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

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.

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

References

1 Wiselogle FW. Survey of Antimalarial Drugs 1941-45   Edwards Brothers; Arn Arbor, Michigan: 1946. 

2 Herndon JL. Ismaiel A. Ingher SP. Teitler M. Glennon RA. J. Med. Chem.  1992,  35:  4903 

3a Marsham PR. Jackman AL. Hayter AJ. Daw MR. Snowden JL. O’Connor BM. Bishop JAM. Calvert AH. Hughes LR. J. Med. Chem.  1991,  34:  2209 

3b Meshnick SR. Thomas A. Ranz A. Xu CM. Pan H. Mol. Biochem. Parasitol.  1991,  49:  181 

3c Pendergast W. Dickerson SH. Dev IK. Ferone R. Duch DS. Smith GK. J. Med. Chem.  1994,  37:  838 

4a Sumitomo CC. inventors; Fr. Pat. Appl.  1572997.  ; Chem. Abstr. 1970, 72, 90495

4b Kusuda F, Murayama M, and Takahashi H. inventors; Jap. Pat. Appl.  7118996.  ; Chem. Abstr. 1971, 75, 49128

4c Takahashi H. inventors; Jap. Pat. Appl.  7118995.  ; Chem. Abstr. 1971, 75, 63823

5a Armarego WLF. Advances in Heterocyclic Chemistry   Vol. 1:  Katritzky AR. Academic Press; New York: 1963.  p.253 

5b Armarego WLF. Advances in Heterocyclic Chemistry   Vol. 24:  Katritzky AR. Academic Press; New York: 1979.  p.1 

5c Brown DJ. Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  p.57 

5d Undheim K. Comprehensive Heterocyclic Chemistry II   Katritzky AR. Rees CW. Scriven EF. Pergamon; Oxford: 1996.  p.93 

6 Weinstein L. Chang TW. Hudson JB. Antibiot. Chemother.  1957,  7:  443 

7 Perlman D. Barrett JM. Can. J. Microbiol.  1958,  4:  9 

8 Ishikawa F. Kosasayama A. Higashi K. Chem. Pharm. Bull.  1980,  28:  2024 

9a Meguro K. Tawada H. Kuwada Y. Chem. Pharm. Bull.  1973,  21:  1619 

9b Derieg ME. Fryer RJ. Hillery SS. Metlesics W. Silverman G. J. Org. Chem.  1971,  36:  782 

9c Hirai K. Fujishita T. Ishiba T. Sugimoto H. Matsutani S. Tsukinoki Y. Hirose K. J. Med. Chem.  1982,  25:  1466 

10 Bahr F. Dietz G. Pharmazie  1980,  35:  256 

11 Hirai K. Ishiba T. Sugimoto H. Fujishita T. J. Org. Chem.  1981,  46:  4489 

12 Hara T. Kayama Y. Sunami T. J. Org. Chem.  1978,  43:  4865 

13a Zimaity T. Anwar M. Abdel-Hay FI. Abdel-Megeid FME. Acta Chim. Acad. Sci. Hung.  1975,  87:  251 

13b Elkaschef MA.-F. Abdel-Megeid FME. Abdel-Kader A. Collect. Czech. Chem. Commun.  1974,  39:  287 

13c Abdel-Megeid FME. Elkaschef MA.-F. Mokhtar K.-EM. Zaki K.-EM. J. Chem. Soc. C  1971,  1055 

14 Yamagishi M. Ozaki K.-I. Yamada Y. Da-te T. Okamura K. Suzuki M. Chem. Pham. Bull.  1991,  39:  1694 

15 Burlaka BM. Khim. Geterotsikl. Soedin.  1980,  708 

16 Kim K. Sulfur Reports  1998,  21:  147 

17 Lee H.-S. Chang Y.-G. Kim K. J. Heterocycl. Chem.  1998,  35:  659 

18 Appel R. Janssen H. Siray M. Knoch G. Chem. Ber.  1985,  118:  1632 

19

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.

20

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.

21 Okabayashi I. Fujiwara H. J. Heterocycl. Chem.  1984,  21:  1401