Solid-phase synthesis of 2-aminoquinazolinone derivatives with two- and three-point diversity

A versatile solid-phase method for the synthesis of various substituted 2-amino-4(3H)-quinazolinones with two- and three-point diversity is described. The synthesis commenced with the generation of polymer-bound S-methylisothiourea followed by N-acylation with different substituted o-nitrobenzoic acid. Finally, reduction of the nitro group triggered intramolecular cyclization via formation of guanidine to afford 2-amino-4(3H)-quinazolinone and its derivatives in high yields and purities.     

Mass spectrometry of 4-amino-4′-nitroazobenzene compounds

The mass spectra of 32 substituted 4-amino-4′-nitroazobenzene compounds have been recorded and the most intense peaks have been used to characterize these spectra. It was found that the spectra of 4-amino-4′-nitroazobenzene compounds are characterized by peaks due to: (1) molecular ions, (2) fragment ions formed by cleavage of one of the carbon-nitrogen bonds adjacent to the azo linkage with the positive charge remaining with the amine fragment, (3) ions formed by cleavage alpha to the amine nitrogen with the charge remaining with the amine substituent, (4) ions formed by cleavage beta to the amine nitrogen with the loss of the amine substituent fragment, (5) secondary ions formed by cleavage beta to the amine nitrogen with the loss of the amine substituent fragment from the primary amine fragment (2), and (6) ions formed by loss of NO from the molecular ion. This work shows that 4-amino-4′-nitroazobenzene compounds exhibit fragmentation which is dependent in a consistent manner on the types of substituents. This work provides a basis for a systematic approach to the identification of 4-amino-4′-nitroazobenzene compounds.     

One-stage synthesis of adamantyl-containing α-aminonitriles

Reactions of 2-adamantan-2-one, acetone cyanohydrin, and amine lead to the formation of substituted 2-amino-2-cyanoadamantanes. The reaction is of a general character as has been proved by examples on a series of ketones and amines and it proceeds through the formation from the acetone cyanohydrin and amines of 2-amino-2-cyanopropane derivatives reacting further with the carbonyl compounds.     

Facile cobalt(III) template synthesis of novel branched hexadentate polyamine monocarboxylates

New hexadentate polyamine monocarboxylate ligands, 11-amino-9-(2-aminoethyl)-3,6,9-triazaundecanoate (tren-engly-), 12-amino-10-(2-aminoethyl)-3,7,10-triazadodecanoate (tren-tngly-) and 13-amino-11-(2-aminoethyl)-3,8,11-triazatridecanoate (tren-bngly-), were synthesized by intramolecular coupling of tetradentate tris(2-aminoethyl)amine (tren) and didentate N-([small omega]-formylalkyl)glycinates, OCH(CH2)nNHCH2CO2-, in easily and stereoselectively assembled cobalt(III) templates, p-[Co(tren){(RO)2CH(CH2)nNHCH2CO2}](O3SCF3)2, n = 1-3 (R = Me or Et). The reaction sequences comprised assembly of the template from [Co(tren)(O3SCF3)2]O3SCF3 (1) and (RO)2CH(CH2)nNHCH2CO2Et, deprotection of the pendant acetal in acid, intramolecular condensation of the resulting aldehyde with a coordinated primary amine at intermediate pH to form the imine and reduction of this by NaBH4. For n= 1, imine formation occurred exclusively at the primary amine trans to the carboxylate producing the hexadentate 11-amino-9-(2-aminoethyl)-3,6,9-triazaundeca-5-enoato (tren-enimgly-) complex, i-[Co(tren-enimgly)]Cl2.3.5H2O. In all instances, subsequent imine reduction gave the s isomer complex, exclusively. Complexes p-[Co(tren){(MeO)2CHCH2gly}](O3SCF3)2 (3), i-[Co(tren-enimgly)]ZnCl4.H2O (5), s-[Co(tren-engly)]ZnCl(4)(s-6), s-[Co(tren-tngly)]ZnCl4.H2O (s-7) and s-[Co(tren-bngly)ZnCl3]2ZnCl4 (s-8) were structurally characterized by X-ray crystallography. Charcoal-catalyzed equilibration of s-[Co(tren-engly)]Cl(2).2H(2)O dissolved in water produced the s- (s-6), p- (p-6) and t-[Co(tren-engly)]2+ (t-6) isomers in comparable amounts. p-6 and t-6 were also structurally characterized as their tetrachlorozincate and chloride salts, respectively. In base-catalyzed reactions, s-6 and t-6 each also formed p-6. Reduction of s-[Co(tren-engly)]Cl2.2H2O with (NH4)2S and acidification liberated the pentaamino carboxylic acid ligand which was isolated as the hydrochloride salt.     

