Radical 3-exo-tet cyclization of 1,3-dihalopropanes with SmI2 to form cyclopropanes

The preparation of 1,1-disubstituted and monosubstituted cyclopropanes from corresponding 2,2-disubstituted and 2-monosubstituted 1,3-dihalopropanes, respectively, with SmI₂ in THF was efficiently carried out. The reaction mechanism was proposed to proceed in a radical 3-exo-tet manner based on Baldwin's rule.     

Facile preparation of cyclopropanes from 2-iodoethyl-substituted olefins and 1,3-dihalopropanes with zinc powder

Two efficient, simple, cheap, and environmentally benign preparations of cyclopropanes were achieved. One is the formation via 3-exo-trig manner from various electron-deficient 2-iodoethyl-substituted olefins with zinc powder in a mixture of t-butyl alcohol and water, and the other is the formation via 3-exo-tet manner from various 1,3-dihalopropanes with zinc powder in ethanol.     

Manganese(III)-mediated facile synthesis of 3,4-dihydro-2(1H)-quinolinones: selectivity of the 6-endo and 5-exo cyclization

The 4,4-bis(ethoxycarbonyl)-3,4-dihydro-2(1H)-quinolinones 2 were easily synthesized by the oxidative 6-endo-trig cyclization of 2-[2-(N-arylamino)-2-oxoethyl]malonates 1 with manganese(III) acetate in good to excellent yields. The same reaction of N-(2,4-dimethoxyphenyl)-substituted malonate 1t exclusively produced the 5-exo-cyclized 4,4-bis(ethoxycarbonyl)-1-azaspiro[4,5]deca-6,9-diene-2,8-dione 5t instead of the corresponding dihydroquinolinone. The regioselectivity during the cyclization could be explained by the difference in the activation energy of the transition state of the 6-endo/5-exo cyclization.     

A novel approach to 3-acylated indolizine structures via iodine-mediated hydrative cyclization

We have discovered a new route to 3-acylated indolizine structures via iodine-mediated hydrative cyclization. Reaction mechanism is proposed for this novel transformation, which involves a 5-exo-dig iodocyclization, deprotonation, incorporation of another iodo group, deprotonation, and subsequent replacement of the diiodo group by H₂O. Various 3-acylated indolizine derivatives were obtained using this mild procedure in good yields.     

Ionic liquids/H2O systems for the reaction of epoxides with NaN3: a new protocol for the synthesis of 2-azidoalcohols

Oxiranes undergo ring opening rapidly with sodium azide in a [bmim]BF₄/H₂O or [bmim]PF₆/H₂O (2:1) solvent system, under mild and neutral reaction conditions to afford the corresponding 2-azidoalcohols in high to quantitative yields. The remarkable features of this procedure are improved yields, enhanced reaction rates, high regioselectivity and ease of recyclability of ionic liquids (ILs). The recovered ionic liquid can be reused for four to five times but with gradual decrease in activity.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

One-pot synthesis of pyrrolidino- and piperidinoquinolinones by three-component aza-Diels-Alder reactions of in situ generated N-arylimines and cyclic enamides

An efficient synthesis of hexahydropyrrolo[3,2-c]quinolin-2-ones and hexahydropyridino[3,2-c]quinolin-2-ones has been developed in moderate to high yields by one-pot two-step aza-Diels-Alder reactions of N-arylimines, formed in situ from anilines and benzaldehydes, with cyclic enamides, formed in situ from 5-hydroxypyrrolidin-2-ones and 6-hydroxypiperidin-2-ones by BF₃·OEt₂-promoted dehydration in dichloromethane at room temperature. The hexahydropyrrolo[3,2-c]quinolin-2-ones were formed as a single exo-stereoisomer in most cases and hexahydropyridino[3,2-c]quinolin-2-ones were formed as a mixture of exo- and endo-isomers favoring the endo-diastereomer.     

Synthesis of nitrogen-containing heterocycles using exo- and endo-selective radical cyclizations onto enamides

The effect of positional change of the carbonyl group of enamides on Bu₃SnH-mediated alkyl radical cyclization leading to five-, six-, seven-, and eight-membered nitrogen-containing heterocycles was examined. A 5-exo cyclization is generally preferred over a 6-endo ring closure in systems having an alkyl radical center on the enamide-acyl side chain, whereas enamides having an alkyl radical center opposite to the acyl side chain predominantly gave 6-endo cyclization products. These results suggest that the exo or endo selectivity of radical cyclization onto the alkenic bond of enamides can be controlled by positional change of the carbonyl group. For an understanding of these selectivities, heat of formation for each transition state was calculated. 6-endo-Selective radical cyclization was applied to the radical cascade, enabling a concise synthesis of a cylindricine skeleton. A 7- or 8-endo alkyl radical cyclization, however, predominated over a corresponding 6- or 7-exo ring closure regardless of the positional change of the carbonyl group of enamides.     

