Overcoming the Potential Window-Limited Functional Group Compatibility by Alternating Current Electrolysis.

The functional group compatibility of an electrosynthetic method is typically limited by its potential reaction window. Here, we report that alternating current (AC) electrolysis can overcome such potential window-limited functional group compatibility. Using alkene heterodifunctionalization as a model system, we design and demonstrate a series of AC-driven reactions that add two functional groups sequentially and separately under the cathodic and anodic pulses, including chloro- and bromotrilfuoromethylation as well as chlorosulfonylation. We discovered that the oscillating redox environment during AC electrolysis allows the regeneration of the redox-active functional groups after their oxidation or reduction in the preceding step. As a result, even though redox labile functional groups such as pyrrole, quinone, and aryl thioether fall in the reaction potential window, they are tolerated under AC electrolysis conditions, leading to synthetically useful yields. The cyclic voltammetric study has confirmed that the product yield is limited by the extent of starting material regeneration during the redox cycling. Our findings open a new avenue for improving functional group compatibility in electrosynthesis and show the possibility of predicting the product yield under AC electrolysis from voltammogram features.

Electrochemical hydrogen isotope exchange of amines controlled by alternating current frequency.

Here, we report an electrochemical protocol for hydrogen isotope exchange (HIE) at α-C(sp3)-H amine sites. Tetrahydroisoquinoline and pyrrolidine are selected as two model substrates because of their different proton transfer (PT) and hydrogen atom transfer (HAT) kinetics at the α-C(sp3)-H amine sites, which are utilized to control the HIE reaction outcome at different applied alternating current (AC) frequencies. We found the highest deuterium incorporation for tetrahydroisoquinolines at 0 Hz (i.e., under direct current (DC) electrolysis conditions) and pyrrolidines at 0.5 Hz. Analysis of the product distribution and D isotope incorporation at different frequencies reveals that the HIE of tetrahydroisoquinolines is limited by its slow HAT, whereas the HIE of pyrrolidines is limited by the overoxidation of its α-amino radical intermediates. The AC-frequency-dependent HIE of amines can be potentially used to achieve selective labeling of α-amine sites in one drug molecule, which will significantly impact the pharmaceutical industry.

Quantum dot gels as efficient and unique photocatalysts for organic synthesis.

Here we report CdS quantum dot (QD) gels as highly efficient and unique photocatalysts for organic synthesis. We found that the photocatalytic activity of CdS QD gel was superior to phosphine oxide- and thiolate-capped CdS QDs for dehalogenation and α-amine arylation reactions because of the high accessibility of its surface sites to the substrates. In addition, we discovered the unique reactivity of CdS QD gel for ring-opening during α-amine arylation of tetrahydroisoquinoline via the reductive cleavage of C-N bonds. QD gels provide new opportunities in photocatalysis due to their unique surface interactions with the substrates or intermediates.

Controlling One- or Two-Electron Oxidation for Selective Amine Functionalization by Alternating Current Frequency.

Here, we report a unique electrosynthetic method that enables the selective one-electron oxidation of tertiary amines to generate α-amino radical intermediates over two-electron oxidation to iminium cations, providing easy access to arylation products by simply applying an optimal alternating current (AC) frequency. More importantly, we have discovered an electrochemical descriptor from cyclic voltammetry studies to predict the optimal AC frequency for various amine substrates, circumventing the time-consuming trial-and-error methods for optimizing reaction conditions. This new development in AC electrolysis provides an alternative strategy to solving challenging chemoselectivity problems in synthetic organic chemistry.

Synthesis of Methyl-Protected (±)-Chlorizidine A.

The first total synthesis of the methyl-protected (±)-chlorizidine A has been achieved in 10 steps. Pd-catalyzed decarboxylative coupling and late-stage oxidation were utilized to construct the 5H-pyrrolo[2,1-a]isoindol-5-one scaffold. Samarium(II) iodide mediated Reformatsky reaction and intramolecular Mitsunobu reactions were efficiently applied for the synthesis of the 2,3-dihydropyrrolizine ring system. Chlorizidine A is highly prone to degradation; hence, methyl-protected (±)-chlorizidine A was prepared.

Pd-catalyzed imine cyclization: synthesis of antimalarial natural products Aplidiopsamine A, Marinoquinoline A, and their potential hybrid NCLite-M1.

Palladium-catalyzed cyclization of imines has been developed to construct the extremely rare 3H-pyrrolo[2,3-c]quinoline ring system for diversity oriented first total synthesis of antimalarial marine natural product Aplidiopsamine A as well as synthesis of Marinoquinoline A and potential natural product hybrid NCLite-M1.