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A new class of heterocyclic N , O -aminal and hemiaminal scaffolds was successfully obtained by means of a three-component reaction (3-CR) of 1,2-diaza-1,3-dienes (DDs), α-aminoacetals and iso(thio)cyanates. These stable imine surrogates are generated from key-substituted (thio)hydantoin intermediates through selective FeCl 3 -catalyzed intramolecular N -annulation., (Copyright © 2024, Mari et al.)

A chemoselective one-pot synthesis of pharmaceutically prospective indole-pyrrole hybrids by the formal [3 + 2] cycloaddition of 3-cyanoacetyl indoles (CAIs) with 1,2-diaza-1,3-dienes (DDs) has been developed. The new indole-pyrrole hybrids were phenotypically screened for efficacy against Leishmania infantum promastigotes. The most active compounds 3c, 3d, and 3j showed IC 50 < 20 μM and moderate cytotoxicity, lower than miltefosine. Compound 3d was the most active with IC 50 = 9.6 μM and a selectivity index of 5. Consequently, 3d could be a new lead compound for the generation of a new class of antileishmanial hybrids., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A practical and environmentally benign protocol for the assembly of poly substituted-thiazolo[3,2- a ]indoles from 3-alkylated indoline-2-thiones and 2-halo-ketones has been developed. This metal-free approach consists in a complete chemo/regioselective formal [3 + 2] annulation that occurs in air, at 60 °C, and in water as the sole reaction medium. The opportunity to vary the substitution pattern up to six different positions, odorless manipulation of sulfurylated compounds, very easy product isolation, and mild reaction conditions are the main synthetic features of this method. The scaled-up experiment and the successive transformations of the products further demonstrate the utility of this chemistry.

A metal-free strategy, alternative to the known complex cycloaddition reactions, towards 2-carboxylated thieno [2,3- b ] indole derivatives has been successfully developed. The novel approach involves as starting materials easy accessible 1,2-diaza-1,3-dienes and indoline 2-thione and requires mild reaction conditions. Furthermore, the easy work-up required makes this method amenable for a one-pot approach as demonstrated in the preparation of thienodolin, a natural product isolated from Streptomyces albogriseolus that exhibits valuable biological properties.

An unprecedented synthesis of polysubstituted indole-fused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO 2 ) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere.

We report the evaluation of a small library of azole-bisindoles for their antileishmanial potential, in terms of efficacy on Leishmania infantum promastigotes and intracellular amastigotes. Nine compounds showed good activity on L. infantum MHOM/TN/80/IPT1 promastigotes with IC 50 values ranging from 4 to 10 μM. These active compounds were also tested on human (THP-1, HEPG2, HaCaT, and human primary fibroblasts) and canine (DH82) cell lines. URB1483 was selected as the best compound, with no quantifiable cytotoxicity in mammalian cells, to test the efficacy on intracellular amastigotes. URB1483 significantly reduced the infection index of both human and canine macrophages with an effect comparable to the clinically used drug pentamidine. URB1483 emerges as a new anti-infective agent with remarkable antileishmanial activity and no cytotoxic effects on human and canine cells., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1 H -pyrazol-5(4 H )-ones and 9-alkyl-7-aryl-1-oxa-7,8-diazaspiro[4.4]nona-3,8-dien-6-ones, starting from 1,2-diaza-1,3-dienes (DDs) and propargyl alcohol. The reaction proceeds through a sequence Michael-type nucleophilic attack/cyclization/[2,3]-Wittig rearrangement. In the same way, the reaction between the aforementioned DDs and allyl alcohol furnished 4-allyl-4-hydroxy-3-alkyl-1-aryl-1 H -pyrazol-5(4 H )-ones. A DFT study was also carried out, in order to have decisive clarifications about the mechanism.

Herein, we report the successful syntheses of scarcely represented indole-based heterocycles which have a structural connection with biologically active natural-like molecules. The selective oxidation of indoline nucleus to indole, hydrolysis of ester and carbamoyl residues followed by decarboxylation with concomitant aromatization of the pyridazine ring starting from tetrahydro-1 H -pyridazino[3,4- b ]indole derivatives lead to fused indole-pyridazine compounds. On the other hand, non-fused indole-pyrazol-5-one scaffolds are easily prepared by subjecting the same C2,C3-fused indoline tetrahydropyridazines to treatment with trifluoroacetic acid (TFA). These methods feature mild conditions, easy operation, high yields in most cases avoiding the chromatographic purification, and broad substrate scope. Interestingly, the formation of indole linked pyrazol-5-one system serves as a good example of the application of the umpolung strategy in the synthesis of C3-alkylated indoles.

