Sequential Cyclizations of 2-Isothiocyanatobenzonitrile with α-Amino­carboxylic Esters and Acids

Abstract

The cyclization of 2-isothiocyanatobenzonitrile with α-aminocarboxylic esters and acids afforded a variety of 2-oxo-2,3,5,6-tetrahydro-5-thioxo-imidazo[1,2-c]quinazolines with very good regioselectivity.

amino acids - cyclizations - domino reactions - isothiocyanates - 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 

For the synthesis of open-chained products:

3a Besson T. Guillard J. Rees CW. Therisod M. Chem. Commun.  1997,  881 

3b Leardini R. Nanni D. Pareschi P. Tundo A. Zanardi G. J. Org. Chem.  1997,  62:  8394 

3c Pavia MR. Lobbestael SJ. Taylor CP. Hershenson FM. Miskell DL. J. Med. Chem.  1990,  33:  854 

3d For the synthesis of 1a: Pfeiffer WD. Pazdera P. Hetzheim A. Muecke J. Pharmazie  1995,  50:  21 

3e For cyclizations with hydrazine: Pfeiffer W.-D. Hetzheim A. Pazdera P. Bodtke A. Mücke J. J. Heterocycl. Chem.  1999,  36:  1327 

3f For reactions with carboxylic hydrazides: 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 

3g Also see: Blank J. Kandt M. Pfeiffer W.-D. Hetzheim A. Langer P. Eur. J. Org. Chem.  2003,  182 

3h For cyclization reactions with aminoketones: Thom A. Zinner G. Arch. Pharm. (Weinheim, Ger.)  1994,  327:  469 

3i See also: Langer P. Bodtke A. Tetrahedron Lett.  2003,  44:  5965 

3j For reactions with nitrile and malonate carbanions: Langer P. Albrecht U. Synlett.  2003,  1503 

3k For an oxidative dimerization: Calestani G. Capella L. Leardini R. Minozzi M. Nanni D. Papa R. Romina R. Zanardi G. Tetrahedron  2001,  57:  7221 

4a Liu KC. Hu MK. Arch. Pharm. (Weinheim, Ger.)  1986,  319:  188 

4b Cianci C. Chung TDY. Menwell N. Putz H. Hagen M. Colonno RJ. Krystal M. Antiviral Chem. Chemother.  1996,  7:  353 

5a Chowdhury AZMS. Shibata Y. Morita M. Kaya K. Sano T. Heterocycles  2001,  55:  1747 

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8

Synthesis of 3-Isopropyl-2-oxo-2,3,5,6-tetrahydro-5-thioxo-imidazo[1,2-c]quinazoline(3e). Typical procedure: Isothiocyanatobenzonitrile (1.0 g, 6.4 mmol) and methyl valine ethyl ester hydrochloride (1.16 g, 6.4 mmol) were suspended in dichloromethane (40 mL). A solution of sodium carbonate (1.38 g) in water (12 mL) was added and the mixture was stirred for 10 minutes at ambient temperature and was subsequently refluxed for 20 minutes. After cooling to room temperature the organic and aqueous layer were separated and the latter was extracted twice with dichloromethane (20 mL). The combined organic layers were concentrated at reduced pressure and the residue (intermediate B) was refluxed in iso-propanol for 10 h. The product crystallized after cooling. Yield: 1.28 g (77%), colorless prisms (iso-propanol), mp 278-288 °C (decomp.). IR (KBr, cm^-1): 3171 (m), 3113 (m), 3079 (m), 3027 (m), 2968 (m), 1733 (s), 1627 (s), 1557 (s), 1529 (s), 1476 (s), 1413 (m), 1348 (s), 1295 (m), 1260 (s), 1207 (s), 1149 (s), 1067 (m), 969 (m), 762 (m). UV: λ_max(nm): 210.3, 247.7, 269.4, 296.3, 352.3. ¹H NMR (DMSO-d ₆, 300 MHz): δ 0.63 (d, J = 6.8 Hz, 3 H, CH₃), 1.20 (d, J = 7.1 Hz, 3 H, CH₃), 3.34-3.38 [m, 1 H, CH(CH₃)₂], 4.51 (d, J = 3.3 Hz, 1 H, C*H), 7.41-7.48 (m, 2 H, ArH), 7.84-8.07 (m, 2 H, ArH), 13.25 (br s, 1 H, NH). ¹³C NMR (DMSO-d ₆, 75 MHz): δ 14.9 (CH₃), 16.9 (CH₃), 25.9 [CH(CH₃)₂], 67.9 (C-3), 110.9 (C-6a), 116.1 (Ar-CH), 125.2 (Ar-CH), 127.6 (Ar-CH), 137.1 (Ar-CH), 139.7 (C), 168.5, 168.5 (C=N, C=S), 186.5 (C=O). MS: m/z = 260 (18), 259 (M⁺, 100), 244 (38), 226 (23), 218 (11), 217 (70), 216 (55), 204 (36), 203 (82), 178 (36), 177 (15), 171 (11), 162 (25), 161 (59), 160 (10), 145 (19), 144 (15), 143 (19), 134 (14), 129 (15), 102 (25), 39 (10). Anal. Calcd for C₁₃H₁₃N₃OS (259.33): C, 60.21; H, 5.05; N, 16.20. Found: C, 60.61; H, 5.48; N, 16.46. All products were obtained as racemic material. All compounds gave correct spectroscopic data and satisfactory elemental analyses and/or high resolution mass data.