Catalyst-Free Decarbonylative Trifluoromethylthiolation Enabled by Electron Donor-Acceptor Complex Photoactivation.

A catalyst- and additive-free decarbonylative trifluoromethylthiolation of aldehyde feedstocks has been developed. This operationally simple, scalable, and open-to-air transformation is driven by the selective photoexcitation of electron donor-acceptor (EDA) complexes, stemming from the association of 1,4-dihydropyridines (donor) with N-(trifluoromethylthio)phthalimide (acceptor), to trigger intermolecular single-electron transfer events under ambient- and visible light-promoted conditions. Extension to other electron acceptors enables the synthesis of thiocyanates and thioesters, as well as the difunctionalization of [1.1.1] propellane. The mechanistic intricacies of this photochemical paradigm are elucidated through a combination of experimental efforts and high-level quantum mechanical calculations [dispersion-corrected (U)DFT, DLPNO-CCSD(T), and TD-DFT]. This comprehensive study highlights the necessity for EDA complexation for efficient alkyl radical generation. Computation of subsequent ground state pathways reveals that SH2 addition of the alkyl radical to the intermediate radical EDA complex is extremely exergonic and results in a charge transfer event from the dihydropyridine donor to the N-(trifluoromethylthio)phthalimide acceptor of the EDA complex. Experimental and computational results further suggest that product formation also occurs via SH2 reaction of alkyl radicals with 1,2-bis(trifluoromethyl)disulfane, generated in-situ through combination of thiyl radicals.

Photocatalyzed Diastereoselective Isomerization of Cinnamyl Chlorides to Cyclopropanes.

Endergonic isomerizations are thermodynamically unfavored processes that are difficult to realize under thermal conditions. We report a photocatalytic and diastereoselective isomerization of acyclic cinnamyl chlorides to strained cyclopropanes. Quantum mechanical calculations (uM06-2X and DLPNO), including TD-DFT calculations, and experimental studies provide evidence for the energy transfer from an iridium photocatalyst to the allylic chloride substrate followed by C-Cl homolytic cleavage. Subsequent Cl• radical migration forms a localized triplet 1,3-diradical intermediate that, after intersystem crossing, undergoes ring-closing to form the desired product. The mild reaction conditions are compatible with a broad range of functional groups to generate chlorocyclopropanes in high yields and diastereoselectivities. A more efficient process is developed by addition of a catalytic amount of a nickel complex, and we propose a novel role for this cocatalyst to recycle an allyl chloride byproduct generated in the course of the reaction. The reaction is also shown to be stereoconvergent, as an E/Z mixture of cinnamyl chlorides furnish the anti-chlorocyclopropane product in high diastereoselectivity. We anticipate that the use of a visible light activated photocatalyst to transform substrates in combination with a transition metal catalyst to recycle byproducts back into the catalytic cycle will provide unique opportunities for the discovery of new reactivity.

Redox-Neutral Photocatalytic Cyclopropanation via Radical/Polar Crossover.

A benchtop stable, bifunctional reagent for the redox-neutral cyclopropanation of olefins has been developed. Triethylammonium bis(catecholato)iodomethylsilicate can be readily prepared on multigram scale. Using this reagent in combination with an organic photocatalyst and visible light, cyclopropanation of an array of olefins, including trifluoromethyl- and pinacolatoboryl-substituted alkenes, can be accomplished in a matter of hours. The reaction is highly tolerant of traditionally reactive functional groups (carboxylic acids, basic heterocycles, alkyl halides, etc.) and permits the chemoselective cyclopropanation of polyolefinated compounds. Mechanistic interrogation revealed that the reaction proceeds via a rapid anionic 3- exo- tet ring closure, a pathway consistent with experimental and computational data.

Programmable late-stage functionalization of bridge-substituted bicyclo[1.1.1]pentane bis-boronates.

Modular functionalization enables versatile exploration of chemical space and has been broadly applied in structure-activity relationship (SAR) studies of aromatic scaffolds during drug discovery. Recently, the bicyclo[1.1.1]pentane (BCP) motif has increasingly received attention as a bioisosteric replacement of benzene rings due to its ability to improve the physicochemical properties of prospective drug candidates, but studying the SARs of C2-substituted BCPs has been heavily restricted by the need for multistep de novo synthesis of each analogue of interest. Here we report a programmable bis-functionalization strategy to enable late-stage sequential derivatization of BCP bis-boronates, opening up opportunities to explore the SARs of drug candidates possessing multisubstituted BCP motifs. Our approach capitalizes on the inherent chemoselectivity exhibited by BCP bis-boronates, enabling highly selective activation and functionalization of bridgehead (C3)-boronic pinacol esters (Bpin), leaving the C2-Bpin intact and primed for subsequent derivatization. These selective transformations of both BCP bridgehead (C3) and bridge (C2) positions enable access to C1,C2-disubstituted and C1,C2,C3-trisubstituted BCPs that encompass previously unexplored chemical space.

