Synthesis of novel N-pyridylpyrazole derivatives containing 1,2,4-oxadiazole moiety via 1,3-dipolar cycloaddition and their structures and biological activities

A series of novel 1,2,4-oxadiazole-containing N-pyridylpyrazole derivatives 12a−h were efficiently synthesized with pivaldehyde, pyridylpyrazole carboxylic acid and arylamine as raw materials via 1,3-dipolar cycloaddition. Their structures were identified by melting points, ¹H NMR, ¹³C NMR and elemental analysis or HRMS. The exploration on the single-crystal structures of 12c and 12g revealed the stereochemical and substituent oriental characteristics, and the relevance of the structure and the reaction activity of this type of compounds. The preliminary bioassays indicated that several compounds had good insecticidal activities, among which 12c showed a lethality rate of 80% towards Mythimna separata Walker at 200 μg/mL; some of the compounds exhibited favorable fungicidal activities at 50 μg/mL against Physalospora piricola, Rhizoctonia cereal, Sclerotinia sclerotiorum, etc. Among which, 12a, 12b, 12c and 12h could be considered as new fungicidal leading compounds for further structural optimization. These discoveries along with the structure-activity relationship analysis in this paper will provide useful guidance for the innovative studies on new pyridylpyrazole derivatives and their applications in agrochemical area.     

Efficient and structurally controlled synthesis of novel polyhydroxylated indolizidine derivatives with an amino group

Novel polyhydroxylated indolizidine derivatives containing an amino group have been efficiently and divergently synthesized from azasugar aldehyde. The key steps of the strategy involved an effectively microwave assisted 1,3-dipolar cycloaddition of azasugar nitrone and methacrylate for installing a potential amino group and an ester group with a extended chain, and a structurally controlled intramolecular cyclo-amidation for constructing the indolizidine ring system via a key tricyclic indolizinone-containing intermediate.     

Synthesis of spiropyrrolidinyl-benzoisothiazoline derivatives by 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide

The new spirocyclic compounds, spiropyrrolidinyl-benzoisothiazoline derivatives were synthesized by the 1,3-dipolar cycloaddition of benzoisothiazole-2,2-dioxide-3-ylidenes and azomethine ylide. The stereochemistry of 1,3-dipolar cycloaddition as well as the stereochemistry of Knoevenagel condensation of benzoisothiazole-2,2-dioxide with aldehydes were studied.     

Syntheses of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid and cyclopropa[c]quinoline-7b-carboxylic acid and their derivatives

The synthesis of spiro[cyclopropane-1,3′-oxindole]-2-carboxylic acid, including novel 3-(2- and 3-pyridyl)-substituted analogues and the novel cyclopropa[c]quinoline-7b-carboxylic acid and their ester and amide derivatives is described. These syntheses involve diastereoselective cyclopropanation reactions of methyl 2-(2-nitrophenyl)acrylate and (3E)-(pyridin-2-ylmethylene)- and (3E)-(pyridin-3-ylmethylene)-1,3-dihydro-2H-indol-2-one with ethyl (dimethyl sulfuranylidene) acetate (EDSA). The synthesis of methyl cyclopropa[c]quinoline-7b-carboxylate involves a regioselective reductive cyclization of a nitro-diester precursor. The relative stereochemistry of key compounds has been determined by single-crystal X-ray structural analysis.     

The model of 1,3-dipolar cycloaddition reaction of 4,5-dihydro-1H-imidazole 3-oxide derivatives with alkynes

The influence of solvents and different structural factors on the rate of 1,3-dipolar cycloaddition reaction of the 4,5-dihydro-1H-imidazole 3-oxide derivatives with alkynes have been studied. Nitrones and alkynes have been ranged by their relative activity in this reaction. Using the DFT calculation with the triple zets basis set, the energy profile of the reaction has been plotted, and the structures and energy characteristics of the transition states have been determined. The mechanism of this reaction has been shown to be concerted and asynchronous. The validity of the used computational approach for the detailed investigation of 1,3-dipolar cycloaddition of nitrones has been demonstrated.     

Highly regio- and stereoselective synthesis of tricyclic frameworks using Baylis-Hillman derivatives

A simple and convenient synthetic route for the synthesis of tricyclic chromeno[4,3-b]pyrrolidine frameworks using Baylis-Hillman bromides involving in situ formation of an imine, decarboxylation and a [3+2] cycloaddition sequence is described.     

