Synthesis of various 3-substituted 1,2,4-oxadiazole-containing chiral beta 3- and alpha-amino acids from Fmoc-protected aspartic acid

Various 3-substituted chiral 1,2,4-oxadiazole-containing Fmoc-beta(3)- and -alpha-amino acids were synthesized from Fmoc-(l or d)-Asp(OtBu)-OH and Fmoc-l-Asp-OtBu, respectively, in three steps (i.e., condensation of an aspartyl derivative with differentially substituted amidoximes, formation of the 1,2,4-oxadiazole, and cleavage of the tert-butyl ester). These compounds represent new series of nonnatural amino acids, which could be used in combinatorial synthesis. A simple protocol has been developed to generate the 1,2,4-oxadiazole ring. Indeed, common methods resulted in cleavage of the Fmoc group or required long reaction times. We found that sodium acetate in refluxing ethanol/water (86 degrees C) was a convenient and efficient catalyst to promote conversion of Fmoc-amino acyl amidoximes to 1,2,4-oxadiazoles, and this procedure proved to be compatible with Fmoc protection. It is shown that these compounds can be prepared without significant loss of enantiomerical purity. Furthermore, the alkaline conditions used to cleave the Fmoc protecting group from these compounds did not induce epimerization of their chiral center.     

Synthesis of 3-Azido-5-amino-1,2,4-triazole

3-Azido-5-amino-1,2,4-triazole was obtained from 3,5-diamino-1,2,4-triazole in two ways: by partial diazotization-substitution directly in the substrate or at its primarily nitrosation, and also with the use of direct or indirect protection of an amino group with subsequent conversion into azido compound followed by deprotection.     

Solvent-free reaction of 3-aryl-6-(3-nitrophenyl)-1,2,4-triazines with 4-(cyclohex-1-en-1-yl)morpholine

The aza-Diels–Alder reaction of 3-aryl-6-(3-nitrophenyl)-1,2,4-triazines with 4-(cyclohex-1-en-1-yl)morpholine as dienophile was accompanied by reduction of the nitro group to amino. In the reaction of 3-(4-methoxyphenyl)-6-(3-nitrophenyl)-1,2,4-triazine with 4-(cyclohex-1-en-1-yl)morpholine, 3-[3-(4-methoxyphenyl)-1,2,4-triazin-6-yl)aniline was formed together with the cycloaddition product.     

Studies on the Reaction of α‐Chloroformylarylhydrazine Hydrochloride with Imidazole and 1,2,4‐Triazole

α‐Imidazolformylarylhydrazine 2 and α‐[1,2,4]triazolformylarylhydrazine 3 have been synthesized through the nucleophilic substitution reaction of 1 with imidazole and 1,2,4‐triazole, respectively. 2,2′‐Diaryl‐2H,2′H‐[4,4′]bi[[1,2,4]‐triazolyl]‐3,3′‐dione 4 was obtained from the cycloaddition of α‐chloroformylarylhydrazine hydrochloride 1 with 1,2,4‐triazole at 60 °C and in absence of n‐Bu₃N. The inducing factor for cycloaddition of 1 with 1,2,4‐triazole was ascertained as hydrogen ion by the formation of 4 from the reaction of 3 with hydrochloric acid. 4 was also acquired from the reaction of 3 with 1 and this could confirm the reaction route for cycloaddition of 1 with 1,2,4‐triazole. Some acylation reagents were applied to induce the cyclization reaction of 2 and 3.1 possessing chloroformyl group could induce the cyclization of 2 to give 2‐aryl‐4‐(2‐aryl‐4‐vinyl‐semicarbazide‐4‐yl)‐2,4‐dihydro‐[1,2,4]‐triazol‐3‐one 6. 7 was obtained from the cyclization of 2 induced by some acyl chlorides. Acetic acid anhydride like acetyl chloride also could react with 2 to produce 7D . 5‐Substituted‐3‐aryl‐3H‐[1,3,4]oxadiazol‐2‐one 8 was produced from the cyclization reaction of 3 induced by some acyl chlorides or acetic acid anhydride. The 1,2,4‐triazole group of 3 played a role as a leaving group in the course of cyclization reaction. This was confirmed by the same product 8 which was acquired from the reaction of 1 , possessing a better leaving group: Cl, with some acyl chlorides or acetic acid anhydride.     

