A novel tunable aromatic bromination method using alkyl bromides and sodium hydride in DMSO MaoJun Guo, * Laszlo Varady, Demosthenes Fokas, Carmen Baldino and Libing Yu ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA Received 26 January 2006; accepted 29 March 2006 Available online 27 April 2006 Abstract—Aromatic bromination on various aromatic systems with different substitutions was performed in the presence of alkyl bromide and sodium hydride in DMSO. Mono-bromination on a wide range of substrates was achieved by selecting proper alkyl bromides and controlling its amount. Further bromination could happen with more active alkyl bromides and additional amount of bromides and sodium hydride. The yields ranged from moderate to excellent. In addition, reaction mechanism was postulated to explain our observations. Ó 2006 Elsevier Ltd. All rights reserved. Bromoarenes continue to be important synthetic inter- mediates for pharmaceutical and or other chemical related industries. The Suzuki coupling reaction 1 using bromoarenes as starting materials has fueled the devel- opment of efficient and selective bromination under milder conditions. 2–4 A variety of electrophilic bromina- tion reagents include NBS/HBF 4 –Et 2 O, Br 2 in haloge- nated hydrocarbons or acetic acid, dioxane dibromide, pyridinum hydrobromide perbromide, DBU hydro- bromide, tetra-alkyl ammonium tribromide, and bromo- dimethylsulfonium bromide [(CH 3 ) 2 SBr 2 ], 5 which have been of choice for different substrates. 6 Herein, we wish to report a novel tunable aromatic bromination method for diverse set of substrates under basic condi- tions, using alkyl bromides and sodium hydride in DMSO. 7 This bromination system was initially discovered in the course of investigating alkylating reaction of dihydro- quinazolin-4-one 1 8 with various alkyl halides including allyl chloride, allyl bromide, allyl iodide, 1-chloro-2- pentyne, and 1-bromo-2-pentyne, for the development of screening libraries. Besides alkylating reaction, an unexpected bromination reaction occurred to produce brominated by-products (compounds 3, 4, and 5) when the reaction was run in DMSO at 80 °C with excess of alkyl bromide and nonnucleophilic base sodium hydride 9 (Scheme 1). The distribution of brominated products (3, 4, and 5) varied with different alkyl bromides used. However, chlorination or iodination did not occurred under the same reaction condition, while alkyl chlorides or alkyl iodides were used in place of bromide correspondingly. It is noteworthy that Fletcher and Fan 10 reported the bromination of anilines in the presence of ethyl bromide in DMSO, but it required a much higher temperature (150 °C). In our case, bromination was observed only when DMSO was used as solvent and sodium hydride was used as base. Other bases, such as t-Bu t OK, did 0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.03.191 * Corresponding author. E-mail: MaoGuo2001@yahoo.com N H N R 2 R 1 O R Br N H N R 2 R 1 O R NH H N R 2 R 1 O NH H N R 2 R 1 O Br NH H N R 2 R 1 O Br Br + + NaH / 2 eq.RBr DMSO 80 ºC 1 4 5 + 2 3 Scheme 1. Bromination of dihydroquinazolin-4-ones (1) with different alkyl bromides. Tetrahedron Letters 47 (2006) 3889–3892