Quinazoline highly functionalized

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

Independently, Zhou and co-workers used the same approach in their synthesis of highly functionalized quinazolines as potential anti-cancer therapeutics. In one example, fusion of 2-amino-3,4,5-trimethoxybenzoic acid with formamide under thermal conditions gave the desired quinazolinone in 25% yield. A dibenzofliran quinazoline derivative produced using this process exhibited anti-proliferative properties against several tumor types, including Bcap-37, PC3, A431, and BGC823 cell lines. 

Several groups explored the use of [2 + 2 + 2] cycloadditions to form highly functionalized quinazolines. Hua andYang developed a new one-pot synthesis of benzo [/]quinazolines 71, involving a trifluoromethanesulfonic-acid-promoted [2 + 2 + 2] cycloaddition of l,4-diaryl-l,3-butadiynes with nitriles and a subsequent intramolecular hydroarylation (Scheme 33) (13CL769).While the yields were low to moderate, the facility of the reaction and availability of starting materials were noted as some of the advantages of this method. 

Saha et al. [103] developed an efficient and one-pot three-component strategy for synthesizing highly functionalized quinazoline derivatives 70. A mixture of 2-ami-nobenzophenone, aromatic aldehyde, and ammonium acetate in the presence of I2 provides desired products in excellent yields even at moderate temperature (40 °C), with no need of chromatographic purification (Scheme 10.52). 

A simple, efficient, and high-yielding synthesis of quinazolin-4-ylamines and thieno[3,2-d]pyridin-4-ylamines based on the condensation of appropriately functionalized N -(2-cyanophenyl)-N,N-dimethylformamidines and primary amines has been reported by Han and coworkers (Scheme 6.253) [440]. Optimization of the reaction parameters resulted in the use of acetonitrile/acetic acid as a solvent mixture and of 1.2 equivalents of the requisite amine. In general, microwave heating at 160 °C for 10 min provided excellent product yields. 

Moreover, 6-trifluoromethyl-12-acylindolo[l,2-c]quinazolines 38 were prepared in high yield through the palladium-catalyzed reaction of bis(o-trifluoroacetamido-phenyl) acetylene with aryl or vinyl halides and triflates, (Scheme 13.22) [48]. The reaction, which tolerates a variety of important functional groups, probably involves... 

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