Palladium-Catalyzed Difunctionalization of Alkenes by Relay Coupling with Propargylic Pyridines: Synthesis of Indolizine and Indolizinone-Containing Bisheterocycles

Abstract

Palladium-catalyzed arylation/heteroarylation of aryl halide-tethered alkenes with propargylic pyridines has been established, which provides direct and efficient access to various oxindole, azaoxindole, dihydrobenzopyran, indole, and benzofuranlinked indolizines in good yields with a broad substrate scope and high functional group tolerance. This process enables the formation of one C−N and two C−C bonds in a single operation through an intramolecular carbopalladation and cycloisomerization sequence. Furthermore, an indolizinone-linked bisheterocyclic framework containing indole and benzofuran could be synthesized conveniently from tertiary propargylic alcohols involving methyl or phenyl migration.

Recent Advances in the Synthesis of Five‐membered Nitrogen Heterocycles Induced by Palladium Ions and Complexes

“…Liu et al published a thorough study about the synthesis of bisheterocyclic indolizine derivatives (compounds 34) containing oxindole, azaoxindole, dihydrobenzopyran, indole, and benzofuran moieties formed through arylation/ heteroarylation. [138] The reaction of propargylic pyridines and substrates 26 d gave medium to high product yields (Scheme 115). Similar results were found using O-allenyl-2iodophenol and N-allenyl-2-iodoaniline in the synthesis of indolizines linked with benzofuran (6 examples, 41-79 %) or indole (7 examples, 46-74 %).…”

“…Liu et al . published a thorough study about the synthesis of bisheterocyclic indolizine derivatives (compounds 34 ) containing oxindole, azaoxindole, dihydrobenzopyran, indole, and benzofuran moieties formed through arylation/heteroarylation [138] . The reaction of propargylic pyridines and substrates 26 d gave medium to high product yields (Scheme 115).…”

Synthetic Strategies for the Construction of Indolizines and Indolizine‐fused Compounds: Thienoindolizines and Indolizinoindoles

“…This process enabled the formation of one CÀ N and two CÀ C bonds in a single operation through an intramolecular carbopalladation and cycloisomerization sequence (Scheme 32). [30] In 2022 Nechaev I. V. and co-authors reported an iodatepromoted multicomponent reaction between 3,3-difluorocyclopropenes 86, anilines 87 and pyridines 88. [31] The resulted substituted indolizines 89 and 90 could be used as intermediates for further targeted synthesis (Scheme 33).…”

Palladium-catalyzed cyclizative cross coupling of ynone oximes with 2-haloaryl N-acrylamides for isoxazolyl indoline bis-heterocycles

“…Representatives of such cascades 26 include the synthesis of bicycles accomplished by trapping an intramolecular Heck-coupling Pd intermediate with 2-alkynyl aniline as recently reported by Lautens 9 and Lin 10 et al and the synthesis of methylene-bridged benzofuranyl indolines achieved by trapping an oxindolyl-Pd intermediate with phenol derivatives as reported by Chen et al 11 Another impressive study was reported by Xu et al 12 for the synthesis of substituted indole scaffolds via dual cyclizative annulation of halo phenyl cyclobutanones with 2-alkynyl aniline. Recently, the Liu group 13 reported the synthesis of indolizine and indolizinone-derived bis-heterocycles through difunctionalization of acrylamide olefin and relay coupling of propargylic systems.…”

“…Temperature was also found to play a significant role in this protocol (Table 1, entries 10 and 11), as we found a clear drop in yields as the temperature was decreased from 80 °C. Of the various solvents that were screened, DCE was found to be most effective for this transformation (Table 1, entries [12][13][14].…”