Trifluoromethylation of Electron-Rich Alkenyl Iodides with Fluoroform-Derived "Ligandless" CuCF3.

We herein present a flexible approach for the incorporation of CF3 units into a predefined site of electron-rich alkenes that exploits the regiocontrolled introduction of an iodine handle and subsequent trifluoromethylation of the C(sp2)-I bond using fluoroform-derived "ligandless" CuCF3. The broad substrate scope and functional group tolerance together with the scalability and purity of the resulting products enabled the controlled, late-stage synthesis of single regioisomers of complex CF3-scaffolds, such as sugars, nucleosides (antivirals), and heterocycles (indoles and chromones), with potential for academic and industrial applications.

Well-defined CuC2F5 complexes and pentafluoroethylation of acid chlorides.

Four new well-defined Cu(I) complexes bearing a C2 F5 ligand have been prepared and fully characterized: [(Ph3 P)2 CuC2 F5 ] (2), [(bpy)CuC2 F5 ] (3), [(Ph3 P)Cu(phen)C2 F5 ] (4), and [(IPr*)CuC2 F5 ] (5). X-ray structures of all four have been determined, showing that the C2 F5 -ligated Cu atom can be di- (5), tri- (2 and 3), and tetracoordinate (4). The mixed phen-PPh3 complex 4 is a highly efficient fluoroalkylating agent for a broad variety of acid chlorides. This high-yielding transformation represents the first general method for the synthesis of RCOC2 F5 from the corresponding RCOCl.

The Trifluoromethyl Anion.

First evidence for the existence of free trifluoromethyl anion CF3 (-) has been obtained. The 3D-caged potassium cation in [K(crypt-222)](+) is inaccessible to CF3 (-) , thus rendering it uncoordinated ("naked"). Ionic [K(crypt-222)](+) CF3 (-) has been characterized by single-crystal X-ray diffraction, solution NMR spectroscopy, DFT calculations, and reactivity toward electrophiles.

Mechanism of trifluoromethylation of aryl halides with CuCF3 and the ortho effect.

A combined experimental (radical clock, kinetic, Hammett) and computational (DFT, MM) study of the trifluoromethylation reaction of aryl halides with CuCF3 reveals a nonradical mechanism involving Ar-X oxidative addition to the Cu(I) center as the rate determining step. The reaction is second order, first order in each reactant with ΔG(⧧) ≈ 24 kcal/mol for PhI (computed ΔG(⧧) = 21.9 kcal/mol). An abrupt change in the gradient on the Hammett plot of log(kR/kH) versus σp for 11 p-RC6H4I substrates produces two correlations (ρ = +0.69 and +1.83), which is temptingly suggestive of two different reaction pathways. Only one mechanism is operational, however, as advocated by a single linear correlation with σp(-) (ρ = +0.91), analysis of the experimental ρ values, close similarity of the transition states varying in R and displaying clear signs of -M interactions, and excellent reproduction of the plot by DFT. The long-known yet previously uncomprehended ortho effect has been quantified, for the first time, using the reaction of CuCF3 with a series of o-RC6H4Br: R(kR/kH) = H (1) < Me (3.5) < MeO (4) < CN (20) < CHO (250) < CO2Me (850) < NO2 (4300) < Ac (7300) < CO2H (150 000). With minor contributions from electronic factors, the ortho effect is largely determined by (i) the stabilizing coordination of the o-substituent to Cu in the transition state with the Cu···O distance varying directly with the barrier and (ii) the steric bulk of the o-substituent that raises the ground state free energy of the haloarene (G(o)ortho - G(o)H or G(o)ortho - G(o)para) by inflicting molecular strain and consequently weakening the Ar-X bond.

Cupration of C2F5H: isolation, structure, and synthetic applications of [K(DMF)2][(t-BuO)Cu(C2F5)]. Highly efficient pentafluoroethylation of unactivated aryl bromides.

Pentafluoroethane, C2F5H (HFC-125), is smoothly cuprated with preisolated or in situ-generated [K(DMF)][(t-BuO)2Cu] to give [K(DMF)2][(t-BuO)Cu(C2F5)] (1) in nearly quantitative yield. Complex 1 has been isolated, structurally characterized, and demonstrated to be an exceedingly versatile pentafluoroethylating reagent for a variety of substrates, including unactivated aryl bromides.

