Carbopalladation/Suzuki Coupling Cascade for the Generation of Quaternary Centers. Access to Pyrrolo[1,2-b]isoquinolines

A convergent route to pyrrolo[1,2-b]isoquinolines with a quaternary center at C-10 has been developed, that implies a sequential Pd(0)-catalyzed carbopalladation followed by cross-coupling reaction with boronic acids. The adequate catalytic system and experimental conditions, with and without the use of phosphane ligands, have been selected to control the chemoselectivity of the process, allowing a 6-exo-carbopalladation to generate a quaternary center, and avoiding a direct Suzuki coupling. A variety of electron rich and electron deficient arylboronic acids can be used providing an efficient route to substituted pyrrolo[1,2-b]isoquinolines in moderate to good yields (up to 94%, 22 examples).Ministerio de Economía y Competitividad (CTQ2016-74881-P) // Gobierno Vasco (IT1045-16

Phenolic Activation in Chiral Brønsted Acid-Catalyzed Intramolecular α‑Amidoalkylation Reactions for the Synthesis of Fused Isoquinolines

An organolithium addition−intramolecular α- amidoalkylation sequence on N-phenethylimides has been developed for the synthesis of fused tetrahydroisoquinoline systems using 1,1′-bi-2-naphthol (binol)-derived Brønsted acids. This transformation is the first in which activated benzene derivatives are used as internal nucleophiles, instead of electron-rich heteroaromatics, generating a quaternary stereocenter. Phenolic substitution on the aromatic ring of the phenethylamino moiety and the use of binol-derived N-triflylphosphoramides as catalysts are determinants to achieve reasonable levels of enantioselection, that is, up to 75% enantiomeric excess, in the α-amidoalkylation step. The procedure is complementary to the intermolecular α-amidoalkylation process, as opposite enantiomers are formed, and to the Pictet− Spengler cyclization, which allows the formation of tertiary stereocentersMinisterio de Economíay Competitividad (CTQ2013-41229-P; CTQ2016-74881-P), Gobierno Vasco (IT1045-16

Transition metal-guanidine complexes as catalysts in organic reactions. Recent developments

Guanidines have received great attention due to their application as superbasic proton sponges and organocatalysts, as well as excellent N-donor ligands able to coordinate with different metals. The introduction of different substituents can modulate the basicity/nucleophilicity of the guanidines, their coordination ability, and thus, the electronic and steric properties of their metal complexes, regulating their catalytic activity. This review presents recent developments on guanidine-based ligand families [monoguanidine, bis(guanidine) and hybrid guanidine ligands], highlighting their potential in transition metalcatalyzed reactions.Ministerio de Economía y Competitividad (CTQ2016-74881-P), Gobierno Vasco (IT1045-16

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

Pd(II)-Catalyzed C-H Acylation of (Hetero)arenes. Recent Advances

Di(hetero)aryl ketones are important motifs present in natural products, pharmaceuticals or agrochemicals. In recent years, Pd(II)-catalyzed acylation of (hetero)arenes in the presence of an oxidant has emerged as a catalytic alternative to classical acylation methods, reducing the production of toxic metal waste. Different directing groups and acyl sources are being studied for this purpose, although further development is required to face mainly selectivity problems in order to be applied in the synthesis of more complex molecules. Selected recent developments and applications are covered in this review.This work is supported by Ministerio de Economía y Competitividad (CTQ2016-74881-P), Ministerio de Ciencia e Innovación (PID2019-104148GB-I00) and Gobierno Vasco (IT1045-16)

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

Microwave-assisted Palladium catalysed C-H acylation with aldehydes. Synthesis and diversification of 3-acylthiophenes

The use of MW allows the efficient palladium(II)-catalysed C-3 acylation of thiophenes with aldehydes via C(sp2)-H activation for the synthesis of (cyclo)alkyl/aryl thienyl ketones (43 examples). Compared to standard thermal conditions, the use of MW reduces the reaction time (15 to 30 min vs. 1 to 3 hours), leading to improved yields of the ketones (up to 92%). Control of positional selectivity is achieved by 2-pyridinyl and 2-pyrimidyl ortho-directing groups at C-2 of the thiophene scaffold. To show the synthetic applicability, selected ketones were subjected to further transformations, including intramolecular reactions to directly embed the directing-group in the core-structure of the new moleculeMinisterio de Ciencia e Innovación (PID2019-104148GB-I00) / Gobierno Vasco (IT1045-16

Selective Pd(II)-catalyzed Acylation of Pyrrole with Aldehydes. Application to the Synthesis of Celastramycin analogues and Tolmetin

The Pd(II)-catalyzed C-2 acylation of pyrrole with aldehydes in the presence of TBHP as oxidant has been studied for the synthesis of di(hetero)aryl ketones. The use of 2-pyrimidine as directing group leads to 2-acylpyrroles in moderate to good yields, although 2,5-diacylpyrroles are obtained as by products. This side-reaction could be avoided using 3-methy-2-pyridine as directing group, obtaining selectively 2-acylpyrroles. The reaction has been extended to a series of aromatic and heteroaromatic aldehydes, obtaining the best results with electron rich aromatic aldehydes. The methodology has been applied in the synthesis of pyrrolomycin alkaloid Celastramycin analogues and for an improved synthesis of Tolmetin, a nonsteroidal anti-inflammatory drugMinisterio de Economía y Competitividad (CTQ2016-74881-P) / Gobierno Vasco (IT1045-16