Practical synthesis of C1 deuterated aldehydes enabled by NHC catalysis

Rerouting an Organocatalytic Reaction by Intercepting its Reactive Intermediates

“…With the conditions-selecting guideline in hand, we wished to further understand the mechanism of the reaction and gain insight on the cause different aldehyde substitution patterns necessitate modified reaction conditions. We hypothesized that the deuteration occurred either as a nucleophilic attack of the Breslow intermediate on a water molecule, as previously suggested, [22][23] or through a Grotthus-type mechanism, by which protons diffuse through a hydrogen bond network. 45 The latter would entail the concomitant formation and cleavage of covalent bonds between the Breslow intermediate and one or more water molecules.…”

“…[8][9][10][11] Furthermore, deuterated compounds are of great value for nuclear magnetic resonance spectroscopy, 12 mass spectrometry [13][14] and the investigation of reaction mechanisms. 10 Despite recent advances, [15][16][17][18][19][20][21][22][23] current approaches for the preparation of deuterium labeled aldehydes (aldehyde-d) are still limited by unselective reactions, harsh reaction conditions, restricted substrate scopes and poor deuterium incorporation. These limitations particularly affect highly substituted and electrophilic aldehydes as they can readily undergo side reactions.…”

“…[21][22][23] Bouffard, Bertrand, Yan and co-workers used mesoionic carbenes with methanol-d as the deuterating reagent, 15 while Chen, Zhang, Wang and coworkers as well as Sawama, Sajiki and coworkers used imidazolium and triazolium NHCs with D2O as the deuterating reagent. [22][23] In our previous work, we used boronic acids to stabilize acyl anion adducts in the NHC catalyzed benzoin reaction. 25 Herein, we exploit mechanistic insights on the stabilization of intermediates in NHC catalysis for the selective deuteration of aromatic aldehydes.…”

“…For example, Chen, Zhang, Wang and coworkers published multiple catalysts and conditions (temperature, solvents, bases) for deuterating different substrates, which required an extensive trial-and-error optimization for each new example. 22 As with many other organocatalytic NHC reactions, this requirement originated from the inherent characteristics of the different substrate-NHC intermediates. Furthermore, since the reactivity trend was not entirely steric or electronic, it has so far been difficult to formulate a clear guideline as to which conditions would work for new substrates.…”

Semiconductor photocatalysis to engineering deuterated N-alkyl pharmaceuticals enabled by synergistic activation of water and alkanols

“…Multi-deuterium atoms incorporation at all α-position of pharmaceutical amines (more than 4.0 deuteriums per molecule) with a wide range of Dincorporation ratio (from 1 to 91%) is generally occurred. Still, the development of a general and mild method for the substitution of the traditional deuterated alkylation from toxic deuterated reagents like CD 3 I is in high demand to effectively and selectively functionalize pharmaceutical amines [39][40][41][42][43] . Further, the precise control of deuterium atoms number at the α-position of N-alkyl drugs with high deuterium incorporation currently remain unexplored, while it is particularly attractive for their potential use in mechanistic and metabolic studies 44,45 .…”