Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012−2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes

Aminotrifluoromethylation of Olefins via Cyclic Amine Formation: Mechanistic Study and Application to Synthesis of Trifluoromethylated Pyrrolidines

We examined the mechanism of our previously reported aminotrifluoromethylation reaction, which proceeds via intramolecular cyclization of alkenylamines in the presence of the combination of copper catalyst and Togni reagent (<b>1</b>). Kinetic studies revealed that the initial rate of the reaction was first order with respect to Togni reagent and CuI, as well as the substrate. Changes of the ¹⁹F NMR chemical shift of Togni reagent during the reaction suggested the existence of a dynamic equilibrium involving coordination of not only Togni reagent, but also the substrate amine and the product aziridine to copper. ESI-MS analysis provided evidence of involvement of reactive Cu­(II) intermediates in the catalytic cycle. Overall, our results indicate that the reaction proceeds at the hypervalent iodine moiety of Togni reagent, which is activated by Cu­(II) species acting as a Lewis acid catalyst. On the basis of these mechanistic considerations, we developed an efficient synthesis of trifluoromethylated pyrrolidine derivatives. This transformation exhibited a remarkable rate enhancement upon addition of Et₃N

Aminotrifluoromethylation of Olefins via Cyclic Amine Formation: Mechanistic Study and Application to Synthesis of Trifluoromethylated Pyrrolidines

We examined the mechanism of our previously reported aminotrifluoromethylation reaction, which proceeds via intramolecular cyclization of alkenylamines in the presence of the combination of copper catalyst and Togni reagent (<b>1</b>). Kinetic studies revealed that the initial rate of the reaction was first order with respect to Togni reagent and CuI, as well as the substrate. Changes of the ¹⁹F NMR chemical shift of Togni reagent during the reaction suggested the existence of a dynamic equilibrium involving coordination of not only Togni reagent, but also the substrate amine and the product aziridine to copper. ESI-MS analysis provided evidence of involvement of reactive Cu­(II) intermediates in the catalytic cycle. Overall, our results indicate that the reaction proceeds at the hypervalent iodine moiety of Togni reagent, which is activated by Cu­(II) species acting as a Lewis acid catalyst. On the basis of these mechanistic considerations, we developed an efficient synthesis of trifluoromethylated pyrrolidine derivatives. This transformation exhibited a remarkable rate enhancement upon addition of Et₃N

Hypophosphatemia occurs with insulin administration during refeeding by total parenteral nutrition in rats

Refeeding syndrome (RFS) is characterized by the metabolic and clinical changes that occur following aggressive nutritional supplementation in malnourished patients. Hypophosphatemia is the hallmark of RFS and is key to its prevention and treatment in clinical practice. However, the mechanism of hypophosphatemia during RFS is unclear because of the lack of an animal model. In this study,we developed a rat RFS model as a first step to clarifying the molecular mechanism. After establishing the parenteral route, rats were fasted for 5 days and refeeding was started using total parenteral nutrition. The animals were infused with a high calorie solution with or without insulin administration. Results showed that plasma phosphate levels did not decrease in rats infused with the high calorie solution alone ; in contrast, a 20% reduction compared to baseline was observed in rats administered insulin. In addition, rats infused with the high calorie solution containing added phosphate did not present with hypophosphatemia. Thus, we developed a rat RFS model with hypophosphatemia by tube feeding and insulin administration, and demonstrated the importance of phosphate in preventing refeeding hypophosphatemia

<i>N</i>‑Heterocycle-Forming Amino/Carboperfluoroalkylations of Aminoalkenes by Using Perfluoro Acid Anhydrides: Mechanistic Studies and Applications Directed Toward Perfluoroalkylated Compound Libraries

This work describes a practical and efficient method for synthesizing a diverse array of perfluoroalkylated amines, including <i>N</i>-heterocycles, to afford perfluoroalkylated chemical libraries as potential sources of drug candidates, agrochemicals, and probe molecules for chemical-biology research. Perfluoro acid anhydrides, which are commonly used in organic synthesis, were employed as a perfluoroalkyl source for intramolecular amino- and carbo-perfluoroalkylations of aminoalkenes, affording perfluoroalkylated <i>N</i>-heterocycles, including: aziridines, pyrrolidines, benzothiazinane dioxides, indolines, and hydroisoquinolinones. Diacyl peroxides were generated <i>in situ</i> from the perfluoro acid anhydrides with urea·H₂O₂, and allowed to react with aminoalkenes in the presence of copper catalyst to control the product selectivity between amino- and carbo-perfluoroalkylations. To illustrate the synthetic utility of bench-stable trifluoromethylated aziridine, which was prepared on a gram scale, we used it to synthesize a wide variety of trifluoromethylated amines including complex molecules, such as trifluoromethylated tetrahydroharmine and spiroindolone. A mechanistic study of the role of the copper catalyst in the aminotrifluoromethylation of allylamine suggested that Cu­(I) accelerates CF₃ radical formation via decomposition of diacyl peroxide, which appears to be the turnover-limiting step, while Cu­(II) controls the product selectivity