Rapid Assembly of Unsymmetrically Linked Bis-heterocycles via Palladium Domino Catalysis.

A palladium-catalyzed domino reaction of alkene-tethered oxime esters is reported. This transformation uses an air-stable palladium precatalyst that initiates a Narasaka-Heck reaction, that is interrupted with a Pd(II)-promoted cyclization. Through this methodology, a novel class of unsymmetrical alkyl-linked bis-heterocycles were synthesized in yields up to 99%. The reaction is scalable up to 1.0 mmol, with simplified purification steps. This transformation expands the scope of accessible bis-heterocycles available through Narasaka-Heck reactions beyond C-H activation and direct anionic capture termination steps.

Palladium-Catalyzed Synthesis of Linked Bis-Heterocycles─Synthesis and Investigation of Photophysical Properties.

A palladium-catalyzed domino C-N coupling/Cacchi reaction is reported. Design of photoluminescent bis-heterocycles, aided by density functional theory calculations, was performed with synthetic yields up to 98%. The photophysical properties of the products accessed via this strategy were part of a comprehensive study that led to broad emission spectra and quantum yields of up to 0.59. Mechanistic experiments confirmed bromoalkynes as competent intermediates, and a density functional theory investigation suggests a pathway involving initial oxidative addition into the cis C-Br bond of the gem-dihaloolefin.

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.

Pd(0)/Blue Light Promoted Carboiodination Reaction - Evidence for Reversible C-I Bond Formation via a Radical Pathway.

A Pd(0)/blue light catalyzed carboiodination reaction is reported. A simple, air-stable catalytic system, utilizing [Pd(allyl)Cl]2 and DPEPhos, generated a variety of iodinated hetero- and carbocycles including oxindoles, dihydrobenzofurans, indolines, a chromane, and a tetrahydronaphthalene. This protocol was tolerant of sensitive functional groups including free carboxylic acids, phenols, and anilines, as well as pyridines, while delivering products in up to 94% yield. Support for a reversible C-I bond formation via a single electron mechanism was obtained using a deuterium labeled substrate and a stoichiometric neopentylpalladium species.

Accessing Unsymmetrically Linked Heterocycles through Stereoselective Palladium-Catalyzed Domino Cyclization.

A palladium-catalyzed strategy is presented to synthesize unsymmetrically linked heterocycles within stereoselective tetrasubstituted olefins. This reaction is proposed to occur via a vinyl-PdII intermediate capable of initiating the cyclization of various alkyne-tethered nucleophiles. Products are formed in up to 96 % yield and excellent stereoselectivities are obtained using low catalyst loadings. This transformation was scalable up to 1 mmol and mechanistic studies suggest a syn-carbopalladation of the carbamoyl chloride followed by PdII -catalyzed cyclization of alkyne-tethered nucleophiles.

Synthesis of 1-Amino-2,2,2-trifluoroalkylphosphonates from Alkene-Tethered Trifluoroacetimidoyl Chlorides.

The reaction of alkene-tethered trifluoroacetimidoyl chlorides with trialkyl phosphites furnishes 1-amino-2,2,2-trifluoroalkylphosphonates. The products were generated in moderate to good yields, and the scalability of this process was showcased. Partial hydrolysis of the phosphonate moiety was achieved. The cyclization is proposed to occur via formation of an imidoyl phosphonate intermediate that becomes susceptible to nucleophilic attack at nitrogen through the strong electron-withdrawing groups at the imidoyl carbon.

Sequential Pd0 - and PdII -Catalyzed Cyclizations: Enantioselective Heck and Nucleopalladation Reactions.

An enantioselective consecutive cyclization/coupling process, catalyzed by palladium is reported. Stereoinduction arises from an enantioselective carbopalladation, generating an intermediate which promotes a nucleopalladation step. The dual cyclization sequence was compatible with a variety of alkyne-tethered oxygen- and nitrogen-centered nucleophiles, and a variety of alkenyl-tethered aryl iodides, to forge numerous bisheterocycles in good yields and high regio- and enantioselectivities.