The Productive Merger of Iodonium Salts and Organocatalysis: A Non-photolyticApproach to the Enantioselective r-Trifluoromethylation of AldehydesAnna E. Allen and David W. C. MacMillan*Merck Center for Catalysis, Princeton UniVersity, Princeton, New Jersey 08544Received January 27, 2010; E-mail: [email protected] the realm of drug design, the stereospecific incorporation ofpolyfluorinated alkyl substituents is a powerful and widely employed tacticto enhance binding selectivity, elevate lipophilicity, and/or circumventmetabolism issues arising from in vivo C-H bond oxidation.1In particular,the catalytic production of CF3-containing stereogenicity has become amethodological goal of central importance to practitioners of chemicaland pharmaceutical synthesis.2Recently, we reported the first highlyenantioselective R-trifluoromethylation of aldehydes using photoredoxorganocatalysis, a protocol that employs fluorescent household lights togenerate · CF3radicals that can intercept stereofacially biased enamines(eq 1).2aIn this communication, we describe a new mechanistic (non-photolytic) approach to the same product class via the merger of Lewisacid and organocatalysis with an electrophilic trifluoromethyl alkylatingreagent (eq 2).3,4Through this alternative chemical pathway, enantioen-riched R-trifluoromethylated aldehydes (and R-CF3carbonyl buildingblocks) can be generated under mild reaction conditions using com-mercially available,5bench-stable6reagents and catalysts without therequirement of a light source.Inspired by the recent studies of Togni, we hypothesized that 3,3-dimethyl-1-trifluoromethyl-1,2-benziodoxole (Togni’s reagent, 1) mightfunction as a trifluoromethylation agent for enamine-activated aldehydesin a manner analogous to that observed for the racemic R-alkylation ofnitroesters, β-ketoesters, silyl enol ethers, and silyl ketene acetals.3Since1 is generally considered to be an electrophilic species that enables C-CF3bond formation via an iodonium addition/reductive elimination mechanism,we felt that such hypervalent iodonic reagents might also functionsuccessfully in enamine catalysis.7As described in Scheme 1, weenvisioned that 1 should undergo Lewis acid-catalyzed bond cleavage togenerate the highly electrophilic iodonium salt 2. At the same time,condensation of amine catalyst 3 with an aldehyde substrate shouldgenerate a chiral enamine 4 that is sufficiently π-electron-rich to participatein an enantioselective C-I bond formation with 2 via a closed-shellpathway. In accord with similar mechanisms described by Togni3eandBaran,8we expected the resulting λ3-iodane species 5 to rapidly undergoreductive elimination with stereoretentive alkyl transfer, a step that wouldforge the critical C-CF3bond. Bifurcation of iminium ion 6 via hydrolysiswould then liberate the imidazolidinone catalyst 3 along with the desiredR-formyl CF3product. As described in previous studies,9we presumedthat high levels of enantioinduction should be possible using catalyst 3on the basis of enamine olefin geometry control and selective Si-facialexposure (via benzyl shielding of the Re face of enamine 4).The proposed R-formyl trifluoromethylation was first evaluated usinghydrocinnamaldehyde, imidazolidinone 3, and a series of Lewis acids at-20 °C (Table 1). To our delight, this new transformation was found toTable 1. Effect of the Lewis Acid Catalyst on R-Trifluoromethylationentry Lewis acid % yielda%eeb1 none 14 922 FeCl37893CuCl2c39 874 Sc(OTf)348 645 Zn(NTf2)252 666 Sm(OTf)366 537 FeCl280 878 FeCl2+ tert-amyl alcohol 76 919CuClc86 94aDetermined by19F NMR spectroscopy using an internal standard.bEnantiomeric excess was determined by chiral HPLC analysis of thecorresponding alcohol.cUsing 5 mol % Lewis acid.Scheme 1. Proposed Mechanism for Direct R-TrifluoromethylationPublished on Web 03/18/201010.1021/ja100748y  2010 American Chemical Society49869J. AM. CHEM. SOC. 2010, 132, 4986–4987be both high yielding and enantioselective using catalytic Fe(II) or Cu(I)salts. Interestingly, the use of stronger Lewis acids led to markedly lowerlevels of enantiomeric excess, presumably because of a post-reactionracemization pathway. Indeed, the addition of tert-amyl alcohol was foundto rescue the product optical purity in the case of the FeCl2system(presumably via in situ hemiacetal formation; entries 7 and 8).10Thesuperior levels of enantiocontrol and reaction yield obtained with CuCland imidazolidinone 3 at -20 °C prompted us to select these conditionsfor further exploration.As highlighted in Table 2, these mild Lewis acid-organocatalyticconditions tolerate a wide range of functional groups in this R-trifluorom-ethylation protocol, including aryl rings, ethers, esters, carbamates, andimides (entries 1-8; 71-87% yield, 93-96% ee). Sterically demandingaldehydes (R ) 4-piperidinyl, cyclohexyl, adamantyl) were also accom-modated with little impact on the yield or enantiocontrol (entries 8-10;70-80% yield, 94-97% ee). In addition, enantiopure β-chiral substratescan be used for the diastereoselective construction of either the syn-oranti-R,β-disubstituted products, highlighting the remarkable catalyst controlof these alkylations (entries 11 and 12; 19-20:1 dr). It should be notedthat catalyst 3 was ineffective in our photolytic trifluoromethylationstudies,2aproviding further evidence that the protocol described hereindoes not involve a radical pathway.To highlight the utility of enantioenriched R-CF3aldehydes, weundertook their conversion to a variety of valuable organofluorinesynthons. As outlined in Scheme 2, in situ reduction or oxidationof the formyl group creates enantioenriched β-CF3alcohols orR-CF3carboxylic acids with excellent stereofidelity. Moreover,reductive amination of these R-CF3aldehydes provides β-CF3amines with only a slight reduction in optical purity (86% ee).In summary, we have introduced a new mechanistic approach tothe enantioselective R-trifluoromethylation of aldehydes using onlycommercially available reagents. We expect that this paradigm ofmerging asymmetric organocatalysis (and Lewis acids) with iodoniumsalts will be broadly useful across many reaction types.Acknowledgment. Financial support was provided by NIGMS(R01 01 GM093213-01) and kind gifts from Merck and Amgen.A.E.A. thanks the Natural Sciences and Engineering ResearchCouncil (NSERC) for a predoctoral fellowship (PGS D).Supporting Information Available: Experimental procedures,structural proofs, and