Synthesis and antiviral evaluation of some novel [1,2,4]triazolo[4,3-β][1,2,4]triazole nucleoside analogs

Ribosylation of 3-amino-5H-[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 1 ) with l-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose and stannic chloride resulted in the following protected nucleoside analogs: 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 4 ), 3-amino-1-(2,3,5-tri-O-benzoyl-α-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), 3-amino-1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)[1,2,4]triazolo[4,3-β][1,2,4]triazole ( 5 ), and 3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) amino-5H-[1,2,4]triazolo[4,3-b]-[1,2,4]triazole ( 7 ). Compounds 4–6 were deprotected to 3-amino-1-β-D-ribofuranosyl[1,2,4]triazolo[4,3-b][1,2,4]-triazole ( 3 ), 3-amino-1-α-D-ribofuranosyl[1,2,4]triazolo[4,5-b][1,2,4]triazole ( 8 ), and 3-imino-2H-2-β-D-ribo-furanosyl[1,2,4]triazolo[4,3-b][1,2,4]triazole ( 9 ), while 7 could not be deprotected without decomposition. Compounds 1, 4, 6, 7 , and 9 were screened and found to have no antiviral activity.     

2,3- and 3,4-Bis(diethoxyphosphorylmethyl)-5-tert-butylfurans

Reduction of 2-, 4-acetoxymethyl derivatives of 5-tert-butylfuran-3-carboxylic acid leads to the corresponding bis(hydroxymethyl)furans. Bis(chloromethyl)furans prepared from the latter were involvedin reaction with sodium diethyl phosphite. In the presence of two equivalents of a phosphorus-containing nucleophile, bis(phosphonomethyl)furans are formed. One equivalent of sodium diethyl phosphite reacts with 3,4-bis(chloromethyl)furan to give a mixture of 3-and 4-phosphorylated products in a 4.5:1 ratio in a low yield. The revealed difference in reactivity between the 3- and 4-chloromethyl groups demonstrates the importance of shielding of the chloromethyl group by the neighboring tert-butyl substituent. Examination of the ¹H NMR spectra of 3,4-bis(hydroxymethyl)-, 3,4-bis(chloromethyl)-, 3,4-bis(diethoxyphosphorylmethyl)-5-tert-butylfurans, and also specially prepared 5-tert-butyl-3-(diethoxyphosphorylmethyl)-4-(ethoxymethyl)-2-methylfuran established that the signal of the substituent neighboring to the tert-butyl group is always shifted downfield.     

Identification of 4,5-unsymmetrically substituted l-amino- and 1-(N-arylacetylamino)-1,2,3-triazoles by 13C-NMR

¹³C nmr chemical shifts are used for the structural assignment of isomeric 1-amino-1,2,3-triazoles and 1-(N-arylacetylamino)-1,2,3-triazoles unsymmetrically substituted with phenyl, methyl or hydrogen in the 4,5-positions of the triazole ring. A signal at 11 ± 0.6 ppm indicates a 4-methyl triazole derivative, whereas a signal at 7.9 ± 1 ppm indicates a 5-methyl triazole. A signal at 120 ± 0.5 ppm (C-5) indicates a hydrogen in the 5-position (unsubstituted triazole).     

Selective Hydrogen Chloride Elimination from Primary Chlorides Induced by the Fluoride Anion. Anchimeric participation of the chloromethyl group in the heterolytic opening of an epoxide. Stereospecific syntheses of 5,6-bis (methylidene)-syn-2-norbornen-7-ol and 5,6-bis (methylidene)-endo-3-chloro-exo-2-norbornanol

Syntheses of the alcohols 10 and 18 , and the corresponding ketones 11 and 19 are presented. Endo-5, exo-6-bis (chloromethyl)-endo-3-chloro-exo-2-norbornanol ( 16 ) and endo-5-(bromomethyl)-exo-6-(chloromethyl)-endo-3-chloro-exo-2-norbornanol ( 17 ) were obtained by HCl- and, respectively, HBr-addition to endo-5, exo-6-bis (chloromethyl)-exo-2, 3-epoxynorbornane ( 5 ). The Wagner-Meerwein rearrangement was precluded in these reactions probably because of the formation of a relatively stable chloronium ion 15 arising from the participation of the 1,4-chlorine atom of the endo-5-chloromethyl group in the heterolytic ring opening of the epoxide 5 . The ‘naked’ fluoride anion (excess CsF in DMF or KF in DMF with 18-crown-6-ether) permitted the selective elimination of 2 equivalents of HCl from 16 and yielded the chlorohydrin-diene 18 .     

