2-substituted Quinolines Research Articles

Facile synthesis of 2-substituted quinolines and 3-alkynyl-2-aryl-2H-Indazole via SnCl2-mediated reductive cyclization

A rapid and efficient SnCl2·2H2O mediated synthesis of quinolines and indazoles has been developed using A3-coupling followed by reductive cyclization. The key highlights are the formation of quinoline in a one-pot fashion and indazole through N–N bond formation.

Metal-free, ionic liquid-mediated synthesis of functionalized quinolines.

An expedient and metal-free synthetic protocol for construction of substituted quinolines has been developed from anilines and phenylacetaldehydes using imidazolium cation-based ionic liquids as the reaction medium. Mechanistic analysis indicated that the reaction occurs through C-C and C-N bond formation to produce isolable 2,3-disubstituted quinoline intermediates, which undergo C-C bond cleavage to produce 3-substituted quinolines. The reaction proceeds smoothly with a range of functionalities in good to excellent yields. Advantages of this protocol include metal-free, environmentally friendly, recyclable reaction media, higher yields and shorter reaction times, and thus is promising for the efficient combinatorial synthesis of structurally diverse 2,3-disubstituted and 3-substituted quinolines.

Investigation of the role of i1- and i2-imidazoline receptors in the mechanіsm of the hypoglycemic action of n,n’-(ethane-1,2 dyyil)bis(quinoline- 2-carboxamide)

The results of the investigation of the hypoglycemic action mechanism of N,N’-(ethane-1,2-dyyil)bis (quinoline-2-carboxamide) are presented. The substance was administered intragastrically in the dose of 11.64 mg/kg on the model of alloxan-induced diabetes mellitus in rats. It should be noted that the test compound in terms of the theory of pharmacophore can be considered as a dimer BU 224, but it is not its dimer in terms of organic chemistry. The information about the influence of the test compound on carbohydrate metabolism is limited. There are data that this compound has antitumor properties іn vitro due to enhanced apoptosis and activation of caspase-3. Proceeding from the chemical structure, the 2-substituted quinoline fragment is present in the structure of the known antagonist of imidazoline receptors I 2 such as 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride, so it can be assumed that N,N’-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide) has the ability to interfere with the mechanisms of the carbohydrate metabolism regulation. These results indicate that N,N’-(ethane-1,2-dyyil)bis(quinolin-2-carboxamide) has an expressed hypoglycemic effect in alloxan-induced diabetes mellitus reducing the blood glucose level by 71.50%. It is an agonist of imidazoline receptors of both types, and it has been proven by blockade with selective antagonists such as efaroxan and 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride. On the background of I 1 -imidazoline receptors blocker efaroxan the glycemia decrease was 45.66% (p<0.05), and on the background of I2-imidazoline receptors blocker 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride it was 54.01% (p<0.05). Diabetes mellitus (DM) type 2 is a chronic disease caused by decrease in sensitivity of the human tissues to insulin [1, 14]. The frequency of diabetes on average ranges from 1.5% to 3%; it is constantly increasing in the developed countries up to 5-7%, in Ukraine the value is twice lower – about 2.9%. There are about 200 million of diabetics in the world; almost 90% of them suffer from type 2 diabetes [5, 15]. The urgency of DM problem is caused by a signifi cant prevalence of the disease, severity of complications, disability and early mortality. Microangiopathies and neuropathies are the basis of diabetic complications. The patients with diabetes have a significant risk of athero sclerosis and coronary heart disease. More than 40% of amputations of lower limbs are a consequence of the diabetic foot syndrome. Diabetes is also the most common cause of blindness in humans [12, 17]. All mentioned above stipulates the necessity of development and research of new effective drugs with the hypoglycemic effect allowing to prevent development of the severe course of DM. The mechanism of action of different antidiabetic drugs consists of a several links. There are data on the role of imidazoline receptors in implementation of the hypoglycemic effect, in particular for biguanides derivatives such as metformin [7]. Imidazoline receptors are the independent type of receptors represented by two subtypes: 11 and 12. Subtypes are distinguished according to the specific ligands that bind with them. Imidazoline receptors mediate the following effects: increase of glucose-dependent insulin release and transport of glucose into the cells and, as a result, decrease of hyperglycemia, improvement of the

ChemInform Abstract: Alkyltriflate‐Triggered Annulation of Arylisothiocyanates and Alkynes Leading to Multiply Substituted Quinolines Through Domino Electrophilic Activation.

AbstractThe structures of products (IVb) and (XIIIb) are confirmed by X‐ray analysis.

ChemInform Abstract: One‐Pot Synthesis of Multiply Substituted Quinoline and Quinazoline Derivatives via [2 + 2 + 2] Cascade Annulation with Diaryliodonium Salts.

AbstractA facile protocol is presented for the three‐component reaction of diaryliodonium salts with nitriles and alkynes to give a wide variety of quinoline derivatives.

Alkyltriflate-Triggered Annulation of Arylisothiocyanates and Alkynes Leading to Multiply Substituted Quinolines through Domino Electrophilic Activation

The reaction of arylisothiocyanate, alkyltriflate, and alkynes leads to variously substituted quinolines in high yields. The reaction undergoes alkyltriflate-triggered domino electrophilic activation and avoids the use of a transition-metal catalyst. A variety of functional groups are tolerated in the quinoline ring.

Deproto-metallation using mixed lithium–zinc and lithium–copper bases and computed CH acidity of 2-substituted quinolines

The metallated quinolines were functionalized by iodolysis or aroylation.

Thiourea as an efficient organocatalyst for the transfer hydrogenation of 2-substituted quinoline derivatives

This study reports on the first transfer hydrogenation of 2-substituted quinolines promoted by a thiourea catalyst with Hantzsch 1,4-dihydropyridine as the hydrogen source.

