A Modular Approach for the Palladium-Catalyzed Synthesis of Bis-heterocyclic Spirocycles

Abstract

A simple and modular approach toward bis-heterocyclic spirocycles using palladium catalysis is reported. The enclosed methodology leverages a Mizoroki–Heck-type reaction to generate a neopentylpalladium species. This species can undergo intramolecular C–H activation on a wide array of (hetero)­aryl C–H bonds, generating a variety of [4.4] and [4.5] bis-heterocyclic spirocycles in up to 95% yield. A diverse range of bis-heterocyclic spirocycles were possible, with 24 examples and 18 different combinations of heterocycles were synthesized. Biologically relevant aza-heterocycles such as purine, pyrazole, (benz)­imidazole, (aza)­indole, and pyridine were readily incorporated into the spirocyclic core. The reaction was readily scalable to 1 mmol using a lower catalyst loading and number of base equivalents, and the product was purified without the use flash column chromatography.

Development of novel transition metal-catalyzed synthetic approaches for the synthesis of a dihydrobenzofuran nucleus: a review

“…Spirocyclic organic compounds have acquired a significant place in medicinal chemistry due to their vast biological potential. 78 Marchese 79 et al in 2022 devised a modular method for the preparation of 2,3-dihydrobenzofuran-based spirocyclic compounds 121 , 122 and 123 via palladium catalysis. In their synthetic approach, o -substituted aryl iodides 120 were transformed into corresponding bis-heterocyclic spirocycles 121 , 122 and 123 by following the Mizoroki–Heck-type reaction pathway in the presence of Cs 2 CO 3 (used as base).…”

Divergent reactivity of acrylamides and β-chloroenones under base-controlled palladium catalysis: construction of spirooxindoles and furan-containing 3,3-disubstituted oxindoles

“…1 Among the various catalytic cascades involving palladium intermediates, the transient σ-alkylpalladium( ii ) species generated from the carbopalladation of a double bond in Heck cyclization has remained a central topic, and it can be utilized as an active intermediate for further functionalization. 2 To date, several representative pathways involving σ-alkylpalladium intermediates have emerged: (1) they can be trapped with a variety of nucleophiles (Scheme 1a); 3 (2) they can coordinate the unsaturated bond and promote the second cyclization via nucleopalladation (Scheme 1b); 4 and (3) they can functionalize the unreactive remote C–H bond to generate spirocyclic palladacycle intermediates, which could undergo direct reductive elimination or further cross-couple with alkyl and aryl halides, diaziridinones, α-diazocarbonyl compounds, and disilanes to form diverse spiro-heterocyclic scaffolds. 5 More importantly, spirocyclic palladacycle intermediates can also be cross-coupled with π-systems such as arynes, 6 a , b alkynes, 6 c and oxabicycles 6 d via migratory insertion to afford interesting hetero-spirocycles, demonstrating the versatility of the palladium-catalyzed remote C–H functionalization (Scheme 1c).…”

Cu-Catalyzed Cyclization/Coupling of Alkenyl Aldimines with Arylzinc Reagents: Access to Indole-3-diarylmethanes

“…These metals enabled the use of N / O -allyl-haloethanes ( 1b – c ) that proceeded via β-H-alkylmetal intermediates. For example, Oshima, Kang, Cárdenas, Lautens, ourselves, and others disclosed Co-, Fe-, Mn-, and Ni-catalyzed cyclization/coupling of 1a – c types of substrates with aryl Grignard and alkyl/arylzinc reagents, arynes, aryl C–H bonds, and CO/ N , O -nucleophiles to furnish cyclic products 2a – c .…”