Cascade Reaction Of Trifluoromethyl Radical By Togni-Ⅱ Reagent Initiated By Amide As A Single Electron Donor

The trifluoromethyl moiety is found in many notable synthetic drugs,leading to altered physical and physiological behaviors of those compounds with respect of their uptake and metabolism.Hence,the development of synthetic methods for incorporation of CF3 groups into biologically and materially valuable compounds is actively pursued in academic research.Togni-Ⅱ reagent was developed by Togni and co-workers 2006 as convenient CF3 sources for trifluoromethylation of biologically important active compounds,owing not only to its easy preparation,preservation and commercially less expensive price,but also to its explosive applications in CF3 radical-initiated trifluoromethylatian/cyclization reactions from the year 2011 up to the present.It is especially interesting to observe from the numerous published Togni-Ⅱ-involved radical trifluoromethylation reactions that the formation of the free CF3 radical was all achieved via a single electron transfer(SET)from an external single electron donor(SED)to Togni-Ⅱ.The single electron donors(SEDs)in fact acted as the catalysts of those CF3-radical-initiated cascade trifluoromethylation/cyclization reactions.Ⅰ)CF3 radical formation with Togni-Ⅱ induced by Single-Electron-Donor(SED):SEDs:[(MeCN)4Cu]PF6,CuX(X=Cl,Br,I),Bu4NI,fac-lr(ppy)3,Ru(bpy)3Cl2,DBN,N,N-diisopropylethylamine(DIPEA),1,2-bis(diphenylphosphino)benzene(dppBz),etc.Ⅱ)Typical CF3-radical-initiated cascade trifluoromethylation/cyclization:In this thesis,we developed a novel and efficient external-catalyst-free trifluoromethylation/cyclization methodology to access a group of trifluoromethylated dihydroisoquinolinones,by reacting different-allylbenzamides with Togni-Ⅱ in one-pot under mild reaction conditions.Meanwhile,this external-catalyst-free trifluoromethylation/cyclization protocol was also well suitable for being employed to synthesize many biologically valuable trifluoromethylated N-acetylindolines,by reacting N-aryl-N-allylacetamides with Togni-Ⅱ in one-pot under mild reaction conditions,exhibiting a good functional group tolerance and reaction efficiency.The discovery that the internal amide groups in N-allylbenzamides and N-aryl-N-allylacetamides can promote the decomposition of Togni-Ⅱ and both the reactants thus can act their own catalysts toward the syntheses of two biologically important heterocycles,trifluoromethylated dihydroisoquinolinones and N-acetylindolines,opens the possibility to access much more structurally diverse trifluoromethylated heterocycles by means of this newly developed efficient and environmentally sustainable strategy.For providing a supportive evidence to our proposed external-catalyst-free CF3 radical-involved trifluoromethylation/cyclization mechanism,several control experiments were conducted.It was proved that N,N-dimethylbenzamide was capable of acting as the SED of Togni-Ⅱ to produce CF3 radical required.Thus,a decisive conclusion can be reached that it is indeed the internal aromatic amide groups in the reactants N-aryl-N-allylacetamides and N-aryl-N-allylacetamides that acted as SEDs to initiate the decomposition of Togni-Ⅱ to the CF3 radical needed for the following trifluoromethylation/cyclization reactions.Main contents of the thesis:a)We started the meaningful research from establishing optimal experimental conditions using the model reactions of N-methyl-N-(2-methylallyl)benzamide 1a with Togni-Ⅱ in one-pot for 12 h.After an extensive experimentation,the optimized reaction conditions were established as follows:la(0.5 mmol),Togni-Ⅱ(1.5 equiv),NaOAc(2 equiv)were mixed in DMF(3 mL)at 80 ℃ for 12 h in one-pot.b)With the optimized conditions in hand,we then explored the substrate scope of this external-SED-free protocol for the synthesis of various trifluoromethylated dihydroisoquinolinones,by examining different substituted N-allylbenzamides.In the following research,we attempted to extend this external-catalyst-free Togni-Ⅱ-involved trifluoromethylation/cyclization protocol to the synthesis of a number of biologically valuable trifluoromethylated N-acetylindolines,by reacting various N-aryl-N-allylacetamides with Togni-Ⅱ under the optimized conditions.c)A conclusion that it is indeed the internal aromatic amide groups in the reactants that acted as SEDs to initiate the decomposition of Togni-Ⅱ to the CF3 radical needed for the following trifluoromethylation/cyclization reactions was further evidenced by our especially designed experiments with the aid of EPR technology.