2-amino-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidines: Synthesis and reactions with electrophilic reagents

The hydrogenation of 2-amino-5-R-7-R′-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines with NaBH₄ led to the formation of 2-amino-5-R-7-R′-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidines. Acylation, sulfonylation, and alkylation of these compounds depending on conditions and the reagent character occur at the amino group, atoms N³ or N⁴. The treatment with alkali of 2-amino-3-benzyl-5-R-7-R′-4,5,6,7-tetrahydro-1,2,4-triazolo-[1,5-a]pyrimidinium bromide resulted in 2-amino-3-benzyl-5-R-7-R′-3,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidine, similar reaction of 2-acetamido-3-benzyl-5-R-7-R′-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]-pyrimidinium bromide gave a mesoionic product of a hydrogen elimination from the amide nitrogen atom.     

New heterocyclic systems based on 1-hydrazino-5,6,7,8-tetrahydro[2,7]naphthyridine: 7,8,9,10-tetra-hydro[1,2,4]triazolo[3,4-a]- and 7,8,9,10-tetra-hydro[1,2,4]triazolo[5,1-a][2,7]naphthyridines

Methods have been developed for the synthesis of new substituted 7,8,9,10-tetrahydro[1,2,4]triazolo-[3,4-a][2,7]naphthyridines from 3-chloro-1-hydrazino-7-methyl-5,6,7,8-tetrahydro-[2,7]naphthyridine-4-carbonitrile. It was shown that on heating in an amine (ethanolamine, pyrrolidine, 2-hydroxy-propylamine), they undergo a Dimroth rearrangement at the triazole fragment, being converted into 7,8,9,10-tetrahydro[1,2,4]triazolo[5,1-a][2,7]naphthyridine derivatives.     

Retinoidal pyrimidinecarboxylic acids. Unexpected diaza-substituent effects in retinobenzoic acids

Several pyridine- and pyrimidine-carboxylic acids were synthesized as ligand candidates for retinoid nuclear receptors, retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Although the pyridine derivatives, 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]pyri dine-3-carboxylic acid (2b) and 6-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carboxamido]py ridine-3-carboxylic acid (5b) are more potent than the corresponding benzoic acid-type retinoids, Am80 (2a) and Am580 (5a), the replacement of the benzene ring of Am580 (5a), Am555 (6a), or Am55 (7a) with a pyrimidine ring caused loss of the retinoidal activity both in HL-60 cell differentiation assay and in RAR transactivation assay using COS-1 cells. On the other hand, pyrimidine analogs (PA series, 10 and 11) of potent RXR agonists (retinoid synergists) with a diphenylamine skeleton (DA series, 8 and 9) exhibited potent retinoid synergistic activity in HL-60 cell differentiation assay and activated RXRs. Among the synthesized compounds, 2-[N-n-propyl-N-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)a mino]pyrimidine-5-carboxylic acid (PA013, 10e) is most active retinoid synergist in HL-60 assay.     

Synthesis and crystal structure of a covalently hydrated 8-thia-1,4-diazacycl[3.3.2]azine

Condensation of ethyl 4-chloroacetoacetate with 4-amino-6-hydroxy-2-pyrimidinethiol produced ethyl 3-hydroxy-5-amino-7-oxothiazolino[3,2-a]pyrimidin-3-acetate ( 7a ) on crystallization. Subsequent ring closure of 7a produced the tricyclic 6a-hydroxy-5,6,6a,7-tetrahydro-8-thia-1,4-diazacycl[3.3.2]azin-2,5-dione ( 8 ). The structure of 8 was confirmed by crystal x-ray diffraction analysis.     

Synthèse et étude physicochimique des 1,2,4-triazolo[4,3-a]-pyridines et des 1,2,4-triazolo[2,3-a]pyridines

The synthesis of 1,2,4-triazolo[4,3-a] and [2,3-a]pyridines 7, 8 was achieved by cyclization of 2-hydrazino-8-nitropyridine 3a with formic acid. The 4,5,6,7-tetrahydro-1,2,4-triazolo[2,3-a]pyridine 13 and 8-amino-1,2,4-triazolo[2,3-a]pyridine 9 were obtained by catalytic hydrogenation. The reduction of triazolo pyridine 8 using stannous chloride led to the intermediate compound 10 which with acetic anhydride afforded 8-acetylamino-5-chloro-1,2,4-triazolo[2,3-a]pyridine 10a . The structure of the derivatives was determined by ¹H-nmr (DMSO-d₆).     

Synthesis of New Heterocyclic Systems on the Basis of 7-Benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthiridine-4-carbonitrile

Methods have been developed for the synthesis of new 8-amino-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine starting from 7-benzyl-3-chloro-1-(morpholin-4-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile. 8-Hydrazinyl-3-benzyl-5-(morpholin-4-yl)-1,2,3,4-tetrahydropyrimido[4′,5′: 4,5]thieno[2,3-c][2,7]naphthyridine has been converted to isomeric pentacyclic structures with a triazole ring fused through the [c] side of the pyrimidine ring, and their Dimroth rearrangement has been accomplished in both acidic and basic media. New heterocyclic systems containing pyrrolo[1,2-a]pyrimidinone and pyrimido[1,2-a]azepinone fragments were obtained on the basis of the thieno-[2,3-c][2,7]naphthyridine derivative.     