Reaction of 1-(o-Aminophenyl)-1,2,3-triazole-5-thiols with Cyclizing Reagents

Reactions of 1-(o-aminophenyl)-1,2,3-triazole-5-thiols with ring-closing reagents destabilize the triazole ring, promoting the Dimroth rearrangement and subsequent cyclization to 5-(1-benzazolyl)-1,2,3-thiadiazoles.     

Diazoaldehyde Chemistry. Part 4vilsmeier-haack formylation of diazo compounds: A re-investigation

Diazomethyl ketones (2-diazoethanones) were reacted with the Vilsmeier reagent ((chloromethylidene)dimethylammonium chloride) to yield α-diazo-β-oxoaldehydes and chloromethyl ketones. 2′,4′-Dimethoxy-α-diazoacetophenone gave 2-chloro-1-(2,4-dimethoxyphenyl)-3-(dimethylamino)prop-2-en-1-one ( 5 ) in addition to the expected products. Phenyldiazomethanes gave the corresponding benzyl chlorides but not the (phenyl)diazoacetaldehydes even at temperatures as low as ?60°. The diazo-transfer reactions of phenylacetaldehydes and 2-azido-1-ethylpyridin-1-ium tetrafluoroborate also did not yield the expected(phenyl)diazoacetaldehydes.     

Polycondensed heterocycles. III. Synthesis of 5,11-dioxo-1,2,3,1 1a-tetrahydro-5H,11H- and 5-oxo-2,3,11,1 1a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzothiazepine

The syntheses of 5,11-dioxo-1,2,3,11a-tetrahydro-5H11H- and 5-oxo-2,3,11,11a-tetrahydro-1H,5H-pyrrolo-[2,1-c][1,4]benzothiazepine 10 and 11 have been studied. The former was obtained by intramolecular cyclization with CDI of N-(2-mercaptobenzoyl)-L-proline 19 , prepared on one hand by demethylation of N-(2-methylthiobenzoyl)-L-proline t-butyl ester 15 , obtained via the Pummerer rearrangement of the corresponding sulphoxide 17 and successive alkaline hydrolysis, and by deprotection of the mercapto ester 18 with TFA or trimethylsilyl iodide. The ester 15 was achieved by reaction of o-(methylthio)benzoic acid 12 with L-proline t-butyl ester or by treatment of the corresponding acid chloride 13 with L-proline and successive esterification of N-(2-methylthiobenzoyl)-L-proline 16 . On the other hand the proline 19 was also obtained by reduction with sodium dithionite of (S)-bis[2-[[2-(hydroxycarbonyl)-1-pyrrolidinyl]carbonyl]phenyl] disulphide 20 , prepared by condensation of bis(2-chlorocarbonylphenyl) disulphide 14 with L-proline. The reduction of (S)-bis[2-[[2-(chloromethyl)-1-pyrrolidinyl]carbonyl]phenyl] disulphide 28 with sodium borohydride in boiling ethanol afforded directly the benzothiazepinone 11 in 85% yield. The disulphide 28 was synthesized treating the corresponding alcohol 24 or N-(2-mercaptoben-zoyl)-L-prolinol 25 with thionyl chloride. Compound 25 was obtained by demethylation of the corresponding methylthio ether 26 oxidized to sulphoxide 27 via the Pummerer rearrangement. The acid chloride 14 by condensation with (S)-2-(chloromethyl)pyrrolidine hydrochloride gave disulphide 28 as well. The acid chlorides 13 and 14 by reaction with L-prolinol provided respectively alcohols 26 and 24 . Attempts to cyclodehydrate the mercapto alcohol 25 , obtained also by reduction of disulphide 24 , failed.     

Synthesis and Antimicrobial Activity of N‐Aryl‐4‐(cyano/alkoxycarbonyl)‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole Derivatives

A convenient synthesis of a new series of N‐aryl‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole‐4‐carbonitriles and alkyl N‐aryl‐5‐(pyridin‐3‐yl)‐1H/3H‐1,2,3‐triazole‐4‐carboxylic acid esters is reported. The newly synthesized 5‐(pyridin‐3‐yl)‐1,2,3‐triazole derivatives are evaluated for their antibacterial and antifungal activity. Some of these triazole derivatives have exhibited moderate antimicrobial activity.     

