Chloride-mediated electrochemical synthesis of oxazolines

Abstract

In this issue of Chem Catalysis, Liang et al. report an efficient electrochemical cyclization reaction of alkenes and amides to produce oxazolines with broad substrate scopes and good selectivities. A chloronium species generated by the chloride-mediated redox catalysis is proposed as a key intermediate.

Oxazoline and its derivatives are valuable pharmaceutical compounds, agro-chemicals, polymer precursors, and ligands for catalysis.^1–3 At present, oxazolines are produced mainly by cyclization between 2-amino alcohols and carboxylic acids,⁴ aldehydes,⁵ or nitrile.⁶ However, these well-known synthetic methods suffer from non-scalability, undesired by-products, or critical reaction conditions. Moreover, the site- and diastereoselectivities of desired oxazolines remain challenging. In this issue of Chem Catalysis, Liang et al. demonstrate an efficient electrochemical methodology to synthesize oxazolines through a 3+2 cyclization reaction between amides and olefins with excellent site- and diastereoselectivities (Figure 1A).⁷

Figure 1. Liang et al.’s electrochemical synthesis of oxazolines and proposed mechanism.

(A) Electrochemical synthesis of oxazolines reported by Liang et al.

(B) Proposed electrocatalytic mechanism.

The oxidation of olefin requires strong oxidants, metal reagents, or iodine reagents in traditional thermal reactions, which increases synthetic cost and complexity.⁸ Under an electrochemical anodic condition, olefins can be oxidized to alkene radicals, but the reactive alkene radicals would be subject to undesired self-dimerization.⁹ To efficiently trap the reactive alkene radical by an amide and form an oxazoline product, Liang et al. proposed using 1,2-dichloroethane (DCE) as a source to in situ generate chloride (Cl⁻) as a redox mediator for the oxidation of alkene. Indene and benzamide were chosen as the model substrates for the optimization of reaction conditions. Under the optimal conditions, the reaction was carried out with DCE as the solvent, sodium acetate as the base, and 0.1 M tetrabutylammonium hexafluorophosphate as the supporting electrolyte, with a current density of 5.3 mA/cm² for electrolysis at 80°C and done under a nitrogen atmosphere (Figure 1A). Substrate scopes for both amides and alkenes were then examined with more than fifty examples. Benzamides bearing an electron-with-drawing (e.g., –Cl, –F, and –CF₃) or electron-donating group (e.g., –CH₃ and –OCH₃) on m-, p-, or o-position exhibited excellent site selectivities (>20 d.r.) and fair-to-good yields (27%–75%) for oxazoline products. Alkyl amides also provided oxazoline products in reasonable yields. On the other hand, indene derivatives and styrene derivatives were tested to produce desired heterocycle products in good yields and high diastereoselectivities.

The team carried out a series of mechanistic experiments to understand this reaction, leading to a proposed electrocatalytic mechanism (Figure 1B). In the absence of the sodium acetate base, a chloride-containing amide product (ii in Figure 1B) with the formation of a new C–N bond was isolated from the reaction of styrene and benzy-lamide. The chloride-containing amide could be further converted to the expected oxazoline after the base was added. These experiments suggest that the chloride-containing amide would be a reaction intermediate. A chloronium species¹⁰ was further postulated as a key intermediate (i in Figure 1B), resulting in the formation of the chloride-containing amide intermediate. It is believed that the in situ-generated chloride from the reduction of DCE (−1.5 V versus Ag/AgCl) functions as a redox mediator for the oxidation of alkene. Specifically, chlorine (Cl₂) generated from the anodic oxidation of chloride (1.5 V versus Ag/AgCl) can undergo a disproportion reaction with the alkene substrate to form the chloronium intermediate and regenerate the Cl⁻ redox mediator. Control experiments using other non-chlorinated solvents confirmed the essential role of the DCE solvent to provide the chloride redox mediator for reaction efficiency. It would be fundamentally interesting to further characterize the chloronium intermediate in future studies.

In summary, the electrochemical cyclization of alkenes and amides reported by Liang et al. in this issue of Chem Catalysis exhibits broad substrate scopes and good selectivities and represents an attractive approach to constructing oxazoline motifs. The chloride-mediated redox catalysis to access reactive intermediates could inspire new designs of electrochemical reactions.