Quinazoline derivatives: synthesis and bioactivities - Chemistry ...

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Wang and Gao Chemistry Central Journal 2013, 7:95 Page 4 of 15 http://journal.chemistrycentral.com/content/7/1/95 O O R H 2 N NH + 2 + O X 25 26 X=O,S R= Cl R-CHO 27 O O MW Solvent and Catalyst free N Cl NH N X H 28 Scheme 7 Solvent-catalyst-free microwave-assisted synthesis of quinazolines. filtered and recrystallized with 95% ethanol to obtain pure product 3-benzimidazolyl-4(3H)-quinazolinone (31) with a yield of 94% (Scheme 8). Metal-mediated reaction Palladium-catalyzed reaction Palladium-catalyzed coupling reaction, which plays a vital role in the pharmaceutical industry, is widely applied in chemical synthesis industry and laboratories as an efficient method for the formation of C-C and C-heteroatom bond. Qiu et al. determined the optimum conditions for the palladium-catalyzed three-component synthesis of quinazolino[3,2-a]quinazolines as follows: amine (3.0 equiv), isocyanide (3.0 equiv), carbodiimide (0.2 mmol), Pd(OAc) 2 (5 mol%) and Cs 2 CO 3 (3.0 equiv) in 3.0 ml toluene (Scheme 9) [36]. McGowan et al. developed a palladium-catalyzed onepot synthesis of quinazoline derivatives [37]. The reaction process was shown in Scheme 10. Zinc-reduced synthesis Zinc is the first capable metal found to participate in water-phase Barbier reaction. It could catalyze the allylation of carbonyl and carbonyl compounds as well as participate in the benzylation of carbonyl and some special alkylation. Apart from participating in the carbon-oxygen double bond Barbier reaction, Zinc could also be applied to carbon-nitrogen double bond Barbier reaction, such as the allylation of imine and α-amino aldehyde. In short, Zinc could stably exist in water phase with relatively strong activity. Active zinc obtained from ultrasonic-electrical method could even improve the reaction efficiency by more than three times. Although it often causes a few side effects, the cost-effectiveness and low-toxicity of zinc made it a good catalyst for organic reduction and synthetic reaction. In the synthetic research of imidazo[1,2-c]quinazoline derivatives designed by Shi et al. [38], 2-(2-nitrophenyl)-1H-imidazoles 39 was reduced by Zn/H + to 2- (2-aminop henyl)-1H-imidazoles 40, which then reacted with isothiocyanates to get intermediate 41. Cylization of compound 41 by nucleophilic attack of the nitrogen atoms on C = S group was afford the intermediates 42. Finally, the desired products 43 were obtained from 42 by losing of H 2 S (Scheme 11). Low-valent titanium reagents, which aroused an increasing concern in the field of organic synthesis, could effectively improve the H N N R H H 2 N N OR' NH p-TsOH (Cat.) N R'O OR' + DMAC, MW N O R O 29 30 31 N Scheme 8 Synthesis of 3-benzimidazolyl-4(3H)-quinazolinones. R 2 R 3 N R 1 N N C I I 32 R 1 + R 2 N CO + R 3 NH 2 33 34 Pd(OAC) 2 (5 mol %) Cs 2 CO 3 , toluene reflux R 1 N N N N 35 R 2 R 1 Scheme 9 Synthesis of quinazolino[3,2-a]quinazolines.
Wang and Gao Chemistry Central Journal 2013, 7:95 Page 5 of 15 http://journal.chemistrycentral.com/content/7/1/95 X HN R 2 R 1 + + NH 2 Ar-CHO i, ii, iii one-pot 36 37 38 R 1 N R 2 Ar N Scheme 10 Palladium-catalyzed one-pot synthesis of quinazolines. coupling of carbonyl compounds [39]. A synthetic method assisted by low-valent titanium reagent was reported by the same group mentioned above [40]. In this synthesis, a series of quinazoline derivatives were afforded by adopting anhydrous THF as solvent and the TiCl 4 -Zn system as reducing agent. Several representative synthetic routes were selected, which were shown in Scheme 12. Copper-catalyzed reaction Aryl ether, alkyl ether, aryl amine, alkyl amine, aryl sulfide, alkyl sulfide, etc., which are all very important structural fragments in many Ar Ar N N H O 2 N Zn / H + Ar Ar N N H H 2 N 39 40 R-N=C=S Ar Ar N N H HN R NH 41 S Ar N Ar N Ar HN R N NH SH Ar 42 43 R N NH N Scheme 11 Synthesis of imidazo[1,2-c]quinazoline derivatives. Ar Ar R R N N H O 2 N 47 NO 2 N H Ar X R TiCl 4 -Zn / THF + HC(OEt) 3 44 45 46 O NO 2 NH 2 + Y TiCl + R-C(OEt) 4 -Zn / THF 3 48 50 51 O TiCl 4 -Zn / THF Ar Ar N N R N N N Ar () n N H () n R 49 O 52 NH X Y Scheme 12 TiCl 4 -Zn-mediated reduced synthesis of quinazoline derivatives.
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