3-(3,4,5-三甲氧基苯基)-4-氨基-5-取代苄巯基-1,2,4-三唑的合成及其生物活性

3-(3,4,5-三甲氧基苯基)-4-氨基-5-巯基-1,2,4-三唑与取代苄氯反应合成了九个新型3-(3,4,5-三甲氧基苯基)-4-氨基-5-取代苄巯基-1,2,4-三唑(2a～2i),其结构经1H NMR,IR和MS表征.初步生物活性测试结果表明,3-(3,4,5-三甲氧基苯基)-4-氨基-5-对氯苄巯基-1,2,4-三唑(2b)对半夏立枯病菌具有抑制活性.     

o-Toluidine in electrochemistry – an overview

Journal of Solid State Electrochemistry - The substituted aromatic amine o-toluidine (2-methylaniline, 1-amino-2-methylbenzene) is frequently encountered in electrochemical research as a soluble...     

Application of bis(iminophosphorane) in heterocyclic synthesis: new entries to symmetrically or unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones

The bis(carbodiimides) 4, obtained from bis-aza-Wittig reactions of bis(iminophosphorane) 3 with 2 equiv of aromatic isocyanates, were reacted with secondary amine to give symmetrically substituted 2,7-diaminothieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-dione 6 in the presence of a catalytic amount of EtO(-)Na(+). Reactions of 4 with phenols or ROH in the presence of a catalytic amount of potassium carbonate or RO(-)Na(+) gave symmetrically substituted 2,7-diaryl(alkyl)oxythieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 6 in satisfactory yields. However, iminophosphoranes 9 were obtained via reaction of bis(iminophosphorane) 3 with 1 equiv of aromatic isocyanate and subsequent reaction with an amine in the presence of a catalytic amount of EtO(-)Na(+). Further reaction of iminophosphoranes 9 with aromatic isocyanates and various nucleophile generated unsymmetrically substituted thieno[2,3-d:5,4-d']dipyrimidine-4,5(3H,6H)-diones 12 in good yields.     

2-氨基取代噻唑基膦酸脂的合成

本文报导一系列2-氨基-5-取代-4-噻唑基膦酸酯和2-氨基-4-取代-5-噻唑基膦酸酯的合成. 这类化合物显示了一定的杀菌活性.     

伊马替尼衍生物的合成及其抗肿瘤活性

以4-硝基-2-氨基甲苯为起始原料,经加成、缩合、环化和还原反应制得中间体N-(2-甲基-5-氨基苯基)-4-(3-吡啶基)嘧啶-2-胺(4),再与取代酰氯反应,合成了7个新型伊马替尼衍生物（5a~5g）,其结构经¹H NMR, ¹³C NMR和HR-MS 表征。采用四甲基偶氮唑盐(MTT)法考察了5对人肝癌细胞(HepG₂)、子宫颈癌细胞（Hela）、肺癌细胞（H460）和乳腺癌细胞（MCF-7）体外抑制活性。结果显示：5e体外抑制活性最优,其IC₅₀分别为10.90±1.00 μmol·L^-1; 8.51±0.90 μmol·L^-1; 13.15±1.11 μmol·L^-1; 14.75±0.78 μmol·L^-1。     

Solid-supported solution-phase synthesis of 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones

Starting from Boc-o-aminomethylphenylalanine, a solution-phase parallel synthesis of 2,4-substituted 4-amino-1,2,4,5-tetrahydro-2-benzazepine-3-ones is described. This heterocycle has two nitrogen functions, which are differentiated and can be selectively substituted. The sources of diversity are aldehydes for the R(1) position and carboxylic acids, sulfonyl chlorides, or isocyanates for the R(2) position. High-throughput synthesis and purification of this multistep synthetic sequence was accomplished using polymer-bound reagents and scavengers and liquid-liquid extraction protocols, and a small library of compounds was prepared. Polymer-bound cyanoborohydride was found to work well for the reductive amination. Scavenging of excess of amine was performed by polymer-bound benzaldehyde, and cyclization was performed in the presence of polymer-bound coupling reagent 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). After Boc-deprotection, the second nitrogen can be acylated using carboxylic acids, sulfonylated or converted to a urea. The acylation is again performed by polymer-bound EDC. Excellent yields and purities were obtained.     

