Visible-Light Promoted Intramolecular para-Cycloadditions on Simple Aromatics.

Dearomative cycloadditions are a powerful tool to access a large chemical space exploiting simple and ubiquitous building blocks. The energetic burden due to the loss of aromaticity has however greatly limited their synthetic potential. We devised a general intramolecular method that overcomes these limitations thanks to the photosensitization of allenamides. The visible-light-promoted process gives complex [2.2.2]-(hetero)-bicyclooctadienes at room temperature, likely through the stabilization of transient (bi)radicals by naphthalene. The reaction tolerates several valuable functionalities, offering a convenient handle for a myriad of applications, including original isoindoles and metal complexes.

Dimerizing cascades of enallenamides reveal the visible-light-promoted activation of cumulated C-C double bonds.

The visible-light-promoted activation of conjugated C-C double bonds is well developed, while that of cumulated systems is underexplored. We present the feasibility of this challenging approach. The localization of a triplet on an allenamide arm can be favored over that on a conjugated alkene. Allenamides with an arylacryloyl arm dimerize at room temperature in the presence of visible light and an iridium(iii) photocatalyst. Two orthogonal polycyclizations took place and their outcome is entirely dictated by the substitution of the alkene partner. Both cascades afford complex molecular architectures with high selectivity. Products form through the ordered rearrangement of twelve π electrons, providing a [3.2.0] bicyclic unit tethered to a fused tricycle, whose formation included an aryl C-H functionalization step, using disubstituted alkenes. The outcome was reverted with trisubstituted ones, which gave rise to taxane-like bridged tricycles that had two six-membered lactams flanking a cyclooctane ring, which was established through the creation of four alternate C-C bonds.

Evolution of Triangular All-Metal Aromatic Complexes from Bonding Quandaries to Powerful Catalytic Platforms.

This manuscript describes an overview on the literature detailing the observation of trinuclear complexes that present delocalized metal-metal bonds similar to those of regular aromatics, which are formed combining main group elements. A particular emphasis is given to the structural and electronic features of aromatic clusters that are sufficiently stable to allow their isolation. In parallel to the description of their key bonding properties, the work presents reported catalytic applications of these complexes, which already span from elaborated C-C-forming cascades to highly efficient cross-coupling methods. These examples present peculiar aspects of the unique reactivity exerted by all-metal aromatic complexes, which can often be superior to their established, popular mononuclear peers in terms of chemoselectivity and chemical robustness.

Is Aromaticity a Driving Force in Catalytic Cycles? A Case from the Cycloisomerization of Enynes Catalyzed by All-Metal Aromatic Pd3+ Clusters and Carboxylic Acids.

The work details a mechanistic study based on density functional theory modeling on the cycloisomerization of polyunsaturated substrates catalyzed by all-metal aromatic tripalladium complexes and carboxylic acids. These clusters are an emerging class of catalysts for a variety of relevant transformations, including C-C forming processes that occur under mild conditions and display synthetic features complementary to those of established mononuclear complexes. This study is the first computational one devoted to the comprehension of the series of elementary steps involved in a synthetic transformation catalyzed by an all-metal aromatic complex. Present results confirm previous experimental hints on the striking mechanistic differences exerted by these clusters with respect to the usual cyclization pathways of related substrates. Moreover, the catalytic cycle involving present all-metal aromatic clusters closely parallels the mechanism of the aromatic substitution of regular arenes.

Photoelectric properties of aromatic triangular tri-palladium complexes and their catalytic applications in the Suzuki-Miyaura coupling reaction.

