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:

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<A NAME="RD16203ST-1B">1b</A> Tietze LF. Chem. Rev.  1996,  96:  115 

For reviews of work from our laboratory, see:

<A NAME="RD16203ST-2A">2a</A> Langer P. Chem.-Eur. J.  2001,  7:  3858 

<A NAME="RD16203ST-2B">2b</A> Langer P. Döring M. Eur. J. Org. Chem.  2002,  221 

<A NAME="RD16203ST-2C">2c</A> Langer P. Synthesis  2002,  441 

For the synthesis of open-chained products:

<A NAME="RD16203ST-3A">3a</A> Besson T. Guillard J. Rees CW. Therisod M. Chem. Commun.  1997,  881 

<A NAME="RD16203ST-3B">3b</A> Leardini R. Nanni D. Pareschi P. Tundo A. Zanardi G. J. Org. Chem.  1997,  62:  8394 

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<A NAME="RD16203ST-3D">3d</A> For the synthesis of 1a: Pfeiffer WD. Pazdera P. Hetzheim A. Muecke J. Pharmazie  1995,  50:  21 

<A NAME="RD16203ST-3E">3e</A> For cyclizations with hydrazine: Pfeiffer W.-D. Hetzheim A. Pazdera P. Bodtke A. Mücke J. J. Heterocycl. Chem.  1999,  36:  1327 

<A NAME="RD16203ST-3F">3f</A> 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 

<A NAME="RD16203ST-3G">3g</A> Also see: Blank J. Kandt M. Pfeiffer W.-D. Hetzheim A. Langer P. Eur. J. Org. Chem.  2003,  182 

<A NAME="RD16203ST-3H">3h</A> For cyclization reactions with aminoketones: Thom A. Zinner G. Arch. Pharm. (Weinheim, Ger.)  1994,  327:  469 

<A NAME="RD16203ST-3I">3i</A> See also: Langer P. Bodtke A. Tetrahedron Lett.  2003,  44:  5965 

<A NAME="RD16203ST-3J">3j</A> For reactions with nitrile and malonate carbanions: Langer P. Albrecht U. Synlett.  2003,  1503 

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<A NAME="RD16203ST-8">8</A>

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.