Electrophilic Bromination of meta-Substituted Anilines with N-Bromosuccin­imide: Regioselectivity and Solvent Effect

Abstract

N-Bromosuccinimide-mediated electrophilic aromatic bromination of a series of anilines substituted with an electron-withdrawing group in the meta position was investigated. The regioselectivity of the reaction is markedly dependent on the polarity of the solvent and the bromination reaction can be tuned by appropriate selection of the reaction medium.Brominated aromatic compounds are of considerable interest, both for their intrinsic properties (numerous biologically active molecules contain a brominated aromatic unit) and for their use as reactive intermediates in the synthesis of important drugs, because of their ability to undergo carbon-carbon and carbon-heteroatom bondformation reactions.Electrophilic aromatic bromination was probably one of the earliest reaction to be discovered and studied by organic chemists. 1 Its mechanism is generally regarded as starting from a p-complex B, 2 a pre-reactive intermediate that evolves into a s-complex C (the Wheland intermediate), the formation of which represents the rate-determining step of the process in most cases (Scheme 1). 3 N-Bromosuccinimide is a well-known reagent for electrophilic aromatic bromination. In 1979, Mitchell et al. 4 reported that N-bromosuccinimide in N,N-dimethylformamide is a mild and selective reagent for nuclear monobromination of reactive aromatic compounds. Since then, several regioselective methods have been developed that use N-bromosuccinimide alone 5 or in combination with a variety of additives, both for deactivated 6 and activated 7 ortho-and para-disubstituted substrates. Surprisingly neither the regioselectivity nor the solvent effect in the bromination of meta-substituted aromatics with Nbromosuccinimide has been extensively investigated. meta-Substituted anilines 1a-h (Scheme 2), all of which contain an electron-withdrawing group, seemed to be appropriate starting points for our study, the aim of which was to explain some unexpected results obtained in our laboratories during routine synthetic work on analogous substrates. Bromination of 1a-h by N-bromosuccinimide was studied in a panel of seven solvents. Scheme 2 X = (a) NO 2 ; (b) CF 3 ; (c) CN; (d) CO 2 Me; (e) COMe; (f) F; (g) Cl; (h) Br The polarity of the solvents examined ranged from low in the case of dioxane [dielectric constant (e) = 2.2] to high in the case of dimethyl sulfoxide (DMSO; e = 47.2). The results obtained (Table 1) confirm that the regioselectivity of the reaction is markedly dependent on the solvent.Plots of the molar fraction of isomers 3a, 3d, 3e, and 3f against e (Figure 1a; curves for 3c, 3d, 3g, and 3h are not reported for the sake of clarity) show an almost linear correlation until e reaches a value of around 20, where the curves reach a plateau. A similar trend is observed with solvent mixtures of tetrahydrofuran (e = 7.5) with increasing fractions of water (e = 80) (Figure 1b; curve for 3b). Regardless of the nature of X, bromination seems to be very selective in polar media (DMF, DMSO), where 3 is formed almost exclusively.

The Synthesis of Chiral Benzothiazine and Thiazinoquinoline Derivatives

“…The preparation of 4a required 3‐amino‐2‐bromoacetophenone ( 6a ), which we intended to prepare by bromination of 3‐aminoacetophenone ( 5 ). Guided by the important findings of Fattori and co‐workers on solvent effects in electrophilic brominations of meta ‐substituted anilines,9 we performed the halogenation of 5 by using N ‐bromosuccinimide (NBS) in 1,4‐dioxane (Scheme ). Unfortunately, this transformation resulted in a rather low site selectivity to afford a mixture of 2‐bromo‐3‐aminoacetophenone ( 6a ) and 3‐amino‐6‐bromoacetophenone ( 6b ) in an almost equimolar ratio (Scheme ).…”