Study On The Photo-driven Remote C(sp~3)– H Chlorination Of Amides

Chlorine-containing organic compounds are not only important bulk chemicals in chemical industry but also play an essential role as synthetic intermediates in the synthesis of natural products and functional materials.The most effective means for the preparation of chlorine-containing compounds is to install the chlorine atom into a molecule via C-H chlorination.Radical C(sp~3)–H chlorination provides a simple direct approach towards structurally important alkyl chlorides.However,despite the apparent feasibility and simplicity,for a long time this method had only found limited applications in practical synthesis because of lack of selectivity.This obstacle can be partly solved by employing nitrogen-centered radical-mediated intramolecular hydrogen atom transfer(Hofmann–L?ffler–Freytag(HLF)reaction)to enable the site-selective generation of carbon radicals.This methodology has found enormous success in the remote functionalization of amides and sulfonamides in an atom-economical and step-economical fashion.In view of the powerfulness of the HLF reaction as a synthetic tool for C(sp~3)-H functionalization,we explored the HLF-based chlorination strategy and developed three new protocols for the selective chlorination of amides and sulfonamides.This dissertation comprises the following four chapters:In Chapter 1 recent progress made on C(sp~3)-H functionalization methods based on intramolecular hydrogen atom transfer(HAT)is reviewed.The literature is introduced according to the type of the radicals(nitrogen-centered radicals,oxygen-centered radicals and carbon-centered radicals)utilized for hydrogen atom abstraction.Chapters 2 to 4 introduce the result obtained during this study,which is summarized as follows(1)The site-selective C(sp~3)-H chlorination of aliphatic sulfonamides was realized by visible light catalysis with Ru(bpy)₃Cl₂ as photocatalsyt and Na OCl?5H₂O crystals as chlorinating reagent.The reaction involves a tandem pattern of in-situ N-H chlorination and Hofmann-L?ffler-Freytag chlorination.A radical chain mechanism is proposed for the reaction on the basis of experimental evidence.(2)A new photochemical method was developed for the site-selective C(sp~3)–H chlorination of amides/sulfonamides which employs tert-butyl hypochlorite as the chlorinating agent and a 45 W household CFL as the light source.The reaction features a sequential N–H chlorination and photo-initiated chlorine atom transfer,which are facilitated by N-heterocyclic carbene SIPr?HCl and(diacetoxyiodo)benzene.The functions of SIPr?HCl and(diacetoxyiodo)benzene can be accounted for by their beneficial effect on the N–H chlorination and subsequent chlorine atom transfer,respectively.This protocol exhibits a broad scope,and is suitable for the chlorination of methyl hydrogen as well as methylene and methine hydrogen.(3)A modifed protocol for the C(sp~3)-H chlorination of amides/sulfonamides was developed by using the reaction combination of tetrabutyl ammonium chloride and Ph I(OAc)₂ to replace that of t-Bu OCl/SIPr?HCl/Ph I(OAc)₂.The N–H chlorination was enabled by the in situ generated electrophilic chlorinating intermediate.This protocol not only exhibits a broad scope,but also has the merit of low toxicity,and thus is more useful in practical synthesis.