Face Selectivity of the Diels-Alder Additions of Exocyclic Dienes Grafted onto 7-Oxabicyclo[2.2.1]heptanes

Stereoselective syntheses of 2exo, 3exo-bis (chloromethyl)-5-[(Z)-chloromethylidene]- ( 9 ), 2exo, 3exo-bis (chloromethyl)5-[(E)-chloromethylidene]- ( 10 ) and 2exo, 3exo-bis(chloromethyl)-5-[(E)-methoxymethylidene]-6-niethylidene-7-oxa-bicyclo[2.2.1]heptane ( 13 ) are presented. Double elimination of HCI from 9, 10 and 13 yielded 2-[(Z)-chloromethylidene]- ( 14 ), 2-[(E)chloromethylidene]- ( 15 ) and 2-[(E)-methoxymethylidene]-3,5,6-mmethylidene-7-oxabicycio[2.2.1]heptane ( 18 ), respectively, without loss of the olefin configuration. Ethylene tetracarbonitrile (TCE) and N-phenyltriazolinedione (NPTAD) added to these new exocyclic dienes and tetraenes preferentially onto their exo-face. The same face selectivity was observed for the cycloadditions of TCE to the (Z)- and (E)-chlorodienes 9 and 10 , thus realizing a case where the kinetic stereoselectivity of the additions is proven not to be governed by the stability of the adducts. The exo-face selectivity of the Diels-Alder additions of dienes grafted onto 7-oxabicyclo [2,2.1]heptanes contrasts with the endo-face selectivity reported for a large number of cycloadditions of dienes grafted onto bicyclo[2.2.1]heptane skeletons.     

Synthesis of new uracil non‐nucleoside derivatives as potential inhibitors of HIV‐1

6‐(2‐Phenylethyl) and 6‐cyclohexyl 5‐cyanouracils ( 1a,b ) were synthesized and reacted with chloromethyl ethyl ether, benzyl chloromethyl ether, chloromethyl methyl sulfide and (2‐acetoxyethoxy)methyl bromide. New uracil analogues of (S)‐DHPA were synthesized by reaction of compounds ( 1a,b ) with ((S)‐2,2‐dimethyl‐1,3‐dioxolane‐4‐yl) alkyl p‐toluenesulfonate.     

Reaction of 2,4-Difunctional Esters of 5-tert-Butylfuran-3-carboxylic Acid with Nucleophilic Reagents

Ethyl 5-tert-butyl-4-(chloromethyl)-2-methylfuran-3-carboxylate was brominated with N-bromo-succinimide to obtain the corresponding 2-bromomethyl derivative. The latter is selectively phosphorylatedwith trimethyl, triethyl phosphites by the bromomethyl group. The resulting [4-(chloromethyl)furyl]methyl-phosphonates in the presence of secondary amines and sodium butanethiolate behave as alkylating agents,while sodium phenolate causes their decomposition. 4-Acetoxymethyl- and 4-phenoxymethyl derivatives of the starting product are also selectively brominated with N-bromosuccinimide by the 2-methyl group. The first of the 2-(bromomethyl)furans formed is smoothly phosphorylated with trimethyl phosphite, while the second one under the action of triethyl phosphite gives a mixture of phosphorylation and debromination products. In all the cases, an additional electron-acceptor group in position 4 of alkyl 2-(bromomethyl)-5-tert-butylfuran-3-carboxylate considerably accelerates the Arbuzov reaction.     

Condensed isoquinolines. 38*. Azolo[<Emphasis Type="Italic">b</Emphasis>]isoquinolines from 2-(halomethyl)benzoic acid derivatives

On interacting 2-(chloromethyl)-, 2-(bromomethyl)benzonitrile or methyl 2-(bromomethyl)benzoate with 1-R-1H-imidazoles and 1-R-1H-benzimidazoles quaternary diazolium salts are formed, the heating of which with bases (K₂CO₃, Et₃N) led to the intramolecular acylation products, 1-alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium halides, 5-alkyl-6-amino-5H-benzimidazo[1,2-b]isoquinolin-12-ium halides, or 1-alkyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate halides.     

