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Synlett 2002(9): 1423-1426
DOI: 10.1055/s-2002-33520
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3-Aryl-3,4-dihydro-4-hydroxy-4-phenylquinazoline-2-
carbonitrile via 2-(Benzoyl)arylimino-4-chloro-5H-1,2,3-dithiazoles

Yong-Goo Chang, Kyongtae Kim*
School of chemistry and molecular engineering, Seoul National University, Seoul 151-742, Korea
Fax: +82(2)8748858; e-Mail: kkim@plaza.snu.ac.kr;
Further Information

Publication History

Received 15 May 2002
Publication Date:
17 September 2002 (online)

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Abstract

Treatment of methyl N-(4-chloro-5H-1,2,3-dithiazole-5-ylidene)anthranilate 1 with TiCl4 (1.5 equiv.) in CH2Cl2 at r.t., followed by addition of arylamines gave quinazolin-4-ones 2 bearing an aryl group at position 3 in moderate yields. Similarly 4-hydroxy-4-phenylquinazolines 6 bearing an aryl group at position 3 were prepared in good to moderate yields from 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)]benzophenones, 5, TiCl4, and arylamines under the same conditions. The 1H NMR spectra of 6 in CDCl3 indicate that the compounds exist as an equilibrium mixture of 6 and the corresponding ring-opened compound, N-(2-benzoylaryl)-2-cyanoamidines 7. However, it is envisaged that compounds 6 exist as a single compound in a solid state in view of IR spectra showing no peak corresponding to a carbonyl absorption.

Key words

1,2,3-dithiazoles - heterocycles - Lewis acid - quinazolines - titanium tetrachloride

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General Procedure for the Synthesis of 3-Aryl-2-cyanoquinazolin-4(3 H )-ones 2. (A) To a solution of methyl N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)anthranilate (1) (0.42-0.94 mmol) in CH2Cl2 (20 mL) was added TiCl4 (0.82-1.37 mmol) by using a hypodermic syringe under nitrogen atmosphere. The solution turned immediately dark red. Arylamines (1.86-3.78 mmol) were added to the dark red solution, which was stirred until no spot corresponding to 1 was observed on TLC (silica gel, R f = 0.6, EtOAc-hexane = 1:3). Water (30 mL) was added and the mixture was extracted with CH2Cl2 (25 mL × 3). The combined extracts were dried over MgSO4, followed by evaporation of the solvent. The residue was chromatographed on a silica gel (70-230 mesh, 2 × 10 cm). Elution with n-hexane gave sulfur. Subsequent elution with a mixture of n-hexane and EtOAc (5:1) gave unknown mixtures and 2. (B) To a solution of 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)]acetophenone (5c) (0.36-0.59 mmol) in CH2Cl2 (15 mL) was added TiCl4 (0.55-0.64 mmol) by using a hypodermic syringe under nitrogen atmosphere. Subsequently arylamines were added. When p-toluidine was added, the reaction mixture showed a yellow spot (R f = 0.7, EtOAc-n-hexane = 1:3), assignable to be 3,4-dihydro-4-methylene-3-(4-tolyl)quinazoline-2-carbonitrile (9a). IR (neat): 2240, 1635, 1603, 1581, 1555, 1504, 1469, 1344, 1322, 1226, 1206, 1110, 816, 762 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 2.47 (s, 3 H, CH3), 3.61 (d, 1 H, J = 2.5 Hz, =CH), 4.65 (d, 1 H, J = 2.5 Hz, =CH), 7.26-7.32 (m, 3 H, ArH), 7.36-7.52 (m, 4 H, ArH), 7.53 (d, 1 H, J = 7.8 Hz, ArH). 13C NMR (CDCl3, 75 MHz): δ = 21.8, 85.0, 112.1, 123.4, 123.7, 128.2, 128.9, 129.4, 131.1, 131.9, 133.1, 135.9, 140.8, 141.0, 142.8. Anal. Calcd for C17H13N3: C, 78.74; H, 5.05; N, 16.20. Found: C, 78.62; H, 5.09; N, 16.35. Compound 9a gradually faded out during chromatography to give a new spot (R f = 0.5, EtOAc-n-hexane = 1: 3), corresponding to 2-cyano-3-(4-tolyl)quinazolin-4(3H)-one (2b), which was eluted with a mixture of EtOAc and n-hexane (1:5) as an eluent to give 2b, which was recrystallized from EtOH. Mp 175-176 °C. IR (KBr): 1677, 1581, 1501, 1456, 1328, 1312, 1274, 1104, 1082, 810, 774 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 2.49 (s, 3 H, CH3), 7.31 (d, 2 H, J = 8.3 Hz, ArH), 7.43 (d, 2 H, J = 8.3 Hz, ArH), 7.67-7.73 (m, 1 H, ArH), 7.82-7.92 (m, 2 H, ArH), 8.38 (d, 1 H, J = 7.6 Hz, ArH). 13C NMR (CDCl3, 75 MHz): δ = 21.9, 111.6, 123.4, 127.9, 128.3, 129.1, 130.7, 131.2, 132.1, 132.9, 135.8, 141.5, 146.9, 160.6. Anal. Calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.50; H, 4.22; N, 16.21.

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General Procedure for the Synthesis of 3-Aryl-3,4-dihydro-4-hydroxy-4-phenylquinazoline-4-carbonitriles 6. To a solution of 2-[N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)]benzophenone (5a) (0.29-0.41 mmol) in CH2Cl2 (15 mL) was added TiCl4 (0.46-0.91 mmol) by using a hypodermic syringe under nitrogen atmosphere, followed by addition of arylamines (0.61-1.03 mmol). The mixture was worked up as described in the general procedure for the synthesis of 2. Elution with a mixture of n-hexane and EtOAc (3:1) gave 6a,b and 6f. 4-Hydroxy-3-(4-methoxyphenyl)-4-phenylquinazoline-2-carbonitrile (6a), which was recrystallized from a mixture of CH2Cl2 and n-hexane. Mp 179-182 °C (dec.). IR (KBr): 3168, 2224, 1597, 1578, 1454, 1467, 1446, 1354, 1290, 1248, 1168, 1030, 995, 819, 765, 733 cm-1. 1H NMR (CDCl3, 300 MHz): δ = 3.73 (s, 3 H, OCH3 of major), 3.84 (s, 3 H, OCH3 of minor), 5.99 (s, br, 1 H, OH of major), 6.60-6.66 (m, 2 H, ArH of major), 6.80-6.82 (m, 1 H ArH of major), 6.89 (d, 1 H, J = 7.4 Hz, ArH of major), 7.12-7.26 (m, 6 H, ArH of major), 7.39-7.53 (m, 2 H, ArH of major), 7.74-7.76 (m, 1 H, ArH of major). 13C NMR (CDCl3, 75 MHz): δ = 55.3, 87.6, 112.0, 113.7, 124.7, 127.6, 128.1, 128.1, 128.2, 128.3, 129.7, 129.8, 131.1, 133.1, 134.3, 139.0, 141.8, 159.7. The aromatic proton signals of minor compound are envisaged to overlap with those of major. Anal. Calcd for C22H17N3O2: C, 74.35; H, 4.82; N, 11.82. Found: C, 74.49; H, 4.80; N, 11.71.