Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. Part 3: Regioselective solid-phase synthesis of a 2,6,8,9-tetrasubstituted purine library

The first regiocontrolled solid-phase synthesis of a 2,6,8,9-tetrasubstituted purine library was performed through on-resin elaboration of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. A series of primary amines were loaded on ArgoGel-MB-CHO resin via reductive amination to yield secondary amines. Subsequent attachment of the starting pyrimidine core unit and C6-chloride substitution by primary amines yielded the resin-bound 4,6-disubstituted-2-methylthio-5-nitropyrimidines. Oxone^® mediated oxidation of the 2-methylthio moiety to the corresponding sulfone allowed facile substitution at the 2-position. CrCl₂ assisted reduction of the nitro group, followed by acid catalyzed orthoester cyclization and finally TFA mediated cleavage provided the tetrasubstituted purine final products. Most of the final purines were cleaved in good to excellent yield and purity, however, it was found that bulky groups at N9 hindered cyclization in C8-substituted derivatives. For these systems, LC purification of the crude cleavage products provided the target purines in high purity.     

EC(EE) processes in the reduction of some 2-methylthio-4,6-di(alkylamino)-1,3,5-triazines on mercury electrodes

Polarographic (direct current, dc, and differential pulse, DP) studies of the electroreduction of the s-triazine derivatives ametryn (2-methylthio-4-ethylamino-6-isopropylamino)-1,3,5-triazine), dimethametryn (2-methylthio-4-ethylamino-6-(1,2-dimethylpropyl) amino-1,3,5-triazine) and simetryn (2-methylthio-4,6-di(ethylamino)-1,3,5-triazine) were made in the acidity range from 2.25 M H₂SO₄ to pH 6.5. Above this last pH value no signals were obtained. In DP polarography, two main reduction peaks were observed, accompanied by a pre-peak due to the adsorption of the herbicides on the electrode. The main peaks corresponded to two-electron irreversible reduction processes, at pH values higher than the protonation pK of the triazine ring (ca. 4). In this pH range, the protonation of the triazine ring preceding the reduction process is responsible for decrease in limiting current. At pH<pK the herbicides suffer a cleavage of the –SCH₃ group via two different intermediates related by a chemical reaction, whose extension depends on the herbicide.     

An iodocyclization approach toward diastereoselective synthesis of highly functionalized tetrasubstituted tetrahydrofurans with 2,5-trans and 2,5-cis relationships from pyranoside derived acyclic oximes

An efficient method to obtain novel tetrasubstituted tetrahydrofurans with C2 and C5 substitution in trans- and cis-relative configurations has been reported.     

The synthesis of novel C2-symmetric P,N-chelation ruthenocene ligands and their application in palladium-catalyzed asymmetric allylic substitution

Novel air-stable C₂-symmetric tetrasubstituted ruthenocene-based ligands were readily synthesized and used for palladium-catalyzed asymmetric allylic substitution showing excellent enantioselectivity and high catalytic activity.     

A facile synthesis of 4,6-dimethoxy-[2-<Superscript>14</Superscript>C]-2-methylsulphonylpyrimidine

Summary 4,6-dimethoxy-2-methylsulphonylpyrimidine is a key intermediate for the synthesis of pyrithiobac-sodium, a selective herbicide for cotton plant. ¹⁴C labeled pyrithiobac-sodium is required for studying the translocation and metabolism in cotton plants. It was prepared by oxidation of 4,6-dimethoxy-[2-¹⁴C]-2-methylmercaptopyrimidine with H₅IO₆/CrO₃ in ethyl acetate at room temperature to give 4,6-dimethoxy-[2-¹⁴C]-2-methylsulphonylpyrimidine in high yields.     