The photoelectric properties and catalytic activities of substituted triphenylphosphine and sulfur/selenium ligand supported aromatic triangular tri-palladium complexes 1-4, abbreviated as [Pd3]+, were investigated. The cyclic voltammogram of [Pd3]+ in CH3CN-nBu4NPF6 showed a single quasi-reversible wave which was consistent with their robust property and provided preliminary proof for their electron transfer processes in catalysis. With excitation at 267 nm, [Pd3]+ exhibited strong ratiometric fluorescence at 550 and 780 nm at a temperature gradient from 77 K to 287 K. These peculiar triangular tri-palladium complexes showed excellent catalytic activities and exclusive reactivity with aryl iodides over the other halogenated aromatics in the Suzuki-Miyaura coupling reaction. The electronic and steric hindrance effects of substituents on the aryl iodides and aryl boronic acids including heteroaromatics like pyridine, pyrazine and thiophenes were explored and most substrates achieved up to 99% of yields. (2-[1,1'-Biphenyl]-2-ylbenzothiazole) which was analogous to the selective cyclooxygenase-2 (COX-2) inhibitors was also synthesized with our tri-palladium catalyst and gave good isolated yield (94%). The study of the catalytic process revealed that the mechanism of the reaction may involve the replacement of the sulphur ligand on [Pd3]+ by iodine from aryl iodides, which was beneficial for the matching of C-I bond energy.

Orthogonal Syntheses of 3.2.0 Bicycles from Enallenes Promoted by Visible Light.

Enallenes can be readily converted into two families of 3.2.0 (hetero)bicycles with high diastereoselectivities through the combination of visible light with a suitable Ir(III) complex (1 mol %). Two complementary pathways, namely, a photocycloaddition versus a radical chain, can then take place. Both manifolds grant complete regiocontrol of the allene difunctionalization. This is accompanied by an original 1,3-group shift using sulfonyl allenamides that deliver a congested tetrasubstituted headbridging carbon in the corresponding product.

Visible-Light-Promoted Polycyclizations of Dienynes.

A variety of linear dienynes can deliver complex tetracyclic frameworks in the presence of an IrIII complex and visible light. Product formation involves the generation of four new C-C bonds and six contiguous stereocenters, which decorate two [3.1.0] bicyclic units tethered through their bridging quaternary carbon atoms. The internal alkyne acts as a formal dicarbenoid for the generation of two cyclopropanes in these radical cation cascades. This behavior has not been previously observed for organic reactive intermediates and can be extended to intermolecular reactions and diendiynes.

Bi-directional alkyne tandem isomerization via Pd(0)/carboxylic acid joint catalysis: expedient access to 1,3-dienes.

An in situ formed palladium hydride catalyst enables the sequential dual isomerization of propargylamide derivatives to 1-amido-1,3-dienes with high chemo- and regioselectivity. The reaction shows ample functional group tolerance, delivering a valuable class of products, including highly deuterated ones, from readily available reagents. The reaction occurs through a complex mechanism studied by DFT modelling.

Synthesis of Carbolines via Palladium/Carboxylic Acid Joint Catalysis.

The combination of a Pd(0) complex with benzoic acid converts propargylic tryptamines to the corresponding tetrahydro-ß-carbolines. The method uses unprotected indoles and affords the desired products with ample functional group tolerance. Detailed modeling studies reveal a close synergy between the organic and metal catalysts, which enables sequential alkyne isomerization, indole C-H activation, and eventual C-C reductive elimination to afford the target heterocycles.

All-metal aromatic cationic palladium triangles can mimic aromatic donor ligands with Lewis acidic cations.

We present that cationic rings can act as donor ligands thanks to suitably delocalized metal-metal bonds. This could grant parent complexes with the peculiar properties of aromatic rings that are crafted with main group elements. We assembled Pd nuclei into equilateral mono-cationic triangles with unhindered faces. Like their main group element counterparts and despite their positive charge, these noble-metal rings form stable bonding interactions with other cations, such as positively charged silver atoms, to deliver the corresponding tetranuclear dicationic complexes. Through a mix of modeling and experimental techniques we propose that this bonding mode is an original coordination-like one rather than a 4-centre-2-electron bond, which have already been observed in three dimensional aromatics. The present results thus pave the way for the use of suitable metal rings as ligands.

