Pyrroles from ketoximes and acetylene. 23. 2-(1-naphthyl)- and 2-(2-naphthyl)pyrroles and their 1-vinyl derivatives

2-(1-Naphthyl)- and 2-(2-naphthyl)pyrroles and their 1-vinyl derivatives were synthesized in 22–64% yields by the reaction of 1- and 2-acetylnaphthalene oximes with acetylene at both atmospheric pressure and elevated pressures in an alkali metal hydroxide-dimethyl sulfoxide system.See [1] for communication 22.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1351–1353, October, 1982.     

2-Nitroguanidine Derivatives. Synthesis and Structure of 1-(2,2,2-Trinitroethylamino)- and 1-(2,2-Dinitroethylamino)- 2-nitroguanidines

Russian Journal of Organic Chemistry -     

Synthesis and properties of 1-(2-bromoethyl)-, 1-(2-alkoxyethyl)- and 1-(2-dialkylaminoethyl)2-alkylpyrroles

The reaction of 3-chloropropenyl alkyl ketones or 2,3-dichloropropyl alkyl ketones with 2-substituted ethylamine derivatives leads to the formation of the hitherto unknown 1-(2-R-ethyl)-2-alkylpyrroles.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1047–1049, August, 1990.     

Nitroimidazoles. VI. Syntheses of 1-methyl-2-(1,3,4-thiadiazol-2-yl)-5-nitroimidazole and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-5-nitroimidazole

Starting from readily available 1-methyl-5-nitroimidazole-2-carboxylic acid hydrazide (1), 1-methyl-2-(1,3,4-thiadiazol-2-yl)-5-nitroimidazole (4) and 1-methyl-2-(1,3,4-oxadiazol-2-yl)-5-nitroimidazole (10) were prepared. The reaction of 1 with formic acid gave 1-(1-methyl-5-nitroimidazole-2-carboxyl)-2-(formyl)hydrazine ( 8 ) in high yield. Refluxing of the latter with phosphorus pentasulfide in xylene yielded compound 4 in 50% yield. Reaction of compound 8 with phosphorus pentoxide afforded compound 10 in 60% yield.     

Chemistry of 2-hetarylbenzimidazoles. 10. Synthesis and properties of 2-(3′-furyl)-1-methyl-1H-benzimidazole

A study was carried out on the electrophilic substitution reactions such as chloromethylation, bromination, sulfonation, nitration, and acylation of 2-(3′-furyl)-1-methyl-1H-benzimidazole in acid media. All these reactions proceed at C₍₂₎ and C₍₅₎ of the furan ring. Quantum-chemical calculations of the three-dimensional structure of such heterocyclic systems are given. Communication 9, see ref. [1]. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1815–1820, December, 2005.     

3-Bromo-2-(tert-butylsulfonyl)-1-propene. A multi-coupling reagent. Part 2. <1

3-bromo-2-(tert-butylsulfonyl)-1-propene 1 reacts in good yields with various electrophiles (aldehydes, ketones, nitriles and alkynes) in the presence of zinc metal to give unsaturated sulfones of type 4. These compounds can further react with soft or hard nucleophiles (alkyl-, vinyl-, aryllithium compounds, a nitroparaffin or dimethylmalonate) to yield highly functionnalized sulfones of type 5 which can be readily transformed into enones or into a dienone. Thus sulfone 1 is a versatile multi-coupling reagent which is synthetically equivalent to the $\text{a}{}^2\text{a}{}^{\mathrm{2\prime }}$ synthon 8 and to the $\text{d}{}^2\text{d}{}^{\mathrm{2\prime }}$ synthons 9 and 10.     

