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Keywords:
automated grinding; chemoselectivity; mechanochemistry; N-bromosuccinimide; PEG-400; regioselectivity; stoichiometry-controlled halogenation
Abstract
A simple electrical mortar-pestle was used for the development of a green and facile mechanochemical route for the catalyst-free halogenation of phenols and anilines via liquid-assisted grinding using PEG-400 as the grinding auxiliary. A series of mono-, di-, and tri-halogenated phenols and anilines was synthesized in good to excellent yields within 10-15 min in a chemoselective manner by controlling the stoichiometry of A-halosuccinimides (NXS. X = Br. I. and Cl). It was observed that PEG-400 plays a key role in controlling the reactivity of the substrates and to afford better regioselectivity. Almost exclusive /wra-selectivity was observed for the aromatic substrates with free o- and /»-positions for mono- and dihalogenations. As known, the decarboxylation (or desulfonation) was observed in the case of salicylic acids and anthranilic acids (or sulfanilic acids) leading to 2.4.6-trihalogenated products when 3 equiv of NXS was used. Simple instrumentation, metal-free approach, cost-effectiveness, atom economy, short reaction time, and mild reaction conditions are a few noticeable merits of this environmentally sustainable mechanochemical protocol.
Introduction
Aryl halides are valuable compounds with potent bioactivities [1-5] (Figure 1) and are utilized as crucial precursors for various metal-catalyzed cross-coupling reactions [6-9]. They are frequently used as synthetic intermediates in several valueadded syntheses of natural products, pharmaceuticals, agrochemicals. and advanced materials [10-14]. The ubiquity of halogen atoms in these synthetic building blocks urges the development of efficient, sustainable, and mild methods for aromatic halogenation.
The century-old classical method of using hazardous and corrosive reagents X2 (X = Br. Cl) suffers from low atom economy (<50%). formation of corrosive byproducts (e.g.. HBr) [15.16], which cause serious environmental issues. To mitigate the problem. several mild and operationally safe halogenating agents have been successfully introduced to replace X2 [17-31]. Among them, the use of A-halosuccinimides has turned out to be a viable alternative to X2 because of their low-cost, ease of handling, and possible recycling of the byproduct succinimide [24-31]. In several earlier cases, the bromination with A-bromosuccinimide (NBS) was carried out in toxic polar solvents (e.g.. DMF). but no iodinated or chlorinated products were obtained because of the low reactivity of NIS and NCS (Scheme la) [2427]. In recent time, the use of Lewis or Brpnsted acids. Lewis...