Oxidative Cross Dehydrogenative Coupling of N-Heterocycles with Aldehydes through C(sp³)–H Functionalization

Abstract

Existing methodologies for metal-catalyzed cross-couplings typically rely on preinstallation of reactive functional groups on both reaction partners. In contrast, C–H functionalization approaches offer promise in simplification of the requisite substrates; however, challenges from low reactivity and similar reactivity of various C–H bonds introduce considerable complexity. Herein, the oxidative cross dehydrogenative coupling of α-amino C­(sp 3)–H bonds and aldehydes to produce ketone derivatives is described using an unusual reaction medium that incorporates the simultaneous use of di-tert-butyl peroxide as an oxidant and zinc metal as a reductant. The method proceeds with a broad substrate scope, representing an attractive approach for accessing α-amino ketones through the formal acylation of C–H bonds α to nitrogen in N-heterocycles. A combination of experimental investigation and computational modeling provides evidence for a mechanistic pathway involving cross-selective nickel-mediated cross-coupling of α-amino radicals and acyl radicals.

Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N–Aryl Azacycle Photomediated Ring Contractions

“…The relative electron richness of the N –Ar substrates opens up several avenues for oxidation that would enable α-functionalization through precedented α-amino radical or iminium intermediates (Figure B). , Initial efforts focused on leveraging emerging photomediated α-acylation techniques, including those reported by Montgomery, Doyle, and Xu. ,− The Xu aroylation chemistry was most applicable for our desired N –aryl substrate classes (Figure C), as we had previously identified aryl ketones as the most effective photoreactive handle (as opposed to aliphatic acyl groups or other functional groups). While photomediated aroylation worked well for most N –aryl precursors, substrates bearing more electron-deficient groups, such as N –pyridyl moieties, were not successfully aroylated.…”

Dehydrogenative Coupling of Alkylamines with Primary Alcohols Forming α-Amino Ketones

“…Among various synthetic strategies for α-amino ketones, intermolecular C–C bond formation between the nitrogen-containing substrates and oxygen-containing counterparts is of particular value because it allows efficient construction of diverse carbon skeletons using readily available starting materials. Representative examples reported in the literature are the aza-benzoin condensation reaction of aldehydes with imines, − the acylation reaction of a C–H bond next to nitrogen with carboxylic acid derivatives, − and denitrogenative coupling reactions of N -sulfonyl-1,2,3-triazoles with alcohols. − Here we present selective dehydrogenative coupling between alkylamines and primary alcohols forming α-amino ketones . C–H bonds adjacent to nitrogen and oxygen are site-selectively cleaved, and a C–C bond is created between the carbon atoms in a cross-selective fashion.…”

Cu-Catalyzed α-Alkylation of Glycine Derivatives for C(sp3)–H/C(sp3)–H Bond Selective Functionalization

“…However, the above-reported typical synthetic methods usually encounter a pricey photocatalyst, elaborate prepreparation of alkyl precursors, finite substrate scope, and especially lack of in-depth investigation for the practicality of these reactions. Considering that both glycine and ethers/alkanes are easily obtainable scaffolds, we supposed that the direct coupling of glycine and frequent ethers/alkanes via double C­(sp 3 )–H/C­(sp 3 )–H bond activation would be a forthright and efficient route to long-chain α-alkyl amino acid motifs.…”

“…Based on the existing experimental results and the literature, ,, a possible catalytic cycle is presented in Scheme . First, the Cu­(I)/Cu­(II)-induced decomposition of t BuOO t Bu provided tert -butoxy radical species A . Then, tetrahydrofuran 1b underwent the HAT (hydrogen atom transfer) process by the radical intermediate A to create a more stable alkyl radical intermediate B . Concurrently, Cu­(II) oxidizes amino acid 1a to produce an amino radical cation C , along with the regeneration of Cu­(I) .…”