Regioselective Cyanation And Applications Of Perfluoroalkylated Indolylmethanols

Indole alkaloids are found in many important natural products and drug molecules,they have excellent performance in many aspects such as anti-cancer,antibacterial and anti-virus,and have broad application prospects.Cyano-containing compounds have been widely used in the fields of medicine,pesticides and materials.In addition,cyano-containing compounds are also an important class of organic synthetic intermediate for the preparation of acids,aldehydes,ketones,amines,amides and heterocyclic compounds by the transformation of functional groups.Fluorine atom has the strongest electronegativity,hindering and osmosis effect,the introduction of fluorine atoms into organic molecules can significantly change the physicochemical properties and physiological activities of the molecules.Among many fluorine-containing compounds,gem-difluoroalkenes are known to serve as bioisosteres of carbonyl groups,many bioactive natural products and drugs can significantly enhance their physiological and pharmacological activities through introducing gem-difluoroalkenes.Gem-difluoroalkenes are also an important intermediate for organic synthesis,which can be used to synthesize various fluorine-containing and nonfluorinated functional molecules.Although there are many methods for the synthesis of gem-difluoroalkenes,they often require the use of explosive azo compounds or multi-step synthesis of raw materials and limited reaction substrates,and methods for the construction of indolyl-substituted gem-difluoroalkenes are extremely scarce.Thus,developing a mild and simple protocol for the preparation of regioselective cyano-and fluorine-containing multifunctional indoles from readily available starting materials is of great significance.The major work of this thesis includes the following two chapters:（1）Regioselective cyanation of perfluoroalkylated indolylmethanolsIn the second chapter of this thesis,we developed a regioselective cyanation of perfluoroalkylated indolylmethanols to achieve efficient syntheses of 2-cyanoindolyl-substituted gem-difluoroalkenes and trifluoromethylated indole-acetonitrile compounds with all-carbon quaternary centers through changing the catalyst only.we have realized the regioselective 1,2addition and 1,4 addition reactions of cyano group by using perfluoroalkylated 3-indolylmethanols and TMSCN as raw material under the action of different Lewis acid catalysts,successfully synthesized 2-cyanoindolyl-substituted gem-difluoroalkenes and trifluoromethylated indole-acetonitrile compounds with all-carbon quaternary centers,respectively.The reaction has good regioselectivity and stereoselectivity,exhibits a wide range of substrates and excellent functional group compatibility.We explored the gram scale-up experiments of the reaction,the standard substrate was scaled up to the gram scale（4 mmol,1.165g）and the expected products were still isolated in high yields.We also studied the transformation experiments of the product,and successfully prepared tryptamines and difluoroalkyl sulfide compounds.The results fully demonstrated the practicality and operability of the method,and finally we proposed a possible reaction mechanism.（2）Simple synthesis of 3-fluoro-β-carbolinesIn the third chapter of this thesis,we developed a new method for the efficient synthesis of3-fluoro-β-carbolines via a new reaction of tandem addition/defluorination cyclization of 2-cyanoindolyl-substituted gem-difluoroalkenes with Grignard reagents.β-carbolines is a class of tricyclic compounds composed of indoles and pyridines,with a wide range of biological and pharmacological activities.The synthesis ofβ-carboline compounds is well documented,but there is no literature on synthesis of 3-fluoro-β-carbolines.Based on the contents of Chapter 2 of the thesis and the fact that cyano and gem-difluoroalkenes can be used as intermediates in organic synthesis to synthesize various polyfunctional molecules,we successfully synthesized 3-fluoro-β-carboline products from the 2-cyanoindolyl-substituted gem-difluoroalkenes with THF as the solvent and using 4 equiv Grignard reagents or diisobutylaluminum hydride,stirred at 0 ℃ for15 h.With the optimized conditions in hand,we studied the substrate scope of the reaction,which showed an excellent range of substrates.Finally,in order to further investigate the application of the prepared 3-fluoro-β-carbolines,we performed activity testing experiments on the synthesized3-fluoro-β-carboline compounds,and the results showed that the most of 3-fluoro-β-carbolines exhibited different degrees of inhibition against human breast cancer cells MCF-7.Among them,3-2an showed the best inhibition and the IC₅₀ is 7.539μM,which is superior to the positive control componds Harmine and Etoposide,which is a cell cycle-specific anticancer drugs.In this thesis,we have developed a regioselective cyanation of perfluoroalkylated indolylmethanols for the synthesis of 2-cyanoindolyl-substituted gem-difluoroalkenes and trifluoromethylated indole-acetonitrile compounds with all-carbon quaternary centers.And realized the simple synthesis of 3-fluoro-β-carboline compounds for the first time.Our study enriches and expands the research of gem-difluoroalkenes,indole-acetonitriles andβ-carbolines and has certain academic significance and potential value.