Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes.

In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters with aldehyde sulfonyl hydrazones, employing Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)-C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic ß-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.

Closing the Cycle as It Begins: Synthesis of ortho-Iodobiaryls via Catellani Reaction.

Despite the advances in the field of carbon-halogen bond formation, the straightforward catalytic access to selectively functionalized iodoaryls remains a challenge. Here, we report a one-pot synthesis of ortho-iodobiaryls from aryl iodides and bromides by palladium/norbornene catalysis. This new example of Catellani reaction features the initial cleavage of a C(sp2 )-I bond, followed by the key formation of a palladacycle through ortho C-H activation, the oxidative addition of an aryl bromide and the ultimate restoration of the C(sp2 )-I bond. A large variety of valuable o-iodobiaryls has been synthesized in satisfactory to good yields and their derivatization have been described too. Beyond the synthetic utility of this transformation, a DFT study provides insights on the mechanism of the key reductive elimination step, which is driven by an original transmetallation between palladium(II)-halides complexes.

Diastereoselective synthesis of tetrahydropyranes via Ag(I)-initiated dimerization of cinnamyl ethers.

We present herein the first synthesis of tetrahydropyranes promoted by a silver salt. Cinnamyl ethers undergo a formal dimerization affording the target heterocycle via sequential C-O bond cleavage/C-H bond functionalization. The cascade allows one to assemble three new bonds and to establish up to four stereocenters. The reaction likely proceeds through a cationic manifold that forms the target in a diastereoselective fashion.

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.

Pd-Catalysed oxidative carbonylation of α-amino amides to hydantoins under mild conditions.

The first example of palladium-catalysed oxidative carbonylation of unprotected α-amino amides to hydantoins is described here. The selective synthesis of the target compounds was achieved under mild conditions (1 atm of CO), without ligands and bases. The catalytic system overrode the common reaction pathway that usually leads instead to the formation of symmetrical ureas.

Inter/Intramolecular Cascade of 1,6-Enynes Catalyzed by All-Metal Aromatic Tripalladium Complexes and Carboxylic Acids.

Trinuclear all-metal aromatic clusters are an original class of molecules with a cyclic and planar metal core. Characterized by peculiar metal-metal delocalized bonds, they represent a new frontier in transition-metal catalysis. We report a study on C-C-forming reactions of polyunsaturated substrates catalyzed by trinuclear all-metal aromatic palladium clusters. The synthesis of two new families of tricyclic compounds was obtained with a broad functional group tolerance under mild reaction conditions. A peculiar regio- and diastereoselectivity characterized the method, demonstrating that trinuclear palladium complexes are complementary to their popular mononuclear peers. Furthermore, preliminary studies on the mechanism of these polycyclization reactions revealed unique features of the homogeneous catalytic system.

Site-Selective Double and Tetracyclization Routes to Fused Polyheterocyclic Structures by Pd-Catalyzed Carbonylation Reactions.

In this contribution, we report novel palladium-catalyzed carbonylative cascade approaches to highly functionalized polyheterocyclic structures. The Pd-catalyzed carbonylative process involves the regioselective insertion of one to three CO molecules and the sequential ordered formation of up to eight new bonds (one C-O, two C-C, five C-N). The exclusive formation of six-membered heterocycles is elucidated by detailed modeling studies.

Synthesis of fluorenyl alcohols via cooperative palladium/norbornene catalysis.

Herein, we report a novel catalytic synthesis of substituted 9H-fluoren-9-ols starting from aryl iodides and secondary ortho-bromobenzyl alcohols in the presence of palladium/norbornene as a catalytic system. The present protocol exhibits high functional group tolerance, mild reaction conditions and moderate to good yields. This transformation is based on two sequential pathways: (i) Pd(ii)-mediated oxidation of the secondary alcohol to the corresponding ketone and (ii) Pd(0)/norbornene-catalyzed reaction of the in situ generated ortho-bromoacetophenone with the aryl iodide.

Catalytic Carbonylative Double Cyclization of 2-(3-Hydroxy-1-yn-1-yl)phenols in Ionic Liquids Leading to Furobenzofuranone Derivatives.

