Synthesis and stereochemistry of benzamidines and acetamidines

Abstract

Phosphoric anhydride reacts with benzanilides and acetanilides in a novel self-condensation reaction to give N-substituted aroyl and acyl amidines (2a-g) and (4a-d) respectively. In contrast, an N-alkylbenzamide (5) gave dibenzamide (6). X-ray crystallographic studies of (2b), (2d), (4f) and(6) are reported. NMR spectroscopy of N-benzoyl-N,N'-bis(2,6-diethylphenyl)-benzamidine (2e), N-benzoyl-N,N'-bis(2,6-diisopropylphenyl)benzamidine (2f), N-acetyl-N,N'-bis(2, 6-diethylphenyl)acetamidine (4e) and N-acetyl-N,N'-bis(2,6-diisopropylphenyl)- acetamidine (4f), revealed diastereotopic ethyl and isopropyl groups, which is attributed to chirality arising from restricted rotation about the aryl-N bonds. The barrier to rotation about the least restricted aryl-N bond of the benzamidine (4f) was 76 kJ mol-1 as determined by variable temperature NMR spectroscopy. Splitting of the NMR methyl signals for N-benzoyl-N,N'-bis(2-methylphenyl)-benzamidine was also observed. Molecular mechanics modelling, together with X-ray crystallography, indicated that this is due to the adoption of an unusual rotamer equilibrium which gives rise to two environments for the amide bound 2-tolyl methyl group. The ambident character of benzanilide and the stabilities of phosphorylated intermediates was studied by semi-empirical and ab initio MO calculations. Evidence for the establishment of an equilibrium mixture of O-phosphorylated and N-phosphorylated amides via phosphorotropy and the intermediate formation of nucleophilic iminol tautomers is discussed as part of a proposed reaction mechanism.