Palladium‐Catalyzed Domino Synthesis of 2,3‐Difunctionalized Indoles via Migratory Insertion of Isocyanides in Batch and Continuous Flow

Abstract

We report, herein, a palladium‐catalyzed cascade comprising carbopalladation, migratory insertion of isocyanide and triple bond activation followed by a nucleophilic attack (OR−) to construct difunctionalized acyl indoles. The process involves multiple bond formations via key palladium‐chemistry steps, to construct these bis‐heterocycles containing two privileged scaffolds (indole and oxindole) in a single operational step, along with attempts to generate enantioselectivity at a quaternary carbon center. The methodology also demonstrates a continuous‐flow process to synthesize aryl isocyanides within minutes and using them in a telescopic manner.

Recent advances in Pd-catalyzed asymmetric cyclization reactions

“…Later, a preliminary exploration of an enantioselective Heck/ isocyanide insertion reaction combined with triple bond activation and a final nucleophilic attack of N-(2-iodophenyl)-Nmethylacrylamide 300 with 2-(2-phenylethynyl)phenyl isocyanides 353 was presented by Sharma's group in 2021, affording 2,3-difunctionalized indoles with 73% ee (Scheme 77). 164 5.3.10. Heck/carbene insertion.…”

Bicyclic Amidine-Triggered Cyclization of o-Alkynylisocyanobenzenes: Synthesis of Lactam-Derived Quinolines

“…Palladium-catalyzed isocyanide insertion is the second approach to synthesize N -heterocycles from o -alkynylisocyanobenzenes. − For instance, Yamamoto and Kamijo developed the synthesis of N -cyanoindoles via the palladium-catalyzed multicomponent coupling reaction from o -alkynylisocyanobenzenes in 2002 . Takemoto and coworkers successively reported the synthesis of indole and several tetracyclic indole derivatives from o -alkynylisocyanobenzenes under palladium catalysis in 2012 and 2013. , By means of a continuous-flow process to synthesize o -alkynylisocyanobenzenes in a telescopic manner, Sharma and coworkers developed an efficient synthetic method to prepare indole-based oxindoles from o -alkynylisocyanobenzenes under palladium catalysis in 2021 …”

“…The first concerns free-radical-initiated 5-exo or 6-endo cyclization of o -alkynylisocyanobenzenes; − for example, Ogawa and coworkers continuously reported the synthesis of 2,4-bistellurated quinolines and 2, 4-diiodoquinolines from o -alkynylisocyanobenzenes through photochemical cyclization in 2009 and 2011. , Recently, Studer et al demonstrated a radical cascade to 2,3-disubstituted indoles via acylation or trifluoromethylation of o -alkynylisocyanobenzenes . Palladium-catalyzed isocyanide insertion is the second approach to synthesize N -heterocycles from o -alkynylisocyanobenzenes. − For instance, Yamamoto and Kamijo developed the synthesis of N -cyanoindoles via the palladium-catalyzed multicomponent coupling reaction from o -alkynylisocyanobenzenes in 2002 . Takemoto and coworkers successively reported the synthesis of indole and several tetracyclic indole derivatives from o -alkynylisocyanobenzenes under palladium catalysis in 2012 and 2013. , By means of a continuous-flow process to synthesize o -alkynylisocyanobenzenes in a telescopic manner, Sharma and coworkers developed an efficient synthetic method to prepare indole-based oxindoles from o -alkynylisocyanobenzenes under palladium catalysis in 2021 …”

“…7,8 By means of a continuous-flow process to synthesize o-alkynylisocyanobenzenes in a telescopic manner, Sharma and coworkers developed an efficient synthetic method to prepare indole-based oxindoles from o-alkynylisocyanobenzenes under palladium catalysis in 2021. 9 Third, o-alkynylisocyanobenzenes can be a precursor for diversification of C-2-functionalized quinolines through nucleophile-triggered cyclization. The nucleophilic group can be the hydroxyl derived from water, alcohols and phenols, diethylamine, the active methylene of diethylmalonate, the mercapto group of thiol and thiophenol, azide groups, halogen atoms from the quaternary ammonium salts [tetrabutylammonium fluoride (TBAF), tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), and tetrabutylammonium iodide (TBAI)], and solvents (CHCl 3 , CHBr 3 , and CHI 3 ).…”

Palladium-Catalyzed Four-Component Cascade Imidoyl-Carbamoylation of Unactivated Alkenes

“…Due to the high affinity of isocyanide in coordinating with transition metals, a functionalized isocyanide has been applied successfully in palladium-catalyzed cascade reactions for the synthesis of a myriad of nitrogen heterocyclic motifs . In these reactions, a key imidoyl Pd­(II) intermediate is formed immediately after the generation of a Pd­(II) species via migratory insertion, followed by reaction with various intramolecular functional groups, such as amides, , aromatic C–H bonds, and alkynes . When an alkene-containing isocyanide is applied under palladium catalysis, sequential isocyanide and alkene insertion takes place selectively, leading to cyclic ketoimine derivatives .…”