A catalytic carbonylative double cyclization method for the synthesis of furo[3,4- b]benzofuran-1(3 H)-ones is reported. It is based on the reaction between readily available 2-(3-hydroxy-1-yn-1-yl)phenols, CO, and oxygen carried out in the presence of catalytic amounts of PdI2 (1 mol %) in conjunction with KI (20 mol %) and 2 equiv of diisopropylethylamine at 80 °C for 24 h under 30 atm of a 1:4 mixture of CO-air. Interestingly, the process was not selective when carried out in classical organic non-nucleophilic solvents (such as MeCN or DME), leading to a mixture of the benzofurofuranone derivative and the benzofuran ensuing from simple cycloisomerization, whereas it turned out chemoselective toward the formation of the double cyclization compound in BmimBF4 as the reaction medium. Moreover, the ionic liquid solvent containing the catalyst could be easily recycled several times without appreciable loss of activity.

Palladium(0)/benzoic acid catalysis merges sequences with D2O-promoted labelling of C-H bonds.

The combination of a Pd(0) complex with benzoic acid in the presence of D2O enables the synthesis of valuable families of highly deuterated organics through elaborate sequential reactions. The catalytic system can convert 2-butyne fragments into the corresponding d-dienamides, which can then readily deliver labeled polycyclic quinone motifs. Propargylated tryptamines lead to formation of highly enriched tetrahydrocarbolines through the C-H activation of their unprotected indole ring. Mechanistic studies reveal the ordered series of events that regulate the outcome of these complex reactions, which include multiple, sequential and selective H/D scrambling from the cheapest and safest deuterium source.

Catalytic Double Cyclization Process for Antitumor Agents against Breast Cancer Cell Lines.

The development of efficient synthetic strategies for the discovery of novel antitumor molecules is a major goal in current research. In this context, we report here a catalytic double cyclization process leading to bicyclic heterocycles with significant antitumor activity on different human breast cancer (BC) cell lines. The products, 6,6a-dihydrofuro[3,2-b]furan-2(5H)-ones, were obtained in one step, starting from simple substrates (4-yne-1,3-diols, CO, and O2), under the catalytic action of PdI2 in conjunction with KI. These compounds have significant antiproliferative activity in vitro on human BC cell lines, both hormone receptor positive (MCF-7) and triple negative (triple-negative breast cancer [TNBC]; MDA-MB-231 and MDAMB-468), while exhibiting practically no effects on normal MCF-10A (human mammary epithelial) and 3T3-L1 (murine fibroblasts) cells. Thus, these compounds have the potential to expand the therapeutic options against BC, and in particular, against its most aggressive forms (TNBCs). Moreover, the present synthetic approach may provide an economic benefit for their production.

Homogeneous and Gas-Liquid Catellani-Type Reaction Enabled by Continuous-Flow Chemistry.

A practical homogeneous and gas-liquid palladium-catalyzed Catellani-type reaction using a continuous-flow platform is described. The implementation of continuous-flow technology allowed the acceleration of the transformation and, for the first time, expansion of the chemical space to gaseous olefins (i.e., ethylene, propylene and 3,3,3-trifluoropropene), thus providing a safe and practical approach to sterically hindered ortho-disubstituted styrenes and vinyl arenes. The complete control over the stoichiometry of gaseous reagents through flow technology proved essential for directing the selectivity of the Catellani reaction to the desired products.

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.

An Unprecedented Pd-Catalyzed Carbonylative Route to Fused Furo[3,4-b]indol-1-ones.

A novel and efficient catalytic approach to functionalized furo[3,4-b]indol-1-ones is reported. It is based on a palladium-catalyzed sequential process involving an initial cyclization of 2-(hydroxypropyn-1-yl)anilines to form the indole moiety, followed by insertion of carbon monoxide and a second annulation step to build a lactone ring. In a single transformation, two fused heterocycles and three new bonds (C-N, C-C and C-O) are generated. The present methodology gives direct access to structurally complex molecules starting from readily available reagents.

Pd-Catalyzed/Iodide-Promoted α-Arylation of Ketones for the Regioselective Synthesis of Isocoumarins.

A variety of isocoumarins have been synthesized directly from 2-halobenzoates and ketones through a palladium-catalyzed α-arylation step followed by an intramolecular cyclization process. The addition of iodide anions to the reaction mixture increased yields and selectivities especially when 2-bromobenzoates were employed. This phosphine-free one-pot synthesis features a high functional group tolerance and gives access to richly decorated isocoumarins. This general methodology was successful in the total synthesis of Xyridin A, an important natural product with antibacterial and antifungal activity.

