Palladium-catalysed Heck-type alkenylation reactions in the synthesis of quinolines. Mechanistic insights and recent applications

Quinoline and quinolone cores are present in a wide variety of pharmaceuticals, agrochemicals and materials, as well in ligands/catalysts in asymmetric synthesis. Transition-metal catalysed based approaches have played a pivotal role in the development of the catalytic methods for their synthesis. This review presents recent developments on palladiumcatalysed Mizoroki-Heck reaction and its dehydrogenative variant (the Fujiwara-Moritani reaction), a C-H activation reaction that does not require the use of prefunctionalized coupling parterns for the synthesis of quinoline frameworks. The mechanistic understanding of both type of reactions, and how the different reaction conditions affect the outcome and the regioselectivity for the synthesis of the quinoline core, which is crucial to achieve target-oriented synthesis successfully, is discussed through selected examples.Ministerio de Economía y Competitividad (CTQ2016-74881-P) // Gobierno Vasco (IT1045-16

Organocatalytic Enantioselective α-Nitrogenation of α,α-Disubstituted Aldehydes in the Absence of a Solvent

A highly efficient enantioselective α-nitrogenation method of α,α-disubstituted aldehydes with azodicarboxylates promoted by a chiral carbamate-monoprotected cyclohexa-1,2-diamine as organocatalyst has been developed. The process was carried out without any solvent, and the corresponding α,α-disubstituted α-nitrogenated aldehydes were obtained with excellent yields and enantioselectivities up to 99% ee. The sustainability of the procedure was established through the calculation of green metrics, such as EcoScale and E-factor. In addition, theoretical calculations have been used to justify the obtained enantioselectivity sense.This work was funded by the Spanish Ministry of Economy, Industry and Competitiveness (PGC2018-096616-B-I00), the Spanish Ministry of Science and Innovation (PID2019-110008GB-I00), and the University of Alicante (VIGROB-173). We also thank SGIker (UPV/EHU) for providing human and computational resources

Palladium-Catalyzed Oxidative Arene C-H Alkenylation Reactions Involving Olefins

The Palladium-catalyzed selective C-H alkenylation reaction has been established as a central synthetic transformation to enable the construction of carbon–carbon bonds in an efficient, atom-economical, and environmentally friendly way. It provides a powerful alternative to classical cross-coupling reactions for the construction of conjugated organic molecules, including late-stage functionalization. The knowledge of mechanisms, the use of different strategies to control site-selectivity, and the development of efficient chiral catalysts for C-H alkenylation reactions has expanded the application of this tool for the synthesis of molecules of increased complexityMinisterio de Ciencia e Innovación (PID2019-104148GB-I00) / / Gobierno Vasco (IT1045-16

Cp*Co(III)-Catalyzed C−H Hydroarylation of Alkynes and Alkenes and Beyond: A Versatile Synthetic Tool

The use of earth-abundant first-row transition metals, such as cobalt, in C−H activation reactions for the construction and functionalization of a wide variety of structures has become a central topic in synthetic chemistry over the last few years. In this context, the emergence of cobalt catalysts bearing pentamethylcyclopentadienyl ligands (Cp*) has had a major impact on the development of synthetic methodologies. Cp*Co- (III) complexes have been proven to possess unique reactivity compared, for example, to their Rh(III) counterparts, obtaining improved chemo- or regioselectivities, as well as yielding new reactivities. This perspective is focused on recent advances on the alkylation and alkenylation reactions of (hetero)arenes with alkenes and alkynes under Cp*Co(III) catalysis.Ministerio de Ciencia e Innovación (PID2019-104148GB-I00), Gobierno Vasco (IT1045-16

Amide-Directed Intramolecular Co(III)-Catalyzed C-H Hydroarylation of Alkenes for the Synthesis of Dihydrobenzofurans with a Quaternary Center

The first example of Cp*Co(III)-catalyzed intramolecular hydroarylation of allyl aryl ethers using an amide directing group for the preparation of 3,3-disubstituted dihydrobenzofurans in high yields is described. The reaction of the unactivated alkene is completely selective for the formation of the quaternary center, allowing different substitution patterns on the aromatic ring and the alkene. The cyclization can also be extended to the formation of six-membered rings and to N-homoallylindoleMinisterio de Economía y Competitividad (CTQ2016-74881-P), Ministerio de Ciencia e Innovación (PID2019-104148GB-I00) and Gobierno Vasco (IT1045-16

