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Synthesis 2010(11): 1865-1882  
DOI: 10.1055/s-0029-1218745
SPECIALTOPIC
© Georg Thieme Verlag Stuttgart ˙ New York

Trifluoromethylation of Organic Compounds and Related Reactions

Kazuyuki Sato, Atsushi Tarui, Masaaki Omote, Akira Ando*, Itsumaro Kumadaki*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
Fax: +81(72)8507020; e-Mail: aando@pharm.setsunan.ac.jp; e-Mail: kumadaki@ba2.so-net.ne.jp;
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Publication History

Received 1 March 2010
Publication Date:
23 April 2010 (online)

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Abstract

This review concentrates on trifluoromethylation and related reactions from the authors’ group. Mainly, our new rhodium complex catalyzed synthesis of trifluoromethyl and other fluorine compounds will be discussed. However, initially we would like to discuss the origins and development of this reaction. Thus, trifluoromethylation of aromatic and aliphatic halides with trifluoromethyl iodide in the presence copper powder will be discussed first, and then the application of this copper-mediated reaction to ethyl bromodifluoroacetate for the synthesis of difluoromethylene compounds will be presented. The investigation of the mechanism of this reaction led us to the Michael addition of the (ethoxycarbonyl)difluoromethyl group to α,β-unsaturated carbonyl compounds. To improve this reaction, we examined the rhodium-catalyzed Michael reaction, and found that the fluorine substituent was introduced surprisingly not to the β-position but to the α-position. This reaction could be used to introduce other fluoroalkyl groups, including­ the trifluoromethyl group, to the α-position of almost all Michael acceptors. Furthermore, this reaction was developed for the introduction of the trifluoromethyl or other fluoroalkyl groups into the α-position of ketones or carboxylic acid derivatives through silyl­ enol ethers or ketene silyl acetals.

1 Introduction

2 Trifluoromethylation Using Trifluoromethyl Iodide and Copper Powder

3 Copper-Mediated Reactions of Ethyl Bromodifluoroacetate

3.1 Coupling Reactions with Alkenyl and Aryl Iodides

3.2 Michael Reaction

4 Rhodium-Catalyzed Reactions

4.1 Attempted Michael-Type Reaction, and a New Type of Reaction­: Introduction of a Fluorine Substituent to the
α-Position of a Carbonyl Group

4.2 Extension of the α-Substitution Reaction to Trifluoro­methylation

4.3 Other α-Perfluoroalkylations of α,β-Unsaturated Ketones

5 Perfluoroalkylation of Ketones via Silyl Enol Ethers

5.1 Reaction of Long-Chain Perfluoroalkyl Iodides

5.2 Improvement of the Reaction for Trifluoromethylation with Diethylzinc

5.3 α-Trifluoromethylation of Other Carbonyl Compounds

5.4 α-Perfluoroalkylation of Other Carbonyl Compounds

6 Conclusion

Key words

trifluoromethylation - perfluoroalkylation - trifluoromethyl iodide - perfluoroalkyl iodide - α,β-unsaturated ketones - silyl enol ethers - rhodium complexes - diethylzinc