Synthesis, spectral characterization and biological activity of zinc(II) complexes with 3-substituted phenyl-4-amino-5-hydrazino-1, 2, 4-triazole Schiff bases

New Zn(II) complexes have been synthesized by the reactions of zinc(II) acetate with Schiff bases derived from 3-substituted phenyl-4-amino-5-hydrazino-1, 2, 4-triazole and benzaldehyde, 2-hydroxyacetophenone or indoline-2,3-dione. All these complexes are soluble in DMF and DMSO; low molar conductance values indicate that they are non-electrolytes. Elemental analyses suggest that the complexes have 1:1 stoichiometry of the type [ZnL(H(2)O)(2)], [ZnL'(OAc)(2)(H(2)O)(2)] (L=dianionic Schiff bases derived from 3-(substituted phenyl)-4-amino-5-hydrazino-1, 2, 4-triazole and 2-hydroxyacetophenone or indoline-2,3-dione; L'=neutral Schiff bases derived from 3-(substituted phenyl)-4-amino-5-hydrazino-1, 2, 4-triazole and benzaldehyde) and they were characterized by FT-IR, (1)H NMR, (13)C NMR and FAB mass. All these Schiff bases and their complexes have also been screened for their antibacterial activities against Bacillus subtilis, Escherichia coli and antifungal activities against Colletotrichum falcatum, Aspergillus niger, Fusarium oxysporium and Carvularia pallescence by petriplates methods.     

Solid-phase synthesis of 5-amino-1-(substituted thiocarbamoyl)pyrazole and 1,2,4-triazole derivatives via dithiocarbazate linker

A general method is reported for the parallel solid-phase synthesis of 5-amino-1-(substituted thiocarbamoyl)pyrazole and 1,2,4-triazole derivatives based on the cyclization of polymer-bound dithiocarbazate 3 with various electrophiles, such as 3-ethoxyacrylonitriles 8 and cyanocarboimidates 9. The polymer-bound dithiocarbazate 3, produced by nucleophilic reaction with carbon disulfide and Fmoc-hydrazine on the Merrifield resin, served as the key intermediate for subsequent heterocycle diversification. Further nucleophilic substitution on these polymer-bound 5-amino-1-dithiocarboxypyrazoles 4 and 1,2,4-triazoles 6 with various amines under thermal cleavage condition produced the desired 5-amino-1-(substituted thiocarbamoyl)pyrazoles 5 and 1,2,4-triazoles 7. The progress of reactions could be monitored as polymer-bound intermediates by ATR-FTIR spectroscopy on single bead. The final compounds, obtained in good four-step overall yields and high purities upon cleavage from the resins, were characterized by LC/MS, 1H NMR, and 13C NMR spectroscopy.     

Imination of N-methylpyridinium salts by liquid ammonia-potassium permanganate. A new synthesis of nudiflorine

Reaction of substituted 1-methyl(benzyl)pyridinium salts ( 1 ) with liquid ammonia/potassium permanganate leads to introduction of the imino group at the carbon adjacent to the nitrogen. The regiospecificity of the reaction strongly depends on substituent X: at C-6 for X = H, CONH₂, C₆H₅ and at C-2 for X = CH₃. 3-Aminocarbonyl-1-t-butylpyridinium iodide ( 5 ) on treatment with liquid ammonia/potassium permanganate exclusively gives the 4-imino compound 8 ; ¹H nmr spectroscopy shows that 5 in liquid ammonia gives a mixture of the σ-adducts 4-amino-1,4-dihydro- and 6-amino-1,6-dihydro-3-pyridinecarbonamide ( 6 and 7 ). Surprisingly, an oxodemethylation reaction is observed on treatment of 3-aminocarbonyl-1,6-dimethylpyridinium iodide ( 13 ) with liquid ammonia/potassium permanganate, 1,6-dihydro-1-methyl-6-oxo-3-pyridinecarboxamide ( 14 ) being obtained. This compound can easily be converted by phosphorus oxychloride into the alkaloid nudiflorine ( 15 ).     

Selective oxidation of polyfunctional 2-amino-1,3-propanediol derivatives

Oxidation of polyfunctional threo-(1S,2S)-2-amino-1,3-propanediol derivatives with a 717 anion-exchange resin-supported bromine has been investigated. The result showed that oxidized products were in close relationship with the substituents at nitrogen in the starting materials. Its primary and secondary amine derivatives were oxidized in the presence of Na(2)HPO(4) to give essentially a substituted chiral oxazoline or C(3)-O acylated product in high yield, while oxidation of its N,N-dimethyl derivative mainly gave a chiral N-methyl oxidation-formylation product. This selective oxidation was first observed in 2-amino-1,3-propanediol chemistry.     

Catalytic synthesis of 1,3-propylenediamines

The hydrogenation on Raney nickel of 3-alkenyl-substituted pyrazolines and also of 3-methyl-5-(2-furyl)-1H-pyrazoline and 3,3′-bipyrazoline afforded substituted 1,3-diaminobutanes, 1,3-diaminopentanes, 1,3-diaminohexane, and 1,3,4,6-tetraaminohexane. Under the same conditions from 3-acetyl-4-(2-furyl)-1H-pyrazoline 3-amino-2-methyl-4-(2-furyl)pyrrolidine was obtained.     

