A Unified Approach to Decarboxylative Halogenation of (Hetero)aryl Carboxylic Acids

Abstract

Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)­aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo­(hetero)­arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro­(hetero)­arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.

Photoactive Copper Complexes: Properties and Applications

“…Notably, stoichiometric amounts of MeCN-soluble NaF and LiClO 4 were employed as tandem anionic activators of the diboron reagent, and the reaction conditions were, moreover, suitable for a one-pot borylation/Suzuki–Miyaura sequence. Control experiments and previous work by the MacMillan group led to a hypothetical mechanism that would rely on a ligand to metal charge transfer (LMCT) of the in situ assembled photoactivatable copper(II)–substrate complex, generating the carboxylate radical and the corresponding copper(I) species. Decarboxylation would then lead to the aryl radical, whose further reaction with the activated borate would afford the desired product 257 .…”

Visible-Light-Induced Decarboxylative Fluorination of Aliphatic Carboxylic Acids Catalyzed by Iron

“…12 For instance, Jin and co-workers 9a first reported the decarboxylative alkylation of various heteroarenes by using iron as the photocatalyst. Despite the developments that have been made, as far as we know, only Ritter 13 and MacMillan 14 have described the stoichiometric Cu-mediated decarboxylative fluorination of (hetero)aryl carboxylic acids via UV light-induced LMCT strategy (Scheme 1 B); the fluorination of aliphatic acids via photocatalysis catalyzed with non-noble metals is still in its infancy. 15 Carboxylic acids are inexpensive, stable, and readily available feedstocks and have also been utilized for diverse transformations.…”

“…Notably, the product βfluoro-γ-butyrolactam 13, which was previously produced with a stoichiometric Ag salt, 18 could be prepared smoothly using a catalytic amount of iron salt. The reaction enjoyed good functional group tolerance with the case of phosphine oxide as an interesting example (14). To our delight, when 2benzylsuccinic acid was chosen as the substrate, the product 15 was produced in 61% isolated yield with the primary carboxylic acid group remaining, offering opportunities for diversified decarboxylative functionalization selectively.…”

Decarboxylative sulfoximination of benzoic acids enabled by photoinduced ligand-to-copper charge transfer

“…1A). 11,12 Given that copper-LMCT relies on the coordination of carboxylates to copper( ii ) species, strong coordination of NH-nucleophiles such as NH-sulfoximines will compete with carboxylates and form undesired copper species that can diminish the reaction efficiency. Though thermal aromatic decarboxylative C–N cross couplings under high reaction temperatures (normally more than 140 °C) have been explored by Jia, Gooβen, and Xie, electron-deficient ortho -substituted benzoic acids are required for efficient CO 2 extrusion (Fig.…”