An unexpected formation of pyrazolopyrimidines during the attempted to obtain 5-substituted tetrazoles from carbonitriles

In this Letter, we described the synthesis of new 5-(5-amino-1-aryl-1H-pyrazole-4-yl)-1H-tetrazoles 2a–c from 5-amino-1-aryl-1H-pyrazole-4-carbonitriles 1a–c as well as the unexpected 1H-pyrazolo[3,4-d]pyrimidine derivatives 6a–c from 5-amino-1-aryl-3-methyl-1H-pyrazole-4-carbonitriles 4a–c, instead of 5-(5-amino-1-aryl-3-methyl-1H-pyrazole-4-yl)-1H-tetrazoles 5a–c as desired. In an attempt to obtain these tetrazole derivatives containing the methyl group at C3-position in the pyrazole ring, the amino group in 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile 4c was protected by the reaction with sodium hydride and di-tert-butyl-dicarbonate (Boc). The tetrazole derivative 5c was synthesized from the protected compound 7c using analogue methodology to obtain 2a–c and 6a–c.     

Synthesis of a new class of azathia crown macrocycles containing two 1,2,4-triazole or two 1,3,4-thiadiazole rings as subunits

A series of new 1,2/1,3-bis[o-(N-methylidenamino-5-aryl-3-thiol-4H-1,2,4-triazole-4-yl)phenoxy]alkane derivatives 3a-d and bis[o-(N-methylidenamino-2-thiol-1,3,4-thiadiazole-5-yl)phenoxy]alkanes 6a-c were prepared by condensation of 4-amino-5-(aroyl)-4H-1,2,4-triazole-3-thiols 2a-b or 2-amino-5-mercapto-1,3,4-thiadiazole with bis-aldehydes 1a-c. Further reaction of compounds 3a-d and 6a-c with dibromoalkanes afforded the new macrocycles 5a-f and 8a-d. The cyclization does not require high dilution techniques and provides the expected azathia macrocycles in good yields, ranging from 55% to 68%.     

Synthesis and reactivity of new functionalized Pd(II) cyclometallated complexes with boronic esters

Treatment of the functionalized Schiff base ligands with boronic esters 1a, 1b, 1c and 1d with palladium (II) acetate in toluene gave the polynuclear cyclometallated complexes 2a, 2b, 2c and 2d, respectively, as air-stable solids, with the ligand as a terdentate [C,N,O] moiety after deprotonation of the -OH group. Reaction of 1j with palladium (II) acetate in toluene gave the dinuclear cyclometallated complex 5j. Reaction of the cyclometallated complexes with triphenylphosphine gave the mononuclear species 3a, 3b, 3c, 3d and 6j with cleavage of the polynuclear structure. Treatment of 2c with the diphosphine Ph₂PC₅H₄FeC₅H₄PPh₂ (dppf) in 1:2 molar ratio gave the dinuclear cyclometallated complex 4c as an air-stable solid.Deprotection of the boronic ester can be easily achieved; thus, by stirring the cyclometallated complex 3a in a mixture of acetone/water, 3e is obtained in good yield. Reaction of the tetrameric complex 2a with cis-1,2-cyclopentanediol in chloroform gave complex 2c after a transesterification reaction. Under similar conditions complexes 3a and 3d behaved similarly: with cis-1,2-cyclopentanediol, pinacol or diethanolamine complexes 3c, 3b, 3g and 3f, were obtained. The pinacol derivatives 3b and 3g experiment the Petasis reaction with glyoxylic acid and morpholine in dichloromethane to give complexes 3h, and 3i, respectively.     

2-(1-Isopropyl-2-benzimidazolyl)-6-(1-aryliminoethyl)pyridyl transition metal (Fe, Co, and Ni) dichlorides: Syntheses, characterizations and their catalytic behaviors toward ethylene reactivity

A series of 2-(1-isopropyl-2-benzimidazolyl)-6-(1-aryliminoethyl)pyridyl metal complexes [iron (II) (1a-6a), cobalt (II) (1b-6b) and nickel (II) (1c-6c)] were synthesized and fully characterized by elemental and spectroscopic analyses. Single-crystal X-ray diffraction analyses of five coordinated complexes 5a, 3b, 5b, 1c and 2c reveal 5a and 5b as distorted trigonal-bipyramidal geometry, and 3b, 1c and 2c as distorted square pyramidal geometry. All complexes performed ethylene reactivity with the assistance of various organoaluminums. The iron complexes displayed good activities in the presence of MAO and MMAO. Upon activated by Et₂AlCl, the cobalt analogues showed moderate ethylene reactivity, while the nickel analogues exhibited relatively higher activities.     

