Generality-oriented optimization of enantioselective aminoxyl radical catalysis.

Catalytic enantioselective methods that are generally applicable to a broad range of substrates are rare. We report a strategy for the oxidative desymmetrization of meso-diols predicated on a nontraditional catalyst optimization protocol by using a panel of screening substrates rather than a singular model substrate. Critical to this approach was rational modulation of a peptide sequence in the catalyst incorporating a distinct aminoxyl-based active residue. A general catalyst emerged, providing high selectivity in the delivery of enantioenriched lactones across a broad range of diols, while also achieving up to ~100,000 turnovers.

Unlocking the Potential of High-Throughput Experimentation for Electrochemistry with a Standardized Microscale Reactor.

Organic electrochemistry has emerged as an enabling and sustainable technology in modern organic synthesis. Despite the recent renaissance of electrosynthesis, the broad adoption of electrochemistry in the synthetic community, and especially in industrial settings, has been hindered by the lack of general, standardized platforms for high-throughput experimentation (HTE). Herein, we disclose the design of the HTe - Chem, a high-throughput microscale electrochemical reactor that is compatible with existing HTE infrastructure and enables the rapid evaluation of a broad array of electrochemical reaction parameters. Utilizing the HTe - Chem to accelerate reaction optimization, reaction discovery, and chemical library synthesis is illustrated using a suite of oxidative and reductive transformations under constant current, constant voltage, and electrophotochemical conditions.

Isolation and X-ray Crystal Structure of an Electrogenerated TEMPO-N3 Charge-Transfer Complex.

Advances in radical-based catalytic reactions have created a demand for understanding their mechanistic underpinnings. Here, we present the isolation, structural elucidation, and theoretical analysis of a catalytically relevant charge-transfer species formed between the azidyl radical and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). The unusual bond angles and pancake bonding between these two fragments highlight the weak bonding interactions present in this complex. This X-ray structure validates computational predictions as well as mechanistic proposals of TEMPO-mediated radical azidation reactions.

An Electroreductive Approach to Radical Silylation via the Activation of Strong Si-Cl Bond.

The construction of C(sp3)-Si bonds is important in synthetic, medicinal, and materials chemistry. In this context, reactions mediated by silyl radicals have become increasingly attractive but methods for accessing these intermediates remain limited. We present a new strategy for silyl radical generation via electroreduction of readily available chlorosilanes. At highly biased potentials, electrochemistry grants access to silyl radicals through energetically uphill reductive cleavage of strong Si-Cl bonds. This strategy proved to be general in various alkene silylation reactions including disilylation, hydrosilylation, and allylic silylation under simple and transition-metal-free conditions.

Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery.

Electrochemistry has been used as a tool to drive chemical reactions for over two centuries. With the help of an electrode and a power source, chemists are bestowed with an imaginary reagent whose potential can be precisely dialed in. The theoretically infinite redox range renders electrochemistry capable of oxidizing or reducing some of the most tenacious compounds (e.g., F- to F2 and Li+ to Li0). Meanwhile, a granular level of control over the electrode potential allows for the chemoselective differentiation of functional groups with minute differences in potential. These features make electrochemistry an attractive technique for the discovery of new modes of reactivity and transformations that are not readily accessible with chemical reagents alone. Furthermore, the use of an electrical current in place of chemical redox agents improves the cost-efficiency of chemical processes and reduces byproduct generation. Therefore, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis and has seen increasingly broad use in the synthetic community over the past several years.While electrochemical oxidation or reduction can provide access to reactive intermediates, redox-active molecular catalysts (i.e., electrocatalysts) can also enable the generation of these intermediates at reduced potentials with improved chemoselectivity. Moreover, electrocatalysts can impart control over the chemo-, regio-, and stereoselectivities of the chemical processes that take place after electron transfer at electrode surfaces. Thus, electrocatalysis has the potential to significantly broaden the scope of organic electrochemistry and enable a wide range of new transformations. Our initial foray into electrocatalytic synthesis led to the development of two generations of alkene diazidation reactions, using transition-metal and organic catalysis, respectively. In these reactions, the electrocatalysts play two critical roles; they promote the single-electron oxidation of N3- at a reduced potential and complex with the resultant transient N3• to form persistent reactive intermediates. The catalysts facilitate the sequential addition of 2 equiv of azide across the alkene substrates, leading to a diverse array of synthetically useful vicinally diaminated products.We further applied this electrocatalytic radical mechanism to the heterodifunctionalization of alkenes. Anodically coupled electrolysis enables the simultaneous anodic generation of two distinct radical intermediates, and the appropriate choice of catalyst allowed the subsequent alkene addition to occur in a chemo- and regioselective fashion. Using this strategy, a variety of difunctionalization reactions, including halotrifluoromethylation, haloalkylation, and azidophosphinoylation, were successfully developed. Importantly, we also demonstrated enantioselective electrocatalysis in the context of Cu-promoted cyanofunctionalization reactions by employing a chiral bisoxazoline ligand. Finally, by introducing a second electrocatalyst that mediates oxidatively induced hydrogen atom transfer, we expanded scope of electrocatalysis to hydrofunctionalization reactions, achieving hydrocyanation of conjugated alkenes in high enantioselectivity. These developments showcase the generality of our electrocatalytic strategy in the context of alkene functionalization reactions. We anticipate that electrocatalysis will play an increasingly important role in the ongoing renaissance of synthetic organic electrochemistry.

New Bisoxazoline Ligands Enable Enantioselective Electrocatalytic Cyanofunctionalization of Vinylarenes.

In contrast to the rapid growth of synthetic electrochemistry in recent years, enantioselective catalytic methods powered by electricity remain rare. In this work, we report the development of a highly enantioselective method for the electrochemical cyanophosphinoylation of vinylarenes. A new family of serine-derived chiral bisoxazolines with ancillary coordination sites were identified as optimal ligands.

Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex.

We report the development of a new aminoxyl radical catalyst, CHAMPO, for the electrochemical diazidation of alkenes. Mediated by an anodically generated charge-transfer complex in the form of CHAMPO-N3, radical diazidation was achieved across a broad scope of alkenes without the need for a transition metal catalyst or a chemical oxidant. Mechanistic data support a dual catalytic role for the aminoxyl serving as both a single-electron oxidant and a radical group transfer agent.

Electrochemical Azidooxygenation of Alkenes Mediated by a TEMPO-N3 Charge-Transfer Complex.

We report a mild and efficient electrochemical protocol to access a variety of vicinally C-O and C-N difunctionalized compounds from simple alkenes. Detailed mechanistic studies revealed a distinct reaction pathway from those previously reported for TEMPO-mediated reactions. In this mechanism, electrochemically generated oxoammonium ion facilitates the formation of azidyl radical via a charge-transfer complex with azide, TEMPO-N3. DFT calculations together with spectroscopic characterization provided a tentative structural assignment of this charge-transfer complex. Kinetic and kinetic isotopic effect studies revealed that reversible dissociation of TEMPO-N3 into TEMPO• and azidyl precedes the addition of these radicals across the alkene in the rate-determining step. The resulting azidooxygenated product could then be easily manipulated for further synthetic elaborations. The discovery of this new reaction pathway mediated by the TEMPO+/TEMPO• redox couple may expand the scope of aminoxyl radical chemistry in synthetic contexts.

Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes.

We report Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines and alkenes. This method provides an efficient approach to the synthesis of pyrrolidines, structural units prevalent in bioactive compounds and organocatalysts, from readily available starting materials. The overall redox-neutral reaction was achieved via a redox-relay mechanism, which harnesses radical intermediates for selective C-N bond cleavage and formation.