An Enantioselective Claisen Rearrangement Catalyzed by N-Heterocyclic Carbenes
07 Jul 2010-Journal of the American Chemical Society (American Chemical Society)-Vol. 132, Iss: 26, pp 8810-8812
TL;DR: Investigations demonstrate that the counterion of the azolium salt plays a key role in the formation of the catalytically active species in the synthesis of enantioenriched kojic acid derivatives.
Abstract: 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.
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TL;DR: A critical consideration of domino, cascade, and tandem catalysis in the case of N-heterocyclic carbenes catalysts is presented and recent publications in this area are highlighted.
Abstract: While organocatalyzed domino reactions or "organocascade catalysis" developed into an important tool in synthetic chemistry during the past decade, the utility of N-heterocyclic carbenes (NHCs) as catalysts in domino reactions has only received growing attention in the past three years. Taking into account the unique activation modes of the substrates by NHC catalysts, it is often difficult to distinguish between a single chemical transformation and a sequential one-pot transformation. Therefore, herein we present a critical consideration of domino, cascade, and tandem catalysis in the case of NHC catalysts and highlight recent publications in this area.
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TL;DR: This Account addresses the mechanistic inquiries about the characterization of the unsaturated acyl triazolium species and its kinetic profile under catalytically relevant conditions and provides explanations for the requirement and effect of the N-mesityl group in NHC catalysis based on detailed experimental data within given reactions or conditions.
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 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.
529 citations
TL;DR: This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal.
Abstract: Homoenolate is a reactive intermediate that possesses an anionic or nucleophilic carbon β to a carbonyl group or its synthetic equivalent. The recent discovery that homoenolates can be generated from α,β-unsaturated aldehydesviaN-Heterocyclic Carbene (NHC) catalysis has led to the development of a number of new reactions. A majority of such reactions include the use of carbon-based electrophiles, such as aldehydes, imines, enones, dienones etc. resulting in the formation of a variety of annulated as well as acyclic products. The easy availability of chiral NHCs has allowed the development of very efficient enantioselective variants of these reactions also. The tolerance showed by NHCs towards magnesium and titanium based Lewis acids has been exploited in the invention of cooperative catalytic processes. This tutorial review focuses on these and other types of homoenolate reactions reported recently, and in the process, updates the previous account published in 2008 in this journal.
502 citations
References
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TL;DR: Not just one but two carbenes of the same structure act cooperatively in oxidative acylations of alcohols with aldehydes by using a readily available cheap organic oxidant.
Abstract: Not just one but two carbenes of the same structure act cooperatively in oxidative acylations of alcohols with aldehydes by using a readily available cheap organic oxidant. Alcohols are selectively acylated in the presence of amines by cooperative carbene catalysis. Quantum chemical calculations support the suggested mechanism.
380 citations
TL;DR: It is reported that treatment of an alpha-haloaldehyde with a nucleophile in the presence of catalytic amounts of nucleophilic carbenes results in an internal redox reaction giving rise to a dehalogenated acylating agent as an intermediate by a new reaction manifold.
Abstract: Reactivity umpolung allows us to consider nontraditional bond disconnections. We report herein that treatment of an α-haloaldehyde with a nucleophile in the presence of catalytic amounts of nucleophilic carbenes results in an internal redox reaction giving rise to a dehalogenated acylating agent as an intermediate by a new reaction manifold. A brief illustration of the scope of this reaction is presented along with evidence supporting the direct intervention of the carbene in the acylation step.
332 citations
TL;DR: A catalyzed internal redox process provides a route from α- reducible aldehydes and amines to α-reduced amides and proceeds in excellent yields using a variety of primary and secondary alkyl and aryl amines.
Abstract: A catalyzed internal redox process provides a route from α-reducible aldehydes and amines to α-reduced amides. The chemistry is catalyzed by nucleophilic carbenes and common peptide cocatalysts such as HOBt and HOAt in a relay fashion. The transformation proceeds in excellent yields using a variety of primary and secondary alkyl and aryl amines. The aldehyde component may be varied from haloaldehydes to epoxy and aziridino aldehydes as well as enals. The latter three substrates provide for a waste-free amide bond forming reaction.
305 citations
TL;DR: 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO), which has been used successfully by the group in transition-metal-mediated reactions and in various radical processes, is used as the oxidant to oxidize enamines of type C by organic single-electron transfer (SET) oxidants.
Abstract: Pyruvate ferredoxin oxidoreductase (PFOR), which catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA and CO2, belongs to the family of 2-keto acid oxidoreductases. This CoA-dependent enzyme uses thiamine pyrophosphate (TPP) as an additional cofactor. The anaerobic decarboxylation is a reversible process, and the two electrons obtained during one turnover are transferred to ferredoxine via [Fe4S4] clusters. [1] The initial steps of the oxidative decarboxylation resemble those of the aerobic TPP-dependent 2-oxoacid dehydrogenases. Pyruvate reacts with A to form B after proton transfer, and B subsequently undergoes CO2 elimination to generate C (Scheme 1). Electron transfer to a [Fe4S4] cluster leads to radical cation D. Although intensive studies (X-ray and EPR) have been conducted on D, the structure of the radical cation is still under debate. Renewed electron transfer in the presence of CoASH eventually leads to CoASAc. In aerobic organisms lacking the [Fe4S4] clusters, C reacts with the dithiolane ring of a lipoyl group in a formal twoelectron transfer to an acetyl lipoamide thioester intermediate, which is further transformed in the presence of CoASH using another enzyme to CoASAc. The liberated dithiol is eventually reoxidized to the cyclic disulfide by a FADdependent dihydrolipoyl dehydrogenase. It is known in synthesis that reaction of aldehydes with thiazolium carbenes leads to intermediates of type C which react as “umpoled” nucleophiles with aromatic aldehydes (benzoin condensation) or with electron-poor olefins (Stetter reaction). Recently, N-heterocyclic carbene (NHC) catalyzed transformations have gained increasing attention. However, these investigations have focused on ionic processes. Guided by PFOR we planned to oxidize enamines of type C by organic single-electron transfer (SET) oxidants. The process would represent a biomimetic transition-metalfree organocatalytic oxidation of an aldehyde. As the oxidant we used 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO), which has been used successfully by our group in transition-metal-mediated reactions and in various radical processes. Hence, the oxidizing [Fe4S4] clusters in PFOR can be replaced by two oxidizing TEMPO units [Eq. (1)].
304 citations
TL;DR: In this article, a catalytic method for the direct synthesis of carboxylic acid amides from amines and α-functionalized aldehydes is proposed through the synergistic role of a Nheterocyclic carbene catalyst and imidazole, affording amides via activated carboxylates catalytically generated via an internal redox reaction of the aldehyde substrates.
Abstract: A catalytic method for the direct synthesis of carboxylic acid amides from amines and α-functionalized aldehydes is possible through the synergistic role of a N-heterocyclic carbene catalyst and imidazole, affording amides via activated carboxylates catalytically generated via an internal redox reaction of the aldehyde substrates. The use of imidazole or other N-heterocycles as an additive is essential to overcoming imine formation and serves as a uniquely reactive substrate for the generation of an acyl imidazolium intermediate that is converted to the final amide product.
301 citations