Microwave-assisted synthesis of novel bis(2-thioxothiazolidin-4-one) derivatives as potential GSK-3 inhibitors

(5Z,5′Z)-3,3′-(1,4-Phenylenebis(methylene)-bis-(5-arylidene-2-thioxothiazolidin-4-one) derivatives (5a-r) have been synthesized by the condensation reaction of 3,3′-(1,4- or 1,3-phenylenebis(methylene))bis(2-thioxothiazolidin-4-ones) (3a,b) with suitably substituted aldehydes (4a-f) or 2-(1H-indol-3-yl)2-oxoacetaldehydes (8a-c) under microwave conditions. The bis(2-thioxothiazolidin-4-ones) were prepared from the corresponding primary alkyl amines (1a,b) and di-(carboxymethyl)-trithiocarbonyl (2). The 2-(1H-indol-3-yl)-2-oxoacetaldehydes (8a-c) were synthesized from the corresponding acid chlorides (7a-c) using HSnBu₃.     

Tetracyclic 1,6-methano-[10]annulenes a novel class of steroidal annulenes

Reaction of 19-hydroxyandrosta-4,6-diene-3,17-dione (8b) and the corresponding Δ⁷-compound (8c) with diethyl-(2-chloro-1,1,2-trifluoroethyl)-amine affords 5β,19-cyclo-Δ^1,6- and 5β,19-cyclo-Δ^1,7-3-ketones (4b) and (4c) respectively. Solvolysis experiments with the 19-tosylates of the 19-hydroxy-Δ^4,6- and Δ^4,7-3-ketones (8b) and 8c) are described as alternate approaches to (4b) and (4c). Exposure of 5β,19-cyclo compounds (4b) and (4c) to acetic anhydride-acetic acid-p-toluenesulfonic acid yields the respective 3-acetoxycycloheptatrienes (5a) and (6a). The latter substance (6a) is converted into the novel tetracyclic 1,6-methano-[10]annulene (2a) on exposure to N-bromosuccinimide in boiling carbon tetrachloride. Synthesis of the corresponding 3-methoxy- and 3-desoxy-1,6-methano-[10]annulenes (2b) and (2c) are also described. The NMR spectra of (2a), (2b) and (2c) and related intermediates are discussed.     

Gold(I) N-heterocyclic carbene based initiators for bulk ring-opening polymerization of l-lactide

Synthesis, structures, and catalysis studies of gold(I) complexes of N-heterocyclic carbenes namely, a di-O-functionalized [1-(2-hydroxy-cyclohexyl)-3-(acetophenone)imidazol-2-ylidene], a mono-O-functionalized [1-(2-hydroxy-cyclohexyl)-3-(benzyl)imidazol-2-ylidene] and a non-functionalized [1,3-di-i-propyl-benzimidazol-2-ylidene], are reported. Specifically, the gold complexes, [1-(2-hydroxy-cyclohexyl)-3-(acetophenone)imidazol-2-ylidene]AuCl (1c), [1-(2-hydroxy-cyclohexyl)-3-(benzyl)imidazol-2-ylidene]AuCl (2c), and [1,3-di-i-propyl-benzimidazol-2-ylidene]AuCl (3b), were prepared from the respective silver complexes 1b, 2b, and 3a by treatment with (SMe₂)AuCl in good yields following the commonly used silver carbene transfer route. The silver complexes 1b, 2b, and 3a were synthesized from the respective imidazolium halide salts by the reactions with Ag₂O. The N-heterocyclic carbene precursors, 1-(2-hydroxy-cyclohexyl)-3-(acetophenone)imidazolium chloride (1a) and 1-(2-hydroxy-cyclohexyl)-3-(benzyl)imidazolium chloride (2a), were synthesized by the direct reactions of cyclohexene oxide and imidazole with chloroacetophenone and benzyl chloride respectively. The gold (1c, 2c, and 3b) and the silver (3a) complexes along with a new O-functionalized imidazolium chloride salt (1a) have been structurally characterized by X-ray diffraction. The structural studies revealed that geometries around the metal centers were almost linear in these gold and silver complexes. The gold (1c, 2c, and 3b) complexes efficiently catalyze ring-opening polymerization (ROP) of l-lactide under solvent-free melt conditions producing polylactide polymer of moderate to low molecular weights with narrow molecular weight distributions.     

