Controlling the Ambiphilic nature of sigma-arylpalladium intermediates in intramolecular cyclization reactions

The reactivity of main group organometallics, such as organolithium compounds (RLi) and Grignard reagents (RMgX), is quite straightforward. In these species the R group usually exhibits nucleophilic reactivity without any possibility of inducing electrophilic character. In contrast, in organopalladium complexes, researchers can switch the reactivity from electrophilic to nucleophilic relatively simply. Although σ-aryl and σ-vinylpalladium complexes are commonly used as electrophiles in C-C bond-forming reactions, recent research has demonstrated that they can also react with carbon-heteroatom multiple bonds in a nucleophilic manner. Nevertheless, researchers have completely ignored the issue of controlling the ambiphilic nature of such species. This Account describes our efforts toward selectively promoting the same starting materials toward either electrophilic α-arylation or nucleophilic addition reactions to different carbonyl groups. We could tune the properties of the σ-arylpalladium intermediates derived from amino-tethered aryl halides and carbonyl compounds to achieve chemoselective transformations. Therefore, chemists can control the ambiphilic nature of such intermediates and, consequently, the competition between the alternative reaction pathways by the adequate selection of the reaction conditions and additives (base, presence/absence of phenol, bidentate phosphines). The nature of the carbonyl group (aldehydes, ketones, esters, and amides) and the length of the tether connecting it to the aniline moiety also play an important role in the outcome of these processes. Our joint computational and experimental efforts to elucidate the reaction mechanism of these palladium-catalyzed transformations suggest that beyond the formation of the four-membered azapalladacycle, two major factors help to control the dual character of the palladium(II) intermediates derived from 2-haloanilines. First, their high nucleophilicity strongly modifies the interaction of the metal center with the carbonyl group. Second, the additive phenol exchanges the iodide ligand to give an arylpalladium(II) phenoxide complex, which has a beneficial effect on the arylation. The formation of this transient intermediate not only stabilizes the arylpalladium moiety, thus preventing the nucleophilic attack at the carbonyl group, but also assists the enolization reaction, which takes place in a more favorable intramolecular manner. The azapalladacycle intermediate is, in the words of J. R. R. Tolkien, "the one ring to bring them all and in the darkness to bind them." With this intermediate, we can easily achieve the synthesis of a variety of heterocyclic systems by selectively promoting electrophilic α-arylation or nucleophilic addition reactions from the same precursors

Contribution of "Omic" studies to the understanding of CADASIL. A systematic review

Altres ajuts: Generación Project, Maestro Project, INVICTUS+ networkAltres ajuts: Fundació la Marató de TV (Epigenesis Project)CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets

A Joint experimental-computational comparative study of the Pd(0)-catalysed reactions of aryl iodides and aldehydes with N, O, and S tethers

The influence of the heteroatom (nitrogen, oxygen, and sulfur) on the course of the palladium‐catalysed intramolecular reactions of aryl iodides and aldehydes having heteroatom‐containing tethers has been explored by an extensive experimental-computational (DFT) study. Two series of substrates were considered, namely aldehydes bearing either the α‐(2‐iodobenzylheteroatom) or β‐(2‐iodophenylheteroatom) moieties. While some experimental differences were observed when changing from nitrogen to oxygen or sulfur in the 2‐iodobenzyl series, the aldehydes in which the heteroatom is directly bonded to the aromatic ring showed common chemical behaviour regardless of the nature of the heteroatom. The different reaction pathways leading to the experimentally observed reaction products were studied by computational means. Our calculations suggest that in all cases the initial nucleophilic addition involving a σ‐aryl-PdII intermediate is preferred over the competing concerted metallation-deprotonation (CMD) process. Keywords: Homogeneous catalysis / Palladium / Cyclization / Heterocycles / Density functional calculation

Synthesis of isoquinolin-4-ols by palladium-catalysed intramolecular nucleophilic addition of aryl iodides to aldehydes

A palladium‐catalysed intramolecular nucleophilic addition of aryl iodides to aldehydes leading to tetrahydroisoquinolin‐4‐ols is reported. A variety of products were isolated in good to excellent yields. The joint experimental‐computational study shows that although two competitive reaction pathways can be promoted by Pd(0) starting from α‐(2‐iodobenzylamino)‐aldehydes, the selectivity of the process can be controlled by the proper selection of the base. While the nucleophilic addition of the aryl‐Pd(II) intermediate to the carbonyl group is selectively promoted by using the base triethylamine (Et3N), the CH bond activation at the formyl group competes with the nucleophilic addition only when the base is replaced by cesium carbonate (Cs2CO3). Keywords: catalysis; cyclization; density functional theory (DFT) calculations; nucleophilic addition; palladiu

Controlling the chemoselectivity of Palladium catalysed cyclizations of (2-iodoanilino)-carbonyl compounds

