Gold Salts as Alternative Catalysts in Promoting Cascade Condensation of 2-Aminobenzaldehydes with Alcohols and Amines.

The distinctive features of gold self-relay catalysts were alternatively utilized in the intriguing cascade condensation of 2-aminobenzaldehydes with alcohols and amines. Using NaAuCl·2HO as a catalyst, a range of 13-alkyloxy-7,11-dihydro-6,13-6,12-[1,2]benzenoquinazolino[3,4-]quinazoline derivatives was produced in good to high yields through AB condensation of various 2-aminobenzaldehydes with alcohols. By carefully choosing the reaction conditions, gold catalysis also proved effective for AB condensation with primary aryl- and benzylamines, facilitating the synthesis of challenging McGeachin bisaminals, including a chiral nonracemic derivative of 2-()-methylbenzylamine.

Product Selectivity Control in the Brønsted Acid-Mediated Reactions with 2-Alkynylanilines.

Brønsted acid-catalysed/mediated reactions of the 2-alkynylanilines are reported. While metal-catalysed reactions of these valuable building blocks have led to the establishment of robust protocols for the selective, diverse-oriented syntheses of significant heterocyclic derivatives, we here demonstrate the practical advantages of an alternative methodology under metal-free conditions. Our investigation into the key factors influencing the product selectivity in Brønsted acid-catalysed/mediated reactions of 2-alkynylanilines reveals that different reaction pathways can be directed towards the formation of diverse valuable products by simply choosing appropriate reaction conditions.

Palladium-Catalyzed Tsuji-Trost-Type Reaction of 3-Indolylmethylacetates with O, and S Soft Nucleophiles.

The chemical valorization of widespread molecules in renewable sources is a field of research widely investigated in the last decades. In this context, we envisaged that indole-3-carbinol, present in different plants, could be a readily available building block for the synthesis of various classes of indoles through a palladium-catalyzed Tsuji-Trost-type reaction with O and S soft nucleophiles. The regiochemical outcome of this high-yielding functionalization shows that the nucleophilic substitution occurs only at the benzylic position.

Experimental Results and Mechanistic Insights on the Reactions of Indolylmethyl Acetates with Soft Carbon Pronucleophiles.

The palladium-catalyzed reaction of -protected 2-indolylmethyl acetates with soft carbon pronucleophiles is described. Besides the formation of the expected coupling reaction at the C1' position, unprecedented attack at the C3 position of the plausible η-indolyl-palladium intermediate has been observed, and the selectivity control C1'/C3 seems to depend on the nature of the protecting group and ligand. The reactivity of 3-indolylmethyl acetates has also been also investigated.

Synthesis of Nitrogen-Containing Heterocyclic Scaffolds through Sequential Reactions of Aminoalkynes with Carbonyls.

Sequential reactions of aminoalkynes represent a powerful tool to easily assembly biologically important polyfunctionalized nitrogen heterocyclic scaffolds. Metal catalysis often plays a key role in terms of selectivity, efficiency, atom economy, and green chemistry of these sequential approaches. This review examines the existing literature on the applications of reactions of aminoalkynes with carbonyls, which are emerging for their synthetic potential.

Direct Regioselective Hydro(hetero)arylation/Cyclocondensation Reactions of β-(2-Aminophenyl)-α,β-ynones by Means of Transition-Metal Catalysis/Brønsted Acid Synergism: Experimental Results and Computational Insights.

Experimental results and computational insights explain the key role of transition-metal catalysis/Brønsted acid synergism in the achievement of the sequential regioselective direct heteroarylation/cyclocondensation reactions of β-(2-aminophenyl)-α,β-ynones with a variety of electron-rich aromatic heterocyclic/arenes to afford quinoline-(hetero)aromatic hybrids. The first approach to the synthesis of 4-(1-pyrrol-2-yl)quinolines is described. The effectiveness of various transition metals is compared.

Synthesis of 3-substituted 2,3-dihydropyrazino[1,2-]indol-4(1)-ones by sequential reactions of 2-indolylmethyl acetates with α-amino acids.

The synthesis of 2,3-dihydropyrazino[1,2-]indol-4(1)-ones from the sequential reaction of amino acid methyl esters with readily available indole-2-ylmethyl acetates is described. The reaction proceeds under basic conditions of highly unstable and reactive 2-alkylideneindolenines followed by Michael-type addition of α-amino acid methyl esters/intramolecular cyclization.

Electrochemical-Induced Cascade Reaction of 2-Formyl Benzonitrile with Anilines: Synthesis of -Aryl Isoindolinones.

An electrochemical initiated tandem reaction of anilines with 2-formyl benzonitrile has been developed. Thus, unprecedented 3--aryl substituted isoindolinones have been conveniently achieved by constant current electrolysis in a divided cell using catalytic amount of electricity and supporting electrolyte and a Pt-cathode as working electrode. The origin of the electrochemical activation as well as the mechanism of the subsequent chemical cascade reactions have been investigated by DFT calculations.

One-pot synthesis of dihydroquinolones by sequential reactions of -aminobenzyl alcohol derivatives with Meldrum's acids.

