Trisubstituted Pyridines Research Articles

Topoisomerase I and II Inhibitors: A Patent Review.

Topoisomerases are a set of nuclear enzymes that play a vital role in handling of topological consequences of DNA during various genetic activities necessary for vitality of cell. Inhibition of these enzymes consequently leads to the blockage of ligation step of the cell cycle which generates single and double strand breakage in DNA strand. Introduction of these breaks subsequently leads to programmed cell death (Apoptosis). In the past several years, topoisomerases have become one of the most expedient and strategic molecular targets for anticancer drugs and numerous patents have been filed and published on topoisomerase inhibitors. This review compiles the patent literature up to 2016 embracing topo I and II inhibitors as well as dual inhibitors which are structurally adjacent to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. The present assemblage can be extremely advantageous for the medicinal chemists who are in crave for the development of potential anticancer agents targeting topoisomerases. Recent patents indicated that some of the nitrogen containing heteroaromatic compounds have immense potential to inhibit topoisomerase enzyme. In particular, fused N-Heterocycles can be anticipated for their promising therapeutic potential alone or in combination with other anticancer agents. Naphthyridinone and indenoisoquinoline derivatives, described in the preceding sections of this review, are endowed with significant potency against topoisomerase I which clearly indicates the need of preclinical and clinical studies to place them in forefront as potential future drug candidates.

Cycloadditions of 1,2,3-Triazines Bearing C5-Electron Donating Substituents: Robust Pyrimidine Synthesis.

The examination of the cycloaddition reactions of 1,2,3-triazines 17-19, bearing electron-donating substituents at C5, are described. Despite the noncomplementary 1,2,3-triazine C5 substituents, amidines were found to undergo a powerful cycloaddition to provide 2,5-disubstituted pyrimidines in excellent yields (42-99%; EDG = SMe > OMe > NHAc). Even select ynamines and enamines were capable of cycloadditions with 17, but not 18 or 19, to provide trisubstituted pyridines in modest yields (37-40% and 33% respectively).

Conjugated donor–acceptor copolymers derived from phenylenevinylene and trisubstituted pyridine units

Copolymers having intramolecular donor–acceptor systems encompassing trisubstituted pyridine derivatives as acceptor and phenylenevinylene (PPV) unit as a donor segment were synthesized. In addition, thiophene-containing random terpolymer PPVPYT via palladium-catalyzing Heck coupling reaction is reported. The novel-substituted pyridine monomers (PYBr) are synthesized by adopting a one-pot synthesis method using p-toluenesulfonic acid as catalyst in ethanol medium, which results in an excellent yield of about 95%. All the copolymers Poly phenylenevinylene-co-Pyridine derivatives (PPVPY) and terpolymers of Polyphenylenevinylene-co-Pyridine and Thiophene (PPVPYT) are found to be soluble in organic solvents, such as tetrahydrofuran, chloroform, and N, N-dimethylformamide. The molecular weights of the synthesized polymers were characterized by gel permeation chromatography (GPC), and their chemical structures were confirmed by infra red and nuclear magnetic resonance spectroscopies. The electrochemical band gaps of PPVPY-1, PPVPY-2, and PPVPY-3 copolymers are estimated to be 2.55, 2.48, and 2.0, respectively. Similarly, the band gap of PPVPY75T25, PPVPY50T50, and PPVPY25T75 random copolymers are estimated as 2.31, 1.95, and 2.23, respectively. These polymers also show excellent optical and thermal properties.

前周期低原子価ニオブ化合物の有機変換反応への利用 —量論反応から触媒反応へ—

This review consists mainly of stoichiometric reaction and catalytic reaction using niobium complexes. As an example of stoichiometric reaction, synthesis of 1H-indenes from the reaction of aliphatic ketones and aryl-substituted alkynes in the presence of stoichiometric amount of NbCl3(DME) has been documented. Alternatively, development of catalytic reaction of using low-valent Nb is intriguing. Our research group reported that low-valent Nb catalyzed intermolecular [2+2+2] cycloaddition reaction of alkynes with alkenes leading to tri- or tetra-substituted 1,3-cyclohexadienes in chemo- and regioselectivity. In addition, low-valent Nb catalyzed cycloaddition reaction of tert-butylacetylene with aryl-substituted nitriles to tri-substituted pyridines has been reported.

Access to pyridines via DMAP-catalyzed activation of α-chloro acetic ester to react with unsaturated imines

Facile access to trisubstituted pyridines from α-chloro acetic ester and unsaturated imines is achieved.