Reactivity of 3H-1,2,4-dithiazole-3-thiones and 3H-1,2-dithiole-3-thiones as sulfurizing agents for oligonucleotide synthesis

The reactivity of 5-amino-3H-1,2,4-dithiazole-3-thiones substituted at their amino group and 5-amino-3H-1,2-dithiole-3-thiones substituted at their amino group and C4 toward compounds containing P(III) atoms has been studied. N,N-Disubstituted-N′-(3-thioxo-3H-1,2,4-dithiazol-5-yl)methanimidamides were selected as novel efficient sulfur transfer reagents suitable for DNA and RNA synthesis.     

Acylation and iodination of 5-(p-R-phenyl)-1,2,4-triazole-3-thiones

The acylation of 5-(p-R-phenyl)-1,2,4-triazole-3-thiones was studied. It was shown that the reaction depends on the nature of the group in the para position of the 5-phenyl substituent. Iodination of the sodium salts of 1,2,4-triazole-3-thiones is accompanied by the formation of disulfides, whereas 1,2,4-triazole-3-thiones that contain an unsaturated substituent with an allylic bond in the 4 position of the ring are iodinated to give condensed thiazolotriazole systems.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 843–846, June, 1984.     

Calculation of the electron structures and electronic spectra of 3-chloro- and 3-amino-1,2,4-triazole derivatives

3-Chloro- and 3-amino-1,2,4-triazole derivatives were subjected to a theoretical study by means of quantum-chemical calculation by the Pariser-Parr-Pople method. The experimentally observed electron transitions were assigned. The Cl atom and the NH₂ group in the 3 position of 1,2,4-triazole subject the electron system of the heteroring to substantial perturbation.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 698–700, May, 1977.     

Synthetic and spectroscopic study of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones

5-Amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 can be synthesized from 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) via a selective acylation with an acid anhydride in pyridine. The ¹H nmr spectral characteristics of 5-amino-2-acyl-1,2,4-thiadiazolin-3-ones 2–1 is in particular, compared with 5-amino-2H-1,2,4-thiadiazolin-3-one ( 1–1 ) and 5-amino-2-alkyl-1,2,4-thiadiazolin-3-ones 1–2, 1–3 . The 5-amino group of 2–1 appeared as two peaks in its ¹H nmr spectrum, which merged to a single peak at a higher temperature, while those of compound 1–1, 1–2 and 1–3 appear only as a single peak. The restricted rotation of the C(5)-N(5) (at amino) bond of 5-amino-2-acetyl-1,2,4-thiadiazolin-3-one (2a-1) is about 14.5 Kcal/mol.     

Heterocyclic nitro compounds. 27. Methods for the synthesis of 3-nitro-5-R-1,2,4-triazoles

A method for the preparation of 3-nitro-5-R-1,2,4-triazoles by reaction of 1-(3'-oxobutyl)-3,5-dinitro-1,2,4-triazole with nucleophilic reagents with various structures with replacement of the nitro group in the 5 position of the triazole ring during subsequent elimination of the oxobutyl fragment in an alkaline medium is examined. A number of previously undescribed NH acids, viz., 1,2,4-triazole derivatives, including 3-nitro-5-azolyl-1,2,4-triazoles, were obtained, and the ionization constants were determined for some of them.See [1] for Communication 26.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp, 1553–1557, November, 1980.     

Solvatochromism of Heteroaromatic Compounds: IX. Anions of 3-Nitro-1,2,4-triazol-5-ones

Solvatochromism of the long-wave band in the electronic absorption spectra of 3-nitro-1,2,4-triazol-5-one anions was studied and quantitatively described with the Kamlet-Taft solvent parameters. Azole anions are specifically solvated in amphiprotic solvents. The strength of the hydrogen bond in H complexes with amphiprotic solvents decreases in going to the Franck-Condon excited state. The UV and IR specrta show that 3-nitro-1,2,4-triazol-5-one anions, in contrast to nitroazole anions, are specifically solvated with participation of the carbonyl group. In highly polar organic solvents the 3-nitro-1,2,4-triazol-5-one anion mainly exists in the form of the 1H tautomer.     

