Regioselective Cyclization of 2-Isothiocyanatobenzonitrile with Carbon 1,1-Dinucleophiles

Abstract

The one-pot cyclization of 2-isothiocyanatobenzonitrile with 1,1-dinucleophiles regioselectively afforded 2-alkylidene-4-imino-1,4-dihydrobenzo[d][1,3]thiazines.

Key words

cyclizations - N-heterocycles - isothiocyanates - nitriles - regioselectivity

References

• For reviews of domino and sequential reactions, see:
• 1a Tietze LF. Beifuss U. Angew. Chem., Int. Ed. Engl.  1993,  32:  131 ; Angew. Chem. 1993, 105, 137
• 1b Tietze LF. Chem. Rev.  1996,  96:  115 
• For reviews of work from our laboratory, see:
• 2a Langer P. Chem. Eur. J.  2001,  7:  3858 
• 2b Langer P. Döring M. Eur. J. Org. Chem.  2002,  221 
• 2c Langer P. Synthesis  2002,  441 
• 3a Houben-Weyl . Methods of Organic Chemistry, Carbocyclic Three-Membered Ring Compounds   Vol. E17:  de Meijere A. Thieme; Stuttgart: 1996. 
• 3b Kaiser EM. Solter LE. Schwarz RA. Beard RD. Hauser CR. J. Am. Chem. Soc.  1971,  93:  4237 
• 3c Giblin GMP. Ramcharitar SH. Simpkins NS. Tetrahedron Lett.  1988,  29:  4197 
• 3d Müller JFK. Neuburger M. Zehnder M. Helv. Chim. Acta  1997,  80:  2182 
• 4a Langer P. Freifeld I. Org. Lett.  2001,  3903 
• 4b Grangier G. Aitken DJ. Guillaume D. Husson H.-P. Tetrahedron Lett.  1994,  4355 
• 4c Benedetti F. Berti F. Risaliti A. Tetrahedron Lett.  1993,  6443 
• 4d Aitken DJ. Royer J. Husson H.-P. J. Org. Chem.  1990,  55:  2814 
• 4e Aitken DJ. Royer J. Husson H.-P. Tetrahedron Lett.  1988,  3315 
• 4f Mouzin G. Cousse H. Bonnaud B. Synthesis  1978,  304 
• 5a Mussatto MC. Savoia D. Trombini C. Umani-Ronchi A. J. Chem. Soc., Perkin Trans. 1  1980,  260 
• 5b Langer P. Wuckelt J. Döring M. Görls H. J. Org. Chem.  2000,  65:  3603 
• 6a Besson T. Guillard J. Rees CW. Therisod M. Chem. Commun.  1997,  881 
• 6b Leardini R. Nanni D. Pareschi P. Tundo A. Zanardi G. J. Org. Chem.  1997,  62:  8394 
• 6c Calestani G. Capella L. Leardini R. Minozzi M. Nanni D. Papa R. Romina R. Zanardi G. Tetrahedron  2001,  57:  7221 
• 6d Pfeiffer WD. Pazdera P. Hetzheim A. Muecke J. Pharmazie  1995,  50:  21 
• 6e Francis JE. Cash WD. Psychoyos S. Ghai G. Wenk P. Friedmann RC. Atkins C. Warren V. Furness P. Hyun JL. Stone GA. Desai M. Williams M. J. Med. Chem.  1988,  31:  1014 
• 6f Pavia MR. Lobbestael SJ. Taylor CP. Hershenson FM. Miskell DL. J. Med. Chem.  1990,  33:  854 
• 6g Pfeiffer W.-D. Hetzheim A. Pazdera P. Bodtke A. Mücke J. J. Heterocycl. Chem.  1999,  36:  1327 
• 6h Blank J. Kandt M. Pfeiffer W.-D. Hetzheim A. Langer P. Eur. J. Org. Chem.  2003,  182 
• 6i Francis JE. Cash WD. Barbaz WD. Bernard PS. Lovell RA. Mazzenga GC. Friedmann RC. Hyun JL. Braunwalder AF. Loo PS. Bennett DA. J. Med. Chem.  1991,  34:  281 
• For related molecules, see:
• 7a Peseke K. Synthesis  1976,  386 
• 7b Bergman J. Bergman S. J. Org. Chem.  1985,  50:  1246 
• 7c Bajardi ML. Daidone G. Raffa D. Plescia S. Heterocycles  1986,  24:  1367 
• 7d Cheng Y. Wang M.-X. Gan W.-X. Huang Z.-T. Synth. Commun.  1996,  26:  475 
• 7e Neidlein R. Sui Z. Kramer W. Boese R. Rev. Roum. Chim.  1991,  36:  601 
• 8a Karwowsky JP. Jackson M. Rasmussen RR. Humphrey PE. Poddig JB. Kohl WL. Scherrr MH. Kadam S. McAlpine JB. J. Antibiot.  1993,  46:  374 
• 8b Hochlowki JE. Mullally MM. Spanton SG. Whittern DN. Hill P. McAlpine JB. J. Antibiot.  1993,  46:  380 
• 8c Marsden SP. Depew KM. Danishefsky SJ. J. Am. Chem. Soc.  1994,  116:  11143 
• 9a Penn J. Mantle PG. Bilton JN. Sheppard RN. J. Chem. Soc., Perkin Trans. 1  1992,  1495 
• 9b Takahashi C. Matsushita T. Doi M. Minoura K. Shingu T. Kumeda Y. Numata A. J. Chem. Soc., Perkin Trans. 1  1992,  1495 
• 9c Numata A. Takahashi C. Matsushita T. Miyamoto T. Kawai K. Usami Y. Matsumura E. Inone M. Ohishi H. Shingu T. Tetrahedron Lett.  1992,  33:  1621 
• 9d Wong S. Musza LL. Kydd GC. Kullnig R. Gillum AM. Cooper R. J. Antibiot.  1993,  46:  545 
• 10 Bergman J. Brynolf A. Tetrahedron  1990,  46:  1295 
• 11a Clardy J. Springer JP. Büchi G. Matsuo K. Wightman R. J. Am. Chem. Soc.  1975,  97:  663 
• 11b Büchi G. Luk KC. Kobbe B. Townsend JM. J. Org. Chem.  1977,  42:  244 
• 12a Petersen S. Herlinger H. Tietze E. Siefken W. Angew. Chem.  1962,  74:  855 
• 12b Johne S. Jung B. Pharmazie  1978,  33:  299 
• 14 For comparison, see: Beckert R. Gruner M. Seidel I. Kuban R.-J. Monatsh. Chem.  1989,  120:  1125 
• 15 Dimroth O. Liebigs Ann. Chem.  1909,  364:  183 