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

The Bohlmann–Rahtz pyridine synthesis and the Hantzsch dihydropyridine synthesis can be carried out in a microwave flow reactor or using a conductive heating flow platform for the continuous processing of material. In the Bohlmann–Rahtz reaction, the use of a Brønsted acid catalyst allows Michael addition and cyclodehydration to be carried out in a single step without isolation of intermediates to give the corresponding trisubstituted pyridine as a single regioisomer in good yield. Furthermore, 3-substituted propargyl aldehydes undergo Hantzsch dihydropyridine synthesis in preference to Bohlmann–Rahtz reaction in a very high yielding process that is readily transferred to continuous flow processing.

Isothiourea‐Mediated One‐Pot Synthesis of Functionalized Pyridines

Isothiourea‐Mediated One‐Pot Synthesis of Functionalized Pyridines

Analgesic and Anticonvulsant Activities of Some Newly Synthesized Trisubstituted Pyridine Derivatives

A series of novel pyridine carbohydrazide derivatives were synthesized from the reaction of 2-chloro-6-hydrazino-isonicotinic acid hydrazide with selected active reagents. All prepared compounds were tested as analgesic and anticonvulsant agents. The pharmacological screening showed that many of these compounds have good activities comparable to those of valdecoxib and carbamazepine as reference drugs.

Synthesis of 2,4,6-Tri-Substituted Pyridine Derivatives in Aqueous MediumviaHantzsch Multi-Component Reaction Catalyzed by Cerium (IV) Ammonium Nitrate

2,4,6-Tri-substituted pyridine derivatives have been efficiently synthesized in excellent yields using catalytic amounts of cerium (IV) ammonium nitrate in aqueous medium via one-pot, multi-component reaction. Condensation of dehydroacetic acid with aldehydes and ammonium acetate afforded corresponding tri-substituted pyridine derivatives in excellent yields by using Hantzsch pyridine synthesis. The structures of all the newly synthesized compounds were confirmed from their analytical and spectral data.

An instantaneous and highly selective chromofluorogenic chemodosimeter for fluoride anion detection in pure water.

The development of chromofluorogenic sensors for anions is a well-established and studied field in the supramolecular chemistry realm.1 This is due to the important roles of anions in biological processes, deleterious effects (such as environmental pollutants), and as toxic compounds and carcinogenic species.2

Highly Regioselective Assembly of Di‐ or Trisubstituted Pyridines from Arynes, Isocyanides, and 3‐Bromo‐ or 3‐Acetoxypropynes

AbstractA facile synthetic method for the preparation of di‐ and trisubstituted pyridines with high regioselectivity through an intramolecular pericyclization strategy is disclosed. The multicomponent reaction of isocyanides, arynes, and 3‐bromopropyne affords disubstituted pyridines in good yields. In contrast, the use of 3‐acetoxypropyne results in the formation of trisubstituted pyridines through intramolecular pericyclization of an in situ formed azatriene. In this way, desirable pyridines can be constructed in a one‐pot manner.

Analgesic and Anticonvulsant Activities of Some Newly Synthesized Trisubstituted Pyridine Derivatives

Analgesic and Anticonvulsant Activities of Some Newly Synthesized Trisubstituted Pyridine Derivatives

Acidic ionic liquid immobilized on cellulose: an efficient and recyclable heterogeneous catalyst for the solvent-free synthesis of hydroxylated trisubstituted pyridines

The synthesis of a novel cellulose supported acidic ionic liquid (Cell-IL) for the solvent-free synthesis of hydroxylated trisubstituted pyridines is reported. Cell-IL was prepared by immobilization of an acidic ionic liquid [1-butyl-3-(3-trimethoxypropyl)-1H-imidazol-3-ium hydrogen sulfate] on cellulose. The viability of this concept has been confirmed by FT-IR, TGA-DTG, 1H NMR and elemental analysis. The Cell-IL showed good thermal stability and exhibited a high catalytic activity in the synthesis of a series of hydroxylated trisubstituted pyridines. It was recovered and reused for the model reaction three times without an appreciable change in its activity.

Regioselective reactions of 3,4-pyridynes enabled by the aryne distortion model

The pyridine heterocycle continues to play a vital role in the development of human medicines. More than 100 currently-marketed drugs contain this privileged unit, which remains highly sought after synthetically. We report an efficient means to access di- and tri-substituted pyridines in an efficient and highly controlled manner using transient 3,4-pyridyne intermediates. Previous efforts to employ 3,4-pyridynes for the construction of substituted pyridines have been hampered by a lack of regiocontrol or the inability to later manipulate an adjacent directing group. The newly developed strategy relies on the use of proximal halide or sulfamate substituents to perturb pyridyne distortion, which in turn governs regioselectivities in nucleophilic addition and cycloaddition reactions. Following trapping of in situ-generated pyridynes, the neighboring directing groups may be removed or exploited using versatile metal-catalyzed cross-coupling reactions. This methodology now renders 3,4-pyridynes useful synthetic building blocks for the creation of highly decorated derivatives of the medicinally privileged pyridine heterocycle.

