4.1 - Overview

Abstract

This chapter presents an overview of the methods of synthesizing heterocyclic compound, either by using a known method or by analogy with existing methods for related compounds. The synthesis of a heterocyclic compound can be divided into two parts: ring synthesis and substituent introduction and modification. The relative importance of the two parts can vary for different classes of heterocycles. The ring synthesis steps of increasing importance relative to substituent modification involve features like increasing number of heteroatoms, increasing number of fused rings, and decreasing number of endocyclic double bonds. Substituent modification is based on substituent reactivity. Ring syntheses in heterocyclic compounds are grouped as: those of related classes of compounds, those from similar precursors, and methods related mechanistically. Ring formation from two components can occur by reaction between electrophilic and nucleophilic centers, either between a binucleophile and a bielectrophile or between two molecules each containing both a nucleophilic and an electrophilic center. Cycloadditions, including [2 + 2] cycloaddition, 1,3-dipolar cycloaddition ([3+2] cycloaddition), and Diels–Alder reaction ([4 + 2] cycloaddition), lead to four-, five-, and six-membered rings, respectively. The Woodward–Hoffmann rules predict high activation energies for the suprafacial–suprafacial addition of two carbon–carbon double bonds, which can be lowered, however, by polar effects. [2 + 2] Photocycloadditions are common and usually involve diradical intermediates. The conversion of one heterocyclic ring into another is achieved by interchange of ring atoms (e.g., in photochemical isomerization), incorporation of new ring atoms but no change in ring size, ring expansions, ring contractions, or ring closure with simultaneous ring opening.