Synthesis of Benzo[b][1,4]thiazines by Hetero-Diels-Alder Reaction of o-Iminothioquinones

Abstract

The regioselective sulfenylation of N-sulfonylanilines with phthalimidesulfenyl chloride afforded the precursors of transient o-iminothioquinones obtained very easily under mild reaction conditions. These species are efficient electron-poor dienes able to react with several electron-rich alkenes to give, with complete control of the regiochemistry, benzo[b][1,4]thiazine cycloadducts.

phthalimidesulfenyl chloride - electrophilic aromatic substitutions - o-iminothioquinones - Diels-Alder - heterocycles

References and Notes

1 Capozzi G. Falciani C. Menichetti S. Nativi C. J. Org. Chem.  1997,  62:  2611 

2 Capozzi G. Falciani C. Menichetti S. Nativi C. Raffaelli B. Chem. Eur. J.  1999,  5:  1748 

3 Arnoldi A. Bassoli A. Merlini L. Ragg E. J. Chem. Soc., Perkin Trans. 1  1993,  1359 

4 Menichetti S. Nativi C. Sarri P. Viglianisi C. J. Sulfur Chem.  2004,  25:  317 

5 Song ZJ. King AO. Waters MS. Lang F. Zewge D. Bio M. Leazer JL. Javadi G. Kassim A. Tschaen DM. Reamer RA. Rosner T. Chilenski JR. Mathre DJ. Volante RP. Tiller R. Proc. Natl. Acad. Sci. U.S.A.  2004,  101:  5776 ; and references cited therein

6a Capozzi G. Lo Nostro P. Menichetti S. Nativi C. Sarri P. Chem. Commun.  2001,  551 

6b Menichetti S. Aversa MC. Cimino F. Contini A. Tomaino A. Viglianisi C. Org. Biomol. Chem.  2005,  3:  3066 

6c Lodovici M. Menichetti S. Viglianisi C. Caldini S. Giuliani E. Bioorg. Med. Chem. Lett.  2006,  16:  1957 

6d Amorati R. Fumo MG. Pedulli GF. Menichetti S. Pagliuca C. Viglianisi C. Helv. Chim. Acta  2006,  89:  2462 

6e Amorati R. Cavalli A. Fumo MG. Masetti M. Menichetti S. Chiara Pagliuca C. Pedulli GF. Viglianisi C. Chem. Eur. J.  2007,  13:  8223 

7a Matsuoka H. Ohi N. Mihara M. Suzuki H. Miyamoto K. Maruyama N. Tsuji K. Kato N. Akimoto T. Takeda Y. Yano K. Kuroki T. J. Med. Chem.  1997,  40:  105 

7b Cecchetti V. Calderone V. Tabarrini O. Sabatini S. Filipponi E. Testai L. Spogli R. Martinotti E. Fravolini A. J. Med. Chem.  2003,  46:  3670 

7c Schou SC. Hansen HC. Tagmose TM. Boonen HCM. Worsaae A. Drabowski M. Wahl P. Arkhammar POG. Bodvarsdottir T. Antoine M.-H. Lebrunb P. Hansen JB. Bioorg. Med. Chem.  2005,  13:  141 

7d Rathore BS. Kumar M. Bioorg. Med. Chem.  2006,  14:  5678 

7e Wei Huang W. Yang G.-FB. Bioorg. Med. Chem.  2006,  14:  8280 

8 To the best of our knowledge only an example of a dienic o-iminothioquinone has been reported in the literature: Diep V. Dannenberg JJ. Franck RW. J. Org. Chem.  2003,  68:  7907 

9 Capozzi G. Menichetti S. Nativi C. Vergamini C. Synthesis  1998,  915 

10 Li B. Franck RW. Capozzi G. Menichetti S. Nativi C. Org. Lett.  1999,  1:  111 

11

A small amount of the bis-sulfenylated derivative (5-10%) was also isolated.