The functionalized 3,4-dihydroquinolin-2-one nucleus has been assembled in good to high yields through the sequential reaction of readily available -Ts--aminobenzyl alcohols with 5-substituted Meldrum's acid derivatives under mild basic conditions. Highly diastereoselective synthesis of 3-substituted-4-phenyl-1-tosyl-3,4-dihydroquinolin-2(1)-ones was accomplished from -(2-(hydroxy(phenyl)methyl)phenyl)-4-methylbenzenesulfonamide under the same reaction conditions. Regarding the reaction mechanism, we hypothesized that the formation of dihydroquinolones proceeds through the generation of aza--QMs followed by conjugate addition of enolate/cyclization/elimination of acetone and CO.

Design, synthesis and biological evaluation of new thiazole scaffolds as potential TRPM8 antagonists.

The preliminary results on the development of a viable methodology for the further functionalization of 4-hydroxythiazole derivatives to afford target TRPM8 antagonists are reported. The combined Sonogashira coupling/annulation reactions of the ethyl 2-(3-fluorophenyl)-4-tifluoromethylsulfonyloxy-1,3-thiazole-5-carboxylate have been applied to the synthesis of analogues of the selective blocker of TRPM8 DFL23448. Among all the synthetised derivatives, the most promising compound resulted to be active as TRPM8 blocker (IC50 = 4.

Synthesis of 4-Substituted-1,2-Dihydroquinolines by Means of Gold-Catalyzed Intramolecular Hydroarylation Reaction of -Ethoxycarbonyl--Propargylanilines.

An alternative Au(I)-catalyzed synthetic route to functionalized 1,2-dihydroquinolines is reported. This novel approach is based on the use of -ethoxycarbonyl protected--propargylanilines as building blocks that rapidly undergo the IMHA reaction affording the 6- cyclization product in good to high yields. In the presence of -ethoxycarbonyl--propargyl-substituted anilines, the regiodivergent cyclization at the -/-position is achieved by the means of catalyst fine tuning.

Sequential condensation/biannulation reactions of β-(2-aminophenyl)-α,β-ynones with 1,3-dicarbonyls.

A divergent domino condensation/biannulation reaction of β-(2-aminophenyl) α,β-ynones with 1,3-dicarbonyls to construct a polycyclic 4H-pyrano[3,4-c]quinoline core has been developed. The p-TsOH·H2O catalyzed reaction of β-(2-aminophenyl) α,β-ynones with β-ketoesters in ethanol proceeds with good to excellent yields to provide a simple and effective method for the synthesis of functionalized 4H-pyrano[3,4-c]quinolinones. Further elaboration of these latter derivatives with an excess of 20% NH4OH in EtOH at 50 °C helps achieve the synthesis of the perlodinine analogues benzo[c][2,7]naphthyridin-4(3H)-one derivatives in high yields.

Palladium-catalyzed Tsuji-Trost-type reaction of benzofuran-2-ylmethyl acetates with nucleophiles.

The palladium-catalyzed benzylic-like nucleophilic substitution of benzofuran-2-ylmethyl acetate with N, S, O and C soft nucleophiles has been investigated. The success of the reaction is dramatically influenced by the choice of catalytic system: with nitrogen based nucleophiles the reaction works well with Pd(dba)/dppf, while with sulfur, oxygen and carbo-nucleophiles [Pd(η-CH)Cl]/XPhos is more efficient. The regiochemical outcome shows that the nucleophilic substitution occurs only on the benzylic position of the η-(benzofuryl)methyl complex.

Synthesis of functionalised 2,3-dihydroquinolin-4(1)-ones quinoline or -alkenylindole derivatives through sequential reactions of 2-alkynylanilines with ketones.

This study describes diversity-oriented synthesis of 2,2,3-substituted-2,3-dihydroquinolin-4(1H)-ones vs. functionalised quinoline or N-alkenylindole derivatives through Brønsted acid mediated or Lewis acid catalyzed sequential reactions of 2-alkynylanilines with ketones. In particular, a series of challenging quinolin-4-one derivatives are prepared with good functional group tolerance in an atom-economical fashion by using p-toluenesulfonic acid monohydrate as a promoter of the reaction of ketones with 2-alkynylanilines in EtOH at reflux, while the same starting materials give the corresponding 4-substituted quinolines in toluene at 110 °C both in the presence of p-toluenesulfonic acid monohydrate as the promoter and FeCl3 as the catalyst.

Experimental and computational evidence on gold-catalyzed regioselective hydration of phthalimido-protected propargylamines: an entry to β-amino ketones.

The results of our investigations on the Au-catalyzed regioselective hydration reaction of both alkyl- and aryl-substituted N-propargyl phthalimides directed to the selective formation of the corresponding β-phthalimido ketones are described. Experimental data, in particular the observed regioselectivity, have been qualitatively supported by quantum-chemical calculations carried out on model systems in the framework of Density Functional Theory (DFT) followed by quantum theory of atoms in molecules (QTAIMS). Our results suggest that the electronic features of the initial adduct between the propargyl triple bond and the Au(i) catalyst, in particular the character of the gold-triple bond interaction, are essential for the observed regioselectivity.

