Synthesis of Azocino[5,4‐b]indoles via Gold‐Catalyzed Intramolecular Alkyne Hydroarylation

Abstract

An efficient procedure for the synthesis of the azocinoA C H T U N G T R E N N U N G [5,4-b]indole framework is presented, relying on a cationic gold-catalyzed intramolecular alkyne hydroarylation of propargylic amides derived from various tryptamines and 3-substituted 2propynoic acids. The triphenylphosphinegold(I) chloride/silver(I) triflate catalytic system was found to be superior to our previously described mercury(II) triflate catalyst, and hence the substrate scope of the process was significantly expanded.Indole-annulated medium-sized rings are important heterocyclic motifs occurring in both natural and synthetic products. Nitrogen-containing seven-and eightmembered rings are the most widespread [1] and have been constructed employing various methods including intramolecular Friedel-Crafts alkylation, [2] intramolecular radical cyclization, [3] ring-closing metathesis, [3b,4] classical [5] and oxidative [6] Heck reaction, onepot/tandem processes, [7] multi-component approaches [8] and ring-expansion protocols.

Silver(I)‐ or Copper(II)‐Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds

“…[2] The dearomatization strategy described herein is based on the conversion of aromatic ynone derivatives into spirocycles through alkyne activation with as imple Lewis or p-acidic catalyst, illustrated by the conversion of indole derivative 1 into 3,3-substituted spirocyclic indolenine 2 ( Figure 1a). [3,4] As ignificant problem with this type of transformation is the proclivity of the spirocyclicp roducts to undergo af acile 1,2 migration under acidic conditions,w hich is driven by the restoration of aromaticity.T his issue is particularly prevalent with indolenines.A ni llustrative example was recently reported by Va nd er Eycken (Figure 1b): [5] spirocyclic indolenine 4a was formed in low yield when alkyne 3 was treated with AuPPh 3 Cl/AgOTf,t he other major product being the rearomatized indole 4b.Indeed, while processes involving the electrophilic activation of alkynes have been well studied in recent years, [6] Va nder Eyckens example is,tothe best of our knowledge,t he highest-yielding acid-catalyzed spirocyclization of its type reported in the literature; [7] in related processes,r earomatized products such as compound 4b are reported far more often (not only with indoles,b ut across ar ange of heteroaromatics). [7,8] Then ew methods described herein provide ag eneral, high-yielding strategy for the conversion of arange of achiral heteroaromatics (left in Figure 2) into complex, spirocyclic enones (right in Figure 2) using low loadings of simple silver(I) or copper(II) salts.T he ynone subunit was chosen on the basis of its synthetic accessibility and the utility of the enone products,b ut is also ak ey design feature,a st he carbonyl group reduces the migratory aptitude of the adjacent alkene,t hus stabilizing the spirocyclicp roducts with respect to 1,2 migration.…”

Metal‐Free Dearomatization: Direct Access to Spiroindol(en)ines in Batch and Continuous‐Flow

“…The synthesis of spiroindol(en)ines and related spirocarbocycles through dearomatization of indole and substituted phenols has captured the close attention of chemist due to their widespread presence in various natural products and biologically relevant molecules . Henceforth, greener and atom economical syntheses of these structures have become imperative for synthetic chemists (Scheme a–c) . Several simple Lewis or π‐acidic catalysts were employed in the last decades for the synthesis of spiroindolenines through dearomatization of indole at the C‐3 position, including nano‐metal catalysts .…”

Synthesis of Spirocyclic Indolenines

“…These cyclisations typically proceed by activation of the alkyne by a π‐acidic catalyst, followed by nucleophilic attack of the indole through its C‐3 position. The first example of this reaction type was reported by Van der Eycken and co‐workers, who isolated spirocyclic indolenines 202 as a side‐product in their synthesis of ring‐fused indole 203 (Scheme ) . Using a typical Au I /Ag I catalyst system, an array of the desired ring‐fused indoles were furnished in high yield; however, the submission of terminal propargyl amide 201 to these reaction conditions afforded only a 1:1 mixture of the desired indole 203 and spirocycle 202 (which is likely an intermediate en route to 203 ).…”

“… Spirocyclisation by addition to a pendant alkyne (Van der Eycken et al. ; Carbery et al. ; Toste et al.…”

“…The first example of this reactiont ype was reported by Vand er Eycken and co-workers, who isolated spirocyclic indolenines 202 as as ide-product in their synthesis of ringfused indole 203 (Scheme 28). [114] Using at ypical Au I /Ag I catalyst system, an array of the desired ring-fused indoles were furnished in high yield;h owever, the submission of terminal propargyl amide 201 to these reactionc onditions afforded Scheme24. Intramolecular addition to p-allyl intermediates generated from propargylic systems (Hamadaetal., [104] Fujii, Ohnoetal.…”