Investigation of regioselectivity in the synthesis of spiro [pyrrolidine-2,3′-oxindoles] by use of the Huisgen reaction

The Huisgen reaction has been used to synthesize five-membered heterocyclic compounds in high yield and with high regio and stereoselectivity. In the synthesis of spiro [pyrrolidine-2,3′-oxindole] derivatives from isatin, α-amino acids, and (E)-β-phenyl nitroolefins, two regioisomers were obtained in each reaction. The regioselectivity of the major product was found to be different from that in reported work, and was investigated at the B3LYP/6-311G* level of theory. On the basis of this new finding, several conditions, for example molar ratio, solvent, and temperature, which affect the regioselectivity of this reaction were investigated; the results obtained are discussed. It was found that the regioselectivity of this reaction was affected by solvent and temperature, irrespective of the ratio of the reactants. Low temperature and high solvent polarity leads to high regioselectivity, and protic solvents result in higher yield and regioselectivity. These results are of benefit for regioselective synthesis of some compounds.     

Catalytic activity of salenCo(III)OAc complex in the reaction of addition of carboxylic acids to terminal epoxides

The catalytic activity and regioselectivity were studied of the salenCo(III)OAc complex in the reaction of addition of aliphatic carboxylic acids to a series of terminal epoxides (epichlorohydrin, 1,2-epoxybutane, propylene oxide, tert-butyl glycidyl ether and 2,3-epoxypropyl phenyl ether). The reduction in the activity in the order: acetic > acrylic > methacrylic acid was found. The regioselectivity of the addition was independent on carboxylic acid nature and depended on the nature of the epoxide. The best regioselectivity for the addition to epichlorohydrin was observed. The catalytic activity and regioselectivity of salenCo(III)OAc were compared with those for chromium(III) acetate catalyst.     

Synthesis and regioselective N- and O-alkylation of 3-alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones and 2-phenyl-9-propyl-9H-purin-6(1H)-one with evaluation of antiviral and antitumor activities

3-Alkyl-5-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones were prepared by nitrosative cyclization of the appropriate 5,6-diamino-2-phenylpyrimidin-4(3H)-ones with nitrous acid and were subjected to regioselective alkylation with several alkylating agents in aprotic solvent at different temperature. Simultaneous 6-N- and 7-O-alkylation were observed and the regioselectivity varied remarkably with size and shape of the alkylating agents as well as with the reaction temperature. Similarly, N- and O-alkylation as well as selectivity was also observed in the case of 2-phenyl-9-propyl-9H-purin-6(1H)-one. Some of the synthesized compounds showed moderate antiviral and antitumor activities.     

An experimental and theoretical investigation of the regio- and stereoselectivity of the polar [3+2] cycloaddition of azomethine ylides to nitrostyrenes

The regio- and stereochemical polar [3+2] cycloaddition of the azomethine ylides, which were generated in situ by the reaction of isatin derivatives and proline, with trans-β-nitrostyrene and (E)-1-phenyl-2-nitropropene were studied using experimental and theoretical methods. In comparison with trans-β-nitrostyrene, when the reactions were performed with (E)-1-phenyl-2-nitropropene, a remarkable inversion in the regioselectively was observed. The regioselectivity of the reactions was investigated using global and local reactivity indices and frontier molecular orbital (FMO) analysis at the B3LYP/6-31G(d,p) level of theory. The effects of the electronic and steric factors on the regioselectivity of the reactions were discussed. The inspection of geometries and energetics of transition states revealed the importance of weak interactions in regioselectivity of the cycloaddition reactions.     

