Doubly Metathetic NiCl-Catalyzed Coupling Between Bis(2-oxazolines) and Aldehydes: A Novel Access to Bis(ester-imine) Derivatives.

The coupling between bis(2-oxazolines) and two equivalents of aromatic aldehydes in the presence of catalytic amounts of NiCl affords an ester-imine product in synthetically useful yields. This virtually unknown, 100% atom-economic transformation involves the formal metathesis between the C=N double bond of the bis(2-oxazoline) moiety, which undergoes ring-opening, and the C=O double bond of the aldehyde. The scope of this transformation is studied, and a mechanism is proposed based on DFT calculations.

Diastereoselective Palladaelectro-Catalyzed Construction of Bromomethyl Morpholines as Key Step To Access Morpholino Homonucleosides.

A synthetic protocol for the preparation of a new class of morpholino homonucleosides in enantiopure form starting from readily available 1,2-aminoalcohols or glycidol has been developed. Key intermediates of the synthetic sequence are 2-bromomethyl morpholines, diastereoselectively achieved from the corresponding alkenols by palladaelectro-catalyzed alkoxybromination of unactivated alkenes. The so obtained bromo derivatives are in turn susceptible to functionalization with nucleic bases for easy access to morpholino homonucleosides.

Phosphine-Catalyzed Domino Regio- and Stereo-Selective Hexamerization of 2-(Bromomethyl)acrylates to 1,2-Bis(cyclohexenyl)ethenyl Derivatives.

A phosphine-catalyzed domino assembly of six units of 2-bromomethyl acrylates afforded polyalkenyl adducts containing two cyclohexenyl rings. This reaction occurs under mild conditions providing the final product by formation of seven carbon-carbon bonds and four stereocenters. Experimental and computational studies support an initial dimerization of the substrate, which in turn trimerizes involving two totally regio- and stereocontrolled Diels-Alder cycloadditions.

Copper(II)-Catalyzed Three-Component Arylation/Hydroamination Cascade from Allyl Alcohol: Access to 1-Aryl-2-sulfonylamino-propanes.

A new straightforward approach to 1-aryl-2-aminopropanes using easily accessible substrates has been developed. Simple allyl alcohol is shown to be an ideal synthetic equivalent of the C3 propane-1,2-diylium bis-cation synthon in three-component cascade reactions with arenes and sulfonamide nucleophiles to regioselectively afford 1-aryl-2-aminopropanes. The reaction is catalyzed by Cu(OTf) and is expected to involve a Friedel-Crafts-type allylation of the arene, followed by hydroamination.

Non-Decarboxylative Ruthenium-Catalyzed Rearrangement of 4-Alkylidene-isoxazol-5-ones to Pyrazole- and Isoxazole-4-carboxylic Acids.

Treatment of 4-(2-hydroaminoalkylidenyl)- and 4-(2-hydroxyalkylidenyl)-substituted isoxazol-5(4)-ones with catalytic amounts of [RuCl(-cymene)], without any additive, afforded pyrazole- and isoxazole-4-carboxylic acids, respectively. The presence of an intramolecular H-bond in these substrates was the key to divert the classical mechanism toward a ring-opening non-decarboxylative path that is expected to generate a vinyl Ru-nitrenoid intermediate, the cyclization of which affords the rearranged products. A gram scale protocol demonstrated the synthetic applicability of this transformation.

Redox-Neutral Ru(0)-Catalyzed Alkenylation of 2-Carboxaldimine-heterocyclopentadienes.

A new Ru(CO)-catalyzed directed alkenylation of 2-carboxaldimine-heterocyclopentadienes has been accomplished. This process allows coupling of furan, pyrrole, indole, and thiophene 2-carboxaldimines with electron-poor alkenes such as acrylates, vinylsulfones, and styrenes. This regio- and chemoselective oxidative C-H coupling does not require the presence of an additional sacrificial oxidant.

Direct Synthesis of Fluorescent Oxazolo-phenoxazines by Copper-Catalyzed/Hypervalent Iodine(III)-Mediated Dimerization/Cyclization of 2-Benzylamino-phenols.