Trifluoromethylation of aryl and heteroaryl halides with fluoroform-derived CuCF3: scope, limitations, and mechanistic features.

Fluoroform-derived CuCF3 recently discovered in our group exhibits remarkably high reactivity toward aryl and heteroaryl halides, performing best in the absence of extra ligands. A broad variety of iodoarenes undergo smooth trifluoromethylation with the "ligandless" CuCF3 at 23-50 °C to give the corresponding benzotrifluorides in nearly quantitative yield. A number of much less reactive aromatic bromides also have been trifluoromethylated, including pyridine, pyrimidine, pyrazine, and thiazole derivatives as well as aryl bromides bearing electron-withdrawing groups and/or ortho substituents. Only the most electrophilic chloroarenes can be trifluoromethylated, e.g., 2-chloronicotinic acid. Exceptionally high chemoselectivity of the reactions (no side-formation of arenes, biaryls, and C2F5 derivatives) has allowed for the isolation of a large number of trifluoromethylated products in high yield on a gram scale (up to 20 mmol). The CuCF3 reagent is destabilized by CuX coproduced in the reaction, the magnitude of the effect paralleling the Lewis acidity of CuX: CuCl > CuBr > CuI. While S(N)Ar and S(RN)1 mechanisms are not operational, there is a well-pronounced ortho effect, i.e., the enhanced reactivity of ortho-substituted aryl halides 2-RC6H4X toward CuCF3. Intriguingly, this ortho-effect is observed for R = NO2, COOH, CHO, COOEt, COCH3, OCH3, and even CH3, but not for R = CN. The fluoroform-derived CuCF3 reagent and its reactions with haloarenes provide an unmatched combination of reactivity, selectivity, and low cost.

Trifluoromethylation of α-haloketones.

The C-X bond (X = Br, Cl) of α-haloketones is smoothly trifluoromethylated with the fluoroform-derived CuCF(3) reagent recently developed in our laboratories. This is the first nucleophilic α-trifluoromethylation reaction of carbonyl compounds and a rare example of CF(3)-C(sp(3)) coupling. The transformation employs only low-cost chemicals and cleanly occurs in up to 99% yield at room temperature, thereby providing an unprecedentedly easy entry to valuable 2,2,2-trifluoroethylketones.

An approach to the regioselective diamination of conjugated di- and trienes.

It's do or diaminate: The selective diamination of 1,3-butadienes in the presence of hypervalent iodine reagents has been developed. This oxidation process proceeds with complete selectivity in favor of diamination. Depending on the substrate, it proceeds either with 1,2- or 1,4-regioselectivity (see scheme).

Fluoroform-derived CuCF3 for low-cost, simple, efficient, and safe trifluoromethylation of aryl boronic acids in air.

Easy does it: Aryl boronic acids undergo smooth and selective trifluoromethylation with low-cost fluoroform-derived CuCF(3) in DMF in non-dried air. The reaction occurs under mild conditions (1 atm, room temperature), exhibits unprecedented functional-group tolerance, and affords trifluoromethylated aromatic compounds in up to 99 % yield.

Trifluoromethylation of arenediazonium salts with fluoroform-derived CuCF3 in aqueous media.

A new protocol has been developed for trifluoromethylation of arenediazonium salts with moisture-sensitive CuCF3 (from fluoroform) in aqueous media. The reaction is governed by a radical mechanism, tolerates a broad variety of functional groups, and is applicable to the synthesis of complex, polyfunctionalized molecules.

Iodine(III)-promoted intermolecular diamination of alkenes.

A rapid and productive vicinal diamination of alkenes takes place in the presence of a hypervalent iodine(III) reagent and bissulfonimides as nitrogen sources. A total of more than 60 examples are presented. The reaction is characterized by its robustness and its wide substrate scope: it proceeds selectively with both terminal and internal alkenes and tolerates a range of functional groups.

Metal-ligand bifunctional activation and transfer of N-H bonds.

The concept of metal-ligand bifunctionality can be employed for an efficient activation of N-H bonds by well-defined ruthenium amido complexes. An enantioselective catalytic aza-Michael reaction was developed on the basis of this process, which gives rise to indoline ß-amino acids.