| Methyl group is one of the most common carbon-containing functional groups that widely found in natural products and organic small molecule drugs.Among the top 100 best-selling drugs in the United States in 2011,67%of the most popular drug molecules have methyl groups the most simple alkyl functional groups directly with carbon atoms.The presence of a linked structure also plays an extremely important role in the regulation of the biological and physicochemical properties of molecules in these drugs.Although many methylation reactions have been developed,in addition to the traditional methylation reagents can be widely used,some new methylation reagents have also successfully attracted the attention of the majority of researchers.In these methylation reactions,most examples of which required a large number of alkali,transition metal catalysts(especially noble metals including Ru,Rh and Pd)and other additives to improve the reactions.To data,the methylation methods for directly attaching a methyl group to a N,an O,a S and other heteroatoms are relatively mature,which have also been widely used in organic synthesis.However,it is very promising to develop new strategy for the formation of a carbon-carbon bond,especially a C(sp3)-C(sp3)bond by means of the driect methylation with a carbon unit.Because of the activity problem,the activation of C(sp3)-H bond for the construction of C(sp3)-C(sp3)bonds is one of a challenge.In recent years,transition metal-catalyzed methylation reaction to directly construct the carbon-carbon bonds has made great progres.For example,transition metal-catalyzed C-H activation forms C-metal intermediates,and then undegoes methylation reaction with the electrophilic or nucleophilic methylation reagents,which has become one of the most effective ways to directly methylation by constructing carbon-carbon bonds.However,the transition metal-catalyzed C-H activation/methylation methods are still limited to the requirement of highly expensive transition metals and other additives,and examples for the methylation reactions via the formation of C(sp3)-C(sp3)bonds are rare.Therefore,it would be urgent to develop a new strategy for methylation of olefins to construct C(sp3)-C(sp3)bonds.On the basis,this dissertation mainly studies on the methylation of acrylamide compounds with peroxide as a methyl source.The contents of this dissertation include three chapters as following:(1)Based on methods for the construction of carbon-carbon bonds,recent progress in the methylation reaction by the formation of carbon-carbon bonds was reviewed in detail,including(i)advances in methylation between methylation reagents with C(sp)atoms to construct C(sp)-C(sp3)bonds;(ii)advances in methylation between methylation reagents with C(sp2)atoms to construct C(sp2)-C(sp3)bonds;(iii)advances in methylation between methylation reagents with C(sp3)atoms to construct C(sp3)-C(sp3)bond,and(iv)advances in methylation using peroxides as the methyl sources.(2)A metal-free methylation annulation cascades of N-(2-(arylethynyl)pheny 1)acrylamides has been developed using di-tert-butylperoxide(DTBP)as the met hyl source.The chemoselectivity of theis reaction rely on the functional groups on the C=C bond of the acrylamide moiety:selective preparation of five-memb ered-ring and six-membered-ring-containing polycycles by either dirext radical methylation/cyclization cascade or methylation/1,5-hydride shift/radical annulatio n cascades.(3)An efficient metal-free oxidative 1,2-arylmethylation cascades of N-(arylsulfonyl)acrylamides using di-tert-butyl peroxide(DTBP)as the methyl resource.The reation proceeds by a sequence of 1,4-aryl transfer/Desulfurization/1,2-aryl methylation,and represents a selective access to quaternary stereocenters by growing a carbon atom leading linear amides and oxindoles. |
