A Oxidative Bromination of (Hetero)Arenes in the TMSBr/DMSO System: A Non‐Aqueous Procedure Facilitates Synthetic Strategies

Abstract

An oxidative bromination protocol for aromatic compounds using trimethylsilyl bromide (TMSBr) and DMSO has been developed. This mild bromination system tolerates a wide variety of functionalities including amide, aldehyde, ester and acetal groups. Arylbromides and heteroarylbromides are produced in up to 95 % yield at 25 °C. Arenes bearing electron‐donating groups are selectively brominated at the para position unless it is blocked. The highlight of this protocol consists in its non‐aqueous conditions, which are fruitful particularly in the context of integrated synthetic systems. The utility of this method was demonstrated with three examples, in either of which the bromination was followed by another reaction: a “click” triazole formation, a Suzuki–Miyaura cross‐coupling, or an aldehyde formation via lithium–bromine exchange, without the isolation of the bromide intermediate in any case. It is particularly remarkable for this non‐aqueous protocol to allow lithiation reactions to sequentially follow the bromination.

Mild and Regioselective Bromination of Phenols with TMSBr

“…Recently, the reactant ratios, the reaction solvents and the bromo surrogates were carefully investigated to improve the reaction yield and selectivity. For example, by careful investigation on the dosage of DMSO, Jiao and co‐workers reported a selective bromination of phenols with HBr/DMSO at 60 °C; Togni and co‐workers developed a much milder bromination of phenols with TMSBr/DMSO at room temperature (as to phenol, p/o = 88:12) . However, obtaining high selectivity at para ‐position of phenols remains challenging, due to the negligibly electronic differences between para ‐position and ortho ‐position of phenols.…”

Recent Update on Transition Metal‐Free C(sp2)−H Bond Halogenation in (Hetero) Arenes

“…An oxidative bromination methodology has been reported by Kajita and Togni using DMSO as the oxidizing agent and TMSBr as the bromine source(Scheme 20). [33] A broad range of functional group was tolerated under this protocol such as amide, aldehyde, amine etc. Arenes ( 30 ) containing electron donating substituent gave para ‐brominated product selectively unless the para position was blocked.…”

Design, synthesis, and evaluation of cytotoxic activities of arylnaphthalene lignans and aza‐analogs

“…Here too, the most significant obstacle in this scheme was the regioselective aromatic bromination as it has been strongly affected by the solvents and brominating agents used together with the substituents on the naphthalene core. [48][49][50][51][52][53][54][55][56][57][58][59][60][61] So, several parameters were examined and trials have been carried out to control the regioselectivity. The best conditions found were, on the one hand, reaction of 1 with pyridinium tribromide at 0°C in tetrahydrofuran (THF), [50] which gave the 3-bromo compound 15 in excellent yield without producing the 1-regioisomer (Scheme 6).…”