Zn(II)-catalyzed divergent synthesis of functionalized polycyclic indolines through formal [3 + 2] and [4 + 2] cycloadditions of indoles with 1,2-diaza-1,3-dienes (DDs) is reported. The nature and type of substituents of substrates are found to act as a chemical switch to trigger two distinct reaction pathways and to obtain two different types of products upon the influence of the same catalyst. The mechanism of both [4 + 2] and [3 + 2] cycloadditions was investigated and fully rationalized by density functional theory (DFT) calculations.

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

A small library of sugar-based (i.e., glucose, mannose and lactose) monoesters containing hydrophobic aliphatic or aromatic tails were synthesized and tested. The antimicrobial activity of the compounds against a target panel of Gram-positive, Gram-negative and fungi was assessed. Based on this preliminary screening, the antibiofilm activity of the most promising molecules was evaluated at different development times of selected food-borne pathogens ( E. coli , L. monocytogenes , S. aureus , S. enteritidis ). The antibiofilm activity during biofilm formation resulted in the following: mannose C10 > lactose biphenylacetate > glucose C10 > lactose C10. Among them, mannose C10 and lactose biphenylacetate showed an inhibition for E. coli 97% and 92%, respectively. At MICs values, no toxicity was observed on Caco-2 cell line for all the examined compounds. Overall, based on these results, all the sugar-based monoesters showed an interesting profile as safe antimicrobial agents. In particular, mannose C10 and lactose biphenylacetate are the most promising as possible biocompatible and safe preservatives for pharmaceutical and food applications.

A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1 H -imidazole-2(3 H )-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS 2 in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained ensures post-modifications in view of N -bridgeheaded heterobicyclic structures.

Substituted hydroxy-benzofurans are easily accessible by treatment of resorcinols and 1,2-diaza-1,3-dienes (DDs) under acidic conditions. The reaction happens through an uncommon Michael reaction between aromatic derivatives as aromatic C(sp 2 )-H nucleophiles and DDs as acceptors. Also, the behavior of different phenols and 2-naphthol was investigated.

An umpolung α-(hetero)arylation strategy that involves the Michael-type reaction between electron-rich (hetero)aromatic substrates and azoalkenes is developed. The reaction proceeds under very mild conditions at room temperature and in the presence of inexpensive, nontoxic ZnCl 2 catalyst to provide access to otherwise inaccessible hydrazone structures. Subsequent hydrolysis of these latter to ketones as well as other valuable synthetic transformations to a variety of heterocyclic scaffolds demonstrate the usefulness of this protocol.

The antimicrobial activity of the marine bisindole alkaloid 2,2-bis(6-bromo-3-indolyl) ethylamine ( 1 ) and related synthetic analogues (compounds 2 ⁻ 8 ) against target microorganisms was investigated by Minimum Inhibitory Concentration (MIC) determination. Compound 1 showed the greatest antimicrobial activity with the lowest MIC (8 mg/L) against Escherichia coli , Staphylococcus aureus , and Klebsiella pneumoniae , while the derivatives exhibited higher MICs values (from 16 to 128 mg/L). Compounds 1 , 3 , 4 , and 8 , the most active ones, were then tested against E. coli , S. aureus , K. pneumoniae , and Candida albicans during biofilms formation as well as on 24 h developed biofilms. The natural alkaloid 1 inhibited the biofilm formation of all the tested microorganisms up to 82.2% and disaggregated biofilms of E. coli , S. aureus , K. pneumoniae , and C. albicans after 30 min of contact, as assessed by viable plate count and crystal violet (CV) staining (optical density at 570 nm). Synthetic derivatives 3 , 4 , and 8 displayed anti-biofilm activity toward individual bacterial populations. This study highlights the potential of marine bisindole alkaloid 1 as anti-biofilm agent and shows, through a preliminary structure activity relationship (SAR), the importance of halogens and ethylamine side chain for the antimicrobial and antibiofilm activities of this bisindole series.

Herein we report a domino protocol able to reach regioselectively thiazolylidene systems by combining the reactive peculiarities of both β-amidothioamides (ATAs) and 1,2-diaza-1,3-dienes (DDs). Depending on the reaction conditions and/or the nature of the residue at C4 of the heterodiene system, ATAs can act as hetero-mononucleophiles or hetero-dinucleophiles in the diversified thiazolylidene ring assembly.

