Gould-Jacobs Reaction Research Articles

Diethyl 2-((aryl(alkyl)amino)methylene)malonates: Unreported Mycelial Growth Inhibitors against Fusarium oxysporum

This paper presents the discovery and development of antifungal agents against Fusarium oxysporum (Fox), a devastating plant pathogen. Diethyl 2-((arylamino)methylene)malonates (DAMMs) were formed as side-products during the synthesis of polysubstituted-2-pyridones through a three-component domino reaction and seemed to have antifungal activity against Fox. DAMMs are typically employed as intermediates or precursors to produce further bioactive compounds, but they have never been examined as antifungals. To confirm this latter characteristic, we employed a single-step procedure (i.e., the first step of the Gould-Jacobs reaction) to prepare five DAMMs (74–96% yields) which were subsequently evaluated against Fox in terms of their abilities to inhibit mycelial growth. The antifungal outcome was promising (0.013 µM < IC50 < 35 µM), involving fungistatic or fungicide effects. This small group of active compounds showed differences in antifungal activity, constituting the basis of further studies to expand the DAMM chemical space and look for improved antifungal activity.

On the Regioselectivity of the Gould–Jacobs Reaction: Gas‐Phase Versus Solution‐Phase Thermolysis

A detailed investigation of the regioselectivity in the thermal cyclization of (pyridyl)aminomethylenemalonates both in the gas‐ and solution phase is presented. Flash vacuum pyrolysis (FVP) as a gas‐phase thermolysis technique is used to study the Gould–Jacobs reaction at temperatures between 450–650 °C, while different solution‐phase heating techniques (reflux, microwave, and continuous flow) were employed at 260–350 °C. Depending on the position of the substituent in the pyridine moiety and the applied thermolysis technique, the regioselectivity of the cyclization can be controlled either in favor of the kinetic (pyridopyrimidinone) or the thermodynamic (naphthyridinone) product. Under FVP conditions, 6‐substituted pyridopyrimidinones were obtained in high regioselectivity, which was not demonstrated before under standard Gould–Jacobs reaction conditions. DFT calculations have been additionally performed to provide further insights into the mechanistic pathways of this specific Gould–Jacobs reaction.

4-Amino and 5-aminobenzothiadiazoles in Gould–Jacobs reaction

4-Amino and 5-aminobenzothiadiazoles were prepared and submitted to reaction with activated enolethers to prepare N-substituted benzothiadiazolylaminoethylene derivatives. Selected aminoethylenes were thermally cyclized to angularly annelated thiadiazolylaminoethylene under Gould–Jacobs reaction conditions. Prepared products were modified to obtain variously substituted thiadiazoloquinolones.

Synthesis and pharmacological evaluation of pyrazolo[4,3-c]quinolinones as high affinity GABAA-R ligands and potential anxiolytics

The synthesis, in vitro ligand binding study and in vivo Elevated Plus Maze test (EPM) of a series of pyrazolo[4,3-c]quinolin-3-ones (PQs) are reported. Multistep synthesis of PQs started from anilines and diethyl 2-(ethoxymethylene)malonate to give the quinolin-4-one nucleus, via the Gould-Jacobs reaction. These quinolinones were transformed to 4-chloroquinolines, which react with aryl-hydrazines affording the final compounds. PQs exhibited different potency in displacing specific [3H]Flunitrazepam binding from the benzodiazepine binding site at the γ-aminobutyric acid receptor (GABAA-R) depending on the substitution of the pyrazoloquinolone nucleus. PCA helped determine how different substituents contributed to the differential behavior of the PQs studied. Compounds with high affinity for the GABAA-R were tested regarding their anxiolytic properties in Wistar adult male rats using the Elevated Plus Maze (EPM). Thus, PQs with a p-methoxy phenyl group at N-1 (7b-ii and 7c-ii) displayed a remarkable anxiolytic activity at low doses (0.5–1.0 mg/kg). Meanwhile, PQs featuring an unsubstituted phenyl (7b-i) or p-fluoro phenyl group (7b-iii) at the N-1 showed anxiogenic effects in the EPM test.

Design, synthesis and biological evaluation of new 4-(4-substituted-anilino)quinoline derivatives as anticancer agents

A new series of 4-(4-substituted-anilino)quinoline derivatives 6a–f was synthesized from amine derivatives via Gould–Jacobs reaction. All synthesized compounds were evaluated for their cytotoxic activity against two human cancer cell lines; breast carcinoma (MCF-7) and non-small cell lung cancer (A549). The tested compounds showed a broad range of activities (IC50 = 3.42–23.32 and 5.97–22.01 µM) in comparison with doxorubicin (IC50 = 2.07 and 0.02 µM) and erlotinib (IC50 = 1.14 and 19.26 µM) for MCF-7 and A549 respectively. The 4-(4-chloroanilino)quinoline derivative (6c, IC50 = 3.42 and 5.97 µM) was the most potent among all compounds against both MCF-7 and A549 cell lines respectively. In addition, molecular docking studies were performed and the results were in agreement with the in vitro cytotoxic data.

