Direct Oxidative C(sp3)-H Cyanation Of Secondary Benzylic Ethers

Direct one step substitution of C-H bonds with C-C bonds represents an economic and efficient alternative to traditional approaches depending on functional group transformations.Among these,considerable efforts have been made in the oxidative C(sp3)-H functionalization of benzylic ethers.However,current studies predominantly focused on the functionalization of the methylene C-H bond of primary benzylic ether for secondary ether construction.The direct manipulation of the methine C-H bond in a secondary benzylic ether for tertiary ether synthesis remains elusive,probably due to the increased steric hindrance of the substrate and 1,1-disubstituted oxocarbenium ion intermediate.The isochroman skeleton is present in a number of natural products and synthetic pharmaceuticals exhibiting a wide range of biological activities.In particular,such structural motif bearing two different substituents at the α-position has been demonstrated to possess antioxidative,anticancer,antibacterial,antifungal,antiviral,and antidepressive activities.On the other hand,the nitrile group is also an important building block in numerous natural products and synthetic materials with important pharmaceutical activities.Moreover,the nitrile moiety also serves as a versatile handle for further carbon elongations and functional group transformations.Accordlingly,direct bimolecular oxidative C-H cyanation of α-monosubstituted isochromans would be a highly desirable project to pursue.DDQ(2,3-dichloro-5,6-dicyano-1,4-benzoquinone)has been widely adopted as an efficient oxidant in the C-H functionalization of a series of primary benzylic ethers.In this context.a-phenyl substituted isochroman la was facilely prepared,and then subjected to the C-H functionalization with trimethylsilyl cyanide(TMSCN)using DDQ as the oxidant for optimization.A systematic investigation of the cyanation source,solvent,and temperature identified that DDQ-mediated C-H cyanation of la with TMSCN proceeded smoothly in toluene at 80 ℃ for 1 h.providing the expected tertiary ether in 92%yield.The scope of oxidative C-H cyanation of a-substituted isochromans was next investigated.Isochromans bearing either electron-donating aryl groups or electron-withdrawing ones at the α-position proved to be suitable components in good yields,though the latter exhibited an inferior efficiency to the former.Substrates with a substituent at either the meta-or ortho-position on the a-aryl group were also well compatible with the C-H cyanation process,though the latter provided a slightly decreased yield.The observation might be ascribed to the increased steric hindrance of both the ether substrate and highly substituted oxocarbenium intermediate Isochroman having a heteroaryl moiety at the a-position was well tolerated,as demonstrated by the generation of 2-thiophenyl substituted product in 90%yield.The substituent effect on the isochroman skeleton was next evaluated.Electronically varied isochromans participated in the oxidative C-H cvanation efficiently,furnishing respective tertiary ethers in 81%-94%yields.No expected tertiary ether was observed for a-alkyl substituted isochromanUnder the standard oxidation conditions,a gram-scale C-H cyanation reaction proceeded in 85%yield,thus suggesting the practicability of the method.Based on the existing mechanistic studies on DDQ-promoted ether oxidation,a mechanism for the C-H cyanation of secondary benzylic ethers was proposed.In summary,we have developed a practical and efficient oxidative C-H cyanation of secondary benzylic ethers with TMSCN in the presence of DDQ.The metal-free process is well tolerated with a wide variety of electronically variedα-monosubstituted isochromans,facilely furnishing a library of isochromans bearingα-aryl α-cyano substituent patterns for further diversification and bioactive small molecule identification.