The effect of substituents on the conformational mobility of the heterocycle in 1,4-dihydropyrimidine and its derivatives

The equilibrium geometry of 1,4-dihydropyrimidine, 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, and their alkyl (Me, Et, Prⁱ, Bu^t) and phenyl derivatives has been calculated by molecular mechanics method. The equilibrium conformation of unsubstituted molecules is planar, but it is easily transformed to the boat conformation with a small change in the conformational energy. The effect of substituents on the geometry and conformational mobility of the dihydropyrimidine ring has been studied.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1394–1397, August, 1994.     

Cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine with hydroxylamine and hydrazine

The cyclocondensation of 6-acetyl-4,7-dihydro-5-methyl-7-phenyl[1,2,4]triazolo[1,5-a]pyrimidine (3) with hydroxylamine or hydrazine leads to 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenylisoxazolo-[5,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4a ) and 3a,4,9,9a-tetrahydro-3,9a-dimethyl-4-phenyl-1H-pyrazolo[3,4-d][1,2,4]triazolo[1,5-a]pyrimidine ( 4b ), respectively. In the presence of methanolic hydrogen chloride, 4b undergoes a cleavage of the pyrimidine ring to yield (5-amino-1,2,4-triazol-1-yl)(3,5-dimethylpyrazol-4-yl)phenylmethane ( 5 ). The structure determination of the compounds obtained is based on ¹H and ¹³C nmr spectra including NOE measurements.     

Imine-enamine tautomerism of dihydroazolopyrimidines 5. Steric effects and the tautomeric equilibrium for dihydro-1,2,4-triazolo[1,5-a]pyrimidines

The reaction of 3-amino-1,2,4-triazole with -dimethylaminopropiophenones or unsaturated ketones gives 5,7-disubstituted 4,7(6,7)-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. An increase in the bulk of the substituent at C₍₇₎ in the bicyclic system leads to relative stabilization of the enamine tautomer of these compounds. An x-ray diffraction structural analysis of 7-tert-butyl-5-(4-methoxyphenyl)-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine showed that the introduction of a tert-butyl group into the dihydropyrimidine ring leads to significant loss of planarity of this system.For Communication 4, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1357–1363, October, 1993.     

An efficient,multicomponent, green protocol to access 4, 7-dihydrotetrazolo [1, 5-a] pyrimidines and 5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-ones using PEG-400 under microwave irradiation

Abstract

A facile one-pot synthesis of ethyl 5-methyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine, 5-tert-butyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine, 6,6-dimethyl-5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-one and 5,6,7,9-tetrahydrotetrazolo[5,1-b]quinazolin-8(4H)-one derivatives were described via a three-component reaction of aldehyde, 5-aminotetrazole and diketones in PEG-400 under microwave irradiation at 110?°C for 30?min. A wide range of diketones such as ethylacetoacetate, tert-butyl acetoacetate, 5,5-dimethylcyclohexane-1,3-dione and 1,3-cyclohexanedione were utilized to carry out the synthesis of different dihydrotetrazolo[1,5-a]pyrimidines and tetrahydrotetrazolo[1,5-a]quinazolinones. This method has the advantage of green protocol, operational simplicity, high yields, recyclability of the solvent and involves isolation of the final product without column purification. The scope of this reaction tolerates with aromatic, heteroaromatic and alicyclic aldehydes.     

On triazoles XXIII [1]. The reaction of 5-amino-1,2,4-triazoles with thiacyclohexane β-oxo esters [2]

Six novel isomeric ring systems, namely the thiopyrano[4,3-d]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[3,4-e]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[4,3-e]-1,2,4-triazolo[1,5-a]pyrimidine, the thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine and the thiopyrano[2,3-e]-1,2,4-triazolo[1,5-a]pyrimidine were synthesised. Spectroscopical evidence was given for the structure of compounds obtained.     

Cyclocondensation of [1-Cyano-2-(methylsulfanyl)vinyl]triphenylphosphonium Iodide with Amidine Nucleophiles

The substituted vinylphosphonium salt (E)-MeSCH=C(CN)P⁺Ph₃I⁻ readily cyclizes under the action of benzamidine and 3-amino-s-triazole, but it does not enter cyclocondensation with 2-aminopyridine. The structure of the cyclization product with 3-amino-s-triazole was confirmed by its transformation to 7-imino-6-(triphenylphosphoranylidene)-6,7-dihydro-s-triazolo[1,5]pyrimidine which was identified by X-ray diffraction. This stabilized ylide and its analogs proved useful starting materials for regioselective syntheses of 2-R-4-alkyl-4,7-dihydro-s-triazolo[1,5-a]pyrimidin-7-ones.__________Translated from Zhurnal Obshchei Khimii, Vol. 75, No. 4, 2005, pp. 565–570.Original Russian Text Copyright © 2005 by Smolii, Muzychka, Chernega, Drach.     

