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

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.