. The crude residue
was purified by column chromatography on silica gel (30% EtOAc: 70% hexane)
33. Beak, P.; Meyers, A. I. Acc. Chem. Res. 1986, 19, 356.
34. Whistler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004,
43, 2206.
to
afford
177 mg
of
1,2,3,4-tetrahydro-3-benzyl-5,7-dimethyl-1-
phenylimidazo[1,2-b][1,2]benzothiazin-2-one 4,4-dioxide (4a). Mp = 99–