3-Amino-2-quinoxalinecarbonitrile. New fused quinoxalines with potential cytotoxic activity

Starting with 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide 1 , a new series of quinoxaline derivatives was prepared through chemical modifications of the 2-cyano and 3-amino groups. Nitration of 3-amino-2-quin-oxalinecarbonitrile 3 afforded the 7-nitro derivative 6 . Diazotation of 3 gave the 3-chloro compound 9 . 2,3-Quinoxalinedicarbonitrile 14 was obtained from 9 . Pyridazino[4,5-b]quinoxalines 15 and 16 were prepared by condensing 14 with hydrazine hydrate. A triazolo[4,5-b]quinoxaline 18 , a isothiazolo[4,5-b]quinoxaline 20 and two pyrazolo[3,4-b]quinoxalines 21 and 22 were identified. Compounds were tested as cytotoxic agents both in oxic and in hypoxic cells.     

Synthesis and characterization of polythiophene derivatives with nitrogen heterocycles on the side chain

The Grignard metathesis reaction of 2,5‐dibromo‐3‐(5′‐hexylpyridine‐2′‐yl)thiophene ( M1 ) with i‐PrMgCl afforded 5‐bromo‐2‐chloromagnesio‐3‐(5′‐hexylpyridine‐2′‐yl)thiophene ( GM1 ) in the 86% selectivity. The Kumada coupling polymerization by Ni(dppp)Cl₂ gave poly M1 having the roughly controlled molecular weight between 6700 and 23,400. The characterization using the gel permeation chromatographic and matrix‐assisted laser desorption/ionization‐time of flight mass spectra indicated the diffusion of the nickel catalyst from the propagating end. Based on the GC and ¹H NMR spectra, the head‐to‐tail content of poly M1 was calculated to be 89%. The regioselective Grignard metathesis reactions of 5,5′‐dibromo‐4‐(5″‐hexylpyridine‐2″‐yl)‐2,2′‐bithiophene ( M2 ) and 5,5′‐dibromo‐4‐(5″‐hexylpyrimidine‐2″‐yl)‐2,2′‐bithiophene ( M3 ) also occurred at the ortho‐position of the nitrogen heterocycle. The Kumada coupling polymerizations gave poly M2 and poly M3 having the head‐to‐tail content of 75% and 85%, respectively. The UV–vis spectra of polymers suggested that the polymer conformation becomes more planar in the order of poly M1 < poly M3 < poly M2 , which was investigated by the theoretical calculation of the model oligomers. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2166–2174     

New proton-conducting phenyl-substituted polyphenylenes with phosphonate groups in side chain

A new method for the synthesis of polyphenylenes with phenylphosphonate side groups was developed. The method is based on transformations of p-bromophenyl-substituted polyphenylenes via the substitution of the diethyl phosphonate group for bromine in the presence of a palladium catalyst and the hydrolysis of this group giving polymers with free phosphonic acid groups.     

New arenemanganese dicarbonyl cyanides with ω-functional groups in side chain

Conclusions New arenemanganese dicarbonyl cyanides with -functional substituents in the side chain were prepared, and a principally new possibility for nitrogen of the CN group coordinated with manganese in arenemanganese dicarbonyl cyanides to enter into additional complex formation with an atom of a transition metal was shown.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1611–1614, July, 1981.     

New polymethacrylic nonlinear optical materials containing multichromophores in the side chain

1. Download high-res image (159KB)
2. Download full-size image

     

An influence of a basic side chain moiety on the tautomer ratio between the enamine and methylene imine forms in azole condensed quinoxalines