A Pd(II)-catalyzed intramolecular oxidative C-H/C-H cross-coupling has been developed for the direct construction of valuable polycyclic heteroarene scaffolds. From a retrosynthetic point of view, the strategic formation of a C-C bond via C(sp 2 )-H/C(sp 2 )-H dehydrogenative coupling across C3,N-linked biheterocyclic precursors may be useful in de novo syntheses of indole-derived natural products and pharmaceuticals. The reaction exhibited good functional group/heterocycle tolerance, and a proposed mechanism involving an azoylpalladium complex is also supported.

The base (NaH)-promoted Michael addition of N-arylhydrazones (AHs) with 1,2-diaza-1,3-dienes (DDs) produces unprecedented β-azohydrazone adducts. Strategically, the use of AHs as acyl anion equivalents (d(1) synthon) and DDs as α-electrophiles (a(2) synthon) of carbonyl compounds open the way to two important classes of pyrazole compounds.

A simple reaction of some oxindole derivatives with 1,2-diaza-1,3-dienes to produce 2-oxo-spiro[indole-3,4'-pyridines] in good yields is described here. This transformation represents a practical two steps approach to new and biologically interesting 2-oxo-spiro[indole-3,4'-pyridine] scaffolds using a double Michael addition/cyclization sequence.

In situ derived acyclic and cyclic 1,2-diaza-1,3-dienes (DDs) were engaged in interceptive [4 + 1] annulation strategy with diazo esters (DEs). The catalytic activity of inexpensive copper(II) chloride allows the direct synthesis of mono-, bi-, and tricyclic 4,5-dihydropyrazole-5-carboxylic acid derivatives in a process that circumvents the use of an anhydrous and inert atmosphere.

A novel and practical two-step approach to an intriguing class of imidazo[1,5-a]pyrazines with exocyclic C=X (X = CH2, O) bonds is described. The process utilizes a sequential three-component reaction of propargyl amine or aminoester, 1,2-diaza-1,3-dienes and isothiocyanates to furnish functionalized 2-thiohydantoins which are transformed into thiohydantoin-fused tetrahydropyrazines by subsequent regioselective base-promoted cyclization.

Structural, conformational properties, and gas phase reactivity of two representative diastereoisomeric members of a series of α,α-tetrahydropyridazine amino acid derivatives have been investigated by using X-ray crystallography, tandem mass spectrometry and theoretical calculations. Both diastereoisomers show an unusual screw-boat conformation of the tetrahydropyridazine ring. While protonated molecules mainly decompose in the gas phase by loss of acetamide, the main reactivity of the [M + Na](+) species consists of loss of PhNCO followed by acetamide and it is strictly dependent upon the stereochemistry of the parent compound. The most stable energy minimized structures obtained by theoretical calculations are in full agreement with the experimental data and allowed us to rationalize the gas phase reaction pathways.

A very simple domino reaction under solvent-free conditions of various pyridine-like heterocycles with 1,2-diaza-1,3-dienes produces in good yields imidazo[1,2-a]pyridines, imidazo[1,2-a]quinolines, and imidazo[2,1-a]isoquinolines. The advantage of this one-pot transformation lies in the use of simple pyridine-like compounds without prefunctionalization of the starting heterocycles.

A domino reaction of vinyl malononitriles (VMs) with 1,2-diaza-1,3-dienes (DDs) produce unprecedented 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazole systems in a chemo-, regio-, and stereoselective fashion. This base promoted (DIPEA) one-pot transformation involving multiple steps constructs one new C-C bond, two C-N bonds, and two new fused heterocyclic rings with total atom economy.

One-pot sequential aza-Michael, Staudinger, and aza-Wittig reactions on 1,2-diaza-1,2-dienes (DDs) can afford fully substituted 1,2-diaminoimidazoles. A plausible mechanism for the imidazole core formation involving an intramolecular ring closure of the carbodiimide-derived phosphazene intermediate is given. The reported strategy has sufficient flexibility to allow substituted 1,2-diaminoimidazoles with orthogonal nitrogen-protective groups to be generated from a variety of heterocumulene moieties linked to the DDs skeleton.

By highly efficient, one-pot, three-component reactions, combining one set of 1,2-diaza-1,3-dienes (DDs), primary amines, and isothiocyanates in a different sequential order of addition, heterocyclic skeletal diversity can be achieved. The key feature discriminating the different heterocyclic core formation is the availability of the N or S heteronucleophile to give the first Michael addition step affording regioselective substituted 2-thiohydantoins or 2-iminothiazolidinones. The hydrazone or enehydrazino side chain at the 5-position of both heterocycles represents a valuable functionality to reach novel 5-hydroxyethylidene derivatives difficult to obtain by other methods.