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;

Auto-Tandem Catalysis in Ionic Liquids: Synthesis of 2-Oxazolidinones by Palladium-Catalyzed Oxidative Carbonylation of Propargylic Amines in EmimEtSO4.

A convenient carbonylative approach to 2-oxazolidinone derivatives carried out using an ionic liquid (1-ethyl-3-methylimidazolium ethyl sulfate, EmimEtSO4) as the solvent is presented. It is based on the sequential concatenation of two catalytic cycles, both catalyzed by the same metal species (auto-tandem catalysis): the first cycle corresponds to the oxidative monoaminocarbonylation of the triple bond of propargylic amines to give the corresponding 2-ynamide intermediates, while the second one involves the cyclocarbonylation of the latter to yield 2-(2-oxooxazolidin-5-ylidene)-acetamides. Reactions are carried out using a simple catalytic system consisting of PdI2 in conjunction with an excess of KI, and the catalyst/solvent system could be recycled several times without appreciable loss of activity after extraction of the organic product with Et2O.

Pd/Norbornene: A Winning Combination for Selective Aromatic Functionalization via C-H Bond Activation.

Direct C-H bond activation is an important reaction in synthetic organic chemistry. This methodology has the potential to simplify reactions by avoiding the use of prefunctionalized reagents. However, selectivity, especially site selectivity, remains challenging. Sequential reactions, in which different molecules or groups are combined in an ordered sequence, represent a powerful tool for the construction of complex molecules in a single operation. We have discovered and developed a synthetic methodology that combines selective C-H bond activation with sequential reactions. This procedure, which is now known as the "Catellani reaction", enables the selective functionalization of both the ortho and ipso positions of aryl halides. The desired molecules are obtained with high selectivity from a pool of simple precursors. These molecules are assembled under the control of a palladacycle, which is formed through the joint action of a metal (Pd) and an olefin such as norbornene. These two species act cooperatively with an aryl halide to construct the palladacycle, which is formed through ortho-C-H activation of the original aryl halide. The resulting complex acts as a scaffold to direct the reaction (via Pd(IV)) of other species, such as alkyl or aryl halides and amination or acylation agents, toward the sp(2) C-Pd bond. At the end of this process, because of steric hindrance, the scaffold is dismantled by norbornene extrusion. Pd(0) is cleaved from the organic product through C-C, C-H, C-N, C-O, or C-B coupling, in agreement with the well-known reactivity of aryl-Pd complexes. The cycle involves Pd(0), Pd(II), and Pd(IV) species. In particular, our discovery relates to alkylation and arylation reactions. Recently, remarkable progress has been made in the following areas: (a) the installation of an amino or an acyl group at the ortho position of aryl halides, (b) the formation of a C-B bond at the ipso position, (c) the achievement of meta-C-H bond activation of aryl rings bearing a chelating directing group by Pd(II)/Pd(IV)/norbornene catalysis, and (d) the activation of N-H and C-H bonds in sequence for indole 2-alkylation. In this Account, we explain the main features of this methodology, describe its synthetic potential, and illustrate some remarkable progress that has been made, emphasizing the most recent developments and applications in total synthesis.

Catalytic Oxidative Carbonylation of Amino Moieties to Ureas, Oxamides, 2-Oxazolidinones, and Benzoxazolones.

The direct syntheses of ureas, oxamides, 2-oxazolidinones, and benzoxazolones by the oxidative carbonylation of amines, ß-amino alcohols, and 2-aminophenols allows us to obtain high value added molecules, which have a large number of important applications in several fields, from very simple building blocks. We have found that it is possible to perform these transformations using the PdI2 /KI catalytic system in an ionic liquid, such as 1-butyl-3-methylimidazolium tetrafluoroborate, as the solvent, the solvent/catalyst system can be recycled several times with only a slight loss of activity, and the product can be recovered easily by crystallization.

Correction: A novel enantioselective synthesis of 6H-dibenzopyran derivatives by combined palladium/norbornene and cinchona alkaloid catalysis.

Correction for 'A novel enantioselective synthesis of 6H-dibenzopyran derivatives by combined palladium/norbornene and cinchona alkaloid catalysis' by Di Xu et al., Org. Biomol. Chem., 2015, DOI: 10.1039/c4ob02551b.