We have presented a method for the efficient generation of distinctively persistent spiroindoleninium intermediates from secondary and tertiary N-acyl tryptamines. The exceptional resilience of the intermediates, accessed under the described reaction conditions, to Wagner–Meerwein rearrangement allows for efficient intra- and intermolecular trapping with nucleophiles, including weak nucleophiles such as deactivated arenes, even after activation and spirocyclization. The use of urea and tertiary amides under our conditions allows for the direct and highly diastereoselective synthesis of spiropyrrolidinoindolines without competitive rearrangement, or the need for an electron-withdrawing group, on the aliphatic or indole nitrogen atoms.
Motivated by a desire to extend the range of diastereoselective trappings of spiroindoleninium intermediates and based on our prior synthetic work, we hypothesized that non-enolizable tertiary amides would, upon activation with Tf2O–2-ClPyr, undergo rapid spirocyclization to afford a putative persistent diiminium dication resilient to Wagner–Meerwein rearrangement. To our delight, treatment of tertiary pivalamide 1f with Tf2O–2-ClPyr at 0 °C in acetonitrile and warming to 23 °C, followed by sequential trapping with triethylsilane and lithium aluminum hydride, afforded spirocyclic indoline (±)-7f as a single diastereomer in 91% yield (), suggesting the in situ formation of a persistent diiminium ion intermediate. The diastereoselectivity is likely a result of the steric bulk of the arene, which blocks approach of lithium aluminum hydride. Use of lithium aluminum deuteride in place of lithium aluminum hydride afforded monodeuterated spirocyclic indoline (±)-7f-d1, demonstrating the regioselective trapping at C2 with triethylsilane. Similarly, activation of lactam 1g followed by tandem reduction with triethylsilane–lithium aluminum hydride afforded tetracyclic indoline (±)-7g in quantitative yield as a single diastereomer ().
Given the enormous resurgence in indole ring synthesis over the past decade highlighted by the power of transition metal catalysis this authoritative guide addresses the need for a comprehensive presentation of the myriad of methods for constructing the indole ring, from the ancient to the modern, and from the obscure to the well-known.
Following presentation of the classic indole ring syntheses and many newer methods, coverage continues with indole ring syntheses via pyrroles, indolines, oxindoles, isatins, radical and photochemical reactions, aryne cycloadditions.
This extensive volume concludes with the modern transition metal catalyzed indole ring syntheses that utilize copper, palladium, rhodium, gold, ruthenium, platinum, and other metals to fashion the indole ring Indole Ring Synthesis is a comprehensive, authoritative and up-to-date guide to the synthesis of this important heterocycle for organic chemists, pharmaceutical researchers and those interested in the chemistry of natural products.
Spirocyclic pyrrolidinoindolines represent a ubiquitous substructure in nature, representing the core of the aspidosperma, strychnos, and kopsia alkaloid families, and are prevalent also in pharmaceutically active compounds and other fine chemicals (). The importance of this structural motif has motivated the development of a number of elegant synthetic strategies in the context of complex alkaloid synthesis. A direct route to the spiropyrrolidinoindoline substructure would involve intramolecular electrophilic trapping of an appropriate tryptamine derivative at C3; however, the inherent tendency of 2H-indole systems to undergo rapid Wagner–Meerwein rearrangement () makes such an approach difficult. Previously reported methods, for such transformations overcome this problem by employing strongly nucleophilic intramolecular traps or electron-withdrawing groups on the indole and aliphatic nitrogen to minimize such rearrangements, which can still occur. We have recently reported the use of an interrupted Bischler–Napieralski reaction as a highly stereoselective and general strategy for the synthesis and arylative dimerization of aspidosperma alkaloids. Herein, we report a method for the efficient synthesis of spiropyrrolidinoindolines by interruption of the Bischler–Napieralski reaction of 2H-N-acyltryptamines via persistent spiroindoleninium intermediates with high resilience to Wagner–Meerwein rearrangements.
The development of a versatile method for the synthesis of spirocyclic pyrrolidinoindolines is discussed. Treatment of N-acyltryptamines with trifluoromethanesulfonic anhydride–2-chloropyridine reagent combination affords highly persistent spiroindoleninium ions which are subject to intra- and intermolecular addition at C2 by nucleophiles.