New tri-tert-alkyl substituted o-quinones of tetraline family

New tri-tert-alkyl substituted o-quinones of 3-tert-alkyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-1,2-dione chemotype were obtained from phenol and 2,5-dichloro-2,5-dimethylhexane, with the SeO₂ oxidation of the sterically hindered phenol moiety having been performed at the final step. The electrochemical reduction of these quinones proceeds in two stages: the first reduction wave (E_1/2 = –0.60 ÷ –0.62 V) is reversible, while the second stage is irreversible.     

Recyclization of dimedone adduct with 2-(2-oxo-2-phenylethylidene)propanedinitrile in the reaction with N-nucleophiles

Three-component condensation of dimedone with phenylglyoxal hydrate and malononitrile gave a polyfunctional 5,6,7,8-tetrahydro-4H-chromene derivative, 2-amino-4-benzoyl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile, which reacted with ammonium acetate to produce pyrrolo[3,4-c]quinoline ring system. Reactions of the condensation product with primary and secondary amines and hydroxylamine hydrochloride afforded polysubstituted pyrroles, whereas the reaction with hydrazine hydrate led to 3-amino-6-phenylpyridazine-4-carbonitrile.     

Reaction of 1-substituted 3,5-diamino-1,2,4-triazoles with β-keto esters: synthesis and new rearrangement of mesoionic 3-amino-2H-[1,2,4]triazolo-[4,3-a]pyrimidin-5-ones

Reaction of 3,5-diamino-1-R-1,2,4-triazoles (R=Ph, Bn) with β-keto esters results in the reversible formation of N-(5-amino-1-R-1,2,4-triazol-3-yl)-substituted enaminoesters (8). Subsequent transformations depended on the reaction conditions. Compounds 8 undergo intermolecular reactions of condensation and amidation in the absence of solvent. However, in the presence of acetic acid they form 3-amino-5-oxo-2-R-2,5-dihydro-[1,2,4]triazolo[4,3-a]pyrimidin-4-ium-8-ides (10) followed by rearrangement to 3-amino-1-R-[1,2,4]triazolo[4,3-a]pyrimidin-5-ones (11). The transformation of 10 into 11 represents a new type of rearrangement in the azolopyrimidine series. Heating of enaminoesters 8 in ethanol with sodium ethoxide present, proved to be a suitable method for the preparation of the mesoionic compounds 10.     

Structure and reactions of a thiazolino[3,2-a]pyrimidine carbinolamine

Ethyl 4-chloroacetoacetate condenses with 4-amino-6-hydroxy-2-pyrimidinethiol to yield ethyl 3-hydroxy-5-oxo-7-aminothiazolino[3,2-a]pyrimidin-3-acetate ( 3 ), and not ethyl 3-hydroxy-5-amino-7-oxothiazolino[3,2-a]-pyrimidin-3-acetate, as previously reported. This compound reacts with ammonia to produce ethyl 4-(6′-amino-4′-oxo-2′-pyrimidinethiol)-3-aminocrotonate ( 8 ), the open chain structure of which accounts for the cyclization of 3 to the poly-cyclic lactam, 6a-hydroxy-5,6,6a,7-tetrahydro-8-thia-1,4-diazacycl[3.3.2]azine-2,5-dione, rather than the sterically more favorable lactone, when 3 was treated with triethylamine. Some other reactions of 3 are described, and the structures of 3 and 8 were comfirmed by single crystal X-ray diffraction analysis.     

Reaction of 3-oxo-N-phenylbutanethioamide with 5-amino-1H-1,2,4-triazoles

Reactions of 3-oxo-N-phenylbutanethioamide with 3-substituted 5-amino-1H-1,2,4-triazoles in acetic acid led to the formation of 5-methyl-7,8-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-7-thiones, 7-methyl-5,8-dihydrol[1,2,4]triazolo[1,5-a]pyrimidine-5-thiones and 7-methyl-5-phenylamino[1,2,4]triazolo[1,5-a]pyrimidines. The structure of the products was proved by the ¹H and ¹³C NMR spectra, X-ray diffraction data, and chemical transformations.     

Reactions of 4-oxobenz[1,3-e]oxazinium perchlorates with α-aminoazoles

Reactions of 4-oxo benz[1,3-e]oxazinium perchlorates with 1-R¹-3-R²-5-aminopyrazoles lead to the formation of derivatives of pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]1,3,5]triazine series, and with 3-amino-1,2,4-triazole, to [1,2,4]triazolo[1,5-a][1,3,5]triazines.     

