Cinnolines and Phthalazines: Chemistry of Heterocyclic Compounds, Supplement II
Abstract
This book provides the most comprehensive, current reference on the synthetic chemistry of cinnolines and phthalazines. Applications to the syntheses of natural products and other chiral compounds are described. Volume 64 contains chapters exploring the following topics: Primary Syntheses of Cinnolines Cinnoline, Alklycinnolines, and Arylcinnolines Halogenocinnolines Oxycinnolines Thiocinnolines Nitro-, Amino-, and Related Cinnolines Cinnolinecarboxylic Acids and Related Derivatives Primary Syntheses of Phthalazines Phthalazine, Alklyphthalazines, and Arylphthalazines Halogenophthalazines Oxyphthalazines Thiophthalazines Phthalazinecarboxylic Acids and Related Derivatives An Appendix of Tables of Simple Cinnolines and Simple Phthalazines.
... Synthesis from benzene substrate and subsidiary component can provide either N (1) -C (2) -C (3)-N (4) [28] or C (2) -C (3) fragment. Synthesis providing C (2) -C (3) fragment is the most widespread approach that includes cyclocondensation of o-phenylenediamine with oxalyl [-C(=O)-C(=O)-] or its isosteric moiety (e.g., chlorides, nitriles) [29][30][31]. Recently some green-chemistry approaches were described, e.g., reaction of o-phenylenediamine with acetic acid [32], (un)substituted glyoxal (the Petasis-type reaction) [24,29,33,34], oxalyl acid and its esters [24,35], condensation with -ketoacid (the Hinsberg reaction) [36], application of molecular sieves [37] or task-specific ionic liquid [38,39]. ...
... Synthesis providing C (2) -C (3) fragment is the most widespread approach that includes cyclocondensation of o-phenylenediamine with oxalyl [-C(=O)-C(=O)-] or its isosteric moiety (e.g., chlorides, nitriles) [29][30][31]. Recently some green-chemistry approaches were described, e.g., reaction of o-phenylenediamine with acetic acid [32], (un)substituted glyoxal (the Petasis-type reaction) [24,29,33,34], oxalyl acid and its esters [24,35], condensation with -ketoacid (the Hinsberg reaction) [36], application of molecular sieves [37] or task-specific ionic liquid [38,39]. Quinoxalines can be effectively synthesized in a few minutes by the condensation reaction of o-phenylenediamine with -dicarbonyl compounds under microwave irradiation or with various catalysts, for example, gallium triflate, polyaniline sulfate salts, CuSO 4 ·5H 2 O, sulfated cellulose, polyethylene glycols, alumina/alumina-supported heteropolyoxometalates, catalysts based on Keggin-type heteropolyacids (e.g., molybdophosphoric acid), sulfated TiO 2 -P 25 (Degussa titania), Montmorillonite K-10, Zn[(L)proline] or o-iodoxybenzoic acid [24,36,. ...
... Oxopyrimido[2',1':5,1]-1,2,4-triazolo[4,3-a]quinoxalines represent fused rigid molecules with antibacterial activity slightly worse than that of ciprofloxacin. Ethyl 6-chloro-9oxo-9H-pyrimido [ (29) showed activity against S. aureus and P. aeruginosa (MICs 6-12 M). From SAR it can be concluded that substitution of chlorine in position C (6) by any other substituent caused the loss of activity. ...
Antimicrobial diazanaphthalenes are indispensable in treatment of various infections. The quinoxaline scaffold possesses unique physicochemical properties and provides a possibility of a great number of targeted modifications. Quinoxaline-based compounds have a wide range of promising biological properties; therefore a special attention is paid to them at research and designing of new drugs. In fact quinoxaline can be considered as a privileged structure. The scaffold can be easily and rapidly constructed, which emphasizes the significance of this favourable structure. The review is focused on recently reported potential antibacterial, antimycobacterial, antifungal and antiprotozoal agents derived from the quinoxaline scaffold, their mechanism of action and structure-activity relationships. A brief classification of synthetic pathways of quinoxaline derivatives is provided too.
... The precursors Q1 and Q2 were prepared from 1,2diphenylethane-1,2-dione with the corresponding bromoaniline derivatives. [33][34][35] Furthermore, the target compounds 1-4 were successfully prepared by Suzuki reaction under palladium catalysis. Although the precursors Q1 and Q2 have poor solubility, the target compounds 1-4 have good solubility in common organic solvents, which is convenient for further development of the photophysical property. ...
... The quantum chemistry calculations were performed using the Gaussian 09 W (RB3LYP/6-311 G(d,p) basis set) software package. 34 The sample was dissolved in tetrahydrofuran at a concentration of 1 Â 10 -5 mol/L and excited by the maximum absorption wavelength on the UV spectrum. Thermogravimetric analysis (TGA) was performed on a high-temperature synchronous thermal analyzer TGA/DSC3+* (Mettler Toledo, Switzerland), with a heating rate and cooling rate of 10K/min, a nitrogen atmosphere, and a test temperature range of 0-600°C. ...
