Chemical and biological studies on dihydro-s-triazines. XVI. Nmr evidence for the formation of 2-guanidino-4-methylquinazolines as anomalous byproducts in the three-component synthesis

The three-component synthesis of 4,6-diamino-1-aryl-1,2-dihydro-2,2-dimethyl-s-triazines from arylamines. cyanoguanidine, and acetone has been studied by nmr spectral analysis in trifluoro-acetic acid solution. The presence of 2-guanidino-4-methylquinazoline contaminants can be discerned clearly at concentrations as low as 1%. Arylamines most likely to give significant proportions of guanidinoquinazoline byproducts are 2-naphthylamines and anilines containing one or more electron-donating meta-substituents.     

Aromatization with dearylation on Hantzsch cyclocondensation of 4-(dimethylamino)benzaldehyde,cyclohexane-1,3-diones,and some 1,3-[N,C]dinucleophiles

The Hantzsch three-component cyclization of 4-(dimethylamino)benzaldehyde, cyclohexane-1,3-diones, and some 1,3-[N,C]-dinucleophiles (5-amino-3-methyl-1-phenylpyrazole, 3,5-dimethoxyaniline, and 4-amino-1,3-dimethylpyrimidine-2,6-dione) proceeds in boiling acetic acid with the splitting off N,N-dimethylaniline and the formation of polycondensed heterocyclic sytems with a γ-unsubstituted pyridine ring (pyrazolo[3,4-b]quinoline, acridine, and pyrimido[4,5-b]quinoline). Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 244-251, February, 2009.     

s-Triazines. I. Linear,sulfur bridged-s-triazine oligomers

A number of new thioether and disulfide oligomers of s-triazine have been prepared and identified. The reactions between 2,4-diphenyl-s-triazine-6-thiol and chloro substituted-s-triazines are described. A suggested mechanism for the formation of 2,2′-thiobis-(4,6-diphenyl-s-triazine) from 2,4-diphenyl-s-triazine-6-thiol is discussed.     

Novel Copolymers of Styrene. 7. Dihalogen Ring-substituted Ethyl 2-Cyano-3-phenyl-2-propenoates

Electrophilic trisubstituted ethylenes, dihalogen ring-substituted ethyl 2-cyano-3-phenyl-2-propenoates, RPhCH?C(CN)CO₂C₂H₅ (where R is 2,3-diCl, 2,4-diCl, 2,6-diCl, 3,4-diCl, 3,5-diCl, 2,3-diF, 2,4-diF, 2,5-diF, 2,6-diF, 3,4-diF, 3,5-diF) were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and ethyl cyanoacetate, and characterized by CHN analysis, IR, ¹H and ¹³C-NMR. All the ethylenes were copolymerized with styrene (M₁) in solution with radical initiation (ABCN) at 70°C. The composition of the copolymers was calculated from nitrogen analysis, and the structures were analyzed by IR, ¹H and ¹³C-NMR. The order of relative reactivity (1/r ₁) for the monomers is 3,4-diCl (1.89) > 2,4-diCl (1.84) > 3,5-diCl (1.40) > 2,6-diCl (1.21) > 2,4-diF (1.16) > 2,3-diF (1.01) > 2,3-diCl (0.74) > 3,4-diF (0.52) > 2,6-diF (0.45) > 3,5-diF (0.44) > 2,5-diF (0.33). Relatively high T_g of the copolymers in comparison with that of polystyrene indicates a decrease in chain mobility of the copolymer due to the high dipolar character of the trisubstituted ethylene monomer unit. Decomposition of the copolymers in nitrogen occurred in two steps, first in the 250–500°C range with residue (2.6–5.0 wt%), which then decomposed in the 500–800°C range.     

