Mild Regioselective Monobromination of Activated Aromatics and Hetero­aromatics withN-Bromosuccinimide in Tetrabutylammonium Bromide

Highly regioselective nuclear bromination of activated aromatic and heteroaromatic compounds has been accomplished us- ing N-bromosuccinimide in tetrabutylammonium bromide. Pre- dominant para-selective monobromination of activated aromatics such as phenols and anilines, rate acceleration of bromination for moderately activated and less reactive substrates on addition of acidic montmorillonite K-10 clay, with or without microwave assis- tance, are the notable features of this protocol. Bromination of aromatics and heteroaromatics is an elec- trophilic substitution reaction of immense synthetic and industrial importance. Brominated arenes and hetero- arenes are useful as pharmaceuticals, flame retardants, agrochemicals, specialty chemicals 1 and synthetic inter- mediates capable of undergoing carbon-carbon bond for- mation via transmetalation reactions such as Heck, Stille, Suzuki, Sonogashira and Tamao-Kumada reactions. 2 In general, ring brominated aromatics and heteroaromatics exhibit interesting biological activities. 3 Halogen substi- tuted pyrimidines and purines are particularly important for their chemotherapeutic, biochemical and biophysical properties. 4 Apart from their usefulness as fluorophores and potential intermediates for photophysical probes, 5a bromocoumarins are also important as synthetic precur- sors of furocoumarins and dihydrofurocoumarins that are widely used as photosensitizers and chemotherapeutic agents to combat skin diseases, 5b-d and naturally abundant linear coumarins. 5e Despite their usefulness, scanty work is documented for regiospecific monobromination of cou- marins. 5f,g Bromination of activated arenes and hetero- arenes is often an unselective reaction resulting in a mixture of mono- and polybrominated derivatives with consequent tedious separation problems and poor atom economy. Therefore, the search for new regioselective methods of bromination has evoked great contemporary interest. Use of NBS for nuclear bromination in polar me- dia such as DMF, 6a MeCN, 6b,c aqueous NaOH, 6d in the presence of acids, 6e,f,g silica gel, 6h zeolite, 6i HZSM-5 6j and isopropylamine 7a is well-documented. These protocols of- fer different levels of selectivity depending primarily on