One‐pot three‐component synthesis of 2‐substituted 4‐aminoquinazolines

A facile and rapid synthesis of the title compounds via one‐pot reaction of 2‐aminobenzonitrile, orthoesters and ammonium acetate under solvent‐free and microwave condition is described.     

An efficient chemoenzymatic method to prepare optically active O-methyl-l-serine

O-Methyl-l-serine and its derivatives are relevant in peptide synthesis (food, pharmaceuticals, and cosmetics). Optically active O-methyl-l-serine was prepared using a chemoenzymatic method from inexpensive acrylamide. Our method is a four step reaction sequence; bromination of acrylamide; etherification of dibromopropionamide; ammonolysis of α-bromo-β-methoxy-propionamide; enzymatic racemization; and selective hydrolysis. The double-enzyme catalyst system, which consists of α-amino-ε-caprolactam racemase (Locus, E01594) and peptidase B (Locus, D84499), was successfully applied to produce enantiopure O-methyl-l-serine (ee >99.9%) in high yield (>99.7%). Optically active O-methyl-l-serine was obtained with a total yield of 82.4%.     

Poly(4‐vinylpyridine)‐supported cationic bis(cyclopentadienyl)zirconocene catalyst: Development of a new simple method to prepare polymer‐supported cationic zirconocene and its application to ethylene polymerization

Bis(cyclopentadienyl)zirconocene dimethyl (Cp₂ZrMe₂) combined with triphenylcarbenium tetrakis(pentafluorophenyl)borate ([Ph₃C][B(C₆F₅)₄]) was brought into contact with a suspension of 2% cross‐linked poly(4‐vinylpyridine) to give a new type of polymer‐supported cationic zirconocene catalyst. The resulting polymer‐supported catalyst system combined with Al(i‐Bu₃) showed markedly high activity for ethylene polymerization in even a non‐polar solvent like hexane at 25–60°C and [Al]/[Zr] molar ratio 40–200. By the analysis of Zr content of the hexane solution, it was found that no Zr was detected in the solution, i. e. no leaching of the cationic catalyst into the hexane medium. The catalytic activity was found to increase with an increase of polymerization temperature and showed the highest at [Al]/[Zr] = 100. The molecular weight, crystalline melting temperature, crystallinity, and bulk density of polyethylene formed were higher than those of the polymer obtained from the homogeneous system.     

An HPLC method for the determination of a novel anti‐hypertension agent 6,7‐dimethoxy‐3‐[4‐(4‐fluorobenzyloxy)‐3‐methoxyphenylmethyl]quinazolin‐4(3H)‐one in rat plasma: application to pharmacokinetic study

6,7‐Dimethoxy‐3‐[4‐(4‐fluorobenzyloxy)‐3‐methoxyphenylmethyl] quinazolin‐4(3H)‐one (DFMQ‐19), a novel analog of 3‐benzylquinazolin‐4(3H)‐ones, may be considered as a drug candidate for the treatment of hypertension. The aim of this study was to develop and validate a reverse‐phase high‐performance liquid chromatography to determine the DFMQ‐19 in plasma and demonstrate its application in pharmacokinetic studies. Separation of DFMQ‐19 and IS (structural analog of DFMQ‐19) was performed using a Shim‐Pack VP‐ODS column and a mixture of acetonitrile and water as mobile phase. The HPLC method was validated according to the International Conference on Harmonization guidelines. The limit of detection and lower limit of quantitation were 0.05 and 0.1 μg/mL, respectively. The recovery rate of DFMQ‐19 from blood samples was >81% of the spiked amount. The RSD of the intra‐ and inter‐day precisions was within 7.5%, and RE of accuracy was between ?14.4 and 4.5%. This method was successfully applied to the pharmacokinetic study after administration of DFMQ‐19. The pharmacokinetic parameters, such as half‐life, mean residence time and maximum concentration were determined. Based on these pharmacokinetic parameters, the oral bioavailability of DFMQ‐19 was calculated to be 13.42% in rat. Copyright © 2016 John Wiley & Sons, Ltd.     

An efficient procedure for the preparation of 4‐methyl‐2‐thiocoumarins by the reaction of 4‐methylcoumarins with lawesson's reagent

A simple and convenient method has been worked out for the preparation of 4‐methyl‐2‐thiocoumarins by the reaction of the appropriate 4‐methylcoumarins with Lawesson's Reagent in hot anhydrous toluene.     

A new efficient synthesis of 3‐(hydroxymethyl)‐4H‐chromen‐4‐ones

An efficient and versatile synthesis of variously substituted 3‐(hydroxymethyl)‐4H‐chromen‐4‐ones is reported. The compounds are prepared by hydroxymethylation of the precursor 2‐hydroxy‐4‐chromanones followed by acid dehydration.     

