Microwave assisted synthesis of novel imidazo [2,1-b]thiazole derivative attached to quinoxalinones

3-(6-Phenylimidazo[2,1-b]thiazol-5-yl)quinoxalin-2(1H)-ones (qunoxalinone) (6a-q) have been synthesized by the reaction of ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) with suitably substituted o-phenylenediamines (5a-f) under microwave heating. The ethyl 2-oxo-2-(6-phenylimidazo[2,1-b]thiazol-5-yl)acetates (4a-e) were prepared by the reaction of 6-phenylimidazo[2,1-b]thiazoles (3a-e) with ethyl chlorooxoacetate in refluxing 1,4-dioxane whereas the thiazoles (3a-e) were synthesized by the reaction of 2-bromo-1-phenylethanones (2a-e) with thiazol-2-amine in refluxing acetone.     

Synthesis of heterocyclic methylenebisphosphonates by 1,3-dipolar cycloaddition of ethyl diazoacetate to 1,2-benzoxaphosphorin-3-phosphonates

Reaction of salicylaldehydes with tetraethyl ester of methylenebisphosphonic acid, under Knoevenagel reaction conditions, gives the corresponding 1,2-benzoxaphosphorin-3-phosphonates 5 in good yields. The [3+2] regio- and stereoselective cycloaddition of 5a and 5b with ethyl diazoacetate gives two P-4 epimers of the corresponding pyrazoline bisphosphonate tetraethyl esters 9 and 10. Analogously, ethyl diazoacetate reacts with 1 and 2 to give the expected pyrazolines 6-8. The structures of the new compounds are revealed and confirmed by analytical, spectroscopic data and X-ray crystallographic analysis.     

A substituent directed regioselective synthesis of aryl/pyronyl pendant unusual adipate and tetrahydronaphthalene

An efficient regioselective synthesis of pyronyl pendant ethyl methylthiocarbonylalkanoates 5 has been delineated from the base catalyzed reaction of suitably functionalized 2-pyranone 1 and 2-carbethoxycycloalkanones 2, 6 through successive substitution and regioselective ring opening by in situ generated mercaptide ion. To assess the effect of C-4 substituent on regioselectivity, reactions of 6-aryl-3-cyano-4-(piperidin-1-yl)-2-oxopyran 8 with 2-carbethoxycyclohexanone 6a and 2-carbethoxy-2-methylcyclohexanone 6b were carried out separately under analogous reaction conditions but the compounds isolated were identical and characterized as 4-aryl-8-methyl-2-piperidin-1-yl-5,6,7,8-tetrahydronaphthalene-1-carbonitriles 9. Ethyl 2-(5-amino-4′-bromo-4,6-dicyanobiphenyl-3-yl)-5-methylsulfanylcarbonylpentanoate 10 has also been prepared through base catalyzed ring transformation of ethyl 2-[6-(4-bromophenyl)-3-cyano-2-oxo-2H-pyran-4-yl]-5-methylsulfanylcarbonylpentanoate 5d by malononitrile in DMF.     

Facile synthesis of 5-amino- and 7-amino-6-azaoxindole derivatives

An efficient approach for the formation of 5-amino- and 7-amino-6-azaoxindole derivatives was developed. 2-Amino-4-chloro-3-nitropyridine (8), and its 5-nitro-substituted regioisomer (9), respectively, were obtained by reaction with ethyl malonate. The resulting 2-amino-3/5-nitropyridine derivatives substituted in the 4-position with malonic acid diethyl ester (10, 11) were subjected to reductive cyclization yielding 3-ethoxycarbonyl-6-azaoxindole derivatives 4a and 5a. Protection of the amino function was not required. Intermediates 10 and 11 could also be converted to the corresponding 4-acetic acid ethyl esters 12 and 13 by dealkoxycarbonylation with LiCl, and subsequently cyclized under reductive conditions yielding 3-unsubstituted 5-/7-aminooxazindoles.     

Facile generation method for conjugated allenyl esters based on retro-Dieckmann-type ring-opening reactions

α-Alkynyl-α-ethoxycarbonyl cyclopentanones 1a-c and cyclohexanones 2a-c were readily synthesized by the reaction of ethyl 2-oxocyclopentanonecarboxylate 6 and ethyl 2-oxocyclohexanonecarboxylate 7 with alkynyllead triacetates 5a-c obtained from lithium acetylides 4a-c and lead tetraacetate. Treatment of 1a-c and 2a-c with 1 N KOH in THF or with n-Bu₄N⁺OEt⁻ in EtOH and THF gave the corresponding conjugated allenyl esters 8a-c, 9a-c, 10a-c, and 11a-c in good to excellent yields, respectively.     

