Programmable Deuteration of Indoles via Reverse Deuterium Exchange

Abstract

Methods for selective deuterium incorporation into drug-like molecules have become extremely valuable due to the commercial, mechanistic, and biological importance of deuterated compounds. Herein, we report a programmable labeling platform that allows access to C2, C3, or C2-and C3deuterated indoles under mild, user-friendly conditions. The C2-deuterated indoles are accessed using a reverse hydrogen isotope exchange strategy which represents the first non-directed C2-deuteration of indoles.

Palladium(II)‐Catalyzed Nondirected Late‐Stage C(sp2)−H Deuteration of Heteroarenes Enabled Through a Multi‐Substrate Screening Approach

“…The D-atom at the 3-position is labile and easily de-deuterated during purification. In analogy to similar protocols, [33] deuteration in this position is therefore often diminished in the isolated products. The same trend was observed in unprotected indole 34.…”

Pd-Catalyzed Regioselective Deuteration of Indole’s C4-Position with Transient Directing Groups

“…The deuterium labeling of indole has been extensively studied previously. Both perdeuteration and selective labeling at C2, C3, and C7 sites had been achieved under the catalysis of transient metals (Scheme A), including Ru, Rh, Ir, Pd, Mn, and Co . In contrast, the selective deuteration at the C4 position is rarely discussed, whose inert feature of metabolism makes it an ideal position for metabolite tracking .…”

Palladium(II)‐katalysierte nicht‐dirigierte late‐stage C(sp2)−H Deuterierung von Heteroaromaten ermöglicht über einen Multi‐Substrat‐Screening‐Ansatz

“…Das D-Atom in der 3-Position ist labil und kann während der Aufreinigung mittels Säulenchromatographie leicht dedeuteriert werden. In Analogie zu verwandten Protokollen [33] [14,34] In Anwesenheit einer elektronenziehenden Estergruppe, wie bei 39, konnte bei 100 °C nur ein mäßiger Deuterierungsgrad erreicht werden.…”