Ruthenium-Catalyzed Mono-Selective C–H Methylation and d₃-Methylation of Arenes

[Image: see text] Site-selective installation of C–Me bonds remains a powerful and sought-after tool to alter the chemical and pharmacological properties of a molecule. Direct C–H functionalization provides an attractive means of achieving this transformation. Such protocols, however, typically utilize harsh conditions and hazardous methylating agents with poor applicability toward late-stage functionalization. Furthermore, highly monoselective methylation protocols remain scarce. Herein, we report an efficient monoselective, directed ortho-methylation of arenes using N,N,N-trimethylanilinium salts as noncarcinogenic, bench-stable methylating agents. We extend this protocol to d(3)-methylation in addition to the late-stage functionalization of pharmaceutically active compounds. Detailed kinetic studies indicate the rate-limiting in situ formation of MeI is integral to the observed reactivity

Palladium(II)-catalyzed Intramolecular C-H Alkenylation for the Synthesis of Chromanes

The intramolecular Pd(II)-catalyzed alkenylation of aryl homoallyl ethers constitutes a mild, versatile, and efficient procedure for the synthesis of highly and diversely substituted chromanes, and 2H-chromenes. The use of p-TsOH as additive allows more efficient reactions that could be carried out a room temperature in most cases. The procedure has a wide scope, allowing the synthesis of alkylidenechromanes and 2H-chromenes substituted at C-2 or C-3 of the chromene moiety, thus accessing relevant flavenes and isoflavenes, and even coumarins, in high yields (59 to 91%, 32 examples)Ministerio de Economía y Competitividad (CTQ2016-74881-P) // Gobierno Vasco (IT1045-16

Palladium-Catalyzed Dehydrogenative Coupling: An Efficient Synthetic Strategy for the Construction of the Quinoline Core

Palladium-catalyzed dehydrogenative coupling is an efficient synthetic strategy for the construction of quinoline scaffolds, a privileged structure and prevalent motif in many natural and biologically active products, in particular in marine alkaloids. Thus, quinolines and 1,2-dihydroquinolines can be selectively obtained in moderate-to-good yields via intramolecular C-H alkenylation reactions, by choosing the reaction conditions. This methodology provides a direct method for the construction of this type of quinoline through an efficient and atom economical procedure, and constitutes significant advance over the existing procedures that require preactivated reaction partners.Ministerio de Economia y Competitividad (CTQ2013-41229-P, CTQ2016-74881-P), Gobierno Vasco (IT1045-16) and Universidad del Pais Vasco/Euskal Herriko Unibertsitatea UPV/EHU are gratefully acknowledged for their financial support. V.O.-d.-E., A.C.-M. wish to thank Gobierno Vasco for grants. Technical and human support provided by Servicios Generales de Investigacion SGIker (UPV/EHU, MINECO, GV/EJ, ERDF and ESF) is also acknowledged

Directed C- H Allylation of Aromatic Carboxamides with Allyl Aryl Ethers under Cp*Co(III)-Catalysis

The Cp*Co(III) C−H allylation of (hetero)arenes with allyl aryl ethers has been developed using an amide as directing group (24 examples). DFT calculations have shed light on the mechanistic course and reactivity pattern, showing that strong electron releasing groups favour the reaction by reducing the activation barrier of the rate-determining C−H activation step. However, the steric strain can increase the energy of the migratory insertion step to the point of completely preventing the reaction, as in the case of the 3,5-dimethylbenzamide. The obtained allylated compounds have been transformed into a variety of interesting heterocyclic and carbocyclic structures, such as isoquinolones and isochromanones.Ministerio de Ciencia e Innovación PID2019-104148G-I00, PID2019–110008GB- I00, PID2022-137365NB-I00, MCIN/AEI/10.13039/501100011033, Gobierno Vasco (IT1558-22

Intramolecular Palladium(II)-catalyzed 6-endo C-H alkenylation directed by the remote N-protecting group. Mechanistic insight and application to the synthesis of dihydroquinolines

A protocol for the Pd(II)-catalyzed C-H alkenylation reaction of substituted N-allylanilines via an unusual 6-endo process has been developed. A DFT study of the mechanistic pathway has shown that the coordination of the remote protecting group to the palladium center is determinant for the control of the regioselectivity in favor of the 6-endo process. The reaction would proceed via prior activation of the alkene. This procedure constitutes a mild and efficient method for the synthesis of 1,4- dihydroquinoline derivatives from simple and readily accessible substrates.Ministerio de Economía y Competitividad (CTQ2016-74881-P; CTQ2016-78083-P) // Gobierno Vasco (IT1045-16