Synthesis and biological evaluation of new 3-trifluoromethylpyrazolesulfonyl-urea and thiourea derivatives as antidiabetic and antimicrobial agents

Fluorinated pyrazoles, and benzenesulfonylurea and thiourea derivatives as well as their cyclic sulfonylthioureas 2-18 were prepared as hypoglycemic and antibacterial agents. The chemistry involves the condensation of 4-hydrazino benzenesulfonamide hydrochloride with 1-trifluoromethyl diketones 1 to give pyrazole derivatives 2 which upon bromination gave the bromopyrazole 3. Reaction of 2 or 3 with isocyanates and isothiocyanates gave the corresponding ureas 4 and 5 and thioureas 6 and 7. Cyclization of thiourea derivatives with ethyl bromoacetate, ethyl β-bromopropionate, 1,3-dichloroacetone and α-bromoacetophenone yielded the corresponding 4-oxothiazolidines 8 and 9, 4-oxo-5,6-dihydrothiazine 10, 5-oxo-4,5-dihydrothiazines 11 and 12 and thiazolines 13 and 14. Preliminary biological screening of the prepared compounds revealed significant antidiabetic and antibacterial activities.     

New synthesis of 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones

N-(1-Ethoxy-2,2,2-trifluoroethyl)anilines 2a-2f, prepared from trifluoroacetaldehyde ethyl hemiacetal and aniline, readily reacted with diethyl malonate in the presence of sodium hydride, giving substituted products 5a-5f in high yields. Compounds 5a-5f subjected to hydrolysis and decarboxylation under specified conditions yielded the 4,4,4-trifluorobutyric acids 6a-6e or 7. Direct ring-closure of 6a-6e with polyphosphoric acid gave 2-trifluoromethyl-2,3-dihydro-1H-quinolin-4-ones 9a-9e.     

Convenient synthesis of 3-fluoro-4,5-diphenylfuran-2(5H)-one from benzoin ethers : Novel and efficient Z-E isomerisation and cyclisation of 2-fluoroalkenoate precursors, substitution of vinylic fluorine

Mixtures of ethyl (E)- and (Z)-4-alkoxy-2-fluoro-3,4-diphenylbut-2-enoates (6-8) prepared from benzoin ethers and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate were transformed in high yields to the target 3-fluoro-4,5-diphenylfuran-2(5H)-one (14) using bromine in tetrachloromethane at room temperature. The non-cyclisable Z-isomers 6b-8b were gradually isomerised to the cyclisable E-isomers 6a-8a during the process. The reaction of the (E)-butenoates 6a-8a with boron trifluoride led to furanone 14, while in Z-isomers 6b-8b both alkoxy group and vinylic fluorine were substituted with bromine during the reaction. Mechanisms for both complex reactions have been proposed. Furanone 14 was transformed to 2-[tert-butyl(dimethyl)silyloxy]-3-fluoro-4,5-diphenylfuran (18) as a novel building block.     

Total synthesis of (+)-epiepoformin, (+)-epiepoxydon and (+)-bromoxone employing a useful chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclohexanecarboxylate

Enantioselective total synthesis of (+)-epiepoformin 1, (+)-epiepoxydon 2 and (+)-bromoxone 3 using a chiral building block, ethyl (1R,2S)-5,5-ethylenedioxy-2-hydroxycyclo- hexanecarboxylate 6, is described. Since the synthesis afforded intermediates 18, 2 and 25, it accomplished a formal synthesis of (−)-theobroxide 19, (−)-phyllostine 22, (+)-herveynone 27 and (−)-asperpentyn 28. The usefulness of 6 for the synthesis of natural epoxycyclohexene derivatives was demonstrated.     

Efficient synthesis and applications of 2-substituted azulene derivatives: towards highly functionalized carbo- and heterocyclic molecules

An efficient synthesis of 2-substituted azulene derivatives (3-6) was accomplished from ethyl 2-oxo-2H-cyclohepta[b]furan-3-carboxylate 1 and its derivative 2, which in turn were prepared from readily available tropolone. Compounds 1 and 2 were utilized to construct densely functionalized benz[a]azulene and azulene-furan frameworks (16-25, 29-34, 37, 38).     

An efficient synthesis of 4H,5H-pyrano[3,4-c]pyran-4,5-diones from a suitably functionalized 2H-pyran-2-one

An efficient synthesis of ethyl 7-aryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-dione-1-carboxylate 5, and ethyl 6-aryl-3-cyano-2H-pyran-2-one-4-acetate 6 has been delineated by reaction of suitably functionalized 2H-pyran-2-ones 1 with ethyl acetoacetate 2.     

