A General Organocatalytic System for Electron Donor-Acceptor Complex Photoactivation and Its Use in Radical Processes.

We report herein a modular class of organic catalysts that, acting as donors, can readily form photoactive electron donor-acceptor (EDA) complexes with a variety of radical precursors. Excitation with visible light generates open-shell intermediates under mild conditions, including nonstabilized carbon radicals and nitrogen-centered radicals. The modular nature of the commercially available xanthogenate and dithiocarbamate anion organocatalysts offers a versatile EDA complex catalytic platform for developing mechanistically distinct radical reactions, encompassing redox-neutral and net-reductive processes. Mechanistic investigations, by means of quantum yield determination, established that a closed catalytic cycle is operational for all of the developed radical processes, highlighting the ability of the organic catalysts to turn over and iteratively drive every catalytic cycle. We also demonstrate how the catalysts' stability and the method's high functional group tolerance could be advantageous for the direct radical functionalization of abundant functional groups, including aliphatic carboxylic acids and amines, and for applications in the late-stage elaboration of biorelevant compounds and enantioselective radical catalysis.

On-DNA Palladium-Catalyzed Hydrogenation-like Reaction Suitable for DNA-Encoded Library Synthesis.

Herein we describe a method to orthogonally remove on-DNA N-Cbz, N-Alloc, N-Allyl, O-Bn, and O-Allyl protecting groups in the presence of other common protecting groups to afford free amines and carboxylic acids, respectively. The developed method uses NaBH4 as the source of hydrogen in the presence of Pd(OAc)2 under DNA aqueous conditions. In addition, under the developed conditions we were able to successfully hydrogenate triple and double bonds to totally saturated compounds. Furthermore, we introduce a new alternative procedure to reduce azides and aromatic nitro compounds to primary amines.

Photochemical generation of acyl and carbamoyl radicals using a nucleophilic organic catalyst: applications and mechanism thereof.

We detail a strategy that uses a commercially available nucleophilic organic catalyst to generate acyl and carbamoyl radicals upon activation of the corresponding chlorides and anhydrides via a nucleophilic acyl substitution path. The resulting nucleophilic radicals are then intercepted by a variety of electron-poor olefins in a Giese-type addition process. The chemistry requires low-energy photons (blue LEDs) to activate acyl and carbamoyl radical precursors, which, due to their high reduction potential, are not readily prone to redox-based activation mechanisms. To elucidate the key mechanistic aspects of this catalytic photochemical radical generation strategy, we used a combination of transient absorption spectroscopy investigations, electrochemical studies, quantum yield measurements, and the characterization of key intermediates. We identified a variety of off-the-cycle intermediates that engage in a light-regulated equilibrium with reactive radicals. These regulated equilibriums cooperate to control the overall concentrations of the radicals, contributing to the efficiency of the overall catalytic process and facilitating the turnover of the catalyst.

Photochemical generation of radicals from alkyl electrophiles using a nucleophilic organic catalyst.

Chemists extensively use free radical reactivity for applications in organic synthesis, materials science, and life science. Traditionally, generating radicals requires strategies that exploit the bond dissociation energy or the redox properties of the precursors. Here, we disclose a photochemical catalytic approach that harnesses different physical properties of the substrate to form carbon radicals. We use a nucleophilic dithiocarbamate anion catalyst, adorned with a well-tailored chromophoric unit, to activate alkyl electrophiles via an SN2 pathway. The resulting photon-absorbing intermediate affords radicals upon homolytic cleavage induced by visible light. This catalytic SN2-based strategy, which exploits a fundamental mechanistic process of ionic chemistry, grants access to open-shell intermediates from a variety of substrates that would be incompatible with or inert to classical radical-generating strategies. We also describe how the method's mild reaction conditions and high functional group tolerance could be advantageous for developing C-C bond-forming reactions, for streamlining the preparation of a marketed drug, for the late-stage elaboration of biorelevant compounds and for enantioselective radical catalysis.

Mild and Efficient Palladium-Mediated C-N Cross-Coupling Reaction between DNA-Conjugated Aryl Bromides and Aromatic Amines.

DNA-encoded library technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C-N bond formation, and its application to DNA-encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd-promoted C-N cross coupling reaction between DNA-conjugated aryl bromides and a wide scope of arylamines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.