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1()-ones.

Cascade cyclocarbopalladation of the readily available aryl/alkyl-substituted propargylic amides containing an aryl iodide moiety, followed by Suzuki-Miyaura coupling with arylboronic acids, allowed an efficient regio- and stereoselective synthesis of tetrasubstituted 4-methylene-3,4-dihydroisoquinolin-1(2)-ones. Moreover, cascade cyclocarbopalladation, followed by the reaction with 2-alkynyltrifluoroacetanilides, accomplished a double cyclization to afford challenging 4-methylene-3,4-dihydroisoquinolin-1(2)-ones bearing a 3-indolyl substituent through aminopalladation/reductive elimination.

Experimental results and computational insight into sequential reactions of β-(2-aminophenyl)-α,β-ynones with aryl isocyanates/benzoyl isothiocyanate.

The investigation on tandem addition/cyclization reactions of β-(2-aminophenyl)-α,β-ynones with aryl isocyanates/benzoyl isothiocyanate is reported. Experimental results show the suitable conditions to selectively direct the reaction outcome towards the product of 6-exo-dig N-, O-, or S-annulation of the in situ generated alkynyl urea/thiourea intermediate. The reaction of a variety of β-(2-aminophenyl)-α,β-ynones with aryl isocyanates/benzoyl isothiocyanate led to the selective formation of quinazoline or benzoxazine/benzothiazine derivatives, respectively.

Synthesis of pyrano[2,3-f]chromen-2-ones vs. pyrano[3,2-g]chromen-2-ones through site controlled gold-catalyzed annulations.

Regioselective access to 10-substituted-2H,8H-pyrano[2,3-f]chromen-2-ones through the gold-catalyzed intramolecular hydroarylation of readily available 7-(prop-2-yn-1-yloxy)-2H-chromen-2-one derivatives at their C-8 congested position was investigated by tuning the electronic and steric properties of the ligand on the gold complex. On the other hand, the combination of the JohnPhosAu(MeCN)SbF6 catalyzed intramolecular hydroarylation of 8-iodo-7-(prop-2-yn-1-yloxy)-2H-chromen-2-one derivatives followed by selective palladium/formate C-I reduction allows for the exclusive formation of 2H,8H-pyrano[3,2-g]chromen-2-one regioisomers. The development of these two protocols provides versatile synthetic tools required for exploring the biological activities of these new pyranocoumarin derivatives.

Synthesis of indolo[1,2-]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed indole formation/cyclization with ,-dimethylformamide dimethyl acetal.

An efficient strategy for the synthesis of 6-unsubstituted indolo[1,2-]quinazolines is described. The Pd-catalyzed reaction of -(-aminophenylethynyl) trifluoroacetanilides with Ar-B(OH) afforded 2-(-aminophenyl)-3-arylindoles, that were converted to 12-arylindolo[1,2-]quinazolines by adding dimethylformamide dimethyl acetal (DMFDMA) to the reaction mixture after extractive work-up. This reaction outcome is different from the previously reported Pd-catalyzed sequential reaction of the same substrates with Ar-I, Ar-Br and ArNBF, that afforded 12-arylindolo[1,2-]quinazolin-6(5)-ones.

Gold-Catalyzed Cascade Reaction of β-(2-Aminophenyl)-α,β-ynones with Ynamides: A Sequential Route to Polysubstituted 2-Aminoquinolines.

A novel, efficient, and mild synthetic route for the preparation of 2-aminoquinolines via a gold-catalyzed cascade reaction of β-(2-aminophenyl)-α,β-ynones with ynamides has been developed. This process tolerates a wide range of functionalities such as halogen, alkyl, aryl, and heteroaryl groups, leading to original heterocycles in fair to very good yields.

Pd- and Rh-Catalyzed Hydroarylation of γ-(2-Methoxycarbonylphenyl)propargylic Alcohols: Approaches to 4- or 5-Substituted Seven-Membered Benzolactones and 3,3-Disubstituted Phthalides.

A study of the palladium-catalyzed hydroarylation/hydrovinylation reaction of γ-(2-methoxycarbonylphenyl)propargylic alcohols with aryl iodides/vinyl triflates and of the rhodium-catalyzed one with organoboron derivatives is described. The opposite regiochemical outcome of the two processes allows an easy selective approach to 5- or 4-substituted benzoxepin-1(3H)-ones by combining the hydroarylative/hydrovinylative step with cyclocondensation between -OH and -COOMe groups in the intermediate γ,γ-disubstituted or β,γ-disubstituted allylic alcohols. A one-flask procedure to give benzo[c]oxepin-1(3H)-ones directly from the starting alkyne has been also developed.

Aminofluorination of 2-alkynylanilines: a Au-catalyzed entry to fluorinated indoles.

The scope and limitations of gold-catalyzed tandem cycloisomerization/fluorination reactions of unprotected 2-alkynylanilines to have access to 3,3-difluoro-2-aryl-3H-indoles and 3-fluoro-2-arylindoles are described. An unprecedented aminoauration/oxidation/fluorination cascade reaction of 2-alkynylanilines bearing a linear alkyl group on the terminal triple bond is reported.