Molecular Docking Studies on Anticonvulsant Enaminones Inhibiting Voltage-Gated Sodium Channels

Epilepsy is described as the most common chronic brain disorder. A typical symptom of epilepsy results in uncontrolled convulsions caused by temporary excessive neuronal discharges. Although several new anticon-vulsants have been introduced, some types of seizures have still not been adequately controlled with these new and current therapies. There is an urgent need to develop new anticonvulsant drugs to control the many different types of seizures. Many studies have shown that the epilepsies involve more than one mechanism and therefore may be responsible for the various types of observed seizures. Recently reported studies have shown that a group of newly synthesized 6 Hz active anticonvulsant fluorinated N-benzamide enaminones exhibited selective inhibitions of voltage-gated sodium (Nav) channels. Nav channels are responsible for the initial inward currents during the depolarization phases of the action potential in excitable cells. The activation and opening of Nav channels result in the initial phases of action potentials. We hypothesize that there is an essential pharmacophore model for the interactions between these enaminones and the active sites of Nav channels. The research reported here is focused on molecular docking studies of the interactions that occur between the fluorinated N-benzamide enaminones and the Nav channels. These studies may open an avenue for designing anticonvulsant drugs by inhibiting Nav channels.

Facile Syntheses of New Pyrazolo[1,5-a]pyrimidines Derivatives via Reactions of Enaminones with Aminopyrazole

Ethyl 7-aryl-2-benzyhhiopyrazolo [ 1,5-a ] pyrimidine-3-carboxylates （3a-3f） were conveniently synthesized through the reactions of enaminones with 5-amino-3-benzyhhio4-ethoxycarbonyl-1 H-pyrazole in good yields and high regioselectivity. The structures of the new compounds were fully characterized by spectroscopic measurmehts, elemental analysis and X-ray diffraction analysis. A plausible reaction mechanism for the formation of the title compounds was also presented.

Synthesis of Novel Bis-enaminones by KHSO4-assisted Facile Michael Addition-elimination Reaction of 3-(dimethylamino)-1-phenylprop-2-en-1-ones with Diamines in Water

3-(Dimethylamino)-1-phenylprop-2-en-1-ones (formylated acetophenones) 1 reacted with aliphatic diamines in water assisted by KHSO4 to give bis-enaminones 2a-h in good yields. Compound 1 also reacted with o-phenylenediamine under similar conditions to produce bis-enaminones 3 instead of benzodiazepines 4 in excellent yields.

Recent advances in visible light-mediated chemical transformations of enaminones

Enaminones,which possesses both the nucleophilic enamine as well as electrophilic enone structures,are well known versatile building blocks in organic synthesis.Meanwhile,visible light-mediated reactions have emerged as useful synthetic strategy with enhanced sustainability.Around the last decade,various photochemical transformations of enaminones have been developed to construct cyclic or acyclic compounds.In this review,we describe the recent advances in visible light-mediated chemical transformations of enaminones.Detailed discussion on the reaction mechanism of the related reactions is given to provide guide to the reader.Finally,a summary on the existing challenges and the future outlook towards the development of practical photocatalytic reactions of enaminones is also presented.

Chemodivergent Synthesis of Benzofurans and 2,3-Dihydrobenzofurans via Tandem Oxidative Annulation of Enaminones and Salicylaldehydes

Chemodivergent synthesis of benzofurans and 2,3-dihydrobenzofurans has been realized.Under a reaction system consisting of DBDMH and K_(2)CO_(3) as promotors,controlled conditions enabled the formation of two sets of valuable heterocycles from the tandem transformation of enaminones and salicylaldehydes.The key to success was the identification of the reaction parameters,in which the imine intermediate which was formed by transient halogenation coupling and substitution processes underwent either aldol condensation/annulation or imine hydrolysis/aldol condensation.The additives NH_(4)Cl or Fe_(2)(SO_(4))_(3) controlled the unique selectivity of this reaction.A broad substrate scope of enaminones and salicylaldehydes has been employed in this reaction,demonstrating excellent functional group tolerance and versatility.

