A proton spin–lattice relaxation rate and nuclear Overhauser effect investigation of the stereochemistry of some 1-aryl derivatives of 1,2-dihydro-s-triazines

Proton spin–lattice relaxation rates (R₁ values) have been measured, at 400 MHz, for a number of 2-methyl- and 2,2-dimethyl-substituted 4,6-diamino-1-aryl-1,2-dihydro-S-triazines. These compounds have high barriers to internal rotation about the aryl C? N bond, and exist in solution as mixtures of enantiomeric or diastereomeric rotational isomers. Diastereotopically related 2-methyl groups in enantiomeric rotamers, and 2-methyl and 2-methine protons in diastereomeric rotamers, typically have different relaxation rates. In favourable circumstances this information may be used to identify the individual rotamers. Unequivocal direct identification of rotamers may be obtained from nuclear Overhauser effect difference spectra.     

Synthesis, structural determination and dynamic behavior of 2-chloro-4,6-bis(pyrazolylamino)-1,3,5-triazines

A series of 2-chloro-4,6-bis(pyrazolylamino)-1,3,5-triazines with applications in crystal engineering have been prepared. At low temperature, the presence of two or three isomers has been detected and these assigned to 4,6-diamino-1,3,5-triazine structures on the basis of comparison with model compounds. 2D-Exchange spectroscopy studies in various solvents and at different temperatures have been used to determine the equilibrium constants and the activation free energies of the restricted rotation about the amino-triazine bond. A plot of the activation free energy versus temperature showed a good linear correlation and confirmed that the same process is present in all of the compounds under investigation. Comparison with model compounds also confirmed both the occurrence of the restricted rotation and the 4,6-diamino-1,3,5-triazine tautomerism for triazines 1-4 in solution. The structure of compound 1 has been determined in the solid state by X-ray crystallography and consists ofa 4,6-diamino- 1,3,5-triazine structure stabilized by intra and intermolecular hydrogen bonds.     

Nucleophilic substitution reactions of 2,4,6-tris(trinitromethyl)-1,3,5-triazine. 2. interaction of 2,4,6-tris(trinitromethyl)-1,3,5-triazine with primary amines and hexamethyldisilazane

2-R-amino-4,6-bis (trinitromethyl)-1,3,5-triazines have been synthesized, and their structures have been established. Dynamic¹³C NMR spectroscopy has been used to measure the rotational barriers of the tertbutylamino group around the C₍₂₎-NHBu-t bond in 2-(tert-butylamino)-4,6-dichloro-1, 3, 5-triazine and 2-(tertbutylamino)-4,6-dimethoxy-1,3,5-triazine. X-ray diffraction was used to investigate the structure of 2-(tertbutylamino)-4,6-bis (trinitromethyl)-1,3,5-triazine. From the results obtained in this work it has been concluded that the bond between the NHBu-t group and the triazine ring has a partial double-bond character.N. D. Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 117913. Translated from ] Khimiya Geterotsikiicheskikh Soedinenii, No. 5, pp. 679–688 May, 1995. Original article submitted March 7, 1995.     

Photooxygenation of 5-aryl-2,4-diaminopyrimidines leading to 4-amino-1,3,5-triazin-2-yl ketones and,in the presence of sodium borohydride,to 5,6-dihyro-4(3H)-pyrimidinones

The photosensitized oxygenation of 5-aryl-2,4-diaminopyrimidines 1 in protic solvent led to the formation of the new 4-amino-1,3-5-triazin-2-yl ketones 2 in high yields. The structures of 2 were elucidated by spectroscopical means, especially by ¹³C-NMR and UV data. Photooxygenation of 2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine 1a under reductive conditions, e.g. In the presence of excess NaBH₄, gave 2-amino-5-(p-chlorophenyl)-t-6-ethyl-5,6-dihydro-r-5-hydroxy-4(3H)-pyrimidinone ( 4a ), the structure of which was determined by X-ray analysis. In the proposed mechanisms for both types of reactions, the dipolar ion 5 is assumed to be a common intermediate. For the new efficient synthesis of 1,3,5-triazines from 2,4-diaminopyrimidines, a 5-aryl substituent seems to be essential.     

Mass spectra of substituted pyrazolo[1,5-a]-1,3,5-triazines

High resolution electron impact mass spectrometric measurements have been made on twelve pyrazolo[1,5-a]-1,3,5-triazines. Substituents attached to carbon atoms 2, 4, 7, and 8 were used to label the various fragments. Three major ions were observed (a) the molecular ion, (b) an ion corresponding to M-RCN where R is the substituent attached to C-4 and (c) an aryl cyclopropenyl cation which was observed in 7-aryl derivatives. Intensities and accurate mass-measurements are given for all ions having intensities exceeding 2% of the base peak. Nine of the twelve pyrazolo-[1,5-a]-1,3,5-triazines included in this study are described here for the first time.     

