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

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.

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

References

<A NAME="RU05004ST-1">1</A> McMurry JE. Fleming MP. J. Am. Chem. Soc.  1974,  96:  4708 

<A NAME="RU05004ST-2">2</A> McMurry JE. Miller DD. Tetrahedron Lett.  1983,  24:  1885 

<A NAME="RU05004ST-3">3</A> Fürstner A. Emst A. Krause H. Ptock A. Tetrahedron Lett.  1996,  52:  7329 

<A NAME="RU05004ST-4">4</A> Zhou LH. Tu SJ. Shi DQ. Dai GY. Chen WX. Synthesis  1998,  851 

<A NAME="RU05004ST-5">5</A> Mariappan P. Gadthula S. Surisetti S. Tetrahedron Lett.  2001,  42:  7123 

<A NAME="RU05004ST-6">6</A> Shi DQ. Chen JX. Chai WY. Chen WX. Kao TY. Tetrahedron Lett.  1993,  34:  2963 

<A NAME="RU05004ST-7">7</A> Shi DQ. Mu LL. Lu ZS. Dai GY. Synth. Commun.  1997,  27:  4121 

<A NAME="RU05004ST-8">8</A> Zhou LH. Shi DQ. Dai GY. Chen WX. Tetrahedron Lett.  1997,  38:  2729 

<A NAME="RU05004ST-9A">9a</A> Billimmoria AD. Cava MP. J. Org. Chem.  1994,  59:  6772 

<A NAME="RU05004ST-9B">9b</A> Blackman A. Hambley TM. Picker R. Taylor WC. Thirasana N. Tetrahedron Lett.  1987,  28:  5561 

<A NAME="RU05004ST-10A">10a</A> Helissey P. Cros S. Giorgi-Renault S. Anti-Cancer Drug Des.  1994,  9:  51 

<A NAME="RU05004ST-10B">10b</A> Ibrahim E. Montgomerie AM. Sneddon AH. Proctor GR. Green B. Eur. J. Med. Chem.  1988,  23:  183 

<A NAME="RU05004ST-10C">10c</A> Riou JF. Helissey P. Grondard L. Giorgi-Renault S. Mol. Pharmacol.  1991,  40:  699 

<A NAME="RU05004ST-10D">10d</A> Brana MF. Castellano JM. Keilhauer G. Machuca A. Martin Y. Redondo C. Schlick E. Walker N. Anti-Cancer Drug Des.  1994,  9:  527 

<A NAME="RU05004ST-11">11</A> Li J. Shi DQ. Chen WX. Heterocycles  1997,  45:  2381 

<A NAME="RU05004ST-12">12</A> Zhou LH. Tu SJ. Shi DQ. Dai GY. J. Chem. Res., Synop.  1998,  398 

<A NAME="RU05004ST-13">13</A> Shi DQ. Rong LC. Wang JX. Zhuang QY. Wang XS. Tu SJ. Hu HW. J. Chem. Res., Synop.  2003,  342 

<A NAME="RU05004ST-14">14</A> 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

<A NAME="RU05004ST-15">15</A>

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.

<A NAME="RU05004ST-16">16</A>

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, C^{2 ′}-H, C^{6 ′}-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, C^{3 ′}-H, C^{5 ′}-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.

<A NAME="RU05004ST-17A">17a</A> Shi DQ. Wang JX. Shi CL. Rong LC. Wang XS. Hu HW. Yu KB. Acta Cryst.  2003,  E59:  o1846 

<A NAME="RU05004ST-17B">17b</A> Shi DQ. Wang JX. Shi CL. Rong LC. Wang XS. Hu HW. Acta Cryst.  2003,  E59:  o1661