A General Method for the One-Pot Reductive Functionalization of Secondary Amides

Abstract

A one-pot reaction for the transformation of common secondary amides into amines with C-C bond formation is described. This method consists of in situ amide activation with Tf2O-partial reduction-addition of C-nucleophiles. The method is general in scope, which allows employing both hard nucleophiles (RMgX, RLi) and soft nucleophiles, as well as enolates. With the use of soft nucleophiles, the reaction proceeded with high chemoselectivity at a secondary amide in the presence of ester, cyano, nitro, and tertiary amide groups.

Ruthenium‐Catalyzed Reductive Arylation of N‐(2‐Pyridinyl)amides with Isopropanol and Arylboronate Esters

“…These reactants typically require a low reaction temperature to control their reactivity and show a limited chemoselectivity and functional‐group compatibility. Moreover, the amide sometimes also has to be preactivated in situ with Tf 2 O, generating a more reactive nitrilium salt to allow the nucleophilic addition –. Amongst these reports on reductive functionalization, there are conspicuously few which describe the use of aryl nucleophiles, despite the fact that this gives rise to synthetically useful benzylic amines.…”

Copper‐Catalyzed Double Decarboxylative Coupling Reactions of Alkynyl Carboxylic Acid and Glyoxylic Acid: Synthesis of Propargyl Amines and Imidazopyridines

“…N ‐(1,3‐Diphenylprop‐2‐ynyl)cyclohexanamine (4 s) : Phenylpropiolic acid (146 mg, 1.0 mmol), phenylglyoxylic acid (150 mg, 1.0 mmol), and cyclohexylamine (198 mg, 2.0 mmol) afforded product 4 s (201.2 mg, 0.77 mmol, 25 % yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ =7.58 (m, 2 H), 7.46 (m, 2 H), 7.36 (m, 2 H), 7.31–7.26 (m, 4 H), 4.89 (s, 1 H), 2.85 (m, 1 H), 2.01 (d, J =12.3 Hz, 1 H), 1.85 (d, J =12.0 Hz, 1 H), 1.78–1.71 (m, 2 H), 1.62 (d, J =12.2 Hz, 1 H), 1.46 (s, 1 H), 1.35–1.10 ppm (m, 5 H); 13 C{ 1 H} NMR (101 MHz, CDCl 3 ): δ =141.3, 131.8, 128.7, 128.3, 128.1, 127.7, 127.6, 123.4, 90.1, 85.0, 54.4, 51.7, 34.1, 32.8, 26.3, 25.1, 24.9 ppm; MS (EI): m / z : 289 [ M ] + .…”

Amide activation: an emerging tool for chemoselective synthesis

“…In addition to ketones and imines, a-secondary amines, the corresponding products of in situ reduction, can be formed using mild reducing agents such as sodium borohydride or triethyl silane. [47][48][49] This sequence has found widespread use in the synthesis of (a-chiral) amine-containing natural products (Scheme 15b). In this context, Huang et al reported a wide range of total syntheses of cyclic alkaloids, employing various reducing agents.…”