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

Abstract

Abstract The lithiation of N -benzyl- β -tosylethanamine ( 10a ) and N -benzyl- α -phenyl- β -tosylethanamine ( 10b ) with n -butyllithium at −78°C leads to monoanions 11a and 11b , respectively. Intermediates 11 react with different monoelectrophiles (D 2 O, 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.