Condensed Tetrazolo-1,3,5-triazines. 1. Synthesis of 5-Polynitromethyltetrazolo[1,5-<Emphasis Type="Italic">a</Emphasis>]-1,3,5-triazin-7-one Salts

The aziridation of 2-R-4,6-bis(trinitromethyl)-1,3,5-triazines containing electron-donor substituents has been studied. It was found that the corresponding 4-azido-2-dialkylamino-6-trinitromethyl-1,3,5-triazines are formed when R = NMe₂, NEt₂. When R = O^–NMe₄ ⁺ a novel reaction route was discovered leading to the tetramethylammonium salt of 5-polynitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one which is formed as a result of azido-tetrazole and lactim-lactam tautomeric conversion. Denitration of this salt at the trinitromethyl group occurs with retention of the tetrazolo-1,3,5-triazine structure. An X-ray analysis was carried out for the denitration product which was the dipotassium salt of 5-dinitromethyltetrazolo[1,5-a]-1,3,5-triazin-7-one.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 259–266, February, 2005.     

P-Triazinylphosphonium chlorides as a new group of coupling reagents

Tertiary phosphines in reaction with 2-chloro-4,6-dialkoxy-1,3,5-triazines gave unstable quaternary P-triazinylphosphonium chlorides, which readily decomposed with a departure of the alkyl group of the triazine ring substituent. Stable quaternary P-triazinylphosphonium chlorides were obtained only in reaction of 2-chloro-4,6-diphenoxy-1,3,5-triazine. Both, stable quaternary P-triazinylphosphonium chlorides as well unstable analogues prepared in situ activated carboxylic acid yielding “superactive” triazine esters, useful as highly efficient reagents in peptide bond synthesis.      

Synthesis of substituted 2-amino-4,6-bis(nonafluoro-tert-butyl)-1,3,5-triazines

A procedure was developed for the synthesis of substituted 2-amino-4,6-bis(nonafluoro-tert-butyl)-1,3,5-triazines from 2-chloro-4,6-bis(nonafluoro-tert-butyl)-1,3,5-triazine and aliphatic and aromatic amines. The data of¹⁹F NMR spectroscopy are indicative of the presence of a barrier to internal rotation. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1568–1572, August, 1999.     

Synthesis and structure of new 1,3,5-triazine-pyrazole derivatives

We have studied the reaction of methylenedicarbonyl compounds with 4,6-disubstituted 2-hydrazinyl-1,3,5-triazine in order to obtain novel coupled biheterocyclic aromatic systems with potential bioactivity. Reaction conditions were studied and optimized, and a series of 4,6-disubstituted 2-(1H-pyrazolyl)-1,3,5-triazines were obtained with good yield.     

Synthetic strategies to prepare 2-alkyl, 2-aryl and 2-acetylenyl substituted 4,6-diamino-1,3,5-triazines

We have developed synthetic protocols to generate 2-alkyl, 2-aryl and 2-acetylenyl substituted 4,6-diamino-1,3,5-triazines from the corresponding 2-chloro compound.     

Syntheses and spectral characteristics of 6-mono-, 3,6-di- and 3,5,6-trisubstituted-1,2,4-triazines

The reaction of acidhydrazides with α-substituted carbonyl compounds in the presence of metal acetates gives substituted 1,2,4-triazines. These cyclisations could be effected without any added acetate by refluxing in dimethyl formamide, pyridine/acetic acid or dimethyl sulfoxide Sixty five 3,5,6-tri-3,6-di and 6 monosubstituted-1,2,4-triazines (in 50–90% yields) with a wide variation in the C₃ substituent (alkyl, aryl or heteryl) and the C₆-substituent (aryl or heteryl) are reported. The mechanistic path followed in the formation of these compounds is discussed.     

Development of a fluorescence polarization immunoassay for the detection of melamine in milk and milk powder