Synthesis and characterization of novel pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoic acids: X-ray structure of 2-pyridylselenoethanoic acid, 2-naphthylselenoethanoic acid and 2-(diphenyl)methylselenoethanoic acid

A number of novel and synthetically important pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoic acids (20-25) have been synthesized using an efficient and operationally simple strategy. Starting substrates, ethyl pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoates (8-13) were easily prepared by treatment of ethyl chloroalkanoates 7(a-c) with nucleophilic selenium reagent RSeNa⁺, generated from the cleavage of dipyridyl/dinaphthyl/bis(diphenylmethyl) diselenide (1-6) with sodium borohydride in ethanol. The ethyl pyridyl/naphthyl/(diphenyl)methylseleno substituted alkanoates (8-13) on basic hydrolysis and subsequent acidification afford pyridyl/naphthyl/(diphenyl) methylseleno substituted alkanoic acids (20-25) in excellent yields. These selenoalkanoates (8-13) and selenoalkanoic acids (20-25) have been characterized by elemental analysis and various spectroscopic techniques viz. NMR (¹H, ¹³C and ⁷⁷Se), IR and mass spectrometry. The molecular structure of 2-pyridylselenoethanoic acid (20a), 2-naphthylselenoethanoic acid (23a) and 2-(diphenyl)methylselenoethanoic acid (24a) has also been established with the help of single crystal X-ray analysis.     

Synthesis of (E)-diethyl 6,6′-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates), a new type of 2,2′-azopyridine dyes

An unexpected, but simple method for the efficient synthesis of new 2.2′-azopyridine dyes, such as (E)-diethyl 6,6′-(diazene-1,2-diyl)bis(5-cyano-2-methyl-4-phenylnicotinates) (2, 4, 6, 8, 10, and 12), based on the treatment of ethyl 6-amino-5-cyano-2-methyl-4-arylnicotinates (1, 3, 5, 7, 9, and 11) with NBS/benzoyl peroxide, is described. The X-ray diffraction analysis and the UV-vis absorption spectra of dye 2 are reported and discussed.     

Preparation of 5-amino-6-oxo-1,6-dihydro[1,2,4]triazine-3-carboxylic acid derivatives and synthesis of compound libraries thereof

Treatment of [1,3,5]triazine-2,4,6-tricarboxylic acid triethyl ester (4) with arylhydrazines provided 5-amino-6-oxo-1,6-dihydro[1,2,4]triazine-3-carboxylic acid ethyl esters 5a-g in moderate to good yields. Hydrolysis under basic conditions gave the corresponding free carboxylic acids 6a-d. Despite the relatively high number of heteroatoms present the amido as-triazine compounds 6a-d showed good solubility in phosphate buffer as determined by a lyophilization solubility assay. Building block 5a served as starting point for the syntheses of two discrete exocyclic 5-amido and 3-amido compound libraries 7 and 8, respectively.     

Solution-phase parallel synthesis of S-DABO analogues

A simple and straightforward methodology for the parallel, solution-phase synthesis of a new series of S-DABO derivatives 1 and 2, bearing aromatic substituents at the C2 and C6 positions, has been developed. Starting from potassium ethyl malonates 3, thiouracil intermediates 5 were prepared through parallel synthesis and isolated as pure products by simple extraction with ethyl acetate. Selective S-benzylation of 5 was achieved in few minutes under microwave irradiation to give the title compounds 1, which were oxidized in parallel to the corresponding sulfones 2. Some of the new compounds 1 showed potent inhibitory activity against HIV-1 RT.     

Kinetics and mechanism of thermal gas-phase elimination of β-substituted carboxylic acids

3-Phenoxypropanoic acid (1), 3-(phenylthio)propanoic acid (2), and 4-phenylbutanoic acid (3) were pyrolysed between 520 and 682 K. Analysis of the pyrolysates showed the elimination products to be acrylic acid and the corresponding arene. Pyrolysis of ethyl 3-phenoxypropanoate (4) and its methyl analogue (5), ethyl 3-(phenylthio)propanoate (6) and its methyl counterpart (7), and 3-phenoxypropane nitrile (8) were also investigated between 617 and 737 K. The thermal gas-phase elimination kinetics and product analysis are compatible with a thermal retro-Michael reaction pathway involving a four-membered cyclic transition state.     

