Thianthrenium-Enabled Sulfonylation via Electron Donor-Acceptor Complex Photoactivation.

Sulfone-containing compounds are prevalent building blocks in pharmaceuticals and other biomolecules, and they serve as key intermediates in the synthesis of complex scaffolds. During the past decade, several methods have been developed to access sulfones. These strategies, however, require the use of strong reaction conditions, limiting their substrate scope. Recently, visible light-mediated transformations have emerged as novel platforms to access unprecedented structural motifs. This report demonstrates a thianthrenium-enabled sulfonylation via intra-complex charge transfer to generate transient aryl- and persistent sulfonyl radicals that undergo selective coupling to generate alkyl- and (hetero)aryl sulfones under ambient conditions. Importantly, this strategy allows retention of halide handles, presenting a complementary approach to transition metal-mediated photoredox couplings. Furthermore, this sulfonylation allows high functional group tolerance and is amenable to late-stage functionalization of complex biomolecules. Mechanistic investigations support the intermediacy of electron donor-acceptor (EDA) complexes.

Nickel-Mediated Synthesis of Non-Anomeric C-Acyl Glycosides through Electron Donor-Acceptor Complex Photoactivation.

The preparation of nonanomeric C-acyl-saccharides has been developed from two different carboxylic acid feedstocks. This transformation is driven by the synergistic interaction of an electron donor-acceptor complex and Ni catalysis. Primary-, secondary-, and tertiary redox-active esters are incorporated as coupling partners onto preactivated pyranosyl- and furanosyl acids, preserving their stereochemical integrity. The reaction occurs under mild conditions, without stoichiometric metal reductants or exogenous catalysts, using commercially available Hantzsch ester as the organic photoreductant.

Photochemical C-H arylation of heteroarenes for DNA-encoded library synthesis.

DNA-encoded library (DEL) technology has emerged as a time- and cost-efficient technique for the identification of therapeutic candidates in the pharmaceutical industry. Although several reaction classes have been successfully validated in DEL environments, there remains a paucity of DNA-compatible reactions that harness building blocks (BBs) from readily available substructures bearing multifunctional handles for further library diversification under mild, dilute, and aqueous conditions. In this study, the direct C-H carbofunctionalization of medicinally-relevant heteroarenes can be accomplished via the photoreduction of DNA-conjugated (hetero)aryl halides to deliver reactive aryl radical intermediates in a regulated fashion within minutes of blue light illumination. A broad array of electron-rich and electron-poor heteroarene scaffolds undergo transformation in the presence of sensitive functional groups.

Photoredox-mediated hydroalkylation and hydroarylation of functionalized olefins for DNA-encoded library synthesis.

DNA-encoded library (DEL) technology features a time- and cost-effective interrogation format for the discovery of therapeutic candidates in the pharmaceutical industry. To develop DEL platforms, the implementation of water-compatible transformations that facilitate the incorporation of multifunctional building blocks (BBs) with high C(sp3) carbon counts is integral for success. In this report, a decarboxylative-based hydroalkylation of DNA-conjugated trifluoromethyl-substituted alkenes enabled by single-electron transfer (SET) and subsequent hydrogen atom termination through electron donor-acceptor (EDA) complex activation is detailed. In a further photoredox-catalyzed hydroarylation protocol, the coupling of functionalized, electronically unbiased olefins is achieved under air and within minutes of blue light irradiation through the intermediacy of reactive (hetero)aryl radical species with full retention of the DNA tag integrity. Notably, these processes operate under mild reaction conditions, furnishing complex structural scaffolds with a high density of pendant functional groups.

Photoinduced 1,2-dicarbofunctionalization of alkenes with organotrifluoroborate nucleophiles via radical/polar crossover.

Alkene 1,2-dicarbofunctionalizations are highly sought-after transformations as they enable a rapid increase of molecular complexity in one synthetic step. Traditionally, these conjunctive couplings proceed through the intermediacy of alkylmetal species susceptible to deleterious pathways including ß-hydride elimination and protodemetalation. Herein, an intermolecular 1,2-dicarbofunctionalization using alkyl N-(acyloxy)phthalimide redox-active esters as radical progenitors and organotrifluoroborates as carbon-centered nucleophiles is reported. This redox-neutral, multicomponent reaction is postulated to proceed through photochemical radical/polar crossover to afford a key carbocation species that undergoes subsequent trapping with organoboron nucleophiles to accomplish the carboallylation, carboalkenylation, carboalkynylation, and carboarylation of alkenes with regio- and chemoselective control. The mechanistic intricacies of this difunctionalization were elucidated through Stern-Volmer quenching studies, photochemical quantum yield measurements, and trapping experiments of radical and ionic intermediates.

