28168-40-3

Upstream product

• 47494-29-1 2-(1-hydroxybenzyl)thiamin kation 
• 100-52-7 benzaldehyde 
• 42784-82-7 2-{2-[2-(4-dimethylamino-2-methyl-pyrimidin-5-yl)-1-phenyl-vinyl]-4-methyl-thiazol-5-yl}-ethanol 

Downstream Products

• 6104-98-9 2-[2-(hydroxy-phenyl-methyl)-4-methyl-thiazol-5-yl]-ethanol 

Relevant academic research and scientific papers

Decomposition of 2-(1-hydroxybenzyl) thiamin in neutral aqueous solutions: benzaldehyde and thiamin are not the products

It has been reported that in neutral aqueous solutions, the adduct of benzaldehyde and thiamin, 2-(l-hydroxybenzyl)thiamin, HBzT (2), undergoes general base-catalyzed reversion to thiamin and benzaldehyde (E. J. Crane, III, and M. W. Washabaugh (1991) Bioorg. Chem.19, 351). An unusual mechanism had been invoked to explain the kinetic observations. In the present study, it is shown that in solutions of pH 8, HBzT fragments at the bridge methylene group to 2,5-dimethyl-4-amino-pyrimidine (3) and 2-benzoyl-5-(2-hydroxyethyl)-4-methylthiazole (4), not thiamin and benzaldehyde (which are the products at higher pH) (Scheme 3). Buffer catalysis is not observed where the products are thiamin and benzaldehyde. In neutral solution under conditions in which the products are 3 and 4, the reaction is general base-catalyzed. It is likely that catalysis assists the cleavage of the methylene bridge. Mechanistic proposals based on the elimination of benzaldehyde from HBzT in neutral and acidic solutions should be reconsidered. Copyright

Diverting thiamin from catalysis to destruction. Mechanism of fragmentation of N(1')-methyl-2-(1-hydroxybenzyl)thiamin

Thiamin (1) promotes reactions involving acyl carbanion equivalents derived from benzaldehyde through a covalent intermediate, 2-(1-hydroxybenzyl)thiamin (HBzT, 2). HBzT reverts to benzaldehyde and thiamin in alkaline solution. However, in neutral solutio

Deuterium labeling as a test of intramolecular hydride mechanisms in the fragmentation of 2-(1-hydroxybenzyl)-N1′-methylthiamin

2-(1-Hydroxybenzyl)-N1′-methylthiamin (1b) is a model for the addition intermediate in the thiamin catalyzed benzoin condensation. However, N-alkylation alters the reactivity of the compound: instead of undergoing base-catalyzed formation of benzaldehyde and N1′-methylthiamin, it rapidly forms trimethyl amino pyrimidine (2b) and phenylthiazole ketone (3). The base-catalyzed fragmentation process is faster than the analogous enzymic reaction (in benzoylformate decarboxylase) under the same conditions. One possible mechanism for the rapid fragmentation is an internal hydride transfer from α-C2 to the methylene bridge between the heterocycles. To test the hydride mechanism we prepared α-C2-deuterated 1b and conducted the fragmentation reaction in normal water. Spectroscopic analysis revealed that the trimethyl aminopyrimidine product does not contain any deuterium, ruling out a hydride transfer mechanism. This supports a mechanism for fragmentation that proceeds instead via a proton transfer from α-C2. Since protonation (and hence, deprotonation) of that site is part of the normal catalytic cycle of benzoylformate decarboxylase, the enzyme must divert the reaction from the lowest energy pathway since it would share a common intermediate with the fragmentation process.

