Green Synthesis of Morpholines via Selective Monoalkylation of Amines.

Morpholines are common heterocycles in pharmaceutical and agricultural products, yet methods to synthesize them from 1,2-amino alcohols are inefficient. We report the simple, high yielding, one or two-step, redox neutral protocol using inexpensive reagents (ethylene sulfate and BuOK) for the conversion of 1,2-amino alcohols to morpholines. Key to this methodology is the identification of general conditions that allow for the clean isolation of monoalkylation products derived from a simple S2 reaction between an amine and ethylene sulfate.

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 ( and -) 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.

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.

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

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.

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).

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.

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.