Nucleosides and nucleotides. 2. Synthesis of both anomers of 1-(5'-O-phosphoryl-2'-deoxy-D-ribofuranosyl)-2(1H)-pyridone

The two anomeric 1-(2′-deoxy-D -ribofuranosyl)-2(1H)-pyridones 6 and 7 were synthesized from 2-pyridone and 3,5-di-(O-p-toluoyl)-2-deoxy-D -ribofuranosyl chloride ( 2 ) via the di-O-p-toluoyl derivatives 3 and 4 using the mercuric halide procedure. Phosphorylation of the nucleosides 6 and 7 by bis-(2,2,2-trichloroethyl)-chlorophosphate gave the phosphate esters 8 and 9 together with some 2-(bis-[2,2,2-trichloroethyl]-phosphoryloxy)-pyridine 10 , which proved to be very labile. Structure and configuration of compounds 6 to 9 were established by spectral methods, the configurations being derived from the chemical shifts of the sugar protons and the splitting patterns of the anomeric protons (‘triplet-quartet rule’). The specific rotations of 3 , 4 , 6 , 7 , 8 and 9 show that the three pairs of anomers represent exceptions to Hudson's rule of isorotation. Reductive removal of the trichloroethyl groups in 8 and 9 with zinc proceeds stepwise, yielding the phosphoro-diesters 13 and 14 and the two desired anomeric 5′-nucleotides 15 and 16 . These latter were purified and characterised as the ammonium salts. Enzymatic cleavage by the 5′-nucleotidase of Crotalus adamanteus venom took place only in the ‘natural’ β-series. The ‘unnatural’ α-anomers were resistent to the enzyme. The structure of 10 was established by spectral methods and confirmed by synthesis.     

Optically active antifungal azoles. VIII. Synthesis and antifungal activity of 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]- 3-(4-substituted phenyl)-2(1H,3H)-imidazolones and 2-imidazolidinones

New optically active antifungal azoles, 1-[(1R,2R)-2-(2,4-difluoro- and 2-fluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl ]-3-(4- substituted phenyl)-2(1H,3H)-imidazolones (1,2) and 2-imidazolidinones (3,4), were prepared in a stereocontrolled manner from (1S)-1-[(2R)-2-(2,4- difluoro- and 2-fluorophenyl)-2-oxiranyl]ethanols (15, 16). Compounds 1-4 showed potent antifungal activity against Candida albicans in vitro and in vivo, as well as a broad antifungal spectrum for various fungi in vitro. Furthermore, the imidazolidinones, 3b--e and 4d, e, were found to exert extremely strong growth-inhibitory activity against Aspergillus fumigatus.     

Optically active antifungal azoles. XIII. Synthesis of stereoisomers and metabolites of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (TAK-456)

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone [(1R,2R)-1: TAK-456] is a new antifungal agent selected as a candidate for clinical trials. The three stereoisomers [(1S,2R)-, (1S,2S)- and (1R,2S)-1] of this compound were prepared as authentic samples to determine the enantiomeric and diastereomeric purity of TAK-456 as well as to compare their in vitro antifungal activity. Pharmacokinetic studies of TAK-456 using rats identified the existence of metabolites in the liver homogenate. The structures of the major metabolites were assigned as 4-hydroxy-2-imidazolidinone (3) and/or 5-hydroxy-2-imidazolidinone (4), based on HPLC and LC/MS/MS analyses. These hydroxylated compounds, 3 and 4, were prepared by reduction of the corresponding imidazolidinediones, 11 and 12, and confirmed to be identical to the metabolites by HPLC. In vitro antifungal activities of the three stereoisomers and the synthesized metabolites were considerably weaker than TAK-456.     

Synthesis of 6-Methyl-4-(1-methyl-2-buten-1-yl)-2-(2-cyclohexen-1-yl)- and 6-Methyl-4-(1-methyl-2-buten-1-yl)-2-(1-cyclohexen-1-yl)anilines

Alkenylation of 6-methyl-2-(2-cyclohexen-1-yl)- and 2-(1-cyclohexen-1-yl)anilines with piperylene in the presence of AlCl₃ and transformation of the resulting cyclohexenylanilines into carbazole structures were studied.__________Translated from Zhurnal Prikladnoi Khimii, Vol. 78, No. 3, 2005, pp. 441–443.Original Russian Text Copyright © 2005 by Gataullin, Ishberdina, Sotnikov, Abdrakhmanov.     

