Organocatalyzed Decarboxylative Trifluoromethylation of β-Ketoacids

Abstract

A new protocol has been developed for the synthesis of α-trifluoromethyl ketones via organocatalyzed decarboxylative trifluoromethylation of β-ketoacids with Togni’s reagent. Among various simple amine catalysts, primary amines and secondary amines were identified to be more effective than tertiary amines, with piperazine being the most effective. Mechanistic investigations suggested that the primary or secondary amine-catalyzed reactions proceed mainly through trifluoromethylation of an enamine intermediate, which is more effective than the tertiary amine-catalyzed pathway that involves an enol intermediate. By using piperazine as the optimal organocatalyst, various β-ketoacids, including the sterically hindered α,α-disubstituted ones, were converted into the corresponding α-trifluoromethyl ketones in good yields. This research not only provides a useful strategy for the efficient synthesis of a wide range of α-trifluoromethyl ketones under mild conditions, but also constitutes one of the few studies on decarboxylative alkylation of β-ketoacids, which can intrigue further exploitation on organocatalyzed asymmetric decarboxylative alkylation reactions.

Graphical Abstract

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Notes

  1. 1.

    It was found that when 1 equiv of K2CO3 was used, the yield of 3a dropped dramatically to 13%, indicating that the carboxylate anion of 1a itself is not the reactive species for trifluoromethylation. In this context, we rationalized that 1a and its salt worked together to promote the trifluoromethylation, where the salt of 1a plays a similar role as TMEDA, for a plausible explanation, see the supplementary material.

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Acknowledgements

Support of our work by the National Basic Research Program of China (2015CB931900), the National Key Research and Development Program of China (2016YFB0101200 and 2016YFB0101204), the National Natural Science Foundation of China (21632009, 21472221, 21421002, 21402227, and 21372246), the Key Programs of the Chinese Academy of Sciences (KGZD-EW-T08), the Key Research Program of Frontier Sciences of CAS (QYZDJ-SSW-SLH049), Shanghai Academic Research Leader Program (15XD1504400), and the Youth Innovation Promotion Association CAS (2014231) is gratefully acknowledged.

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Correspondence to Jinbo Hu.

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In memory of Professor George A. Olah (1927–2017)

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1

Supplementary material 1 (DOCX 1334 KB). Results for Cu(OAc)2-catalyzed decarboxylative trifluoromethylation of β-ketoacids; NMR spectra of compounds 3

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Zhang, R., Ni, C., He, Z. et al. Organocatalyzed Decarboxylative Trifluoromethylation of β-Ketoacids. Top Catal 61, 664–673 (2018). https://doi.org/10.1007/s11244-018-0973-7

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Keywords

  • Organocatalysis
  • Trifluoromethylation
  • Carboxylic acids
  • Decarboxylation
  • β-Ketoacids
  • α-Trifluoromethyl ketones
  • Togni’s reagent
  • Piperazine