A dimerization/cyclization reaction of 2-benzylamino-phenols for the direct synthesis of the oxazolo-phenoxazine skeleton is reported. The reaction occurs under copper catalysis in the presence of hypervalent iodine(III), giving selectively the 5-oxazolo[4,5-]phenoxazine compounds. The cascade process, which allows the conversion of the substrates into the tetracyclic products, involves three C-H functionalization steps.

Divergent Conversion of 4-Naphthoquinone-substituted 4-Isoxazolones to Different Benzo-fused Indole Derivatives.

4,4-Disubstituted 4-isoxazol-5-ones bearing a 1,4-naphthoquinone moiety undergo transformation into different types of benzoindolyl products depending on the different reaction conditions. A decarboxylative ring opening/ring closure promoted by catalytic [Ru(-cymene)Cl] yields benzo[]indole-4,9-diones. Alternatively, hydrogenation reactions provide the conversion of 4-(1,4-naphthoquinone)-substituted isoxazol-5-ones to benzo[]indole compounds, with the level of reduction depending on the substituents present on the ring.

Intramolecular Aminoazidation of Unactivated Terminal Alkenes by Palladium-Catalyzed Reactions with Hydrogen Peroxide as the Oxidant.

The palladium-catalyzed aminoazidation of aminoalkenes yielding azidomethyl-substituted nitrogen-containing heterocycles was developed. The procedure requires oxidative conditions and occurs at room temperature in the presence of hydrogen peroxide and NaN as the azide source. These conditions provide selective -cyclization/azidation of the carbon-carbon double bond, furnishing a versatile approach toward five-, six-, and seven-membered heterocyclic rings.

Synthesis and Biological Evaluation of Pyrimidine-oxazolidin-2-arylimino Hybrid Molecules as Antibacterial Agents.

Pyrimidine-1,3-oxazolidin-2-arylimino hybrids have been synthesized as a new class of antibacterial agents. The synthetic approach exploits a Cu(II)-catalyzed intramolecular halkoxyhalogenation of alkynyl ureas, followed by a Suzuki coupling reaction with 2,4-dimethoxypyrimidin-5-boronic acid. Biological screenings revealed that most of the compounds showed moderate to good activity against two Gram-positive (, ) and three Gram-negative (, , ) pathogenic strains.

Copper(II)-Catalyzed Alkoxyhalogenation of Alkynyl Ureas and Amides as a Route to Haloalkylidene-Substituted Heterocycles.

A highly effective synthesis of haloalkylidene-substituted heterocycles by copper(II)-catalyzed cyclization of alkynyl ureas and secondary amides has been developed. The reaction, which involves a catalytic amount of CuCl2 and a stoichiometric amount of N-halosuccinimide, occurs selectively through an alkoxyhalogenation process. Alternatively, alkoxychlorination and alkoxybromination reactions can be performed working solely with stoichiometric CuCl2 and CuBr2, respectively.

Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2.

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines (CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range.

Recent advances in heterobimetallic palladium(II)/copper(II) catalyzed domino difunctionalization of carbon-carbon multiple bonds.

The double functionalization of carbon-carbon multiple bonds in one-pot processes has emerged in recent years as a fruitful tool for the rapid synthesis of complex molecular scaffolds. This review covers the advances in domino reactions promoted by the couple palladium(ii)/copper(ii), which was proven to be an excellent catalytic system for the functionalization of substrates.

Palladium-catalyzed dual C-H or N-H functionalization of unfunctionalized indole derivatives with alkenes and arenes.

This review highlights the development of palladium-catalyzed C-H and N-H functionalization reactions involving indole derivatives. These procedures require unactivated starting materials and are respectful of the basic principle of sustainable chemistry tied to atom economy.

Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes.

In a simple procedure, the intramolecular hydroarylation of N-propargyl-pyrrole-2-carboxamides was accomplished with the aid of gold(III) catalysis. The reaction led to differently substituted pyrrolo[2,3-c]pyridine and pyrrolo[3,2-c]pyridine derivatives arising either from direct cyclization or from a formal rearrangement of the carboxamide group. Terminal alkynes are essential to achieve bicyclic pyrrolo-fused pyridinones by a 6-exo-dig process, while the presence of a phenyl group at the C-C triple bond promotes the 7-endo-dig cyclization giving pyrrolo-azepines.

