Dearomatizing Anionic Cyclization of N-Alkyl-N-benzyl(dinaphthyl)phosphinamides.A Facile Route to gamma-(Amino)dihydronaphthalenylphosphinic Acids

摘要

The dearomatizing anionic cyclization of N-alkyl-N-benzyldi(n-naphthyl)phosphinamides(n= 1,2)and subsequent trapping with a series of electrophiles(MeOH,Mel,CF3SO3Me,Me3O~+BF_4~-,AllylBr,and PhCH2Br)have been accomplished.Optimized reaction conditions(base,temperature,reaction time)allow for synthesizing tetrahydro-1H-naphtho[1,2-c][1,2]-azaphosphole 1-oxides 13 and 18 and tetrahydro-1H-naphtho[2,1-c][1,2]azaphosphole 3-oxides 16 and 27-29 in high yield and diastereoselectivity.Appropriate selection of the base proved to be critical for promoting anionic cyclization of 2-naphthyl derivatives.The dearomatized heterocycles are transformed quantitatively into gamma-(N-alkylamino)phosphinic acids by acid hydrolysis of the P-N linkage.Bioactivity assays on five human tumor cell lines for one of these amino acids revealed growth inhibition factors(GI50)at a micromolar scale.Additionally,evidence for the feasibility of intermolecular nucleophilic dearomatization and sequential nucleophilic attack to both aromatic rings of dinaphthylphosphinamides have been obtained.