Synthesis of α-Deuterated Primary Amines via Reductive Deuteration of Oximes Using D₂O as a Deuterium Source

Abstract

Selective introduction of the deuterium atom into the α-position of amines is important for the development of all types of novel deuterated drugs and agrochemicals due to the pervasive presence of amines. In this study, we report the first general single-electron-transfer reductive deuteration of both ketoximes and aldoximes using SmI2 as an electron donor and D2O as a deuterium source for the synthesis of α-deuterated primary amines with excellent levels of deuterium incorporations (>95% [D]). This protocol exhibits excellent chemoselectivity and tolerates a variety of functional groups. The potential application of this new method was showcased in the synthesis of deuterated drugs, such as rimantadine-d 4, the tebufenpyrad analogue, derivatives of nabumetone and pregnenolone, and a series of building blocks for the rapid and general assembly of deuterated drugs and pesticides.

Recent Developments for the Deuterium and Tritium Labeling of Organic Molecules

“…Extending the substrate scope of nitrile reduction to aromatic nitriles and precluding the concomitant β-deuteration by enolization observed in the sodium dispersion-mediated reductions, samarium iodide represents an attractive alternative as an efficient SET reducing agent, affording high deuterium incorporations and yields on a broad scope of aromatic and aliphatic substrates (Scheme c) . The samarium iodide-mediated reductive deuteration of oximes afforded the same products (Scheme d) …”

“…263 The samarium iodidemediated reductive deuteration of oximes afforded the same products (Scheme 83d). 264 A continuous-flow reductive deuteration of nitriles to access to α,α-dideutero amines was described by Fulop and co-wokers (Scheme 84). They established an individual flow-chemistrybased method for deuteration reactions using deuterated water in an H-Cube system.…”

Reactivity of oximes for diverse methodologies and synthetic applications

“…89 ). h, Oxime 175 is reduced with SmI 2 in D 2 O to incorporate deuterium 90 . i, Reduction of oxime 177 while keeping the n-O bond intact to form hydroxylamine 178 via Ir(III) complex 179 (ref.…”

Selective Reduction of Quinolinones Promoted by a SmI2/H2O/MeOH System

“…SmI 2 , as a mild one-electron transfer reagent, participates in a variety of reactions and is actually applied to natural products and multistep synthesis . Reduction is one of the basic reactions in which SmI 2 participates, and the reduction system of SmI 2 is convenient and efficient for accomplishing functional-group transformation, with groups such as nitro groups, an ester group, an amide, a carboxylic acid, acid fluorides, and oximes, which determines that it plays an important role in reducing agents. In the past few decades, samarium diiodide has been reported to be able to selectively reduce various α,β-unsaturated carbonyl compounds with diverse additives, and Inanaga first reported the selective reduction of α,β-unsaturated amides with samarium diiodide .…”