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Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes Rong Zhu, and Stephen L. Buchwald J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja305840g • Publication Date (Web): 17 Jul 2012 Downloaded from http://pubs.acs.org on July 18, 2012
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Journal of the American Chemical Society
Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes Rong Zhu and Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States Supporting Information Placeholder hypothesized that either a single electron oxidation of the radiABSTRACT: A mild, versatile and convenient method for the cal intermediate followed by trapping the resulting carbocation efficient oxytrifluoromethylation of unactivated alkenes has (Path A) or copper-mediated C−Nu bond formation (Path B) been developed based on a copper-catalyzed oxidative difuncwould lead to the desired difunctionalization product (III).8 tionalization strategy. This methodology provides access to a The success of this strategy lies in the identification of a catavariety of classes of synthetically useful CF3-containing buildlytic system efficient for both the C−CF3 bond formation and ing blocks from simple starting materials. the subsequent functionalization steps, as well as the ability to inhibit the competitive elimination pathway. Herein we describe a copper(I)/2,2’-biquinoline catalytic system that incorporates these qualities with oxygen-based nucleophiles. The incorporation of fluoroalkyl groups and particularly the We began our study by examining the reaction of 4trifluoromethyl (CF3) group in pharmaceutical and agrochemipentenoic acid (2a) in the presence of Togni’s reagent 19 and a cal relevant molecules has a significant impact on their physicatalytic amount of Cu(MeCN)4PF6 in methanol. Only allylic cal and biological properties, mainly because of the unique trifluoromethylated product 4a was observed in this case, sugmetabolic stability, lipophilicity and electron-withdrawing 1 gesting elimination as the major pathway (Table 1, entry 1). nature of the trifluoromethyl substituent. The importance of After examining the effects of solvents and additives, we CF3-containing compounds provides a continuing driving found that switching to acetonitrile, in the presence of a cataforce for the development of more efficient and versatile tri2 lytic amount of 2,2’-bipyridyl (L1), the desired oxytrifluorofluoromethylation methods. Our research group has focused methylation product 3a was obtained in 10% yield (entry 3). on the development of new fluorination3 and trifluoromethylaEncouraged by this result, we evaluated a series of different tion4 reactions using transition-metal catalysis. Herein we rebidentate pyridine-based ligands, which finally led to the idenport a mild and versatile copper-catalyzed oxytrifluoromethyltification of di-2-pyridylketone (L4) and 2,2’-biquinoline (L5) ation reaction of unactivated alkenes that allows rapid access as being optimal (entry 6 and 7). A nearly 90 % yield of 3a to a variety of CF3-containing building blocks from simple could be obtained in the presence of either L4 or L5, with only starting materials. trace of 4a observed. Both the copper salt and ligand proved to Recently, our group, as well as that of Liu and Wang, indebe essential in order for the oxytrifluoromethylation reaction pendently reported the copper-catalyzed allylic trifluoromethto take place as no 3a was observed in the absence of either of 4d,5 ylation of unactivated alkenes (Scheme 1). During the these components (entry 2 and 8). course of our studies, we proposed that this transformation Table 1. Ligand effect.a might involve either an α-CF -alkyl radical (I) or α-CF 3
3
alkylcopper species (II), which subsequently undergoes elimination to afford the allylic trifluoromethyl product. We became interested in the possibility of intercepting this putative intermediate (I or II), as a means for the synthesis of a number of structurally diverse CF3-containing building blocks in a step-economical fashion. Scheme 1. Copper-catalyzed trifluoromethylation of unactivated alkenes. O
R Cu(MeCN)4PF6 (15 mol%)
O
+
R
1
I CF3
HO
MeOH, 0 °C to RT
R
CF3
CF3
NuH
NuH
CF3
-1e
Path B
NuH
CF3
-