One-step synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')- 2H,4H-dihydropyrazolo[3,4-b]pyrans

Three-component condensation of 4-piperidinones (7), 5-pyrazolones (8), and malononitrile (4) proceeds chemically and electrochemically and is a convenient one-step means of synthesis of substituted 6-amino-5-cyanospiro-4-(piperidine-4')-2H,4H-dihydropyrazolo[3,4-b]pyrans (12). The electrochemical reactions proceed under milder conditions and with yields 12-15% greater than those of the reactions catalyzed by chemical bases.     

Dihydrogen generation from amine/boranes: synthesis, FT-ICR, and computational studies

A Fourier transform ion cyclotron resonance spectrometry (FT-ICR) study of the gas-phase protonation of ammonia-borane and sixteen amine/boranes R(1)R(2)R(3)N-BH(3) (including six compounds synthesized for the first time) has shown that, without exception, the protonation of amine/boranes leads to the formation of dihydrogen. The structural effects on the experimental energetic thresholds of this reaction were determined experimentally. The most likely intermediate and the observed final species (besides H(2)) are R(1)R(2)R(3)N-BH(4)(+) and R(1)R(2)R(3)N-BH(2)(+), respectively. Isotopic substitution allowed the reaction mechanism to be ascertained. Computational analyses ([MP2/6-311+G(d,p)] level) of the thermodynamic stabilities of the R(1)R(2)R(3)N-BH(3) adducts, the acidities of the proton sources required for dihydrogen formation, and the structural effects on these processes were performed. It was further found that the family of R(1)R(2)R(3)N-BH(4)(+) ions is characterized by a three-center, two-electron bond between B and a loosely bound H(2) molecule. Unexpected features of some R(1)R(2)R(3)N-BH(4)(+) ions were found. This information allowed the properties of amine/boranes most suitable for dihydrogen generation and storage to be determined.     

New practical synthesis of prazosin

A new four step synthesis of prazosin, 2-[4-(2-furoyl)piperazin-l-yl]-4-amino-6,7-dimethoxyquinazoline, has been described. The method is also adaptable for the preparation of other substituted 4-aminoquinazolines. The yields are good in every step and the reactions are performed with ease. Prazosin hydrochloride of high purity is obtained directly in the last step.     

Azines and azoles: CXXV. New regioselective synthesis of 1-amino-6-methyluracils

Readily accessible 5-acetyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione reacts with substituted hydrazines and carboxylic acid hydrazides under mild conditions to give the corresponding hydrazones. Under severe conditions (heating in boiling dimethylformamide) the reaction is accompanied by extrusion of COS with formation of substituted 1-amino-6-methyluracils. Reactions of 5-acetyl-4-hydroxy-3,6-dihydro-2H-1,3-thiazine-2,6-dione with monosubstituted alkyl-and arylhydrazines take different pathways, depending on the conditions. Heating of equimolar mixtures of the reactants in ethanol or propan-1-ol leads to the formation of 2-substituted 5-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxamides rather than 1-amino-6-methyluracil derivatives.     

Toward a 6pi+6pi zwitterion or a bioinhibitors-related OH-substituted aminoquinone: identification of a key intermediate in their pH controlled synthesis

Their pH-controlled reactivity places the N,N'-dialkyl-2-amino-5-lithium alcoholate-1,4-benzoquinonemonoimines [C(6)H(2)(NHCH(2)R') (=NCH(2)R')(=O)(OLi)] 7 (R'=tBu) and 8 (R'=p-C(6)H(4)-tBu) at the crossroads of a new versatile strategy for the preparation of two very different classes of substituted quinones. We describe new 2-(N-alkyl)amino-5-hydroxy-1,4-benzoquinones, which are parent molecules to biologically active substituted aminobenzoquinones, for which changes of the N-substituent will become readily possible. The results of the first X-ray structural determination of such compounds ([C(6)H(2)(NHCH(2)tBu)(OH)(=O)(2)] 13) are also reported and we compare the influence of the number of N-substituents of the C(6) ring on the supramolecular networks resulting from self-assembling of 13, zwitterionic N,N'-dineopentyl-2-amino-5-alcoholate-1,4-benzoquinonemonoiminium [C(6)H(2)(=NHCH(2)tBu)(2)(=O)(2)] 9 and N,N',N",N"'-tetraneopentyl-2,5-diamino-1,4-benzoquinone diimine [C(6)H(2)(NHCH(2)tBu)(2)(=NCH(2)tBu)(2)] 15.