Hydrogen Atom Transfer Strategy Enabled C(sp~3)-H Bonds Radical Functionalization Reactions

Selective functionalization of the unactivated C-H bonds is one of the most important and popular research fields and also remains a great challenge for organic synthetic chemists.In recent years,transition metal-catalyzed C-H activation reactions have been employed with increasing frequency to address the challenges of the unactivated C-H bond selective functionalization.Meanwhile,radical-mediated C-H bond functionalization is one of the most important strategies.A lthough radical-mediated C-H bond functionalization has been discovered earlier,its inherent limitations allow it to play a much less significant role in the field of selective C-H bond functionalization in recent years than the C-H bond activation strategy.Hydrogen atom transfer(HAT)strategy represents a mild,high site selective tool for selective functionalization of unactivated C-H bonds using a radical process,thus providing rather wide applications in synthesis.Hydrogen atom transfer(HAT)strategy is one of the earliest and most widely studied methods in the radical-mediated C-H functionalization field,which proceed through the heteroatom-centred radical generation followed by the formation of carbon-centred radicals by HAT.Typical methodologi es include the Hofmann-L(?)ffler-Freytag(HLF)reaction and the Barton reaction.However,these classical methodologies are limited to intramolecular cyclization with the heteroatoms:the nitrogen-or oxygen-centred radical is first formed,which enable the generation of the carbon-centred radical through HAT with C(sp~3)-H bondδto the nitrogen or oxygen atoms,and intramolecular heteroannulation to access five-memebered heterocycles.However,examples of HAT with C(sp~3)-H bondβorγto the heteroatoms,especially methods for intermolecar reaction of C(sp~3)-H bonds with the external functional groups,are rare and remain a formidable challenge.Furthermore,most of these reported transformations suffer from limited unstable heteroatom-centred radicals precursors and relatively harsh reaction conditions,thus largely impeding the synthetic applications.Therefore,developing new hydrogen atom transfer strategies to achieve selective functionalization of inert C(sp~3)-H bonds under mild conditions has undoubtfully important research significance and application value.This thesis mainly studies the C(sp~3)-H bond radical functionalization reaction s using HAT)strategy and/or the radical relay strategy.The contents of this thesis includes the following four parts:(1)Recent progress in the unactivated C(sp~3)-H bond functionalization enabled by hydrogen atom transfer(HAT)strategy was systematically reviewed(Chapter 1).The experimental results and reaction mechanism of three modes,including nitrogen-center radicals,oxygen-center radicals and carbon-center radicals initiated HAT,were discussed in detail.(2)A copper-catalyzed cascade annulation of N-fluoro-N-alkylsulfonamides with terminal alkynes enabled by remote C(sp~3)-H bonds functionalization for producin g2,3-dihydro-1H-pyrroles and 1,2,3,4-tetrahydropyridines is disclosed(Chapter 2).Using a terminal alkyne to capture an amidyl radical results in the formation a vinyl carbon-centered radical,which would sequentially perform 1,5-or 1,6-hydrogen atom transfer(HAT)to site-selectively allow functionalization of the challenging C(sp~3)-H bonds at theβ-orγ-position to the nitrogen atom in N-fluorosulfonamides,thus enabling the N-fluorosulfonamides as three-or four-atom units to accomplish the(3+2)or(4+2)heteroannulation reactions.(3)A general,site-selective copper-catalyzed fluoroamide-directed remote benzylic C-H olefination of N-fluoroamides with terminal alkenes for producing internal alkenes is established(Chapter 3).This protocol proceeds via a hybrid Cu-radical mechanism,which synergistically composes the favorable features of the radical transformations(such as a site-selective remote C-H hydrogen atom transfer(HAT)step)with those of the transition-metal catalysis(such as a selectiveβ-hydrogen elimination step).The cooperative Cu and dinitrogen-based ligand catalytic systems are crucial as they not only preferentially enable the coupling of terminal alkenes with the remote benzylic C-H bonds though chemoselectivity recognition of two remoteδ-C(sp~3)-H bonds respectively existed in two distinct alkyl-based chains linked to the nitrogen atom of the N-fluoroamides,but also precisely control site-selectivity toward olefination of remote benzylic C-H bondsδto the amidyl nitrogen atom.(4)A visible light-mediatedα-C(sp~3)-H arylation of N-(benzyloxy)phthalimides with cyanopyridines for the construction of highly valuable pyridinyl-containing diarylmethanols,including bioactive motif-based analogues,is developed(Chapter 4).The method enables the arylation of the C(sp~3)-H bonds adjacent to an oxygen atom via the alkoxy radical formation by O-N bond cleavage,1,2-hydrogen atom transfer(HAT),arylation and C-CN bond cleavage cascades,and offers a route to exploit1,2-HAT modes to incorporate functional groups for constructing functionalized alcohols.