A series of quinoxaline-based compounds 1–4 have been synthesized by a palladium-catalyzed cross-coupling reaction and their photophysical properties have been extensively studied. Compounds 1–4 show deep blue light emission both in solution (λem ≤ 425 nm, Commission Internationale de L’Eclairage y (CIEy) ≤ 0.03) and in the solid state. Moreover, compounds 1–3 show a non-typical aggregation-induced enhanced emission (AIEE), which would be effective deep blue light-emitting materials. The DFT calculation indicated that the HOMO energy levels of compounds 1–3 are distributed throughout the molecule, and the LUMO energy levels are mainly concentrated on the quinoxaline group. However, the HOMO of compound 4 is mainly on the benzene ring at 2,3 position, and the LUMO is distributed both of the quinoxaline and the benzaldehyde group at the 6,7 position.
... The structure assignment of the prepared quinoxaline glycosides 3a-f was based on 1 H and 13 C NMR spectroscopy, as well as on physicochemical analysis. The 1 H NMR spectra give clear evidence for both the chemoselective and stereospecific reaction product formation. Thus, the 1 H NMR spectrum of compound 3e exhibits a doublet signal at 6.30 ppm with coupling constant of J = 3.9 Hz. ...
... Acetamido-2-deoxy--D-glucopyranosyloxy)-3-methylquinoxaline (8b). Yield 2.73 g (59%), white crystals, mp 241-242°C.1 H NMR spectrum (CDCl 3 ), δ, ppm (J, Hz): 1.76 (3H, s, NHCOCH 3 ), d, J = 7.8, NH). ...
A series of quinoxaline O-nucleosides, 3,6,7-trisubstituted 2-(2,3:5,6-di-O-isopropylidene-β-D-mannofuranosyl-1-yl)quinoxalines and 2-(2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl)quinoxalines, was prepared by the reaction of 3,6,7-trisubstituted quinoxalin-2(1H)-ones with the corresponding protected α-chlorosugars in the presence of NaH. The reaction proceeded chemoselectively to give products of O-substitution with β-configuration at anomeric carbon, as proved by NMR data. The deprotection of the 1-(2-acetamido-2-deoxy-3,4,6-tri-O-acetyl-β-D-glucopyranosyl)quinoxalines was achieved by stirring in ammonia-methanol mixture to afford free O-quinoxaline nucleoside analogs.
... Conse‐ quently, there has been tremendous interest in developing efficient synthetic strategies for preparing quinoxalines due to their widespread applications in the fields of medicinal, industrial and synthetic organic chemistry. Commonly employed method involves condensation of an aryl‐1,2‐diamine with a 1,2‐dicarbonyl in refluxing ethanol or acetic acid for 2‐ 12 h yielding 34‐85% of product [10]. Several improved methods reported in the literature for the synthesis of quinoxalines include microwave synthesis [11], the use of PEG‐ 400 [12], RuCl‐(PPh3)3‐TEMPO [13], CAN [14], CuSO4.5H2O ...
... Conse‐ quently, there has been tremendous interest in developing efficient synthetic strategies for preparing quinoxalines due to their widespread applications in the fields of medicinal, industrial and synthetic organic chemistry. Commonly employed method involves condensation of an aryl‐1,2‐diamine with a 1,2‐dicarbonyl in refluxing ethanol or acetic acid for 2‐ 12 h yielding 34‐85% of product[10]. Several improved methods reported in the literature for the synthesis of quinoxalines include microwave synthesis[11], the use of PEG‐ 400[12], RuCl‐(PPh3)3‐TEMPO[13], CAN[14], CuSO4.5H2O[15], ...
An efficient method for synthesis of quinoxalines and substituted pyrido-pyrazines has been developed from different 1,2-dicarbonyl compounds and substituted 1,2-diamines using Indion 190 resin as a solid acid catalyst. Ambient reaction conditions, high product yield and reusability of the catalyst with minimal loading are the salient features of the present protocol.
... Looking to the applications of quinoxaline derivatives, enormous methodologies are developed for their synthesis. The most common method for the synthesis relies on the condensation of an aryl 1,2-diamines with 1,2-dicarbonyl compounds, [17][18][19][20][21] . Similarly, 1,2-keto hydroxyl compounds undergo reaction via tandem oxidation procedure involving catalysts such as Pd(OAc)2, [22][23] MnO2, 24 I2/DMSO, [25][26] . ...
... Extensive researches have generated numerous synthetic approaches for the construction of the skeleton of such heterocycles. Among the methods, the most widely used one relies on the condensation of aryl-1,2-diamines with 1,2-dicarbonyl compounds or their equivalents [29]. Considering the significant applications in the fields of medicinal, industrial and synthetic organic chemistry, there has been tremendous interest in developing efficient methods for the synthesis of quinoxalines. ...
The review article attempts to give recent advances on quinoxaline and its derivatives. Some pathways to the synthesis of quinoxaline, quinoxaline-2-one and quinoxaline-2,3-dione were reported using simple reactive quinoxaline synthon. In addition, the reactions, biological and technological applications of derivatives of quinoxaline and related compounds were reported.