SOME CHLOROHYDROXYBENZENESULFONYL DERIVATIVES

Abstract

2,4-; 2,6-; 2,3-; 3,4-; 2,5-; and 3,5-dichlorophenols by reaction with chlorosulfonic acid were converted to the following substituted benzenesulfonyl chlorides: 3,5-dichloro-2-hydroxy-; 3,5-dichloro-4-hydroxy-; 2,3-dichloro-4-hydroxy-; 4,5-dichloro-2-hydroxy-; 2,5-dichloro-4-hydroxy-; and 2,6-dichloro-4-hydroxy-respectively. In addition o-chlorophenol gave 5-chloro-4-hydroxybenzene-1,3-bis-sulfonyl chloride. The various sulfonyl chlorides have been condensed with nucleophilic reagents, e.g. ammonia, amines, hydrazine, phenylhydrazine, N, N-dimethylhydrazine, and sodium azide. 3,5-Dichloro-2-hydroxybenzenesulfonyl azide has been reacted with norbornene, triphenylphosphine, dimethylsulfoxide, and cyclohexene. 3,5-Dichloro-2-hydroxybenzenesulfonyl chloride with phenylisocyanate gave the 2-(N-phenyl-carbamoyloxy) derivative which on heating gave a heterocyclic compound. The chlorohydroxybenzenesulfonyl derivatives are of interest as potential herbicides and their ir and nmr spectral characteristics are briefly discussed.     

Vibrational analysis of substituted nitrobenzenes. I—Vibrational spectra,normal coordinate analysis and transferability of force constants of some chlorinated nitrobenzenes

The Raman and Fourier transform infrared spectra of 2,3-dichloro-, 2,4-dichloro-, 2,5-dichloro-, 3,4-dichloro-, 3,5-dichloro-, 2,3,4-trichloro-, 2,4,5-trichloro-, 2,4,6-trichloro-, 2,3,5,6-tetrachloro- and pentachloronitrobenzene were recorded. Raman polarization measurements were made wherever possible. A normal coordinate analysis was carried out for both the in-plane and out-of-plane vibrations of these molecules using a 59-parameter modified valence force field. The force constants were refined using an Overlay least-squares technique employing 352 frequencies of 10 molecules. The reliability of the force constants so obtained was tested by making a zero-order calculation for p-, m- and o-dinitrobenzenes, 1-fluoro-, 1-chloro- and 1-bromo-, 2,4-dinitrobenzenes, 2,4-difluoro- and 2,5-difluoro- and 2,5-dibromonitrobenzenes. Unambiguous vibrational assignments of all the fundamentals were made using the potential energy distribution and eigen vectors.     

New syntheses of condensed heterocycles from isoxazole derivatives. V. Pyrrolo[3,4-b ]pyridin-4-ones

Hydrogenolysis with Raney-Nickel or iron powder in acetic acid of 2,5-diphenyl-4-nitro-3-(3,5-R,R-4-isoxazolyl)pyrrolyl ketones, prepared by the Grignard reaction of 2,5-diphenylpyrrole and 3,5-R,R-4-isoxazolecarboxilic acid chlorides followed by nitration, afforded directly the desired 6H-pyrrolo[3,4-b ]pyridin-4-ones.     

Application of the Thorpe—Ziegler reaction for the synthesis of functionalized thiophenes,thienopyrimidines, and thienotriazines

Approaches to the synthesis of 3-aminothiophene-2,4-dicarboxylic acid derivatives and to their conversions into thieno[3,4-d]pyrimidines, thieno[3,4-d]-1,2,3-triazines, and thieno[3,2-d]pyrimidines are developed.     

Three-component reaction of methyl 2,4-dioxo-4-phenylbutanoate and methyl 2,4-dioxopentanoate with aromatic aldehydes and propane-1,2-diamine and chemical properties of the products

The reactions of methyl 2,4-dioxo-4-phenylbutanoate and methyl 2,4-dioxopentanoate with a mixture of an aromatic aldehyde and propane-1,2-diamine, depending on the initial reactant ratio, gave 4-acyl-1-(2-aminopropyl)-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones and 1,1′-(propane-1,2-diyl)bis(4-acetyl-3-hydroxy-5-phenyl-2,5-dihydro-1H-pyrrol-2-one). Reactions of substituted 1-(2-aminopropyl)-2,5-dihydro-1H-pyrrol-2-ones with aromatic amines and hydrazines were studied, and the structure of one of the products, 5-(2-aminopropyl)-3,4-diphenylpyrrolo[3,4-c]pyrazol-6-one, was proved by X-ray analysis.     