A novel and simple one-pot synthesis of 3-substituted 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones from 1,2-diaza-1,3-dienes (DDs) and N-unsubstituted aliphatic 1,3-diamines is described. Here we also report a procedure to selectively obtain alkyl 5H-1,4-benzodiazepine-3-carboxylates from the DDs and 2-aminobenzylamine. Both processes occur by means of sequential 1,4-conjugated addition followed by regioselective 7-exo cyclization. The behavior of N-methyl- and N,N'-dimethyl-1,3-diaminopropanes toward the DDs furnished pyrazol-3-ones and bis-α-aminohydrazones, respectively.

A new and efficient synthesis of polysubstituted pyrroles by a sequential one-pot three-component reaction between primary aliphatic amines, active methylene compounds, and 1,2-diaza-1,3-dienes (DDs) is reported. The reactions were performed without catalyst and under solvent-free conditions with complete control of pathway selectivity. Notably, the ready availability of the starting materials and the high level of practicability of the reaction and work up make this approach an attractive complementary method for access to unknown polysubstituted pyrroles.

Hydrogenated cardanol and cardols, contained in industrial grade cardanol oil and obtained by distillation of the raw "cashew nut shell liquid" (CNSL), are easily transformed into efficient 4-thiaflavane antioxidants bearing a long alkyl chain on A ring and a catechol group on B ring.

1,2-Diaza-1,3-dienes (DDs) react as Michael acceptors with primary amines to afford α-aminohydrazone derivatives that were in situ coupled with isocyanates. Intramolecular ring closure of the asymmetric urea derivatives so formed allows for a selectively substituted hydantoin ring to be obtained. The hydrazone side chain introduced by the conjugated heterodiene system at the 5-position of the heterocycle represents a valuable functionality for accessing novel 5-acyl derivatives difficult to obtain by other methods.

Diversely functionalized imidazole-4-carboxylates were synthesized by microwave-assisted 1,5-eletrocyclization of 1,2-diaza-1,3-diene-derived azavinyl azomethine ylides. 1,2-Diaza-1,3-dienes were treated with primary aliphatic or aromatic amines and subjected to microwave irradiation in the presence of aldehydes. 3-Alkyl- and 3-arylimidazole-4-carboxylates were prepared in good yields through a one-pot multicomponent procedure. Modulation of the substituents at C-2, N-3 and C-5 was possible, and 2-unsubstituted imidazoles were obtained when paraformaldehyde was used.

A one-pot Cu(II)-catalyzed aza-Michael addition of trimethylsilyl azide to 1,2-diaza-1,3-dienes and Cu(I)-catalyzed 1,3-dipolar cycloaddition of in situ generated alpha-azidohydrazones with alkynes is reported. This process combining two consecutive steps with recycling of the catalyst (Cu(OAc)(2).H(2)O) represents a useful protocol for the smooth synthesis of novel pyrazolone-triazole derivatives.

An efficient and practical method for the preparation of alpha-imidazol-1-yl esters from 1,2-diaza-1,3-dienes (DDs), alpha-amino esters, and aldehydes is described. The overall sequence features a Michael-type conjugate addition between the alpha-amino ester and the DD, followed by iminium ion formation via condensation with the aldehyde and 1,5-electrocyclization of the resulting thermally generated azavinyl azomethine ylide to afford eventually alpha-imidazol-1-yl esters. Such a protocol allows access to enantiomerically pure imidazoles from optically pure alpha-amino esters.

A novel three-component synthesis of 5-hydrazinoalkylidene rhodanine derivatives starting from aliphatic primary amines, carbon disulfide, and 1,2-diaza-1,3-dienes is described. The reaction proceeds successfully under both solution and solid-phase conditions.

A new flexible strategy for the synthesis of diversely functionalized pyridazines from 4-chloro-1,2-diaza-1,3-butadienes and active methylene compounds is reported. The high chemoselectivity of this approach offers access to structural precursors of GABA-A antagonist analogues.

The versatility of the Mukaiyama-Michael-type addition/heterocyclization of Danishefsky's diene with 1,2-diaza-1,3-butadienes was applied to the synthesis of both 4 H-1-aminopyrroles and 4,5 H-pyrazoles. Thus, the same reagents furnished different types of highly functionalized azaheterocycles essentially depending on their structure: as a matter of fact, R1 = COOR or CONR 2 differently affects the acidity of the proton at the adjacent carbon. An unexpected formation of 5 H-1-aminopyrroles from the reactions carried out in water was also observed.

