DOI: 10.1002/chem.201201707 Trifluoromethylation of Allylsilanes under Copper Catalysis Satoshi Mizuta, [a] Oscar Galicia-López, [a] Keary M. Engle, [a] Stefan Verhoog, [a] Katherine Wheelhouse, [b] Gerasimos Rassias, [b] and VØronique Gouverneur* [a] Medicinal chemists commonly incorporate a trifluorometh- yl group into druglike molecules to enhance binding selec- tivity, improve metabolic stability and increase lipophilici- ty. [1] To date, various methods are available for the introduc- tion of the CF 3 group onto functionalized arenes and hetero- arenes. [2] Numerous catalytic trifluoromethylation reactions of ketones or aldehydes have also been developed, leading to the formation of C sp 3–CF 3 bonds, including elegant asym- metric variants. [3] The construction of C sp 3–CF 3 stereogenicity from poorly activated substrates is less common. In this con- text, the direct selective installation of a CF 3 group on an al- lylic position remains a challenging synthetic problem. [4] Iso- lated examples of Pd-catalyzed trifluoromethylation of allyl- stannanes with CF 3 I [5] and Cu-mediated nucleophilic tri- fluoromethylation of allyl bromide using the Ruppert–Pra- kash reagent (CF 3 SiMe 3 ) are known, [6] giving linear allylic CF 3 products. Recently, Buchwald, [7] Wang, [8] and Liu [9] and their co-workers reported that terminal alkenes are amena- ble to allylic trifluoromethylation under copper catalysis, a reaction also affording linear allylic CF 3 products with very good control over E :Z geometry. Access to branched acyclic allylic CF 3 products has not been demonstrated, and only two branched cyclic products have been prepared through application of this C ÀH functionalization methodol- ogy. [7–9] To address this synthetic challenge, we reasoned that we could access allylic CF 3 products using alkenes tempora- rily activated with a regiodirecting silyl group. Since our first report in 2003, we have demonstrated that a diverse range of allylic fluorides are accessible upon electrophilic fluorination of allylsilanes under very mild conditions and have found that this reaction is broad in scope and tolerant of various functional groups. [10] The presence of the allylic trimethylsilyl group is essential to increase the nucleophilici- ty of the proximal alkene and to dictate the regiochemistry of the fluorination. Based on these principles and the availa- bility of various electrophilic trifluoromethylating re- agents [11] (e.g., hypervalent iodine reagents I and II, [12] and the sulfonium salts III [13] and IV [14] ), we describe herein a copper-catalyzed trifluoromethylation reaction to prepare various branched allylic CF 3 products from allylsilanes (Figure 1). Preliminary experiments with the model substrate 1a served to demonstrate that the trifluoromethylation of a silyl-activated alkene could be a valid route to access the allylic CF 3 product 2a. The trifluoromethylation of trimeth- yl(2-phenylallyl)silane (1a) with Togni)s reagent I was suc- cessfully performed in methanol at 70 8C in the presence of 20 mol % of CuCl. Compound 2a was isolated in 70 % yield. In the absence of CuCl, no reaction took place. A control experiment with a-methylstyrene established that the trime- thylsilyl (TMS) group is critical to induce allylic trifluorome- thylation. When this structurally related non-silylated pre- cursor was allowed to react under the same conditions as 1a, adduct 3 was isolated in 36 % yield with only 4 % of the desired product 2a (Scheme 1). With this result in hand, we next examined the trifluoro- methylation of allylsilane (Z)-1b, a substrate that would po- tentially lead to the allylic product 2b featuring C sp 3–CF 3 stereogenicity. Our optimization study is presented in Table 1. [15] In the absence of catalyst, no reaction took place [a] Dr. S. Mizuta, O. Galicia-López, K.M. Engle, S. Verhoog, Prof. V. Gouverneur Chemistry Research Laboratory University of Oxford 12, Mansfield Road, Oxford OX1 3TA (UK) E-mail : veronique.gouverneur@chem.ox.ac.uk [b] Dr. K. Wheelhouse, Dr. G. Rassias Medicines Discovery & Development GlaxoSmithKline R&D Gunnels Wood Road Stevenage SG1 2NY (UK) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201201707. Figure 1. Trifluoromethylation of allylsilanes. Chem. Eur. J. 2012, 00,0–0 # 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! ÞÞ &1& COMMUNICATION