title: Lewis Acid Catalyzed Condensation-Cyclization Cascade: Direct Synthesis of Di/Trifluoromethyl-1,2,3,4-tetrahydroquinazolines.
abstract: Condensed heterocycles such as quinazolines constitute the framework of many promising drugs. The great impact of the dramatic fluorine effect in pharmaceuticals prompted a great surge in the quest for fluorinated drug design resulting in over 20 % fluorine-containing drugs in the market today. Therefore, finding an efficient and cost-effective method for the direct synthesis of fluorine-tagged quinazoline systems is of great significance in the pharmaceutical arena. For the first time, a one-pot sequential condensation-cyclization reaction to form selectively the difluoro/trifluoromethylated tetrahydroquinazolines from simple components difluoro/trifluoroacetaldehyde hemiacetal and aromatic amines is reported. Our recent studies using difluoro/trifluoroacetaldehyde hemiacetal as simple and elegant difluoro/trifluoromethyl synthons and metal triflates such as gallium triflate as safe and stable Lewis acid catalysts led us to this direct synthesis protocol for the expedient and convenient synthesis of fluorinated quinazolines. DFT calculations at PCM/B3LYP/6-31++G** were carried out for evaluating a possible reaction mechanism for this cyclization. According to the DFT calculations, product stereochemistry is thermodynamically driven, favoring the cis isomer as the major product, which is also confirmed experimentally.
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA). gprakash@usc.edu.
authors.forename: G K Surya
authors.initials: GK
authors.lastname: Prakash
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA).
authors.forename: Attila
authors.initials: A
authors.lastname: Papp
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA).
authors.forename: Socrates B
authors.initials: SB
authors.lastname: Munoz
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA).
authors.forename: Nathan
authors.initials: N
authors.lastname: May
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA).
authors.forename: John-Paul
authors.initials: JP
authors.lastname: Jones
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA).
authors.forename: Ralf
authors.initials: R
authors.lastname: Haiges
authors.affiliation: Instituto de Química, Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos, 149, CT, A-622, Rio de Janeiro, RJ, 21941-909 (Brazil).
authors.forename: Pierre Mothé
authors.initials: PM
authors.lastname: Esteves
authors.affiliation: Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, California 90089-1661 (USA). tmathew@usc.edu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mathew
keywords: condensation/cyclization; gallium triflate; one-pot synthesis; quinazolines; solvent-free