Radical [1,3] Rearrangements of Breslow Intermediates

Abstract

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 ...

The Need for an Alternative to Radicals as the Cause of Fragmentation of a Thiamin‐Derived Breslow Intermediate

“…Since we can detect the presence of fragmentation products at about 1 mol %, the rate constant for reaction of 4‐hydroxy‐TEMPO with 2 must be at least 10 6 s −1 . This suggests why McIntosh and co‐workers do not isolate TEMPO‐radical conjugates …”

The Need for an Alternative to Radicals as the Cause of Fragmentation of a Thiamin‐Derived Breslow Intermediate

“…They ascribe the results to reactions of radicals from homolysis of the Breslow intermediate observed in EPR spectra and computations. They propose that radicals lead to the products from 1 in Scheme , both the rearrangement and fragmentation forming via a radical pair from homolysis of the Breslow intermediate (Scheme ) . Recombination and disproportionation lead to both sets of products.…”

“…These potential side reactions and lack of controls permit neither confident assignment of a signal to the proposed radical pair nor a basis for quantitation. Attempts to detect or isolate TEMPO adducts that would be expected from radicals also gave negative results …”

Metal-Free and Selective Oxidation of Furfural to Furoic Acid with an N-Heterocyclic Carbene Catalyst

“…The carbene species generated in situ then reacts with furfural to form a highly reactive Breslow intermediate 3. 34,35 Complex formation between the intermediate 3 and molecular O 2 readily proceeds if O 2 is present in the reaction mixture, which affords complex 4. Heat treatment enhances the reaction of activated O 2 in complex 4 with an additional furfural molecule and gives two furoic acid molecules through the formation of complexes 5 and 6, and finally, the active carbene species can be recovered on BTIC.…”