Chemoselective Bromination of Active Methylene and Methyne Compounds by Potassium Bromide, Hydrochloric Acid and Hydrogen Peroxide

Abstract

Active methylene and methyne compounds can be chemoselectively brominated in high yields using potassium bromide, hydrochloric acid, and hydrogen peroxide at room temperature.Halogenated active methylene and methyne compounds are very important synthetic intermediates for the nucleophilic substitutions in synthetic organic chemistry. The classical methods of halogenation of active methylene and methyne compounds 1 are the reaction with bromine 1 or sulfuryl chloride, 2 however, they suffer from drawbacks such as toxicity of the reagents, generation of acidic gasses after the reaction, or overhalogenation of the aromatic rings in 1. Although a number of new methods of this transformation have previously been developed, most of them have severe disadvantages such as the production of undesirable waste. [3][4][5] Khan and co-workers recently developed chemoselective bromination of active methylene compounds by employing the vanadium pentoxide catalyzed (V 2 O 5 ) oxidation of ammonium bromide (NH 4 Br) by hydrogen peroxide (H 2 O 2 ). 5 The reaction conditions of this method are very mild, and the reaction affords a product in high yield with high chemoselectivity. However, there are still some problems such as the use of a toxic vanadium compound as the catalyst and dichloromethane as the solvent.We now describe the chemoselective bromination of 1 by potassium bromide, hydrochloric acid and 30% hydrogen peroxide in toluene (Scheme 1). This method provides the desired monobromide 2 in high yields, while producing only nontoxic potassium chloride and water as waste.During the course of our study of the tantalum(V)-catalyzed oxidation of halogen anions to halogen cation equivalents, 6-8 we found that 1,3-diphenylpropane-1,3-dione could be quantitatively monobrominated by treatment with TaCl 5 (0.1 equiv), KBr (8.0 equiv), H 2 O 2 (8.0 equiv) and aqueous HCl (8.0 equiv) in chloroform. 6 We further examined the reaction, and found that the monobrominated compound could be obtained in the absence of the tantalum(V) catalyst. The most appropriate conditions are the treatment of 1 with KBr (5.0 equiv), HCl (5.0 equiv), and H 2 O 2 (20.0 equiv) in toluene at room temperature with stirring by a magnetic stirrer (Table 1).Several compounds with general structure 1 were examined under the reaction conditions, and the monobrominated compounds 2 quantitatively obtained in most cases. These results are summarized in Table 2. It is notable that the aromatic ring (entries 1 and 2), the ester group (entries 3-6), the amide group (entries 1 and 2) were inert under the given reaction conditions. Unfortunately, allyl acetoacetate (1k) did not provide the desired compound but complex mixture (entry 8). In this case, the alkene part of 1k also might react with the bromonium ion equivalent. Furthermore, we found that the use of a mechanical stirrer instead of a magnetic stirrer is effective in driving the reaction. In the case of using a mechanical stirrer, 1 quantitatively reacted with KBr (1.0 equiv), HCl (1.0 equiv), and H 2 O 2 (1.2 e...

Oxidative Halogenation with “Green” Oxidants: Oxygen and Hydrogen Peroxide

“…[10] A combination of KBr, HCl (5 equiv of each), and an excess of H 2 O 2 have been applied to the chemoselective bromination of the active methylene group of 1,3-dicarbonyl compounds in toluene at room temperature (Scheme 23). [101] Interestingly, it was observed that the use of a mechanical stirrer instead of a magnetic one was more effective in driving the reaction, and that only 1 equivalent of KBr and HCl and 1.2 equivalents of H 2 O 2 were sufficient to obtain quantitative yields of brominated products.…”

Synthesis, biological investigation and molecular docking study of N-malonyl-1,2-dihydroisoquinoline derivatives as brain specific and shelf-stable MAO inhibitors

“…A plausible reaction mechanism is that bromide ion is oxidized by hydrogen peroxide into the bromo ion (Br þ ) which reacts with the enol form of the active methylene compound providing selectively the desired monobromo derivative while only nontoxic potassium chloride and water are produced as a waste [30].…”

“…The freshly prepared solution of DHIQCDS (18) (25 mg/mL in DMSO) was injected through the external jugular vein at a dose of 20 mg/kg of body weight. At appropriate time intervals (5,15,30,45, 60, 75 min) blood samples were withdrawn from the eyeball and added immediately to a previously weighted centrifuge tubes containing 4 mL of acetonitrile, then reweighed to determine the amount of the blood added. The animal was then decapitated, and the brain was removed quickly, washed with ice cold saline solution, weighed, wrapped in aluminum foil and immediately kept in the freezer together with the blood samples.…”

Halogenation of β-keto-sulfones using KX/H2O2in aqueous medium: Synthesis of α-halo β-keto-sulfones and α-halomethyl sulfones

“…Masayuki et al reported chemoselective bromination of active methylene and methine compounds using potassium bromide, hydrochloric acid and hydrogen peroxide [47]. Recently, we have reported the facile synthesis of β-keto-sulfones [48] and direct synthesis of α-iodo β-keto-sulfones and their base-induced cleavage to afford α-iodomethyl sulfones [49].…”