... However, we find the synthesis of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3dione (1) from the addition of ethyl benzoylpyruvate to phenyl isothiocyanate and KOH in DMF with stirring at room temperature [16]. In addition, 4-acylated-5substituted thiophene-2,3-diones are feasible and beneficial intermediates for the synthesis of a vast variety of substituted heterocyclic compounds [17][18][19]. In addition, 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3dione (1) has been recognized as a particularly significant starting material or intermediate for the synthesis of diverse sulfur-and nitrogen-containing heterocyclic compounds [16,[20][21][22][23]. ...
The reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with aminoheteroaryls, lamotrigine, 1,3-diaminoheteroaryls, dapsone, NH2R (hydroxylamine, DL-1-phenylethylamine, and metformin), and 4,4′-bipyridine in THF/H2O (1 : 1) at room temperature led to 3-N-phenylthiocarbamoyl-2-butenamides 2–5, while that with naphthylamines and 1,3-phenylenediamine in ethanol at high temperature led to 5-phenylamino-2,5-dihydrothiophene-2-ones 6–8 as organic ligands in the medium to good yields. These showed the nucleophilic attacks of N-nucleophiles, except primary aromatic amines, on thioester carboxyl group (C-2) of thiophene-2,3-dione ring 1. However, the nucleophilic attacks of primary aromatic amines on the carbonyl group (C-3) of thiophene-2,3-dione 1 occurred in the form of substituted thiophenes.
... [1] Due to their potential value, diverse synthetic methodologies have been developed to access functionalized quinoxalin-2(1H)-ones, such as the condensing aryl-1,2-diamines with two carbon building units. [2] More recently, direct modification of quinoxalin-2(1H)ones at the C3-position has been reported, including C3À H arylation, [3] phosphonation, [4] amination, [5] and acylation of quinoxalin-2(1H)-ones, [6] providing efficient and straightforward methods to assemble complex molecular skeletons. We then speculated that, direct incorporation of alkyl substituents into quinoxalin-2(1H)-ones will provide more opportunity to synthesize diverse functionalized quinoxalin-2(1H)-ones, which could help to modulate their bioactivity and promote their applications in structure-activity relationship research in medical and agricultural chemistry (Scheme 1). ...
Blue light: A decarboxylative‐catalyzed Minisci‐type cross coupling reaction of quinoxalin‐2(1H)‐ones with aliphatic carboxylic acids using iridium as photocatalyst is described herein. Varieties of quinoxalin‐2(1H)‐ones could be successfully converted into the alkylated quinoxalin‐2(1H)‐one motifs. The reaction has been successfully applied to the late stage functionalization carboxylic acid‐containing bioactive molecules, and a mechanistic study indicates a radical mechanism. Moreover, preliminary antibacterial evaluation against Magnaporthe grisea showed a promising inhibitory rate. image
... Various other methods for the synthesis of amino-pyridazines from polyfunctionalized nitriles, especially via the Japp-Klingemann reaction [33,34], have resulted in formation of pyridazines and pyridazinones in three-component reactions between active methylenes, benzil and hydrazine [35,36]. 4-Acylated-5-substituted 2,3-dihydrothiophene-2,3-diones are versatile and useful starting materials or intermediates for the synthesis of various substituted heterocyclic compounds [37][38][39]. Earlier we found that the reactions of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) with N,N-dinucleophiles such as 1-aminoguanidine, guanidine, urea, 1,2-phenylenediamine and diaminomaleonitrile provided heterocyclic compounds that have N-phenylthiocarbamoyl group [40,41]. ...
Seven, novel pyrrolo[2,3-c]pyrazol-3(2H)-one and 1,2-dihydro-5H,6H- pyridazine-5,6-dione chromophores were synthesized by the reac- tion of 4-aroyl-5-phenylamino-2,3-dihydrothiophene-2,3-diones with cyanoacetohydrazide and arylhydrazines such as phenylhy- drazine and 4-nitrophenylhydrazine. These derivatives were charac- terized by elemental analysis, IR, UV-Visible, 1 H, 13 C NMR and mass spectroscopy. Spectral characteristics of the compounds were stud- ied in four organic solvents of differing polarity.
... The synthesis of reduced cinnolines [30] and regular aromatic cinnolines [31] have been possible through this method. 2,3,5-Trimethyl-6-phenacyl-1,4-benzoquinone (18) on heating with hydrazine hydrate at 20 o C in toluene for 18 h gave 5,7,8-trimethyl-3-phenyl-6(2H)-cinnolinone (19) ...
Cinnoline or Benzo-pyridazine have its place in the family of fairly well-known benzfused-diazine heterocycles. Because of its natural occurrence and synthetic exploration, cinnoline compounds validated its thought-provoking bioactivity through a number of research publications and patents during last few decades. A creative consideration has been rewarded to the synthesis of cinnoline based heterocyclic compounds, mostly due to their widespread range of diverse pharmacological activities. The present review covers almost all biological properties of 115 cinnoline derivatives reported during the last 65 years from natural and synthetic origin with 132 references.
