Chapter 4 - The Annulation of 2-Imidazolines

Abstract

Publisher Summary This chapter focuses on the annulation of imidazolines to produce novel heterocyclic molecules. Imidazolines substituted with alkyl groups at C-2 should display two sites of nucleophilic reactivity—namely, at N-1 and at C-2(α). This chapter describes the enabling synthetic methodology underpinning the double nucleophile–double electrophile annulation. For this the first steps are to generate suitable imidazoline substrates to establish the C-2(α) nucleophilic reactivity, and prepare 1-benzyl-2-methylimidazoline by straightforward reaction of N-benzyl-1,2-diaminoethane with a C-2 unit at the carboxylic oxidation level, using which 1-benzyl-2-(ethoxycarbonylmethylene)-1,2,3,4tetrahydroimidazole is prepared. Much of the annulation work described in the chapter is performed on this enamino ester as a stable substrate. The range of C-2(a)-unactivated, N-unsubstituted 2-alkyl-2-imidazolines made available by the deprotonation-alkylation-deprotection protocol from N-tert-butyloxycarbonyl-2-methyl-2-imidazoline, opens up further avenues for annulation. The chapter discusses various types of annulations such as annulations using chiral imidazolines and annulation via the conjugate addition route with singly activated alkenes and with alkynes, along with some intermediate chemical reactions such as azomethine ylides by alkylation-deprotonation, azomethine ylides by carbene insertion in a catalytic cycle, and azomethine ylides by conjugate addition-proton transfer. The sequence developed for annulation of the imidazoline enamino ester with α,β-unsaturated ketones could be applied to the optically active 4-phenyl enamino ester enantiomers. Thus conjugate C-addition to but-3-en-2-one followed by borane reduction, gives optically active piperidine enamino esters, from which imidazo[1,2-a] pyridines could be formed oxidatively (Br 2 —Et 3 N) or on acid treatment. In the end the chapter emphasizes that many of the annulation products have been demonstrated to be building blocks for onward transformations in heterocyclic synthesis.