Jessada Mahatthananchai

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

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 and its kinetic profile under catalytically relevant conditions. We also provide explanations for the requirement and effect of the N-mesityl group in NHC catalysis based on detailed experimental data within given specific reactions or conditions. We hope that our studies provide a roadmap for catalyst design/selection and new reaction discovery based on a fundamental understanding of the mechanistic course of NHC reactions.

An Enantioselective Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes

In the presence of a chiral azolium salt (10 mol %), enols and ynals undergo a highly enantioselective annulation reaction to form enantiomerically enriched dihydropyranones via an N-heterocyclic carbene catalyzed variant of the Claisen rearrangement. Unlike other azolium-catalyzed reactions, this process requires no added base to generate the putative NHC-catalyst, and our investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species. Detailed kinetic studies eliminate a potential 1,4-addition as the mechanistic pathway; the observed rate law and activation parameters are consistent with a Claisen rearrangement as the rate-limiting step. This catalytic system was applied to the synthesis of enantioenriched kojic acid derivatives, a reaction of demonstrated synthetic utility for which other methods for catalytic enantioselective Claisen rearrangements have not provided a satisfactory solution.

Catalytic Selective Synthesis

Complete control of the product of a catalytic reaction can be achieved on the basis of catalyst structure, even when the reaction conditions are nearly identical. Catalyst-controlled selectivity is well established for enantioselective catalysis but less formulated for catalytic regio-, chemo-, or product-selective reactions. This Review describes selective transformations of the same starting materials into two or more different products simply by the choice of catalyst. By collecting and highlighting examples of selective catalysis, we hope that the field will be encouraged by the progress that has been made while bringing attention to unmet needs in the design and mechanistic understanding of selective catalysts.

The effect of the N-mesityl group in NHC-catalyzed reactions.

The majority of N-heterocyclic carbene catalyzed reactions of α-functionalized aldehydes, including annulations, oxidations, and redox reactions, occur more rapidly with N-mesityl substituted NHCs. In many cases, no reaction occurs with NHCs lacking ortho-substituted aromatics. By careful competition studies, catalyst analogue synthesis, mechanistic investigations, and consideration of the elementary steps in NHC-catalyzed reactions of enals, we have determined that the effect of the N-mesityl group is to render the initial addition of the NHC to the aldehyde irreversible, thereby accelerating the formation of the Breslow intermediate. These studies rationalize the experimentally observed catalyst preference for all classes of NHC-catalyzed reactions of aldehydes and provide a roadmap for catalyst selection and design.

Enantioselective Synthesis of Dihydropyridinones via NHC-Catalyzed Aza-Claisen Reaction

N-Heterocyclic carbene catalyzed aza-Claisen annulations of enals or their α-hydroxyenone surrogates with vinylogous amides afford dihydropyridinones. The reaction proceeds with a broad range of substrates, and no nitrogen protecting group is required.

α,β-Unsaturated Acyl Azoliums from N-Heterocyclic Carbene Catalyzed Reactions: Observation and Mechanistic Investigation

Catalytically generated acyl azoliums I and their a,b-unsaturated counterparts II are thought to be key reactive intermediates in a rapidly growing number of transformations promoted by N-heterocyclic carbene (NHC) catalysts. Acyl azoliums are invoked in the postulated catalytic cycles of nearly all of the new NHC-catalyzed reactions of a-functionalized aldehydes reported since 2004, in which they are generally assumed to possess the reactivity of an activated carboxylic acid, that is, analogous to an activated ester. In NHC-catalyzed processes, they are most often obtained through internal redox reactions of functionalized aldehydes but have also been prepared by oxidations of the Breslow intermediates or additions to ketenes. Acyl azoliums I are important intermediates in thiamine pyrophosphate (ThPP) dependent enzymatic reactions. Townsend et al. have recently proposed that unsaturated acyl azolium III is the key intermediate in clavulanic acid biosynthesis; despite careful efforts, III or its analogues II have never been characterized or independently synthesized. Here, we document the observation and characterization of a,b-unsaturated acyl azoliums 1 and 2 (Scheme 1) and demonstrate that their corresponding hemiacetals (1’ and 2’) are the kinetically important intermediates in both their acylation and annulation reactions. Simple acyl azoliums prepared under stoichiometric conditions were extensively studied in a seminal work by Breslow and continued by Daigo, White and Ingraham, Bruice, Lienhard, and Owen. These investigations revealed the unique and rich chemistry of acyl azoliums, including their remarkable reluctance to acylate amines and high preference for reactions with water or alcohols. Despite the more than 120 publications since 2004 that feature acyl azoliums, including the rediscovery of their unusual chemoselectivity, there have been no reports of the isolation, detection, or properties of novel acyl azoliums thought to be generated under catalytic conditions. Even at high catalyst loadings, most NHC-catalyzed reactions do not give any detectable intermediates that can be observed with conventional techniques such as UV, IR, NMR spectroscopy, or MS methods. For example, no intermediates could be observed during the redox esterification of cinnamaldehyde, even when the reaction was run with high catalyst loadings or in the absence of base to ensure slow reaction. This is consistent with NMR studies of the redox esterification of ynals by Zeitler, in which the postulated a,bunsaturated acyl azolium II was not observed. Our recent studies of reactions of ynals catalyzed by azolium salts revealed that the rate-limiting step of the catalytic cycle occurs after the formation of the acyl azolium. These findings strongly suggested that generation of substantial amounts of the a,b-unsaturated acyl azolium intermediate should be possible in the absence of a nucleophile. Careful preparation of a mixture of triazolium 3 and para-chlorophenyl ynal 4 in anhydrous CDCl3 gives a clear solution (Figure 1). Upon addition of NaOAc, the solution rapidly becomes yellow, and turns deep red within 20 minutes. The color change was monitored by UV/Vis spectroscopy, and we observed a maximum absorption at 355 nm, with a significantly smaller absorption at 520 nm, for the solution containing acyl azolium 1 (Figure 2). Townsend et al. have speculated that the related protein-bound species III (Scheme 1) has a characteristic UV/Vis absorption at 310– 320 nm. Our mixture was further investigated by electrospray ionization–high resolution mass spectrometry (ESIHRMS), which verified the molecular formula of 1 (Figure 2). Scheme 1. Various acyl azoliums and the hemiacetals.

Oxyanion steering and CH-π interactions as key elements in an N-heterocyclic carbene-catalyzed [4 + 2] cycloaddition.

The N-heterocyclic carbene catalyzed [4 + 2] cycloaddition has been shown to give γ,δ-unsaturated δ-lactones in excellent enantio- and diastereoselectivity. However, preliminary computational studies of the geometry of the intermediate enolate rendered ambiguous both the origins of selectivity and the reaction pathway. Here, we show that a concerted, but highly asynchronous, Diels-Alder reaction occurs rather than the stepwise Michael-type or Claisen-type pathways. In addition, two crucial interactions are identified that enable high selectivity: an oxyanion-steering mechanism and a CH-π interaction. The calculations accurately predict the enantioselectivity of a number of N-heterocyclic carbene catalysts in the hetero-Diels-Alder reaction.