Highly selective synthesis of functionalized morphan derivatives through a multi-component cascade reaction of 3-formylchromones, 2-naphthols, and enaminones

A novel protocol for the preparation of highly functionalized 2-azabicyclo[3.3.1]nonane(morphan)derivatives via a multicomponent cascade reaction,involving 3-formylchromones,2-naphthols,and enaminones in the ionic liquid[BMIM]PF6 as the solvent and promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU),was developed,which involved the cleavage of one C–O bond and formation of four bonds(1 C–O,1 C–N,and 2 C–C bonds).As a result,a series of morphan derivatives were produced through a cascade reaction,including a sequence of 1,2-addition,enol-keto tautomerization,Michael addition,dehydration,another Michael addition,imine-enamine tautomerization,and N-alkylation reactions,which were accompanied by a ring-opening reaction.This protocol was suitable for combinatorial and parallel syntheses of natural product-like morphan compounds in a one-pot reaction rather than through tedious multi-step reactions.

A solvent-free synthesis of 1,2,3,5-tetrasubstituted pyrroles from enaminones and α-haloketones

A simple synthesis of 1,2,3,5-tetrasubstituted pyrrole derivatives from the reaction of enaminone withα-haloketones,under solvent-free conditions,is described.

Base-Promoted Synthesis of 3-Alkenyl-2-pyridones from N-Propargyl-β-enaminones and Aryl Aldehydes

Main observation and conclusion In this article,we report a base-promoted sequential cyclization/aldol-type condensation/isomerization cascade reaction of N-propargyl-β-enaminones with aryl aldehydes.The key step in this protocol is the generation of 1,4-oxazepine anions from N-propargyl-β-enaminones under basic conditions,which are captured by aryl aldehydes.The method allows the formation of one pyridone core and one C—C double bond in“one pot”,and the preparation of a variety of densely decorated pyridone derivatives in moderate to good yields with broad functional group tolerance.

Metal-free C(sp^(2))-H perfluoroalkylsulfonylation and configuration inversion:Stereoselective synthesis ofα-perfluoroalkylsulfonyl E-enaminones

The perfluoroalkylsulfonylation(CF_(3)SO_(2),C_(2)F_(5)SO_(2)and CHF_(2)SO_(2))in the enaminone C-H bonds has been developed simply via the promotion of molecular iodine by using stable and cheap sodium perfluoroalkyl sulfinates as coupling partners.The stereoselective synthesis of E-configuratedα-perfluoroalkylsulfonyl enaminones has been realized via unprecedented C-H bond elaboration and C=C double bond configuration inversion by free radical process.

Reaction of Enaminones with Aminopyrazoles： Synthesis,Structures and Bioactivities of 7-Aryl-3-cyano-2-substituted Pyrazolo[1,5-a]pyrimidines

The condensation reactions of 5-amino-4-cyano-3-substituted-1H-pyrazole 2 or 3 with enaminones 1 in the presence of glacial acetic acid gave twelve new 7-aryl-3-cyano-2-substituted pyrazolo[1,5-a]pyrimidines 4 and 5 at room temperature. Their structures were characterized by elemental analysis, IR and 1H NMR. The structure of 4a was further confirmed by X-ray crystallography analysis. A plausible reaction mechanism for the formation of the title compounds was also proposed. The bioassay tests showed that compounds 4a, 4e, 4e, 4f, 5a and 5d possessed moderate herbicidal activity.

Synthesis and Crystal Structure of 5-Cyclopropyl- 10-(4-fluorophenyl)-7,7-dimethyl-7,8-dihydro-5H- indeno[1,2-b]quinoline-9,11(6H,10H)-dione

The title compound 5-cyclopropyl-10-（4-fluorophenyl）-7,7-dimethyl-7,8-dihydro- 5H-indeno[1,2-b]quinolne-9,11（6H,10H）-dione was obtained by the reaction of 4-fluorobenzal- dehyde, 2H-indene-1,3-dione and 3-（cyclopropylamino）-5,5-dimethylcyclohex-2-enone in the presence of acetic acid under microwave irradiation. Its structure was confirmed by IR and 1H- NMR spectra. The crystal is of monoclinic, space group P21/c with a = 14.138（3）, b = 8.952（2）, c = 17.140（3）A, β = 102.253（3）°, C27H24FNO2, Mr = 413.47, Z = 4, V = 2119.9（8）A^3, Dc = 1.296 g/cm^3, μ（MoKα） = 0.087 mm^-1, F（000） = 872, the final R = 0.0425 and wR = 0.0905 for 2336 observed reflections （I 〉 2σ（I））. X-ray analysis revealed that the pyridine ring adopts a boat conformation and the six-membered ring fused with it assumes a twist boat conformation.

