Palladium-Catalyzed Synthesis of 1-Vinyltetrahydro-β-carbolines and Aza-spiroindolenines: Access to the Syntheses of 1-Vinyl-β-carbolines and Eudistomins Y1 and Y2

Abstract

A general synthesis of 1-vinyltetrahydro-β-carbolines (THBCs) has been achieved via palladium(0)-catalyzed cyclocondensation between allenyltryptamines and aryl iodides. Aza-spiroindolenines could also be accessed from the N-unsubstituted indole substrates by simply tweaking the reaction conditions. DDQ-mediated oxidation of THBCs easily afforded β-carbolines, which could be synthetically transformed into 1-aroyl-β-carbolines of pharmacological interest. Formal total syntheses of eudistomins Y1 and Y2 have also been achieved.

Direct Synthesis of Benzo[c]carbazoles by Pd-Catalyzed C–H [4 + 2] Annulation of 3-Arylindoles with External 1,3-Dienes

“…20 To obtain insights into the mechanism of the domino sequence, the influence of indole N-substitution was investigated, 20 and it turned out that the free NH of the indole is crucial for the annulation step. Unlike the work of interception of π-allyl-palladium intermediate in the presence of free NH indole recently developed by Chinmay, 16 no spiroindolenine derivatives were isolated and observed during our study. On the basis of these experimental results and in accordance with DFT modeling described by Maestry, 15b a plausible reaction mechanism is proposed in Scheme 6 via a C 2 −H allylation through an outer-sphere CMD pathway.…”

“…On the basis of these experimental results and in accordance with DFT modeling described by Maestry, a plausible reaction mechanism is proposed in Scheme via a C 2 –H allylation through an outer-sphere CMD pathway. Nevertheless, we cannot totally rule out an intramolecular nucleophilic attack by C 3 of the indole moiety to π-allyl-palladium complex B followed by an allylic group migration from the C3 position of indole to the C2 position, as reported by Chinmay and You. , Initially, the oxidative addition of indole 2 by the ligated Pd(0) species generates the Pd­(II) complex A . The subsequent cyclocarbopalladation step leads to the π-allylpalladium intermediate B .…”

“…Nevertheless, some potential challenges arise in this reaction, including (1) the functionalization of the C–H bond at the C 2 position of the indole; (2) the formation of the π-allylpalladium intermediate to prevent the β-H elimination and hence the formation of the resulting Heck product; and (3) the regioselective insertion of the 1,3-diene while avoiding the 1,4-palladium migration (Scheme ). Based on these considerations, we hypothesized that the interception of the π-allylpalladium intermediate would take place at the C-2 versus C-3 position by C–H allylation according to a CMD mechanism instead of an electrophilic metalation or Heck-type reaction in the presence of an N -unprotected 3-arylated indole, avoiding thus the formation of the spirocyclopentaneindoline derivative. Moreover, it is noteworthy that the use of N -unprotected indole should prevent the 1,4-palladium migration, a process well-known in the presence of protected indoles .…”

“…Nevertheless, we cannot totally rule out an intramolecular nucleophilic attack by C 3 of the indole moiety to π-allylpalladium complex B followed by an allylic group migration from the C3 position of indole to the C2 position, as reported by Chinmay and You. 16,25 Initially, the oxidative addition of indole 2 by the ligated Pd(0) species generates the Pd(II) complex A. The subsequent cyclocarbopalladation step leads to the π-allylpalladium intermediate B.…”

Regiodivergent cascade cyclization/alkoxylation of allenamides via N-protecting group driven rearrangement to access indole and indoline derivatives

“…Certainly, the cascade Heck-type cyclizations of the aryl halide tethered allenamides have witnessed considerable development recently to access valuable indoles and other heterocycles via the generation of π-allyl-Pd( ii ) intermediates. 4 Typically, the Pd( ii ) intermediate is captured in a cascade sequence by organometallics, nucleophiles, or oxidants highly regio-selectively at the γ-position (Scheme 1a). 5 On the other hand, the α-selectivity is established with intramolecular nucleophiles on allenamides.…”