13

General procedure A: To a THF suspension of 2-isothiocyanatobenzonitrile (1a) and sodium hydride was added phenylacetonitrile (2a) at 0 °C. The mixture was heated at reflux for 72 h, cooled to room temperature and subsequently an aqueous solution of NH₄Cl (20 mL, 1 M) was added. The organic and the aqueous layers were separated and the latter was extracted three times with ether (30 mL). The combined organic layers were dried (Na₂SO₄), filtered and the solvent of the filtrate was removed in vacuo. The residue was recrystallized from ethanol. Starting with 2a (0.351 g, 3.0 mmol), 1a (0.320 g, 2.0 mmol), sodium hydride (0.096 g, 3.0 mmol) and 15 mL of THF, 3a was obtained as a pale yellow solid (0.345 g, 62%, E/Z = 8:1).
General procedure B: To a THF solution of phenylacetonitrile was added n-BuLi (1.6 M solution in hexane) at 0 °C. After stirring for 1 h at 0 °C, the solution was cooled to -78 °C and a THF solution of 2-isothiocyanatobenzonitrile was added. After stirring for 30 min at -78 °C an aqueous solution of NH₄Cl (20 mL, 1 M) was added. After warming to room temperature the organic and the aqueous layers were separated and the latter was extracted three times with ether (30 mL). The combined organic layers were dried (Na₂SO₄), filtered and the solvent of the filtrate was removed in vacuo. The residue was recrystallized from ethanol. Starting with 2a (0.28 g, 2.3 mmol), n-BuLi (3.3 mL, 1.6 M), 1a (0.32 g, 2.0 mmol) and 15 mL of THF, 3a was obtained as a pale yellow solid (0.24 g, 43%).
¹H NMR (DMSO-d ₆, 300 MHz): δ 7.24-7.41 (m, 3 H, CH), 7.43-7.65 (m, 5 H, CH), 8.68 (dd, ⁴ J = 1 Hz, ³ J = 8 Hz, 1 H, CH), 9.30 (s, 1 H, NH), 12.34 (s, 1 H, NH). ¹³C NMR (DMSO-d ₆, 75 MHz, major isomer): δ_c 82.29 (C), 114.67 (CN), 116.30 (CH), 121.20 (C), 124.44, 124.95, 128.92, 129.21, 129.96 (CH), 132.64 (C), 133.69 (CH), 136.80, 141.75, 170.63 (C). MS (70 eV): m/z (%): 277 (100, M⁺), 244(9), 217(18), 190(12), 165(4). IR (KBr, cm^-1): 3370 (s), 3207 (w), 3174 (m), 3143 (w), 3309 (m), 3068 (w), 2194 (s), 1608 (s), 1589 (s), 1551 (m), 1496 (s), 1449 (m), 1417 (m). Anal.: Calcd. for C₁₆H₁₁N₃S: C 69.29, H 4.00; found C 69.64, H 3.97.