Gold‐Catalyzed Oxidative Cyclization of Tryptamine Derived Enynamides: A Stereoselective Approach to Tetracyclic Spiroindolines

Abstract

In this work, we describe a new goldcatalyzed oxidative cascade cyclization of conjugated enynamides. The reaction could be carried out under relatively mild condition. In presence of a cationic gold catalyst bearing an N-heterocyclic carbene ligand, enynamides derived from tryptamine react with pyridine N-oxide, leading to the formation of a variety of tetracyclic spiroindolines in a stereoselective manner.

Synthesis of Thiomorpholin‐3‐ones by a Gold‐Catalysed Oxidative Cyclisation‐Rearrangement Cascade from Ynamides

“…Gold salts such as Au I chloride and picolinate gold(III) chloride were superior to a triphenylphosphine ligated gold(I) system, which favoured the formation of 3a , but were less effective than an NHC ligated gold(I) species (Table , entries 1–4). Simple pyridine N ‐oxide 5 proved superior to the other oxidants screened, including the methyl picolinate N ‐oxide 6 that we have found to be effective in other ynamide reactions,[11g], [14c] and the ethylquinoline N ‐oxide 10 widely used in other oxidations (Entries 4–9) . Using acetonitrile as the solvent saw further improvement (Entry 10).…”

“…Over‐oxidation pathways have completely dominated in a number of oxidative N ‐cyclisation reactions when the ynamide bears electron‐donating groups. [14f], [14g] However, they are tolerated here ( 3b – d ), as are electron‐withdrawing substituents ( 3e – f ). The mesyl‐protected ynamide 1g was less stable, and afforded 3g in poor yield alongside over‐oxidised material and recovered 1g in approximately equal quantities.…”

“…Several powerful nitrogen heterocycle‐forming transformations have been developed in recent years based on the oxidative N ‐cyclisation of ynamides under π‐acid catalysis . A common challenge lies in favouring cyclisation onto the N ‐substituent over a second oxidation process.…”

“…A common challenge lies in favouring cyclisation onto the N ‐substituent over a second oxidation process. [14a], [14b], [14c], [14d], [14e], [14f], [14g], [14h], The proposed thiomorphilinone synthesis appeared to offer a further level of complexity to this oxidative N ‐cyclisation strategy. Seemingly viable cyclisation and oxidation processes are in competition at two distinct stages of the reaction and a switch in selectivity between these processes must occur as the reaction proceeds (Scheme ).…”

Gold‐Catalyzed Oxidative Alkyne Functionalization by N−O/S−O/C−O Bond Oxidants

“…Another gold-catalyzed oxidative cyclization of enynamides prepared from tryptamines has been established [97] by Chen, Mao, Huang and their coworkers where versatile tetracyclic spiroindolines were formed stereoselectively (Scheme 66). In this goldcatalyzed oxidative annulation protocol, pyridine Noxide is used as an external oxidant for oxygenation of electron-rich enynamides.…”