Imino Diels-Alder Reaction Research Articles

A mild catalyzed imino Diels-Alder reaction for the synthesis of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide derivatives as regulators of Quorum Sensing in Pseudomonas aeruginosa

Bacterial resistance is one of the major global public health problems. In addition, virulence factors promoted multiple drug resistance through cell-to-cell communications by molecules within microbial communities, denominated Quorum Sensing (QS). The regulation of QS by small molecules appears as a therapeutic alternative through the use of synthetic analogs of agonists. The present work developed the construction of a series of derivatives of N-(2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl) formamide (1a-h) via Povarov-type sequential reactions to deliver the tetrahydroquinoline (THQ) derivatives in moderate to good yields (24–78%). To evaluate the potential in molecular diversity of THQ-type autoinducers, a study of these agents as potential inhibitors of bacterial growth and virulence factors involved in QS systems on P. aeruginosa was carried out both as antibacterial evaluation on E. coli strain. THQs showed significant activity values for molecules with halogen substituents at the C-6 position (-F, -Cl, and I), revealing at a concentration of 75 µg/mL a percentage inhibition between 27 and 40%. Furthermore, autoinducers with halogen substitutes in phenotypic studies on P. aeruginosa showed good results. Also, they exhibited weak formation of both biofilm and low pyocyanin formation, which are indicators of virulence in P. aeruginosa. Overall, the results suggest that compound N-(6-fluor-2-(o-tolyl)-1,2,3,4-tetrahydroquinoline-4-yl)formamide (1a) stands out as the most representative within this series of THQ derivatives.

Design, Synthesis, and Cytotoxicity and Topoisomerase I/IIα Inhibition Activity of Pyrazolo[4,3-f]quinoline Derivatives.

With the several targets of cancer treatment, inhibition of DNA topoisomerase activity is one of the well-known focuses in cancer chemotherapy. Here, we describe the design and synthesis of a novel series of pyrazolo[4,3-f]quinolines with potential anticancer/topoisomerase inhibition activity. Forty newly designed pyrazolo[4,3-f]quinoline derivatives were synthesized via inverse imino Diels–Alder reaction. The antiproliferative activity of the synthesized derivatives was initially measured in the human NUGC-3 cancer cell line. Then, the selected compounds 1B, 1C, 1M, 2A, 2D, 2E, 2F, and 2R with higher activity among tested compounds were screened against six cancer cell lines, including ACHN, HCT-15, MM231, NCI-H23, NUGC-3, and PC-3. The results demonstrated that the compounds 1M, 2E, and 2P were most effective in all cancer cell lines exhibiting GI50 below 8 µM. Among them, 2E showed an equivalent inhibition pattern of topoisomerase IIα activity to that of etoposide, positive control at a 100 µM dose.

Synthesis and Biological Activities of New 1,2,3,4- Tetrahydroquinoline Derivatives Using Imino Diels-Alder Reaction

This research contains the preparation of some novel derivatives of tetrahydro quinolone. First step, includeprepared new Schiff’s bases compounds (I1-I5) were prepared by the direct condensation between diaminecompounds and aromatic aldehydes substituted by different groups. Tetrahydroquinoline derivativescompounds (I6-I10) were prepared through imino Diels-Alder reaction using the derivatives of Schiff basewith cinnamic acid, and Boron tri fluoride ethyl etherate (BF3.Et2O) as a catalyst. The prepared compoundswere identified by infrared spectra, 1H-NMR, and 13C-NMR. Antibacterial activity of the prepared compoundswas measured by using three pathogenic microorganisms including Staphyloccus haemolyticus, Klebsiellapneumonia,and Candida albicans. Also, a comparative study was achieved to study the biological activityof these prepared compounds using Agar Diffusion method.

Imino Diels-Alder/transition metal catalyzed reactions to synthesise fused ring heterocycles

Imino Diels-Alder reactions were tactically combined with various transition metal catalysed [2 + 2], [3 + 2] and [4 + 2] cycloaddition reactions to form novel syntheses for biologically relevant fused-ring heterocycles with molecular complexity in good yields.

Synthesis of dihydroisoindolo[2,1-a]quinolin-11-ones, their in silico ADMET properties and in vitro antitumor activities.

