Herein, we report the use of isonitriles as alkyl radical precursors in light-mediated hydro- and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late-stage functionalization. Importantly, the method is general for Cα -primary, Cα -secondary and Cα -tertiary alkyl isonitriles. For most examples, high yields were obtained through direct visible-light irradiation of the isonitrile in the presence of a silyl radical precursor. Interestingly, in the presence of an organic photocatalyst (4CzIPN) a dramatic acceleration was observed. In-depth mechanistic studies using UV/Vis absorption, steady-state and time-resolved photoluminescence, and transient absorption spectroscopy suggest that the excited state of 4CzIPN can engage in a single-electron transfer with the isonitrile.
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.
The development of mild and practical conditions for the fluoroalkylation of arenes is an ongoing challenge in chemical organic synthesis. Herein, we report a metallaphotoredox method for the preparation of fluoroalkyl arenes based on the synergistic combination of Ir/Cu dual catalysis from boronic acids. The mild conditions allow broad functional group tolerance, including substrates containing aldehydes, free phenols, and N-Boc-protected amines. Mechanistic investigations support a process proceeding via photoredox/copper dual catalysis.
Boronic Acids , Copper , Aldehydes , Amines , Catalysis
The synthesis of sulfides has been widely studied because this functional subunit is prevalent in biomolecules and pharmaceuticals, as well as being a useful synthetic platform for further elaboration. Thus, various methods to build C-S bonds have been developed, but typically they require the use of precious metals or harsh conditions. Electron donor-acceptor (EDA) complex photoactivation strategies have emerged as versatile and sustainable ways to achieve C-S bond formation, avoiding challenges associated with previous methods. This work describes an open-to-air, photoinduced, site-selective C-H thioetherification from readily available reagents via EDA complex formation that tolerates a wide range of different functional groups. Moreover, C(sp2 )-halogen bonds remain intact using this protocol, allowing late-stage installation of the sulfide motif in various bioactive scaffolds, while allowing yet further modification through more traditional C-X bond cleavage protocols. Additionally, various mechanistic investigations support the envisioned EDA complex scenario.
Electrons , Salts , Halogens , Metals , Oxidants
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.
Nickel , Reducing Agents , Electrons , Glycosides , Molecular Structure
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.
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.
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.
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.