Synthesis and biological evaluation of 2-substituted quinoline 6-carboxamides as potential mGluR1 antagonists for the treatment of neuropathic pain.

A series of 2-amino and 2-methoxy quinoline-6-carboxamide derivatives have been synthesized and their metabotropic glutamate receptor type 1 (mGluR1) antagonistic activities were evaluated in a functional cell-based assay. The compound 13c showed the highest potency with IC50 value of 2.16 µM against mGluR1. Finally, in vivo evaluation of 13c in the rat spinal nerve ligation (SNL) model exhibited weak analgesic effects with regard to both mechanical allodynia and cold allodynia.

One-Pot Synthesis of Multiply Substituted Quinoline and Quinazoline Derivatives via [2+2+2] Cascade Annulation with Diaryliodonium Salts

An efficient and regioselective method to multisubstituted quinoline and quinazoline derivatives with diaryliodonium salts catalyzed by Cu(OTf)2 has been presented. The reaction proceeded via cascade annulation in the mode of [2+2+2] form. This novel strategy enables use of readily available materials and bears great flexibility on the substitution groups.

Design, synthesis and biological evaluation of 2-substituted quinolines as potential antileishmanial agents

An analogous library of 2-substituted quinoline compounds was synthesized with the aim to identify a potential drug candidate to treat visceral leishmaniasis. These molecules were tested for their in vitro and in vivo biological activity against Leishmania donovani. Metabolic stability of these compounds was also improved through the introduction of halogen substituents. Compound (26g), found to be the most active; exhibited an IC50 value of 0.2 μM and >180 fold selectivity. The hydrochloride salt of (26g) showed 84.26 ± 4.44 percent inhibition at 50 mg/kg × 5 days (twice daily, oral route) dose in L. donovani/hamster model. The efficacy was well correlated with the PK data observed which indicating that the compound is well distributed.

ChemInform Abstract: Halogenated Quinolines as Substrates for the Palladium‐Catalyzed Cross‐Coupling Reactions to Afford Substituted Quinolines.

AbstractReview: 85 refs.

Copper(II)‐Catalyzed Three‐Component Cascade Annulation of Diaryliodoniums, Nitriles, and Alkynes: A Regioselective Synthesis of Multiply Substituted Quinolines

A regioselective synthesis of a variety of substituted quinolines is developed using a Cu(II)-catalyzed three-component [2 + 2 + 2] cyclocondensation of diaryliodonium ions, nitriles, and alkynes, whereat the aryl group of the diaryliodonium serves as a C2 building block.

Copper(II)‐Catalyzed Three‐Component Cascade Annulation of Diaryliodoniums, Nitriles, and Alkynes: A Regioselective Synthesis of Multiply Substituted Quinolines

Copper(II)‐Catalyzed Three‐Component Cascade Annulation of Diaryliodoniums, Nitriles, and Alkynes: A Regioselective Synthesis of Multiply Substituted Quinolines

Studies on Quinolin-2(1H)-One Derivatives: Synthetic Access to Pyrano[3,2-c] Quinoline and 3-Substituted Quinoline Derivatives

Studies on Quinolin-2(1H)-One Derivatives: Synthetic Access to Pyrano[3,2-c] Quinoline and 3-Substituted Quinoline Derivatives

Halogenated Quinolines as Substrates for the Palladium‐Catalyzed Cross‐Coupling Reactions to Afford Substituted Quinolines

The use of palladium complexes in catalyzing the cross‐coupling of halogenated quinolines with various organometalic reagents has led to the development of radically new methods of synthesizing novel substituted quinoline derivatives. The focus of this review is on the application of the following palladium‐catalyzed reactions of halogenated quinolines with organometalic reagents to afford substituted quinoline derivatives: Kumada, Stille, Negishi, Sonogashira, Suzuki, Heck, and Hiyama cross‐coupling reactions.

Studies on 2(1H)-Quinolone Derivatives: Synthetic Access to Pyrano[3,2-c] Quinoline and 3-Substituted Quinoline Derivatives

Studies on 2(1H)-Quinolone Derivatives: Synthetic Access to Pyrano[3,2-c] Quinoline and 3-Substituted Quinoline Derivatives

ChemInform Abstract: Palladium‐Catalyzed Approach for the General Synthesis of (E)‐2‐Arylmethylidene‐N‐tosylindolines and (E)‐2‐Arylmethylidene‐N‐tosyl/nosyltetrahydroquinolines: Access to 2‐Substituted Indoles and Quinolines.

A facile and efficient method for the synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinoline variants has been developed through palladium-catalyzed cyclocondensation of aryl iodides with readily available 1-(2-tosylaminophenyl)prop-2-yn-1-ols and their higher homologues, respectively. The proposed reaction mechanism invokes the operation of trans-aminopalladation during cyclization (5/6-exo-dig), which ensures exclusive (E)-stereochemistry in the products. The method is fast, operationally simple, totally regio- and stereoselective, and versatile enough to access a variety of 2-substituted indoles and quinolines. The reactions proceeded efficiently with a wide variety of substrates and afforded the corresponding products in moderate to excellent yields.

Development of potent macrocyclic inhibitors of genotype 3a HCV NS3/4A protease

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.

Palladium‐Catalyzed Sequential Formation of CC Bonds: Efficient Assembly of 2‐Substituted and 2,3‐Disubstituted Quinolines

A series of substituted quinolines was prepared from arylamines, aldehydes, and terminal olefins (see scheme). The palladium-catalyzed sequential formation of C-C bonds proceeds smoothly with both electron-deficient and electron-rich olefins. When acrylic acid is used as terminal olefin, decarboxylation occurs to provide 2-substituted quinolines.