Solvent-free, microwave-assisted N-arylation of indolines by using low palladium catalyst loadings.

Indoline-based compounds are abundant in nature, and the indoline skeleton is an often-encountered scaffold in a range of biologically active alkaloids, pharmaceutically active compounds, and functional molecules (e.g., sensitizers for solar cells).

Tunable Pd-catalyzed cyclization of indole-2-carboxylic acid allenamides: carboamination vs microwave-assisted hydroamination.

A variety of 3-vinyl-substituted imidazo[1,5-a]indole derivatives were synthesized by intramolecular Pd-catalyzed cyclization of the title allenamides through either a domino carbopalladation/exo-cyclization process or a novel hydroamination reaction that proceeds smoothly under microwave irradiation. Both the observed pathways involve a π-allyl-palladium(II) complex arising from insertion of the allene group into a palladium(II) species, the latter being formed in situ by the intervention of an aryl iodide or of the N-H group. In both cases, the role of nucleophile is covered by the indole nitrogen.

Sigma-alkylpalladium intermediates in intramolecular Heck reactions:isolation and catalytic activity.

The isolation of sigma-alkylpalladium Heck intermediates, possible when beta-hydride elimination is inhibited, is a rather rare event. Performing intramolecular Heck reactions on N-allyl-2-halobenzylamines in the presence of [Pd(PPh(3))(4)], we isolated and characterized a series of stable bridged palladacycles containing an iodine or bromine atom on the palladium atom. Indolyl substrates were also tested for isolation of the corresponding complexes.

Palladium-catalyzed domino carbopalladation/5-exo-allylic amination of alpha-amino allenamides: an efficient entry to enantiopure imidazolidinones.

Allenamides of alpha-amino acids were converted into enantiopure 2-vinylimidazolidin-4-ones by a carbopalladation/exo-cyclization process. The products were obtained in 2.5:1-5.

Intramolecular Pd(II)-catalyzed cyclization of propargylamides: straightforward synthesis of 5-oxazolecarbaldehydes.

Direct synthesis of 2-substituted 5-oxazolecarbaldehydes was performed by intramolecular reaction of propargylamides through treatment with a catalytic amount of Pd(II) salts in the presence of a stoichiometric amount of reoxidant agent. The heterocyclization process was well-tolerated by a wide range of aryl, heteroaryl, and alkyl propargylamides. This protocol constitutes a valuable synthetic pathway to 5-oxazolecarbaldehydes, alternative to the formylation on oxazole rings, often unsatisfactory in term of regioselectivity and yields.

New 4-spiroannulated tetrahydroisoquinolines by a one-pot sequential procedure. isolation and characterization of sigma-alkylpalladium heck intermediates.

A simple and efficient entry to new tetrahydroisoquinolines 4-spiroannulated to a five-membered heterocyclic ring has been achieved starting from secondary N-allylamines and involving sequential 2-iodobenzylation/intramolecular Heck reaction/1,3-dipolar cycloaddition. A variety of Heck cyclization conditions were surveyed. When using Pd(PPh(3))(4) as catalyst, stable sigma-alkylpalladium iodide complexes were isolated and characterizated.

Efficient synthesis of N-methoxyindoles via alkylative cycloaddition of nitrosoarenes with alkynes.

[reaction: see text] N-Methoxyindoles are produced in moderate to excellent yields from the reaction between nitrosoarenes and alkynes in the presence of K2CO3/(CH3)2SO4. Terminal alkynes with conjugating substituents afford 3-substituted N-methoxyindoles exclusively. The analogous reactions with methyl propiolate provide a one-step preparation of phytoalexin analogues from Wasabi.

Regioselective formation of six- and seven-membered ring by intramolecular Pd-catalyzed amination of N-allyl-anthranilamides.

A divergent synthesis of quinazolin-4-ones and 1,4-benzodiazepin-5-ones by Pd(II)-catalyzed intramolecular amination of tosylated N-allyl-anthranilamides is described. Both kinds of products were available in high yields depending on the different reaction conditions.