Synthesis of the methanesulfonates of α-(4-chlorophenyl)-α-[1-(2-chlorophenyl)emenyl]-1H-1,2,4-triazole-1-ethanol and α-[1-(2-chlorophenyl)ethenyl]-α-(2,4-difluorophenyl)-1H-1,2,4-triazole-1-ethanol,alpha styryl carbinol antifungal agents

The methanesulfonates of (α-(4-chlorophenyl)-α-[1-(2-chlorophenyl)ethenyl]-1H-1,2,4-triazole-1-ethanol and α-[1-(2-chlorophenyl)ethenyl]-α-(2,4-difluorophenyl)-1H-1,2,4-triazole-1-ethanol ( 1a, b ) are orally effective α-styryl carbinol derivatives developed for the treatment and prevention of systemic fungal infections. Practical new processes amenable for the large-scale production of these compounds are described. Of note is the selection of dichlorostyrene as a convenient precursor of the styryl portion, modification of a sensitive Grignard addition into a realistic preparative reaction and the use of 1,2,4-triazole simultaneously as a base transfer agent and nucleophile.     

Enzymatic kinetic resolution of 1-(3′-furyl)-3-buten-1-ol and 2-(2′-furyl)-propan-1-ol

The enzymatic kinetic resolution of the racemic alcohols 1-(3′-furyl)-3-buten-1-ol (±)-1 and 2-(2′-furyl)propan-1-ol (±)-2 was investigated by screening a range of lipases and esterases for enantioselective transacylation, as well as for enantioselective hydrolysis. For both alcohols, lipase-catalyzed hydrolysis of the derived racemic acetate gave the best results for accessing the desired (S)-enantiomers. In the case of the secondary alcohol (±)-1, ASL turned out to be the optimum enzyme, whereas PPL was found to be superior in the case of the primary alcohol (±)-2. Additionally, an alternative access to (S)-2 via Oppolzer's camphor sultam methodology is described.     

Microwave-assisted synthesis of 1-{2-[(1-benzyl-1<Emphasis Type="Italic">H</Emphasis>-1,2,3-triazol-4-yl)methoxy]phenyl}-3-(3-aryl-1-phenyl-1<Emphasis Type="Italic">H</Emphasis>-pyrazol-4-yl)prop-2-en-1-ones and their antimicrobial activity

A series of new (E)-1-{2-[(1-benzyl-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3i) has been synthesized via copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction (CuAAC) of benzyl azide with substituted (E)-3-(3-aryl-1-phenyl-1H-pyrazol-4-yl)-1-[2-(prop-2-ynyloxy)phenyl]prop-2-en-1-ones (2a–2i). The synthesized compounds have been characterized by their IR, ^lH, ¹³C NMR spectra, and mass spectroscopy data. All the compounds have been screened for antimicrobial activity.     

Reaction of 5-(2-furyl)-1-methyl-1<Emphasis Type="Italic">H-</Emphasis> and 1-methyl-5-(2-thienyl)-1<Emphasis Type="Italic">H</Emphasis>-imidazoles with electrophilic reagents

5-(2-Furyl)-1-methyl-1H- and 1-methyl-5-(2-thienyl)-1H-imidazoles were synthesized. The electronwithdrawing effect of the 5- and 2-imidazole substituents on the furan ring was studied by ¹H NMR spectroscopy and quantum-chemical calculations. Some electrophilic substitution reactions were investigated (nitration, bromination, sulfonation, hydroxymethylation, formylation, and acylation). In some cases, depending on the reaction conditions, both the furan and thiophene ring and the imidazole fragment undergo electrophilic attack.     

Synthesis and reactions with <Emphasis Type="Italic">N</Emphasis>-nucleophiles of 1-(thien-2-yl)- and 1-(4-hydroxyphenyl)-3,4,4-trichloro-3-buten-1-ones

Acylation of thiophene and phenol with 3,4,4-trichloro-3-butenoyl chloride afforded the corresponding 1-(thien-2-yl)- and 1-(4-hydroxyphenyl)-3,4,4-trichloro-3-buten-1-ones, whose reaction with amines led to the formation of 3-amino-1-(thien-2-yl, 4-hydroxyphenyl)-4,4-dichloro-2-buten-1-ones The heterocyclization of the initial ketones into pyrazole structure was not observed, and the reaction with hydrazine hydrate provided bispyrazole products, N,N′-bis(5-thien-2-yl)- and N,N′-bis[5-(4-hydroxyphenyl)-1H-pyrazol-3-ylmethylene]hydrazines.     