We evaluated the antitumoral activity of diverse series of 5-aryl-dihydroisoindolo[2,1-a]quinolin-11-ones, AIIQ (Aryl IsoIndolo-Quinoline, 4a–m), and 5-vinyl dihydroisoindolo[2,1-a]quinolin-11-ones, VIIQ (Vinyl IsoIndolo-Quinoline, 6a–l), obtained using three component imino Diels–Alder (DA) reaction of anilines, o-phthalaldehyde and dienophiles. The first series was obtained in previous work employing isoeugenol and anethole as dienophiles, whereas the vinyl series was synthesized in high yields (75–90%) using isoprene as a dienophile. The cytotoxic activity of both AIIQ and VIIQ series was evaluated against four cancer lines, identifying a new lead compound 4h from the AIIQ series, active against MCF-7 (310 nM), SKBR3 (1434 nM), PC3 (210 nM) and HeLa (79 nM) cells with high selectivity. In addition, in silico ADMET properties for the two series were assessed and discussed.

Anti-leishmanial effect of spiro dihydroquinoline-oxindoles on volume regulation decrease and sterol biosynthesis of Leishmania braziliensis

Diverse spiro dihydroquinoline-oxindoles (JS series) were prepared using the BF3•OEt2-catalyzed imino Diels-Alder reaction between ketimine-isatin derivatives and trans-isoeugenol. Ten spiro-oxiindole derivatives were selected and evaluated at different stages of the life cycle of Leishmania braziliensis parasites, responsible for cutaneous leishmaniasis in South America. Among them, the 8′-ethyl-4‘-(4-hydroxy-3-methoxyphenyl)-3′-methyl-3′,4′-dihydro-1′H-spiro[indoline-3,2′-quinolin]-2-one called JS87 was able to inhibit the growth of promastigotes without affecting the mammalian cells viability, and to decrease the number of intracellular amastigotes of L. braziliensis. This spiro compound was found to act through the alteration of parasite internal regulation by disrupting the regulatory volume decrease (RVD), and to affect the sterol biosynthetic pathway at level of squalene epoxidase (SE) enzyme. These results revealed that the spiro annulation between quinoline and oxindole scaffolds enhances the anti-leishmanial activity, and could assist in the development of potent quinoline-oxindole hybrids against Leishmania braziliensis, the main etiological agent of cutaneous leishmaniasis in South America.

Rapid construction of tetrahydropyridine scaffolds via formal imino Diels-Alder reactions of Schiff bases and Nazarov reagents.

Described is a one-flask, two-step method for the synthesis of highly functionalized piperidines. The process involves formal [4 + 2] cycloadditions of Schiff bases and Nazarov reagents, followed by facile elaborations of the initial cycloadducts. Notably, these aza-annulations are facilitated by protic solvents and proceed smoothly under ambient conditions, without other additives. The synthetic utility of this annulation protocol is further showcased through a concise, convergent synthesis of (±)-tetrabenazine.

Oxone promoted dehydrogenative Povarov cyclization of N-aryl glycine derivatives: an approach towards quinoline fused lactones and lactams.

Oxone promoted intramolecular dehydrogenative imino Diels–Alder reaction (Povarov cyclization) of alkyne tethered N-aryl glycine esters and amides has been explored, thus affording biologically significant quinoline fused lactones and lactams. The reaction is simple, scalable, and high yielding (up to 88%). The method was further extended to prepare biologically important luotonin-A analogues and the quinoline core of uncialamycin.

Brønsted and Lewis Solid Acid Catalysts in the Valorization of Citronellal

Terpenes are valuable starting materials for the synthesis of molecules that are of interest to the flavor, fragrance, and pharmaceutical industries. However, most processes involve the use of mineral acids or homogeneous Lewis acid catalysts. Here, we report results obtained in the liquid-phase reaction of citronellal with anilines under heterogeneous catalysis conditions to give tricyclic compounds with interesting pharmacological activity. The terpenic aldehyde could be converted into octahydroacridines with a 92% yield through an intramolecular imino Diels–Alder reaction of the imine initially formed in the presence of an acidic clay such as Montmorillonite KSF. Selectivity to the desired product strongly depended on the acid sites distribution, with Brønsted acids favoring selectivity to octahydroacridine and formation of the cis isomer. Pure Lewis acids such as silica–alumina with a very low amount of alumina gave excellent results with electron-rich anilines like toluidine and p-anisidine. This protocol can be applied starting directly from essential oils such as kaffir lime oil, which has a high citronellal content.