Gas-phase synthesis of 3-carboethoxy-quinolin-4-ones. A comprehensive computational mechanistic study to uncover the dark side of the Gould–Jacobs reaction

A set of 3-carboethoxy-quinolin-4-ones were synthesized from diethyl 2-((arylamino)methylene) malonates through a Gould–Jacobs cyclization using flash vacuum pyrolysis (FVP). A detailed mechanistic study was done using DFT and Coupled Clusters models.

ChemInform Abstract: Synthesis of Condensed Heterocycles by the Gould—Jacobs Reaction in a Novel Three‐Mode Pyrolysis Reactor.

AbstractThe synthesis of a series of fused pyrimidine heterocycles (including some novel ones) via Gould‐Jacobs reactions using an in‐house‐built vacuum‐to‐high pressure multipurpose pyrolysis reactor is described.

Synthesis and biological evaluation of new nucleosides derived from trifluoromethoxy-4-quinolones

The synthesis of new nucleoside derivatives from 6- and 7-trifluoromethoxy-4-quinolones is described. The present synthesis is a combination of the Gould–Jacobs reaction for the preparation of 4-quinolones and a modified Vorbrüggen reaction for the construction of nucleoside derivatives. The target compounds were tested against murine gammaherpesvirus MHV-68 type.

Synthesis of Condensed Heterocycles by the Gould–Jacobs Reaction in a Novel Three-Mode Pyrolysis Reactor

In the present paper we report the synthesis of condensed pyrimidone heterocycles (including novel ones) prepared by the Gould–Jacobs reaction using an in-house-built vacuum-to-high pressure multipurpose “three-mode” pyrolysis reactor. Four of the ring systems have not been described in the literature to date. The pyrolysis reactor has (i) a flash vacuum pyrolysis (FVP) module that applies high vacuum (10–3 mbar), letting the starting material through the reactor chamber heated up to 1000 °C; (ii) a pneumatic spray pyrolysis (PSP) module that can inject nonvolatile reactants to the heated reactor zone; and (iii) a high-pressure pyrolysis (HPP) continuous-flow module that operates from atmospheric to 400 bar pressure and between room temperature and 600 °C. The capabilities of the pyrolysis reactor were demonstrated by comparison experiments on two different condensed pyrimidone bicyclic ring systems, and the established reaction conditions were then successfully applied to the synthesis of another six condensed pyrimidone bicyclic systems.

Microwave Assisted Gould-Jacobs Reaction for Synthesis of 3-Acetyl-4-hydroxyquinoline Derivatives

Microwave Assisted Gould-Jacobs Reaction for Synthesis of 3-Acetyl-4-hydroxyquinoline Derivatives

Synthesis of 9-ethyl[1,2,5]selenadiazolo[3,4-h]quinolones by the application of modified Gould-Jacobs reaction to N-ethyl-2,1,3-benzoselenadiazol-4-amine

An effective method for the synthesis of N-ethyl-2,1,3-benzoselenadiazolamines 11 and 15 has been described. Modified Gould-Jacobs reaction of N-ethylbenzoselenadiazol-4-amine 15 provided 9-ethylselenadiazoloquinolone derivatives 2 and 19 in high yields. Acid-promoted ring closure of enamine 18c unexpectedly afforded completely deacetylated product - 9- ethylselenadiazoloquinolone 2. Identical product was obtained by ethylation of selenadiazolo(3,4-h)quinolone 1 and by basic hydrolysis of ethyl ester 19b followed by thermal decarboxylation of the corresponding acid 20 .

Emergence of pyrido quinoxalines as new family of antimalarial agents

A series of novel N-alkyl dihydro pyrido quinoxaline derivatives were synthesized using Gould–Jacobs reaction and evaluated their antimalarial activity in vitro against chloroquine sensitive (3D7) and drug resistant (Dd2) strains of Plasmodium falciparum. Among the compounds tested, 10 compounds were more potent than their structural standard analog ciprofloxacin, including 2 derivatives 5e and 5h, which showed 3.3–7.4 times more potency than ciprofloxacin against both the parasite strains. The results are encouraging and a lead molecule may emerge which is useful alone or in combination therapy.

Heterocycles [f]-Fused onto Quinolones. Synthesis of Novel Dioxo-Nethylpyrano[ 2,3-f ]- and [3,2-f ]quinoline-10-carboxylic Acids

A model N-ethyl-1,10-dioxo-3-phenylpyrano[3,2- f ]quinoline-9-carboxylic acid (8) and the isomeric (2-substituted) pyrano[2,3- f ]quinoline-9-carboxylic acids (6 and 7) were prepared from the corresponding 6/7-aminochromen-4-ones via the Gould-Jacobs reaction. The new tricyclic heterocycles 6-8 exhibit moderate antibacterial activity (MIC=16 - 64 μgmL-1) against E. coli and S. aureus

Synthesis and antimicrobial activity of novel substituted ethyl 2-(quinolin-4-yl)-propanoates.