Ringschlussreaktionen von 1-(2-Aminophenyl)-1-phenyl-äthylenen durch Kondensation mit Phosgen

Cyclization of 1-(2-aminophenyl)-1-phenyl-ethylenes or 1-(2-aminophenyl)-1-phenyl-propenes (II) by condensation with phosgene led to 4-phenyl-carbostyrils (III) or 2-chloro-4-phenyl-quinolines (IV). Similarly, thiophosgene afforded 4-phenyl-thiocarbostyril. Treatment of 1-(2-aminophenyl)-2-methyl-1-p-tolyl-propene (VII) with phosgene led to the corresponding isocyanate IX, which cyclized in the presence of aluminum chloride with loss of a methyl group to 3-methyl-4-p-tolyl-carbostyril (III-6). However, 1-(2-aminophenyl)-2-methyl-1-phenyl-propene (VIII) treated with phosgene gave the isocyanate XI and 3-phenyl-3-isopropenyloxindole (X). Cyclization of the isocyanate XI with aluminium chloride led simultaneously to 3-methyl-4-phenyl-carbostyril (XIV), and with migration of a methyl group to 3-methylene-4-methyl-4-phenyl-3. 4-dihydro-carbostyril (XV).     

Nucleoside und Nucleotide. Teil 16. Verhalten von 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyrimidinon-5′-triphosphat, 1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)pyridinon-5′-triphosphat und 4-Amino-1-(2′-Desoxy-β-D-ribofuranosyl)-2(1 H)-pyridinon-5′-triphosphat gegenüber DNA-Polymerase

Nucleosides and Nucleotides. Part 16. The Behaviour of 1-(2′-Deoxy-β-D -ribofuranosyl)-2(1H)-pyrimidinone-5′-triphosphate, 1-(2′-Deoxy-β-D -ribofuranosyl-2(1H))-pyridinone-5′-triphosphate and 4-Amino-1-(2′-desoxy-β-D -ribofuranosyl)-2(1H)-pyridinone-5′-triphosphate towards DNA Polymerase The behaviour of nucleotide base analogs in the DNA synthesis in vitro was studied. The investigated nucleoside-5′-triphosphates 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyrimidinone-5′-triphosphate (pppM_d), 1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppII_d) and 4-amino-1-(2′-deoxy-β-D -ribofuranosyl)-2(1 H)-pyridinone-5′-triphosphate (pppZ_d) can be considered to be analogs of 2′-deoxy-cytidine-5′-triphosphate. However, their ability to undergo base pairing to the complementary guanine is decreased. When pppM_d, pppII_d or pppZ_d are substituted for pppC_d in the enzymatic synthesis of DNA by DNA polymerase no incorporation of these analogs is observed. They exhibit only a weak inhibition of the DNA synthesis. The mode of the inhibition is uncompetitive which shows that these nucleotide analogs cannot serve as substrates for the DNA polymerase.     

5-nitro-5-(1′-cyclohexenyl)- and 5-nitro-5-(1′-cycloheptenyl)-3-benzyl- and 3-cyclohexyl tetrahydro-1,3-oxazines

1-(Cyclohexenyl- and 1-cycloheptenylnitromethane have been used as starting substances to yield 2-nitro-2-(1′-cyclohexenyl)- and 2-nitro-2-(1′-cycloheptenyl)-propanediol-1,3 (B) respectively. By reacting them with formaldehyde and benzylamine or formaldehydes and cyclohexylamine, derivatives of tetrahydro-1,3-oxazine (B) have been prepared. Acid hydrolysis of tetrahydro-1,3-oxazine derivatives results in the formation of 3-hydroxy-2-nitro-2-(1′-cyclohexenyl)- and 3-hydroxy-2-nitro-2-(1′-cycloheptenyl)-propylamine derivatives (E). Both aminoalcohols (E) react with formaldehyde to again yield tetrahydro-1,3-oxazine derivatives (C).

