The amide bond is one of the most fundamental functional groups in chemistry and biology and plays a central role in numerous processes harnessed to streamline the synthesis of key pharmaceutical and ...industrial molecules. Although the synthesis of amides is one of the most frequently performed reactions by academic and industrial scientists, the direct transamidation of tertiary amides is challenging due to unfavorable kinetic and thermodynamic contributions of the process. Herein, we report the first general, mild, and highly chemoselective method for transamidation of unactivated tertiary amides by a direct acyl N–C bond cleavage with non-nucleophilic amines. This operationally simple method is performed in the absence of transition metals and operates under unusually mild reaction conditions. In this context, we further describe the direct amidation of abundant alkyl esters to afford amide bonds with exquisite selectivity by acyl C–O bond cleavage. The utility of this process is showcased by a broad scope of the method, including various sensitive functional groups, late-stage modification, and the synthesis of drug molecules (>80 examples). Remarkable selectivity toward different functional groups and within different amide and ester electrophiles that is not feasible using existing methods was observed. Extensive experimental and computational studies were conducted to provide insight into the mechanism and the origins of high selectivity. We further present a series of guidelines to predict the reactivity of amides and esters in the synthesis of valuable amide bonds by this user-friendly process. In light of the importance of the amide bond in organic synthesis and major practical advantages of this method, the study opens up new opportunities in the synthesis of pivotal amide bonds in a broad range of chemical contexts.
Nonplanar, electronically destabilized amides have emerged as powerful intermediates in organic synthesis. We report a highly selective method for transamidation of common secondary amides under ...mild, metal-free conditions that relies on transient N-selective functionalization to weaken amidic resonance. The combination of rational modification of the amide bond with nucleophilic addition mechanism, and the thermodynamic collapse of the resultant tetrahedral intermediate constitutes a two-step procedure to accomplish a challenging transamidation of secondary amides under mild conditions.
The discovery of NHCs (NHC = N‐heterocyclic carbenes) as ancillary ligands in transition‐metal‐catalysis ranks as one of the most important developments in synthesis and catalysis. It is now ...well‐recognized that the strong σ‐donating properties of NHCs along with the ease of scaffold modification and a steric shielding of the N‐wingtip substituents around the metal center enable dramatic improvements in catalytic processes, including the discovery of reactions that are not possible using other ancillary ligands. In this context, although the classical NHCs based on imidazolylidene and imidazolinylidene ring systems are now well‐established, recently tremendous progress has been made in the development and catalytic applications of BIAN‐NHC (BIAN = bis(imino)acenaphthene) class of ligands. The enhanced reactivity of BIAN‐NHCs is a direct result of the combination of electronic and steric properties that collectively allow for a major expansion of the scope of catalytic processes that can be accomplished using NHCs. BIAN‐NHC ligands take advantage of (1) the stronger σ‐donation, (2) lower lying LUMO orbitals, (3) the presence of an extended π‐system, (4) the rigid backbone that pushes the N‐wingtip substituents closer to the metal center by buttressing effect, thus resulting in a significantly improved control of the catalytic center and enhanced air‐stability of BIAN‐NHC‐metal complexes at low oxidation state. Acenaphthoquinone as a precursor enables facile scaffold modification, including for the first time the high yielding synthesis of unsymmetrical NHCs with unique catalytic properties. Overall, this results in a highly attractive, easily accessible class of ligands that bring major advances and emerge as a leading practical alternative to classical NHCs in various aspects of catalysis, cross‐coupling and C−H activation endeavors.
A comprehensive overview of BIAN‐NHC (BIAN = bis(imino)acenaphthene), NHC = N‐heterocyclic carbene) ligands in transition‐metal‐catalysis with a focus on both the catalyst structure and the scaffold's role in catalysis is presented.
N-Protonation of amides is critical in numerous biological processes, including amide bonds proteolysis and protein folding as well as in organic synthesis as a method to activate amide bonds towards ...unconventional reactivity. A computational model enabling prediction of protonation at the amide bond nitrogen atom along the C-N rotational pathway is reported. Notably, this study provides a blueprint for the rational design and application of amides with a controlled degree of rotation in synthetic chemistry and biology.
Palladium-catalyzed decarbonylative Heck reaction of amides by chemoselective N–C activation using N-acylsaccharins as coupling partners has been accomplished. These studies represent only the second ...example of amide-Heck reactions reported to date. A broad range of electronically diverse amide and olefin coupling partners is amenable to this transformation. Orthogonal site-selective Heck cross-couplings by C–Br/N–C cleavage and mechanistic studies are reported. This report introduces readily available, bench-stable, cheap, and benign N-acylsaccharins as aryl transfer reagents to access versatile aryl-metal intermediates.
Transamidation reactions represent a fundamental chemical process involving conversion of one amide functional group into another. Herein, we report a facile, highly chemoselective method for ...transamidation of N-tert-butoxycarbonylation (N-Boc) activated secondary amides that proceeds under exceedingly mild conditions in the absence of any additives. Because this reaction is performed in the absence of metals, oxidants, or reductants, the reaction tolerates a large number of useful functionalities. The reaction is compatible with diverse amides and nucleophilic amines, affording the transamidation products in excellent yields through direct nucleophilic addition to the amide bond. The utility of this methodology is highlighted in the synthesis of Tigan, a commercial antiemetic, directly from the amide bond. We expect that this new metal-free transamidation will have broad implications for the development of new transformations involving direct nucleophilic addition to the amide bond as a key step.
Pd-PEPPSI-IPr serves as a highly reactive precatalyst in the direct Suzuki–Miyaura cross-coupling of amides. An array of amides can be cross-coupled with a range of arylboronic acids in very good ...yields using a single, operationally simple protocol. The studies described represent the first use of versatile PEPPSI type of Pd-NHC complexes as catalysts for the cross-coupling of amides by N–C bond activation. The method is user-friendly, since it employs a commercially available, air- and moisture-stable Pd-PEPPSI-IPr complex. Pd-PEPPSI-IPr provides a significant improvement over all current Pd/phosphane catalysts for amide N–C bond activation. Mechanistic studies provide insight into the reaction rates of Pd-NHC-catalyzed cross-coupling of different amides, with Pd-PEPPSI-IPr being particularly effective for the cross-coupling of N-Boc carbamates under the developed conditions.
Herein, we show that acyclic amides that have recently enabled a series of elusive transition‐metal‐catalyzed N−C activation/cross‐coupling reactions are highly twisted around the N−C(O) axis by a ...new destabilization mechanism of the amide bond. A unique effect of the N‐glutarimide substituent, leading to uniformly high twist (ca. 90°) irrespective of the steric effect at the carbon side of the amide bond has been found. This represents the first example of a twisted amide that does not bear significant steric hindrance at the α‐carbon atom. The 15N NMR data show linear correlations between electron density at nitrogen and amide bond twist. This study strongly supports the concept of amide bond ground‐state twist as a blueprint for activation of amides toward N−C bond cleavage. The new mechanism offers considerable opportunities for organic synthesis and biological processes involving non‐planar amide bonds.
Let′s twist again! Acyclic amides that have recently been shown to be active in a series of elusive transition‐metal‐catalyzed N−C activation/cross‐coupling reactions are highly twisted around the N−C(O) axis by a new destabilization mechanism of the amide bond (see scheme).
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