Michael-type addition of aziridinecarboxylates to 1,2-diaza-1,3-butadienes under solvent-free conditions (SFC) resulted in the formation of alpha-aziridinohydrazone adducts. In toluene under reflux, alpha-aziridinohydrazones gave imidazoles in moderate to good yields. Such a reactivity pattern is explained by 1,5-electrocyclization of azavinyl azomethine ylide generated through thermal ring opening of alpha-aziridinohydrazones.

2,4,4,6-Tetrabromo-3-n-pentadecyl-2,5-cyclohexadienone (TBPCO) has been synthesized and used as a new efficient, convenient, and environmentally friendly brominating agent.

[reaction: see text] Here, we report the protocol for the preparation of new poly(ethylene glycol)-supported 1,2-diaza-1,3-butadiene. In addition, we discuss an application of this supported reagent in an efficient and environmentally friendly one-pot synthesis of 2-thiazol-4-one derivatives by reaction with thioamides.

We observed a nucleophilic attack by the ene-amino carbon of 3-dimethylaminopropenoates at the terminal carbon of the azo-ene system of 1,2-diaza-1,3-butadienes. In tetrahydrofuran at 65 degrees C, this attack produced 1-aminopyrrolines with a high degree of cis-stereoselectivity by means of an unusual zwitterionic adduct intermediate followed by intramolecular ring closure. In toluene under reflux, 1-aminopyrrolines produced oxazoline-fused 1-aminopyrrolines. Oxazoline-fused 1-aminopyrrolines were directly obtained by reaction of 1,2-diaza-1,3-butadienes with 3-dimethylaminopropenoates in toluene under reflux. The ring opening of oxazoline-fused 1-aminopyrrolines in acidic or basic media provides highly substituted 1-aminopyrroles. 5-Unsubstituted 1-aminopyrrole derivatives were obtained from 1-aminopyrrolines under basic conditions by loss of dimethylamino and ester groups. We discuss the plausible mechanisms of the ring closure and opening.

New and interesting 2-oxofuro[2,3-b]pyrroles and 19-methyl-15-oxa-20-azatricyclo[12.3.3.0(1,14)]icos-18-en-18-carboxylates have been obtained in good yields by the one-pot reaction, in basic medium, of 1,2-diaza-1,3-butadienes with diethyl or dimethyl acetylsuccinate or methyl 2-(1,3-dioxo-2-cyclotetradecyl)acetate, respectively, under mild conditions. Treatment of the same starting materials with diethyl 2-acetylglutarate, in acidic medium, afforded unknown 2-methylenepyrrole derivatives in high yields. Novel 4-(3-oxopropyl)-2,5-dimethyl-1H-pyrrole-3-carboxylates also have been achieved by reacting 1,2-diaza-1,3-butadienes with ethyl or methyl 4-acetyl-5-oxo-hexanoate.

Alpha-substituted hydrazones obtained from 1,2-diaza-1,3-butadienes and methylenic or methinic activated substrates gave rise to a wide range of cyclic compounds. In particular, in the presence of thionyl chloride as solvent-reagent, they were transformed into 1,2,3-thiadiazoles,(1) with selenium oxychloride in new 4-substituted 2,3-dihydro-1,2,3-selenadiazoles, while with selenium dioxide, they were transformed into 4-substituted 1,2,3-selenadiazoles. We have also examined the nucleophilic behavior of 1,2,3-thiadiazole 4a in the reaction with 1,2-diaza-1,3-butadienes that produced, under basic conditions, 4-hydrazono-1-(1,2,3-thiadiazolyl)pentane derivatives. This event represents an interesting example of stereoselective synthesis because it leads exclusively to the formation of the RR/SS racemic mixture. These latter compounds, treated with thionyl chloride, gave the corresponding 1,3-di-1,2,3-thiadiazolylpropane derivatives, while with sodium methoxide they afforded 1,2,3-thiadiazolyl-2-oxo-2,3-dihydro-1H-pyrrole systems.

The synthesis of 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and 5-unsubstituted-1-aminopyrrole-3-carboxylic acid derivatives from 1,2-diaza-1,3-butadienes and aldehydes is presented. These domino reactions offer the advantage of executing multistep transformation without intermediate workup procedures. The stereoselectivity of ring closure to 5-hydroxy-1-aminopyrroline-3-carboxylic acid derivatives and phenyl transposition to 2,3-diphenyl-1-aminopyrrole-3-carboxylic acid derivatives are also studied.