Decarboxylative alkylation of alkenes | Nature

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Subjects

- Synthetic chemistry methodology

Abstract

Alkenes are widely used functional groups in synthetic chemistry, important for producing polymers, detergents, agrochemicals and pharmaceuticals. When treated with electrophiles, alkenes typically undergo addition, not substitution, reactions1. As a consequence, the intuitive retrosynthetic disconnection to form a substituted alkene from the parent alkene does not exist in the toolbox of the chemist. For example, conversion of tri-substituted into tetra-substituted alkenes, or late-stage alkylation of complex alkenes, would provide access to molecules that are currently difficult to construct. Alkene cross-metathesis can formally alkylate appropriately substituted alkenes, but diastereoselectivity and alkene–alkyl combinations are restricted to specific cases2, and several classes of alkenes, such as internal or cyclic alkenes, cannot be readily alkylated with known methods3. Here we report a formal regio- and diastereoselective C−H alkylation of alkenes with carboxylic acids as alkyl source, readily available in large diversity. Key to the development is a polar decarboxylative alkylation that deviates from the current model of radical-mediated C−C bond formation from carboxylic acid derivatives, enabled by a previously unappreciated access to persistent alkylzinc intermediates from redox-active esters. A Pd-catalysed cross-coupling of the alkylzinc species with alkenyl thianthrenium salts accessed from alkenes affords the substituted alkenes in high diastereoselectivity. The transformation offers alkylation of cyclic, acyclic, terminal, internal, mono-substituted, di-substituted and tri-substituted alkenes with diverse alkyl groups.

Main

Arenes and alkenes share the presence of C(sp2)–H bonds of similar bond dissociation energy, yet their reactivity differs fundamentally. Arenes undergo electrophilic substitution because of aromatic stabilization, for example, in Friedel–Crafts alkylation. By contrast, alkenes react by electrophilic addition (Fig. 1a), which prevents analogous substitution chemistry, so there is no alkene analogue to Friedel–Crafts alkylation, and the general alkylation of alkenes remains unknown. Current strategies for substituted alkene synthesis commonly rely on alkenation reactions such as the Wittig4, Horner–Wadsworth–Emmons (HWE)5,6 and Julia protocols7, which proceed from carbonyl compounds. Reductive alkylation of alkynes8,9,10 offers an alternative. Alkene cross-metathesis provides a formal alkylation pathway directly from alkenes by transalkenylidination, but the types of alkene suitable for cross-metathesis with one another must be carefully selected, and the reaction is restricted to alkene pairs of appropriate reactivity11. Moreover, E-selective cross-metathesis of 1-alkenes and 1,1-di-substituted alkenes remains unknown, and several alkene classes, such as tri-substituted and cyclic alkenes, cannot be alkylated with alkene metathesis at all due to the mechanism-based alkylidene transfer that breaks the C=C double bond before a new one is formed12,13,14. An alternative approach to alkene synthesis involves cross-coupling between alkenyl nucleophiles or electrophiles and appropriate alkyl donors. Examples include alkenyl organometallic reagents that react with alkyl (pseudo)halides or redox-active esters, or conversely, alkenyl (pseudo)halides that react in cross-coupling reactions with alkyl nucleophiles or electrophiles15,16,17. However, alkenyl nucleophiles such as Grignard reagents often require multistep preparation from alkenes, show low tolerance to functional groups, and are generally not readily available in large scope18. Alkenyl electrophiles such as halides or triflates are, while synthetically immensely versatile19, similarly difficult to access directly from alkenes, typically using multistep sequences, such as dibromination followed by elimination, which can form multiple constitutional isomers that reduce practicality20. Alkylation of alkenylthianthrenium salts is known as demonstrated in our previous work, but so far limited to a few simple, available alkylzinc reagents and restricted to terminal 1-alkenes and vinyl groups only21,22,23. Alkylation of other alkenyl sulfonium salts is confined only to styrenes24,25. Efforts to alkylate alkenes have so far been limited to electronically activated alkenes, such as styrenes26 or Michael acceptors27, and the diversity of applicable alkyl groups is narrow28. Heck-type alkylations typically involve the addition of alkyl halides or equivalents under palladium catalysis26 or through photo-induced radical pathways but are generally limited to styrenes or other activated alkenes29,30,31. Alkyl carboxylic acids are excellent alkyl sources because they offer a massive, structurally diverse pool of bench-stable resources. Alkenes and alkyl carboxylic acids are among the most abundant functional groups in organic synthesis, and a general method to use the