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Synlett 2004(6): 1098-1100  
DOI: 10.1055/s-2004-822893
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Quinazolines and Imidazo[1,2-c]quinazolines with the Aid of a Low-Valent Titanium Reagent

Daqing Shi*a-c, Juxian Wangb, Chunling Shib, Liangce Rongb, Qiya Zhuanga,b, Hongwen Huc
a Department of Chemistry, Xuzhou Normal University, Xuzhou 221116, P. R. China
b Key Laboratory of Biotechnology on Medical Plant , Jiangsu Previne, Xuzhou 221116, P. R. China
c Department of Chemistry, Nanjing University, Nanjing 210093, P. R. China
Fax: +86(516)3403164; e-Mail: dqshi@263.net;
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Publication History

Received 20 February 2004
Publication Date:
25 March 2004 (online)

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Synthesis of Quinazolines and Imidazo[1,2-c]quinazolines with the Aid of a Low-Valent Titanium ReagentSynlett 2004; 2004(11): 2050-2050
DOI: 10.1055/s-2004-831321

Abstract

A short and facile synthesis of a series of quinazolines and imidazo[1,2-c]quinazolines was accomplished in good yields via the novel reductive cyclization of 2-nitrobenzyl amines or 2-(2-nitrophenyl)imidazoles with ortho-ester, aldehydes or ketones ­promoted by TiCl4/Zn system. The structures were established by spectroscopic data and confirmed by X-ray analysis.

Key words

low-valent titanium - quinazoline - imidazo[1,2-c]quinazoline - 2-nitrobenzyl amine - 2-(2-nitrophenyl)imidazole

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  • 14 The general procedure is represented as follow: TiCl4 (2.2 mL, 20 mmol) was added dropwise using a syringe to a stirred suspention of zinc dust (2.6 g, 40 mmol) in freshly distilled anhyd THF (20 mL) at r.t. under anhyd nitrogen atmosphere. After completion of the addition, the mixture was refluxed for 2 h. The suspension of the low-valent titanium reagent formed was cooled to r.t. and a solution of 2-nitrobenzyl amine 1 (5 mmol) and triethyl orthoformate (2) (10 mmol) in anhyd THF (10 mL) was added carefully at r.t. When the reaction was completed (at refluxing for 5 h under N2), most of the solvent was removed in vacuo. The residue was poured into 10% HCl (100 mL), and extracted with CHCl3 (3 × 50 mL). The combined organic layers were washed with water (3 × 50 mL), dried (Na2SO4), and the solvent was removed in vacuo to give the crude product to give the pure product 3
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15

The general procedure is represented as follow: A solution of 2-(2-nitrophenyl) imindazole 4 (2 mmol) and ortho-ester 5 (4mmol) in anhyd THF (10 mL) was added carefully at r.t. to a suspension of low-valent titanium reagent (10 mmol) prepared as mentioned above. When the reaction was completed (at r.t. under N2), the reaction mixture was poured into 10% HCl, and extracted with CHCl3. The combined organic layers were washed with water, dried (Na2SO4), and the solvent was removed in vacuo to give the crude product. The crude product was purified by column chromatography on silica gel (200-300 mesh) using petroleum ether (bp 60-90 °C)-acetone (5:1) as eluent.

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Typical physical data for representative compounds: Compound 3a: mp 140-141 °C. IR (KBr): 3067, 1600, 1565, 1550, 1470, 1290, 1230, 1160, 920, 800, 735 cm-1. 1H NMR (400 MHz, CDCl3): 4.92 (s, 2 H, C4-H), 7.01 (d, J = 6.4 Hz, 1 H, C5-H), 7.10 (d, J = 8.8 Hz, 2 H, C2 ′-H, C6 ′-H), 7.15 (d, J = 7.6 Hz, 1 H, C8-H), 7.21-7.29 (m, 2 H, C6-H, C7-H), 7.40 (d, J = 8.8 Hz, 2 H, C3 ′-H, C5 ′-H), 7.56 (s, 1 H, C2-H). Anal. Calcd for C14H11ClN2: C, 69.29; H, 4.57; N, 11.54. Found: C, 69.53; H, 4.26; N, 11.72%. Compound 6a: mp 193-195 °C. IR (KBr): 3058, 1603, 1473, 1379, 1353, 1310, 1262, 1235, 894, 778, 746, 704, 693 cm-1. 1H NMR (400 MHz, CDCl3): 7.30-7.41 (m, 3 H, ArH), 7.53-7.59 (m, 5 H, ArH), 7.70-7.74 (m, 4 H, ArH), 7.86 (d, J = 8.0 Hz, 1 H, ArH), 7.97 (d, J = 7.6 Hz, 1 H, ArH), 8.72 (s, 1 H, ArH). Anal. Calcd for C22H15N3: C, 82.22; H, 4.70; N, 13.08. Found: C, 82.41; H, 4.46; N, 13.16. Compound 8a: mp 240-241 °C. IR (KBr): 3240, 3012, 2979, 1614, 1512, 1479, 1444, 1367, 1275, 1211, 1161, 1072, 964, 916, 791, 773, 752, 698 cm-1. 1H NMR (400 MHz, DMSO-d 6): 1.36 (s. 6 H, 2 × CH3), 6.52 (s, 1 H, NH), 6.79 (d, J = 8.8 Hz, 1 H, ArH), 6.83 (d, J = 7.2 Hz, 1 H, ArH), 7.08-7.19 (m, 4 H, ArH), 7.36 (d, J = 7.2 Hz, 2 H, ArH), 7.51-7.54 (m, 5 H, ArH), 7.84 (d, J = 7.2 Hz, 1 H, ArH). Anal. Calcd for C24H21ClN2: C, 82.02; H, 6.02; N, 11.96. Found: C, 82.25; H, 5.89; N, 12.10.