Reduction and Reductive Deuteration of Tertiary Amides Mediated by Sodium Dispersions with Distinct Proton Donor-Dependent Chemoselectivity

Abstract

A practical and scalable single electron transfer reduction mediated by sodium dispersions has been developed for the reduction and reductive deuteration of tertiary amides. The chemoselectivity of this method highly depends on the nature of the proton donor. The challenging reduction via C-N bond cleavage has been achieved using Na/EtOH, affording alcohol products, while the use of Na/NaOH/HO leads to the formation of amines via selective C-O scission. Sodium dispersions with high specific surface areas are crucial to obtain high yields and good chemoselectivity. This new method tolerates a range of tertiary amides. Moreover, the corresponding reductive deuterations mediated by Na/EtOD- d and Na/NaOH/DO afford useful α,α-dideuterio alcohols and α,α-dideuterio amines with an excellent deuterium content.

Palladium doping of In2O3 towards a general and selective catalytic hydrogenation of amides to amines and alcohols

“…4 Traditionally, amide reduction reactions have been carried out using (over)stoichiometric amounts of classical reagents such as lithium aluminum hydride (LiAlH 4 ) or boranes (B 2 H 6 ), which require tedious workup procedures and generate large amounts of waste. 5 Recently emerged non-catalytic protocols using samarium iodide (SmI 2 )/amine/H 2 O, 6 sodium dispersions with different proton donors, 7 or sodium hydride (NaH) with zinc halides (ZnX 2 ; X = Cl, I) 8 have similar limitations. Different catalytic strategies have been developed for the reduction of amides to amines under hydrosilylation, 9 hydroboration 10 and transfer-hydrogenation 11 conditions, which are methodologies with wide applicability for functionalized amides, but they suffer from low atom-efficiency.…”

KOtBu‐Catalyzed Michael Addition Reactions Under Mild and Solvent‐Free Conditions

“…When phenothiazine reacted with acrylonitrile and N , N ‐dimethyl acrylamide under base catalysis, the corresponding aza‐Michael adducts 9 and 11 were obtained in good yields. Notably, compounds 9 and 11 can be formally transformed directly to commercial drug molecule promazine ( 12 ), used for the treatment of schizophrenia (Scheme ).…”

Selective C-N σ Bond Cleavage in Azetidinyl Amides under Transition Metal-Free Conditions

“…Our study began with the optimization of the reaction conditions for the C-N σ bond cleavage process in azetidinyl amides, using 1a as a model substrate. In the previous work, we have demonstrated that 1a can be converted into the corresponding alcohol via C-N cleavage, using Na/EtOH [5]. We hypothesized that the absence of the proton donor would suppress the amide reduction pathway, and lead to the formation of 2a via the C-N σ bond cleavage.…”

“…Amide is among the most ubiquitous functional groups [1]. Although the reductive functionalization of amides has been studied extensively, the majority of strategies have focused on the amide reductions via C-O or C-N cleavage, to afford the corresponding amines or alcohols (Scheme 1) [2,3,4,5,6,7,8,9,10,11]. Only a few examples were reported for the amide bond functionalization via the selective activation of the non-carbonyl, C-N σ bond, despite its considerable potential in the synthesis of amide linkage in both chemistry and biology (Scheme 1) [12,13].…”