Crystal solvates and polymorphs of N-(3-methylthio-1,2,4-thiadiazol-5-yl-aminocarbonylmethyl)cytisine

A polymorphs, crystallohydrate and crystallosolvates of N-(3-methylthio-1,2,4-thiadiazol-5-yl-aminocarbonylmethyl)cytisine, C₁₆H₁₉N₅O₂S₂, with chloroform, methanol, benzene have been obtained and crystal structures have been determined by the method of single crystal X-ray diffraction. In the investigated crystals N-(3-methylthio-1,2,4-thiadiazol-5-yl-aminocarbonylmethyl)cytisine have taken four types of conformation due to intra-molecular rotations around N–C and C–C bonds. So free rotations in the molecule assisted in formation a different crystallosolvates and polymorphs depending on nature of solvents. The thermal decomposition of the hydrate and methanol solvated crystals was studied by means of a TG-DSC.     

Preparation and characterization of symmetrical bis[4-chloro-2-pyrimidyl] dichalcogenide (S, Se, Te) and unsymmetrical 4-chloro-2-(arylchalcogenyl) pyrimidine: X-ray crystal structure of 4-chloro-2-(phenylselanyl) pyrimidine and 2-(p-tolylselanyl)-4-chloropyrimidine

Synthesis of a novel class of multinucleate pyrimidine chalcogen (S/Se/Te) derivatives has been successfully attempted for the first time by the selective substitution of chlorine at the C-2 position of 2,4-dichloropyrimidine with nucleophilic dichalcogenide anion E₂²⁻ (E = S, Se, Te) to afford bis[4-chloro-2-pyrimidyl] dichalcogenide. The highly electrophilic nature of 2,4-dichloropyrimidine compared to aryl chlorides has been further exploited to prepare a variety of 4-chloro-2-(arylchalcogenyl) pyrimidine compounds by substituting the chlorine exclusively at the C-2 position of 2,4-dichloropyrimidine with a variety of chalcogen bearing aryl anions ArE⁻ (Ar = phenyl, 1-naphthyl, p-tolyl, 4,6-dimethyl-2-pyrimidyl, 2-pyridyl, 4-methyl-2-pyridyl). All the newly prepared symmetrical and unsymmetrical pyrimidyl chalcogen compounds have been thoroughly characterized with the help of various spectroscopic techniques viz., NMR (¹H, ¹³C, ⁷⁷Se), FT-IR and mass spectrometry (in representative cases). The crystal structures of 4-chloro-2-(phenylselanyl) pyrimidine and 2-(p-tolylselanyl)-4-chloropyrimidine have been determined by X-ray crystallography.     

Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines using Weinreb amide

A method of convergent synthesis of novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines 7 is developed. The synthetic intermediate of 7, 4,6-unsubstituted 2-aminodihydropyrimidines 9 having a Weinreb amide at the 5-position, is prepared by the sequential Staudinger/aza-Wittig/cyclization reactions of (E)-tert-butyl{3-azido-2-[methoxy(methyl)carbamoyl]allyl}carbamate (E)-10. The transformation of the Weinreb amide of 9 to an acyl group proceeds smoothly by a substitution reaction using aryllithiums or alkyllithiums in the presence of a catalytic amount of BF₃ etherate, affording 7 in good to high yield. The N-protecting group of 7 can be easily removed to obtain N-unsubstituted 2-amino-5-acyldihydropyrimidines 8, and the derivatives are observed as a single isomer in ¹H NMR spectroscopy. All dihydropyrimidines in this study were hitherto unavailable and difficult to synthesize by conventional methods.     

Synthesis of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes

A combinatorial library of 4-(2-hydroxyaryl)-3-nitro-4H-chromenes was synthesized in high yield by C4-SMe substitution in N-alkyl/phenyl 4-(methylthio)-3-nitro-4H-chromen-2-amines with a variety of phenols. The reaction always provided C2 substitution in the phenol ring, dictated by hydrogen bond interactions between the phenolic hydroxyl group and the nitro group in 3-nitro-4H-chromenes. Reduction of the nitro group with concomitant hydrolysis of the enamine in 4-(2-hydroxyaryl)-3-nitro-4H-chromenes with Zn, Ac₂O in AcOH furnished hybrid amino-acid lactone incorporating ortho-tyrosine and phenyl alanine moieties.     