Ni(II) and Cu(II) complexes of phenoxy-ketimine ligands: Synthesis,structures and their utility in bulk ring-opening polymerization (ROP) of l-lactide

Synthetic, structural and catalysis studies of Ni(II) and Cu(II) complexes of a series of phenoxy-ketimine ligands with controlled variations of sterics, namely 2-[1-(2,6-diethylphenylimino)ethyl]phenol (1a), 2-[1-(2,6-dimethylphenylimino)ethyl]phenol (1b) and 2-[1-(2-methylphenylimino)ethyl]phenol (1c), are reported. Specifically, the ligands 1a, 1b and 1c were synthesized by the TiCl₄ mediated condensation reactions of the respective anilines with o-hydroxyacetophenone in 21–23% yield. The nickel complexes, {2-[1-(2,6-diethylphenylimino)ethyl]phenoxy}₂Ni(II) (2a) and {2-[1-(2,6-dimethylphenylimino)ethyl]phenoxy}₂Ni(II) (2b), were synthesized by the reaction of the respective ligands 1a and 1b with Ni(OAc)₂ · 4H₂O in the presence of NEt₃ as a base in 71–75% yield. The copper complexes, {2-[1-(2,6-diethylphenylimino)ethyl]phenoxy}₂Cu(II) (3a), {2-[1-(2,6-dimethylphenylimino)ethyl]phenoxy}₂Cu(II) (3b) and {2-[1-(2-methylphenylimino)ethyl]phenoxy}₂Cu(II) (3c) were synthesized analogously by the reactions of the ligands 1a, 1b and 1c with Cu(OAc)₂ · H₂O in 70–87% yield. The molecular structures of the nickel and copper complexes 2a, 2b, 3a, 3b and 3c have been determined by X-ray diffraction studies. Structural comparisons revealed that the nickel centers in 2a and 2b are in square planar geometries while the geometry around the copper varied from being square planar in 3a and 3c to distorted square planar in 3b. The catalysis studies revealed that while the copper complexes 3a, 3b and 3c efficiently catalyze ring-opening polymerization (ROP) of l-lactide at elevated temperatures under solvent-free melt conditions, producing polylactide polymers of moderate molecular weights with narrow molecular weight distributions, the nickel counterparts 2a and 2b failed to yield the polylactide polymer.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Rapid syntheses of (±)-pterocarpans and isoflavones via the gold-catalyzed annulation of aldehydes and alkynes

(±)-Pterocarpan and analogues (4a-c) have been synthesized efficiently via the annulation of salicylaldehydes (1a, 1b and 1c) and o-methoxymethoxylphenylacetylene (2a), followed by a one-pot reduction and acidic cyclization of the ketones (3a-c). In addition, isoflavone derivatives (5a-c) have been synthesized rapidly, in two steps, via the annulation of salicylaldehyde (1a) and arylacetylenes (2b, 2c and 2d), followed by IBX/DMSO oxidation of the isoflavanones (3d, 3e and 3f).     

Synthesis and evaluation of bipendant-armed (oligo)thiophene crown ether derivatives as new chemical sensors

Three new (oligo)thiophene bipendant-armed ligands 2a-c, derived from 2-(aminomethyl)-15-crown-5, have been synthesized and characterized. Compounds 2a-c were prepared by reductive amination of the corresponding macrocycle with formyl thiophene derivatives 1a-c in the presence of NaBH(OAc)₃ in fair to good yields. The photophysical properties of ligands 2a-c were studied and they were also evaluated as chemosensors in the presence of Na(I), Ag(I), Pd(II) and Hg(II) cations in acetonitrile solution.     

An efficient electrochemical method for a unique synthesis of new derivatives of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one

The electrochemical oxidation of catechols (1a-c) has been studied in the presence of 6-methyl-1,2,4-triazine-3-thion-5-one 3 in aqueous sodium acetate, using cyclic voltammetry and controlled-potential coulometry. A plausible mechanism for the oxidation of catechols and their reaction with 3 is presented. All the catechol derivatives (1a-c) were converted into 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives (6a-c) through a Michael-type addition reaction of 3 to anodically generated o-quinones. The electrochemical syntheses of 6a-c were successfully performed in one pot in an undivided cell using an environmentally friendly method with high atomic economy.     

