Synthesis and a Kinetic Study of the Reactivity of 1-Amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one in Alkylation Reactions with Structurally Similar Amines

Abstract

Amine-containing natural products have garnered much attention in synthetic chemistry owing to their potential as starting points in medicinal chemistry. In this study, we present an improved method for the synthesis of (1S,4R)-1-amino-7,7-dimethylbicyclo[2.2.1]heptan-2-one (1) and conduct a comparative analysis of its reactivity in alkylation reactions with structurally related amines. The synthetic route involved the activation of the carboxylic group using an acid chloride for acyl azide synthesis, isolation of the acyl azide in its pure form, and subsequent rearrangement via reflux in toluene, enabling the preparation of target amine 1. The reactivity of amine 1 was investigated in comparison with a series of other amines in alkylation reactions. The reaction of each amine with methyl iodide resulted in nonspecific alkylation, giving rise to mono- and dialkylated products. Reactions with allyl and benzyl bromide yielded only monoalkylated products. Kinetic analysis revealed that the alkylation of each amine with MeI and allyl bromide proceeded via the SN2 mechanism. In contrast, amine 1 reacted with benzyl bromide via the SN1 mechanism, whereas the other amines followed the SN2 pathway. Calculations of nucleophilicity parameters also showed that amine 1 manifests reduced nucleophilicity compared to the other studied amines.