Challenge - versus -six-membered annulation: FeCl-catalyzed synthesis of heterocyclic ,-aminals.

A new class of heterocyclic ,-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-catalyzed intramolecular -annulation.

Easy one-pot synthesis of multifunctionalized indole-pyrrole hybrids as a new class of antileishmanial agents.

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 promastigotes. The most active compounds 3c, 3d, and 3j showed IC < 20 μM and moderate cytotoxicity, lower than miltefosine.

Useful Access to Uncommon Thiazolo[3,2-]indoles.

A practical and environmentally benign protocol for the assembly of poly substituted-thiazolo[3,2-]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.

A facile protocol for the preparation of 2-carboxylated thieno [2,3-] indoles: a access to alkaloid thienodolin.

A metal-free strategy, alternative to the known complex cycloaddition reactions, towards 2-carboxylated thieno [2,3-] 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 that exhibits valuable biological properties.

Synthesis of Azacarbolines via PhIO-Promoted Intramolecular Oxidative Cyclization of α-Indolylhydrazones.

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

Experimental and Theoretical DFT Investigations in the [2,3]-Wittig-Type Rearrangement of Propargyl/Allyl-Oxy-Pyrazolones.

Here we report the synthesis of interesting 3-alkyl-4-hydroxy-1-aryl-4-(propa-1,2-dienyl)1-pyrazol-5(4)-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.

Synthesis of Novel Tryptamine Derivatives and Their Biological Activity as Antitumor Agents.

We synthesized five novel tryptamine derivatives characterized by the presence of an azelayl chain or of a 1,1,1-trichloroethyl group, in turn connected to another heterocyclic scaffold. The combination of tryptamin-, 1,1,1-trichloroethyl- and 2-aminopyrimidinyl- moieties produced compound identified as the most active compound in hematological cancer cell lines (IC = 0.57-65.

Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1-pyridazino[3,4-]indoles.

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-pyridazino[3,4-]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).

Synthesis of Polycyclic Fused Indoline Scaffolds through a Substrate-Guided Reactivity Switch.

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.

Synthesis of new dihydroberberine and tetrahydroberberine analogues and evaluation of their antiproliferative activity on NCI-H1975 cells.

Dihydroberberine (DHBER), the partially reduced form of the alkaloid berberine (BER), is known to exhibit important biological activities. Despite this fact, there have been only few studies that concern the biological properties of functionalized DHBER. Attracted by the potentiality of this latter compound, we have realized the preparation of new arylhydrazono-functionalized DHBERs, starting from BER and some α-bromohydrazones.

Sequential MCR via Staudinger/Aza-Wittig versus Cycloaddition Reaction to Access Diversely Functionalized 1-Amino-1-Imidazole-2(3)-Thiones.

A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1-imidazole-2(3)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS 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.

Metal and Oxidant-Free Brønsted Acid-Mediated Cascade Reaction to Substituted Benzofurans.

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)-H nucleophiles and DDs as acceptors. Also, the behavior of different phenols and 2-naphthol was investigated.

Zn(II)-Catalyzed Addition of Aromatic/Heteroaromatic C(sp)-H to Azoalkenes: A Polarity-Reversed Arylation of Carbonyl Compounds.

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 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.

Synthesis and biological evaluation of novel heteroring-annulated pyrrolino-tetrahydroberberine analogues as antioxidant agents.

Tetrahydroberberine (THB), otherwise known as canadine, is a natural alkaloid showing significant pharmacological properties and antioxidant protection against oxidative damage. Herein, we synthetized structurally complex THB analogues, namely pyrrolino-tetrahydroberberines (PTHBs) 4a-g, containing the pyrrolino[2,3-b]pyridine system, by means of the reactions of 1,2-diaza-1,3-dienes and 7,8-dihydroberberine. Aim of the study was to explore the in vitro antioxidant properties of PTHBs in comparison to THB thus to identify the most effective against free radical-induced oxidative injury, by using three different antioxidant tests: the ORAC method, the DNA nicking assay, and the DCFH-DA cellular assay.

Divergent Approach to Thiazolylidene Derivatives: A Perspective on the Synthesis of a Heterocyclic Skeleton from β-Amidothioamides Reactivity.

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.

Palladium(II)-Catalyzed Intramolecular Oxidative C-H/C-H Cross-Coupling Reaction of C3,N-Linked Biheterocycles: Rapid Access to Polycyclic Nitrogen Heterocycles.

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)-H/C(sp)-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.

Divergent construction of pyrazoles via Michael addition of N-arylhydrazones to 1,2-diaza-1,3-dienes.

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.

Synthesis of novel symmetrical 2-oxo-spiro[indole-3,4'-pyridines] by a reaction of oxindoles with 1,2-diaza-1,3-dienes.

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.

Interceptive [4 + 1] annulation of in situ generated 1,2-diaza-1,3-dienes with diazo esters: direct access to substituted mono-, bi-, and tricyclic 4,5-dihydropyrazoles.

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 solvent-free approach to imidazole containing nitrogen-bridgehead heterocycles.

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.

Synthesis of densely functionalized 3a,4-dihydro-1H-pyrrolo[1,2-b]pyrazoles via base mediated domino reaction of vinyl malononitriles with 1,2-diaza-1,3-dienes.

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.

Divergent regioselective synthesis of 2,5,6,7-tetrahydro-1H-1,4-diazepin-2-ones and 5H-1,4-benzodiazepines.

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.

Synthesis of functionalized pyrroles via catalyst- and solvent-free sequential three-component enamine-azoene annulation.

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.

Copper(II)/copper(I)-catalyzed aza-Michael addition/click reaction of in situ generated alpha-azidohydrazones: synthesis of novel pyrazolone-triazole framework.

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.

Alpha-aminoester-derived imidazoles by 1,5-electrocyclization of azavinyl azomethine ylides.

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.