Photoactive electron donor-acceptor complex platform for Ni-mediated C(sp3)-C(sp2) bond formation.

A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp3)-C(sp2) linkages is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE) functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-based radical generation through electron donor-acceptor (EDA) complex activation. This homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp3)-centered radical architectures (including primary, secondary, stabilized benzylic, α-oxy, and α-amino systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.

Nickel-Catalyzed Decarboxylative Cross-Coupling of Bicyclo[1.1.1]pentyl Radicals Enabled by Electron Donor-Acceptor Complex Photoactivation.

The use of bicyclo[1.1.1]pentanes (BCPs) as para-disubstituted aryl bioisosteres has gained considerable momentum in drug development programs. Carbon-carbon bond formation via transition-metal-mediated cross-coupling represents an attractive strategy to generate BCP-aryl compounds for late-stage functionalization, but these typically require reactive organometallics to prepare BCP nucleophiles on demand from [1.1.1]propellane. In this study, the synthesis and Ni-catalyzed functionalization of BCP redox-active esters with (hetero)aryl bromides via the action of a photoactive electron donor-acceptor complex are reported.

Accessing Aliphatic Amines in C-C Cross-Couplings by Visible Light/Nickel Dual Catalysis.

A general aminoalkylation of aryl halides was developed, overcoming intolerance of free amines in nickel-mediated C-C coupling. This transformation features broad functional group tolerance and high efficiency. Taking advantage of the fast desilylation of α-silylamines upon single-electron transfer (SET) facilitated by carbonate, α-amino radicals are generated regioselectively, which then engage in nickel-mediated C-C coupling. The reaction displays high chemoselectivity for C-C over C-N bond formation. Highly functionalized pharmacophores and peptides are also amenable.

Developments in Photoredox-Mediated Alkylation for DNA-Encoded Libraries.

Recently, DNA-encoded library (DEL) technology has emerged as an innovative screening modality for the rapid discovery of therapeutic candidates in pharmaceutical settings. This platform enables a cost-effective, time-efficient, and large-scale assembly and interrogation of billions of small organic ligands against a biological target in a single experiment. An outstanding challenge in DEL synthesis is the necessity for water-compatible transformations under ambient conditions. To access uncharted chemical space, the adoption of photoredox catalysis in DELs, including Ni-catalyzed manifolds and radical/polar crossover reactions, has enabled the construction of novel structural scaffolds through regulated odd-electron intermediates. Herein, a critical discussion of the validation of photoredox-mediated alkylation in DEL environments is presented. Current synthetic gaps are highlighted and opportunities for further development are speculated upon.

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.

Stereoinduction in Metallaphotoredox Catalysis.

Metallaphotoredox catalysis has evolved into an enabling platform to construct C(sp3 )-hybridized centers under remarkably mild reaction conditions. The cultivation of abundant radical precursor feedstocks has significantly increased the scope of transition-metal-catalyzed cross-couplings, especially with respect to C(sp2 )-C(sp3 ) linkages. In recent years, considerable effort has been devoted to understanding the origin of stereoinduction in dual catalytic processes. In this context, Ni- and Cu-catalyzed transformations have played a predominant role exploiting this mode of catalysis. Herein, we provide a critical overview on recent progress in enantioselective bond formations enabled by Ni- and Cu-catalyzed manifolds. Furthermore, selected stereochemical control elements within the realm of diastereoselective transformations are discussed.

Developments in Photoredox/Nickel Dual-Catalyzed 1,2-Difunctionalizations.

Progress in Ni/photoredox dual catalysis has enabled the construction of C(sp3)-hybridized centers under extremely mild reaction conditions in the presence of diverse functional groups. These strategies, however, are mainly restricted to the assembly of one C-C or C-heteroatom linkage because of the competitive two-component reactions and facile ß-hydride elimination from alkylmetal complexes. Recently, photoinduced nickel-catalyzed 1,2-difunctionalizations of alkenes and alkynes have attracted extensive research efforts as they allow the construction of two sequential chemical bonds from inexpensive starting materials in one pot. Herein, we explore recent advances, state the current challenges, and discuss perspectives on the design of new catalytic systems.

On the Nature of C(sp3)-C(sp2) Bond Formation in Nickel-Catalyzed Tertiary Radical Cross-Couplings: A Case Study of Ni/Photoredox Catalytic Cross-Coupling of Alkyl Radicals and Aryl Halides.

