Seven‐Membered Heterocycles: Azepines, Benzo Derivatives and Related Systems

Abstract

The replacement of a carbon atom by a heteroatom in a seven-membered carbocycle leads to the corresponding seven-membered heterocyclic ring system. Different types of heterocycles can be formed depending on the nature of the carbocycle. In a cycloheptatriene the replacement can involve any of the six sp 2 hybridized carbons or the sp 3 carbon atom, whereas in cycloheptane all carbon atoms are equivalent and replacement affords exclusively the fully saturated heterocyclic systems. Partially saturated seven-membered heterocycles can be viewed as derivatives or related systems of these two main seven-membered heterocyclic units arising from carbon replacement in cycloheptatriene and in cycloheptane. Replacement of the sp 3 hybridized carbon atom in cycloheptatriene by a nitrogen leads to an azacycloheptatriene known as 1H-azepine (1) and the corresponding 2H-, 3H-, and 4H-azepines (2-4) are the tautomeric forms generated by the replacement of the sp 2 carbons. 1H-Azepine is an unstable red oil that is prone to rearrange to the also unstable 3H-azepine in the presence of acids and bases. However, this tautomer seems to be more stable than both 4H-and 2H-azepine. The structures related to 1H-azepine that bear an oxygen or sulfur atom are known as oxepine (5) and thiepine (6) (thiepin is favored by Chemical Abstracts Service). Oxepine is much more stable than thiepine and has been synthesized, isolated, and characterized at room temperature while thiepine has not been detected to date. Stable monocyclic thiepines were prepared and characterized in the 1980s. Azepines, oxepines, and thiepines that are constrained to planar or almost planar conformations should be antiaromatic molecules with negative resonance energy and, as a consequence, these compounds are unknown.The fully saturated seven-membered heterocycle containing one nitrogen is azepane (7) (hexahydroazepine or perhydroazepine); the oxygen and sulfur analogues are known as oxepane (8) and thiepane (9). All of these compounds are stable and show typical behavior of secondary amine, ether and thioether, respectively. TwoModern Heterocyclic Chemistry, First Edition. Edited

Asymmetric (4 + 3) and (4 + 1) Annulations of Isatin-derived Morita–Baylis–Hillman Carbonates to Construct Diverse Chiral Heterocyclic Frameworks

“…The seven-membered N -heterocyclic motif is a privileged scaffold in diverse bioactive natural products and pharmaceuticals, and thus the development of effective protocols to construct these architectures has attracted growing interest for synthetic chemists . Nevertheless, compared with five- or six-membered rings via classic [3 + 2] or [4 + 2] cycloadditions or (3 + 3) annulations, the formation of seven-membered hetero- or carbocycles, especially via asymmetric catalysis, is more challenging, as harsh conditions are usually required to overcome entropic and enthalpic penalties .…”

Meta-Hybrid Density Functional Theory Prediction of the Reactivity, Stability, and IGM of Azepane, Oxepane, Thiepane, and Halogenated Cycloheptane

“…Heterocyclic compounds are readily applicable in the synthesis of naturally occurring pigments, vitamins, and antibiotics, and some act as hallucinogens. 1 , 2 …”

“…Heterocyclic compounds are readily applicable in the synthesis of naturally occurring pigments, vitamins, and antibiotics, and some act as hallucinogens. 1,2 The most common heterocyclic compounds are the fiveor six-membered rings containing heteroatoms of nitrogen (N), oxygen (O), and sulfur (S). Over the years, much attention has been paid to the fully saturated and unsaturated three-and fourmembered rings because of their small sizes and well-known reactive nature and uses as intermediates, but the saturated and unsaturated seven-membered rings and higher members are stable but less investigated.…”

Chemoselective Aza-[4+3]-annulation of N-Perfluoroalkyl-1,2,3-triazoles with 1,3-Dienes: Access to N-Perfluoroalkyl-Substituted Azepines

“…Substituted azepine and azepane derivatives are well-known as bioactive natural products, as well as pharmaceutically relevant compounds. − Among different methods of their preparation, aza-[4+3]-cycloaddition is the most straightforward approach. Unlike most of the fluoroalkylated and in particular trifluoromethylated compounds, which are known to possess a broad spectrum of applications, including a design of new pharmaceuticals and materials, − N -perfluoroalkylated compounds are almost unexplored. − We have recently reported the synthesis of N -fluoroalkyl-1,2,3-triazoles , and their transannulation reaction with different 2π-components, affording N -fluoroalkylated five-membered heterocycles (Scheme ).…”