Direct (LC-)MS Identification of Regioisomers from C–H Functionalization by Partial Isotopic Labeling

Abstract

C–H functionalization of complex substrates is highly enabling in total synthesis and in the development of late-stage drug candidates. Much work has been dedicated to developing new methods as well as predictive modeling to accelerate route scouting. However, workflows to identify regioisomeric products are arduous, typically requiring chromatographic separation and/or nuclear magnetic resonance spectroscopy analysis. In addition, most reports focus on major products or do not assign regioisomeric products, which biases predictive models constructed from such data. Herein, we present a novel approach to complex reaction analysis utilizing partial deuterium labels, which enables direct product identification via liquid chromatography–mass spectrometry. When combined with spectral deconvolution, the method generates product ratios while circumventing chromatography altogether. Competitive kinetic isotope effects can also be determined. The resultant data are expected to be useful in the construction of predictive models across several dimensions including reaction selectivity, the impact of structure on mechanism, and mass spectral ionization patterns and expedite the identification of drug metabolites.

Partial isotopic labels allow direct identification of regioisomers via their distinct isotopic distributions. Alternately, spectral deconvolution of unseparated mixtures delivers regioisomer ratios.