A convenient and regioselective oxidative bromination of electron-rich aromatic rings using potassium bromide and benzyltriphenylphosphonium peroxymonosulfate under nearly neutral reaction conditions Hadi Adibi, a, * Abdol R. Hajipour b,c and Majid Hashemi d a Department of Medicinal Chemistry, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah 67168-67346, Iran b Pharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran c Department of Pharmacology, University of Wisconsin, Medical School, 1300 University Avenue, Madison, Wisconsin 53706-1532, USA d Research and Petroleum Engineering Center of Kermanshah (A Branch of RIPI), Kermanshah 67146-77717, Iran Received 1 November 2006; revised 25 November 2006; accepted 8 December 2006 Available online 4 January 2007 Abstract—Regioselective oxidative bromination of electron-rich aromatic rings has been studied using potassium bromide as a bro- mine source in the presence of benzyltriphenylphosphonium peroxymonosulfate as oxidant under nearly neutral reaction conditions. In most cases we obtained monobrominated derivatives regioselectively and in good to high yields without the aid of strong acids. Ó 2006 Elsevier Ltd. All rights reserved. Brominated aromatic compounds have gained increas- ing interest as versatile intermediates for the synthesis of biologically active compounds such as potent anti- tumour, antibacterial, antifungal, antiviral, and anti- oxidizing agents. 1 Conventional bromination methods typically use elemental bromine, generating toxic, and corrosive hydrogen bromide, leading to environmental pollution. 2 Traditional methods of aromatic bromina- tion involve the use of nonselective hazardous acidic reagents such as mineral acids and metal halides, which can lead to separation difficulties and toxic and corro- sive wastes. Examples of conventional and traditional methods include: Br 2 –Lewis acids, 3 NBS–H 2 SO 4 – CF 3 CO 2 H, 4 NBS–PTSA, 5 NBS–NaOH, 6 NBS–SiO 2 , 7 Br 2 –Al 2 O 3 , 8 Br 2 –Zeolite, 9 NBS–Amberlyst, 10 NBS- HZSM-5, 11 Clayzib, 12 tert-BuOOH– or H 2 O 2 –HBr, 13 and HBr–DMSO. 14 The replacement of such reagents with non-toxic and more selective reagents is very desir- able and represents an important goal in the context of clean synthesis. The use of potassium bromide as bromi- nating reagent in the presence of sodium tungstate or ammonium molybdate as catalyst using hydrogen peroxide or sodium perborate as an oxidant has been developed. 15 Oxone Ò (2KHSO 5 ÆKHSO 4 ÆK 2 SO 4 ) is an inexpensive, water-soluble, and stable oxidizing reagent that is commercially available, however, this reagent is insoluble in organic solvents and buffering is needed due to its acidity. 16 Recently, sodium bromide or potas- sium bromide combined with Oxone Ò has been used as an effective reagent for the bromination of activated arenes. 17 Replacement of the potassium cation in potassium peroxymonosulfate with quaternary phos- phonium is very desirable and increases its solubility in organic solvents. Recently, we reported benzyltriphenylphosphonium per- oxymonosulfate BTPPMS as a mild, inexpensive and efficient reagent in organic transformations. 18 Following our continued interest in BTPPMS and in the course of our studies on the halogenation of organic com- pounds, 19 we herein report highly efficient and selective bromination reactions of activated arenes employing potassium bromide as the bromine source and BTPPMS as the oxidant under non-aqueous conditions. 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.12.033 Keywords: Activated arenes; Benzyltriphenylphosphonium peroxy- monosulfate; Oxidative bromination; Potassium bromide. * Corresponding author. Tel.: +98 831 4276482; fax: +98 831 4276493; e-mail: hadibi@kums.ac.ir Tetrahedron Letters 48 (2007) 1255–1259