Destruction of vitamin B1 by benzaldehyde. Reactivity of intermediates in the fragmentation of N1'-benzyl-2-(1- hydroxybenzyl)thiamin

Thiamin (vitamin B 1) combines with benzaldehyde in alkaline solutions to form 2-(1-hydroxybenzyl)thiamin (HBzT), a reactive intermediate in the thiamin-catalyzed benzoin condensation. In neutral solutions, HBzT fragments into pyrimidine and thiazole constituents by cleavage of the bridging methylene-thiazole bond. The fragmentation is promoted by protonation of the pyrimidine moiety of HBzT. The N1'-benzyl derivative of HBzT (4 in Scheme 4, BHT) also undergoes fragmentation in neutral and alkaline solutions, consistent with fragmentation being driven by positive charge on the pyrimidine derived from thiamin. Anionic Bronsted bases catalyze the reaction (β = 0.5, for a series of substituted acetates). The dependence of the observed first-order rate coefficient for fragmentation of BHT on buffer concentration is nonlinear, becoming buffer-independent at concentrations above 0.05 M. This is consistent with a change in rate-determining step with buffer concentration from proton removal to subsequent fragmentation of the conjugate base of BHT. The solvent isotope effect is inverse, also consistent with reversible formation of the conjugate base. Analysis of the kinetic data reveals that the fragmentation step is very fast (k(f) = 1.2 x 105 s-1 at 40 °C). Such a low barrier is consistent with electron-shift mechanisms for the fragmentation step.

Fast fragmentation and slow protonation: A buffer-dependent isotope effect in reactions of N-methyl hydroxy(benzylthiamine) analyzed by the Keeffe-Jencks equations

The fragmentation of 2-(1-hydroxybenzyl)thiamine in neutral solution (to cleave the pyrimidine and thiazolium) has been shown to compete very effectively with elimination of benzaldehyde to produce thiamine in neutral solution. The fragmentation is believed to involve protonation competing with C-N bond cleavage in the C2α conjugate base as a rate-determining step. We report that proton removal from C2α of N1′-methyl-2-(1-hydroxybenzyl) thiamine (MHBnT) is rate-limiting in low concentrations of pH 6 phosphate buffer: reprotonation competes with the subsequent fragmentation step (cleaving the pyrimidine-thiazolium bridge derived from thiamine) at higher buffer concentrations. Comparison of the observed rates of reaction of protio and C2α-deutero MHBnT reveals a non-linear variation of the kinetic isotope effect that fits precisely to a ratio derived from the Keeffe-Jencks rate law formulation for ElCB reactions. The fragmentation step is clearly distinct from the proton removal step and the isotope sensitivity is limited to the initial step. The variation of the isotope effect is a result of changes due to differing contributions from the hydroxide and buffer-catalyzed reaction mechanisms. Copyright

Decomposition of 2-(1-hydroxybenzyl)thiamin. Ruling out stepwise cationic fragmentation.

[reaction: see text] The rapid fragmentation of 2-(1-hydroxybenzyl)thiamin (1) is initiated by transfer of a proton from C2alpha to give an enamine. The subsequent irreversible process can be written as a concerted (or stepwise) rearrangement involving migration of the hydroxyl hydrogen to the methylene bridge. An attractive alternative is internal addition of C2alpha to the pyrimidine, generating a carbocation. However, addition of azide to the reaction solution, which could trap the carbocation, has no effect on the rate or products of reaction.

Reactivity of intermediates in benzoylformate decarboxylase: Avoiding the path to destruction

Benzoylformate decarboxylase forms a covalent intermediate from thiamin diphosphate (TDP) and benzoylformate, α-mandelylTDP. This loses carbon dioxide to form a carbanion (enamine). Protonation of the carbanion and elimination of benzaldehyde regenerate e

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

Mandelylthiamin (1) is a conjugate of benzoylformate and thiamin that loses CO2 to form the classic Breslow intermediate (2), whose expected fate is formation of the thiamin conjugate of benzaldehyde (3). Surprisingly, it was observed that 2 decomposes to 4 and 5 and rearranges to 6 in competition with the expected protonation to give 3. Recent reports propose that the alternatives to protonation arise from homolysis followed by radical-centered processes. It is now found, instead, that the spectroscopic observations cited in support of the proposed radical pathways are likely to be the result of other events. An alternative explanation is that ionization of the enolic hydroxy group of 2 and resultant electronic reorganization leads to C?C bond cleavage and non-radical intermediates that readily form 4, 5, and 6.