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2,5-disubstituted N,N'-alkylpiperazines represent an interesting target in organic synthesis both for pharmaceutical or agrochemical applications and as a promising class of ligands in coordination chemistry. We report here a microwave-enhanced synthesis of these compounds starting from non-activated N-alkyl aziridines in the presence of catalytic amounts of simple ammonium metallates. A remarkable TOF of 2787.9 h -1 has been observed in the case of [TBA] 2 [ZnI 4 ] as the catalyst (catalyst loading 0.1 mol %) and with an almost complete selectivity (up to 97 %) in favor of both diastereoisomers (meso and chiral form) of the target 2,5-disubstituted piperazines, obtained in 1 : 1 ratio. The two isomers are easily separated, because the meso form precipitates in pure from the reaction crude. A stereochemical investigation and the unprecedented isolation of 2,6-disubstituted N,N'-alkylpiperazines allowed us to shed light on the reaction mechanism., (© 2024 The Authors. Chemistry - An Asian Journal published by Wiley-VCH GmbH.)

In this study, we explored and optimized a MW-enhanced divergent approach for the synthesis of 2-substituted benzofurans and chromenes, starting from seventeen substituted o -propargylphenols characterized by a monoaryl substitution on the propargylic sp 3 carbon. Firstly, we developed a robust platform for the preparation of a library of o -propargylphenols. Under basic conditions, o -propargylphenols reacted regioselectively to yield benzofurans in yields ranging from 43% to 100%. Conversely, under cationic gold catalysis, we were able to obtain the corresponding 4 H -chromenes, albeit in more variable yields (from 25% to 93%) and slightly lower regioselectively. We also proposed plausible mechanisms to explain the divergent outcomes observed. Our findings underscore the potential of diversity-oriented synthesis in the investigation of molecular complexity. Our neglected o -propargylphenols have proven to be versatile and strategic starting materials for accessing oxygen-containing heterocyclic scaffolds through intramolecular cyclization reactions.

A redox umpolung strategy for the synthesis of complex tetrahydrocarbazoles is reported. The reaction involves a visible light promoted radical cation [4+2] cycloaddition between 2-vinylindoles and conjugated alkenes that proceeds with good yields and diastereoselectivity.

Several isocoumarins have been synthesised in good to excellent yields starting from 2-alkynylbenzoates and arenediazonium salts. The strategy involves a domino arylation/oxo-cyclization catalysed by a dual photoredox/gold catalytic system. The reactions run under mild conditions at room temperature in wet acetonitrile under irradiation with a blue-LED lamp, in the presence of a cationic gold catalyst and a cheap organic photocatalyst. The scope is quite broad and allows the preparation of isocoumarins differently disubstituted in positions 3 and 4. A plausible reaction mechanism is proposed.

Two sets of unprecedented push-pull isoquinolines, characterized by an opposite "dipolar moment" with respect to the longitudinal axis of the molecule, have been prepared. The key step of the approach is the microwave-promoted domino imination/cycloisomerization of 2-alkynyl benzaldehydes in the presence of methanolic ammonia. Absorption spectra and emission spectra of the D-π-A isoquinolines and their alkynyl precursors in nine different solvents have been recorded. The absolute QYs of all compounds have been recorded in three solvents with different polarities, i.e. toluene, DMSO and ethanol. Among the D-π-A isoquinolines prepared - nicknamed QuinaChroms - two compounds characterized by opposite dipolar moments, i.e. 3-(4-methoxyphenyl)-7-nitroisoquinoline 1a and N,N-diethyl-3-(4-(methylsulfonyl)phenyl)isoquinolin-7-amine 2b displayed more interesting photophysical profiles, whereas 5-(diethylamino)-2-(A)arylethynylbenzaldehydes precursors 8a-c - having a free aldehyde group that is suitable for possible conjugation - exhibited strong fluorescence and wide Stokes shifts. These products are interesting for potential use as polarity-sensitive fluorescent probes or advanced functional materials.