... The compounds of quinoxalines used to develop organic semiconductors [41,42], dehydroannulenes [43], and also used in dyes [44]. Various methods have been reported in literature for the synthesis of quinoxalines, i.e. condensation of 1,2-diketone with phenylene diamine to yield the desired quinoxaline under reflux condition at ambient temperature with various solvents such as benzene, ethanol [45] with use of different catalyst like molecular iodine, copper(II) sulphate, indium(III) chloride, o-iodoxybenzoic acid, ceric ammonium nitrate, silica gel, gallium(III) triflate phosphorus oxychloride, oxidative coupling of epoxides with ene-1,2-diamines [46], 1,4-addition of 1,2-diamines to diazenylbutenes [47], cyclization-oxidation of phenacyl bromides with 1,2-diamines by HClO 4 -SiO 2 [48] and by using solid phase synthesis [49,50]. Quinoxaline has also been synthesized by the chemical reaction of phenylene diamine and different substituted phenacyl bromides via solid phase [49,50], synthesis by using different catalyst like 1,4-diazabicyclo [2,2,2]octane, trimethylsilyl chloride, perchloric acid supported on silica, KF-alumina, β-cyclodextrin. ...
... Scientific data concerning the potential relevance of quinoxaline and derivatives in the literature were ana- lyzed. The most common method for the synthesis of qui- noxaline derivatives is the coupling reaction of 1,2-dicarbo- nyles and o-phenylenediamines in the presence of an acidic catalysts [14][15][16][17][18]. Also, numerous methods are available for the synthesis of quinoxaline derivatives which involve con- densation of 1,2-diamines with α-diketones [19][20][21], oxida- tive coupling of epoxides with ene-1,2-diamines [22,23] and cyclization-oxidation of phenacyl bromides [24,25]. Also, α-hydroxyketones react with o-phenylenediamines in the presence of transition metals such as Ru and Pd to give 1 3 quinoxalines [26]. ...
A novel method for the synthesis of pyrazines and quinoxalines has been developed using α-hydroxyketones and 1,2-diamines in the presence of cross-linked poly(4-vinylpyridine)-stabilized Pd(0) nanoparticles, [P4-VP]-PdNPs. The catalyst was easily prepared and characterized using various techniques such as FT-IR and UV–Vis spectroscopy, AAS, TEM, FESEM, EDX analysis and XRD. The results confirm a good dispersion of palladium nanoparticles on the polymer support. The catalyst displayed good catalytic activity when applied to the synthesis of quinoxalines via condensation of α-hydroxyketones with 1,2-diamines. A few pyrazine derivatives and various quinoxalines are prepared via coupling reaction of α-hydroxyketones and 1,2-diamines in high–excellent yields (81–99%) with short reaction times. The quinoxalines products were characterized by FT-IR, 1H and 13C NMR spectroscopy, and the physical properties were compared to the literature values of known compounds. The advantages of the present method over conventional classical methods are rapid and very simple work-up, and the catalyst is reusable many times without a significant loss in its activity.
... The introduction of a nitrogen atom into the benzo ring of phthalazines leads to pyridopyridazines. This scaffold can be easily functionalized at different ring positions, which makes it attractive compound for designing and development of the new pyridopyridazine drugs 21,22 . The pyridopyridazine ring attracted many pharmaceutical industries for their sensible biological activities. ...
Pyridopyridazine compounds are important nitrogen atom containing heterocyclic compounds due to their pharmacological versatility. This heterocycle system characterized a structural feature for different types of bioactive compounds that exhibiting various types of biological activities which make it an attractive scaffold for the design and development of new drug molecules. This article provided information about the pharmacological properties of pyridopyridazines derivatives.
... Generally, condensation of 1,2-dicarbonyl compounds with aryl 1,2-diamines affording pyridopyrazines is an interesting target in modern organic chemistry. [4][5][6] These compounds have great synthetic potential due to applications in many aspects of pharmaceutical and medicinal chemistry such as antibiotic, 7 potent inhibitors, 8,9 binding to DNA, 10 antimicrobial, [11][12][13] receptor antagonists, 14,15 activities. ...
Ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate (1) and 2-
Chloro-3-nitro-6-methoxypyridine react each other to offer Ethyl 4-
(trifluoromethyl)-1-(6-methoxy-3-nitropyridin-2-yl)-1H-imidazole-5-
carboxylate (2). Compound 2 cyclised with Sodiumdithionate to form 2-
Methoxy-7-(trifluoromethyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-
one(3) which on chlorination offers 6-Chloro-2-methoxy-7-(trifluoromethyl)
imidazo[1,5-a]pyrido[3,2-e]pyrazine(4). The structures of all synthesized
compounds were confirmed by IR, NMR and mass spectral data.
... In recent years, the synthesis of quinoxalines has attracted considerable attention [14] and a wide range of synthetic methods has been developed for the synthesis of quinoxaline derivatives [15][16][17]. The conventional synthetic methods of quinoxaline derivatives were carried out in organic solvent via the condensation of arene-1,2-diamines with 1,2-dicarbonyl compounds for 2-12 hours under refluxing conditions with the yields of 34-85% [18] or in high boiling point solvent such as dimethylsulfoxide (DMSO) using the molecular iodine as the catalyst [19]. Now a days research effort has been focused on finding new catalysts to improve the yield of this condensation reaction. ...