The reaction of 7-chloro-4-(2-cyano-2-hydroxyvinyl)tetrazolo[1,5-α]quinoxaline 2a with 4-aminopyridine, p-toluidine or p-aminophenol gave 7-chloro-4-(4-pyridylcarbamoylmethylene)-4,5-dihydrotetrazolo[1,5-α]-quinoxaline 7a , 7-chloro-4-(p-tolylcarbamoylmethylene)4, 5-dihydrotetrazolo[1,5-α]quinoxaline 8a or 7-chloro-4-(p-hydroxyphenylcarbamoylmethylene)-4,5-dihydrotetrazolo[1,5-α]quinoxaline 9a , respectively. The reaction of 7-chloro-4-(2-cyano-2-hydroxyvinyl)-1,2,4-triazolo[4,3-α]quinoxaline 2b with 4-aminopyridine, p-toluidine or p-aminophenol afforded 7-chloro4-(4-pyridylcarbamoylmethylene)-4,5-dihydro-1,2,4-triazolo-[4,3-α]quinoxaline 7b , 7-chloro-4-(p-tolylcarbamoylmethylene)-4,5-dihydro-1,2,4-triazolo[4,3-α]quinoxaline 8b or 7-chloro-4-(p-hydroxyphenylcarbamoylmethylene)-4,5-dihydro-1,2,4-triazolo[4,3-α]quinoxaline 9b , respectively. The reaction of compound 2a with 2-aminopyridine or 3-aminopyridine provided 7-chloro-4-(2-pyridyl-carbamoylmethylene)-4,5-dihydrotetrazolo[1,5-α]quinoxaline 10 or 7-chloro-4-(3-pyridyl-carbamoylmethylene)-4,5-dihydrotetrazolo[1,5-α]quinoxaline 11 , respectively. Compounds 7a,b (4-pyridylcarbamoyl) predominated as the enamine tautomer A in a trifluoroacetic acid solution, while compounds 8a,b (p-tolylcarbamoyl) and compounds 9a,b (p-hydroxyphenylcarbamoyl) coexisted as the enamine A and methylene imine B tautomers in a trifluoroacetic acid solution. Moreover, the ratio of the enamine tautomer A elevated in an order of compound 11 (3-pyridylcarbamoyl), compound 10 (2-pyridylcarbamoyl) and compound 7a (4-pyridylcarbamoyl), reflecting an order of the increase in the pKa values of the aminopyridine side chain moieties. In general, the ratio of the enamine tautomer A was higher in the basic carbamoyl derivatives 7–11 than in the neutral ester derivatives 3a,b . From these results, the basic side chain moiety of the tetrazolo[1,5-α]quinoxalines 7a-11 or 1,2,4-triazolo[4,3-α]quinoxalines 7b-9b was found to increase the ratio of the enamine tautomer A in trifluoroacetic acid media.     

New side chain liquid crystalline polymers: synthesis and thermal properties of side chain polyacrylates having segmented spacers

In order to acquire high mobility of a mesogenic group, we propose a new type of side chain liquid crystal polymer having segmented spacers, consisting of binary moieties of an oligo(ethylene oxide) segment and analkylene segment. Six kinds of polyacrylates having segmented spacers consisting of different lengths of an oligo(ethylene oxide) and an alkylene, and having 4'-cyanobiphenyl as a mesogenic group have been synthesized, and their thermal properties investigated. Some of these polyacrylates exhibit a mesophase and show an extremely low glass transition temperature compared with LC polyacrylates having ordinary alkylene spacers.     

New side chain liquid crystalline polymers: synthesis and thermal properties of side chain polyacrylates having segmented spacers

In order to acquire high mobility of a mesogenic group, we propose a new type of side chain liquid crystal polymer having segmented spacers, consisting of binary moieties of an oligo(ethylene oxide) segment and analkylene segment. Six kinds of polyacrylates having segmented spacers consisting of different lengths of an oligo(ethylene oxide) and an alkylene, and having 4'-cyanobiphenyl as a mesogenic group have been synthesized, and their thermal properties investigated. Some of these polyacrylates exhibit a mesophase and show an extremely low glass transition temperature compared with LC polyacrylates having ordinary alkylene spacers.     

Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites*

The clinical use of currently available drugs acting at the5-HT₄ receptor has been hampered by their lack of selectivityover 5-HT₃ binding sites. For this reason, there is considerableinterest in the medicinal chemistry of these serotonin receptor subtypes, andsignificant effort has been made towards the discovery of potent and selectiveligands. Computer-aided conformational analysis was used to characterizeserotoninergic 5-HT₃ and 5-HT₄ receptorrecognition. On the basis of the generally accepted model of the5-HT₃ antagonist pharmacophore, we have performed a receptormapping of this receptor binding site, following the active analog approach(AAA) defined by Marshall. The receptor excluded volume was calculated as theunion of the van der Waals density maps of nine active ligands(pK_i 8.9), superimposed in pharmacophoric conformations.Six inactive analogs (pK_i < 7.0) were subsequently used todefine the essential volume, which in its turn can be used to define theregions of steric intolerance of the 5-HT₃ receptor. Five activeligands (pK_i 9.3) at 5-HT₄ receptors wereused to construct an antagonist pharmacophore for this receptor, and todetermine its excluded volume by superimposition of pharmacophoricconformations. The volume defined by the superimposition of five inactive5-HT₄ receptor analogs that possess the pharmacophoric elements(pK_i 6.6) did not exceed the excluded volume calculated forthis receptor. In this case, the inactivity may be due to the lack of positiveinteraction of the amino moiety with a hypothetical hydrophobic pocket, whichwould interact with the voluminous substituents of the basic nitrogen ofactive ligands. The difference between the excluded volumes of both receptorshas confirmed that the main difference is indeed in the basic moiety. Thus,the 5-HT₃ receptor can only accommodate small substituents inthe position of the nitrogen atom, whereas the 5-HT₄ receptorrequires more voluminous groups. Also, the basic nitrogen is located at ca.8.0 Å from the aromatic moiety in the 5-HT₄ antagonistpharmacophore, whereas this distance is ca. 7.5 Å in the5-HT₃ antagonist model. The comparative mapping of bothserotoninergic receptors has allowed us to confirm the three-componentpharmacophore accepted for the 5-HT₃ receptor, as well as topropose a steric model for the 5-HT₄ receptor binding site. Thisstudy offers structural insights to aid the design of new selective ligands,and the resulting models have received some support from the synthesis of twonew active and selective ligands: 24 (K_i(5-HT₃)= 3.7 nM; K_i(5-HT₄) > 1000 nM) and 25(K_i(5-HT₄) = 13.7 nM;K_i(5-HT₃) > 10 000 nM).     

Synthesis of novel quinoxalines by ring transformation of 3-quinoxalinyl-l,5-benzodiazepine

Ring transformation of the 3-quinoxalinyl-l,5-benzodiazepine ( 2 ) gave 3-(benzimidazol-2-ylmethylene)-2-oxo-l,2,3,4-tetrahydroquinoxaline hydrochloride ( 4a ), whose treatment with 5% sodium hydroxide provided the free base 5a , while refluxing of the 3′-chloro-l-formyl derivative 3 in acetic acid and in 10% hydrochloric acid/acetic acid afforded 3-(3-oxo-3,4-dihydroquinoxalin-2-yl)-1,2-dihydro-1-formyl-2-oxo-3H-1,5-benzodiazepine hydrochloride ( 7 ) and 3-methyl-2-oxo-l,2-dihydroquinoxaline ( 6 ), respectively. Compounds 4a and 5a were converted into 3-(α-hydroxyiminobenzimidazol-2-ylmethyl)-2-oxo-l,2-dihydroquinoxaline ( 8 ) and 3-(benzimidazol-2-ylcarbonyl)-2-oxo-l,2-dihydroquinoxaline ( 10 ), respectively, which were further transformed into 3-(benzimidazol-2-yl)isoxazolo[4,5-b]quinoxaline ( 9 ) and 12 -(benzimidazol-2-yl)-6H-quinoxalino[2,3-b I 1,5]benzodiazepine ( 11 ), respectively.     