4‐(4‐Chlorobenzylidenehydrazonomethyl)benzonitrile and the bromo and iodo analogs

4‐Cyano‐4′‐chlorobenzalazine [systematic name: 4‐(4‐chlorobenzylidenehydrazonomethyl)benzonitrile], C₁₅H₁₀ClN₃, occurs in two polymorphs. Polymorph A is isostructural with the corresponding dichloro compound. Polymorph B is isostructural with the bromo and iodo analogs, viz. C₁₅H₁₀BrN₃ and C₁₅H₁₀IN₃, respectively. The latter three structures all have approximately linear C—N...X—C intermolecular contacts in which the N...X contact distances are longer than those in the corresponding benzylideneanilines.     

Studies with 2‐arylhydrazononitriles: A novel simple,efficient route to 5‐acyl‐2‐substituted‐1,2,3‐triazol‐4‐amines

Efficient route to 5‐acyl‐2‐substituted‐1,2,3‐triazol‐4‐amines via reaction of 3‐oxo‐2‐(arylhydrazono)‐pentanenitrile with hydroxylamine hydrochloride is reported. X‐ray crystal structure has been made to confirm the structure of reaction products.     

An efficient and regiospecific preparation of trifluoromethyl substituted 4‐( 1H‐pyrazol‐1 ‐yl)‐7‐chloroquinolines

A new series of 4‐[3‐alkyl(aryl)(heteroaryl)‐5‐hydroxy‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl]‐7‐chloroquinolines, where [alkyl = CH₃; aryl = C₆H₅, 4‐CH₃C₆H₄, 4‐FC₆H₄, 4‐ClC₆H₄, 4‐BrC₆H₄, 4‐CH₃OCgH₄, 4‐NO₂CgH₄, 4‐biphenyl, 1‐naphthyl; heteroaryl = 2‐furyl and 2‐thienyl] has been regiospecifi‐caly obtained from the reaction of 7‐chloro‐4‐hydrazinoquinoline with 4‐substituted‐l,1,1‐trifluoro‐4‐methoxybut‐3‐en‐2‐ones in 61 ‐ 96 % yield. Subsequently, dehydration reaction of 4,5‐dihydropyra‐zolylquinolines under acid conditions furnished a new series of 4‐(3‐substituted‐5‐trifluoromethyl‐1H‐pyra‐zol‐1‐yl)‐7‐chloroquinolines in 73 ‐ 96 % yield.     

DIRECT‐ID: An automated method to identify and quantify conformational variations—application to β2‐adrenergic GPCR

The conformational dynamics of a macromolecule can be modulated by a number of factors, including changes in environment, ligand binding, and interactions with other macromolecules, among others. We present a method that quantifies the differences in macromolecular conformational dynamics and automatically extracts the structural features responsible for these changes. Given a set of molecular dynamics (MD) simulations of a macromolecule, the norms of the differences in covariance matrices are calculated for each pair of trajectories. A matrix of these norms thus quantifies the differences in conformational dynamics across the set of simulations. For each pair of trajectories, covariance difference matrices are parsed to extract structural elements that undergo changes in conformational properties. As a demonstration of its applicability to biomacromolecular systems, the method, referred to as DIRECT‐ID, was used to identify relevant ligand‐modulated structural variations in the β₂‐adrenergic (β₂AR) G‐protein coupled receptor. Micro‐second MD simulations of the β₂AR in an explicit lipid bilayer were run in the apo state and complexed with the ligands: BI‐167107 (agonist), epinephrine (agonist), salbutamol (long‐acting partial agonist), or carazolol (inverse agonist). Each ligand modulated the conformational dynamics of β₂AR differently and DIRECT‐ID analysis of the inverse‐agonist vs. agonist‐modulated β₂AR identified residues known through previous studies to selectively propagate deactivation/activation information, along with some previously unidentified ligand‐specific microswitches across the GPCR. This study demonstrates the utility of DIRECT‐ID to rapidly extract functionally relevant conformational dynamics information from extended MD simulations of large and complex macromolecular systems. © 2015 Wiley Periodicals, Inc.     

An efficient chemoenzymatic method to prepare optically active primary-tertiary trans-cycloalkane-1,2-diamines

Optically active trans-N-Boc-cyclopentane- and cyclohexane-1,2-diamines (7) were prepared by a chemoenzymatic method from the corresponding (±)-trans-N,N-diallylcycloalkane-1,2-diamine. These mono-carbamates 7 (ee=99%) were used as the starting materials in the syntheses of different vicinal primary-tertiary diamines. Thus, by means of a simple three-step sequence involving a reductive-amination of an aromatic aldehyde with 7, N-methylation and finally, cleavage of the Boc group, several trans-N-(arylmethyl)-N-methylcyclopentane- and cyclohexane-1,2-diamines were obtained in high yields.     