(Salen)Ti(IV) complex catalyzed asymmetric ring-opening of epoxides using dithiophosphorus acid as the nucleophile

A series of chiral bis-Schiff bases were synthesized starting from (1R,2R)-(+)-diaminocyclohexane, (+)-cis-1,2,2-trimethyl-1,3-diaminocyclopentane, (R)-2,2^′-diamino-1,1^′-binaphthalene, and (1S,2S)-diphenyl-1,2-ethanediamine. The enantioselective ring-opening of meso epoxides with dithiophosphorus acids catalyzed by a (salen)Ti(IV) complex formed in situ upon the treatment of Ti(OPr-i)₄ and the aforementioned chiral Schiff base was realized. The resulting products were obtained with low to good enantioselectivities (up to 73% ee). The (salen)Ti(IV) complex containing the backbone of 1,2-diaminocyclohexane exhibited the best enantioselectivity. The substituents in dithiophosphorus acids and those on the salen aromatic ring have a significant influence on the reaction. Moderate enantioselectivity were obtained for the (salen)Ti(IV) complex catalyzed ring-opening of racemic monosubstituted epoxides. High regioselectivity was observed for the alkyl substituted epoxides, whereas poor regioselectivity was obtained for the aryl substituted ones.     

Assessment of the regioselectivity in the condensation reaction of unsymmetrical o-phthaldialdehydes with alanine

One approach for the synthesis of isoindolinones, a privileged bioactive heterocyclic core structure, involves a condensation reaction of o-phthaldialdehydes with a suitable nitrogen-containing nucleophile. This fascinating reaction is revisited here in the context of the use of o-phthaldialdehydes that contain additional substituents in the aromatic ring leading to a detailed analysis of the regioselectivity of the reaction. Eleven monosubstituted o-phthaldialdehydes were synthesised and reacted with alanine. The regioselectivity observed across the eleven substrates led to the design of a disubstituted substrate that reacted with very high control. A gram-scale reaction followed by esterification gave one major regioisomer in high yield. In addition, the regioselectivity observed on reaction of two novel monodeuterated substrates led to an increased mechanistic understanding.     

Total synthesis of (±)-lantalucratins A and B by CAN-mediated oxidative cyclization

The first total synthesis of (±)-lantalucratins A and B is described. Introduction of an alkyl side chain at the 6-position was proceeded by directed ortho-lithiation and subsequent alkylation reaction to afford 6-alkyl-5,7,8-trimethoxy-1-naphthol as a synthetically important intermediate for (±)-lantalucratins A and B in excellent yield with complete regioselectivity. The 1,2-naphthoquinone fused five-membered cyclic ether framework was constructed directly from 3-hydroxyalkyl-naphthalenes by oxidative intramolecular cyclization reaction with diammonium cerium(IV) nitrate. (±)-Lantalucratins A and B were obtained in 69% and 45% overall yields, respectively.     

Asymmetric organocatalytic N-nitroso-aldol reaction of oxindoles

An organocatalytic enantioselective N-nitroso-aldol reaction of 2-oxindoles promoted by a cinchona alkaloid catalyst has been developed. The reaction shows exclusively N-selectivity, affording corresponding products with good to excellent yields (up to 100%) and moderate enantioselectivity. The regioselectivity of nitroso-aldol reaction being controlled by different cinchona catalysts was also observed.     

有机磷化合物的研究 XXV: 溶剂性质对烯丙在膦酸酯碳阴离子和芳醛反应区域选择性的影响

本文研究烯丙基膦酸二乙酯碳阴离子和苯甲醛, 对甲基苯甲醛的反应, 考察了溶剂对反应区域选择性的影响.     

Study of regioselectivity of reactions between 3(5)-aminopyrazoles and 2-acetylcycloalkanones

Regioselectivity was examined of reactions between nine 3(5)-aminopyrazoles and 2-acetylcyclopentanone and 2-acetylcyclohexanone under various conditions. A series of cyclopenta[e]pyrazolo-[1,5-a]pyrimidines was obtained. The highest regioselectivity of the reaction was observed in alcohol at 20°C in the presence of a catalytic quantity of trifl uoroacetic acid. The regiostructure of compounds was established by ¹H and ¹³C NMR spectroscopy.     

