Tungstate-Catalyzed Biomimetic Oxidative Halogenation of (Hetero)Arene under Mild Condition

Abstract

Aryl halide (Br, Cl, I) is among the most important compounds in pharmaceutical industry, material science, and agrochemistry, broadly utilized in diverse transformations. Tremendous approaches have been established to prepare this scaffold; however, many of them suffer from atom economy, harsh condition, inability to be scaled up, or cost-unfriendly reagents and catalysts. Inspired by vanadium haloperoxidases herein we presented a biomimetic approach for halogenation (Br, Cl, I) of (hetero)arene catalyzed by tungstate under mild pH in a cost-efficient and environment- and operation-friendly manner. Broad substrates, diverse functional group tolerance, and good chemo- and regioselectivities were observed, even in late-stage halogenation of complex molecules. Moreover, this approach can be scaled up to over 100 g without time-consuming and costly column purification. Several drugs and key precursors for drugs bearing aryl halides (Br, Cl, I) have been conveniently prepared based on our approach.

Keywords: Green Chemistry; Organic Chemistry; Pharmaceutical Engineering.

Graphical abstract

Figure 1

Previous Approach for Halogenation (Br, Cl, I) and Our Strategy (A) Typical examples of biologically important (hetero)aryl halides. (B–D) (B) Previous reported approaches for halogenation developed in laboratories. (C) The reaction mechanism of vanadium haloperoxidases (V-HPO) and comparison of V-η²-peroxy and W-η²-peroxy intermediates. (D) Biomimetic halogenation catalyzed by tungstate. HMPT, hexamethylphos-phor triamide.

Figure 2

Application in Synthesis of Selected Drugs and Key Precursors (A) Synthesis of quinoline drugs or key precursors, including clioquinol, iodoquinado, broxyquinoline, and precursor for broxaldine. (B) Synthesis of key precursor for brimonidine, a drug to treat ocular hypertension, rosacea, and open-angle glaucoma. (C) Synthesis of key precursor bromopride and metoclopramide, antiemetic drugs. (D) Synthesis for benzofuran drugs: benzbromaron, benziodarone, and amiodarone.

Figure 3

Hypothesis of Mechanism of Bromination/Iodination and Control Experiments (A) Radical trapping experiment. (B) Hypothesis of H-bonding effect with Brønsted acid. (C) Control experiments to probe the importance of H-bonding. (D) Effects of metal ion in chloride salts in chlorination.

Figure 4

Proposed Reaction Mechanism