Selective lithiation of 2,4-lutidine: Role of transition states of lithium dialkylamides

Abstract

The lithiation of 2,4-lutidine (1) with non-nucleophilic bases, such as lithium diisopropylamide (LDA) and lithium diethylamide (LDEA) affords different regioisomers under similar reaction conditions. The mechanism of these reactions and the factors determining selectivity have not been well understood.The present endeavor explores experimental and quantum chemical approaches to investigate factors that determine regioselectivity of the reaction. It has been found that transition states of LDA/LDEA determine regioselectivity and the presence of acatalyst (LiCl) plays a vital role. The LDA mediated lithiation of 1 proceeds through a disolvated open dimer of LDA, leading to a 2-methyl lithiated product. LDEA mediated lithiation is dominated by a route involving interception of 1 with a trisolvated monomer-based transition state of LDEA resulting in a 4-methyl lithiated product. The mechanism is supported by LiCl catalyzed reactions. LiCl has also been found to effect a change in selectivity of the lithiation of BF3-complexed 2,4-lutidine.