Pd Catalysis in Cyanide-Free Synthesis of Nitriles from Haloarenes via Isoxazolines.

A method to obtain aryl nitriles from the corresponding halides by Pd catalysis, in the absence of any cyanide source, is reported. The reaction of an aryl halide, ethyl nitroacetate, and an olefin readily delivers an aromatic nitrile. A variety of aryl iodides/bromides have been converted into the corresponding cyanoarenes in fair to excellent yields. The reaction likely involves the following steps: (a) Pd-catalyzed α-arylation of ethyl nitroacetate; (b) nitrile oxide formation;

Boosting catalyst activity in cis-selective semi-reduction of internal alkynes by tailoring the assembly of all-metal aromatic tri-palladium complexes.

Highly symmetric [Pd3]+ clusters that present delocalized metal-metal bonds can catalyse the selective semi-reduction of internal alkynes to cis-alkenes. Studies on factors governing the formation of all-metal aromatics enabled the design of an optimised catalytic system that delivers cis-alkenes with almost complete selectivity on a gram scale with very low catalyst loadings (0.03 mol%).

Synthesis of marmycin A and investigation into its cellular activity.

Anthracyclines such as doxorubicin are used extensively in the treatment of cancers. Anthraquinone-related angucyclines also exhibit antiproliferative properties and have been proposed to operate via similar mechanisms, including direct genome targeting. Here, we report the chemical synthesis of marmycin A and the study of its cellular activity. The aromatic core was constructed by means of a one-pot multistep reaction comprising a regioselective Diels-Alder cycloaddition, and the complex sugar backbone was introduced through a copper-catalysed Ullmann cross-coupling, followed by a challenging Friedel-Crafts cyclization. Remarkably, fluorescence microscopy revealed that marmycin A does not target the nucleus but instead accumulates in lysosomes, thereby promoting cell death independently of genome targeting. Furthermore, a synthetic dimer of marmycin A and the lysosome-targeting agent artesunate exhibited a synergistic activity against the invasive MDA-MB-231 cancer cell line. These findings shed light on the elusive pathways through which anthraquinone derivatives act in cells, pointing towards unanticipated biological and therapeutic applications.

A Simple Synthesis of Triangular All-Metal Aromatics Allowing Access to Isolobal All-Metal Heteroaromatics.

A simple synthetic method allows the one-pot assembly of C3 -symmetric, 44-core-valence-electron, triangular Pd or Pt clusters and their heterobimetallic mixed Pd/Pt analogues. These mixed metal complexes are the first examples of stable triangular all-metal heteroaromatics. In contrast to traditional heteroaromatic molecules formed combining main-group elements, they actually retain structural and electronic features of their homonuclear analogues.

Intramolecular anion effect in polyoxometalate-based organocatalysts: reactivity enhancement and chirality transfer by a metal oxide-organic cation interaction.

An α1 -Dawson polyanion bearing a lateral side chain with a 4-aminopyridine end group was synthesized. This organopolyoxometalate catalyzes the addition of indenyl allyl silanes to cinnamoyl fluorides. The polyanionic framework influences the organocatalyst activity and selectivity. A moderate but nonzero chirality transfer from the chiral inorganic framework to the organic substrate was observed.

Molecular complexity from polyunsaturated substrates: the gold catalysis approach.