Synthesis of diverse 6-(1,2-disubstituted ethyl)purine bases and nucleosides via 6-(oxiran-2-yl)purines

Dihydroxylation of 6-vinylpurines with t-BuOOH and OsO₄ gave 6-(1,2-dihydroxyethyl)purines 2, while the epoxidation with H₂WO₄ and t-BuOOH afforded 6-(oxiran-2-yl)purines 3. Oxirane ring-opening reactions of 3 with diverse nucleophiles gave a series of title 6-(1,2-disubstituted ethyl)purine bases and nucleosides, which were tested for cytostatic and antiviral activities.     

Synthesis of 5-(4,6-dimethyl-2-pyrimidinyl)-1,3,4-oxadiazole-2-thione and its alkylation,aminomethylation, and acylation

The reaction of the hydrazide of 4,6-dimethyl-2-pyrimidinecarboxylic acid with potassium ethylxnthate gave 5-(4,6-dimethyl-2-pyrimidinyl)-1,3,4-oxadiazole-2-thione. The alkylation of this product in an alkaline medium proceeds at the sulfur atom, while the aminomethylation and acylation proceed at the nitrogen atom. The major criterion for the structure of the S- and N-derivatives is the chemical shift of C₍₂₎ in the 1,3,4-oxadiazole ring in the ¹³C NMR spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 700–705, May, 1993.     

Stereospecific synthesis of some polycyclic cis-β-lactams

Amides 1 on reaction with P₂S₅ in pyridine give thioamides 2 which on treatment with methyl iodide afford the corresponding 1-methylthio-3,4-dihydroisoquinolines 3. Annelation of these imines with phenoxyacetyl chloride in the presence of triethylamine furnish 6-methylthio-7-phenoxy-2',3' - dimethoxybenzo[a]octem 4a and 6-methylthio-7-phenoxy-2,3-methylenedioxybenzo[a]octem 4b respectively. Desulphurisation of these β-methylthio-β-lactams with Raney nickel yield the novel polycyclic cis-β-lactams 5a and 5b.     

Stereoselective generation of cis-2-lithio-3-CF3-oxirane via CF3-substituted β-oxido carbenoids. Highly stereoselective synthesis of CF3-substituted tri- and tetrasubstituted oxiranes and tetrasubstituted alkenes

Treatment of 2-substituted 3,3-dichloro-1,1,1-trifluoropropan-2-ols with organolithium reagents R²Li in THF at −98°C stereoselectively produces 2,3-disubstituted 2-lithio-3-trifluoromethyloxiranes with Li and CF₃cis. The reagents react with electrophiles El-X or organoboranes R³BR₂ to give CF₃-containing tri- and tetrasubstituted oxiranes or tetrasubstituted alkenes, respectively, with high diastereoselectivities.     

Peculiarities of the reaction of (SPY-5-34)-dichloro-(κ2(C,O)-2-formylbenzylidene)(1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene)ruthenium with potassium hydridotris(pyrazolyl)borate