The phototransposition in acetonitrile and the photoaddition of 2,2, 2-trifluoroethanol to the six isomers of dimethylbenzonitrile

The six dimethylbenzonitriles can be divided into two independent triads in their photochemical reactivity. The first triad is comprised of the 2,3-dimethyl, 3,4-dimethyl, and 2,6-dimethyl isomers (11-2,3, 11-3,4, and 11-2,6, respectively); the second triad is comprised of the 2,4-dimethyl, 2,5-dimethyl, and 3,5-dimethyl isomers (11-2,4, 11-2,5, and 11-3,5, respectively). In acetonitrile, phototransposition converts the members of one triad to other members of the same triad, although only 11-3,4 was reactive enough to have significant conversion approaching a steady-state composition. Irradiation in 2,2,2-trifluoroethanol (TFE) resulted in the formation of addition products, 6-cyano-X,Y-dimethylbicyclo[3.1. 0]hex-3-en-2-yl 2,2,2,-trifluoroethyl ethers, but in significant yield only from 11-3,4 of the first triad and 11-2,4 of the second triad. The 11-3,4 isomer gave seven major regio- and stereoisomers; the 11-2,4 isomer gave three different regio- and stereoisomers. These addition products were all explained by formation of bicyclo[3. 1.0]hex-3-en-1-yl cations resulting from protonation by TFE at C6 followed by nucleophilic trapping by TFE. From these and previous results on aromatic nitriles, a consistent mechanistic picture is obtained where the critical carbon in determining the products of the phototransposition and photoaddition reactions is the cyano substituted one.     

Investigation of the reaction products of 5-amino-1,3-disubstituted-pyrazoles with aromatic aldehydes. synthesis of new fluorinated 1,3,4-trisubstituted-4H-pyrazolo[3,4-e][1,4]thiazepin-7-ones

The condensation products of 5-amino-1,3-disubstituted-pyrazoles with aromatic aldehydes were identified as 2,4-dihydro-2,5-diphenyl-4-(phenylmethylene)-3H-pyrazol-5-imine derivatives Treatment of these products with mercaptoacetic acid gave new fluorine containing 1H-pyrazolo[3,4-e][1,4]thiazepin-7-ones.     

Two electronic transitions in the near-UV region of six isomeric difluorobenzonitriles—I

A new technique—photoacoustic spectroscope (PAS)—is applied to the study of the electronic transitions in the six isomers 3,5-; 2,4-; 2,5-; 3,4-; 2,3-; and 2,6-difluorobenzonitriles. The PAS spectra are compared with solution spectra recorded. The two π-π* transitions analogous to the benzene strong 200 nm, and weak and forbidden 260 nm transitions could be identified in these molecules. An interesting observation is that the origins of the electronic transitions in these molecules are in fairly good agreement with the additive rule which is routed through different starting points and also a prediction of the origin of meta fluorobenzonitrile at 37,536.1 cm⁻¹ from the data of 3,4- and 2,5-difluorobenzonitriles.The fluorescence spectrum for all six isomers is reported here for the first time.     

层状水滑石对吡啶二甲酸异构阴离子的选择性插层行为

本文采用焙烧复原法研究了镁铝水滑石与吡啶二甲酸异构阴离子单体及其混合体的插层反应，实验发现镁铝水滑石对吡啶二甲酸异构阴离子存在着明显的选择性，有机酸异构体优先进入层间的顺序是：2,3-吡啶二甲酸>2,5-吡啶二甲酸>2,4-吡啶二甲酸>3,5-吡啶二甲酸>3,4-吡啶二甲酸>2,6-吡啶二甲酸。利用XRD、IR和TG测试技术对样品进行了表征，同时采用Gaussian-98软件包中ab initio 分子轨道法（HF/6-31G）计算了吡啶二甲酸异构阴离子的分子结构，理论结合实验探讨了阴离子在水滑石层间可能的空间构型，分析了其结构与插层行为的关系。研究表明镁铝水滑石层状材料插层过程中具有分子识别能力，可用于分离有机异构阴离子。     

Rearrangement of 1,4-benzodiazepin-2,4-diones to 3,l-benzoxazin-4-ones

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia → 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione → 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione → IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.     

Carbon-13 n.m.r. studies of substituted bisalkylamino-s-triazines in acidic media

The carbon-13 n.m.r. spectra of six substituted bisalkylamino-s-triazines are reported. The site of protonation of 2-methoxy-s-triazines is shown to be at N-1 or N-3. The effect of trifluoroacetic acid on 2-chloro-s-triazines is also discussed.     