Improved synthesis of 2-amino-1,2,4-triazolo[1,5-a]pyrimidines

An improved procedure is suggested for preparing 2-amino-1,2,4-triazolo[1,5-a]pyrimidines from 3,5-diamino-1,2,4-triazole and unsaturated aromatic ketones, with acetyl protection of the amino group in the step of oxidation of 2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines.     

1-Acylmethylbenzimidazole-2-sulfonic acids and their cyclization by N-nucleophiles

New preparation method was developed for derivatives of 1,4-dihydro-1,2,4-triazino[4,3-a]-, 2-aryl-1(9)H-, and 1-R-imidazo[1,2-a]benzimidazole underlain by newly synthesized 1-acylmethylbenzimidazole-2-sulfonic acids. The latter react with 2-aminoethanol affording along with the previously described compounds of the 1-(2-hydroxyethyl)imidazobenzimidazole series also compounds of formerly unknown polycyclic system, 2,3,11,12-tetrahydro-1,3-oxazolo[2,3-a]imidazo[1,2-a]benzimidazole.     

Cyclocondensation of 3-Amino-1,2,4-triazoles with Esters of Substituted Cinnamic Acids and Aromatic Unsaturated Ketones

We have studied the reactions of 3-amino, 3,5-diamino-, and 3-amino-5-trifluoromethyl-1,2,4-triazole with esters of substituted cinnamic acids and aromatic unsaturated ketones; we have established the directionality of formation of the tetrahydrooxopyrimidine ring. We have carried out hydrolysis and hydrazinolysis of 7-phenyl-4,5,6,7-tetrahydro-1,2,4-triazolo[1,5-a]pyrimidin-5-one. We have conducted an X-ray diffraction study of isopropylidene hydrazide of 3-(5-amino-1,2,4-triazol-1-yl)-3-phenylpropionic acid.     

Synthesis of 7-(2-R-pyrimidin-4-yl)- and 7-(2-R-[1,2,4]triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-7-yl)-2,2,4,6-tetramethyl-1,2,3,4-tetrahydroquinolines

Cyclization of 3-(dimethylamino)-1-(2,2,4,6-tetramethyl-1,2,3,4-tetrahydroquinolin-7-yl)prop-2-en-1-one with carboximidamides, guanidines, and 1,2,4-triazol-5-amines afforded a number of new 2,2,4,6-tetramethyl-7-(2-R-pyrimidin-4-yl)-1,2,3,4-tetrahydroquinolines and 2,2,4,6-tetramethyl-7-(2-R-[1,2,4]triazolo-[1,5-a]pyrimidin-7-yl)-1,2,3,4-tetrahydroquinolines.     

Novel retinoidal tropolone derivatives. Bioisosteric relationship of tropolone ring with benzoic acid moiety in retinoid structure

Several tropolone derivatives (4-7) were designed as novel retinoids on the assumption that the tropolone ring may mimic the benzoic acid moiety in retinoid structures, such as Am80 (2). Among the synthesized compounds, 5-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)ethynyl]tropolone (7a) showed moderate potency as a differentiation-inducer of HL-60 cells. The activities of the tropolones were greatly enhanced in the presence of HX630, an RXR agonist (retinoid synergist).     

A new approach to synthesis of 2-sulfonylamino-1,2,4-triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidines

A procedure for synthesis of 2-sulfonylamino-1,2,4-triazolo[1,5-a]pyrimidines by sulfonylation of 2-amino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines, followed by oxidation of intermediate 2-sulfonylamino-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines, was suggested.     

2-aryl(hetaryl)-4H-[1,2,4]triazolo[1,5-a]benzimidazoles

2-(4-Methylphenyl)-4H-[1,2,4]triazolo[1,5-a]benzimidazole and its previously unknown 2-(2-furyl)- and 2-(2-thienyl)-substituted analogs were synthesized by cyclization of benzimidazole-1,2-diamine with the corresponding carboxylic acid chlorides. The IR, ¹H, ¹³C, and ¹⁵N NMR, and mass spectra of the cyclization products in combination with the results of quantum-chemical calculations of NMR chemical shifts showed radical differences of [1,2,4]triazolo[1,5-a]benzimidazoles having no substituent on N⁴ from the recently reported low-melting products of oxidation of 2-amino-1-arylmethylideneaminobenzimidazoles with (diacetoxy-λ³-iodanyl)benzene, which, as we believe, were erroneously assigned analogous structure.     

Synthesis and Chemical Transformations of 5-Alkyl(phenyl)-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidin-7-oles

5,5,7-Trimethyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-7-ol was synthesized by cyclocondensation of 3-amino-1,2,4-triazole with 4-methylpent-3-en-2-one; its chemical transformations, and also the transformations of 5-phenyl-4,5,6,7-tetrahydro[1,2,4]triazolo[1,5-a]pyrimidin-7-ol were investigated in reactions with reagents of diverse electronic nature.