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Synfacts 2014; 10(1): 0013
DOI: 10.1055/s-0033-1340420
Synthesis of Heterocycles
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 2-Trifluoromethylquinolines via a [2+3] Cycloaddition

Contributor(s):
Victor Snieckus
,
Suneel P. Singh (Snieckus Innovations)
Li Y, Zhang L, Zhang L, Wu Y, * Gong Y. * Shanghai Institute of Organic Chemistry, Huazhong University of Science and Technology, Wuhan, and Shanghai University, P. R. of China
Cu-Catalyzed Tandem Reactions of Fluorinated Alkynes with Sulfonyl Azides En Route to 2-Trifluoromethylquinolines.

Org. Biomol. Chem. 2013;
11: 7267-7270
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Publication History

Publication Date:
13 December 2013 (online)

 
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Key words

quinolines - trifluoromethyl group - copper catalysis - ketenimines - [2+3] cycloaddition

Significance

Reported is the synthesis of 2-tri­fluoromethyl quinolines 3 and 4 via a copper-catalyzed Huisgen [2+3]-cycloaddition reaction of sulfonyl azides 2 with terminal alkynes 1. The starting material 1 was obtained by the reaction of 2,2,2-trifluoro-N-phenylacetimidoyl chloride with [(trimethylsilyl)ethynyl]magnesium bromide, followed by trimethylsilyl deprotection. Optimum reaction conditions, as presented in the scheme, were used to obtain a variety of quinolines (3). Alkynes 1 containing electron-withdrawing groups as R1 resulted in poor yield; those with electron-donating groups as R1 resulted in moderate to good yields. Compound 3 was isolated as a mixture of isomers (C-5/C-7 from 1:1.7 to 1:1.8) when a meta substituent as R1 on 1 was used. The method was also extended to the synthesis of 2-perfluoroalkylated quinolines (R2 = C2F5, C3F7) and related analogous (R2 = CF2Br, CF2Cl). Use of phosphoryl azide instead of 2 under similar conditions resulted in the formation of 4. A mechanism involving a copper-catalyzed azide–alkyne cycloaddition, followed by the loss of N2 to give intermediate aza-allene A, and followed by electrocyclic ring closure to quinolines 3 was proposed without experimental evidence.


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Comment

The importance of the trifluoromethyl group in drug discovery programs has resulted in the development of new and improved methods for the introduction of CF3 groups onto (hetero)arenes. Although recent focus has been on the transition-metal-mediated cross-couplings and direct C–H trifluoromethylations (see Reviews below), methods such as the present one provide competitive alternatives, especially when suitable starting material can be obtained easily. The current method can tolerate a wide range of functional groups, but the yield is lower with electron-poor alkynes. Also, this method was not tested on internal alkynes.


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Reviews

X.-F. Wu, H. Neumann, M. Beller Chem. Asian J. 2012, 7, 1744–1754; H. Liu, Z. Gu, X. Jiang Adv. Synth. Catal. 2013, 355, 617–626; T. Besset, C. Schneider, D. Cahard ­Angew. Chem. Int. Ed. 2012, 51, 5048–5050.


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