Keeping the objective to build up a new structural class of quinoxaline, a new series of quinoxaline derivatives bearing the pyridinyl thiazole nucleus have been synthesized by base-catalyzed chloro-amine condensation reaction approach. The protocol offers expeditious and easy synthesis with excellent yield. The chemical structures of the synthesized compounds were elucidated by ¹ H NMR, ¹³ C NMR, FT-IR, elemental analysis, and mass spectral data.
... Numerous methods are available for the synthesis of quinoxaline derivatives which involve condensation of 1,2-diamines with α-diketones [19,20], 1,4-addition of 1,2-diamines to diazenylbutenes [21], cyclization-oxidation of phenacyl bromides [22,23] and oxidative coupling of epoxides with ene-1,2-diamines [24], 2,3-Disubstituted quinoxalines have also been prepared via the Suzuki-Miyaura coupling reaction [25], condensation of o-phenylenediamines with 1,2dicarbonyl compounds in MeOH/AcOH under microwave irradiation [26] and iodine catalyzed cyclocondensation of 1,2-dicarbonyl compounds with substituted o-phenylenediamines in DMSO [27] or CH 3 CN [28]. ...
A new series of thiophenyl thiazole based novel quinoxaline derivatives 4a-4t have been synthesized by base catalysed condensation reaction. In which 6-substituted 2,3-dichloroquinoxaline 1a and 4-(thiophen-2-yl) thiazol-2-amine 2b reacted in basic condition to afford intermediate 3c which reacts with various aromatic amine to form final compounds. Easy experimental procedure, high yield, and selectivity are the imperative features of this method. The identity of all the compounds has been established by ¹ H NMR, ¹³ C NMR, FT-IR, and elemental analysis.
... Iodopyridazines are important representatives of halopyridazines. [1][2][3] Their simple and straightforward preparation is based on a nucleophilic halogen displacement reaction. This was carried out by the treatment of chloropyridazine have been treated with 57% hydrogen iodide, 4,5 hydrogen iodide with iodine monochloride 6 or hydrogen iodide with sodium iodide 7 as iodide source. ...
... Quinoxaline ring is also part of various antibiotics such as echinomycin, levomycin and actinomycin [5,6] which are known to inhibit the growth of Gram positive bacteria and are active against various transplantable tumors [7]. The classical synthesis of quinoxaline derivatives involves the double condensation of aryl 1,2-diamines with 1,2-dicarbonyl compounds in refluxing ethanol or acetic acid for 2 -12 h in 34-85% yield [8], Synthesis with molecular iodine in ethanol have also been reported [9]. Recently, improved synthetic methods have been reported and to mention a few are the oxidative coupling of epoxides and ene-1,2diamines catalyzed by Bi(0) [10] , reaction of αhydroxyketones via a tandem oxidation process using Pd(OAc)2 or RuCl2-(PPh3)3-TEMPO [11] and MnO2 [12], cyclization of α-arylimino oximes of α-dicarbonyl compounds under reflux in acetic anhydride [13] and finally condensation of 1,2-diamine with 1,2-dicarbonyl compounds in MeOH/AcOH under microwave irradiation at 100 0 C [14] . ...
An efficient environmentally benign condensation of 1,2 diketones and 1,2-diamines for a facile synthesis of quinoxalines was carried out in aqueous medium in the presence of tetraethylammonium bromate. Short reaction time , environmentally benign condition , easy workup and high yield are the special features of this method. INTRODUCTION Quinoxaline and its derivatives are integral part of several bioactive molecules which finds applications as anathematic, anticancer [1], antimicrobial [2], antifungal, and antidepressant activities [3,4]. Quinoxaline ring is also part of various antibiotics such as echinomycin, levomycin and actinomycin [5,6] which are known to inhibit the growth of Gram positive bacteria and are active against various transplantable tumors [7]. The classical synthesis of quinoxaline derivatives involves the double condensation of aryl 1,2-diamines with 1,2-dicarbonyl compounds in refluxing ethanol or acetic acid for 2 -12 h in 34-85% yield [8], Synthesis with molecular iodine in ethanol have also been reported [9]. Recently, improved synthetic methods have been reported and to mention a few are the oxidative coupling of epoxides and ene-1,2-diamines catalyzed by Bi(0) [10] , reaction of α-hydroxyketones via a tandem oxidation process using Pd(OAc)2 or RuCl2-(PPh3)3-TEMPO [11] and MnO2 [12], cyclization of α-arylimino oximes of α-dicarbonyl compounds under reflux in acetic anhydride [13] and finally condensation of 1,2-diamine with 1,2-dicarbonyl compounds in MeOH/AcOH under microwave irradiation at 100 0 C [14] . Further, such condensations have also been affected by palladium acetate catalyzed aerobic oxidation in toluene at ambient temperatures. However , long time required for completion (about 24 h) is a drawback. Other methods using catalytic amount of a variety of metal precursors, acids, zeolites, and molecular iodine have been reported [15, 16a-g, 17a-d]. Recently, quinoxaline derivatives were synthesized using cupric sulfate pentahydrate, IBX, and Zn [l-proline] [18a-c], MnCl2[19] , ruthenium catalyzed direct approach [20] , MnO2 [21], CAN [22] , MnO2 and octahedral molecular sieves [23], PbO [24] , and solid acids [25]. It my however, be mentioned that these methods suffer from drawbacks such as the requirement of excess reagents (usually 10 equiv) particularly in the case of MnO2 and high boiling solvents in most cases. This has resulted in their reduced commercial attractiveness and green credentials. In view of the disadvantages, there remains a scope for the development of facile and green method for the synthesis of the quinoxaline derivative .