Composite spectral density functions for the interpretation of the 13C NMR relaxation behavior of polymers containing hydrocarbon side chains. Free and restricted side chain motion

¹³C NMR NT₁ and NOE have been calculated by using composite spectral density functions describing polymer chain segmental motion and internal rotation of a hydrocarbon side chain attached to the polymer backbone. Numerical results at two magnetic fields are presented as a function of the various motional parameters characterizing the various models. NT₁ and NOE relaxation parameters are well behaved and appear to have practical value for describing the dynamics of these systems. The models have been applied to the relaxation data of poly(n-butyl methacrylate) and poly(n-hexyl methacrylate) in toluene solutions. The dynamics of the two polymers are characterized by a very localized backbone motion and restricted internal rotation about successive C? C bonds of the side chains. © 1995 John Wiley & Sons, Inc.     

Enhanced guest affinity and enantioselectivity through variation of the Gd3+ [15-metallacrown-5] side chain

Supramolecular hosts that bind guests reversibly are investigated for potential catalysis and separations applications. Chiral Ln(3+)[15-Metallacrown-5] metallocavitands bind carboxylate guests in hydrophobic cavities generated by their ligand side chains. A thermodynamic study on Gd(3+)[15-metallacrown-5] hosts with ligands bearing phenyl side chains containing 0, 1, and 2 methylene spacers (1-pgHA, 1-pheHA, 1-hpheHA, respectively) is presented to quantitatively assess how guest affinity and chiral selectivity can be enhanced through changes to the ligand side chain. Guest binding affinity was measured with cyclic voltammetry using ferrocene carboxylate as a redox probe. K(a) values between ferrocene carboxylate and 1-pgHA and 1-pheHA were 4800 ± 400 M(-1) and 4400 ± 700 M(-1), respectively. Significantly stronger binding affinity of 12,100 ± 700 M(-1) was measured with 1-hpheHA, a result of the longer side-chains more completely encapsulating the guest. A similar trend was observed with benzoate. The side chain also influenced enantioselectivity, as K(S)/K(R) values of up to 2.2 ± 0.6 were measured. The side chain dependent guest binding supports the development of highly selective Ln(3+)[15-Metallacrown-5] hosts for use in catalysis and separations through careful ligand design.     

Regioorientation in the reaction of side chain activated alkylpyridines with electrophiles

X-ray structural data has shown that condensation of sym-3-nitrocollidine with benzaldehyde occurs at the 6-methyl group. The presence of an acceptor group in the side chain of 2,6-dimethyl-4-cyanomethyl-3-nitropyridine causes condensation to occur at the activated methylene group in the 4-position.M. V. Lomonosov State University, Moscow 119899. A. N. Nesmeyanov Institute of Organoelemental Compounds, Moscow 117813. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11. pp. 1543–1550, November, 1995. Original article submitted June 10, 1995.     

Copolymerization of acrylonitrile. I. Copolymerization with styrene derivatives containing nitrile groups in the side chain

Acrylonitrile was copolymerized in bulk with cinnamonitrile (I), ethyl benzylidenecyanoacetate (II), and benzylidenemalononitrile (III) by radical initiation up to low conversions. The conventional scheme of copolymerization fitted all the three copolymer pairs.     

Heterocycles structurally influenced by a side chain. X. Effect of temperature and side chain on the imine-enamine tautomerism in the quinoxalinone and pyridopyrazinone systems

3-(1-Benzoyl)ethyl-1H-pyrido[2,3-b]pyrazin-2-one ( 7 ), 3-(1-ethoxycarbonyl)ethyl-1H-pyrido[2,3-b]-pyrazin-2-one ( 8 ), and 3-(1-benzoyl)ethyl-1H-quinoxalin-2-one ( 9 ) exist only in the imine form due to the steric effect of the methyl substituent. As regards the imine-enamine tautomerism, 3-(β-carbonylmethylene) derivatives of 1,2-dihydro-4H-pyrido[2,3-b]pyrazin-3-one such as 12 and 15–18 gradually change from the enamine form to the imine form with elevated temperatures; however, 3-(carbonylmethylene) derivatives of 3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one such as 10, 19 and 20 show little temperature effect. 2-Phenacylidene-1,2-dihydro-4H-pyrido[3,4-b]pyrazin-3-one ( 21 ) and 3-phenacylidene-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one ( 22 ), which exist in the enamine form, show no temperature effect.