Alkyl sulfinates as cross-coupling partners for programmable and stereospecific installation of C(sp3) bioisosteres.

In recent years, a variety of cycloalkyl groups with quaternary carbons, in particular cyclopropyl and cyclobutyl trifluoromethyl groups, have emerged as promising bioisosteres in drug-like molecules. The modular installation of such bioisosteres remains challenging to synthetic chemists. Alkyl sulfinate reagents have been developed as radical precursors to prepare functionalized heterocycles with the desired alkyl bioisosteres. However, the innate (radical) reactivity of this transformation poses reactivity and regioselectivity challenges for the functionalization of any aromatic or heteroaromatic scaffold. Here we showcase the ability of alkyl sulfinates to engage in sulfurane-mediated C(sp3)-C(sp2) cross-coupling, thereby allowing for programmable and stereospecific installation of these alkyl bioisosteres. The ability of this method to simplify retrosynthetic analysis is exemplified by the improved synthesis of multiple medicinally relevant scaffolds. Experimental studies and theoretical calculations for the mechanism of this sulfur chemistry reveal a ligand-coupling trend under alkyl Grignard activation via the sulfurane intermediate, stabilized by solvation of tetrahydrofuran.

Dearomatization of aromatic asmic isocyanides to complex cyclohexadienes.

A dearomatization-dislocation-coupling cascade rapidly transforms aromatic isocyanides into highly functionalized cyclohexadienes. The facile cascade installs an exceptional degree of molecular complexity: three carbon-carbon bonds, two quaternary stereocenters, and three orthogonal functionalities, a cyclohexadiene, a nitrile, and an isocyanide. The tolerance of arylisocyanides makes the method among the mildest dearomatizations ever reported, typically occurring within minutes at -78 °C. Experimental and computational analyses implicate an electron transfer-initiated mechanism involving an unprecedented isocyanide rearrangement followed by radical-radical anion coupling. The dearomatization is fast, proceeds via a complex cascade mechanism supported by experimental and computational insight, and provides complex, synthetically valuable cyclohexadienes.

Oxa- and Azabenzonorbornadienes as Electrophilic Partners under Photoredox/Nickel Dual Catalysis.

Herein, the introduction of oxa- and azabenzonorbornadienes into photoredox/nickel dual catalysis in a regioselective and diastereoselective transformation is disclosed. The inherent advantages of this dual catalytic system allow the use of alkyl motifs forming exclusively cis-1,2-dihydro-1-naphthyl alcohol backbones using readily accessible 4-alkyl-1,4-dihydropyridines (DHPs). Whereas previous studies have emphasized the use of nucleophilic organometallic coupling partners, this protocol grants access to a rather unexplored core featuring alkyl residues, while avoiding the use of highly reactive organometallic species (i.e., M = Al, Mg, Li, Zn, Zr). DFT calculations support a oxidative addition/reductive elimination mechanism, followed by a Curtin-Hammett scenario that controls the regioselectivity of the process, unlike previously reported transformations that proceed via a carbometalation/ ß-oxygen elimination mechanism.

Engaging sulfinate salts via Ni/photoredox dual catalysis enables facile Csp2 -SO2R coupling.

This report details the development and implementation of a strategy to construct aryl- and heteroaryl sulfones via Ni/photoredox dual catalysis. Using aryl sulfinate salts, the C-S bond can be forged at room temperature under base-free conditions. An array of aryl- and heteroaryl halides are compatible with this approach. The broad tolerance and mild nature of the described reaction could potentially be employed to prepare sulfones with biological relevance (e.g., in bioconjugation, drug substance synthesis, etc.) as demonstrated in the synthesis of drug-like compounds or their precursors. When paired with existing Ni/photoredox chemistry for Csp3 -Csp2 cross-coupling, an array of diverse sulfone scaffolds can be readily assembled from bifunctional electrophiles. A mechanistic manifold consistent with experimental and computational data is presented.