Synthesis of complex dispirocyclopentanebisoxindoles via cycloaddition reactions of 4-dimethylamino-1-alkoxycarbonylmethylpyridinium bromides with 2-oxoindolin-3-ylidene derivatives

The cycloaddition reactions of 4-dimethylamino-1-alkoxycarbonylmethylpyridinium bromides with various 2-oxoindolin-3-ylidene derivatives in ethanol in the presence of triethylamine afforded the unprecedented dispirocyclopentanebisoxindole derivatives in good yields and in high diastereoselectivity. Under similar reaction conditions, the reactions of 1-alkoxycarbonylmethylpyridinium bromides with 3-phenacylideneoxindoles only resulted in 4-oxo-3-(2-oxoindolin-3-ylidene)-4-arylbutanoates. The stereochemistry of the complex spirooxindoles was established by ¹H NMR data and single crystal structures.     

Enantioselective synthesis of homocarbocyclic-2′-oxo-3′-azanucleosides

The enantioselective synthesis of homocarbocyclic-2′oxo-3′-azanucleosides has been performed by cycloaddition reaction of the N-glycosyl nitrones with allyl nucleobases. The use of nitrones originated from two different carbohydrates, the N-ribosyl nitrone and the N-mannosyl nitrone, proceeded in a stereocontrolled and predictable manner with a good degree of enantioselectivity, so allowing an easy entry to both enantiomers.     

Chemo-, regio- and stereoselective 1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones over 3,5-bis(arylidene)-1-methylpiperidin-4-ones: synthesis of highly substituted novel spiro-isoxazolidines

1,3-Dipolar cycloaddition of C-aryl-N-phenylnitrones to 3,5-bis-(arylidene)-1-methylpiperidin-4-ones affords novel mono- and bis-spiroisoxazolidines in moderate yields. In general, this reaction predominantly yields mono-spiroisoxazolidine, wherein the oxygen of the nitrone is linked to the β-carbon of the benzylidene moiety, while 3,5-bis-(2-chloro- and 3-nitro-benzylidene)-1-methylpiperidin-4-ones afford predominantly bis-spiroisoxazolidines. The cycloaddition of mono-spiroisoxazolidines occurs with facial diastereoselectivity to furnish bis-spiroisoxazolidines. The nitrogen in the heterocyclic ring of the 3,5-bis-(arylidene)-1-methylpiperidin-4-ones facilitates the cycloaddition through transannular (NCO) and/or homoconjugative (NCC) interactions.     

An efficient and stereoselective cycloaddition of C-aryl and C-amido nitrones to dimethyl 2-benzylidenecyclopropane-1,1-dicarboxylate

1,3-Dipolar cycloadditions of dimethyl 2-benzylidenecyclopropane-1,1-dicarboxylate and a number of C-aryl or C-amido nitrones proceed with high efficiency and selectivity with the formation of only one isomeric spiro[cyclopropane-1,4-isoxazolidine] cycloadduct.     

Synthesis of 4′-thionucleosides by 1,3-dipolar cycloadditions of the simplest thiocarbonyl ylide with alkenes bearing electron-withdrawing groups

Reactions of the simplest thiocarbonyl ylide with a variety of appropriate alkenes bearing electron-withdrawing substituents afforded the corresponding tetrahydrothiophenes, which could be easily elaborated into hydroxy and hydroxymethyl derivatives and then coupled with nucleobases to produce different 4′-thionucleosides. Particularly, α- and β-anomers of 1-[3,4-bis(hydroxymethyl)tetrahydro-2-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with dimethyl fumarate and maleate, while 1-[4-(hydroxymethyl)tetrahydro-2-thienyl]- and 1-[4-(hydroxymethyl)tetrahydro-3-thienyl]-thymine, -cytosine, -uracil and -fluorouracil were prepared with a chiral α,β-unsaturated amide. These processes, simple in the experimental conditions and large availability of the starting materials, affording moderate to good yields of 4′-thionucleosides, represent an optimum alternative to those, already known, based on sugars, which often have the drawbacks of a higher number of steps and lower yields.     

Synthesis of Functionalized Pyrazoles via 1,3‐Dipolar Cycloaddition of α‐Diazo‐β‐ketophosphonates,Sufones and Esters with Electron‐Deficient Alkenes

1,3‐Dipolar cycloaddition of diazo compounds with olefinic substrates is a promising atom‐economic strategy for the construction of functionalized pyrazoles. Over the last few years, our group has been engaged in the synthesis of phosphonyl/sulfonylpyrazoles and pyrazole esters by employing Bestmann‐Ohira Reagent (BOR) and its sulfur and ester analogs as 1,3‐dipole precursors with various dipolarophiles. This account describes the novel synthetic methods developed in our laboratory, in the perspective of closely related work by others, for the synthesis of phosphonyl/sulfonylpyrazoles, pyrazole esters and the total synthesis of Withasomnine, a natural product, by using 1,3‐dipolar cycloaddition as the key step.     

