Lithiated β-aminoalkyl sulfones as mono and dinucleophiles in the preparation of nitrogen heterocycles: Application to the synthesis of capsazepine

Article abstract of DOI:10.1016/S0040-4020(97)00163-4

The lithiation of N-benzyl-β-tosylethanamine (10a) and N-benzyl-α-phenyl-β-tosyl-ethanamine (10b) with n-butyllithium at -78°C leads to monoanions 11a and 11b, respectively. Intermediates 11 react with different monoelectrophiles (D₂O, alkyl halides, and carbonyl compounds) at the α-position with respect to the sulfone, and with dielectrophiles (1,3-, 1,4-dihalides, α-bromoacetates, and α-chloroketones) to afford the corresponding 6, 7, and 5-membered nitrogen heterocycles. The benzoazepine derivative 13ae, obtained by reaction of 11a with 4,5-bis(chloromethyl)-1,2-dimethoxybenzene, are transformed into the inmediate precursor 24 of capsazepine 25 an antagonist of the sensory neuron excitants capsaicin and resiniferatoxin. Cyclic β-amino sulfone: N-benzyl-3-tosylpiperidine (13aa) suffers lithiation at the axial position reacting with electrophiles to give compounds 27. In the case of the Michael addition to methyl crotonate the corresponding adducts are converted into 1-azabicyclo[3.3.1]nonan-2-one derivatives. Finally, base-induced dehydrosulfinylation, reductive desulfonylation, and Julia's methylenation are studied with some representative derivatives.