Reaction of the 5-Azoniafulvene Ion with Enamines: A New Approach to Pyrrolizines

The synthesis of N,N-dimethyl-N-[(pyrro-1-yl)methyl]anilinium chloride ( 14 ) and of the corresponding p-toluidinium salt 15 is described. These salts, when dissolved in polar solvents, are shown to be in equilibrium with 1-(chloromethyl)pyrrole ( 17 ) and thereby potentially with the 5-azoniafulvene ion ( 2 ). Consequently, they react under very mild conditions (MeCN, 60°) with enamines to give pyrrolizine derivatives in acceptable yield (40–50°). The process is rationalized in terms of an initial Mannich-type reaction which is immediately followed by acyclization.     

Chiral benzimidazole derived bis-phenyl triazoles as chiroptical sensors for iodide and chiral amines

A series of chiral 2-hydroxy ethyl/benzyl benzimidazole based aryl triazole tweezers have been prepared using click chemistry in high yields. Chiral pool strategy has been used to obtain the benzimidazole-based tweezers in very high enantiomerically enriched form. The aryl triazole tweezers, S -(−)- 5a and S -(+)- 8a displayed a high degree of selectivity for iodide anion over other anions, including other halides. The aryl triazole tweezers, S -(−)- 5a and S -( + )- 8a display significant enantio-discrimination for chiral amines. The chiral recognition studies were carried out using UV and circular dichroism (CD) spectroscopy. NMR analysis has been used for establishing the sites for ligation of the iodide anion.     

A short synthesis of 5-methylhistamine

Methoxybromination of 4,5-dihydro-2-methylfuran ( 4 ), followed by treatment of the resulting bromoketal 5 with hot formamide, gave 4-(2-hydroxyethyl)-5-methyl-1H-imidazole ( 3 ) in 25% yield. This method provides easy access to the selective H₂-agonist 4-methylhistamine ( 1 ) via the chloromethyl intermediate 2 .     

Silver Salt and Derivatives of 5‐Azido‐1H‐1, 2, 4‐triazole‐3‐­carbonitrile

This study features the preparation of three new energetic C‐azido‐1, 2, 4‐triazoles, with the anion of one being a new binary C–N compound. 5‐Azido‐1H‐1, 2, 4‐triazole‐3‐carbonitrile ( 1 ) was prepared from 5‐amino‐1H‐1, 2, 4‐triazole‐3‐carbonitrile and further derivatized to 5‐azido‐1H‐1, 2, 4‐triazole‐3‐carbohydroximoyl chloride ( 5 ) with 3‐azido‐1H‐1, 2, 4‐triazole‐5‐carboxamidoxime ( 3 ) as an intermediate. The ability of 1 and 3 for salt formation was shown with the respective silver salts 2 and 4 . All compounds were well characterized by various means, including IR and multinuclear NMR spectroscopy, mass spectrometry, and DSC. The molecular structures of 1 , 3 , and 5 in the solid state were determined by single‐crystal X‐ray diffraction. The sensitivities towards various outer stimuli (impact, friction, electrostatic discharge) were determined according to BAM standards. The silver salts were additionally tested for their potential as primary explosives.     

Carbamates,thiolcarbamates, dithiocarbamates and thioncarbamates derived from 2-benzothiazolinone and benzoxazolinone

The reaction of 3-(2-hydroxyethyl)-2-benzothiazoline with methyl, phenyl isocyanate, or dimethylcarbamoyl chloride afforded the carbamates 1–4 . The carbanilate 5 was prepared by the reaction of 2-benzothiazolinone with 3-chloropropyl-N-methylcarbanilate under basic conditions. The reaction of the appropriate 2-benzothiazolinone with the appropriate 2-chloro or 3-chloropropyl disubstituted thiolcarbamate under basic conditions furnished the thiolcarbamates 6–14 . The thiolcarbamate 15 was prepared by the reaction of sodium di-isopropylthiolcarbamate with 3-(chloromethyl)-2-benzothiazolinone. The reaction of 3-(chloromethyl)-2-ben-zothiazolinone and related compound with the appropriate sodium or triethylamine salt of disubstituted dithiocarbamate afforded the dithiocarbamate 16–22 . The reaction of the appropriate xanthate with the potassium salt of bromoacetic acid and the appropriate secondary amine afforded the thionocarbamates 23–29 . The thionocarbamate 30 was synthesized by the reaction of 5-chloro-2-benzothiazolinone with 3-chloropropyl diethylthionocarbamate.     