An Inverse Electron Demand Azo-Diels-Alder Reaction of o-Quinone Methides and Imino Ethers: Synthesis of Benzocondensed 1,3-Oxazines.

We have studied the reactions of o-quinone methide precursors with imino ethers. The reaction provides a versatile route to substituted 1,3-benzoxazines. The proposed reaction mechanism involves the generation of the o-quinone methide intermediates, imino-Diels-Alder reaction, and elimination. This cascade process is a rare example of the participation of imino ethers as dienophiles.

Design, synthesis and biological evaluation of 1,3-diphenylbenzo[f][1,7]naphthyrdines

A novel series of twenty 1,3-diphenylbenzo[f][1,7]benzonaphthyrdine derivatives were designed and synthesized through intermolecular imino Diels-Alder reaction. Their in vitro cytotoxic activities were evaluated against six human cancer cell lines (NCIH23, HCT15, NUGC-3, ACHN, PC-3, and MDA-MB-231). Majority of synthesized compounds exhibited significant cytotoxic activities against all tested human cancer cell lines. Among them 4l, 4m, and 4o derivatives exhibited most promising cytotoxic activities. Furthermore these compounds were evaluated against human Topoisomerase IIα inhibition. Interestingly, the compound 4l exhibited 1.3 and 1.2 times more potent human Topoisomerase IIα inhibition than the reference drug etoposide in both 100µM and 20µM concentrations respectively. Molecular docking studies for the compound 4l have also been executed by Sybyl X-2.1 in which it reveals the binding site of the compound 4l with topo IIα DNA cleavage site where etoposide was situated. The benzo[f][1,7]naphthyridine ring was stacked between the DNA bases of the cleavage site.

Highly Diastereoselective Synthesis of New trans-Fused Octahydro­acridines via Intramolecular Cationic Imino Diels–Alder Reaction of N-Protected Anilines and Citronellal or Citronella Essential Oil

The one-pot diastereoselective synthesis of new N-substituted octahydroacridines was successfully achieved via BiCl3-catalyzed intramolecular cationic imino Diels–Alder reaction in good yields employing N-protected anilines and (±)-citronellal as substrates under mild conditions. It was observed that bulky N-substituent groups (allyl, propargyl, and benzyl substituent) play a key role in the cis/trans ratio of the thus-formed octahydroacridines. Increasing bulkiness permits preferential formation of the trans-fused heterocycles. It was found that use of the N-benzyl group resulted in a highly diastereoselective process that gives easily separable trans-fused N-substituted octahydroacridines. The developed protocol was extended to involve the use of citronella essential oil from Cymbopogon nardus as a renewable source of these biologically important heterocyclic molecules.

A facile one-pot regioselective synthesis of functionalized novel benzo[f]chromeno[4,3-b][1,7]naphthyridines and benzo[f][1,7]naphthyridines via an imino Diels-Alder reaction

A novel series of functionalized 13H-benzo[f]chromeno[4,3-b][1,7]naphthyridines and 1,3-diphenylbenzo[f][1,7]naphthyridines have been synthesized by an efficient regioselective one-pot multicomponent synthesis through intra and intermolecular imino Diels-Alder reaction. In this method, we have achieved complete regioselectivity and atom economy with polysubstituted core motifs in moderate to good yields. The proposed mechanism of this reaction has also discussed.

ChemInform Abstract: Versatile and Mild HCl‐Catalyzed Cationic Imino Diels—Alder Reaction for the Synthesis of New Tetrahydroquinoline Derivatives.

ABSTRACTA simple, inexpensive, and mild one-pot methodology for the synthesis of novel 4-aryl-3-methyl-1,2,3,4-tetrahydroquinolines derivatives using aqueous HCl as catalyst has been developed. The key step involves the formal inverse-electron-demand [4π+ + 2π] cycloaddition reaction of in situ–generated cationic 2-azadienes with arylpropenes (isoeugenol and trans-anethole). Iminium ion intermediates are generated through the condensation between N-benzylanilines and formalin. The products are obtained with good to excellent yields and high trans-diastereoselectivity. Further catalytic hydrogenation (Pd/C) allowed debenzylation to successfully obtain the respective 4-aryl-3-methyl-N-H-tetrahydroquinolines of interest. Recent reports suggest that these compounds could serve as interesting models in pharmacological studies against parasites that cause the most common tropical diseases.

