One-pot reductive cyclization to antitumor quinazoline precursors

Abstract

A highly efficient and versatile synthetic approach to the central core of anti-cancer quinazolinone derivatives is reported. Intermolecular reductive N-heterocyclizations of various 2-nitrobenzoic acid derivatives with formamide were catalyzed by indium(III) or bismuth(III) salts to yield the title compounds in high yields and excellent purities. In the present one-pot sequence, the arylnitro group is apparently reduced by formamide decomposition product carbon monoxide and the resultant anthranilic acid derivative proceeds to Niementowski cyclocondensation to form quinazolinones. The transformation is robust for diverse substituents on the aryl group and In(III) counterions, and is also compatible with N-alkyl formamides but not dimethylformamide.

Molecular Construction Using Formamide as a C1 Feedstock

“…in 2007 [8b] that compared quinazolinone production through anthranilic acid (yield: 81 %) and the corresponding amide (yield: 93 %) with microwave irradiation (300 W, 5 min) in the presence of acetic acid (1 equivalent) and formamide (5 equivalents). Kundu et al [8c] . used different nitrophenyls, analogs of anthranilic acid, and formamide in excess.…”

One-pot synthesis of quinazolin-4(3H)-ones and2,3-dihydroquinazolin-4(1H)-ones utilizingN-(2-aminobenzoyl)benzotriazoles

“…Recent advancements in the field of synthetic methodologies for the quinazolinone scaffold were discussed in detail by Rohokale and Kshirsagar,He et al,and Kshirsagar [1,2,5]. Classical routes in the preparation of quinazolin-4(3 H)-one have been mostly based on the Niementowski reaction, which utilizes the ring closure of anthranilic acid or its derivatives with an amine and a carbonyl group, whereas nonclassical methods utilize metal-catalyzed coupling reactions by C-C or N-C bond formations [25][26][27][28] and the metal-catalyzed reduction of nitroarenes and subsequent cyclizations [29,30]. The classical routes are often boosted by 1-pot multicomponent procedures, by featuring higher yields in a shorter reaction time and fewer side products when compared to divergent pathways.…”

Synthesis of New 2-(N'-Allylidene-hydrazino)quinazolinones and 2-(4,5-Dihydropyrazolyl)-quinazolinones and Their Antimicrobial and Antifungal Activity Screening

“…The biological importance of these heterocyclics has lead synthetic organic chemists to explore new synthetic routes and thus their syntheses are available in literature [5][6][7] . A brief search on the pharmaceutical activities of quinazolin-4(3H)-ones showed antiinflammatory 8 , antitumor 9 , anti HIV 10 , antibacterial 11 , CNS depressant 12 and anticonvulsant 12,13 activities. 3H-Quinazoline-4-one framework is commonly found unit in natural product alkaloids, such as L-vasicinone (1) 14 and drugs such as diuretic and antihypertensive metolazone (2) 15 .…”

“…-3H-quinazolin-4-one (8f): Obtained according to the general procedure, by using 7f (277 m, 1.0 mmol), as a white solid (374 mg, 81 %); m.p. 206-207 °C; Rf 0.36 (CHCl3); 1 H NMR (400 MHz, CDCl3) δH 9.13 (1H, br-s, NH), 7.92 (1H, d, J = 7 9. Hz, 5-CH), 7.82 (1H, d, J = 16.7 Hz, 3′-CH), 7.57 (1H, t, J = 7.1 Hz, 7-CH), 7.39 (2H, d, J = 8.5 Hz, 2 × CH(Ar)), 7.27 (2H, d, J = 8.5 Hz, 2 × CH(Ar)), 7.23 (2H, d, J = 8.7 Hz, 2 × CH(Ar)), 7.16 (2H, d, J = 8.4 Hz, 2 × CH(Ar)), 6.95 (1H, t, J = 7.2 Hz, 6-CH), 6.81 (1H, d, J = 8.2 Hz, 8-CH), 6.63 (1H, d, J = 16.7, 2′-CH), 4.15 (2H, q, J = 7.0 Hz, NCH2CH3), 1.23 (3H, t, J = 7.0 Hz, NCH2CH3); 13 C NMR (100 MHz, CDCl3) δC 160.36 (4-C), 158.20 (1′-C), 149.45 (2-C), 138.…”