Synthesis and Characterization of Bis(triaminoguanidinium) 5,5′‐Dinitrimino‐3,3′‐azo‐1H‐1,2,4‐triazolate – A Novel Insensitive Energetic Material

The synthesis of 5,5′‐diamino‐3,3′‐azo‐1H‐1,2,4‐triazole ( 3 ) by reaction of 5‐acetylamino‐3‐amino‐1H‐1,2,4‐triazole ( 2 ) with potassium permanganate is described. The application of the very straightforward and efficient acetyl protection of 3,5‐diamino‐1H‐1,2,4‐triazole allows selective reactions of the remaining free amino group to form the azo‐functionality. Compound 3 is used as starting material for the synthesis of 5,5′‐dinitrimino‐3,3′‐azo‐1H‐1,2,4‐triazole ( 4 ), which subsequently reacted with organic bases (ammonia, hydrazine, guanidine, aminoguanidine, triaminoguanidine) to form the corresponding nitrogen‐rich triazolate salts ( 5 – 9 ). All substances were fully characterized by IR and Raman as well as multinuclear NMR spectroscopy, mass spectrometry, and differential scanning calorimetry. Selected compounds were additionally characterized by low temperature single‐crystal X‐ray diffraction measurements. The heats of formation of 4 – 9 were calculated by the CBS‐4M method to be 647.7 ( 4 ), 401.2 ( 5 ), 700.4 ( 6 ), 398.4 ( 7 ), 676.5 ( 8 ), and 1089.2 ( 9 ) kJ · mol^–1. With these values as well as the experimentally determined densities several detonation parameters were calculated using both computer codes EXPLO5.03 and EXPLO5.04. In addition, the sensitivities of 5 – 9 were determined by the BAM drophammer and friction tester as well as a small scale electrical discharge device.     

Organosilicon derivatives of 2-mercapto-substituted benzoxazoles,benzothiazoles and benzimidazoles

The interactions of sodium salts of 2-mercaptobenzoxazole, 2-mercaptobenzothiazole and 2-mercaptobenzimidazole with (chloromethyl)trimethyl-, chloromethyl(dimethoxy)methylor (chloromethyl)trimethoxysilanes have been shown to result in the corresponding previously unknown (2-heterylthiomethyl)triorganylsilanes. Transetherification of (2-heteryl-thiomethyl)trimethoxysilanes with triethanolamine gives 1-(2-benzoxazolylthiomethyl)-, 1-(2-benzothiazolylthiomethyl)- and 1-(2-benzimidazolylthiomethyl)silatranes. The reaction of the corresponding alkoxysilanes with boron trifluoride etherate leads to (2-benzoxazolylthiomethyl)- and (2-benzothiazolylthiomethyl)-substituted trifluorosilanes and methyldifluorosilanes having a dragonoid chelate structure. By the hydrolysis of (2-heterylthiomethyl)trimethoxysilanes, new organosilicon sorbents, poly(2-heteryl-thiomethyl)silsesquioxanes have been synthesized.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1965–1969, November, 1993.     

A facile synthesis of 4‐, 6‐ and 7‐formyl‐1H‐indole‐2‐carboxylates: The CH2SO3H functionality as a masked formyl group

The valuable new synthetic intermediates, ethyl 4‐, 6‐ and 7‐formyl‐1H‐indole‐2‐carboxylates ( 10, 11, 12 ) were prepared from 2‐ethoxycarbonyl‐1H‐indole‐4‐, 6‐ and 7‐methanesulfonic acids ( 1, 2, 3 ), respectively. The transformation of sulfomethyl group to formyl function was accomplished through elimination of SO₂ to yield ethyl 4‐, 6‐ and 7‐chloromethyl‐1H‐indole‐2‐carboxylates ( 4, 5, 6 ), hydrolysed to ethyl 4‐, 6‐ and 7‐hydroxymethyl‐1H‐indole‐2‐carboxylates ( 7, 8, 9 ), then oxidized to aldehydes ( 10, 11, 12 ). Protection at N1 of indole was not necessary. A marked increase in the rate of hydrolysis of 7‐chloromethyl‐indoles compared to that of 4‐ and 6‐(chloromethyl)indoles was observed.