Over the last two decades, electrophilic catalysis relying on platinum(II), gold(I), and gold(III) salts has emerged as a remarkable synthetic methodology. Chemists have discovered a large variety of organic transformations that convert a great assortment of highly functionalized precursors into valuable final products. In many cases, these methodologies offer unique features, allowing access to unprecedented molecular architectures. Due to the mild reaction conditions and high function compatibility, scientists have successfully developed applications in total synthesis of natural products, as well as in asymmetric catalysis. In addition, all these developments have been accompanied by the invention of well-tailored catalysts, so that a palette of different electrophilic agents is now commercially available or readily synthesized at the bench. In some respects, researchers' interests in developing homogeneous gold catalysis can be compared with the Californian gold rush of the 19th century. It has attracted into its fervor thousands of scientists, providing a huge number of versatile and important reports. More notably, it is clear that the contribution to the art of organic synthesis is very valuable, though the quest is not over yet. Because they rely on the intervention of previously unknown types of intermediates, new retrosynthetic disconnections are now possible. In this Account, we discuss our efforts on the use of readily available polyunsaturated precursors, such as enynes, dienynes, allenynes, and allenenes to give access to highly original polycyclic structures in a single operation. These transformations transit via previously undescribed intermediates A, B, D, F, and H that will be encountered later on. All these intermediates have been determined by both ourselves and others by DFT calculations and in some cases have been confirmed on the basis of experimental data. In addition, dual gold activation can be at work in some of these transformations, for instance, from E to F. Strikingly, we have found propargyl acetates to be particularly productive precursors. In a preliminary step upon electrophilic activation (complex I), they can lead to oxonium J or a vinylcarbenoid species K after 1,2-migration or complexed allenylester M from a formal 1,3-migration. All of them can serve as versatile entries for multievent processes. The propargyl cycle, sometimes called the golden carousel, involves species I-N), which lie in a close equilibrium. The control of this merry-go-round and its offshoots depends on the energy barriers associated with the subsequent reactions of these intermediates. We illustrate these themes in this Account, focusing on the intriguing characteristics of gold catalysis.

Diastereoselective synthesis of dibenzoazepines through chelation on palladium(IV) intermediates.

Joint palladium/norbornene organometallic catalysis allows for straightforward access to dibenzo[c,e]azepines. These synthetically challenging polycyclic frameworks form in one pot via a three-component coupling of an aryl iodide, a bromobenzylamine, and an olefin. A key, atroposelective aryl-aryl coupling from chelated Pd(IV) intermediates dictates the outcome of the cascade. DFT modeling sheds light on the complex mechanism that allows the complete diasteroselectivity to be observed.

Synthesis of triangular tripalladium cations as noble-metal analogues of the cyclopropenyl cation.

The first C3 -symmetric 44-core-valence-electron triangular palladium clusters, [{(SAr')(PAr3 )Pd}3 ](+) , have been synthesized by activation of the CS bond of isothioureas. Owing to delocalized metal-metal bonding, these stable complexes are the first noble-metal analogues of the π-aromatic cyclopropenyl cation [C3 H3 ](+) , with their all-metal aromaticity involving d-type atomic orbitals.

Radical Pd(III)/Pd(I) reductive elimination in palladium sequences.

Open-shell mechanisms are often at work in catalytic sequences involving first-row transition metals while usually not considered in palladium chemistry. Herein a computational study suggests their possible relevance in catalytic methods involving paramagnetic Pd(iii) intermediates. Indeed C-C bond forming reductive elimination previously thought to occur in Pd(iv) complexes has lower barriers in neutral, radical Pd(iii) intermediates instead. These species could form upon addition on Pd(ii) of an aryl radical generated via single electron transfer from a photo-active ruthenium complex and have the perfect stereoelectronic arrangement to smoothly undergo the coupling process.

Atroposelective [2+2+2] cycloadditions catalyzed by a rhodium(I)-chiral phosphate system.

Enantioselective cationic Rh(I)-catalyzed [2+2+2] cycloaddition reactions between diynes and isocyanates relying on the chiral anion strategy have been devised. In the presence of [Rh(cod)Cl]2, 1,4-bis(diphenylphosphino)butane, and the silver phosphate salt Ag(S)-TRIP as the unique source of chirality, axially chiral pyridones were isolated with ees up to 82%. This approach is novel in the field of chiral anion-mediated asymmetric catalysis since atroposelective transformations have so far remained unprecedented. It also proves to be complementary to the classical strategy based on chiral L-type ligands.