Lewis Acid Catalyzed Condensation-Cyclization Cascade: Direct Synthesis of Di/Trifluoromethyl-1,2,3,4-tetrahydroquinazolines

摘要: Condensed heterocycles such as quinazolines constitute the framework of many promising drugs. The great impact dramatic fluorine effect in pharmaceuticals prompted a surge quest for fluorinated drug design resulting over 20 % fluorine-containing drugs market today. Therefore, finding an efficient and cost-effective method direct synthesis fluorine-tagged quinazoline systems is significance pharmaceutical arena. For first time, one-pot sequential condensation–cyclization reaction to form selectively difluoro/trifluoromethylated tetrahydroquinazolines from simple components difluoro/trifluoroacetaldehyde hemiacetal aromatic amines reported. Our recent studies using elegant difluoro/trifluoromethyl synthons metal triflates gallium triflate safe stable Lewis acid catalysts led us this protocol expedient convenient quinazolines. DFT calculations at PCM/B3LYP/6-31++G** were carried out evaluating possible mechanism cyclization. According calculations, product stereochemistry thermodynamically driven, favoring cis isomer major product, which also confirmed experimentally.