Thiazolium catalyzed acyl anion

Figure 2 Thiazolium Catalyzed Acyl Anion Additions...

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde... 

A different approach toward highly substituted pyrroles involving a one-pot sila-Stetter/Paal-Knorr strategy was realized by Bharadwaj and Scheidt (Scheme 6.182) [343]. In this multicomponent synthesis, catalyzed by a thiazolium salt, an acyl anion conjugate addition reaction of an acylsilane (sila-Stetter) was coupled in situ with the conventional Paal-Knorr approach. Employing microwave conditions at 160 °C for 15 min, the acylsilane was combined with the cx/l-unsaturated ketone in... 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

Mattson AE, Bharadwaj AR, Zuhl AM, Scheldt KA (2006a) Thiazolium-catalyzed additions of acylsilanes a general strategy for acyl anion addition reactions. J Org Chem 71 5715-5724... 

In a different approach, the reactivity of thiazolium salts derived acyl anion equivalents (biological active aldehyde ) toward sulfur electrophiles has been examined recently (329) and provides a model for the thioester-forming step catalyzed by the lipoic acid containing enzymes. The results suggest that the biological generation of thioesters of coenzyme A from a-keto acids occurs via the direct reductive acylation of enzyme-bound lipoic acid by the active aldehyde, as already shown on page 453. 

Abstract The discovery and development of new A-heterocyclic carbene-catalyzed reaction is described. Based on inspiration from nature, we have taken thiazolium-based approaches to umpolung reactivity and invented a suite of related reactions involving acyl anions, homoenolate, and enolate nucleophiles all generated under catalytic conditions. 

In addition, the use of thiazolium catalyzed processes to prepare conq)ounds which are the result of an acyl anion addition reaction have shown utility in synthetic organic chemistry. The benzoin condensation (21-24) and the Stetter reaction (25-27) represent two of the most powerful exan5>les of these types of transformations (Figure 2.). 

Evaluation of the four routes discussed above revealed that the acyl anion addition provided the most convergent approach to this compound and was selected for further development. While the route disclosed in Scheme 5 provides the desired product in four steps, a more convergent approach may arise from introducing the amine side chain earlier in the sequence (i.e. in the pyridine aldehyde). Thus to optimize this route we would need to have a practical synthesis of 2-[(l-phenylethyl)amino]-4-pyridinecarboxaldehyde 19, optimize and understand the thiazolium catalyzed cross coupling process, and investigate the Cbz-deprotection and final salt formation... 

Masked acyl anions feature as reactive intermediates in the dimerization of aldehydes to a-hydroxyketones catalyzed by thiazolium salts. Thiazole is a heteroaromatic compound (Section 25-4) containing sulfur and nitrogen. The salts are derived from thiazoles by alkylation at nitrogen and contain a resonance-stabilized positive charge (margin). 

In Summary a-Hydroxyketones are available from addition of masked acyl anions to aldehydes and ketones. The conversion of aldehydes into the anions of the corresponding 1,3-dithiacyclohexanes (1,3-dithianes) illustrates the method of reverse polarization. The electrophilic carbon changes into a nucleophilic center, thereby allowing addition to an aldehyde or ketone carbonyl group. Thiazolium ions catalyze the dimerization of aldehydes, again through the transformation of the carbonyl carbon into a nucleophilic atom. 

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