24,24-Dimethylvitamin D3-26,23-lactones and their 2α-functionalized analogues as highly potent VDR antagonists

Novel vitamin D receptor (VDR) antagonists, 24,24-dimethyl-1α-hydroxyvitamin D₃-26,23-lactones (8 and 9) and their C2α functionalized analogues (8a-c and 9a-c) were efficiently synthesized and their biological activities were evaluated. The construction of vitamin D₃ triene skeleton was achieved by palladium-catalyzed alkenylative cyclization of A-ring precursor enyne (22 and 22a-c) with CD-ring bromoolefin having a 24,24-dimethyl-α-methylene-γ-lactone unit on the side chain (13 and 14). The CD-ring precursors 13 and 14 were prepared by using chromium-mediated allylation of the aldehyde 10 derived from vitamin D₂. On the other hand, the A-ring enyne having 2α-(3-hydroxypropyl) group (22b) was newly synthesized from epoxide 15 using regio- and stereoselective alkylation methodology. The potency of the antagonistic activity of the newly designed analogues (8 and 9) increased up to 12 times that of TEI-9647 (2). Furthermore, introduction of the three motifs, that is, a methyl (8a and 9a), an ω-hydroxypropyl (8b and 9b) or an ω-hydroxypropoxyl group (8c and 9c) into the C2α position of 8 and 9, respectively, resulted in remarkable enhancement, up to 89 times, of the antagonistic activity on VDR.     

Manganese(III) acetate based oxidative cyclizations of 3-oxopropanenitriles with conjugated alkenes and synthesis of 4,5-dihydrofuran-3-carbonitriles containing heterocycles

4,5-Dihydrofuran-3-carbonitriles 3a-i were obtained through oxidative cyclizations of 3-oxo-3-phenylpropanenitrile 1a, 3-oxo-3-thien-2-ylpropanenitrile 1b, 3-(2-furyl)-3-oxopropanenitirle 1c, 3-(1-benzofuran-2-yl)-3-oxopropanenitrile 1d, and 4,4-dimethyl-3-oxopropanenitrile 1e mediated manganese(III) acetate with 1,1-diphenyl-1-butene 2a and 1,2-diphenyl-1-pentene 2b. The treatments of these 3-oxopropanenitriles with 2-thienyl substituted alkenes such as 2-[(E)-2-phenylvinyl]thiophene 2c, 2-[(E)-1-methyl-2-phenylvinyl]thiophene 2d, and 2-(1-phenylvinyl)thiophene 2e formed 5-(2-thienyl)-4,5-dihydrofuran-3-carbonitriles 3j-r in good yields (45-93%). As a result, 2-thienyl substituted alkenes formed products in higher yields than phenyl substituted derivatives.     

Transannular Anti-Michael Addition: Formation of 4H-Pyrazolo[5,1-c]thiazines

The reaction of 2-(diphenylmethylene)thietan-3-one (2) with 1,2,4,5-tetrazines (3a-c) in KOH/MeOH/THF gives 4H-pyrazolo[5,1-c]thiazines (7a-c). This novel condensation reaction proceeds via the intermediacy of an 8-(diphenylmethylene)-2H-1,4,5-thiadiazocin-7(8H)-one (5), which undergoes a multi-step rearrangement including a rare anti-Michael addition.     

Microwave-assisted manganese(III) acetate based oxidative cyclizations of alkenes with β-ketosulfones

The microwave-assisted synthesis of 5-(4-nitrophenyl)-2-phenyl-4-(phenylsulfonyl)-2,3-dihydrofuran (5a) was performed via manganese(III) acetate based oxidative cyclization of 1-(4-nitrophenyl)-2-(phenylsulfonyl)ethanone (3a) with vinylbenzene (4a). This new protocol was applied to four sulfone derivatives (3a-d), using vinylbenzene (4a) and diphenylethene (4b), affording a series of 2,3-dihydrofurans (5a-d, 6a-d) in moderate to good yields (26-55%). Similar methodology, applied on allylbenzene (4c), surprisingly, led to dehydronaphthalene derivatives (7a-d) in moderate yields. The unexpected mechanism and the role of allylbenzene (4c) are herein discussed.     

Phosphorus–nitrogen compounds: Part 19. Syntheses,structural and electrochemical investigations,biological activities,and DNA interactions of new spirocyclic monoferrocenylcyclotriphosphazenes