Temperature dependent selective synthesis of linear 2-bromo and 2-alkoxyfuro[2,3-b]quinolines: reaction of 3-(2,2-dibromovinyl-)quinolin-2(1H)-ones with alcoholic KOH

Base promoted and temperature dependent reactions of 3-(2,2-dibromovinyl)quinolin-2(1H)-ones have been described. At 50 °C, the cyclization reactions afforded 2-bromofuro[2,3-b]quinolines in good yields. However, at elevated temperature (80 °C) the domino reaction proceeded affording 2-alkoxyfuro[2,3-b]quinolines via cyclization and nucleophilic substitution reactions.     

Synthesis of aza-aromatic hydroxylamine-O-sulfonates and their application to tandem nucleophilic addition-electrophilic 5-endo-trig cyclization

Hydroxylamine-O-sulfonic acid (HOSA) was used as an efficient nucleophilic amination reagent for 2-chloropyrimidines, 2-chloroquinolines, and 1-chloroisoquinoline. The newly obtained heteroaromatic hydroxylamine-O-sulfonates subjected to the reaction with acyl isothiocyanates underwent tandem nucleophilic addition-electrophilic 5-endo-trig cyclization. The mechanism of the cyclization was investigated with use of the long-range corrected hybrid density functional ωB97X-D/6-31+G^∗ and SM8 (DMF) solvation model. The structures of the heteroaromatic hydroxylamine-O-sulfonates and N-(5-methoxy-2H-[1,2,4]thiadiazolo[2,3-a]pyrimidin-2-ylidene)benzamide were confirmed by single crystal X-ray analysis. N-(2H-[1,2,4]thiadiazolo[3,2-a]isoquinolin-2-ylidene)benzamide exhibited a pronounced in vitro cytostatic activity against human tumor cell lines SISO, LCLC, A-427, DAN-G, and RT-4 (IC₅₀ in the range 1.47-2.97 μM).     

Ionic liquid-catalyzed and microwave-assisted syntheses of pyrrolizine- and indolizinedione derivatives

3H-Pyrrolo[2,1-a]isoindole-2,5-diones and isoindolo[2,1-a]quinoline-5,11-diones were synthesized by intramolecular cyclization of N-[2-oxo-3-(triphenyl-??⁵-phosphanylidene)propyl]- and N-[2-(triphenyl-??⁵-phosphanylidene)acetyl]phthalimides, respectively, in the presence of ionic liquid ([bmim][BF₄], 10 mol %) as catalyst or under microwave irradiation.     

Ultrasound-promoted synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitriles using ZrOCl2·8H2O/NaNH2 as the catalyst in the ionic liquid [bmim]BF4 at room temperature

We herein present an efficient and environmentally benign protocol for the synthesis of 2-amino-6-(arylthio)-4-arylpyridine-3,5-dicarbonitrile derivatives via the three-component condensation of a variety of aldehydes, arylthiols, and malononitrile catalyzed by ZrOCl₂·8H₂O/NaNH₂ (20 mol %) in the ionic liquid [bmim]BF₄ under ultrasound irradiation at room temperature.     

Selective reduction of aromatic azides in solution/solid-phase and resin cleavage by employing BF3·OEt2/EtSH. Preparation of DC-81

An efficient method for the reduction of aromatic azides in both solution and solid-phase has been developed by employing BF₃·OEt₂/EtSH. This report also describes resin cleavage employing this reagent system. Further, this protocol has been utilized for the solution as well as the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines, including the naturally occurring antibiotic DC-81 and fused [2,1-b]quinazolinones.     

Skeletal Wagner-Meerwein rearrangement of perhydro-3a,6;4,5-diepoxyisoindoles

An investigation of a skeletal Wagner-Meerwein rearrangement of variously substituted or quinoline-annulated 3a,6;4,5-diepoxyisoindol-1-ones is reported. Optimum reaction conditions (Ac₂O, BF₃·OEt₂, rt) were discovered for the formation of the target 4,6-epoxycyclopenta[c]pyridines in 40-80% yields. It was shown that the direction of the sigmatropic rearrangement of 3a,6;4,5-diepoxyisoindol-1-ones depended dramatically on the carboxyl group position (exo-/endo-) in the oxabicyclo[2.2.1]heptane moiety. The spatial structure of previously unknown 7,9-epoxycyclopenta[4,5]pyrido[1,2-a]quinolines derived from Wagner-Meerwein rearrangement of 2,11b-epoxyoxireno[6,7]isoindolo[2,1-a]quinolines was established based on the X-ray analysis data. The skeletal rearrangement proceeded regio- and stereospecifically in all the cases examined due to the absence of the epimerization of the carbon atoms adjacent to the carbocation centres.     