ChemInform Abstract: Solvent‐ and Catalyst‐Free Synthesis of New Hydroxylated Trisubstituted Pyridines under Microwave Irradiation.

AbstractThe expected products are obtained through a simplified purification procedure without protection of the hydroxyl group.

Flexible and Scalable Route to HDAc Inhibitors Containing an Unusual Trisubstituted Pyridine Core

A scalable route to histone deacetylase inhibitors containing an unusual 2-aryl-3-cyano-5-aminomethylpyridine core has been developed which has the flexibility to deliver a range of compounds on at least a multigram scale. The key step involves a novel Mannich reaction using 3-dimethylaminoacrolein, formaldehyde, and a secondary amine to yield a 2-(alkylaminomethyl)-3-dimethylaminoacrolein. Tuning of this reaction in process development was fundamental to the success of the approach in terms of flexibility and operability on scale-up. This new methodology will also enable access an underutilised family of 3,5-disubstituted pyrid-2-ones and 2,3,5-trisubstituted pyridines.

Solvent- and catalyst-free synthesis of new hydroxylated trisubstituted pyridines under microwave irradiation

A facile solvent- and catalyst-free method for the synthesis of a series of new hydroxylated 2,4,6-trisubstituted pyridines under microwave irradiation was developed. The expected products were obtained through a simplified purification process without protection of the hydroxyl group. UV-Vis and fluorescence spectra of these conjugated multi-hydroxyl compounds were also investigated.

ChemInform Abstract: Highly Efficient and Enantioselective Hydrogenation of Quinolines and Pyridines with Ir‐Difluorphos Catalyst.

The combination of the readily available chiral bisphosphine ligand Difluorphos with [Ir(COD)Cl]2 in THF resulted in a highly efficient catalyst system for asymmetric hydrogenation of quinolines at quite low catalyst loadings (0.05–0.002 mol%), affording the corresponding products with high enantioselectivities (up to 96%), excellent catalytic activities (TOF up to 3510 h−1) and productivities (TON up to 43000). The same catalyst was also successfully applied to the asymmetric hydrogenation of trisubstituted pyridines with nearly quantitative yields and up to 98% ee. In these two reactions, the addition of I2 additive is indispensable; but the amount of I2 has a different effect on catalytic performance.

Highly Enantioselective Hydrogenation of Quinoline and Pyridine Derivatives with Iridium‐(P‐Phos) Catalyst

AbstractThe use of a chiral iridium catalyst generated in situ from the (cyclooctadiene)iridium chloride dimer, [Ir(COD)Cl]2, the P‐Phos ligand [4,4′‐bis(diphenylphosphino)‐2,2′,6,6′‐tetramethoxy‐3,3′‐bipyridine] and iodine (I2) for the asymmetric hydrogenation of 2,6‐substituted quinolines and trisubstituted pyridines [2‐substituted 7,8‐dihydroquinolin‐5(6H)‐one derivatives] is reported. The catalyst worked efficiently to hydrogenate a series of quinoline derivatives to provide chiral 1,2,3,4‐tetrahydroquinolines in high yields and up to 96% ee. The hydrogenation was carried out at high S/C (substrate to catalyst) ratios of 2000–50000, reaching up to 4000 h−1 TOF (turnover frequency) and up to 43000 TON (turnover number). The catalytic activity is found to be additive‐controlled. At low catalyst loadings, decreasing the amount of additive I2 was necessary to maintain the good conversion. The same catalyst system could also enantioselectively hydrogenate trisubstituted pyridines, affording the chiral hexahydroquinolinone derivatives in nearly quantitative yields and up to 99% ee. Interestingly, increasing the amount of I2 favored high reactivity and enantioselectivity in this case. The high efficacy and enantioselectivity enable the present catalyst system of high practical potential.

Highly efficient and enantioselective hydrogenation of quinolines and pyridines with Ir-Difluorphos catalyst

The combination of the readily available chiral bisphosphine ligand Difluorphos with [Ir(COD)Cl](2) in THF resulted in a highly efficient catalyst system for asymmetric hydrogenation of quinolines at quite low catalyst loadings (0.05-0.002 mol%), affording the corresponding products with high enantioselectivities (up to 96%), excellent catalytic activities (TOF up to 3510 h(-1)) and productivities (TON up to 43000). The same catalyst was also successfully applied to the asymmetric hydrogenation of trisubstituted pyridines with nearly quantitative yields and up to 98% ee. In these two reactions, the addition of I(2) additive is indispensable; but the amount of I(2) has a different effect on catalytic performance.