Asymmetric hydroesterification of styrene using catalysts with planar-chiral ferrocene oxazoline ligands

Chiral P,N-ferrocene ligands, 1-diphenylphosphino-1′-[(S)-4-isopropyl-2.5-oxazolinyl]-2′-(S_p)-(trimethylsilyl)-ferrocene and its diastereomer, and 1-diphenylphosphino-1′-[(S)-4-isopropyl-2.5-oxazolinyl]-2′(S_p)-(diphenylphosphino)-ferrocene and its diastereomer were used in the palladium-catalyzed asymmetric hydroesterification of styrene. The role of these ligands, which contain central, axial, and planar chirality, on the stereochemical outcome was investigated. A significant effect of using CuCl₂ as a co-catalyst on the reaction was observed. Excellent regioselectivity (b/n >99:1) with low ee (28%) was obtained in the presence of CuCl₂; moderate enantioselectivity (64% ee) but low regioselectivity (b/n, 40/60) was obtained in the absence of CuCl₂.     

Regiocontrol in the palladium-catalyzed hydrophosphinylation of terminal alkynes

The regioselectivity of the palladium-catalyzed hydrophosphinylation of terminal alkynes was investigated. Complementary conditions to achieve the predominant formation of either the linear or the branched alkenyl-H-phosphinate products were identified. With Pd/xantphos in acetonitrile, the linear isomer is generally obtained with good to excellent selectivity, and E-stereospecificity. On the other hand, by using Pd/dppf in the non-polar solvent toluene, good selectivity for the branched alkenyl-H-phosphinate is typically observed. The role of various reaction parameters is studied.     

A DFT study of the mechanism of palladium-catalyzed alkoxycarbonylation and aminocarbonylation of alkynes: Hydride versus amine pathways

A DFT study on the palladium-bisphosphine catalyzed alkoxycarbonylation and aminocarbonylation of alkyne (propyne) is reported. The theoretical study explores the feasibility and the regioselectivity control of two independent mechanisms: the first is based on the active intermediate [Pd(II)(P₂)(H)]⁺ (where P₂ = PH₂CH₂CH₂CH₂CH₂PH₂) for the alkoxycarbonylation reaction, and the second is based on the active species [Pd(II)(P₂)(NR₂)]⁺ for the aminocarbonylation reaction. The study explains the role of solvent in increasing the yield and in controlling the selectivity of reaction to produce selectively the trans isomer in the alkoxycarbonylation reaction (hydride cycle) and the gem isomer in the aminocarbonylation reaction (amine cycle). In hydride cycle, the regioselectivity is mainly determined by the stability of the complex [Pd(II)(P₂)(COC₃H₅)(CH₃CN)]⁺; however, for the amine cycle, the regioselectivity is determined by the stability of the complex [Pd(II)(P₂)(C₃H₅CON(CH₃)₂)]⁺. The calculations reveal that ligand simplification is not valid in addressing the regioselectivity behavior of alkoxycarbonylation and aminocarbonylation reactions. The kinetic data for the formation of the two key complexes show no difference between the gem and trans isomers which predict the regioselectivity to be a thermodynamically controlled process.     

Nanoflow microreactor for dramatic increase not only in reactivity but also in selectivity: Baeyer–Villiger oxidation by aqueous hydrogen peroxide using lowest concentration of a fluorous lanthanide catalyst

Not only the reaction rate but also the regioselectivity in the scandium bis(perfluorooctanesulfonyl)amide-catalyzed Baeyer–Villiger reaction is remarkably increased by the development of the fluorous nanoflow microreactor system continuously controlled by the nanofeeder DiNaS (Direct Nanoflow System) even in the lowest concentration of the catalyst (≪0.1 mol%). The Baeyer–Villiger reaction completes within few seconds as a contact time in the nanoflow microreactor to give the lactone products with high regioselectivity without hydrolysis.     