Substituted 4-hydroxyquinolines were synthesized from anilines and diethyl 2-(ethoxymethylene)malonate by the Gould-Jacobs reaction via cyclization of the intermediate anilinomethylenemalonate followed by hydrolysis and decarboxylation. The 4-hydroxyquinolines reacted with phosphorous oxychloride to form 4-chloroquinolines, which reacted on heating with diethyl sodiomethylmalonate in DMF to yield moderate yields of substituted ethyl 2-(quinolin-4-yl)propanoates, many of which showed potent antimicrobial activity against Helicobacter pylori.

Synthesis of [1,2,5]selenadiazolo[3,4-f]quinolone derivatives by the Gould-Jacobs reaction of 5-amino-2,1,3-benzoselenadiazole

The Gould-Jacobs reaction of 5-amino-2,1,3-benzoselenadiazole afforded solely angularly annulated 8-substituted 9-oxo-6,9-dihydro-(1,2,5)selenadiazolo(3,4-f)quinoline derivatives. In the course of thermal cyclization no linear products were observed. Nucleophilic vinylic substitution of activated enolethers with 5-amino-2,1,3-benzoselenadiazole was also studied.

Synthetic Applications of Diethyl Ethoxymethylenemalonate

Diethyl ethoxymethylenemalonate (EMME, Figure [¹] ), a liquid with a boiling point of 279-281 ˚C, is a very versatile reagent, extensively used for the synthesis of heterocyclic systems. The main application of this reagent is its use in the Gould-Jacobs reaction.

Application of the Gould–Jacobs reaction to 4-amino-2,1,3-benzoselenadiazole

An effective method for the synthesis of 4-amino-2,1,3-benzoselenadiazole (4) has been described. Reduction of readily available 4-nitrobenzothiadiazole 6 with SnCl2·2H2O afforded 1,2,3-triaminobenzene dihydrochloride 2. The latter upon treatment with aqueous SeO2 solution provided desired amine 4. Nucleophilic vinylic substitution of activated enol ethers 7 with amine 4 led to (benzoselenadiazol-4-ylamino)methylene derivatives 8. Thermal cyclization of derivatives 8a–c, e, f under Gould–Jacobs reaction conditions gave angularly annelated 7-(non)substituted selenadiazolo[3,4-h]quinolones 9. Acid hydrolysis of etyl ester 9c afforded corresponding acid 10. All prepared selenadiazoloquinolones were tested for antimicrobial activity.

ChemInform Abstract: Dichloro‐4‐quinolinol‐3‐carboxylic Acid: Synthesis and Antioxidant Abilities to Scavenge Radicals and to Protect Methyl Linoleate and DNA.

AbstractFollowing the Gould—Jacobs reaction, a series of 4‐quinolinol‐3‐carboxylic acids (III) is prepared and investigated for their antioxidant properties in chemical and biological experiments.

An alternative approach toward 2-aryl-2 H-pyrazolo[4,3- c]-quinolin-3-ones by a multistep synthesis

A series of 2-aryl-2 H-pyrazolo[4,3- c]quinolin-3-ones derivatives 6 and 7 was conveniently prepared. A multistep synthesis was carried out starting from dichloro- and bromoanilines ( 1a– b) and diethyl 2-(ethoxymethylene)malonate using a slightly modified Gould-Jacobs reaction. In this work we present a novel chlorination strategy to prepare quinoline derivatives 4 in excellent yields as key intermediates in the synthesis of the target compounds. Several reaction conditions were evaluated to optimize the formation of pyrazoloquinolinone nucleus. Differences in chemical behavior of both chloroquinolinones 4a–b with aryl and benzyl-hydrazines are also discussed.

Novel ESIPT fluorescent benzazolyl-4-quinolones: Synthesis, spectroscopic characterization and photophysical properties

Two, novel, benzazolyl-quinolone heterocycles, fluorescent by virtue of intramolecular proton transfer mechanism in the excited state (ESIPT), were obtained using the Gould-Jacobs reaction. The intramolecular cyclization step in the preparation of the anilinomethylene malonate derivatives was carried out using polyphosphoric acid, heat transfer fluids ( Dowtherm A Fluid, mineral oil and diphenyl ether) as well as tandem methodology, at temperatures ranging from 180 °C to 250 °C. Tandem methodology provided better yields and lower by-product formation. The synthesized quinolones were characterized using elemental analysis, IR, 13C and 1H NMR spectroscopy. Photophysical behaviour was studied using UV–Vis and steady-state fluorescence, both in solution and in solid state. The quinolones were fluorescent in solution in the orange-red region (500–800 nm), under UV radiation, and displayed a large Stokes shift (165–194 nm).