Atmospheric pressure chemical ionization negative mass spectra of the dinitrotoluene isomers

The atmospheric pressure chemical ionization of the dinitrotoluene isomers in ambient air was studied with a quadrupole mass spectrometer operating in the negative mode. The isomers can be grouped on the basis of the product ions: 2,5-, and 2,6- and 3,5-dinitrotoluene give the molecular anion with little fragmentation; 2,3- and the 3,4-dinitrotoluene behave similarly but with more extensive fragmentation; 2,4-dinitrotoluene gives the quasimolecular [DNT ? H]^? ion with little fragmentation. The results are discussed in terms of the molecular structure of the isomers.     

Friedel-crafts cyclisations. II. Further studies of polyphosphoric acid-catalysed cyclisations of N-cinnamoyl derivatives of aromatic amines

Further studies of the effects of substituents in the N-phenyl nucleus on the polyphosphoric acid-catalysed cyclisation of cinnamanilide to 4-phenyl-3,4-dihydrocarbostyril have confirmed that the isomerisation is prevented by a nitro group and retarded by other substituents in the ortho position to the NH- group. Although a methyl group ortho to the only position at which cyclisation can occur was also shown to retard the reaction, N-cinnamoyl-2,4,5-trichloroaniline was cyclised in moderate yield after prolonged heating, but the 2,4-dibromo and 2,5-dimethoxy analogues were not isomerised. Isomerisation of 2-cinnamamidobiphenyl to 4,8-diphenyl-3,4-dihydrocarbostyril was accompanied by cyclodehydration to 6-styrylphenanthridine. Five new derivatives of cinnamanilide and eight new derivatives of 4-phenyl-3,4-dihydrocarbostyril are described.     

Synthesis and Properties of sym-Triazine Derivatives. 18. Synthesis of N-Substituted 2,4-Diamino-6-(benzothiazolyl-2-thiomethyl)-sym-triazines

The condensation of methyl benzothiazolyl-2-thioacetate with N-substituted biguanides in the presence of sodium methylate gave 2-amino-4-(RR'-amino)-6-(benzothiazolyl-2-thiomethyl)-sym-triazines. In a number of cases the 1,1-disubstituted 5-(benzothiazolyl-2-thioacetyl)biguanides could also be separated and these could be cyclized by refluxing in DMF to the corresponding substituted sym-triazines described. The latter type of compound was also synthesized by treating 2-amino-4-trichloromethyl-6-(benzothiazolyl-2-thiomethyl)-sym-triazine with primary and secondary aliphatic and heterocyclic amines or by the reaction of N-substituted 2,4-diamino-6-chloromethyl-sym-triazines with 2-mercaptobenzothiazole.     

POTENCY AND SELECTIVE TOXICITY OF TETRA(HYDROXYPHENYL)- AND TETRAKIS(DIHYDROXYPHENYL)PORPHYRINS IN HUMAN MELANOMA CELLS, WITH AND WITHOUT EXPOSURE TO RED LIGHT

Abstract A series of tetra(hydroxyphenyl)-(2-, 3- and 4-hydroxy; THPP) and tetrakis(dihydroxyphenyl)porphyrins (2,3-, 2,4-, 2,5-, 3,4-, and 3,5-dihydroxy; TDHPP) was synthesized and tested for toxicity in HeLa cells and human melanoma cell lines. Irradiation of drug-treated cells with >600 nm light greatly increased the toxicity of all drugs except the 2,5- and 3,5-TDHPP. The THPP were more toxic than TDHPP in all cell lines, with or without irradiation; of the dihydroxy derivatives, the 3,4- and 2,4-isomers were the most toxic and the 2,5-isomer was the least toxic. The MM96E melanoma cell line, shown previously to be sensitive to hydrogen peroxide and superoxide ion, was not hypersensitive to killing by any of the above agents. HeLa cells, which lacked glutathione- S -transferase activity, were sensitive to the 4- and 2,3-isomers after irradiation; similar amounts of all drugs were taken up by HeLa cells. The pigmented melanoma cell line MM418, resistant to UV-B and in situ -generated hydrogen peroxide but sensitive to glutathione (GSH) depletion, was found to be resistant to the 2,3-isomer (no irradiation) and sensitive to the 3,4-isomer. The results indicate that (1) phototoxicity in these phenylporphyrins is not mediated by superoxide ions or hydroxyl radicals, (2) toxicity is dependent on the orientation of the hydroxy groups, (3) GSH transferase and possibly GSH itself offer protection from the 4- and 3,4-derivatives, respectively, and (4) the 3,4-derivative and analogues of similar selectivity should be evaluated further for the treatment of primary melanoma.