Reactivity of 7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines: Synthesis of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as potential benzodiazepine receptor ligands. 1

A series of 7-methylpyrazolo[1,5-a]pyrimidines were reacted with dimethylformamide dimethylacetal to give the corresponding dimethylaminovinyl derivatives. These were reacted with ammonium acetate affording, through a ring closure, a number of 6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidines bearing various substituents on the pyrazole ring. The 6-acetyl-2-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine was used as starting material for obtaining some O-alkyl derivatives. Catalytic transfer hydrogenation of 2-benzyloxy-6-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidine led to the 2-hydroxy derivative.     

On triazoles. X. The reaction of 5-amino-1,2,4-triazoles with tetrahydrothiophene β-keto esters

Three novel ring systems, namely the thieno[3,4-d]-1,2,4-triazolo[1,5-a]pyrimidine, the thieno[3,4-e]-1,2,4-triazolo[1,5-a]pyrimidine and the thieno[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine were synthesised. The structure of compounds obtained was proved with the help of their uv and cmr spectra using model compounds prepared for this purpose.     

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.     

Platinum(IV) complexes with purine analogs. Studies of molecular structure and antiproliferative activity in vitro

A series of tetrachloride platinum(IV) compounds of the general formulae PtCl₄L₂, where L = 1,2,4-triazolo[1,5-a]pyrimidine (tp) (1), 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine (dmtp) (2), 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine (dbtp) (3) and 5-methyl-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one (HmtpO) (4) have been prepared and characterized by thermal analysis, ¹H, ¹³C, ¹⁵N, ¹⁹⁵Pt NMR and IR spectroscopy. Spectral data suggest that the triazolopyrimidines act as a monodentate ligand via the nitrogen atom N(3). The preliminary assessments of antitumor properties of the four complexes were evaluated as in vitro antiproliferative activity against three cell lines: HL-60 human acute promyelocytic leukemia, SW707 rectal adenocarcinoma and HCV29T bladder cancer. PtCl₄(dbtp)₂ exhibits high cytotoxic activity against all human cell lines, whereas the other complexes are only moderately active.     

Imidazo- und Diazino-Anellierungen an das [1]Benzothieno[2,3—d]pyrimidin-System

Derivatives of the following six ring systems were synthesized:

1. 3,10-Dihydro-[1]benzothieno[2,3-d]imidazo[1,5-a]-pyrimidine (I)
2. 6H-[1]Benzothieno[2,3-d]pyrazino[1,2-a]pyrimidine (II)
3. 1,5-Dihydro-[1]benzothieno[2,3-d]imidazo[1,2-a]-pyrimidine (III)
4. 6H-[1]Benzothieno[2,3-d]pyrimido[1,2-a]pyrimidine (IV)
5. 1,5-Dihydro-imidazo[1,2-a]thieno[2,3-d]pyrimidine (V)
6. 4H-Pyrimido[1,2-a]thieno[2,3-d]pyrimidine (VI)

The first four types are new heterocyclic systems. 2-Aminomethyl-5,6,7,8-tetrahydro-[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (5), which was used as intermediate for typesI andII, was synthesized by various methods. TypesIII andIV were prepared from 2-methylthio-5,6,7,8-tetrahydro-[1]-benzothieno[2,3-d]pyrimidin-4(3H)-one via the corresponding 2-benzylamino derivatives, followed by ring closure.     

Reactions of 4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidines with α,β‐unsaturated carbonyl compounds

The reaction of 5,7‐diphenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine ( 1 ) with α,β‐unsaturated carbonyl compounds 2a‐f led to the formation of the alkylated heterocycles 3a‐f (Figure 1). However, the reaction of 5‐methyl‐7‐phenyl‐4,7‐dihydro‐1,2,4‐triazolo[1,5‐a]pyrimidine ( 5 ) with 2a‐c yielded under the same conditions the triazolo[5,1‐b]quinazolines 6a‐c (Figure 3). In this case, the alkylation is followed by a cyclocondensation. The structure elucidation of the products is based on ir, ms, ¹H and ¹³C nmr measurements and on an X‐ray diffraction study.     

Benzannulation of 5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine with chalcones and their synthetic equivalents as a method for the synthesis of tetrazolo[5,1-b]quinazolines

Derivatives of tetrahydrotetrazolo[5,1-b]quinazolines were synthesized by the reactions of 5-methyl-7-phenyl-4,7-dihydrotetrazolo[1,5-a]pyrimidine with α,β-unsaturated carbonyl compounds and their synthetic equivalents in methanol in the presence of sodium methoxide. The spontaneous or specifically target oxidation of these derivatives gives rise to aromatic tetrazoloquinazolines. The reaction pathways and mechanisms were discussed. The structures of the resulting compounds were confirmed by IR and ¹H NMR spectroscopy, mass spectrometry, and elemental analysis. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1971–1976, September, 2008.     

