Continuous‐Flow Hydrogenation and Reductive Deuteration of Nitriles: a Simple Access to α,α‐Dideutero Amines

Abstract

A simple and efficient continuous flow methodology has been developed for hydrogenation and reductive deuteration of nitriles to yield primary amines and also valuable α,α‐dideutero analogues. Raney nickel proved to be a useful catalyst for the transformation of a wide range of nitriles under reasonably mild conditions with excellent deuterium incorporation (>90 %) and quantitative conversion. Among known model compounds, three new deuterated primary amines were prepared. The large‐scale synthesis of deuterated tryptamine was also carried out to deliver 1.1 g product under flow conditions.

Deuterium labelling by electrochemical splitting of heavy water

“…also a reactive motif in electrochemical deuteration. Potentially reducible C-Br, C=O and C=C groups were well preserved in the products during nitro reduction according to previous reports [43,44] . For organic halides, the C-I bond is relatively easy to dissociate even at mildly reductive potentials, while the cleavage of C-F bonds is almost impossible in the water splitting window.…”

Exploiting a silver–bismuth hybrid material as heterogeneous noble metal catalyst for decarboxylations and decarboxylative deuterations of carboxylic acids under batch and continuous flow conditions

“…[84][85][86] As exemplified by Austedo®, the first deuterated drug marketed, pharmaceutical ingredients may also be potentiated by deuterium exchange. 87,88 In contrast to deuterations of C-C or C-X (X = hetero atom) multiple bonds, [89][90][91][92][93] synthetic processes for the site-specific incorporation of a single deuterium into an aromatic ring are more challenging. 74,76,77,94,95 In most cases, these methods involve halogen/D exchange and are commonly mediated by strong bases which severely limits the functional group tolerance.…”

Recent Progress in Continuous‐Flow Hydrogenation

“…However, D 2 gas, as a common deuterium source, is expensive and difficult to manipulate. In 2019, Fülöp and co‐workers used the H‐Cube flow system to perform hydrogenation and reductive deuteration reactions of nitriles . Either H 2 or D 2 gas was generated in situ via electrolysis of water or deuterated water.…”

“…Moreover, ethyl acetate (EtOAc) as an aprotic solvent was used to avoid D–H exchange. Using this new flow system, the Fülöp group reported the Raney‐Ni‐catalyzed reduction of 4‐phenylbutyronitrile ( 63 ) at minimum 40 bar H 2 . It afforded quantitative conversion and >99 % selectivity (Scheme ).…”