A simple and efficient approach for the synthesis of 2-spirocyclopropyl-indolin-3-ones is herein described. The method involves a diasteroselective cyclopropanation of aza-aurones with tosylhydrazones, selected as versatile carbene sources, and represents a remarkable synthetic alternative to get access to this class of C2-spiropseudoindoxyl scaffolds. The reactions proceed in the presence of a base and catalytic amounts of benzyl triethylammonium chloride and well-tolerate a broad range of substituents on both aza-aurones and tosylhydrazones to afford a series of C2-spirocyclopropanated derivatives in high yields. In addition, selected functional group transformations of the final products were explored demonstrating the synthetic potential of these indole-based derivatives.

The urgent need to develop a detection system for Staphylococcus aureus , one of the most common causes of infection, is prompting research towards novel approaches and devices, with a particular focus on point-of-care analysis. Biosensors are promising systems to achieve this aim. We coupled the selectivity and affinity of aptamers, short nucleic acids sequences able to recognize specific epitopes on bacterial surface, immobilized at high density on a nanostructured zirconium dioxide surface, with the rational design of specifically interacting fluorescent peptides to assemble an easy-to-use detection device. We show that the displacement of fluorescent peptides upon the competitive binding of S. aureus to immobilized aptamers can be detected and quantified through fluorescence loss. This approach could be also applied to the detection of other bacterial species once aptamers interacting with specific antigens will be identified, allowing the development of a platform for easy detection of a pathogen without requiring access to a healthcare environment.

The synthesis of cyclohepta[ b ]indole derivatives through the dearomative (4 + 3) cycloaddition reaction of 2-vinylindoles or 4 H -furo[3,2- b ]indoles with in situ generated oxyallyl cations is reported. Oxyallyl cations are generated from α-bromoketones in the presence of a base and a perfluorinated solvent. Cyclohepta[ b ]indole scaffolds are obtained under mild reaction conditions, in the absence of expensive catalysts, starting from simple reagents, in good to excellent yields and with complete diasteroselectivity. Preliminary expansion of the scope to 3-vinylindoles and to aza-oxyallyl cations is reported.

Merging the ability of cationic gold(I) catalysts to activate unsaturated π-systems with the electrophiles-driven ring-opening reactions of furans, we describe a new approach to synthesize 2-spiroindolin-3-ones from 4 H-furo[3,2- b]indoles. The reaction occurs through a cascade sequence involving addition of a gold-activated allene to the furan moiety of the starting furoindole followed by a ring-opening/ring-closing event affording 2-spirocyclopentane-1,2-dihydro-3 H-indolin-3-ones in moderate to good yields.

In this paper, we describe the silver triflate/p-toluenesulfonic acid co-catalysed synthesis of seventeen isocoumarins and two thieno[2,3-c]pyran-7-ones starting from 2-alkynylbenzoates and 3-alkynylthiophene-2-carboxylates, respectively. The reaction proceeds with absolute regioselectivity under mild reaction conditions and low catalyst loading, to afford the desired products in good to excellent yields. A conceivable reaction mechanism is proposed and supported by isotope-exchange tests, 1H NMR studies and ad hoc experiments.

A new gold-catalyzed reaction of ynamides with 3-substituted indoles as nucleophiles is reported. The reaction allows for the synthesis of a new class of 2-vinylindole derivatives in good yields via the intermediacy of a cyclopropyl gold-carbenoid species.

A study on the SN2-type ring opening reactions of aziridines with indoles as nucleophiles is reported. Under gold(i) catalysis a great variety of tryptamine derivatives were prepared in good to excellent yields with complete stereocontrol when chiral aziridines were used. We demonstrated that cationic gold(i) catalysts are superior Lewis acids to the previously reported group 3, 12 and 13 metals in terms of catalyst loading and reaction yields. Moreover, complete regioselectivity was observed for 2-phenyl-N-tosylaziridine; whereas, regioselectivity up to 10 : 1 ratio was observed with 2-methyl-N-tosylaziridine. Finally, a preliminary study on the dearomatization reactions giving rise to pyrroloindolines is also reported.