Recyclable 2nd generation ionic liquids as green solvents for the oxidation of alcohols with hypervalent iodine reagents

Alcohols undergo smooth oxidation with iodoxybenzoic acid (IBX) or with Dess-Martin-Periodinane (DMP) in hydrophilic [bmim]BF₄ and hydrophobic [bmim]PF₆ ionic liquids at room temperature under mild conditions to afford the corresponding carbonyl compounds in excellent yields with high selectivity. IBX and DMP promoted oxidations are faster in ionic liquids when compared to conventional solvents such as DMSO, DMF, EtOAc and H₂O. The recovery of the byproduct iodosobenzoic acid (IBA) is especially simple in ionic liquids. The recovered ionic liquids can be recycled in subsequent reactions with consistent activity.     

Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,aldehydes and alkynecarboxylic acids

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomponent reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K₂CO₃, the pyrimido [1,2-a]benzimidazole or imidazo [2,1-b]benzothiazole scaffold could be rapidly constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary mechanistic study suggested that the formation of 2,3- disubstituted pyrimido [1,2-a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A [3] coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.     

Optical and Bioelectrochemical Characterization of Water‐Miscible Ionic Liquids Based Composites of Multiwalled Carbon Nanotubes

Acidic treated multiwalled carbon nanotubes (AMWNTs) were ground with water‐miscible room temperature ionic liquids, 1‐butyl‐3‐methylimidazolium tetrafluoroborate ([bmim]BF₄), and resulted in AMWNTs‐[bmim]BF₄ composite. Its electrical‐ionic conductivity and optical properties were compared with the other two types of carbon materials‐[bmim]BF₄ composites: pyrolytic graphite powder (PGP), pristine multiwalled carbon nanotubes (PMWNTs), through the ac impedance technology and Raman spectroscopy. The impedance data show that AMWNTs‐[bmim]BF₄ composite exhibits the highest conductivity. Raman spectra study exhibits that the [bmim]BF₄ can form gel with PMWNTs and AMWNTs but only form a viscous liquid with PGP. AMWNTs‐[bmim]BF₄ gel modified GC electrode was applied in direct electrochemistry of heme proteins (Hb and HRP) and it catalysis to the reduction of H₂O₂ was investigated.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

Polymerization of phenylacetylene catalysed by RhTp(cod) and RhBp(cod) in ionic liquids: effect of alcohols and of tetraammonium halides

RhTp(cod) ( 1 ) and RhBp(cod) ( 2 ), almost inactive in CH₂Cl₂, became good catalysts of phenylacetylene polymerization in ionic liquids ([bmim]Cl, [bmim]BF₄: bmim = 1‐butyl‐3‐methylimidazolium, [mokt]BF₄: mokt = 1‐methyl‐3‐oktylimidazolium, [bumepy]BF₄: 1‐butyl‐4‐methylpyridinium) and in CH₂Cl₂ in the presence of tetraammonium halides ([R₄N]X, R = Bu, Et; X = Cl, Br). The highest yields of polyphenylacetylene with catalyst 1 were obtained in [bmim]Cl at 65°C (64% after 2 h) and in [mokt]BF₄ at 20°C (56% after 24 h). In alcohols (CH₃OH, (CH₃)₂CHOH, (CH₃)₃COH) as solvents, up to 100% of the polymer was produced. When a mixture of an ionic liquid and CH₃OH was used as the reaction medium, the polymer yield was similar to the yield achieved in an ionic liquid only, but the molecular weight increased remarkably. Tetraammonium salts, [R₄N]X, are co‐catalysts for 1 , and the yield of the polymer increased in the order [Et₄N]Br < [Bu₄N]Br < [Et₄N]Cl < [Bu₄N]Cl. Polymers with molecular weights from 6900 to 38 800 Da were obtained with catalyst 2 in [R₄N]Br or [R₄N]Cl, whereas in ionic liquids ([bmim]Cl, [bmim]BF₄) the corresponding molecular weights were higher, from 51 300 to 60 300 Da. Copyright © 2004 John Wiley & Sons, Ltd.     

Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols

An efficient, regioselective Cu(OTf)₂-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been developed. A wide range of substrates possessing terminal, internal, and heteroaromatic alkynes can be efficiently transformed into the targeted phthalans. Substrates with primary, secondary, and tertiary benzyl alcohols also proceed well to produce the corresponding phthalans in good yields. Irrespective of the nature of the substrates, the cyclization follows highly selective 5-exo-dig regiochemistry when regioselectivity is an issue.