Search

A metal-free strategy towards thieno [2,3-b] indoles from 1,2-diaza-1,3-dienes and indoline 2-thione is described. The mild reaction conditions required make this method amenable for a one-pot approach to thienodolin, a valuable natural alkaloid.

The direct synthesis of pyrrolo[2,3-b]indoles is developed using a Cu/Fe cocatalyzed intramolecular cycloamination of α-indolylhydrazones. This transformation proceeds cleanly and selectively at 50 °C in air, with water as the only reaction medium.

An unprecedented synthesis of polysubstituted indole-fused pyridazines (azacarbolines) from α-indolylhydrazones under oxidative conditions using a combination of iodylbenzene (PhIO2) and trifluoroacetic acid (TFA) has been developed. This transformation is conducted without the need for transition metals, harsh conditions, or an inert atmosphere.

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(sp2)-H nucleophiles and DDs as acceptors. Also, the behavior of different phenols and 2-naphthol was investigated.

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

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. On the other hand, also the fully reduced form of BER, namely tetrahydroberberine (THBER), and its derivatives have proven to present different biological activities. Therefore, the obtained arylhydrazono-functionalized DHBERs were reduced to the corresponding arylhydrazono-THBERs. The antiproliferative activity of both arylhydrazono-DHBERs and -THBERs has been evaluated on NCI-H1975 lung cancer cells.

Here we report a robust and operationally simple base-promoted N–N bond cleavage by means of a Michael type addition/E1cb elimination sequence, assisted by 1,2-diaza-1,3-dienes (DDs) on a series of N-aminoheterocycles, to obtain exclusively the corresponding NH-free hetero-ring derivatives, under very mild conditions. The method developed highlights a new and hitherto unexplored face of DDs and opens up fascinating new opportunities for their application in organic chemistry.

1,4,5,6-Tetrahydropyridazine featuring an iminium cation flanked by an exocyclic double bond was successfully employed as an N-acyliminium acceptor. Thus, in the presence of a Lewis acid (BF3·OEt2), generation and in situ interception of 5-methylene N-acyl dihydropyridazinium species with a range of various nucleophiles afforded diversified and functionalized 5-methylenyl-1,4-dihydropyridazine derivatives in good yields with excellent γ′-regioselectivity.

A new and efficient synthesis of fully substituted 2,5-dihydrothiophenes by a sequential one-pot four component reaction between primary amines, β-ketoesters, aryl isothiocyanates and 1,2-diaza-1,3-dienes (DDs) is reported. A careful selection of the starting materials enables the choice of up to six different variations in the architecture of the final products. Furthermore, the acidic treatment of the so-obtained 2,5-dihydrothiophenes furnishes the corresponding 5-amino thiophene-2,4-dicarboxylates.

Bis adducts derived from a double Michael addition of rhodanine to an azo-ene system of two molecules of 1,2-diaza-1,3-dienes (DDs) have furnished the corresponding 2,3,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyridine-1,3,6-triones by means of a CS2 extrusion/double cyclization sequence. The incorporation of two units (4 and 2 atoms) of DDs into the fused bicyclic heterocycles represents a new application of this versatile class of molecules in heterocyclic synthesis.

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

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 ZnCl2 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.

Pegylated (PEG) surfactants are widely used for material and biomedical applications. Their use, however, is limited by the radical-mediated oxidation of the OCH2 moieties by atmospheric oxygen, that produces unwanted and toxic products such as hydroperoxides. We show herein that cardanols, natural alkylphenols byproducts of cashew nut processing, are able to form stable co-micellar systems with a model PEG-containing surfactant (Triton X-100, i.e. p-tert-octylphenoxy polyethylene-glycol ether) and display antioxidant activity toward PEG degradation by O2. The cardanols investigated were 6-tert-butyl-3-pentadecylphenol and 4-hydroxy-6-tert-butyl-3-pentadecylphenol. The ability of cardanols to form co-micelles with Triton X-100 was investigated by determining the critical micelle concentration (CMC), the microviscosity, the polarity and the aggregation number. The antioxidant activity of cardanol derivatives in dispersed systems of Triton X-100 was evaluated by studying the reaction with DPPH radical and the protecting activity toward the peroxidation of the polyethylene-glycol tails. The obtained activity of cardanol derivatives was similar or better than that of commercial synthetic antioxidants BHT (2,6-di-tert-butyl-4-methylphenol) and DTBQ (2,5-di-tert-butylhydroquinone), taken as reference, under the same conditions. This study enlightens the ability of hydrogenated cardanol derivatives to act as radical-trapping agents and/or as protective co-surfactants toward the oxidative degradation PEG-coated nanoaggregates used in food and drug science.