The factors which control the chemoselectivity of palladium catalyzed cyclizations of (2- haloanilino) carbonylic compounds have been explored by an extensive experimental-computational (DFT) study. It was found that the selectivity of the process, i.e. the formation of fused six versus fivemembered rings, can be controlled by the proper selection of the initial reactant, reaction conditions and the additives. Thus, esters or amides produce ketones by a nucleophilic addition process, whereas the addition of PhO- leads to the formation of indolines by an α-arylation reaction. In contrast, the corresponding ketone reactants yield mixture of both reaction products in the presence of phenol whose ratio depends on the base used. The outcome of the processes can be explained by the formation of a common four-membered palladacycle intermediate from which the competitive nucleophilic addition and α-arylation reactions occur. The remarkable effect of phenol in the process, which makes the αarylation reaction easier, was found to favor the formation of enol-complexes which are stabilized by an intramolecular hydrogen bond between the hydroxyl group of the enol moiety and the oxygen atom of the phenoxy ligand. Moreover, the chemoselectivy of the process can be also controlled by the addition of bidendate ligands leading to the almost exclusive formation of indoles at expenses of the corresponding alcohols

Palladium-catalysed intramolecular carbenoid insertion of α-diazo α-(methoxycarbonyl)acetanilides for oxindole synthesis

A novel, selective palladium-catalysed carbenoid C(aryl)-H insertion of α-diazo-α-(methoxycarbonyl)acetanilides leading to oxindoles is described

Palladium-catalyzed intramolecular carbene insertion into C(sp3)-H bonds

A palladium‐catalyzed carbene insertion into C(sp3)−H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd0 and PdII, is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium‐catalyzed C(sp3)−C(sp3) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp3)−H bond functionalization reaction involves an unprecedented concerted metalation-deprotonation step

Palladium catalysis in intramolecular carbene C-H insertion of α-diazo-α-(methoxycarbonyl)acetamides to form β-lactams

The intramolecular carbene C-H insertion of α‐diazo‐α‐(methoxycarbonyl)acetamides leading to β‐lactams is effectively catalyzed by palladium complexes. It is found that although Pd0 catalysts typically produce mixtures of β‐lactams together with Buchner‐type reaction products, the use of PdII catalysts results in highly chemoselective transformations. According to DFT calculations, this insertion reaction occurs stepwise and involves an unprecedented PdII‐promoted Mannich‐type reaction through a metallacarbene‐induced zwitterionic intermediate

Exploring Partners for the Domino α‐Arylation/Michael Addition Reaction Leading to Tetrahydroisoquinolines

Sulfonates, sulfonamides, and phosphonates have proven useful nucleophiles for palladium‐catalyzed intramolecular α‐arylation reactions leading to tetrahydroisoquinolines. Although the sulfonate α‐arylation reaction can be successfully combined in a domino process with a broad range of Michael acceptors, only vinyl sulfones can be used in Michael additions when starting from sulfonamides. No domino process was developed with the phosphonate derivative. DFT calculations were carried out to gain more insights into the experimental differences observed in the reactions involving these substrates

Transition Metal-catalysed intramolecular carbenoid C-H insertion for pyrrolidine formation by decomposition of α-diazoesters

The use of Pd‐, Rh(II)‐ and Ru(II)‐based catalysts has been explored in the transition metal‐catalysed intramolecular carbenoid C−H insertion of α‐diazoesters leading to pyrrolidines. Although the outcome of the reaction was highly substrate‐dependent, in general, it was possible to control the chemoselectivity of the process towards pyrrolidines by adequate catalyst selection. The Pd(0)‐catalysts were as efficient as [Rh(Ph3CCO2)2]2 in promoting the C(sp3)−H insertion of ortho‐substituted anilines. In contrast, for anilines bearing meta‐ and para‐substituents, the Rh(II)‐catalyst provided the best chemoselectivities and reaction yields. On the other hand, [Ru(p‐cymene)Cl2]2 was the most efficient catalyst for the insertion reaction of the N‐benzyl‐N‐phenyl and N,N‐dibenzyl α‐diazoesters, while the C(sp3)−H insertion of the N‐benzylsulfonamide substrate was only promoted by [Rh(Ph3CCO2)2]2. According to density functional theory (DFT) calculations, the mechanism involved in the Pd(0)‐ and Ru(II)‐catalysed C(sp3)−H insertions differs considerably from that typically proposed for the Rh(II)‐catalysed transformation. Whereas the Pd(0)‐catalysed reaction involves a Pd‐mediated 1,5‐H migration from the C(sp3)−H bond to the carbenoid carbon atom leading to the formal oxidation of the transition metal, a Ru(II)‐promoted Mannich type reaction involving a zwitterionic intermediate seems to be operative in the Ru(II)‐catalysed transformation. Keywords: carbenoid insertion; diazo compounds; pyrrolidines; palladium-catalysis; density functional theory calculation