Highly enantioselective synthesis and potential biological activity of chiral novel nucleoside analogues containing adenine and naturally phenol derivatives

This paper described an efficient synthetic strategy for chiral acyclic nucleoside analogues containing both the phenoxy components of some bioactive natural compounds and a heterocyclic base. The phenoxy components with adenine moiety were incorporated into the chiral acyclic nucleoside analogues through two key synthetic tactics. Chiron 5-(R)-menthyloxy-2(5H)-furanone 5 was obtained in good yield from the cheap starting material furfural via a valuable synthetic route. The asymmetric Michael addition of 5 with adenine and the subsequent reduction reaction afforded the key chiral intermediate, 2-(R)-(9′-adeninyl)-1,4-butanediol 8. The absolute configuration of 8 was established by X-ray crystallography. The intermolecular dehydration reaction between 2-(9′-adeninyl)-1,4-butanediol 8 and phenoxy components 9 on treatment with diethyl azodicarboxylate and triphenylphosphine was carried out to give the chiral acyclic nucleoside analogues 1a-1e. The regioselectivity of the reaction was established by NMR methods, especially through ¹³C NMR shifts and NOE effect observed in the target molecule 1c, as well as by HMBC/HMQC experiments. The target compounds were tested for inhibition of cytopathogenicity against different cancer cells and exhibited potential anticancer activity.     

Synthesis and aminolysis of N-(bicyclo[2.2.1]hept-5-en-endo-2-ylmethyl)-N-(oxiran-2-ylmethyl)(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide

A new N-(oxiran-2-ylmethyl) (glycidyl) derivative has been obtained by reaction of N-(bicyclo-[2.2.1]hept-5-en-endo-2-ylmethyl)(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonamide with epichlorohydrin. Its epoxidation and aminolysis have been studied, and the regioselectivity of these transformations has been determined by IR and ¹H NMR spectroscopy and mass spectrometry.     

Convenient synthesis of pyrrolo[3,4-g]indazole

The synthesis of a novel class of tetrahydropyrrolo[3,4-g]indazoles is reported, by annelation of the pyrazole ring on the isoindole moiety by means of 5-hydroxymethylene tetrahydroisoindole-4-ones key intermediates, with good regioselectivity. Dihydroderivatives were also obtained by oxidation with DDQ of the corresponding tetrahydropyrrolo[3,4-g]indazoles. The growth inhibitory effect was evaluated at the National Cancer Institute of Bethesda and some derivatives showed modest activity.     

Paternò-Büchi反应的区域选择性

Paternò-Büchi(P-B)反应,即羰基-烯的[2+2]光环化加成反应,利用其特殊的区域及立体选择性可以合成一些结构精巧的取代氧杂环丁烷。随着P-B反应在有机合成中越来越广泛的应用,人们对P-B反应的区域选择性的研究也越来越深入。在P-B反应发现之初,人们一直用“最稳定的双自由基规则”解释其区域选择性,这一规则对有些体系却不适用,近年来有人开始运用“自旋化学”理论来解释区域选择性。本论文结合作者的研究工作,评述了近年来P-B反应的区域选择性的研究进展,重点阐述了反应温度、反应物的取代基对P-B反应区域选择性的影响及其规律。     

The first enantioselective [3+2] cycloaddition of epoxides to arylisocyanates: asymmetric synthesis of chiral oxazolidinone phosphonates

A [3+2] cycloaddition of diethyl 1,2-oxiranephosphonate to aryl isocyanates catalyzed by lanthanide cations is described. The reaction is highly regioselective and 5-substituted 2-oxazolidinone phosphonates are obtained with a regioselectivity greater than 95:5 with respect to the 4-substituted regioisomer, and in up to 84% yield. When 20 mol % of Pybox-Yb³⁺ is used as a catalyst, enantiomerically enriched products are obtained in up to 75% ee, depending on the reaction conditions, and the nature of the isocyanate. Low temperatures benefit asymmetric induction, but have an adverse effect on the regioselectivity for para-substituted aryl isocyanates.     

Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin

A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl₂ and Cl₂CHOCH₃ as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery.