Development Of Selective And Catalytic Arylation Methods For Sp2 And Sp3 C H Bonds In Complex Organic Molecules PDF Download

C-H functionalization reactions are among the most useful and synthetically applicable approaches to access structurally complex organic molecules, including pharmaceuticals and agrochemicals. While methods promoting functionalization and cross coupling of C(sp2)-H bonds have found broad applications, a growing number of reactions have focused on functionalizing C(sp3)-H bonds to incorporate three-dimensionality and expand the chemical space. Radical C-H functionalization reactions initiated by hydrogen-atom transfer and proceeding via radical intermediates introduce strategic opportunities to functionalize C(sp3)-H bonds. In addition to the commonly seen radical-chain and biomimetic radical-rebound mechanisms, radical-relay reactions provide the basis for versatile C-H cross-coupling methods with diverse partners. This thesis discloses our recent development of radical-relay and radical-chain (hetero)benzylic C(sp3)-H functionalization and their synthetic utility in accessing three-dimensional chemical space. Chapter 2 discussed our recent development of a copper-catalyzed benzylic C-H esterification reaction enabled by a "photochemical redox buffering" strategy using tert-butyl peroxybenzoate as the oxidant. Copper(I)/peroxide (or Kharasch-Sosnovsky-typed) reactions historically require excess of C-H substrates and forcing reaction conditions, leading to poor synthetic applicability. Copper(I) catalysts interact rapidly with peroxide-based oxidants, resulting in a pool of inactive copper(II) species, which are incapable of activating oxidants. Our recent efforts in copper/NFSI-catalyzed radical relay functionalization and cross coupling of benzylic C(sp3)-H bonds revealed a ''redox buffering'' strategy enabling the controlled regeneration of copper(I). For copper/NFSI systems, we have identified that certain nucleophiles (i.e. cyanides and arylboronic acids) can promote the reduction of CuII to CuI, whereas nucleophiles like alcohols and azoles requires additional chemical reductants (i.e. dialkylphosphites) to promote ''redox buffering.'' To address the issues with copper/peroxide system, we have developed a 2,2'-biquinoline/copper-catalyzed reaction under photoirradiation to promote benzylic esterification using limiting C-H substrates. Mechanistic interrogation revealed that light promoted carboxylate-to-copper charge transfer enables the regeneration of copper(I) catalyst, similar to the aforementioned ''redox buffering'' approach. Chapter 3 disclosed our recently developed chlorination/ diversification sequence of heterobenzylic C(sp3)-H bonds in 3-alkylpyridines via radical chain. Alkylpyridines are important and prevalent classes of substrates in medicinal chemistry with the (hetero)benzylic C-H bonds having similar bond dissociation energies to alkylarenes. However, copper/NFSI-catalyzed reactions are unsuccessful in accessing these C-H bonds due to the deleterious reactivity between the pyridyl nitrogen atom and NFSI. While chlorination of 2- and 4-alkylpyridines can be achieved using a polar activation strategy, heterobenzylic C-H bonds of 3-alkylpyridines are more amenable to radical-based chlorination. Experimental and density functional theory identified an N-chlorosulfonamide reagent for selective chlorination at the heterobenzylic C-H site. Subsequent diversification of heterobenzyl chlorides with a broad scope of nucleophiles enabled facile access to complex cross-coupled products. This method should find broad application for building block modification and library synthesis in drug discovery. Chapter 4 detailed our investigation in copper/NFSI-catalyzed fluorination of benzylic C-H bonds followed by diversification with various nucleophiles. Redox buffering promoted by addition of boron-based reductants enabled successful fluorination with limiting C-H substrates. Benzyl fluorides were subsequently subjected to nucleophilic displacement catalyzed by Lewis acidic additives, affording C-O, C-N, and C-C bond formations. This method inspired later developments of other radical halogenation/diversification methods to functionalize (hetero)benzylic C-H bonds. Chapter 5 disclosed our development of a copper/NFSI-catalyzed cross couplings of benzylic C(sp3)-H bonds and azoles enabled by redox buffering. In addition to excellent benzylic selectivity, N-site selectivity of azoles was achieved by modifying the reaction conditions. Diverse N-H heterocycles were compatible coupling partners, including pyrazoles, purines, and sultams. The ability to access both regioisomers of azoles via a cross coupling array validated the synthetic utility of this method in pharmaceutical research. Collectively, radical (hetero)benzylic C(sp3)-H functionalization contributed to a growing number of methods in accessing more three-dimensional chemical space. Mechanistic insights from these reactions will enable further development of more synthetically useful methodologies. Additionally, the synthetic applications should allow chemists to assemble compound libraries with higher complexity and expand the accessible chemical space.