The reaction of (SPY-5-34)-dichloro-(κ²(C,O)-2-formylbenzylidene)(H₂IMes)ruthenium (H₂IMes=1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene) with potassium hydridotris(pyrazolyl)borate (KTp) in dichloromethane yielded an unusual ruthenium complex chloro(κ³(N,N,N)-chlorotris(pyrazolyl)borate)(κ²(C,C)-1-(2,4,6-trimethylphenyl)-3-(4,6-dimethylphenyl-2-methylidene)-4,5-dihydroimidazol-2-ylidene)ruthenium (2). In 2, a chlorotris(pyrazolyl)borate ligand, which had been created during this reaction, binds in κ³(N,N,N)-mode to the central ruthenium atom. Additionally, a double C–H activation of a methyl group of the H₂IMes resulted in the formation of a chelating N-heterocyclic biscarbene ligand and liberation of the former 2-formylbenzylidene as 2-methylbenzaldehyde. Formally, a double hydrogen transfer from a methyl group of the H₂IMes to the initial carbene carbon occurred. 2 was characterized by NMR spectroscopy, elemental analysis and single crystal X-ray structure determination. The reaction of KTp with (SPY-5-34)-dichloro(κ²(C,O)-2-ethoxycarbonylbenzylidene)(H₂IMes)ruthenium, on the other hand, gave the expected product chloro(κ³(N,N,N)-hydridotris(pyrazolyl)borate)(H₂IMes)(2-ethoxycarbonylbenzylidene)ruthenium (6). Compound 6 was characterized by NMR spectroscopy, elemental analysis and single crystal X-ray structure determination. Investigations of the relative activities of these complexes in model ring opening metathesis polymerizations showed a pronounced thermal latency. Polymerizations proceeded at temperatures above 100 °C in case of 6 and 130 °C in case of 2.     

Synthesis,photophysical properties and DFT studies of 2-(3-cyano-4-((2-(4,6-dimethyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)hydrazono)methyl)-5,5-dimethylfuran-2(5H)-ylidene)malononitrile dye

The chromophore 2-(3-cyano-4-((2-(4,6-dimethyl-5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl) hydrazono)methyl)-5,5-dimethylfuran-2(5H)-ylidene)malononitrile (PPHTCF) was synthesized through coupling of diazotized 3-amino-4,6-dimethyl-5-nitropyrazolo[3,4-b]pyridine with 3-cyano-2-(dicyanomethylene)-4,5,5-trimethylfuran (TCF). The absorption solvatochromism behaviour of PPHTCF, in various solvents, presented ΔE_max = +5.40 where the positive sign suggested red shift occurrence, implying that the PPHTCF has more polar lowest excited state than its ground one. While, the PPHTCF fluorescence spectra afforded λ_em, in 575–633 nm range, and was more dependent on the solvent polarity than the absorption λ^max, despite both exhibited red shift by 58 and 42 nm, respectively. To discover the PPHTCF solvatochromism behaviour in term of “Stokes’ shift”, both of Lippert-Mataga and linear solvation-energy relationship (LSER) formulations have been utilized and the outcomes endorsed that the later was better than the former (R² = 0.9728). Finally, TD-DFT simulated absorption and emission spectra in EtOH revealed that λ^max has been resulted mainly from HOMO → LUMO; HOMO-5 → LUMO and HOMO-2 → LUMO transitions, respectively.     

Synthesis of 8-amino-4-methylthio-6-methyl-2-(β-D-ribofuranosyl)-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene and an unusual reductive ring-opening of the 1,2,3,5,6,7-hexaazaacenaphthylene ring system

The tricyclic nucleoside 8-amino-4-methylthio-6-methyl-2-(β-D-ribofuranosyl)-1,2,3,5,6,7-hexaazaacenaphthylene ( 3 ) was synthesized from 3-cyano-4,6-bis(methylthio)-1-(β-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidine ( 1 ). Attempts to synthesize 8-amino-6-methyl-2-(β-D-ribofuranosyl)-1H-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene ( 5 ) ([an aza analog of 6-amino-4-methyl-8-(β-D-ribofuranosyl)-1,3,4,5,8-pentaazaacenaphthylene (TCN)], which is a potent antitumor agent), by the treatment of 3 with Raney nickel did not afford the desired aza analog of TCN. Instead, it was established that a reductive cleavage of the pyridazine moiety of 3 had occurred to give 4-methylamino-6-methylthio-1-(β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 6 ). Assuming that solubility was a problem in the reductive step, the isopropylidene derivative of 3 , 8-amino-6-methyl-4-methylthio-2-(2,3-O-isopropylidene-β-D-ribofuranosyl)-2,6-dihydro-1,2,3,5,6,7-hexaazaacenaphthylene ( 8 ), was treated with Raney nickel, only to observe that a similar reductive ring cleavage of 8 had occurred to afford 4-methylamino-6-methylthio-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 10 ) and 4-methylamino-1-(2,3-O-isopropylidene-β-D-ribofuranosyl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamidine ( 11 ). Structural assignments for all products were established by physico-chemical procedures.     

