Studies On C-H Functionalization With Esters Or Amides And Transformation Of Products

Ester and amide derivatives represent key structural motifs that are frequently found in a variety of natural products,pharmaceuticals,biologically active molecules,and functional materials.These motifs have also been identified as important synthetic intermediates for the synthesis of a series of organic compounds containing different functional groups through structural modification or functionalization,which has become an interesting topic in organic chemistry.So it is of great practical significance to develop convenient and efficient methods for functionalization of esters or amides.In this dissertation,esters and amides were used as coupling partners to realize remote aromatic C–H alkylation and aromatic C–H acylation,respectively.The C–H acylation products containing pyridine skeleton can be used as synthetic precursors for the synthesis of chiral indolizidine alkaloids through sequential ring-fused pyridinium formation/asymmetric hydrogenation strategy.The detailed research contents of the thesis were shown as follows:In the first part,a novel palladium-catalyzed remote C–H bond alkylation of 1-chloromethylnaphthalene derivatives was successfully developed using phenylacetic acid derivatives(esters and amides)as nucleophiles.Under the optimized conditions,the desiredα-arylated products with various functional groups were obtained in 55%–88%yields.The effect of carbonyl nucleophile’s p K_a value on reactivity and regioselectivity was also demonstrated.The mechanism study showed that the remote C–H alkylation proceeded via the nucleophilic substitution-dearomatization procedures ofπ-benzyl palladium intermediates with phenylacetic acid derivatives and subsequent 1,5-hydrogen migration-aromatization procedures.In the second part,the first ruthenium-catalyzed selective C–H acylation of 2-phenylpyridine derivatives was developed using amides as acylated electrophile through dual C–H/C–N activation.Under the optimized conditions,the selective acylation of 2-phenylpyridine derivatives with various amides proceeded smoothly to provide the desired products of aryl ketones containing pyridine skeleton in 34%–85%yields.The mechanism study showed that the C–H bond cleavage was not involved in the rate-determining step,the aromatic C–H bond activation occurred before amide C–N bond activation and the in situ formed cycloruthenated complexes through C–H cyclometallation process might not be the key active species for amide C–N bond cleavage.In the last part,the formed aryl ketones containing pyridine skeleton in the second part were used as starting materials for applied transformation.The chiral indolizidine alkaloids in high to excellent yields(70%–95%)with moderate enantioselectivity(up to 86:14 er)and excellent diastereoselectivity(>20:1 dr)were synthesized by multi-step procedures including reduction,cyclization for ring-fused pyridiniums formation and subsequent Ir-catalyzed asymmetric hydrogenation.The absolute configuration of the indolizidine products was determined to be 6S,10b R based on X-ray crystallographic analysis.The strong acidity of benzylic hydrogen atom in the formed ring-fused pyridiniums plays a key role in changing the configuration of achiral benzylic sp~3 carbon atoms in asymmetric hydrogenation.