Novel N-allyl/propargyl tetrahydroquinolines: Synthesis via Three-component Cationic Imino Diels-Alder Reaction, Binding Prediction, and Evaluation as Cholinesterase Inhibitors.

New N‐allyl/propargyl 4‐substituted 1,2,3,4‐tetrahydroquinolines derivatives were efficiently synthesized using acid‐catalyzed three components cationic imino Diels–Alder reaction (70–95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl‐cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af (IC 50 = 72 μ m) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity (SI = 2), while the best inhibitory activity on butyryl‐cholinesterase was exhibited by compound 4ae (IC 50 = 25.58 μ m) with considerable selectivity (SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl‐cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆G and the experimental activity values in both targets.

Versatile and mild HCl-catalyzed cationic imino Diels-Alder reaction for the synthesis of new tetrahydroquinoline derivatives

ABSTRACTA simple, inexpensive, and mild one-pot methodology for the synthesis of novel 4-aryl-3-methyl-1,2,3,4-tetrahydroquinolines derivatives using aqueous HCl as catalyst has been developed. The key step involves the formal inverse-electron-demand [4π+ + 2π] cycloaddition reaction of in situ–generated cationic 2-azadienes with arylpropenes (isoeugenol and trans-anethole). Iminium ion intermediates are generated through the condensation between N-benzylanilines and formalin. The products are obtained with good to excellent yields and high trans-diastereoselectivity. Further catalytic hydrogenation (Pd/C) allowed debenzylation to successfully obtain the respective 4-aryl-3-methyl-N-H-tetrahydroquinolines of interest. Recent reports suggest that these compounds could serve as interesting models in pharmacological studies against parasites that cause the most common tropical diseases.

Magnetically Separable Iron Oxide Nanoparticles: An Efficient and Reusable Catalyst for Imino Diels–Alder Reaction

Iron oxide nanoparticles were synthesized using Saururus chinensis (S. chinensis) leaf extract as a reducing and stabilizing agent via ultrasonication. The size, morphology, crystallinity, elemental composition, weight loss, surface chemical state, and magnetic properties of the synthesized nanoparticles were investigated. The synthesized nanoparticles were used as an efficient and recyclable catalyst for the synthesis of a variety of 2‐methyl‐4‐substituted‐1,2,3,4‐tetrahydroquinoline derivatives by the imino Diels–Alder reaction. After the reaction, the catalyst was recovered by an external magnetic field. The recovered catalyst was then reused in a subsequent reaction under identical conditions. The recycled iron oxide nanoparticles (IONPs) were reused five times without any significant loss of catalytic activity.

Highly stereoselective and catalyst-free synthesis of annulated tetrahydropyridines by intramolecular imino-Diels–Alder reaction under microwave irradiation in water

Highly stereoselective intramolecular imino-Diels–Alder reaction without any catalyst in water and under microwave irradiation for the synthesis of complex organic systems.

ChemInform Abstract: Mechanochemical Milling Promoted Solvent‐Free Imino Diels—Alder Reaction Catalyzed by FeCl3: Diastereoselective Synthesis of cis‐2,4‐Diphenyl‐1,2,3,4‐tetrahydroquinolines.

ChemInform Abstract: Mechanochemical Milling Promoted Solvent‐Free Imino Diels—Alder Reaction Catalyzed by FeCl₃: Diastereoselective Synthesis of cis‐2,4‐Diphenyl‐1,2,3,4‐tetrahydroquinolines.

Stereoselective synthesis of a natural product inspired tetrahydroindolo[2,3-a]-quinolizine compound library

A natural product-inspired synthesis of a compound collection embodying the tetrahydroindolo[2,3-a]quinolizine scaffold was established with a five step synthesis route. An imino-Diels–Alder reaction between Danishefsky’s diene and the iminoesters derived from tryptamines was used as a key reaction. Reductive amination of the ketone function and amide synthesis with the carboxylic acid derived from the ethyl ester, were used to decorate the core scaffold. Thus a compound library of 530 tetrahydroindolo[2,3-a]quinolizines was generated and submitted to European lead factory consortium for various biological screenings.