Syntheses of pyrrolo- and indoloisoquinolinones by intramolecular cyclizations of 1-(2-arylethyl)-5-benzotriazolylpyrrolidin-2-ones and 3-benzotriazolyl-2-(2-arylethyl)-1-isoindolinones.

1,5,6,10b-Tetrahydropyrrolo[2,1-alpha]isoquinolin-3(2H)-ones 17a,b, 17d,e, and 5,12b-dihydroisoindolo[1,2-alpha]isoquinolin-8(6H)-ones 22a-e were prepared by intramolecular cyclizations of 1-(2-arylethyl)-5-benzotriazolyl-pyrrolidin-2-ones 15a,b, 15d,e, and 3-benzotriazolyl-2-(2-arylethyl)-1-isoindolinones 20a-e, respectively, in the presence of titanium chloride. Products from chiral amines were obtained with stereoselectivities of > or = 94%.     

Optically active antifungal azoles. XII. Synthesis and antifungal activity of the water-soluble prodrugs of 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone

1-[(1R,2R)-2-(2,4-Difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2-imidazolidinone (1: TAK-456) was selected as a candidate for clinical trials, but since its water-solubility was insufficient for an injectable formulation, the quaternary triazolium salts 2 were designed as water-soluble prodrugs. Among the prodrugs prepared, 4-acetoxymethyl-1-[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3-[2-oxo-3-[4-(1H-1-terazolyl)phenyl]-1-imidazolidinyl]butyl]-1H-1,2,4-triazolium chloride (2a: TAK-457) was selected as an injectable candidate for clinical trials based on the results of evaluations on solubility, stability, hemolytic effect and in vivo antifungal activities.     

2-Substituted imidazoles. 3. Metallation of 1-methyl-2-phenyl- and 1-methyl-2-(furyl-2)imidazoles

1-Methyl-2-phenylimidazole reacts with butyllithium to give 5-lithium substituted products. On the other hand, 1-methyl-2-(furyl-2)imidazole is metallated under the same conditions exclusively on the furan ring and primarily in the 3 position. The introduction of triethylamine into the reaction mixture, or replacement of butyllithium by lithium 2,2,6,6-tetramethylpiperidide leads to the formation of a lithium derivative substituted at the 5-position of the furan ring exclusively.For Communication 2, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 61–66, January, 1992.     

Crystal structure of Diels-Alder cycloadduct formed from 1-(1,2,3-1H-benzotriazol-1-yl)-2-(4-methylphenyl)-2H-isoindole and dimethyl acetylenedicarboxylate.

The structure of the Diels-Alder cycloadduct formed from 2-(1,2,3-1H-benzotriazol-1-yl)-2-(p-tolyl)-2H-isoindole and dimethyl acetylenedicarboxylate was proved as 11-aza-1-(1,2,3-1H-benzotriazol-1-yl)-11-(4-methylphenyl)-tricyclo-[5.2.1.0(2.7)]undeca-2,4,6.9-tetraene-9,10-dioic acid dimethyl ester. The benzotriazole moiety was located as its 1-yl form, analogous to previous reports. The benzotriazole and the benzene (of tricyclo framework) planes were twisted with an angle of 115.83 degrees. Intramolecular close contacts between benzotriazole and ester are characteristic [N(3)...C(26), 2.754(3)A; N(3)...H(22), 3.26(4)A]. The shortest contact of N(3)...H(22) accounting for the rotation of the methyl group is estimated to be 3.10 A, which might be reasonable as C-H...N-type hydrogen bonding.     

Purinenucleoside analogs. 2. 9-(1-Alkoxyethyl-1)-6-substituted purines

Vinyl ethers react with 6-chloro- and 6-methylthiopurines in acid medium to give 9-(1-alkoxyethyl-1)-6-chloro- and 6-methylthiopurines. The 6-chloro compounds were used to prepare 9-(1-alkoxyethyl-1)-6-mercaptopurines. All the synthesized compounds proved to be inactive against lympholeucosis P 388, and Lewis carcinona grafted under kidney capsules in mice.For Communication 1, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 403–406, March, 1986.