Efficient One-Pot,Four-Component Synthesis of 1,2,3-Triazole-Linked Tetrahydrobenzo[b]pyrans

A one-pot procedure has been developed for the synthesis of (1,2,3-triazolyl) methoxyphenyl tetrahydro-5-oxo-4H-chromene derivatives by concurrent reaction of aryloxy propargylated aldehydes, various azides, active methylene compounds, and 1,3-cyclohexanediones using catalytic amounts of Cu(OAc)₂ / sodium ascorbate and diammonium hydrogen phosphate in aqueous ethanol media. Excellent conversion of starting materials was achieved to the desired (1,2,3-triazolyl) methoxyphenyl tetrahydro-5-oxo-4H-chromene products.     

A sort synthesis of polyhydroxylated pyrrolizidines via sequential 1,3-dipolar cycloaddition and reductive amination

Polyhydroxylated pyrrolizidines bearing a methyl group at C-5 have been synthesized by 1,3-dipolar cycloaddition of five membered cyclic nitrones with methyl vinyl ketone followed by a N–O reductive cleavage and in situ intramolecular reductive amination. The stereochemistry of the obtained compounds is examined in relation to the reactions mechanism.     

Synthesis of novel,azasugar-modified anthraquinone derivatives and their cytotoxicity

A series of novel, azasugar-modified 2-monosubstituted, 2,6- and 2,7-bissubstituted anthraquinone derivatives have been synthesized by the nucleophilic substitution of N-alkylamino azasugar with mono-, bis（2-chloroacetamido）anthraquinones. Their cytotoxic activities against HeLa and MCF-7 ceils were preliminarily evaluated and compound 9a with mono-azasugar pendant at 2-position showed similar activity to the control drug （Cisplatin）.     

Synthesis and thermal transformations of spiro-fused N-phthalimidoaziridines

Oxidation of N-aminophthalimide in the presence of 2-arylideneinden-1,3-diones with electron-withdrawing substituents gives the corresponding 3-aryl-1-phthalimidospiro[aziridine-2,2′-indene]-1′,3′-diones in good yields. Heating these aziridines with standard dipolarophiles (N-phenylmaleimide, dimethyl acetylenedicarboxylate, maleate, and fumarate) leads, in most cases, to spiro[inden-2,2′-pyrrole] derivatives as products of 1,3-dipolar cycloaddition of the intermediate azomethine ylides with up to 70–95% yields in the case of N-phenylmaleimide. As is typical for 2-acylaziridines, the competing rearrangement into 2-aryl-4H-indeno[2,1-d][1,3]oxazol-4-ones prevails for less active dipolarophiles. Increasing the electron-releasing properties of the 3-aryl ring allows the observation of the push–pull effect of electron-donating and electron-withdrawing substituents on the ease of the three-membered ring-opening.     

Synthesis of novel pyrano[2,3-b]quinolines from simple acetanilides via intramolecular 1,3-dipolar cycloaddition

Some novel isoxazole and pyrazole fused pyrano[2,3-b]quinolines were synthesized from simple acetanilides via intramolecular 1,3-dipolar cycloaddition reactions involving nitrones, nitrile oxides and nitrile imines as 1,3-dipoles, in a regioselective manner.     

A regioselective 1,3-dipolar cycloaddition for the synthesis of novel spiro-chromene thiadiazole derivatives

A variety of 4′-(4-R-phenyl)-4-(methylthio)-2′-phenyl-2′H-spiro[chromene-2,5′-[1,2,3]thiadiazole] 5a–d and 5′-(4-R-phenyl)-4-(methylthio)-3′-phenyl-3′H-spiro[chromene-2,2′-[1,3,4]thiadiazole] 6a–d were synthesized regioselectively through the reaction of 4-(methylthio)-2H-chromene-2-thione 2 with diarylnitrilimines under refluxing dry chloroform. Whilst the reaction of 4-(allylthio)-2H-chromene-2-thione 3 with diarylnitrilimines under similar reaction conditions afforded the corresponding 4-(allylthio)-5′-(4-R-phenyl)-3′-phenyl-3′H-spiro[chromene-2,2′-[1,3,4]thiadiazole] 7a–d and 5-(4-R-phenyl)-2′-methyl-3-phenyl-2′,3′-dihydro-3H-spiro[[1,3,4]thiadiazole-2,4′-thieno[3,2-c]chromene] 9a–d as two unisolable diastereoisomeric forms. The structures of the obtained spiro cycloadduct thiadiazoles have been assigned by means of spectroscopic measurements.     

An expedient approach for the regio- and stereoselective synthesis of novel spiroindolizidines via [3+2] cycloaddition

A new series of spiroindolizidines was synthesized by one-pot, three-component condensation of azomethine ylides, generated from 1,2,3,4-tetrahydroisoquinoline with ninhydrin or isatin derivatives by a 1,5-prototropic shift route, with various derivatives of trans-β-nitrostyrene in a regio- and stereoselective manner. X-ray crystal structure analysis and NMR spectroscopic data confirmed the structure outcome of the cycloaddition reaction.