Reactivity of 1-methylisoquinoline synthesis of pyrazolyl triazoloisoquinoline and thia-diazolyl isoquinoline derivatives

The reaction of 1-methylisoquinoline 1 with hy-drazonoyl halides 2 in ethanol in the presence of chitosan under microwave irradiation affords triazoloisoquinoline 4. Product 4 reacts with dimethylformamide-dimethylacetal to give ena- minones 7 which react with hydrazonoyl halides to give pyrazolyl triazoloisoquinoline 13. Also, 1-methylisoquinoline 1 reacts with arylisothio-cyanate to give thioanilide 15 which reacts with hydrazonoyl halides to give the corresponding thiadiazolyl isoquinoline derivatives 20, 24.

Switchable Multicomponent Cyclization Reactions to Access Fluoroalkylated Dihydropyrimidines and Pyrimidines under Solvent-Free Conditions

Comprehensive Summary The development of switchable solvent-free multicomponent reactions to build high-value-added products is an important demand for organic synthesis.Herein,we detailed the successful implementation of a switchable strategy for the construction of diverse 4-fluoroalkyl-1,4-dihydropyrimidines and 4-fluoroalkyl-pyrimidines via a solvent/additive-free[3+2+1]annulation,starting from readily available enamines,trifluoroacetaldehyde hydrate or 1-ethoxy-2,2-difluoroethanol and amidines hydrochloride.This reaction conforms to the concept of green synthesis,and provides a new avenue to access valuable fluorinated heterocycles.

Catalytic C-H activation-initiated transdiannulation:An oxygen transfer route to ring-fluorinated tricyclic γ-lactones

Catalytic C–H activation-initiated annulation reactions have emerged as a versatile strategy for the efficient construction of diverse ring structural units and complex cyclic molecules in synthetic chemistry.Herein,we describe a new Rh(Ⅲ)-catalyzed C–H activation-initiated transdiannulation reaction of N,Ndimethyl enaminones with gem-difluorocyclopropenes in the presence of H_(2)O,enabling a facile and oxygen transfer access to ring-fluorinated tricyclicγ-lactones with a 6-5 ring-junction tetrasubstituted stereocenter.This approach features bond-forming/annulation efficiency,good functional group tolerance and complete regioselectivity,which may include a complex process consisting of Rh(Ⅲ)-catalyzed C(sp2)–H activation,cyclic alkene insertion,defluorinated ring-opening of gem-difluorocyclopropane,intramolecular oxygen transfer,intramolecular cyclization and oxidative hydration.

Visible-Light-Induced Domino Cyclization to Access Pyrido[2,3-d]pyrimidine-2,4-diones via a Radical-Polar Crossover Reaction

Comprehensive Summary Catalytic and green strategies for the synthesis of privileged scaffolds are synthetically appealing.We now report a radical-polar crossover(RPC)-enabled three-component cyclization of bromodifluoroalkyls with enaminones and 6-aminouraciles via a visible-light-induced domino cyclization.The reaction exhibited a broad substrate scope(>40 examples)including complex molecules,which highlighted the utility of this strategy for the construction of a library of bioactive analogs.

A two-step approach to 2-polyfluoroalkyl quinolines from N-aryl polyfluoroalkyl imidoyl iodides

2-Polyfluoroalkyl quinoline derivatives were synthesized from the enaminones which were obtained from the reaction of FT-aryl polyfluoroalkyl imidoyl iodides with methyl ketones.

Amine-catalyzed synthesis of N^(2)-sulfonyl 1,2,3-triazole in water and the tunable N^(2)-H 1,2,3-triazole synthesis in DMSO via metal-free enamine annulation

The selective synthesis of N^(2)-sulfonyl and N^(2)-H 1,2,3-triazoles via organocatalytic annulation of enaminone/enaminoester with sulfonyl azide has been realized. The unconventional selectivity providing N^(2)-sulfoyl 1,2,3-triazoles takes place in pure water, wherein the hydrogen bond effect between water and the intermediate resulting from enamine-azide corporation accounts for the novel reaction selectivity. On the other hand, the reactions conducted in DMSO specifically afford N^(2)-H 1,2,3-triazoles in the absence of such hydrogen bond effect.