A small library of six polarity-sensitive fluorescent dyes, nicknamed MediaChrom, was prepared. This class of dyes is characterized by a pyrimidoindolone core fitted out with a conjugated push-pull system and a carboxy linker for a conceivable coupling with biomolecules. The optimized eight-step synthetic strategy involves a highly chemo- and regioselective gold-catalyzed cycloisomerization reaction. The photophysical properties of MediaChrom dyes have been evaluated in-depth. In particular, the MediaChrom bearing a diethylamino as an electron-donating group and a trifluoromethyl as an electron-withdrawing group displays the most interesting and advantageous spectroscopic features (e.g., absorption and emission in the visible range and a good quantum yield). Promising results in terms of sensitivity have been obtained in vitro on this dye as a membrane/lipophilic probe and as a peptide fluorescent label.

A Lewis acid-catalysed diastereoselective [4 + 2] cycloaddition of vinylindoles and methyl 2-acetamidoacrylate, leading to methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate derivatives, is described. Treatment of the obtained cycloadducts under hydrolytic conditions results in the preparation of a small library of compounds bearing the free amino acid function at C-3 and pertaining to the class of constrained tryptophan analogues.

An easy entry to uncommon 2-propargylbenzaldehydes was developed. 2-Propargylbenzaldehydes demonstrated to be suitable building blocks for the synthesis of 3-benzyl isoquinolines by microwave promoted domino imination/cycloisomerisation in the presence of ammonium acetate. A small library of 3-benzyl isoquinolines was obtained in good yields under mild reaction conditions. Two alternative plausible reaction mechanisms are proposed.

Two original macrocyclic silver(I)(pyridine-containing ligand) complexes [Ag(I)(Pc-L)] were synthesized and characterized. Their ability to catalyze the coupling among aldehydes, terminal alkynes and amines (A(3)-coupling) was demonstrated. The reaction could be performed under conventional as well as dielectric heating. The catalysts were effective in both cases, but dielectric heating allowed a lower catalyst loading and reduced ratio among reaction partners in shorter reaction times. The reaction scope was broad, including aryl/alkyl aldehydes, aryl/alkyl acetylenes and secondary aliphatic amines. Some unprecedented propargylamines have been prepared. The new catalytic system was also tested with more challenging coupling partners such as aniline and ketones.

The synthesis of 3-substituted-1-alkoxyisochromenes starting from 2-alkynylbenzaldehydes and different alcohols is reported. The reaction is catalyzed by a silver(I) complex with an original macrocyclic pyridine-containing ligand. The approach is characterized by absolute regioselectivity, mild reaction conditions, good to excellent reaction yields, cleanness of the reaction, and reduced purification steps. The reaction mechanism was investigated by in-depth (1)H NMR experiments and an aimed "trapping" experiment.

Silver and gold salts and complexes mainly act as soft and carbophilic Lewis acids even if their use as σ-activators has been rarely reported. Recently, transformations involving Au(I)/Au(III)-redox catalytic systems have been reported in the literature. In this review we highlight all these aspects of silver and gold-mediated processes and their application in multicomponent reactions.

Methyl 2-acetamidoacrylate reacted with various 2-substituted indoles in the presence of catalytic amounts of AgSbF6 or AuPPh3NTf2 to provide the corresponding methyl 2-(2-substituted-1H-indol-3-yl)acrylates.

Two unprecedented oxygenated aaptaminoids have been synthesized starting from cheap and easily available 2,3-dihydroxybenzoic acid with the satisfactory overall yields of 31% and 34%. The key step of the procedure is the divergent thermic 5-exodig vs base-promoted 6-endodig cyclization of a 5-alkynylquinolinone derivative.