12

The following procedures for the preparation of 3a, by sulfenylation of 2a with sulfenyl chloride 1, and synthesis of thiazine 5e, by cycloaddition of an o-iminothioquinone with p-methoxystyrene (4e), can be regarded as general procedures as well.
Synthesis of N -Thiophthalimide 3a: A solution of PhthNSCl (1; 0.788 g, 3.47 mmol) in anhyd CHCl₃ (10 mL) was added to a solution of N-tosyl aniline 2a (0.890 g, 2.89 mmol) in anhyd CHCl₃ (10 mL). The reaction mixture was stirred at r.t. for 3.5 h, diluted with CH₂Cl₂, washed with a sat. solution of NaHCO₃, and H₂O, and dried over Na₂SO₄. The material obtained after evaporation of the solvent was purified by flash chromatography on silica gel using CHCl₃ as eluent. o-N-Tosyl-N-thiophthalimide 3a was obtained as a white powder (0.390 g, 73% yield). IR (KBr disc): 3193, 2946, 2845, 1784, 1733, 1728, 1337, 1269, 1158, 1051 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 9.48 (s, 1 H, NH), 7.86-7.88 (m, 2 H), 7.73-7.75 (m, 4 H), 7.19-7.21 (m, 2 H), 6.86 (d, J = 2.4 Hz, 1 H), 6.15 (d, J = 2.4 Hz, 1 H), 3.83 (s, 3 H), 3.81 (s, 3 H), 2.36 (s, 3 H). ¹³C NMR (50 MHz, CDCl₃): δ = 168.2, 164.4, 162.5, 143.8, 143.6, 135.8, 131.9, 104.8, 134.6, 129.5, 128.6, 127.4, 99.0, 95.4, 56.1, 55.7, 21.6. Anal. Calcd for C₂₃H₂₀O₆N₂S₂: C, 57.01; H, 4.16; N, 5.78. Found: C, 57.40; H, 4.11; N, 5.76.
Synthesis of Benzo[ b ][1,4]thiazine 5e: To a solution of sulfenamide 3a (0.250 g, 0.52 mmol) in anhyd CHCl₃ (4 mL), p-methoxystyrene (4e; 0.103 g, 0.77 mmol) and Et₃N (0.053 g, 0.52 mmol) were added in sequence. The solution was stirred at 60 °C for 17 h. The crude product was concentrated and purified by flash chromatography on silica gel (eluent: CH₂Cl₂-PE, 8:2) to give thiazine 5e as a yellow oil (0.200 g, 81% yield). IR (CHCl₃): 3017, 3000, 2913, 2836, 1350, 1247, 1165, 1036 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.52 (m, 2 H), 7.29-7.32 (m, 2 H), 7.18-7.20 (m, 2 H), 6.79-6.81 (m, 2 H), 7.04 (d, J = 2.4 Hz, 1 H), 6.29 (d, J = 2.4 Hz, 1 H), 5.72 (app t, X part of an ABX system, J = 6.0 Hz, 1 H), 3.82 (s, 3 H), 3.754 (s, 3 H), 3.746 (s, 3 H), 3.04 (AB part of an ABX system, J _AB = 13.2 Hz, 2 H), 2.38 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 158.70, 157.55, 155.86, 143.69, 136.25, 134.81, 131.09, 129.44, 127.56, 127.29, 113.80, 110.7, 105.89, 97.05, 58.21, 55.95, 55.61, 55.15, 31.68, 21.59. MS (rel. int.%): m/z (%) = 471 (100), 316 (98) [M⁺· - tosyl]. Anal. Calcd for C₂₄H₂₅O₅NS₂: C, 61.70; H, 5.80; N, 2.88. Found: C, 61.96; H, 5.75; N, 2.96.

13 Cardullo F. Donati D. Merlo G. Paio A. Salaris M. Taddei M. Synlett  2005,  2996