Palladium-NHC (NHC = N-heterocyclic Carbene)-Catalyzed Suzuki–Miyaura Cross-Coupling of Alkyl Amides

Abstract

We report the Pd-catalyzed Suzuki−Miyaura cross-coupling of aliphatic amides. Although tremendous advances have been made in the cross-coupling of aromatic amides, C−C bond formation from aliphatic amides by selective N−C(O) cleavage has remained a major challenge. This longstanding problem in Pd catalysis has been addressed herein by a combination of (1) the discovery of N,N-pym/Boc amides as a class of readily accessible amide-based reagents for cross-coupling and (2) steric tuning of well-defined Pd(II)-NHC catalysts for cross-coupling. The methodology is effective for the cross-coupling of an array of 3°, 2°, and 1°aliphatic amide derivatives. The catalyst system is user-friendly, since the catalysts are readily available and are air-and benchstable. Mechanistic studies strongly support an amide bond twist and external n N → π* CO/Ar delocalization as a unified enabling feature of N,N-pym/Boc amides in selective N−C(O) bond activation. The method provides a rare example of Pd-NHC-catalyzed cross-coupling of aliphatic acyl amide electrophiles.

Nickel-Catalyzed Electro-Reductive Cross-Coupling of Aliphatic Amides with Alkyl Halides as a Strategy for Dialkyl Ketone Synthesis: Scope and Mechanistic Investigations

“…19 Notably, complex I represents the first example of structurally characterized Ni(II) acyl succinimidate ensuing from C-N bond oxidative addition. 32,33 While aliphatic amides are reputed to be challenging substrates in cross-coupling reactions, 13,14 we provide direct evidence that the Cacyl-N bond oxidative addition of aliphatic amides to Ni(0) is a very favorable process. The cyclic voltammogram of complex I carried out in DMF displays two quasi-reversible reduction waves assigned to single electron reduction to Ni(I) at -1.74 V (R1) and Ni(0) at -1.96 V (R2) species (see Figure 3 and Figure S13).…”

“…With the optimized conditions in hand, the scope of the nickelcatalyzed ERCC was examined with a variety of stable amides and commercially available alkyl halides (Scheme 1A). Pleasingly, primary (3)(4)(5)(6)(7)(8), secondary (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) as well as tertiary alkyl amides (20)(21)(22)(23)(24)(25) were suitable substrates under the reaction conditions affording the desired products in moderate to excellent yields. Notably, aliphatic amides bearing a chlorine atom attached to the carbon chain (5 and 6) that can act as an effective chemical handle for further derivatization was tolerated under the reaction conditions.…”

“…trifluoromethyl (10,20), carboxylic ester (4, 21), Boc-protected amines (8,19), including also sensitive functionalities like acetals (5,22), and unsaturated moieties (9). (12)(13)(14) as the sole reaction products, with no a-branched benzylic ketone being formed. This result nicely differentiates our method from the one recently reported by Mei and co-workers.…”

Fe(iii)-catalysed selective C–N bond cleavage of N-phenylamides by an electrochemical method

“…Based on the above experimental results and literature survey, 13 a plausible reaction pathway for Fe( iii )-catalysed selective C–N bond activation of N -phenyl amides promoted by regioselective C–H oxygenation was proposed (Fig. 2).…”

Nickel-Catalyzed Electro-Reductive Cross-Coupling of Aliphatic N-Acyl Imides with Alkyl Halides as a Strategy for Dialkyl Ketone Synthesis: Scope and Mechanistic Investigations

“…Indeed, amides offer the advantage to be unreactive under a variety of reaction conditions, which allows their use at the end of a multi-step synthetic sequence in a late-stage functionalization fashion. Several key reports have demonstrated the use of aryl N -acyl imides as acyl-transfer reagents in various cross-coupling reactions. , However, as recently reported by Garg and Szostak, catalytic methods to forge C–C bonds from aliphatic N -acyl imides remain challenging. Furthermore, nickel-catalyzed reductive cross-electrophile coupling reactions of N -acyl imides are still underdeveloped, and no electrochemical method has been so far documented regarding the use of amide electrophiles in cross-coupling reactions .…”