Synthesis of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione and its reactions with C-electrophiles

4-Amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-trazole-3-thione is formed from the reaction of 4,6-diphenylpyrimidinecarboxylic acid or its ethyl ester with thiocarbonyl hydrazide. Alkylation of the product leads to S-alkyl derivaties or 6-substituted 3-(4,6-diphenyl-2-pyriimidinyl)-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazine. Acetylation of 4-amino-5-(4,6-diphenyl-2-pyrimidinyl)-3,4-dihydro-2H-1,2,4-triazole-3-thione gave under different conditions monoacetyl-, diacetyl, and triacetyl derivatives at the amino group and the N₍₂₎ atom, whereas benzoylation gave a benzoyl group at the amino group and 3-(4,6-diphenyl-2-pyrimidinyl)-6-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, 1088–1094, July, 2007.     

Structural modification studies of 3-piperonylsydnone. III. Some analogs of 3-piperonylsydnone and 2,4-diamino-5-piperonylpyrimidine

In a continued structural modification study of the antimalarial compounds 3-piperonylsydnone and 2,4-diamino-5-piperonylpyrimidine, the related piperonyl derivatives of ψ-1,2,3;4-oxatriazole, ψ-1,3,5-oxadiazole, pyrazole, tetrazole, 1,2,4-triazine, pyrrolidine, amino- and sulfamoyl-1,2,4-triazole, as well as some sydnones and diaminopyrimidines with side chains other than the piperonyl group have been synthesized. 3-(3,4-Ethylenedioxyphenyl)sydnone was found to double the survival time of Plasmodium berghei infected mice. The other compounds are not as active.     

Heterocyclic nitro compounds. 28. 1-(Oxoalkyl)-3-nitro-5-r-1,2,4-triazoles in reactions with hydrazine and hydroxylamine

The reaction of 1-(oxoalkyl)-3-nitro-5-R-1,2,4-triazoles with hydroxylainine and hydrazine takes place at the keto group to give azines and oximes (R = H, CH₃), with reduction of the nitro group (R = NO₂, hydroxylamine), or with participation of both reaction centers with annelation and conversion to triazolo[3,2-c]-1,2,4-triazines and -1,2,4-triazepines, depending on the character of the substituent in the 5 position of the triazole ring and the type of reagent.See [1] for Communication 27.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1113–1117, August, 1982.     

Isomeric 3‐Isoxadiazolylcoumarins and Their Derivatives

Here, we represent preparative methods of synthesis of isomeric 3‐isoxadiazolylcoumarins and their derivatives. Two new synthetic methods have been developed for 3‐[1,2,4‐oxadiazol‐5‐yl]coumarins I . The first method is based on a three‐component condensation of coumarin‐;3‐carboxylic acids, 1,1′‐carbonyldiimidazole, and amidoximes. The second method essentially uses the interaction of 5‐cyanomethyl‐1,2,4‐oxadiazoles with salicylic aldehydes. General approach for preparation of 3‐[1,2,4‐oxadiazol‐3‐yl]coumarins II has been worked out. Moreover, aforementioned synthetic ways open the way for the synthesis of 2‐iminoderivatives III and IV not described before, those were diversified by reaction of nucleophilic substitution of 2‐imino group with a numerous amino compounds.     

A Novel Rearrangement Cyclization of 3-Amino-2-benzyl-6-hydrazino-1,2,4-triazin-5-one

A facile ring closure reaction with the N-l nitrogen of the 1,2,4-triazine ring occurs when 3-amino-6-hydrazino-1,2,4-triazin-5-one(1) is refluxed in either acid, orthoester/dimethylformamide, carbon disulfide, cyanogen bromide or nitrous acid. 3-amino-2-benzyl-6-hydrazino-1,2,4-triazin-5-one(2), containing the benzyl group on the 2-position of 1, can not be cyclized under the above reaction conditions except refluxed with carbon disulfide in pyridine-water(1:1), which will pass through a novel rearrangement cyclization to afford a bicycloheterocyclic compound,6-amino-3-benzylmercapto-1,2,4-triazolo[3,4-f][l,2,4]triazin-8(7H)-one(3). The mechanisms of their ring closure and rearrangement cyclization will be presented in detail.     