The reactions of hexachlorocyclotriphosphazatriene, N₃P₃Cl₆, with N-alkyl-N-ferrocenylmethylethylene diamines, FcCH₂NH(CH₂)₂NHR₁ [R₁ = Me (1) and Et (2)], and sodium [3-(N-ferrocenylmethylamino)-1-propanoxide] (3) produce spirocyclic monoferrocenyl tetrachlorophosphazenes (1a–3a). The tetrapyrrolidinophosphazenes (1b–3b) are prepared from the reactions of corresponding phosphazenes (1a–3a) with excess pyrrolidine. The reaction of 1a with excess morpholine affords geminal-morpholino phosphazene (1c), whilst the reactions of 2a and 3a give diethylaminotrimorpholino (2c) and fully substituted morpholino products (3c), respectively. The structural investigations of the compounds are examined by Fourier transform IR, MS, ¹H, ¹³C, ³¹P NMR, DEPT, HETCOR, and HMBC techniques. The crystal structures of 3b and 3c are determined using X-ray crystallography. Cyclic voltammetric and chronoamperometric data show that compounds 1a–3a, 1b–3b, and 1c–3c exhibit electrochemically reversible one-electron oxidation of Fc redox centers which are hardly affected by the substituents on the phosphazene ring. The compounds 1b, 2b, 3b, and 3c are screened for antibacterial activities against Gram-positive and Gram-negative bacteria and for antifungal activities against yeast strains. In addition, the antituberculosis activities (in vitro) of these compounds are evaluated against INH-susceptible reference strain M. tuberculosis H37Rv, and six multi-drug resistant clinical M. tuberculosis isolates. Compound 2b is found to be the most active against the susceptible the reference strain. In addition, 1b, 2b, and 3c are active against all the multidrug-resistant clinical isolates at the highest concentrations. Gel electrophoresis data indicate that the compounds promote the formation of strand breaks in plasmid DNA. Almost all the concentrations lost of supercoiled DNA suggests that the compound 3b is very efficient plasmid-modifier. The compounds inhibit BamHI cleavage of pUC18 DNA while restricting HindIII.     

Synthesis and properties of 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H)-triones

The synthesis and properties of a novel type of 5-[bis(1-heteroazulen-3-yl)methylidene]pyrimidine-2,4,6(1,3,5H)-triones (13a-c) and (14a-c) are studied. The synthetic procedure is based on addition of bis(1-heteroazulen-3-yl)methyl cations with barbituric acid and subsequent oxidation by o-chloranil. Structural characteristics of 13a-c and 14a-c were clarified on inspection of the ¹³C NMR spectral data and X-ray crystal analysis. Based on the investigation of the UV-vis spectra of 13a-c and 14a-c and their protonated cations, conformational change of the heteroazulene-moiety and the barbituric acid-moiety is suggested. In the CV measurements of 13a-c and 14a-c, two reversible reduction waves are observed, indicating the stabilizing ability of heteroazulenes toward the corresponding radical and anion species. Furthermore, 13a-c and 14a-c exhibit one irreversible oxidation wave and the corresponding reduction wave appearing in a far negative region, which suggested a conformational change in the radical cation during the redox process. The conformational change is rationalized on the basis of the MO calculations.     

Synthesis of fluorine containing glycolurils and oxazolines from oxides of internal perfluoroolefins

The reaction of oxides of internal perfluoroolefins 1-3 with urea gave two kinds of novel fluorine containing N-heterocyclic compounds depending on the solvent nature: 1,5-bis(perfluoroalkyl)tetraazabicyclo[3.3.0]octane-3,7-diones 4a-c and 2-amino-5-fluoro-4,5-bis(perfluoroalkyl)-4,5-dihydrooxazol-4-ols 7a-d. Use of polar dimethylsulfoxide, N,N-dimethylacetamide and acetonitrile afforded glycolurils 4a-c in moderate yields. In dioxane, unexpected cyclization occurred resulting in oxazolines 7a-d in high yields. A similar reaction of oxiranes 2, 3 with urea in aqueous dioxane gave mixtures of 4,5-dihydroxy-4,5-bis(perfluoroalkyl)imidazolidine-2-ones 9b, c, glycolurils 4b, c and oxazolines 7b-d. The molecular structure of trans-isomers of oxazoline 7b and imidazolidine 9b has been established by X-ray crystallography.     

A convenient synthesis of benzofuro[3,2-c]isoquinolines and naphtho[1′,2′:4,5]furo[3,2-c]isoquinolines

A convenient method for the preparation of benzofuro[3,2-c]isoquinoline derivatives is described. The condensation reaction of methyl 2-(chloromethyl)-benzoate with substituted salicylonitriles 7a-c and intramolecular cyclization of the resulting substituted methyl 2-[(2-cyanobenzyl)oxy]benzoates 10a-c using potassium tert-butoxide results in the substituted benzofuro[3,2-c]isoquinolin-5(6H)-ones 1a-c. The same sequence of reactions starting from 2-(chloromethyl)benzonitrile and compounds 7a-c gave substituted 5-aminobenzofuro[3,2-c]isoquinolines 13a-c. In addition, this method is useful for the synthesis of other heterocycles. For example, using 1-cyano-2-naphthol 16, instead of the salicylonitriles 7a-c, gives naphtho[1′,2′:4,5]furo[3,2-c]isoquinolines.