Pd-catalyzed Suzuki-type cross-coupling of 2-pyridyl carbamoyl fluorides.

We describe a palladium-catalyzed Suzuki-type cross-coupling reaction of 2-pyridyl carbamoyl fluorides with boronic acids, which provides entry to medicinally relevant pyridyl amides. Mechanistic studies, including the synthesis and reactivity of carbamoyl Pd-F complexes, reveal the importance of both the fluoride electrophile and nitrogen directing group for aiding reactivity.

Fluoride-Catalyzed Cross-Coupling of Carbamoyl Fluorides and Alkynylsilanes.

We report the synthesis of alkynamides via the cross-coupling of carbamoyl fluorides and alkynylsilanes catalyzed by tetrabutylammonium fluoride (TBAF). In contrast to previously reported transformations of carbamoyl fluorides, C-F bond cleavage is achieved under exceptionally mild conditions (room temperature, low catalyst loadings, and short reaction times) without the need for strongly nucleophilic reagents and/or catalysts. This method offers distinct advantages over transition-metal-catalyzed approaches, such as tolerance to aryl halide moieties and complementary chemoselectivity.

BF3-Catalyzed Intramolecular Fluorocarbamoylation of Alkynes via Halide Recycling.

A BF3-catalyzed atom-economical fluorocarbamoylation reaction of alkyne-tethered carbamoyl fluorides is reported. The catalyst acts as both a fluoride source and Lewis acid activator, thereby enabling the formal insertion of alkynes into strong C-F bonds through a halide recycling mechanism. The developed method provides access to 3-(fluoromethylene) oxindoles and γ-lactams with excellent stereoselectivity, including fluorinated derivatives of known protein kinase inhibitors. Experimental and computational studies support a stepwise mechanism for the fluorocarbamoylation reaction involving a turnover-limiting cyclization step, followed by internal fluoride transfer from a BF3-coordinated carbamoyl adduct. For methylene oxindoles, a thermodynamically driven Z-E isomerization is facilitated by a transition state with aromatic character. In contrast, this aromatic stabilization is not relevant for γ-lactams, which results in a higher barrier for isomerization and the exclusive formation of the Z-isomer.

Synthesis of Carbamoyl Fluorides Using a Difluorophosgene Surrogate Derived from Difluorocarbene and Pyridine N-Oxides.

We report a method for the synthesis of carbamoyl fluorides from secondary amines using bench-stable, inexpensive, and readily accessible starting materials that, when combined, yield a surrogate for toxic difluorophosgene (COF2) gas. In contrast to state-of-the-art methods for the synthesis of carbamoyl fluorides, our protocol does not require the use of pre-functionalized substrates, the preparation of light-, temperature-, and/or moisture-sensitive chemicals, or the application of explosive fluorinating reagents.

Cooperative Stereoinduction in Asymmetric Photocatalysis.

Stereoinduction in complex organic reactions often involves the influence of multiple stereocontrol elements. The interaction among these can often result in the observation of significant cooperative effects that afford different rates and selectivities between the matched and mismatched sets of stereodifferentiating chiral elements. The elucidation of matched/mismatched effects in ground-state chemical reactions was a critically important theme in the maturation of modern stereocontrolled synthesis. The development of robust methods for the control of photochemical reactions, however, is a relatively recent development, and similar cooperative stereocontrolling effects in excited-state enantioselective photoreactions have not previously been documented. Herein, we describe a tandem chiral photocatalyst/Brønsted acid strategy for highly enantioselective [2 + 2] photocycloadditions of vinylpyridines. Importantly, the matched and mismatched chiral catalyst pairs exhibit different reaction rates and enantioselectivities across a range of coupling partners. We observe no evidence of ground-state interactions between the catalysts and conclude that these effects arise from their cooperative behavior in a transient excited-state assembly. These results suggest that similar matched/mismatched effects might be important in other classes of enantioselective dual-catalytic photochemical reactions.

Mechanistic insights on the Pd-catalyzed addition of C-X bonds across alkynes - a combined experimental and computational study.