The merger of photoredox and nickel catalysis has enabled the construction of quaternary centers. However, the mechanism, role of the ligand, and effect of the spin state for this transformation and related Ni-catalyzed cross-couplings involving tertiary alkyl radicals in combination with bipyridine and diketonate ligands remain unknown. Several mechanisms have been proposed, all invoking a key Ni(III) species prior to undergoing irreversible inner-sphere reductive elimination. In this work, we have used open-shell dispersion-corrected DFT calculations, quasi-classical dynamics calculations, and experiments to study in detail the mechanism of carbon-carbon bond formation in Ni bipyridine- and diketonate-based catalytic systems. These calculations revealed that access to high spin states (e.g., triplet spin state tetrahedral Ni(II) species) is critical for effective radical cross-coupling of tertiary alkyl radicals. Further, these calculations revealed a disparate mechanism for the C-C bond formation. Specifically, contrary to the neutral Ni-bipyridyl system, diketonate ligands lead directly to the corresponding tertiary radical cross-coupling products via an outer-sphere reductive elimination step via triplet spin state from the Ni(III) intermediates. Implications to related Ni-catalyzed radical cross-couplings and the design of new transformations are discussed.

Multifunctional Building Blocks Compatible with Photoredox-Mediated Alkylation for DNA-Encoded Library Synthesis.

DNA-encoded library (DEL) technology has emerged as a novel interrogation modality for ligand discovery in the pharmaceutical industry. Given the increasing demand for a higher proportion of C(sp3)-hybridized centers in DEL platforms, a photoredox-mediated cross-coupling and defluorinative alkylation process is introduced using commercially available alkyl bromides and structurally diverse α-silylamines. Notably, no protecting group strategies for amines are necessary for the incorporation of a variety of amino-acid-based organosilanes, providing crucial branching points for further derivatization.

Photoredox-Catalyzed Multicomponent Petasis Reaction with Alkyltrifluoroborates.

A redox-neutral alkyl Petasis reaction has been developed that proceeds via photoredox catalysis. A diverse set of primary, secondary, and tertiary alkyltrifluoroborates participate effectively in this reaction through a single-electron transfer mechanism, in contrast to the traditional two-electron Petasis reaction, which accommodates only unsaturated boronic acids. This protocol is ideal to diversify benzyl-type and glyoxalate-derived aldehydes, anilines, and alkyltrifluoroborates toward the rapid assembly of libraries of higher molecular complexity important in pharmaceutical and agrochemical settings.

Deaminative Reductive Arylation Enabled by Nickel/Photoredox Dual Catalysis.

Described is a cross-electrophilic, deaminative coupling strategy harnessing Katritzky salts as a new species of electrophile in Ni/photoredox dual catalytic reductive cross-coupling reactions. Distinguishing features of this arylation protocol include its mild reaction conditions, high chemoselectivity, and adaptability to a variety of complex substrates [i.e., pyridinium salts derived from amines and partners derived from (hetero)aryl bromides].

Alkyl Carbon-Carbon Bond Formation by Nickel/Photoredox Cross-Coupling.

The union of photoredox and nickel catalysis has resulted in a renaissance in radical chemistry as well as in the use of nickel-catalyzed transformations, specifically for carbon-carbon bond formation. Collectively, these advances address the longstanding challenge of late-stage cross-coupling of functionalized alkyl fragments. Empowered by the notion that photocatalytically generated alkyl radicals readily undergo capture by Ni complexes, wholly new feedstocks for cross-coupling have been realized. Herein, we highlight recent developments in several types of alkyl cross-couplings that are accessible exclusively through this approach.

Synthesis of Reversed C-Acyl Glycosides through Ni/Photoredox Dual Catalysis.

The incorporation of C-glycosides in drug design has become a routine practice for medicinal chemists. These naturally occurring building blocks exhibit attractive pharmaceutical profiles, and have become an important target of synthetic efforts in recent decades. Described herein is a practical, scalable, and versatile route for the synthesis of non-anomeric and unexploited C-acyl glycosides through a Ni/photoredox dual catalytic system. By utilizing an organic photocatalyst, a range of glycosyl-based radicals are generated and efficiently coupled with highly functionalized carboxylic acids at room temperature. Distinctive features of this transformation include its mild conditions, impressive compatibility with a wide array of functional groups, and most significantly, preservation of the anomeric carbon: a handle for further, late-stage derivatization.