Chemical Transformations of 4,6-Dimethyl-2β-hydroxy-8-oxo-3,5,7-trioxatetracyclo[7.2.1.04,11.06,10]dodecane

Reactions of 4,6-dimethyl-2β-hydroxy-8-oxo-3,5,7-trioxatetracyclo-[7.2.1.0.^4,11.0^6,10]dodecane 1 with nucleophiles have been studied. Reaction of 1 with alcohols, triethylsilane, allyltrimethylsilane, and methylthiotrimethylsilane in CH₂Cl₂ in the presence of TiCL₄, gave the substitution products 2,7a, 7b, and 7c in 80-90% yields. The substitution reaction took place chemoselectively on the hemiacetal group of I. Reaction of 1 with cyanotrimethylsilane in CH₂C1₂ in the presence of TiCL₄, gave compound 8 and the rearranged product 9. The structure of 9 was proven by X-ray analysis.     

Potentiell tumorhemmende wirkstoffe. IX. 4,5,6-trialkylierte 2-methoxy- und 2-(methylthio)pyrimidine

The interaction of O-methylisourea sulfate ( 1a ) or S-methyl-isothiourea sulfate ( 1b ), respectively, with 3-methyl-2,4-pentanedi-one ( 2a ) yields 2-methoxy-( 3a )and 2-methylthio-4,5,6-trimethyl-pyrimidine ( 3b ). The 5-ethylpyrimidines ( 3c and 3d ) obtained by the analogous reactions with 3-ethyl-2,4-pentanedione ( 2b ), in contact with air exhibit a tendency to cleave off the 5-ethyl group and give 4,6-dimethyl-2-methoxypyrimidine ( 4a ) and 4,6-dimethyl-2-(melhylthio)pyrimidine ( 4b ).     

Synthesis and structural study of N′-(4,6-diphenylpyrimidin-2-yl)-2-methylpropanoic hydrazide

Reaction of 1-(4-methoxyphenyl)-3-isopropyl-5-(4,6-diphenylpyrimidin-2-yl)formazan with nickel nitrate in acid medium yields N′-(4,6-diphenylpyrimidin-2-yl)-2-methylpropanoic hydrazide. Its crystal and molecular structure is studied by single crystal X-ray diffraction.     

Green synthesis of 4,6-bisarylpyrimidin-2(1H)-ones and azo-linked 4-arylpyrimidin-2(1H)-ones using NiFe2O4@SiO2nPr@glucose amine as a mild nano catalyst

The clean, environmentally benign and effective synthesis of novel azo-linked 4-arylpyrimidin-2(1H)-one derivatives and 4,6-bisarylpyrimidin-2(1H)-ones via three-component reaction of various aldehydes or synthetized azo-linked aldehydes, urea, and acetophenone promoted by NiFe₂O₄@SiO₂ⁿPr@glucose amine at room temperature (25 °C) was reported. NiFe₂O₄@SiO₂ⁿPr@glucose amine were synthesized and characterized by transmission electron microscope (TEM), fourier transform infrared spectroscopy (FT-IR), vibrating sample magnetometry (VSM), X-ray powder diffraction (XRD) and X-ray spectroscopy (EDX). These compounds were obtained in high yields and short reaction times. The catalyst could be easily recovered and reused for six cycles with almost consistent activity. The structures of the synthesized 4,6-bisarylpyrimidin-2(1H)-one compounds were confirmed by ¹H NMR, ¹³C NMR and FTIR spectral data and elemental analyses.