The Pd-catalyzed intramolecular addition of carbamoyl chlorides and aryl halides across alkynes is investigated by means of DFT calculations and mechanistic test experiments. The data suggest a mechanistic pathway that involves oxidative addition, alkyne insertion, cis → trans isomerization and reductive elimination. Our data indicate that oxidative addition is the reactivity limiting step in the addition of aryl chlorides and bromides across alkynes. However, for the corresponding addition of carbamoyl chlorides, alkyne insertion is found to be limiting. Full energetic reaction pathways for the intramolecular additions across alkynes are presented herein and the role of ligands, alkyne substituents and tether moieties are discussed. Notably, the calculations could rationalize a pronounced effect of the alkyne substituent, which accounts for the exceptional reactivity of TIPS-substituted alkynes. In particular, the bulky silyl moiety is shown to significantly destabilize the formed Pd(ii)-intermediates, thus facilitating both cis → trans isomerization and reductive elimination, which overall results in a flatter energetic landscape and a therefore increased catalytic efficiency.

Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides.

We report a highly robust, general and stereoselective method for the synthesis of 3-(chloromethylene)oxindoles from alkyne-tethered carbamoyl chlorides using PdCl2(PhCN)2 as the catalyst. The transformation involves a stereo- and regioselective chloropalladation of an internal alkyne to generate a nucleophilic vinyl PdII species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases and can be used to access biologically relevant oxindole cores. Through combined experimental and computational studies, we provide insight into stereo- and regioselectivity of the chloropalladation step, as well as the mechanism for the C-C bond forming process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a high valent PdIV species, which then undergoes facile C-C reductive elimination to form the final product. Overall, the transformation constitutes a formal PdII-catalyzed intramolecular alkyne chlorocarbamoylation reaction.

An Exclusively trans-Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst.

Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0)-catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition-metal-catalyzed atom-economic addition of a carbamoyl chloride across an alkyne.

Synergistic steric effects in the development of a palladium-catalyzed alkyne carbohalogenation: stereodivergent synthesis of vinyl halides.

We report our finding that by exploiting the synergistic steric effects between substrate and catalyst, an intramolecular Pd-catalyzed alkyne carbohalogenation can be achieved. This operationally simple method uses the bulky Pd/Q-Phos combination and allows access to tetrasubstituted vinyl halides from the corresponding aryl chlorides, bromides, and iodides. Steric effects in the substrate play a key role by promoting C sp 2-halogen reductive elimination and enabling catalytic turnover. Through a reversible oxidative addition mechanism, a thermodynamically driven isomerization reaction is observed at elevated temperatures. Thus by changing the reaction temperature, both stereoisomers of the reaction become readily accessible.

The use of silyl ketene acetals and enol ethers in the catalytic enantioselective alkylative ring opening of oxa/aza bicyclic alkenes.

Silyl ketene acetals and enol ethers are employed as reactive and functional group tolerant nucleophiles in the enantioselective rhodium-catalyzed alkylative ring opening of a diverse class of oxa/azabicyclic alkenes. This method provides access to enantioenriched dihydronaphthalene and cyclohexene scaffolds, which have the potential to be derivatized toward core motifs of naphthoquinone and sesquiterpene natural products.

Rhodium-phosphoramidite catalyzed alkene hydroacylation: mechanism and octaketide natural product synthesis.

We describe a method that allows salicylaldehyde derivatives to be coupled with a wide range of unactivated alkenes at catalyst loadings as low as 2 mol %. A chiral phosphoramidite ligand and the precise stoichiometry of heterogeneous base are key for high catalytic activity and linear regioselectivity. This protocol was applied in the atom- and step-economical synthesis of eight biologically active octaketide natural products, including anticancer drug candidate cytosporone B. Mechanistic studies provide insight on parameters affecting decarbonylation, a side reaction that limits the turnover number for catalytic hydroacylation. Deuterium labeling studies show that branched hydride insertion is fully reversible, whereas linear hydride insertion is largely irreversible and turnover-limiting. We propose that ligand (R(a),R,R)-SIPHOS-PE effectively suppresses decarbonylation, and helps favor a turnover-limiting insertion, by lowering the barrier for reductive elimination in the linear-selective pathway. Together, these factors enable high reactivity and regioselectivity.

Remarkably stable chalcogen(II) dications.

Air-stable, chalcogen-centered dications have been synthesized and comprehensively characterized. These represent the first diiminopyridine (DIMPY) complexes of the chalcogens as well as the single nonmetallic (sulfur) complex of this ubiquitous ligand. Their stability under ambient conditions is a distinct contrast to other highly charged main-group cations.