RESUMEN
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.
RESUMEN
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 FeCl3-catalyzed intramolecular N-annulation.
RESUMEN
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.
Asunto(s)
Alcaloides , Antineoplásicos , Ácidos Carboxílicos , Reacción de Cicloadición , Indoles , TiofenosRESUMEN
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.
Asunto(s)
Estrés Oxidativo , Ciclización , Oxidación-Reducción , Ácido TrifluoroacéticoRESUMEN
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.
RESUMEN
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 9 identified as the most active compound in hematological cancer cell lines (IC50 = 0.57-65.32 µM). Moreover, keeping constant the presence of the tryptaminic scaffold and binding it to the azelayl moiety, the compounds maintain biological activity. Compound 13 is still active against hematological cancer cell lines and shows a selective effect only on HT29 cells (IC50 = 0.006 µM) among solid tumor models. Compound 14 loses activity on all leukemic lines, while showing a high level of toxicity on all solid tumor lines tested (IC50 0.0015-0.469 µM).
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Factores Biológicos/química , Factores Biológicos/farmacología , Triptaminas/química , Triptaminas/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Células HT29 , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
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.
RESUMEN
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.
Asunto(s)
Indoles/química , Oxígeno/química , Piridazinas/química , Piridinas/química , Cromatografía , Espectroscopía de Resonancia Magnética , Oxidantes/química , Oxidación-Reducción , Solventes/química , Espectroscopía Infrarroja por Transformada de Fourier , Temperatura , Ácido Trifluoroacético/químicaRESUMEN
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.
RESUMEN
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.
RESUMEN
A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS2 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.
Asunto(s)
Imidazoles/síntesis química , Tionas/síntesis química , Técnicas de Química Sintética , Reacción de Cicloadición , Imidazoles/química , Estructura Molecular , Tionas/químicaRESUMEN
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 3â¯h) and long (24â¯h) period of incubation, possibly suggesting increased cell membrane permeability and/or intracellular stability of 4d as compared to THB.
Asunto(s)
Antioxidantes/farmacología , Berberina/análogos & derivados , Pirroles/farmacología , Antioxidantes/síntesis química , Antioxidantes/química , Berberina/síntesis química , Berberina/química , Berberina/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , ADN/efectos de los fármacos , Roturas del ADN , Relación Dosis-Respuesta a Droga , Compuestos Ferrosos/antagonistas & inhibidores , Compuestos Ferrosos/farmacología , Radicales Libres/antagonistas & inhibidores , Radicales Libres/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
Herein we report a domino protocol able to reach regioselectively thiazolylidene systems by combining the reactive peculiarities of both ß-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.
RESUMEN
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.
Asunto(s)
Alquenos/química , Indoles/química , Piridinas/química , Piridinas/síntesis química , Compuestos de Espiro/química , Técnicas de Química Sintética , OxindolesRESUMEN
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.
RESUMEN
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 IC50 < 20 µM and moderate cytotoxicity, lower than miltefosine. Compound 3d was the most active with IC50 = 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.
RESUMEN
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.
RESUMEN
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.
Asunto(s)
Benzodiazepinas/síntesis química , Química Farmacéutica/métodos , Diaminas/síntesis química , Psicotrópicos/síntesis química , Alcanos/química , Compuestos Aza/química , Benzodiazepinas/análisis , Ácidos Carboxílicos/química , Cromatografía en Capa Delgada , Ciclización , Diaminas/análisis , Descubrimiento de Drogas , Humanos , Hidrazonas/síntesis química , Espectroscopía de Resonancia Magnética , Imitación Molecular , Péptidos/química , Psicotrópicos/análisis , Pirazolonas/síntesis química , EstereoisomerismoRESUMEN
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.
RESUMEN
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.