Synthesis of new condensed heterocyclic systems

Two new diamines — [1,3-bis(5-phenyl-1,2,4-triazol-3-yl)-4,6-diamino]benzene and [1,3-di-(2-benzimldazolyl)-4,6-diamino]benzene — were synthesized from 4,6-dinitroisophthalic acid. Newheterocyclic systems — 3,5,9,11-tetraphenyl[benzo[1,2-a; 4,5-a]bis(1,2,4-triazolo[4,3-c]pyrimidine)] and 2,16-diphenyl[benzo[1,2-a;4,5-a']bis(pyrimido[1,6-a]benzimidazole)]—were obtained by reaction of the diamines with benzoyl chloride and subsequent cyclization.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1274–1277, September, 1977.     

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.     

Synthesis of 6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]pyrimidine-5-carboxylic acids and their methyl esters

6-Acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylic acids and methyl 6-acyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-5-carboxylates were synthesized by fusion of 4-aryl-2,4-dioxobutanoic acids and their methyl esters, respectively, with 1H-tetrazol-5-amine and aromatic aldehydes. The reaction of methyl 2,4-dioxopentanoate with 1H-tetrazol-5-amine and 2-fluorobenzaldehyde in boiling acetic acid gave methyl 6-acetyl-5-hydroxy-7-(2-fluorophenyl)-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidine-5-carboxylate.     

A solution of structural ambiguity: s-Triazolo[1,5-a] – and s-triazolo[4.3-a] pyrimidines

The condensation of 3-amino-5-benzylthio-s-triazole ( 2 ) with acetylacetone in refluxing acetic acid has been reported to have given 3-benzylthio-5,7-dimethyl-s-triazolo[4,3-a]pyrimidine ( 3 ). However, it has now been established, with the aid of ¹³C spectra and a modification of the original synthetic work, that only 2-benzylthio-5,7-dimethyl-s-triazolo[1,5-a]pyrimidine ( 4 ) can be obtained by this method of condensation. The erroneously reported, but previously unknown 6 was synthesized and its structure and that of 4 was firmly established by ir, uv, pmr,¹³ C nmr, tlc and mixed melting point data. The correct structures of 3-mercapto-5,7-dimethyl-s-triazolo-[4,3-a]pyrimidine ( 5 ) and 2-mercapto-5,7-dimethyl-s-triazolo[1,5-a]pyrimidine ( 6 ) were also established and the facile rearrangement of 5 to 6 was demonstrated.     

A synthesis of 6-functionalized 4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidines

6-Unsubstituted 7-R-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines (R = H or Me) were synthesized via two pathways: (a) deacylation of the corresponding 5-acetyl Biginelli-like precursors in KOH/H₂O and (b) reduction of the corresponding 1,2,4-triazolo[1,5-a]pyrimidines using LiAlH₄. The products could be easily formylated at position 6, which is promising for the further synthesis of functionalized 6-substituted derivatives of 4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidines. In contrast, 6-acetyl-7-(4-(N,N-dimethylaminophenyl))-5-methyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine undergoes a cascade process in KOH/H₂O, leading to the formation of a 4,5,8,9-tetrahydro[1,2,4]triazolo[5,1-b]quinazoline derivative.     

SnAr Reactions of 2,4-Diazidopyrido[3,2-d]pyrimidine and Azide-Tetrazole Equilibrium Studies of the Obtained 5-Substituted Tetrazolo[1,5-a]pyrido[2,3-e]pyrimidines

A straightforward method for the synthesis of 5-substituted tetrazolo[1,5-a]pyrido[2,3-e]pyrimidines from 2,4-diazidopyrido[3,2-d]pyrimidine in SnAr reactions with N-, O-, and S- nucleophiles has been developed. The various N- and S-substituted products were obtained with yields from 47% to 98%, but the substitution with O-nucleophiles gave lower yields (20–32%). Furthermore, the fused tetrazolo[1,5-a]pyrimidine derivatives can be regarded as 2-azidopyrimidines and functionalized in copper(I)-catalyzed azide-alkyne dipolar cycloaddition (CuAAC) and Staudinger reactions due to the presence of a sufficient concentration of the reactive azide tautomer in solution. In total, seven products were fully characterized by their single crystal X-ray studies, while five of them were representatives of the tetrazolo[1,5-a]pyrido[2,3-e]pyrimidine heterocyclic system. Equilibrium constants and thermodynamic values were determined using variable temperature ¹H NMR and are in agreement of favoring the tetrazole tautomeric form (ΔG₂₉₈ = −3.33 to −7.52 (kJ/mol), ΔH = −19.92 to −48.02 (kJ/mol) and ΔS = −43.74 to −143.27 (J/mol·K)). The key starting material 2,4-diazidopyrido[3,2-d]pyrimidine presents a high degree of tautomerization in different solvents.