The kinetic isotope effect effected by deuterium’s greater mass than hydrogen has been utilized to elucidate reaction mechanisms for a wide range of fields. However, an enhanced understanding of drug of metabolism has underscored its potential value within the medicinal field. The substitution of deuterium for hydrogen at certain critical positions can significantly alter the chemoselectivity of drug metabolism and/or induce a longer drug half-life. This was the rationale behind the development of deutetrabenazine, the first FDA-approved small molecule drug to include deuterium. However, the increasing demand for deuterated scaffolds has necessitated general methods for both incorporating and quantitively analyzing deuterium. Piperidine, the most commonly occurring nitrogen heterocycle in FDA-approved small molecule drugs, in particular represents an attractive scaffold to target for deuteration. Previous studies have demonstrated that an N-H pyridinium 2-coordinated to a TpW(NO)(PMe3) fragment will undergo two tandem electrophilic/nucleophilic additions, resulting in highly functionalized tetrahydropyridines (THPs) that can be isolated from the metal. This work utilizes a similar approach to incorporate deuterium across the ring for the synthesis of various THP isotopologues and isotopomers. These liberated THPs were then analyzed via molecular rotational resonance (MRR) to quantitatively determine the location and extent of deuterium incorporation. This methodology was then applied to synthesizing N-mesylated THP isotopologues/-mers of erythro Ritalin, a commonly prescribed ADHD treatment.

Applied dearomatization of pyridine: Synthesis of tetrahydropyridine isotopologues and isotopomers

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