A mild, sequential multicomponent reaction strategy for the regioselective synthesis of functionalized pentasubstituted pyrroles from readily accessible primary amines, 1,2-diaza-1,3-dienes, and 2,3-allenoates, has been developed. The process allows a [1N+2C+2C] annulation to be achieved through two sequential hydroamination reactions followed by an enamine-carbocyclization. Moreover, allenoates, as synthetic equivalents of monoactived alkynes, permit the specific preparation of multifunctionalized pyrroles.

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. As a result, PTHB 4d emerged among the other THB analogues by exhibiting the best antioxidant properties. First, it was the only compound having an ORAC value completely comparable to that of THB, indicating the same ability to neutralize peroxyl radicals. Secondly, 4d showed an even better antioxidant capacity than THB in protecting DNA against ferrous ion-induced strand breaks. These observations were also confirmed in NCTC-2544 human keratinocytes exposed to hydrogen peroxide. Indeed, 4d protected cells against oxidation more efficiently than THB both in the short (1 and 3 h) and long (24 h) period of incubation, possibly suggesting increased cell membrane permeability and/or intracellular stability of 4d as compared to THB.

With the aim to improve the features of surfactant solutions in terms of sustainability and renewability we propose the use of hydrogenated natural and sustainable plant-derived cardanol as an additive to com- mercial surfactants. In the present study we demonstrated that its addition, in amounts as high as 10%, to commercial surfactants of different charge does not significantly affect surfactant properties. Conversely, the presence of hydrogenated cardanol can strongly affect spectrophotometric determination of CMC if preferential interactions with the dyes used take place. This latter evidence may be profitably exploited in surfactant manufacturing by considering that the concurrent presence of a rigid organic molecule such as Orange OT and 10% hydrogenated cardanol decreases the CMC of CTAB up to 65 times.

A straightforward method for the synthesis of spaced, phenyl-linked bis(thiohydantoin) derivatives and (thio)hydantoins spiro-fused to pyrroline ring has been developed. All the synthetic strategies here presented rely on initial aza-Michael addition followed by acylation/regioselective ring-closure step involving DD, primary amine and iso(thio)cyanate in a 3-CR providing 1,3,5-trisubstituted (thio)hydantoins. The choice of opportune acyclic reagents in the sequential 3-CR followed by 1,4-nucleophilic addition/intramolecular ring closing and 1,3-dipolar cycloaddition permits a number of C–N and C–C formation that realizes different kind of linkage between several pharmacophores.

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.

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 mild, sequential multicomponent reaction strategy for the regioselective synthesis of functionalized pentasubstituted pyrroles from readily accessible primary amines, 1,2-diaza-1,3-dienes, and 2,3-allenoates, has been developed. The process allows a [1N+2C+2C] annulation to be achieved through two sequential hydroamination reactions followed by an enamine-carbocyclization. Moreover, allenoates, as synthetic equivalents of monoactived alkynes, permit the specific preparation of multifunctionalized pyrroles.

The zinc(II) triflate-catalyzed synthesis of highly functionalized pyrroles is described. The se- quence involves the preliminary preparation of a- aminohydrazones by Michael addition of primary amines to 1,2-diaza-1,3-dienes. The treatment of these intermediates with dialkyl acetylenedicarboxy- lates produces a-(N-enamino)-hydrazones that are converted into the corresponding pyrroles. The sub- stituents on the carbon in position four of 1,2-diaza- 1,3-dienes drive the regioselectivity of the ring clo- sure process. Starting from 4-aminocarbonyl-1,2- diaza-1,3-dienes only dialkyl 1-substituted 5-amino- carbonyl-1H-pyrrole-2,3-dicarboxylates are achieved by Lewis acid-catalyzed ring closure. A screening of several Lewis/Bronsted acid catalysts is performed. Zinc(II) triflate is the most efficient catalyst. Under similar reaction conditions, employing 4-alkoxycar- bonyl-1,2-diaza-1,3-dienes, only 4-hydroxy-1H-pyr- role-2,3-dicarboxylates are synthesized. These latter reactions can be accomplished regioselectively also in one pot. Using 4-aminocarbonyl-1,2-diaza-1,3- dienes, diamines and dialkyl acetylenedicarboxylates the sequence provides the corresponding a,w-di(N- pyrrolyl)alkanes.

