Tris(4-bromophenyl)aminium Hexachloroantimonate-Mediated Intermolecular C(sp²)–C(sp³) Free Radical Coupling of Vindoline with β-Ketoesters and Related Compounds

Abstract

A powerful tris­(4-bromophenyl)­aminium hexachloro­antimonate (BAHA) mediated regioselective intermolecular coupling reaction of vindoline with a wide range of substrates that include β-ketoesters, β-diketones, β-ketoaldehydes, β-ketonitriles, β-ketolactones, β-ketolactams, β-cyanoesters, and malononitriles is detailed. The BAHA-promoted intermolecular sp3/sp2 coupling, representing a special class of selective C–H functionalization reactions with direct carbon–carbon bond formation, proceeds with generation of a quaternary center bound to the aryl C15 center of vindoline capable of accommodating of the vinblastine C16′ methyl ester and functionalized for subsequent divergent heterocycle introduction. A comprehensive examination of the reaction scope, optimization of subtle reaction parameters, and key insights into the reaction mechanism are described. Contrary to what might be prevailing expectations, studies suggest the plausible mechanism entails initial single-electron oxidation of the substrate enolate, not vindoline, and subsequent regiospecific addition of the resulting electrophilic radical to vindoline. As such and beyond the new arylation reaction with vindoline, the studies define a host of new, previously unrecognized, applications of BAHA and related triarylaminium radical cations that arises from their ability to generate stabilized electrophilic radicals from β-ketoesters and related substrates under nonreducing and metal-free conditions. Those exemplified herein include mediating stabilized enolate free radical arylation, dimerization, allylation, alkene addition, and α-oxidation reactions.

Aryl Annulation: A Powerful Simplifying Retrosynthetic Disconnection

“…and vindoline (7), exploiting a powerful hypervalent iodine coupling reaction 47 or a recent BAHA 48,49 variant that was developed specifically for this purpose. As the plans for these studies evolved, we came to recognize that this approach is not only enabling for late-stage divergent introduction of indole replacements, but also represents an unappreciated powerful synthetic design element substantially increasing the molecular complexity of the resulting products.…”

“…Scheme 2 Increase in complexity (C m ) 51 or intricacy (°I) 55 for Fischer indole annulation, a powerful simplifying retrosynthetic disconnection Compound 8 was selected as a suitable simplified substrate with which to conduct the studies, since it contains the fully functionalized intact lower subunit (vindoline) found in vinblastine, includes the desired C2′ carbonyl to direct the aryl annulation, and incorporates the adjacent quaternary center and its methyl ester (Scheme 3). Compound 8 is readily available in a single step and was prepared as a 1:1 mixture of diastereomers by both a bis(trifluoroacetoxy)iodobenzene (PIFA; 67-71%) 47 or BAHA (55%) 48 medi-ated oxidative coupling reaction of the -keto ester 2-(methoxycarbonyl)cyclohexanone and vindoline (7). Summarized in Scheme 3 are key and representative aryl annulations conducted on 8 with a focus on those that would be integral to a first-level interrogation of their impact when incorporated into the vinblastine core structure.…”

Dual-Catalyzed Stereodivergent Electrooxidative Homocoupling of Benzoxazolyl Acetate

“…In terms of simplicity and atom economy, the dehydrogenative homocoupling reaction of carbonyl compounds, pioneered in 1935 by Ivanoff and Spassoff, has emerged as a fundamental transformation that represents a unique type of C­(sp 3 )–C­(sp 3 ) bond formation . However, the programmable synthesis of complete stereoisomers of dl / meso molecules from a single set of racemic starting materials poses a significant challenge (Scheme A). , …”

Recent advances in the electrochemical generation of 1,3-dicarbonyl radicals from C–H bonds

“…9 In addition, photocatalysis provides an alternative and efficient route to produce 1,3-dicarbonyl radicals from C–H bonds, but the use of oxidants or metal reagents in oxidation-type reactions is unavoidable. 10…”