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 costefficient 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.

From Reactive Oxygen Species to Reactive Brominating Species: Fenton Chemistry for Oxidative Bromination

“…With the discovery and optimized conditions of in situ RBS generation from FeBr 2 –H 2 O 2 and CeBr 3 –H 2 O 2 , we set out to expand the scope of arene bromination ,,− (Table -1). Brief examination of the substrate scope revealed that only electron-rich arenes were suitable for bromination to provide p -bromoarene products ( 2a – 2g ) in 52–97% yields ( p : o > 20:1) (Table -1).…”

Metalloenzyme-Inspired Ce-MOF Catalyst for Oxidative Halogenation Reactions

“…According to the reported mechanism for the halogenation process when using haloperoxidase enzymes, a metal-η 2 -peroxy intermediate is first formed in the presence of hydrogen peroxide with the corresponding metal oxidation (see II in Figure 7 a). 12 , 49 , 50 Afterward, this generated peroxide is opened by the halide species, resulting in the formation of an electrophilic hypohalite (see IV in Figure 7 a), which acts as an active electrophilic agent.…”

“…This experimental evidence of the formation of η 2 -peroxy species in aerobic conditions in the Ce-based catalysts, together with the excellent oxidase activity, in particular when using UiO-66(Ce) as a catalyst, could indicate that the reaction mechanism may be analogous to that reported for the homogeneous biomimetic catalysts with redox metal active sites. 12 Indeed, a possible oxidative halogenation mechanism when using oxidase-like UiO-66(Ce) with intrinsic redox sites can be proposed.…”

“…It is worth noting that the electrophilicity of the Ce-η 2 -peroxy species can be further enhanced by OH sites. 12 Finally, the peroxide species generated and the halide would yield an electrophilic hypobromite, which would act as an active electrophilic agent to halogenate arenes (see IV in Figure 7 b).…”

“… 10 Nevertheless, the incompatibility with some functional substituents in substrates, high deactivation under severe reaction conditions (pH, solvent, or temperature), and the difficult isolation of the enzyme from the reaction media are some serious limitations for large-scale applications. Inspired by metalloenzymes, vanadium-, 11 tungsten-, 12 and molybdenum-biomimetic 13 catalysts have attracted significant attention. However, these metals show serious health and environmental concerns.…”