... In recent years, the synthesis of quinoxalines has attracted considerable attention [12] and a wide range of synthetic methods has been developed for the synthesis of quinoxaline derivatives [13]. The conventional synthetic methods of quinoxaline derivatives were carried out in organic solvent via the condensation of arene-1,2-diamines with 1,2-dicarbonyl compounds for 2-12 hours under refluxing conditions with the yields of 34-85% [14], or in high boiling point solvent such as dimethylsulfoxide (DMSO) using the molecular iodine as the catalyst [15]. ...
The room temperature ionic liquid 1-n-butyl-3-methylimmidazolium tetrafluoroborate ([bmim]BF4) was used to promote the synthesis of quinoxaline derivatives under grinding condition. The yields were ranged in 86.0-95.1%. It was shown that the proposed method is fast, efficient and environmentally benign.
An eco‐conscious, metal‐free protocol has been developed to synthesize a diverse collection of biologically and pharmacologically active quinoxaline and pyrazine derivatives. The protocol involves a one‐pot condensation of various 1,2‐diamines with 1,2‐diones using thiourea dioxide as a catalyst and water as a solvent at ambient temperature. Notably, the catalyst can be reused up to five times without any significant loss of efficacy. The green aspects of this method involved milder reaction conditions, higher yields with shorter reaction times, simple work‐up, non‐chromatographic separations, good reusability, and easy catalyst recovery by simple filtration. Moreover, the reaction is successfully accelerated to a multigram scale, making it favourable for production at a larger scale.
Herein, we report a practical and simple mono- and di-C(sp3)-O cross-coupling of tautomerizable N-heterocycles (dihydrophthalazine-1,4-diones, pyridone, quinoxalinone and pyrimidinone) with ketones, β-dicarbonyl compounds and nitroalkane, leading to substituted imidate derivatives under visible-light conditions. The combination of rose bengal as the photocatalyst and TBHP enables sustainable reaction conditions, operational simplicity, and high chemo- and regioselectivity with exceptional yields (up to 94%), good functional group tolerance and substrate generality. In the case of unsymmetrical ketones, the less substituted end is functionalized selectively. The di-C-O coupling products are generally obtained with ketones containing three enolizable 'H' at the reaction site while ketones with two enolizable 'H' furnished only single coupling products. Radical inhibition experiments revealed the involvement of a radical pathway in this coupling strategy. The coupling products are also scaled up to the gram scale, offering scope for further functionalizations via C-H bond activation.
Background and objective:
Tubulin inhibitors have proved to be a promising treatment against cancer. Tubulin inhibitors target different areas in microtubule structure to exert their effects. The colchicine binding site (CBS) is one of them for which there is no FDA-approved drug yet. This makes CBS a desirable target for drug design.
Materials and methods:
Primary virtual screening is done by developing a possible pharmacophore model of colchicine binding site inhibitors of tubulins, and 2,3-diphenylquinoxaline is chosen as a lead compound to synthesis. In this study, 28 derivatives of 2,3-diphenylquinoxalines are synthesized, and their cytotoxicity is evaluated by the MTT assay in different human cancer cell lines, including AGS (Adenocarcinoma gastric cell line), HT-29 (Human colorectal adenocarcinoma cell line), NIH3T3 (Fibroblast cell line), and MCF-7 (Human breast cancer cell).
Results:
Furthermore, the activity of the studied compounds was investigated using computational methods involving molecular docking of the 2,3-diphenylquinoxaline derivatives to β-tubulin. The results showed that the compounds with electron donor functionalities in positions 2 and 3 and electron-withdrawing groups in position 6 are the most active tubulin inhibitors.
Conclusion:
Apart from the high activity of the synthesized compounds, the advantage of this report is the ease of the synthesis, work-up, and isolation of the products in safe, effective, and high-quality isolated yields.
A metal-catalyst-free synthesis of substituted quinoxalin-2-ones from 2,2-dibromo-1-arylethanone by employing an oxidative amidation–heterocycloannulation protocol is reported. The substrate scope of the reaction has been demonstrated and a possible mechanism for this reaction has also been proposed.
