Synthesis of Azepines via a [6 + 1] Annulation of Ynenitriles with Reformatsky Reagents

Abstract

A protocol for the direct synthesis of azepines using a hafnium(III)-catalyzed [6 + 1] annulation of N-tethered ynenitriles with Reformatsky reagents is reported. A broad range of 3-amino-2,7-dihydro-1H-azepine-4-carboxylates 4aa-4he were obtained in high yields and with excellent functional group tolerance. The copper-mediated reactions of isolable Blaise intermediates (enamino esters 3), uniquely underwent 5-endo cyclization to afford the β-2,5-dihydropyrrolyl α,β-unsaturated esters 5aa-5fc, which exhibit anticancer activity.

Sequential Two‐Fold Claisen Rearrangement, One‐Pot Ring‐Closing Metathesis and Cross‐Metathesis as a Route to Substituted Benzo[b]azepine‐2‐one, Benzo[b]azepine and Benzo[b]oxepine Derivatives

“…[2 -6] Recent progress in various metal-catalyzed ring-forming reactions has facilitated access to these classically otherwise difficult-to-make ring systems. [7][8][9][10][11][12][13][14] In particular, olefin-metathesis mediated transformations, [15][16][17][18][19][20][21][22][23][24][25][26][27][28] either in tandem or in sequence with other named and unnamed reactions, [29,30] have provided rapid access to several structurally embellished entities accommodating the core ring systems. However, comparatively less attention has been paid to develop synthetic methodologies that simultaneously address incorporation of functionalities within the core ring system.…”

Heterogeneous Gold(I)‐Catalyzed Oxidative Ring Expansion of 2‐Alkynyl‐1,2‐Dihydropyridines or ‐Quinolines Towards Functionalized Azepines or Benzazepines

“…Recently, transition-metal-catalyzed intramolecular or intermolecular cyclization reactions have provided a powerful and useful alternative strategy for the construction of azepine derivatives with various catalysts such as Rh, [12] Ir, [13] Ru, [14] Pd, [15] Ag [16] and Hf. [17] Nevertheless, the use of expensive catalysts and non-recyclability of the catalysts, complicated operation, or employment of an extra oxidant impose restrictions on application in organic synthesis. Based on the importance and wide applications of such compounds in organic chemistry, searching for alternative synthetic routes to azepine derivatives from readily available starting materials under mild conditions is still attractive to researchers.…”

“…Besides, Lewis acid‐catalyzed intramolecular or intermolecular cyclo‐addition and Et 3 N‐catalyzed tandem formal [4+3] annulation/decarboxylation/isomerization of methyl coumalates with imine esters have also proven to be alternative routes for the construction of azepine derivatives, but the starting materials require multi‐step preparation. Recently, transition‐metal‐catalyzed intramolecular or intermolecular cyclization reactions have provided a powerful and useful alternative strategy for the construction of azepine derivatives with various catalysts such as Rh, Ir, Ru, Pd, Ag and Hf . Nevertheless, the use of expensive catalysts and non‐recyclability of the catalysts, complicated operation, or employment of an extra oxidant impose restrictions on application in organic synthesis.…”

Phosphine‐Catalyzed Chemoselective [4+3] Cycloaddition of Alminine Esters and β′‐acetoxy Allenoates for Divergent Synthesis of Azepines

“…[2b] Securinine [2c] and neostenine [2d] isolated from the plants, are used in traditional Chinese medicine. [4] Among various synthetic approaches to azepines, cycloadditions have been demonstrated as a reliable and atom-economical method for the synthesis of functionalized azepines, such as [6 + 1] cycloadditions, [5] [5 + 2] cycloadditions, [6] [4 + 3] cycloadditions, [7] [2 + 2 + 3] cycloadditions. Consequently, the synthesis of azepines is of great interest in organic and medicinal chemistry.…”

“…Consequently, the synthesis of azepines is of great interest in organic and medicinal chemistry. [4] Among various synthetic approaches to azepines, cycloadditions have been demonstrated as a reliable and atom-economical method for the synthesis of functionalized azepines, such as [6 + 1] cycloadditions, [5] [5 + 2] cycloadditions, [6] [4 + 3] cycloadditions, [7] [2 + 2 + 3] cycloadditions. [8] Considering the huge potential in drug discovery of the azepines, it is highly desirable and a great challenge to develop facile and efficient methodologies to access structural diversity and complexity of azepines from certain intermediates.…”