Development of a Method for the Synthesis of 4-Aryl-Functionalized 2-Azabicyclo[3.2.1]octanes

Abstract

A method for the synthesis of 4-substituted azabicyclo[3.2.1]octanes from N-tosyl-2-azabicyclo[3.2.1]octa-3,6-diene, a versatile bicyclic heterocycle not commonly used in medicinal chemistry research, is presented. The method uses bromination, followed by Suzuki­ coupling, and subsequent reduction and deprotection. The desired 4-substituted azabicyclo[3.2.1]octanes were obtained in moderate to high yields.

Designed Bifunctional Phosphine Ligand-Enabled Gold-Catalyzed Isomerizations of Ynamides and Allenamides: Stereoselective and Regioselective Formation of 1-Amido-1,3-dienes

“…In contrast, the related 1-amidofurans are frequently employed in total synthesis . The reported synthetic methods include the following: (a) the thermal rearrangements of propargylic trichloroacetimidates to form (1 Z )-1-amido-1,3-dienes, which is less desirable for the D–A reaction, and upon Et 3 N treatment affords a mixture of (1 E ) and (1 Z ) isomers (e.g., 85/15); (b) metal-mediated/-catalyzed amidative or C­(sp 2 )–C­(sp 2 ) cross-couplings, which, however, suffers from the need for halodiene substrates of preinstalled regio- and stereochemistry in the former and the need for controlling stereochemistry of both reacting partners in the latter (Scheme A); (c) allenamide isomerization under excessive heating (e.g., 135 °C 5 ) or in the presence of an acid catalyst (Scheme B), which is limited in scope to products that avoid regio- or stereochemical issues at the distal C–C double bond. , …”

2-Azabicyclo[3.2.1]octane scaffold: synthesis and applications

“…The bicyclic core of the 2-azabicyclo[3.2.1]octane scaffold may also be accessed through different types of rearrangement reactions, typically through ring-enlargement reactions. Such reactions include Beckmann rearrangements, 16 norbornadiene cascade rearrangements, 17 and rearrangement of bicyclo[2.2.1]heptanes. 18…”