Aims
Aims:The application of 3,5-Bis(trifluoromethyl) phenyl ammonium triflate(BFPAT) as a convenient and novel organocatalyst for the synthesis of quinoxalines.
Background
Recently, ammonium triflate-based organocatalysts have been rapidly evolved, and most of them have been synthesized and utilized in several organic transformations.
Objective
1) introducing a new organocatalyst 2) introducing a practical method for the synthesis of quinoxalines 3) to overcome some problem in this method 4) using water as a green solvent.
Method
A water solution (3 ml) of 1,2-dicarbonyl compounds (1 mmol) and aryl 1,2-diamines (1 mmol) was mixed with BFPAT (10 mol%), and the resulting mixture was stirred at rt for an appropriate time. Upon completion of the reaction, (monitored by TLC), the resultant was cooled with the ice bath, filtered and washed with ethanol and purified by recrystallization from hot ethanol to afford pure products.
Result
A wide variety of quinoxaline derivatives was achieved by the reaction of various substituted o-phenylenediamines and 1,2-diketones in water.
Conclusion
A simple and new ammonium triflate-based organocatalyst was shown to effectively promote the highly efficient synthesis of quinoxalines in water as a green reaction medium. Compared to prior studies, the substrate scope of the starting material was largely extended. In particular, the synthesis avoids the toxic metals in the products, which provides a green and practical method for organic synthesis.
Other
In particular, the synthesis avoids the toxic metals in the products, which provides a green and practical method for organic synthesis.
The synthesis of modified RGD peptides and their conjugation to the pyrazine skeleton at their N-terminus is described. To modify and alter the RGD sequence, short bioactive peptides such as FALKF and NGRG were added to the RGD N-terminus. Moreover, the in vitro investigation of these modified peptides, by cell adhesion assay using the melanoma cell line M21 expressing ανβ3 and M21L lacking αv expression, was made and interestingly peptide 4 containing the pyrazine moiety with linear RGDFAKLF sequence gave the best IC50 value with M21 and all the peptides were unable to bind to M21L demonstrating the selective recognition to ανβ3. The results showed the existence of pyrazine has an essential role in the activity of the peptides. From these results, we can suggest that these peptides can affect cancer cells by abrogation of cell adhesion (cell migration).
Quinoxalines are benzopyrazines containing benzene and pyrazine rings fused together. In the recent past, quinoxalines have attracted Medicinal Chemists considerably for their syntheses and chemistry due to their distinct pharmacological activities. Diverse synthetic protocols have been developed via multicomponent reactions, single pot synthesis and combinatorial approach using efficient catalysts, reagents, and nano-composites etc. Further, the versatility of the quinoxaline core and its reasonable chemical simplicity devise it extremely promising source of bioactive compounds. Therefore, a wide variety of bioactive quinoxalines has been realised as antitumour, antifungal, anti-inflammatory, antimicrobial, and antiviral agents. Already, a few of them are clinical drugs while many more are under various phases of clinical trials. Present review focuses on chemistry and pharmacology (both efficacy and safety) of quinoxalines and also provides some insight in to their structure–activity relationship.
A domino one‐pot strategy for the diversified synthesis of phthalazines, phthalazinones and benzooxazinones, was presented. This strategy proceeds via [Pd]‐catalyzed acylation and nucleophilic cyclocondensation with dinucleophilic reagents. Simple bench‐top aldehydes and nitrogen nucleophiles were utilized, as non‐toxic agents. This process was based on direct coupling with aldehydes, without the assistance of directing group and without activating the carbonyl group. Significantly, the strategy was applied to one‐pot synthesis of PDE‐4 inhibitor.
Ions corresponding to protonated imines appear in the positive ion electrospray mass spectra of mixtures of the parent aromatic aldehyde and arylamine. The formation of these imine products occurs readily in the electrospray source nebuliser, even without the application of a spray potential. This accelerated formation of C=N bonds in the nebuliser has been extended to encompass the preparation of quinoxalines from a range of substituted phenylenediamines and benzils. The condensation may be induced either under conventional positive ion electrospray conditions (to give the protonated quinoxalines) or when the nebuliser is disconnected from the mass spectrometer (to give the neutral quinoxaline). Ions corresponding to intermediate adducts formed by condensation of the phenylenediamine component with the protonated benzil are observed in many cases when the condensation occurs in the mass spectrometer. This finding supports an interpretation based on nucleophilic addition in droplets generated by the nebuliser.
A green method to synthesize cinnolines by 6π electrocyclic reaction with alkenyl amines and TBN has been developed. TBN plays a dual role both as the nitrogen atom source and...
A facile and efficient method was investigated for the synthesis of different quinoxalines by the reaction of o-phenylene diamine and 2-bromoacetophenones. This procedure was carried out in ethanol under catalyst-free conditions. Several sulfonamides were synthesized from 2-(4-methoxyphenyl)-quinoxaline in two steps. At first chlorosulfonation of 2-(4-methoxyphenyl) quinoxaline was done using chlorosulfonic acid and led to 2-methoxy-5-quinoxalin-2-yl-benzenesulfonyl chloride. Then quinoxaline sulfonamides were synthesized by the reaction of quinoxaline sulfonyl chloride with different aromatic amines under solvent-free conditions. All the products were obtained in excellent yields after an easy work-up and were evaluated for antibacterial activities against Staphylococcus spp. and Escherichiacoli bacteria.