Infra-red spectra of C and E and their hydrochlorides D and F were examined and structure assignments made of the principal bands.     

Synthesis of <Emphasis Type="Italic">N</Emphasis>-[4-hydroxy(alkoxy,acyloxy)-3-alkoxy-benzylidene]-1-(1-adamantyl)ethanamines from 1-(1-adamantyl)ethanamine hydrochloride (Rimantadine)

Reactions of 1-(1-adamantyl)ethanamine with vanillin, vanillal, veratraldehyde, 3-ethoxy-4-methoxybenzaldehyde, and 4-formyl-2-methoxy(ethoxy)phenyl esters gave previously unknown Schiff bases containing an adamantane fragment.     

Reaction of 1-[2-(vinyloxy)ethyl]-1<Emphasis Type="Italic">H</Emphasis>-pyrroles with trifluoroacetic anhydride

Chemo- and stereoselectivity of the reaction of 1-[2-(vinyloxy)ethyl]-1H-pyrroles with trifluoroacetic anhydride have been studied. The reaction with an equimolar amount of trifluoroacetic anhydride chemoselectively involves the free α-position of the pyrrole ring with formation of the corresponding α-trifluoroacetylpyrroles. In the reaction with 2 equiv of trifluoroacetic anhydride, acylation of both α-position of the pyrrole ring and β-position of the vinyloxy group leads to the formation of 1-(2-{[(1E)-4,4,4-trifluoro-3-oxobut-1-en-1-yl]oxy}ethyl)-2-trifluoroacetyl derivatives with high stereoselectivity.     

Nucleosides and Nucleotides. Part 13. Synthesis and spectral properties of 1- (3′-O-Phosphoryl-2′-deoxy-β -D-ribofuranosyl)-2(1H)-pyridone-(3′-5′)-1-(2′-deoxy-β-D-ribofuranosyl)-2 (1H)-pyridone

The dinucleoside phosphate Π_dpΠ_d ( 4 ) was synthesized from the monomers 1-(5′-O-monomethoxytrityl - 2′ - deoxy - β - D - ribofuranosyl) - 2 (1 H) - pyridone ((MeOTr) Π_d, 2 ) and 1-(5′-O-phosphoryl-3′-O-acetyl-2′-deoxy-β-D -ribofuranosyl)-(1H)-pyridone (pΠ_d(Ac), 3 ). Its 6.4% hyperchromicity and an analysis of the ¹H-NMR. spectra indicate that the conformation and the base-base interactions in 4 are similar to those in natural pyrimidine dinucleoside phosphates.     

Acid-catalyzed reactions of 1- and 3-(α-hydroxybenzyl)indolizines

Treatment of 1-(α-hydroxybenzyl)- and 3-(α-hydroxybenzyl)indolizines with trifluoroacetic acid in dichloromethane gave phenylbis(α-indolizinyl)methanes, bis[α-(indolizinyl)benzyl] ethers and indolizines, depending upon the presence or absence of the substituent at the 2- or 5-position and the reaction conditions used.     

Fischer Synthesis of 1-; 5-; and 7-Substituted 3-(N-Acylamino)-2-phenylindoles

Arylhydrazones were obtained by the reaction of arylhydrazines with -(N-acylamino)acetophenones and were converted into 3-(N-acylamino)-2-phenylindoles with substituents at positions 1, 5, 6, and 7 by Fischer cyclization.     

Synthesis of substituted 2-(thiophen-2-yl)-1<Emphasis Type="Italic">H</Emphasis>-imidazol-1-ols

Substituted 2-(thiophen-2-yl)-1H-imidazol-1-ols were synthesized by cyclization of the corresponding α-thienyl nitrones in alkaline medium. α-Thienyl nitrones were obtained by reaction of N-(1-hydroxyimine-1-R-propan-2-yl)hydroxylamines with thiophene-2-carbaldehyde in methanol. At boiling α-thienyl nitrones in methanol in the presence of sodium methylate 5-aryl(hetaryl)-2-(thiophen-2-yl)-1H-imidazol-1-ols are formed chemoselectively.     

