Theoretical studies on the free-radical bromination of methyl-pyridazines in the synthesis of novel heterocyclic analogues of neurotransmitters

Abstract Free-radical bromination by N-bromosuccinimide has been performed on a range of methyl 3-methoxy pyridazine derivatives. Depending on the substitution pattern, various products and selectivities have been observed, including atypical N-methyl bromination. The hypothesis that selectivity is dependent primarily on the stability of the free-radical intermediate formed in the reaction has been examined, and a range of semiempirical and ab initio molecular orbital methods has been used to calculate these stabilities and evaluated for agreement with experiment. Semiempirical calculations using the PM3 Hamiltonian gave the best qualitative predictions of the methods trialed, thus providing a rapid method for predicting the selectivity of reactions used in the synthesis of novel heterocyclic analogues of the neurotransmitters GABA and glutamate.