A fluorescence polarization immunoassay (FPIA) based on a polyclonal antibody was developed for the determination of melamine in milk. To obtain an antibody with improved sensitivity and specificity, 6-hydrazinyl-1,3,5-triazine-2,4-diamine was coupled to bovine serum albumin and used as the immunogen for the rabbit immunization. Three fluorescein-labeled melamine tracers with different structures and spacer bridges were synthesized. The structural effect of the tracers on the assay characteristics was investigated. 6-(4,6-Diamino-1,3,5-triazin-2-ylamino)-N-(2-(3-(3′,6′-dihydroxy-3-oxo-2,3-dihydrospiro[indene-1,9′-xanthene]-5-yl)thioureido)ethyl)hexanamide demonstrated better sensitivity than 5-(2-(4,6-diamino-1,3,5-triazin-2-yl)hydrazinecarbothioamido)-2-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic acid and 3-(4,6-diamino-1,3,5-triazin-2-ylthio)-N-(2-(3-(3′,6′-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9′-xanthene]-5-yl)thioureido)ethyl)propanamide. The limit of detection (10% inhibition) of the FPIA was 9.3 ng mL^-1 and the IC₅₀ (50% inhibition) value was 164.7 ng mL^-1. The antibody in the FPIA showed 21.2% cross-reactivity to the fly-killing insecticide cyromazine, but had no cross-reactivity to other natural structurally related compounds. Recoveries, measured in spiked milk and milk powder samples, ranged from 79.4 to 119.0%. Milk samples fortified with melamine were analyzed by this method and confirmed by high-performance liquid chromatography–mass spectrometry. Excellent recoveries and correlation with spiked levels were observed, suggesting that this immunoassay could be applied to the screening of melamine residues in milk and milk powder after a simple dilution procedure.      

Hapten synthesis and antibody production for the development of a melamine immunoassay

The incorporation of melamine into food products is banned but its misuse has been widely reported in both animal feeds and food. The development of a rapid screening immunoassay for monitoring of the substance is an urgent requirement. Two haptens of melamine were synthesized by introducing spacer arms of different lengths and structures on the triazine ring of the analyte molecular structure. 6-Aminocaproic acid and 3-mercaptopropionic acid were reacted with 2-chloro-4,6-diamino-1,3,5-triazine (CAAT) to produce hapten 1 [3-(4,6-diamino-1,6-dihydro-1,3,5-triazin-2-ylamino) hexanoic acid] and hapten 2 [3-(4,6-diamino-1,6-dihydro-1,3,5-triazin-2-ylthio) propanoic acid], respectively. The molecular structures of the two haptens were identified by ¹H nuclear magnetic resonance spectrometry, mass spectrometry and infrared spectrometry. An immunogen was prepared by coupling hapten 1 to bovine serum albumin (BSA). Two plate coating antigens were prepared by coupling both haptens to egg ovalbumin (OVA). A competitive indirect enzyme-linked immunosorbent assay (ciELISA) was developed to evaluate homogeneous and heterogeneous assay formats. The results showed that polyclonal antibodies with high titers were obtained, and the heterogeneous immunoassay format demonstrated a better performance with an IC₅₀ of 70.6 ng mL⁻¹, a LOD of 2.6 ng mL⁻¹ and a LOQ of 7.6 ng mL⁻¹. Except for cyromazine, no obvious cross-reactivity to common compounds was found. The data showed that the hapten synthesis was successful and the resultant antisera could be used in an immunoassay for the rapid and sensitive detection of this banned chemical.     

An efficient microwave-assisted synthesis and biological properties of polysubstituted pyrimidinyl- and 1,3,5-triazinylphosphonic acids

Polysubstituted pyrimidinylphosphonic and 1,3,5-triazinylphosphonic acids with potential biological properties were prepared in high yields by the microwave-assisted Michaelis–Arbuzov reaction of trialkyl phosphite with the corresponding halopyrimidines and halo-1,3,5-triazines, respectively, followed by the standard deprotection of the phosphonate group using TMSBr in acetonitrile. 4,6-Diamino-5-chloropyrimidin-2-ylphosphonic acid (7a) was found to exhibit a weak to moderate anti-influenza activity (28–50 μM) and may represent a novel hit for further SAR studies and antiviral improvement.     

<Emphasis Type="Italic">sym</Emphasis>-triazines. 8. Synthesis and some reactions of 4,6-disubstituted 2-(1H-pyrrolyl)-1,3,5-triazines

We have studied the reaction of 2,5-dimethoxytetrahydrofuran with 4,6-disubstituted 2-amino-1,3,5-triazines with the aim of obtaining novel coupled polyheterocyclic systems with potential bioactivity. Reaction conditions were optimized. A series of novel 4,6-disubstituted 2-(1H-1-pyrrolyl)-sym-triazines was obtained. It was found that the product yields depended on the nature of the substituent in the 4 and 6 positions of the triazine ring and on the reaction conditions. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 440–451, March, 2008.     

Synthesis of 4-amino-6-chloro-1,3,5-triazin-2(1H)-ones

Conditions for selective substitution for one chlorine atom in 2-(R,R??-amino)-4,6-dichloro-1,3,5-triazines with a hydroxide ion were elaborated. Spectral and calculation methods showed that the products formed are in the lactam form, i.e., have the structure of 4-chloro-6-(R,R??-amino)-1,3,5-triazin-2(1H)-ones.     

