Synthesis of 4- to 7-membered Heterocycles by Ring Expansion

Ring expansions promoted by ring strain in aziridines and azetidines are reviewed in this chapter, putting emphasis on recent applications from the last decade. This vast subject cannot be surveyed here exhaustively, and the reader will be guided to relevant precedent reviews or key reports. Rather, special attention will be put on selected examples and their mechanistic details, aiming to demonstrate that high selectivity can be reached in these reactions. In this issue, this fast-growing topic has been divided into two distinct chapters, this one dealing with “nonactivated” aziridines and azetidines. Therefore, the reader will only find here examples involving NH- or N-alkylaziridines and N-azetidines as substrates for ring expansions, while N-acyl, N-carbamoyl, or N-tosyl compounds, defined as “activated” substrates, will be presented in the next chapter. This distinction can appear quite arbitrary at first sight but is amply justified by the great difference in reactivity of these distinct substrates. The first part focuses on the ring expansions of nonactivated aziridines into up to seven-membered rings and is further divided into expansions involving the incorporation of one (or more) heteroatoms, followed by ring expansions involving only incorporation of carbon atoms. The same model is then followed for azetidines.

Facile construction of small and normal-sized, or more precisely, four to seven-membered aza-heterocyclic ring systems is always a challenging yet rewarding task for the synthetic organic chemists. Fortunately, activated aziridines and azetidines provide a direct and convenient access to this coveted molecular architectures through several elegant ring-expansion approaches. This chapter presents some of the illustrative and contemporary examples to demonstrate the synthetic diversity and efficiency of the ring-expansion strategies of activated aziridines and azetidines towards a vast array of small to normal-sized aza-heterocyclic moieties.

The syntheses of various heterocycles based on the ring expansion of azirines and azetines are described. A structural diversity of heterocycles can be prepared starting from these strained compounds due to their extremal reactivity involving nucleophilic, electrophilic, and metal-catalyzed additions, cycloadditions of different types, and thermal and catalytic isomerizations. Although the chemistry of azetines is not so diverse, some specific heterocyclic compounds can be synthesized only from azetines. The present survey covers research published up to early beginning of 2015.

The skeleton of β-lactams and β-lactones is present in biologically active compounds. For example, the β-lactam ring is present in classical antibiotics such as penicillins and cephalosporins. On the other hand, there are several natural products containing a β-lactone moiety, with interesting inhibitory activity. In addition, both fragments are very useful synthetic intermediates for the preparation of cyclic and acyclic compounds. The ring strain present in both motifs is involved in this versatile reactivity. This chapter is devoted to the synthesis of five- to seven-membered heterocycles by ring expansion of β-lactams and β-lactones. Different methodologies have been described, and the mechanism for the formation of the products has been discussed. In addition, the applicability of some of the processes has been demonstrated by the synthesis of fragments of natural or biologically relevant compounds. The contributions presented in this chapter have been selected mainly from the developments achieved in the last decade.

This chapter is focused on recently published (2006–2014) oxirane and oxetane ring-expansion reactions. The majority of these advances employ oxirane substrates, the discussion of which is broken into five thematic sections representing insertions, cascades, metal-free, metal-catalyzed, and miscellaneous strategies. Oxetane ring-expansion reactions are still rare and are discussed together in one section. A concise graphical summary has been created for every new contribution to this area, highlighting reagents, reaction conditions, scope, mechanistic proposals, and asymmetry where applicable. This review chapter should enable researchers new to the field to quickly assess the current state of the art.

Thiiranes and thietanes are important intermediates in organic synthesis, just as their oxygen and nitrogen analogs (oxiranes and aziridines, and oxetanes and azetidines). They have been widely applied in the preparation of sulfur-containing compounds. Thiiranes undergo ring expansions to generate various four-, five-, six-, and seven-membered heterocyclic products, even larger heterocycles. Thietanes also undergo ring expansions to produce five-, six-, and seven-membered heterocyclic compounds, even larger heterocycles as well. The ring expansions include insertion, nucleophilic and electrophilic ring opening, and subsequent cyclization. The regioselectivities in nucleophilic ring-opening reactions of unsymmetrical thiiranes and thietanes are discussed. Generally, nucleophiles attack on the less substituted vicinal carbon atom to the sulfur in unsymmetrical thiiranes and thietanes, controlled by steric hindrance. In the presence of Lewis acids, the electronic effect significantly impacts the regioselectivity in ring-opening reactions. 2-Arylthiiranes and 2-alkenylthiiranes are attacked on their more substituted vicinal carbon atom with nucleophiles (the electronic effect control). For thietanes, electrophilic ring expansion is one of the major processes. Unsymmetrical thietanes undergo electrophilic ring expansion with carbenes and nitrenes through electrophilic attack and subsequent Stevens-type rearrangement, with the more substituted vicinal carbon shifting. Mechanisms on some of the most important ring expansions of thiiranes and thietanes are introduced.