New Thiazolium-Based Strategies for Acyl Anion Addition Reactions

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Two new strategies have been developed to accomplish direct nucleophilic acylation reactions. In the first approach, acylsilanes are added to various electrophiles using N-heterocyclic carbenes as catalysts. The second method utilizes O-silyl thiazolium carbinols as stoichiometric acyl anion precursors to afford acylated products under mild reaction conditions. N-heterocyclic carbenes generated in situ from thiazolium salts catalyze the addition of acylsilanes to α,β-unsaturated systems and N-phosphinoyl imines in the presence of alcohol additives. The resulting 1,4-diketones and α-amino ketones are isolated in high yields. The use of carbenes in these reactions is novel since it avoids anionic catalysts typically required to access acyl anion reactivity from acylsilanes. Benzoin side product formation is not observed in these processes strongly indicating that the acyl anion intermediate generated in the reaction does not add to another equivalent of acylsilane. Studies conducted to probe the potential reaction pathways of these processes included the independent preparation of an O-silyl thiazolium carbinol, a proposed reaction intermediate. All reactions conducted with this species provided evidence that it is an intermediate in the reaction pathway. The results of the experiments conducted with these unique carbinols demonstrate that these molecules are stable, stoichiometric acyl anion reagents. O-Silyl thiazolium carbinols operate as stoichiometric acyl anion equivalents when treated with fluoride. The notable features of these unusual acylating agents include their straightforward preparation, stability, and ease of handling. The direct nucleophilic acylation of nitroalkenes has been developed by combining these carbinols with a fluoride anion and thiourea. Importantly, this process has been rendered asymmetric when a chiral thiourea is added to the reaction. Similarly, the synthesis of α-aryl ketones by the direct nucleophilic acylation of o-quinone methides has been developed. In this new transformation, two reactive intermediates, acyl anions and o-quinone methides, are generated in the same flask upon treatment of the corresponding thiazolium carbinols and silyl-protected phenols with a fluoride source. This strategy has been used to facilitate a short synthesis of demethylmoracin I, a naturally occurring aromatase inhibitor. Finally, further experiments indicate that these carbinols can undergo productive nucleophilic additions to aldehydes for the synthesis of acyloin products.

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  • 05/14/2018
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