The kinetics of the reactions of 1,2-diaza-1,3-dienes 1 with acceptor-substituted carbanions 2 have been studied at 20 °C. The reactions follow a second-order rate law, and can be described by the linear free energy relationship log k(20 °C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile-specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2-diaza-1,3-dienes 1 were determined. With E parameters in the range of -13.3 to -15.4, the electrophilic reactivities of 1a-d are comparable to those of benzylidenemalononitriles, 2-benzylideneindan-1,3-diones, and benzylidenebarbituric acids. The experimental second-order rate constants for the reactions of 1a-d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2-diaza-1,3-dienes 1. Enamines 5 react up to 10(2) to 10(3) times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers.

The synthesis of highly functionalized pyrroles is described. The sequence involves the preliminary preparation of α-aminohydrazones by Michael addition of primary amines to 1,2-diaza-1,3-butadienes. The treatment of these compounds with dialkyl acetylenedicarboxylates produces α-(N-enamino)-hydrazones that were converted into the corresponding pyrroles by Lewis acid-catalyzed ring closure. A screening of several Lewis/Bronsted acid catalysts was also performed.

The reaction of 1,2-diaza-1,3-butadienes with dibenzyl diisopropylphosphoramidite, methyl tetraisopropylphosphorodiamidite or tris(dimethylamino)phosphane under solvent-free conditions gave stable α-phosphoranylidene-hydrazones that, in turn, were transformed into the corresponding 5-oxo-4-phosphoranylidene-4,5-dihydro-1H-pyrazoles. X-ray diffraction analysis of one of these derivatives is reported. α-Phosphoranylidene-hydrazones, derived from the reaction between 1,2-diaza-1,3-butadienes with dibenzyl diisopropylphosphoramidite, were converted by hydrolytic cleavage into (E)-hydrazono-phosphonates, which are useful for the preparation of the corresponding (3-oxo-2,3-dihydro-1H-pyrazol-4-yl)phosphonamidates.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,2′-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,2′-[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N′-dialkylthioureas on N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(ω-carboxyalkyl)-4-thiazolidinones.

A simple one-pot procedure for the preparation of symmetrical bis-hydrazone functionalized barbiturates, and a step-by step sequence for the synthesis of analogous unsymmetrical derivatives were developed. Their treatment in acid conditions furnish the symmetrical- and unsymmetrical-spirobarbiturate-pyridines, respectively.

The practical two-step reaction sequence is based on a Michael addition/cyclization approach.

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.

3-{[(tert-Butoxy)carbonyl]diazenyl}but-2-enoates react in tetrahydrofuran at room temperature with aromatic 1,2-diamines to give 3-methylquinoxaline-2-carboxylates. These products were also obtained in solid-phase synthesis, by using polymer-bound 3-diazenylbut-2-enes.

The solid-phase synthesis of 4-triphenylphosphoranylidene-4,5-dihydropyrazol-5-ones, 4-aminocarbonyl-pyrroles, 4-methoxy-1 H -pyrazol-5(2 H )-ones and 2-thiazolin-4-ones using polymer-bound 1,2-diaza-1,3-butadienes is reported.

In the presence of a catalytic amount of sodium methoxide, 1-aminocarbonyl-1,2-diaza-1,3-butadienes react with bromonitromethane to give stereoselectively β-nitro-α,β-olefinated hydrazones as E,Z stereoisomers. In the presence of a stoichiometric amount of sodium hydride, the same substrates with dialkyl halomalonates furnish the expected α,β-olefinated hydrazones, and in the presence of a stoichiometric amount of sodium hydroxide, the unexpected dialkyl 3-methyl-6-oxo-1,6-dihydropyridazine-4,5-dicarboxylates are obtained in one pot by a domino process concluding in a [4 + 2] cyclization. α,β-Olefinated hydrazones have been shown to be the possible intermediates in the formation of 1,6-dihydropyridazine derivatives. The domino reaction of 1-aminocarbonyl-1,2-diaza-1,3-butadienes with α,α-dichloroacetophenone produces directly alkyl 4-chloro-2(chloromethyl)-5-phenyl- or alkyl 4-chloro-2(methoxymethyl)-5-phenyl-1H-aminopyrrole-3-carboxylates as a consequence of [3 + 2] cyclization and chlorine transfer.