A new one-pot approach was developed to construct the 11H-indolo[3,2-c]quinoline scaffold through a gold-catalysed reaction of 2-[(2-aminophenyl)ethynyl]phenylamine derivatives with aldehydes. The broad scope and the high regioselectivity of this new protocol as well as the mild and neutral reaction conditions make it a viable alternative to the previously reported procedures.

Silver-catalysed/microwave-assisted domino reactions of 2-alkynyl-acetophenones and 3-acetyl-2-alkynylpyridines in the presence of ammonia are widely described. In most cases the reaction give a mixture of the imino- and carbo-cyclisation products, with a general preference for the former. A plausible mechanism is proposed and the dual activity of silver salts is supported by NMR experiments.

[reaction: see text] An original TiCl(4)/t-BuNH(2)-mediated hydroamination/annulation domino reaction of delta-keto-acetylenes is described. The synthesis of pyrrolo[1,2-a]indole-2-carbaldehydes, starting from 2-carbonyl-1-propargyl-1H-indoles runs under mild reaction conditions. A conceivable mechanism is also discussed. TiCl(4) has proved to be an effective multiactivity reagent: catalyst/Lewis acid/water scavenger. Some unpublished 2-carbonyl-1-propargyl-1H-indoles are prepared by means of Suzuki- and Negishi-type reactions.

A palladium-mediated multicomponent domino reaction leading to 2-aryl-4-amino-quinolines and 2-aryl-4-amino[1,8]naphthyridines is reported. The scope of the reaction was examined using carbon monoxide, two 2-ethynyl-arylamines, four aryl iodides, and 10 primary amines as substrates. The selection of the appropriate catalytic system was achieved testing several palladium/phosphine systems and overrides previously reported drawbacks associated with the use of primary amines in related reactions. Moreover several features concerning the role of both palladium [(0) and (II)] and phosphines are reported.

[reaction: see text] The synthesis of the pyrazino[1,2-a]indole nucleus was achieved by intramolecular cyclization of several 2-carbonyl-1-propargylindoles in the presence of ammonia. The reaction conditions were optimized using microwave heating and a pool of catalysts. Cyclization of 1-alkynylindole-2-carbaldehydes was easily accomplished under standard heating conditions, whereas microwave heating contributed to reduced reaction times and improved overall yields. Moreover, a fine-tuning of the microwave irradiation time made possible the selective synthesis of both pyrazino[1,2-a]indole isomers. TiCl4 proved the catalytic system of choice to achieve pyrazinoindoles in satisfactory yields starting from 1-alkynyl-2-acetylindoles and 1-alkynyl-2-benzoylindole derivatives. Also in these cases, microwave heating contributed to faster reactions and improved yields. The uncatalyzed versus catalyzed reaction mechanism is discussed.

Indole 2-carboxamide derivatives 4 underwent palladium-catalyzed intramolecular cyclization reactions to afford beta-carbolinones or pyrazino[1,2-a]indoles according to different reaction pathways. The complete regioselectivity of the reactions was obtained in different reaction conditions.

A general one-pot synthesis of pyridines 4a-t from the reaction of dialkyl acyclic/cyclic ketones 1a-i, methyl, aryl/heteroaryl ketones 1m-r, and aldehydes bearing alpha-hydrogens 1s,t with propargylamine 2 is described. Gold and copper salts are efficient catalysts for the reaction of ketones with 2. The formation of the pyridines 4 is suggested to proceed through the sequential amination of carbonyl compounds followed by regioselective 6-endo-dig cyclization of the N-propargylenamine (N-propargyldienamine) intermediate 3(5) and aromatization reaction. Whereas the preparation of linear polycyclic pyridine 4i can be carried out by reacting cholestan-3-one 1i with 2, the angular polycyclic pyridine 4j has been obtained starting from cholest-5-en-3-one 1j. Selectivity of the reaction of polycyclic dicarbonyls 1k,l with 2 has also been investigated.