Umpolung by N‐Heterocyclic Carbenes: Generation and Reactivity of the Elusive 2,2‐Diamino Enols (Breslow Intermediates)

Berkessel, Albrecht; Elfert, Silvia; Yatham, Veera Reddy; Neudörfl, Jörg‐M.; Schlörer, Nils; Teles, J. Henrique

doi:10.1002/anie.201205878

Cited by 170 publications

(108 citation statements)

References 25 publications

(11 reference statements)

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“…Proton transfer then leads to the enamine-like 'Breslow intermediate' 29, which is nucleophilic at carbon as a result of p-donation from the ring heteroatoms. The involvement of these species in NHC organocatalysis has been recently supported by the isolation and characterization of representative examples derived from SIPr (2b) by Berkessel and co-workers 92 . In the case of the benzoin condensation described above, nucleophilic attack of intermediate 29 onto another equivalent of the aldehyde followed by elimination of the NHC leads to product formation.…”

Section: Research Reviewmentioning

confidence: 86%

An overview of N-heterocyclic carbenes

Hopkinson

Richter

Schedler

et al. 2014

Nature

3,551

1,907

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The successful isolation and characterization of an N-heterocyclic carbene in 1991 opened up a new class of organic compounds for investigation. From these beginnings as academic curiosities, N-heterocyclic carbenes today rank among the most powerful tools in organic chemistry, with numerous applications in commercially important processes. Here we provide a concise overview of N-heterocyclic carbenes in modern chemistry, summarizing their general properties and uses and highlighting how these features are being exploited in a selection of pioneering recent studies.

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Section: Research Reviewmentioning

confidence: 86%

An overview of N-heterocyclic carbenes

Hopkinson

Richter

Schedler

et al. 2014

Nature

3,551

1,907

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“…Adding to the conjecture,t he inhibition of AHAS by herbicides has,i ns ome cases,b een reported to be irreversible, [2a,4] which is inconsistent with am echanism of slowbinding inhibition. In addition, it is also feasible that thiamin diphosphate (ThDP;aBreslow intermediate), ac ofactor in the active site,can participate in alternative reactions with the herbicide (for example by protonation of the enamine or by formation of the keto form through tautomerization), [5] thereby influencing inhibition.Herein, we report our investigations into the process of AHAS inhibition at suboptimal concentrations using penoxsulam (PS;F igure 1B), as al ead example of the triazolopyrimidine sulfonamide family of herbicides.T he kinetic curves (Figure 2A)resemble those reported previously for inhibitors of AHAS where the time dependence of the inhibition was accredited to reversible slow-binding inhibition. [2c,6] However, in this case,s low-binding inhibition is not involved because the amount of inhibition of AHAS at low concentrations of inhibitor exceeds stoichiometric equivalence.F or example,at ac oncentration of 25 nm,P Si nactivated approximately 1 mm of Saccharomyces cerevisiae AHAS (ScAHAS) within 50 min ( Figure 2A,c urve e).…”

mentioning

confidence: 99%

Commercial Herbicides Can Trigger the Oxidative Inactivation of Acetohydroxyacid Synthase

et al. 2016

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Acetohydroxyacid synthase (AHAS) inhibitors are highly successful commercial herbicides.N ew kinetic data show that the binding of these compounds leads to reversible accumulative inhibition of AHAS.C rystallographic data (to aresolution of 2.17 ) for an AHAS-herbicide complex shows that closure of the active site occurs when the herbicidal inhibitor binds,t hus preventing exchange with solvent. This feature combined with new kinetic data shows that molecular oxygen promotes an accumulative inhibition leading to the conclusion that the exceptional potency of these herbicides is augmented by subversion of an inherent oxygenase side reaction. The reactive oxygen species produced by this reaction are trapped in the active site,triggering oxidation reactions that ultimately lead to the alteration of the redox state of the cofactor flavin adenine dinucleotide (FAD), af eature that accounts for the observed reversible accumulative inhibition.Acetohydroxyacid synthase (AHAS;E C2 .2.1.6), the first enzyme in the branched chain amino acid biosynthesis pathway,catalyzes either the conversion of two molecules of pyruvate into 2-acetolactate,orone molecule of pyruvate and one molecule of 2-ketobutyrate to 2-aceto-2-hydroxybutyrate ( Figure 1). This enzyme is found in plants,bacteria, and fungi but not in animals,m aking it an attractive target for biocide discovery.I ndeed, inhibitors of AHAS have been highly successful commercial herbicides for more than thirty years. [1] However,alack of clarity surrounds the mechanism of inhibition of AHAS by these herbicides.T he reaction has been reported to be time-dependent and biphasic, [2] corresponding to slow-binding inhibition. However,inAHAS,this process has only been observed under turnover conditions, [3] suggesting that there may be an alternative explanation for the observed time-dependent and biphasic inhibition profiles. Adding to the conjecture,t he inhibition of AHAS by herbicides has,i ns ome cases,b een reported to be irreversible, [2a,4] which is inconsistent with am echanism of slowbinding inhibition. In addition, it is also feasible that thiamin diphosphate (ThDP;aBreslow intermediate), ac ofactor in the active site,can participate in alternative reactions with the herbicide (for example by protonation of the enamine or by formation of the keto form through tautomerization), [5] thereby influencing inhibition.Herein, we report our investigations into the process of AHAS inhibition at suboptimal concentrations using penoxsulam (PS;F igure 1B), as al ead example of the triazolopyrimidine sulfonamide family of herbicides.T he kinetic curves (Figure 2A)resemble those reported previously for inhibitors of AHAS where the time dependence of the inhibition was accredited to reversible slow-binding inhibition. [2c,6] However, in this case,s low-binding inhibition is not involved because the amount of inhibition of AHAS at low concentrations of inhibitor exceeds stoichiometric equivalence.F or example,at ac oncentration of 25 nm,P Si nactivated approximately 1 mm ...

