Transition Metal-Catalyzed Synthesis Of 2-(Trifluoromethyl)Quinazolin-4(3H)-Ones

Quinazolinone is a kind of nitrogen-containing heterocyclic compound with good biological activity,which has widely found in natural products and pharmaceutical molecules.They exhibit various biological and pharmaceutical activities,such as anticancer,antiviral,anticonvulsant,anti-inflammatory activities and so on.Due to the unique properties of fluorine atoms,the physical and chemical properties of parent molecules can be significantly improved by incorporating fluorine atoms or fluorine-containing groups into specific sites of organic molecules.In recent years,2-（trifluoromethyl）quinazolin-4（3H）-ones have attracted widespread attention from chemists,and have been extensively applied in the fields of organic synthesis,medicine,agrochemicals,and materials science.Compared with the common quinazolin-4（3H）-ones,the synthetic strategy of2-（trifluoromethyl）quinazolin-4（3H）-ones has rarely been reported.The previously reported methods usually suffer from several drawbacks,such as tedious reaction procedures,inaccessible starting materials,poor efficiency and harsh reaction conditions.Trifluoroacetimidoyl chlorides are a kind of commonly used trifluoromethyl synthons,which feature simple preparation,stable property,and multiple reaction sites.Therefore,the employment of trifluoroacetimidoyl chloride as a trifluoromethyl synthon to construct2-（trifluoromethyl）quinazolin-4（3H）-ones and their derivatives has obvious advantages compared with other traditional synthetic methods.In recent years,our research group has continuously focused on transition-metal-catalyzed carbonylation reactions and heterocyclic synthesis.Through the deep exploration of the synthetic approaches of 2-（trifluoromethyl）quinazolin-4（3H）-ones,we have developed different routes to access to this important heterocyclic scaffold.This paper mainly introduces the following works:（1）Through intensive research on the decarbonylative process of isatins and the properties of trifluoroacetimidoyl chlorides,we have disclosed a Fe Cl₃-mediated cascade coupling/decarbonylative annulation reaction of isatin with fluorinated imidoyl chlorides,which provides a straightforward and efficient approach for the assembly of pharmaceutically valuable 2-（trifluoromethyl）quinazolin-4（3H）-ones.The transformation has several notable features,including readily available reagents,non-expensive iron catalyst,broad substrate scope,high efficiency,and easy scalability.A reasonable reaction mechanism has been proposed according to the preliminary mechanistic investigations.（2）Trifluoroacetimidoyl chloride was used as the trifluoromethyl synthon,and TFben（benzene-1,3,5-triyl triformate）was used as the CO surrogate.A palladium-catalyzed three-component carbonylative reaction of trifluoroacetimidoyl chlorides and amines for the synthesis of valuable 2-（trifluoromethyl）quinazolin-4（3H）-ones has been developed.The transformation has several advantages over the traditional synthetic routes,including easily accessible reagents,no manipulation of CO gas,a broad substrate scope,high efficiency and scalability.Additionally,the current method has been successfully applied to the late-stage modification of natural molecules and to synthesize the bioactive alkaloid molecule Rutaecarpine.（3）After completing the carbonylative reaction of trifluoroacetimidoyl chloride and amine,we continue to study the carbonylative reaction of nitro compounds.Trifluoroacetimidoyl chloride was used as the trifluoromethyl synthon,and nitro compounds as a cheaper and more readily available nitrogen source.Mo（CO）₆is regarded as both convenient CO surrogate and reducing reagent in the transformation,thereby no manipulating the toxic CO gas.Herein we have developed a general and efficient pathway for the assembly of useful 2-（trifluoromethyl）quinazolin-4（3H）-ones through palladium-catalyzed carbonylative reaction of trifluoroacetimidoyl chlorides and nitro compounds.This newly developed protocol can be compatible with various kinds of nitro compounds...