Regioselective Syntheses of 2,3,5-Trisubstituted Pyridines via 5-Chloro-3-fluoro-2-(methylsulfonyl)pyridine.

We report the high-yielding, large-scale, one-pot synthesis of two versatile building blocks (1-Cl and 1-Br) for the regioselective synthesis of a variety of 2,3,5-trisubstituted pyridines from inexpensive materials. These molecules are readily derivatized at positions 2, 3, and 5. These building blocks can also be used for the synthesis of fused pyrido-oxazines and for the synthesis of 2,3,4,5-tetrasubstituted pyridines.

Mediator-Enabled Electrocatalysis with Ligandless Copper for Anaerobic Chan-Lam Coupling Reactions.

Simple copper salts serve as catalysts to effect C-X bond-forming reactions in some of the most utilized transformations in synthesis, including the oxidative coupling of aryl boronic acids and amines. However, these Chan-Lam coupling reactions have historically relied on chemical oxidants that limit their applicability beyond small-scale synthesis. Despite the success of replacing strong chemical oxidants with electrochemistry for a variety of metal-catalyzed processes, electrooxidative reactions with ligandless copper catalysts are plagued by slow electron-transfer kinetics, irreversible copper plating, and competitive substrate oxidation. Herein, we report the implementation of substoichiometric quantities of redox mediators to address limitations to Cu-catalyzed electrosynthesis. Mechanistic studies reveal that mediators serve multiple roles by (i) rapidly oxidizing low-valent Cu intermediates, (ii) stripping Cu metal from the cathode to regenerate the catalyst and reveal the active Pt surface for proton reduction, and (iii) providing anodic overcharge protection to prevent substrate oxidation. This strategy is applied to Chan-Lam coupling of aryl-, heteroaryl-, and alkylamines with arylboronic acids in the absence of chemical oxidants. Couplings under these electrochemical conditions occur with higher yields and shorter reaction times than conventional reactions in air and provide complementary substrate reactivity.

Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reaction in Flow.

The application of a Buchwald's third generation palladacycle containing a dihydrobenzooxaphosphole-based ligand (e.g., BIDIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

Mechanism of the Ullmann Biaryl Ether Synthesis Catalyzed by Complexes of Anionic Ligands: Evidence for the Reaction of Iodoarenes with Ligated Anionic CuI Intermediates.

A series of experimental studies, along with DFT calculations, are reported that provide a detailed view into the mechanism of Ullmann coupling of phenols with aryl halides in the presence of catalysts generated from Cu(I) and bidentate, anionic ligands. These studies encompass catalysts containing anionic ligands formed by deprotonation of 8-hydroxyquinoline, 2-pyridylmethyl tert-butyl ketone, and 2,2,6,6-tetramethylheptane-3,5-dione. Three-coordinate, heteroleptic species [Cu(LX)OAr]- were shown by experiment and DFT calculations to be the most stable complexes in catalytic systems containing 8-hydroxyquinoline or 2-pyridylmethyl tert-butyl ketone and to be generated reversibly in the system containing 2,2,6,6-tetramethylheptane-3,5-dione. These heteroleptic complexes were characterized by a combination of 19F NMR, 1H NMR, and UV-vis spectroscopy, as well as ESI-MS. The heteroleptic complexes generated in situ react with iodoarenes to form biaryl ethers in high yields without evidence for an aryl radical intermediate. Measurements of 13C/12C isotope effects showed that oxidative addition of the iodoarene occurs irreversibly. This information, in combination with the kinetic data, shows that oxidative addition occurs to the [Cu(LX)OAr]- complexes and is turnover-limiting. A Hammett analysis of the effect of phenoxide electronic properties on the rate of the reaction of [Cu(LX)OAr]- with iodotoluene also is consistent with oxidative addition of the iodoarene to an anionic phenoxide complex. Calculations by DFT suggest that this oxidative addition is followed by dissociation of I- and reductive elimination of the biaryl ether from the resulting neutral Cu(III) complex.

Fluorodecarboxylation for the Synthesis of Trifluoromethyl Aryl Ethers.

The synthesis of mono-, di-, and trifluoromethyl aryl ethers by fluorodecarboxylation of the corresponding carboxylic acids is reported. AgF2 induces decarboxylation of aryloxydifluoroacetic acids, and AgF, either generated in situ or added separately, serves as a source of fluorine to generate the fluorodecarboxylation products. The addition of 2,6-difluoropyridine increased the reactivity of AgF2 , thereby increasing the range of functional groups and electronic properties of the aryl groups that are tolerated. The reaction conditions used for the formation of trifluoromethyl aryl ethers also served to form difluoromethyl and monofluoromethyl aryl ethers.

Palladium-Catalyzed Arylation of Fluoroalkylamines.

We report the synthesis of fluorinated anilines by palladium-catalyzed coupling of fluoroalkylamines with aryl bromides and aryl chlorides. The products of these reactions are valuable because anilines typically require the presence of an electron-withdrawing substituent on nitrogen to suppress aerobic or metabolic oxidation, and the fluoroalkyl groups have steric properties and polarity distinct from those of more common electron-withdrawing amide and sulfonamide units. The fluoroalkylaniline products are unstable under typical conditions for C-N coupling reactions (heat and strong base). However, the reactions conducted with the weaker base KOPh, which has rarely been used in cross-coupling to form C-N bonds, occurred in high yield in the presence of a catalyst derived from commercially available AdBippyPhos and [Pd(allyl)Cl]2. Under these conditions, the reactions occur with low catalyst loadings (<0.50 mol % for most substrates) and tolerate the presence of various functional groups that react with the strong bases that are typically used in Pd-catalyzed C-N cross-coupling reactions of aryl halides. The resting state of the catalyst is the phenoxide complex, (BippyPhosPd(Ar)OPh); due to the electron-withdrawing property of the fluoroalkyl substituent, the turnover-limiting step of the reaction is reductive elimination to form the C-N bond.

Site-selective aliphatic C-H bromination using N-bromoamides and visible light.

Transformations that selectively functionalize aliphatic C-H bonds hold significant promise to streamline complex molecule synthesis. Despite the potential for site-selective C-H functionalization, few intermolecular processes of preparative value exist. Herein, we report an approach to unactivated, aliphatic C-H bromination using readily available N-bromoamide reagents and visible light. These halogenations proceed in useful chemical yields, with substrate as the limiting reagent. The site selectivities of these radical-mediated C-H functionalizations are comparable (or superior) to the most selective intermolecular C-H functionalizations known. With the broad utility of alkyl bromides as synthetic intermediates, this convenient approach will find general use in chemical synthesis.

Enantioselective intermolecular [2 + 2 + 2] cycloadditions of ene-allenes with allenoates.

An enantioselective [2 + 2 + 2] cycloaddition of ene-allenes with allenoates is described, which transforms simple π-components into stereochemically complex carbocycles in a single step. The rhodium(I)-catalyzed cycloaddition proceeds with good levels of enantioselectivity, and with high levels of regio-, chemo-, and diastereoselectivity. Our results are consistent with a mechanism involving an enantioselective intermolecular allene-allene oxidative coupling.