5-(α-Fluorovinyl)tryptamines and 5-(α-Fluorovinyl)-3-(N-methyl-1′,2′,5′,6′,-tetrahydropyridin-3′- and -4′-yl)indoles—5-(α-Fluorovinyl)tryptamines

5-(α-Fluorovinyl)tryptamines 4a, 4b and 5-(α-fluorovinyl)-3-(N-methyl-1′,2′,5′,6′-tetrahydropyridin-3′- and -4′-yl) indoles 5a, 5b were synthesized using 5-(α-fluorovinyl)indole ( 7 ). The target compounds are bioisosteres of 5-carboxyamido substituted tryptamines and their tetrahydropyridyl analogs.     

Synthesis,characterization, and antimicrobial activity of novel (<Emphasis Type="Italic">E</Emphasis>)-1-(aryl)-3-{3, 5-dimethoxy-4-[(1-(aryl)-1<Emphasis Type="Italic">H</Emphasis>-1,2,3-triazol-4-yl)methoxy]phenyl}prop-2-en-1-ones

The new chalcone derivatives containing the 1,2,3-triazole ring system, namely, (E)-1-(aryl)-3-{3,5-dimethoxy-4-[(1-(aryl)-1H-1,2,3-triazol-4-yl)methoxy]phenyl}prop-2-en-1-ones, were synthesized in 65–88% yield by the “click chemistry” reactions of substituted acetophenones, 4-hydroxy-3,5-dimethoxy-benzaldehyde, and different substituted azides. The structure of the compounds was determined by the FT-IR, ¹H NMR, ¹³C NMR, and mass spectroscopic analyses. Compounds 6a–6l were screened for in vitro antimicrobial activity by the agar disc diffusion method.     

Synthesis of 5-aryl(hetaryl)-4-methyl-2-(furan-2-yl)-1<Emphasis Type="Italic">H</Emphasis>-imidazol-1-oles

Reaction of 2-(hydroxyamino)-1-R-propan-1-one oximes with furfural in methanol afforded the corresponding α-furylnitrones. The cyclization of α-furylnitrones in alkaline medium results in the formation of 5-aryl(hetaryl)-2-(furan-2-yl)-1H-imidazol-1-oles.     

Ultrasound Irradiation Promoted Enzymatic Transesterification of (<em>R/S</em>)-1-Chloro-3-(1-naphthyloxy)-2-propanol

(R)-1-Chloro-3-(1-naphthyloxy)-2-propanol (3), which is the key intermediate of (S)-propranolol, was successfully prepared via enantioselective transesterification catalyzed by lipase under ultrasound irradiation. Compared with conventional shaking, the enzyme activity and enantioselectivity were dramatically increased under ultrasound exposure. Effects of various reaction conditions on the synthetic activity of enzyme as well as enantioselectivity, including the type of enzyme, ultrasound power, solvent, acyl donor, temperature and substrate molar ratio, were investigated. Pseudomonas sp. lipase (PSL) showed an excellent catalytic performance under optimum conditions (enzyme activity: 78.3 ± 3.2 μmol·g^-1·min^-1, E value: 98 ± 6).     

Reaction of ethyl 4-[(<Emphasis Type="Italic">E</Emphasis>)-1-chloro-3-oxoprop-1-en-1-yl]-3,5-dimethyl-1<Emphasis Type="Italic">H</Emphasis>-pyrrole-2-carboxylate with hydrazines

Ethyl 4-[(E)-1-chloro-3-oxoprop-1-en-1-yl]-3,5-dimethyl-1H-pyrrole-2-carboxylate reacted with substituted hydrazines in different solvents to give mixtures of regioisomeric 3- and 5-substituted pyrazoles. Conditions were found for selective formation of 1-aryl(alkyl)-5-(5-ethoxycarbonyl-2,4-dimethyl-1H-pyrrol-3-yl)-1H-pyrazoles.     

Synthesis of α-2′-deoxynucleosides

α-Thymidine (4) was synthesized from thymidine (1) in 3 steps in 36% overall yield without using chro-matography and with the possibility of increasing the yield to 85% by reusing the remaining α,β-mixture. 1-(2-Deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl)thymine (3) was further converted to 1-(2-deoxy-α-D-erythro-pentofuranosyl)-5-methylcytosine (5) .