Accelerating reaction generality and mechanistic insight through additive mapping

Abstract

Reaction generality is crucial in determining the overall impact and usefulness of synthetic methods. Typical generalization protocols require a priori mechanistic understanding and suffer when applied to complex, less understood systems. We developed an additive mapping approach that rapidly expands the utility of synthetic methods while generating concurrent mechanistic insight. Validation of this approach on the metallaphotoredox decarboxylative arylation resulted in the discovery of a phthalimide ligand additive that overcomes many lingering limitations of this reaction and has important mechanistic implications for nickel-catalyzed cross-couplings.

Fig. 1.. High-throughput additive mapping to understand and improve organic methods.

Shown are the traditional approach and select successes, as well as the proposed HTE additive mapping approach.

Fig. 2.. Additive mapping applied to the decarboxylative reaction.

(A) Metallaphotoredox decarboxylative arylation. (B) High-throughput additive screening on challenging coupling partners revealing the imide effect. (C) Left: SAR studies to identify the ideal five-membered imide. A set of 64 imides was evaluated in 48 couplings to reveal the best imide. Right: Phthalimide can counteract the poisoning effect of problematic functionalities.

Fig. 3.. Scope of the decarboxylative arylation.

(A) Scope of the Aryl Halide Informer Library investigated against tetrahydropyran-4-carboxylic acid (% CAD yield reported). (B) Nanoscale high-throughput scope evaluation (% isolable reported). A product is deemed isolable if the CAD yield is ≥10%. n, number of evaluated compounds in this category; EDG, electron-donating group.

Fig. 4.. Mechanistic insight.

(A) Decrease of protodehalogenation observed with phthalimide caused by stabilization of the OAC. For the x-ray structure (50% probability ellipsoids), hydrogens and tBu/CF3 disorder are omitted for clarity. (B) Slower quenching is tolerated because of the increased OAC concentration. (C) Increasing active Ni on cycle by activation of low-valent Ni oligomers.