Mono‐, bis‐ and tris‐piperidine fused imidazolinium salts: their in situ catalytic applications for C?C bond formation in aqueous solutions

The 1,5,6,7,8,8a‐hexahydroimidazo[1,5‐a]pyridine, 3, was quaternized with 2‐(bromomethyl‐1,3,5‐trimethylbenzene, 1,4‐bis(bromomethyl)‐2,3,5,6‐tetramethylbenzene, 2,4‐bis(bromomethyl)‐1,3,5‐trimethylbenzene, 1,3,5‐tris(bromomethyl)‐2,4,6‐trimethylbenzene and 1,3,5‐tris(bromomethyl)‐2,4,6‐triethylbenzene to obtain mono‐, bis‐ and tris‐imidazolinium salts (4–7) which were characterized by elemental analysis and NMR spectroscopy. In order to understand the effects of these changes on the N‐substituent and how they translate to catalytic activity, these new salts (4–7) with Pd(OAc)₂ were applied as in situ catalysts for Suzuki‐Miyaura and Heck‐Mirozoki cross‐coupling reactions of aryl chlorides and aryl bromides, respectively. The tris‐imidazolinium salts (7) were found to be more efficient than the related analogs 4–6. Copyright © 2009 John Wiley & Sons, Ltd.     

4-(<Emphasis Type="Italic">N,N</Emphasis>-Dialkylthiocarbamoylthio)-5-nitropyrimidines as new potential nitric oxide donors

On heating at pH 6.86, 4-(N,N-dialkylthiocarbamoylthio)-5-nitropyrimidines are transformed into dithiolopyrimidines, which are either oxidized to bis(4-dialkylthiocarbamoylpyrimidin-5-yl) disulfides or converted into 4,6-diamino-5-nitropyrimidine derivatives with carbon disulfide elimination. The direction of the reaction is determined by the nature of a substituent in position 2 of pyrimidine and the bulk of the thiocarbamate substituent. Mechanistic schemes for these processes were proposed. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2777–2783, December, 2005.     

Synthesis and properties of z-1,3-bis-(aryl)-4-bromo-2-buten-1-ones

Bromination of 1,3-bis(aryl)-2-buten-1-ones by N-bromosuccinimide in anhydrous carbon tetrachloride gives Z-1,3-bis(aryl)-4-bromo-2-buten-1-ones. The effect of the nature of substituent in the benzene ring on the course of a reaction with nucleophiles has been studied. Heating an alcohol solution of these ketones (Ar = 4-MeOC₆H₄, 4-ClC₆H₄) in the presence of acid or in the presence of base (Ar = Ph) gave 2,4-bis(aryl)furans. Treatment of 1,3-bis(aryl)-4-bromo-2-buten-1-ones with thioacetamide gave 2,4-bis(aryl)thiophenes. The oxidation of the halo-substituted dypnones with H₂O₂/NaOH gave (3-bromomethyl-3-aryl-2-oxiranyl)(aryl)methanones. The reaction of halo-substituted dypnones with aryl hydrazines gave 1,3,5-triaryl-1,6-dihydropyridazines or 1,3,5-triarylpyridazinium bromides depending on the structure of the reagents.     

Relation of the chemical structure of polycyanurates to thermal and mechanical properties

Forty polycyanurates were prepared by the interfacial polycondensation of 2-substituted 4,6-dichloro-s-triazines with various aromatic diols. Nitrobenzene was used as a solvent, aqueous sodium hydroxide as an acid acceptor, and a cationic emulsifier as an accelerator. The rate of reaction was largely increased by ultrasonic irradiation. The polymer yield was in the range 57–91%, and the reduced viscosity was 0.41–3.5. The polymers were soluble in chloroform, nitrobenzene, and o-dichlorobenzene but insoluble in common organic solvents such as alcohol, acetone, and hydrocarbons. A clear film was obtained from the chloroform-soluble polymers after evaporation of the solvent. The softening temperature and the thermal stability of each polycyanurate was significantly related to the substituent on the s-triazine nucleus as well as to the diol component in the molecular chain. Polymers of favorable properties were derived from 2-substituted 4,6-dichloro-s-triazines with R = ? C₆H₅, ? N(C₆H₅)₂, ? N(C₆H₁₁)₂, ? N(C₆H₅)(SO₂C₆H₄CH₃), or carbazyl and aromatic diols such as 4,4′-dihydroxybenzophenone, Bisphenol A, or phenolphthalein. These polymers showed tensile strength of 500–670 kg/cm², elongation at break of 2.9–6.0%, and a minor weight loss at 300–350°C.