Polymerization of 1-vinyl-3-amino-1,2,4-triazole and some properties of related polymers

The kinetics of radical polymerization of 1-vinyl-3-amino-1,2,4-triazole was studied. The results show that the presence of the amino group as a substituent on the heterocycle decreases the polymerization activity of the triazole-containing monomer. It was found that water has an accelerating effect on the 1-vinyl-3-amino-1,2,4-triazole polymerization process. The substitution of the amino group on the triazole cycle enhances the hydrophilic properties of the polymer relative to those of unsubstituted polyvinyltriazole and opens up possibilities for its further modification.     

Synthesis and study of thermal stability of 3-nitro-1,2,4-triazole N-nitroxy-and N-azidomethyl derivatives

A method for the preparation of new 3-nitro-1,2,4-triazole derivatives has been suggested based on modification of the N-hydroxymethyl group by nitration and nucleophilic substitution reactions. Thermal stability of 3-nitro-1,2,4-triazole N-nitroxy- and N-azidomethyl derivatives, as well as of dinitrates, 5,5′-dinitro-2,2 ′-bisnitroxymethyl-2 H,2′H-3,3 ′-bi(1,2,4-triazole) and -(nitromethylene)bis(1,2,4-triazole), has been studied.     

Reactivity of some 3-substituted-6,8-dimethylchromones toward some nucleophilic reagents

The reactivity of 3-substituted-6,8-dimethylchromone derivatives 1 - 5 was investigated toward selected nucleophilic reagents namely; 3-amino-1,2,4-triazole, 2-aminobenzimidazole, 7-chloro-4-hydrazinoquinoline, and 5,6-diphenyl-3-hydrazino-1,2,4-triazine. These nucleophiles were allowed to react with 6,8-dimethylchromone-3-carboxaldehyde ( 1 ) through condensation with the aldehyde group with opening of γ-pyrone ring giving compounds 6 , 7 , 10, and 11 . Reactions with 6,8-dimethylchromone-3-carbonitrile ( 2 ), and 6,8-dimethylchromone-3-carboxylic acid ( 3 ) occur via attack at position 2 in both compounds followed by cycloaddition onto the nitrile function (in case of carbonitrile 2 ) or decarboxylation and cyclocondensation with the carbonyl group (in case of carboxylic acid 3 ). The current nucleophilic reagents reacted with simple condensation products 4 and 5 , in boiling dioxane, through nucleophilic addition at the exocyclic vinyl bond followed by addition at the CN group giving 6,8-dimethylchromone linked various heterocyclic systems 20 - 27 .     

An unusual transformation of 5-acyl-1,2,4-triazines into 3-pyridyl-1,2,4-triazines via tandem Stille cross-coupling/aza Diels-Alder reaction

A new route to 3-heteroaryl-1,2,4-triazines possessing a keto substituent at C-5 of the 1,2,4-triazine core using a Stille cross-coupling procedure and their unexpected ring transformation into pyridyltriazines as a result of enolization of an acyl group catalyzed by metal ions, are reported.     

A convenient synthesis of 3-substituted 5-guanidino-1,2,4-oxadiazoles

The reaction of amidoximes with cyanoguanidine in the presence of Lewis acids affords 3-substituted 5-guanidino-1,2,4-oxadiazoles. A study of the reaction of¹⁵N-labeled chloroacetamidoxime with cyanoguanidine showed that the formation of the oxadiazole ring occursvia the elimination of the amino group from the amidoxime fragment. 1,2,4-Oxadiazoles bearing the imidazole or pyrimidine moiety were synthesized.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 118–121, January, 1994.