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“…This and related heterocyclic enaminols have collectively been called "Breslow intermediates." 4 Only recently have such compounds been rigorously characterized, 5,6 and new chemistry continues to be revealed. 7 We recently reported that Breslow intermediates such as 2a derived from N-allyl benzothiazolium bromide and aromatic aldehydes could be captured in a unique Claisen rearrangement to provide 2-butenyl benzothiazoles (Scheme 2, R=H).…”

Section: N-heterocyclic Carbene; Breslow Intermediate; Radical; Rearrmentioning

confidence: 99%

Radical [1,3] Rearrangements of Breslow Intermediates

Alwarsh

Qian

et al. 2015

Angewandte Chemie

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Breslow intermediates that bear radical stabilizing N-substituents including benzyl, cinnamyl, and diarylmethyl undergo facile homolytic C-N bond scission under mild conditions to give products of formal [1,3]-rearrangement rather than benzoin condensation. EPR experiments and computational analysis support a radical mechanism. Implications for thiamine based enzymes are discussed. Keywords N-heterocyclic carbene; Breslow intermediate; radical; rearrangement; thiamineThiamine diphosphate (TDP) is an essential cofactor for all living things. It is involved in several critical metabolic processes, including the tricarboxylic acid cycle, the pentose phosphate pathway, and amino acid catabolism. 1,2 In 1958, Ronald Breslow postulated that key intermediates in thiamine catalyzed enzymatic pathways included an N-heterocyclic carbene (1) and an enaminol, e.g. 2 (Scheme 1). 3 In pyruvate decarboxylation, for example, addition of the TDP carbene to pyruvate is followed by extrusion of CO 2 to provide unstable enaminol 2. This and related heterocyclic enaminols have collectively been called "Breslow intermediates." 4 Only recently have such compounds been rigorously characterized, 5,6 and new chemistry continues to be revealed. 7 We recently reported that Breslow intermediates such as 2a derived from N-allyl benzothiazolium bromide and aromatic aldehydes could be captured in a unique Claisen rearrangement to provide 2-butenyl benzothiazoles (Scheme 2, R=H). 8,9 In the course of examining the scope of the reaction, we were surprised to find that N-cinnamyl substituted salt 3b provided principally [1,3]-rearrangement product 4b upon reaction with benzaldehyde, accompanied by only ca. 5% of the nominal [3,3]-product. The [1,3]-rearrangement product clearly implied a stepwise process in competition with the concerted rearrangement.Correspondence to: Matthias C. McIntosh, mcintosh@uark.edu. Supporting information for this article is given via a link at the end of the document. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptReaction of N-benzyl and N-diphenylmethyl benzothiazolium salts under the same conditions also yielded [1,3]-rearrangement products, albeit in diminished yield in the case of benzyl salt 3c (Scheme 3). The structures were confirmed by X-ray crystallography.Many NHC catalyzed reactions of aldehydes are presumed to proceed via a Breslow intermediate, 10 so these observations are relevant to NHC catalysis and catalyst design. Since benzothiazolium salts are only occasionally employed as NHC catalysts, 11 we exposed thiazolium and triazolium salts to the reaction conditions (Scheme 4). Reaction of thiazolium salt 3e with benzaldehyde gave high yield of [1,3]-rearrangement product 4e, as well as a few percent of ketone 5e. Treatment of symmetrically substituted 1,2,4-triazole 3f provided rearrangement product 4f in low yield as the only isolable product, although interestingly as a single regioisomer resulting from migration of the N-4 substituent. No significant ...

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Umpolung by N‐Heterocyclic Carbenes: Generation and Reactivity of the Elusive 2,2‐Diamino Enols (Breslow Intermediates)

Cited by 170 publications

References 25 publications

An overview of N-heterocyclic carbenes

An overview of N-heterocyclic carbenes

Commercial Herbicides Can Trigger the Oxidative Inactivation of Acetohydroxyacid Synthase

Radical [1,3] Rearrangements of Breslow Intermediates

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