Synthesis of 2-azaspiro[4.4]nonan-1-ones via phosphine-catalysed [3+2]-cycloadditions

The phosphine-catalyzed [3+2]-cycloaddition of the 2-methylene γ-lactams 4 and 5 and the acrylate 6 with the ylides derived from the ethyl ester, the amide or the chiral camphor sultam derivative of 2-butynoic acid (7a-c) give directly, or indirectly after reductive cyclization, spiro-heterocyclic products. The acid 32 underwent Curtius rearrangement and then acid hydrolysis to give two novel spiro-cyclic ketones, 41 and 42.     

[4+2] Cycloaddition reactions of 4-sulfur-substituted 2-pyridones with electron-deficient dienophiles

[4+2] Cycloaddition reactions of 4-(phenylthio)-1-tosyl-2-pyridone (6a) and 4-(phenylsulfonyl)-1-tosyl-2-pyridone (6b) with electron-deficient dienophiles 7 (N-methylmaleimide, N-phenylmaleimide, and methyl acrylate) gave new isoquinuclidine products 8-10. The N-tosyl group of 6a and 6b was also efficiently converted to N-alkyl derivatives 6c-f, which showed different stereoselectivity toward reactions with dienophiles 7. Several other dienophiles 15 (dimethyl acetylenedicarboxylate, methyl vinyl ketone, ethyl vinyl ether, and methyl methacrylate) were found not to react with 6a or 6b, but led to the formation of tosyl migration products 4-(phenylthio)-O-tosyl-pyridinol (16a) and 4-(phenylsulfonyl)-O-tosyl-2-pyridinol (16b), respectively. The reactivity, regioselectivity, and stereoselectivity of the cycloaddition reactions were also compared with semi-empirical calculations.     

Half sandwich complexes of Ru(II) and complexes of Pd(II) and Pt(II) with seleno and thio derivatives of pyrrolidine: Synthesis, structure and applications as catalysts for organic reactions

The reactions of PhSe⁻, PhS⁻ and Se²⁻ with N-{2-(chloroethyl)}pyrrolidine result in N-{2-(phenylseleno)ethyl}pyrrolidine (L1), N-{2-(phenylthio)ethyl}pyrrolidine (L2), and bis{2-pyrrolidene-N-yl)ethyl selenide (L3), respectively, which have been explored as ligands. The complexes [PdCl₂(L1/L2)] (1/7), [PtCl₂(L1/L2)] (2/8), [RuCl(η⁶-C₆H₆)(L1/L2)][PF₆] (3/9), [RuCl(η⁶-p-cymene)(L1/L2)][PF₆] (4/10), [RuCl(η⁶-p-cymene)(NH₃)₂][PF₆] (5) and [Ru(η⁶-p-cymene)(L1)(CH₃CN)][PF₆]₂·CH₃CN (6) have been synthesized. The L1-L3 and complexes were found to give characteristic NMR (Proton, Carbon-13 and Se-77). The crystal structures of complexes 1, 3-6, 9 and 10 have been solved. The Pd-Se and Ru-Se bond lengths have been found to be 2.353(2) and 2.480(11)/2.4918(9)/2.4770(5) Å, respectively. The complexes 1 and 7 have been explored for catalytic Heck and Suzuki-Miyaura coupling reactions. The value of TON has been found up to 85 000 with the advantage of catalyst’s stability under ambient conditions. The efficiency of 1 is marginally better than 7. The Ru-complexes 3 and 9 are good for catalytic oxidation of primary and secondary alcohols in CH₂Cl₂ in the presence of N-methylmorpholine-N-oxide (NMO). The TON value varies between 8.0 × 10⁴ and 9.7 × 10⁴ for this oxidation. The 3 is somewhat more efficient catalyst than 9.     

Bimacrocyclic NHC transition metal complexes

The preparation of seven concave NHC metal complexes derived from bimacrocyclic imidazolinium salt 1 is reported. The silver complex 2, obtained in 86% yield by reacting 1 with silver(I) oxide, was used to give copper complex 3, rhodium complex 5 and iridium complex 6 by transmetalation in good yields. Palladium complex 4 was obtained by reaction of the azolium salt 1 with palladium dichloride in 3-chloropyridine. The rhodium and iridium dicarbonyl complexes 7 and 8 were prepared via ligand exchange from the COD complexes 5 and 6. Silver complex 2, copper complex 3 and palladium complex 4 were characterized by single-crystal X-ray analysis. Silver complex 2 and copper complex 3 were tested in the cyclopropanation of styrene and indene with EDA (ethyl diazoacetate), where good results were obtained with 3, while low conversion and catalyst decomposition was observed with 2.