Chemoenzymatic Asymmetric Synthesis of Pyridine-Based α-Fluorinated Secondary Alcohols.

Fluoro-substituted and heteroaromatic compounds are valuable intermediates for a variety of applications in pharma- and agrochemistry and synthetic chemistry. This study investigates the chemoenzymatic preparation of chiral alcohols bearing a heteroaromatic ring with an increasing degree of fluorination in α-position. Starting from readily available picoline derivatives prochiral α-halogenated acyl moieties were introduced with excellent selectivity and 64-95 % yield. The formed carbonyl group was subsequently reduced to the corresponding alcohols using the alcohol dehydrogenase from Lactobacillus kefir, yielding an enantiomeric excess of 95->99 % and up to 98 % yield.

Electrochemically Catalyzed Newman-Kwart Rearrangement: Mechanism, Structure-Reactivity Relationship, and Parallels to Photoredox Catalysis.

The facilitation of redox-neutral reactions by electrochemical injection of holes and electrons, also known as "electrochemical catalysis", is a little explored approach that has the potential to expand the scope of electrosynthesis immensely. To systematically improve existing protocols and to pave the way toward new developments, a better understanding of the underlying principles is crucial. In this context, we have studied the Newman-Kwart rearrangement of O-arylthiocarbamates to the corresponding S-aryl derivatives, the key step in the synthesis of thiophenols from the corresponding phenols. This transformation is a particularly useful example because the conventional method requires temperatures up to 300 °C, whereas electrochemical catalysis facilitates the reaction at room temperature. A combined experimental-quantum chemical approach revealed several reaction channels and rendered an explanation for the relationship between the structure and reactivity. Furthermore, it is shown how rapid cyclic voltammetry measurements can serve as a tool to predict the feasibility for specific substrates. The study also revealed distinct parallels to photoredox-catalyzed reactions, in which back-electron transfer and chain propagation are competing pathways.

An Electrocatalytic Newman-Kwart-type Rearrangement.

An electrochemical approach toward rearrangement of O-aryl thiocarbamates to the corresponding S-aryl thiocarbamates is presented. The protocol requires only catalytic amounts of electric charge and allows for operation at room temperature. The electrolysis can be carried out with the simplest equipment, i.e., under galvanostatic conditions in an undivided cell. Furthermore, it is demonstrated that when the electrolysis is performed in a microflow reactor, almost quantitative yields can be achieved without using supporting electrolyte.

Synthesis of Benzoxazoles Using Electrochemically Generated Hypervalent Iodine.

The indirect ("ex-cell") electrochemical synthesis of benzoxazoles from imines using a redox mediator based on the iodine(I)/iodine(III) redox couple is reported. Tethering the redox-active iodophenyl subunit to a tetra-alkylammonium moiety allowed for anodic oxidation to be performed without supporting electrolyte. The mediator salt can be easily recovered and reused. Our "ex-cell" approach toward the electrosynthesis of benzoxazoles is compatible with a range of redox-sensitive functional groups. An unprecedented concerted reductive elimination mechanism for benzoxazole formation is proposed on the basis of control experiments and DFT calculations.

Electrosynthesis Using a Recyclable Mediator-Electrolyte System Based on Ionically Tagged Phenyl Iodide and 1,1,1,3,3,3-Hexafluoroisopropanol.

A new type of redox mediator for electrosynthesis based on the iodine(I)/iodine(III) redox couple is reported. It is demonstrated that the use of 1,1,1,3,3,3-hexafluoroisopropanol as solvent plays a crucial role for both the selective anodic generation of the active iodine(III) species and the subsequent chemical transformation. Furthermore, the supporting electrolyte is merged with the mediator by tethering the redox-active iodophenyl moiety to an alkylammonium group, allowing for straightforward recovery and reuse of both components.