Intercepting the Breslow Intermediate via Claisen Rearrangement: Synthesis of Complex Tertiary Alcohols without Organometallic Reagents

Alwarsh, Sefat; Ayinuola, Kolawole; Dormi, Silvana S.; McIntosh, Matthias C.

doi:10.1021/ol303053c

Cited by 17 publications

(11 citation statements)

References 45 publications

(35 reference statements)

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“…We recently reported that Breslow intermediates such as 2 a derived from N ‐allyl benzothiazolium bromide and aromatic aldehydes could be captured in a unique Claisen rearrangement to provide 2‐butenyl benzothiazoles (Scheme ; R=H) 8. 9 In the course of examining the scope of the reaction, we were surprised to find that N ‐cinnamyl‐substituted salt 3 b provided principally [1,3] rearrangement product 4 b upon reaction with the benzaldehyde, accompanied by only circa 5 % of the nominal [3,3] product.…”

Section: Methodsmentioning

confidence: 99%

Cover Picture: Hydroformylation in the Realm of Scents (ChemCatChem 2/2014)

Gusevskaya

Jiménez-Pinto²,

Börner

2014

ChemCatChem

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Breslow intermediates that bear radical‐stabilizing N substituents, such as 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‐based mechanism. Implications for thiamine‐based enzymes are discussed.

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Section: Methodsmentioning

confidence: 99%

Cover Picture: Hydroformylation in the Realm of Scents (ChemCatChem 2/2014)

Gusevskaya

Jiménez-Pinto²,

Börner

2014

ChemCatChem

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“…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.…”

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

confidence: 99%

“…From a synthetic perspective, this reaction extends the scope of complex 3° alcohols that can be prepared via Breslow intermediates beyond those that can participate in a Claisen rearrangement. 8 We note that the radical homolysis of Breslow intermediates may have implications in enzymology as well. Benzoylformate decarboxylase is a thiamine containing enzyme that catalyzes the conversion of benzoylformate to benzaldehyde and CO 2 .…”

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confidence: 95%

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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“…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.…”

mentioning

confidence: 99%

mentioning

confidence: 99%