Photoinduced and Palladium-Catalyzed Remote Desaturation of Amide Derivatives

Abstract

A photoinduced and palladium-catalyzed remote desaturation of O-acyl hydroxamides to unsaturated amides under mild conditions has been achieved. The formation of the alkyl Pd(II) intermediate by the recombination of alkyl radical and Pd(I) species is critical to achieve this efficient and selective desaturation of alkanes. This reaction features good site-selectivity, is terminal oxidant-free, and produces moderate to excellent yields for a variety of unsaturated amides. Remarkably, this approach enables late-stage desaturation of complex and biologically important molecules.

An efficient and straightforward approach for accessing thionoesters via palladium-catalyzed C–N cleavage of thioamides

“…Based on the known palladium chemistry, 106–109 a plausible mechanism for the catalytic reaction was proposed (Scheme 7): (i) oxidative addition takes place at the C–N bond of thioamide 1a to give thio-acylpalladium( ii ) complex II ; (ii) following transmetalation, complex III is produced by the reaction of benzyl alcohol 2a ; and (iii) then, reductive elimination occurs to form thionoester product 3a and regenerates the Pd(0) species I .…”

γ C–H Functionalization of Amines via Triple H-Atom Transfer of a Vinyl Sulfonyl Radical Chaperone

“…In these examples, multiple substitution patterns (α, β, γ, δ), rings (polycyclics, arenes), and divergent core functionalities (anilines, endo -amide 18 ) are tolerated. Formation of nonconjugated systems ( 17 vs styrene; 1,4-diene 18 vs enone or 1,3-diene) is illustrative of the orthogonal selectivity of this desaturation method. , As a solution to the central challenge of accessing medicinally relevant, unnatural amino acids, we were pleased to find several Cy-alanine (Cha) esters are selectively and efficiently dehydrogenated ( 19 – 21 ; >20:1 rr in all cases; see the SI for the X-ray structure of 19 ). Similarly, leucine (Leu) 22 and various dipeptides of Leu ( 23 – 25 ) are selectively desaturated at the γ C–H of the Leu residue, even in the presence of weak C–H bonds (Leu-Val, Leu-Phe) or unprotected indoles (Leu-Trp).…”

“…Given the high value, yet ongoing limitations, of double C–H desaturation technologies, − we set out to probe the utility of a new chaperone in addressing this synthetic challenge. Radical desaturations typically require adjacent functional groups (e.g., arene, heteroatom, carbonyl) − as well as stoichiometric oxidants. , Among the rare examples of catalytic or regioselective desaturation, it is instructive to note how oxidized precursors are used to access radicals centered on O (via O–O), N (via N–F, N–O), , or C (via Ar–N 3 R, Ar–I, SiCH 2 I) − (Figure a). Collectively, these pioneering strategies overcome the thermodynamic challenge of C–H abstraction by generating a strong O–H, N–H, and primary or aryl C–H bond.…”

Aza-heterocycles via copper-catalyzed, remote C–H desaturation of amines

“…Notably, Gevorgyan has extended the latter approach to a, b, and g desaturation of amines via Pd-catalysis, 34 and Yu has applied this approach to amides. 35 However, the remote, d desaturation remains elusive, despite its inherent synthetic utility as a precursor for favored 5-exo-trig and 6-endo-trig cyclizations. 36…”