On the Mechanism of N-Heterocyclic Carbene-Catalyzed Reactions Involving Acyl Azoliums

Abstract

Catalytic reactions promoted by N-heterocyclic carbenes (NHCs) have exploded in popularity since 2004 when several reports described new fundamental reactions that extended beyond the long-studied generation of acyl anion equivalents. These new NHC-catalyzed reactions allow chemists to generate unique reactive species from otherwise inert starting materials, all under simple, mild reaction conditions and with exceptional selectivities. In analogy to transition metal catalysis, the use of NHCs has introduced a new set of elementary steps that operate via discrete reactive species, including acyl anion, homoenolate, and enolate equivalents, usually generated by oxidation state reorganization ("redox neutral" reactions). Nearly all NHC-catalyzed reactions offer operationally simple reactions, proceed at room temperature without the need for stringent exclusion of air, and do not generate reaction byproducts. Variation of the catalyst or reaction conditions can profoundly influence reaction outcomes, and researchers can tune the desired selectivities through careful choice of NHC precursor and base. The catalytically generated homoenolate and enolate equivalents are nucleophilic species. In contrast, the catalytically generated acyl azolium and α,β-unsaturated acyl azoliums are electrophilic cationic species with unique and unprecedented chemistry. For example, when generated catalytically, these species transformed an α-functionalized aldehyde to an ester under redox neutral conditions without coupling reagents or waste. In addition to providing new approaches to catalytic esterifications, acyl azoliums offer unique reactivities that chemists can exploit for selective reactions. This Account focuses on the discovery and mechanistic investigation of the catalytic generation of acyl azoliums and α,β-unsaturated acyl azoliums. These chemical species are fascinating, and their catalytic generation is an important development. Studies of their unusual chemistry, however, date back to the intense investigation of thiamine-dependent enzymatic processes in the 1960s. Acyl azoliums are remarkably reactive in acylation chemistry and are unusually chemoselective. These two properties have led to a new wave of reactions such as redox esterification reaction (1) and the catalytic kinetic resolution of challenging substrates (i.e., 3). Our group and others have also developed methods to generate and exploit α,β-unsaturated acyl azoliums, which have facilitated new C-C bond-forming annulations, including a catalytic, enantioselective variant of the Claisen rearrangement (2). From essentially one class of catalysts, the N-mesityl derived triazolium salts, researchers can easily prepare highly enantioenriched dihydropyranones and dihydropyridinones. Although this field is now one of the most explored areas of enantioselective C-C bond forming reactions, many mechanistic details remained unsolved and in dispute. In this Account, we address the mechanistic inquiries about the characterization of the unsaturated acyl triazolium species...

Stability of electrogenerated 1-butyl-3-methylimidazol-2-ylidene in DMF. Part 2. Role of acid substrates. [1]

“…As expected, the ip ox values decrease on increasing η irrespective of the nature of X (BF 4 , NTf 2 , Cl) and of the acid (3 or 4). Nevertheless, the decrease extent strongly depends on the nature of X: it is comparable using BF 4 -or NTf 2 -, while it is substantially higher using Cl -.…”

“…The remarkable versatility of N-heterocyclic carbenes (NHCs) is attested by their frequent utilization as organocatalysts [2][3][4][5][6][7][8][9][10][11], as ligands for transition metals [12][13][14][15], and as catalysts in metal free polymer synthesis [16][17]. Moreover, electrogenerated NHC 8 was used in some baseinduced organic electrosyntheses [18][19][20][21][22].…”

Advances in the Knowledge of N-Heterocyclic Carbenes Properties. The Backing of the Electrochemical Investigation

“…According to the hypothesis of Breslow, the heart of the mechanism is the nucleophilic attack of NHC to the carbonyl function of an aldehyde yielding a zwitterionic structure, which is converted (by an intramolecular proton transfer) into an acylanion equivalent (the Breslow intermediate). The coupling of the Breslow intermediate with a second aldehyde molecule yields the product (α-hydroxyketone, benzoin) and regenerates the NHC [15][16][17][18].…”

Dekonstruktion kovalenter Organokatalyse

“…Gilmour und M. C. Holland als Breslow-Intermediate bekannt sind (Abbildung 7, oben). [95] Obgleich diese und verwandte Intermediate für mechanistische Arbeiten in situ generiert werden kçnnen, [49,96] bleibt ihre Isolierung anspruchsvoll. [97] Jüngst zeigten die Forschungen von Berkessel, Te les und Mitarbeitern erste Erfolge in der NMR-spektroskopischenC harakterisierung der Ketoform dieser wichtigen primären Katalyse-Intermediate und in der anschließenden Analyse verwandter 2,2-Diaminoenole (47).…”