Construction Of C(sp3)-P Bond By Radical-Coupling Reaction

The construction of C(sp3)-P bond via the cross coupling of an C(sp3)-centered radical with a phosphorus radical is a challenging area in modern day organic synthesis.This dissertation focuses on the development of important and efficient strategies to couple these radicals in a highly selective manner.For clear understanding,this study has been divided into four parts as described below.(1)Decarboxylative phosphorylation of C(sp3)radicals generated via the decomposition of alkyl diacyl peroxidesFirstly,the reaction of methyl carbazate with indoles,pyrimidines and pyridines were performed.Then,the selective cross-coupling reaction of alkyl radicals and phosphorus radical generated from alkyl diacyl peroxides and diarylphosphine oxides/dialkyl phosphites respectively was achieved in the presence of catalytic copper salt and an appropriate ligand.The protocol was accommodated various aliphatic acids including linear and branched chain(C4 to C16),alicyclic(C3 to C6)and those containing heteroatoms were compatible with this reaction.Furthermore,a variety of diarylphosphine oxides and dialkyl phosphites were suitable coupling partners in this reaction.Notable features include the broad substrate scope and good functional group tolerance.Mechanistic investigations indicate that the alkyl diacyl peroxides(generated in situ from aliphatic acids)initially decomposes under heat to produce acyloxy radicals.Due to the intrinsic instability of the formed acyloxy radicals,they rapidly undergo decarboxylation to generate alkyl radicals.Subsequent interaction of alkyl radicals with diarylphosphine oxides or dialkyl phosphites affords phosphorus radical which is further stabilized by a Cu-Ligand species.The coupling of the Cu-stabilized phosphorus radical species and alkyl radical afforded the product.This novel strategy provides a general access to numerous phosphorus-containing aliphatic compounds.Notably,some of products had further application in the synthesis of phosphorus-containing ligands and fosinopril.(2)Decarboxylative phosphorylation of C(sp3)radical generated from carboxylic acid derivativesC(sp3)-centered radicals and phosphorus radicals generated from carboxylic acid derivatives and organophosphorus reagents,respectively were coupled in the presence of catalytic Ag2SO4 salt to synthesize(hetero)arylmethyl phosphine oxide products.A variety of(hetero)arylacetic acids such as phenylacetic acids,naphthylacetic acid,pyridylacetic acid,furanylacetic acid,thiophenylacetic acid and di(hetero)arylphosphine oxides were compatible with this reaction.Mechanistic studies indicated that the di(hetero)arylphosphine oxides could be oxidized by a sulfate radical anion under assistance by Ag(?)to generate the phosphorus radical,which is further stabilized by Ag(?).Meanwhile,the formed Ag(?)species could interact with the(hetero)arylacetic acid.Subsequent decarboxylation could produce(hetero)aryl methyl radical which couples with phosphrous radical to form C(sp3)-P bond.Furthermore,the reaction of 1,3-dicarbonyl compounds with trialkyl phosphites were also performed,successfully constructing C(sp3)-P bond.(3)Deboronative phosphorylation of C(sp3)radicals generated from potassium benzyltrifluoroborate derivativesIn the presence of catalytic Cu(OTf)2,the selective coupling C(sp3)-centered radicals and phosphorus radicals(obtained from potassium(hetero)arylmethyl trifluoroborates and di(hetero)arylphosphine oxides,respectively)afforded(hetero)arylmethyl phosphine oxide derivatives.Various di(hetero)arylphosphine oxides and potassium(hetero)arylmethyltrifluoroborates including those substituted with benzyl-,naphthyl-,picolinyl-,furfuryl-and thienyl were compatible with this reaction.Mechanistic investigation showed that persulfate could oxidize diarylphosphine oxides and potassium benzyltrifluoroborates in the presence of catalytic Cu(OTf)2 to produce Cu-stabilized phosphrous radical and benzyl radical respectively.Afterwards,the two radical species could combine to generate a Cu(?)species,which disintegrates into the product and Cu(I)species after reductive elimination..This novel reaction provides a general method to synthesize a number of(hetero)arylmethyl phosphine oxide derivatives.(4)Phosphorylation of C(sp3)radical via ring-opening of 1-substituted cyclobutanol derivativesThe radical reaction between 1-susbstituted cyclobutanol derivatives and di(hetero)arylphosphine oxides was carried out in the presence of catalytic Ag salt to synthesize 1-heteroaryl-4-phosphoryl-ketone products.A wide range of di(hetero)arylphosphine oxides and cyclobutanol derivatives including those containing phenyl-,naphthyl-,furanyl-,thienyl-and benzyl were amenable to this reaction.Mechanistic studies indicated that the di(hetero)arylphosphine oxides is oxidized by sulfate radical anion in the presence of Ag(?)to produce the phosphorus radical,which is further stabilized by Ag(?)to give a Ag(?)species.Subsequent interaction of this species with the cyclobutanol derivative,followed by a ring-opening process furnishes a C(sp3)-centered radical.The coupling of C(sp3)-centered radical with a Ag(?)-P species leads to the formation of the C(sp3)-P bond.This novel reaction offers a general route to numerous 1-(hetero)aryl-4-phosphoryl-ketone compounds.