An efficient synthesis of new pyrido[4′,3′:4,5]thieno[2,3‐d]‐pyrimidin‐4(3H)‐one derivatives

The carbodiimides 5 , obtained from reactions of iminophosphorane 4 with aromatic isocyanates, reacted with amines, phenols or ROH to give 2‐substituted 5,6,7,8‐tetrahydropyrido[4′,3′:4,5]thieno[2,3‐d]‐pyrimidin‐4(3H)‐one 7 in the presence of catalytic amount of sodium alkoxide or solid potassium carbonate in satisfactory yields.     

An efficient electrochemical method for synthesis of (1h‐1,2,4‐triazol‐3‐ylthio)benzen‐1,2‐diol derivatives

Electrochemical oxidation of catechols ( 1a–c ) has been studied in the presence of 3‐mercapto‐1,2,4‐triazole ( 3 ) as a nucleophile in water/acetonitrile (90/10) solutions. The results revealed that the quinones derived from catechols ( 1a–c ) participate in the Michael addition reactions with anion of 3‐mercapto‐1,2,4‐triazole ( 3 ) and are converted to the corresponding (1H‐1,2,4‐triazol‐3‐ylthio)benzen‐1,2‐diol derivatives ( 4a–c ). © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:644–649, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20359     

Quinolone analogs 11: Synthesis of novel 4‐quinolone‐3‐carbohydrazide derivatives with antimalarial activity

The reaction of the 6‐substituted 1‐methyl‐4‐quinolone‐3‐carboxylates 10a , 10b with hydrazine hydrate gave the 3‐carbohydrazides 7a , 7b , respectively, whose reaction with 2‐, 3‐, and 4‐pyridinecarbaldehydes afforded the 3‐(N²‐pyridylmethylene)carbohydrazides 8a , 8b , 8c and 9a , 9b , 9c . The Curtius rearrangement of compound 7b provided the N,N′‐bis(4‐quinolon‐3‐yl)urea 14 presumably via the 3‐carboazide 11 and then 3‐isocyanate 12 . Compounds 7a , 8a , and 9a were found to possess antimalarial activity from the in vitro screening data. J. Heterocyclic Chem.,(2011).     

Investigations on regio‐ and stereoselectivities in cycloadditions involving α‐ (3‐pyridyl)‐N‐phenylnitrone: Development of an efficient route to novel nicotine analogs

Thermal reactions of hitherto α‐(3‐pyridyl)‐N‐phenylnitrone ( 1 ) with mono‐substituted electron‐rich and electron‐neutral dipolarophiles are regio‐, and stereo‐selective (exo‐selective), controlled by LUMO ‐ dipole ‐ HOMO‐ dipolarophile interaction, and furnish syn‐5‐substituted‐3‐(3‐pyridyl)‐isoxazolidines ( 5 ) in high yields. With electron deficient dipolarophiles such as acrylonitrile there is observed a loss of regioselectivity as well as stereoselectivity and the regioselectivity is reversed in reactions with methyl vinyl ketone and methyl acrylate, due to intervention of HOMO‐dipole ‐ LUMO‐dipolarophile interaction, affording 4‐substi‐tuted‐3‐(3‐pyridyl)‐isoxazolidines ( 7 ) as major products. Reactions of nitrone ( 1 ) with disubstituted dipolarophiles such as methyl methacrylate and ethyl coronate furnish methyl syn‐5‐methy‐3‐pyridyl‐1‐phenyl‐isoxazolidine‐5‐carboxylate ( 8 ) and ethyl anti‐5‐methy‐3‐pyridyl‐1‐phenyl‐isoxazolidine‐4‐carboxylate ( 10 ), respectively, in high yields. Reaction with N‐Phenylmaleimide affords novel isoxazolidino‐pyrro‐lidinediones bearing a 3‐pyridyl moiety ( 11, 12 ). A mechanistic rationalization of the obtained results in terms of electronic, steric and secondary interactions is proffered.     

Chemistry and application of 4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehyde

The Chemistry and application of the title aldehyde and some simple derivatives thereof are reviewed.     

An efficient synthesis of 1‐H‐pyrazole‐4‐carboxylic acid esters with vilsmeier reagent under neat conditions

A convenient, solvent‐free Vilsmeier reagent is experimented under neat condition (both thermal and microwave conditions). An efficient method for the synthesis of various substituted 1H‐pyrazole‐4‐carboxylic acid esters is reported.     

An efficient synthetic approach to novel nickel(II) 2‐benzazolo‐5,10,15,20‐tetraphenylporphyrins

A simple and efficient synthesis of nickel(II) 2‐benzazolo‐5,10,15,20‐tetraphenylporphyrins from nickel(II) 2‐formyl‐5,10,15,20‐tetraphenylporphyrin and o‐arylenediamines, o‐aminophenols or o‐aminothiophenol in 1,2‐dichlorobenzene is described. A diverse range of novel β‐substituted azoloporphyrins has been successfully synthesized in good yields and their structures are confirmed on the basis of spectral data. J. Heterocyclic Chem., (2012).