The synthesis of brominated quinoxaline derivatives starting from several kinds of quinoxaline by different bromination strategies was studied. First the synthesis of some brominated quinoxalines was accomplished along with the development of an alternative and effective synthesis of some known compounds. A new, clean, and effective synthetic method for selective reduction of quinoxaline to 1,2,3,4-tetrahydroquinoxaline was also developed. The products obtained were characterized by means of NMR spectroscopy, elemental analyses, and mass spectrometry.
Herein, we describe a highly efficient and eco-friendly protocol for the synthesis of benzimidazoles, benzothiazoles and quinoxalines using VOSO4 as a catalyst in ethanol. Use of nontoxic and recyclable catalyst, clean reaction profile, high yields, scalability and broad substrate scope are the important practical features of the present protocol.
-Chloroketones–accessed by atom-economic chlorination of ketones with trichloroisocyanuric acid (TCCA) in the presence of p-TSA under ball-milling condition–were set up for sequential base–mediated condensation reaction with thiourea/thiosemicarbazides, o-phenylenediamine and salicyladehyde to afford 2-aminothiazoles, 2-hydrazinylthiazole, quinoxalines and benzoylbenzofurans, respectively, in respectable yields. The viability of one-pot sequential acid– and base–mediated reactions in the solid state under ball-milling condition is thus demonstrated.
Efficient alkylsulfonate functionalized metal organic frameworks (MOFs), MIL-101-Cr-NH-RSO3H, has been successfully synthesized through a post-synthetic modification strategy of MIL-101-Cr-NH2 with 1,3-propanesultone reagent. The high surface area of MIL-101-Cr-NH2 MOF guaranteed the high dispersion of -SO3H active species and large pore size improved the contacting ability between the substrate and these active sites. The solid MIL-101-Cr-NH-RSO3H catalyst exhibited high catalytic performance in the preparation of quinoxaline derivatives by the condensation of benzene-1,2-diamines with 1,2-dicarbonyl compounds. Furthermore, the MIL-101-Cr-NH-RSO3H catalyst exhibits good stability, general applicability and excellent recycling performance.
The syntheses of quinoxalines derived from 1,2-diamine and 1,2-dicarbonyl compounds under mild reaction conditions was carried out using a nanoparticle-supported cobalt catalyst. The supported nanocatalyst exhibited excellent activity and stability and it could be reused for at least ten times without any loss of activity. No cobalt contamination could be detected in the products by AAS measurements, pointing to the excellent activity and stability of the Co nanomaterial.
Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. This chapter summarizes the recent advances in the investigations of synthesis and biological activities of quinazoline derivatives. According to the main method the authors adopted in their research design, those synthetic methods include microwave assisted reaction, ultrasound-promoted reaction, metal-mediated reaction, water reaction, and phase-transfer catalysis reaction. The biological activities of the synthesized quinazoline derivatives are also discussed.
A wide range of benzo[c]cinnolines are prepared through a sequential C-C and C-N bond formation by means of an oxidative C-H functionalization. The reaction proceeds via the C-arylation of 1-arylhydrazine-1,2-dicarboxylate with aryl iodide using Pd(OAc)2/AgOAc followed by an oxidative N-arylation in the presence of PhI/oxone in trifluoroacetic acid. It is entirely a new strategy to generate the benzo[c]cinnoline libraries with a diverse substitution pattern.
The use of molecular iodine as the catalyst for a one-pot synthesis of quinoxaline derivatives at room temperature is reported. (c) 2005 Elsevier Ltd. All rights reserved.
Cu3(BTC)2 deactivates by deterioration of its crystal structure during the use of this metal organic framework as catalyst in the synthesis of 2-phenylquinoxaline from phenacylbromide and o-phenylenediamine at room temperature. The material resulting from the use of Cu3(BTC)2 as catalyst was characterized by powder XRD, UV–Vis diffuse reflectance spectra and EPR showing that the crystal structure collapses and Cu2+ becomes reduced under the reaction conditions. Graphical Abstract: [Figure not available: see fulltext.]
A series of pyrido[2,3-b]pyrazine derivatives were synthesized in good to excellent yields by condensation reactions of arylglyoxals with 2,3-diaminopyridine in dimethylformamide and ethanol at 90 oC.
Two catalysts, alumina and manganese oxide supported on alumina, have been prepared by calcination and precipitation-impregnation methods, respectively. The catalysts are characterised by the following techniques: Brunner-Emmett-Teller-N2 adsorption-desorption for surface area, temperature programmed desorption of NH3 and n-butyl amine back titration methods for surface acidity, powder X-ray diffraction for textural properties, and Fourier transform infrared spectroscopy for the anionic radicals. The catalytic activity has been determined under heterogeneous conditions in the condensation reaction between o-phenylenediamine and benzil. The product purity is checked by thin-layer chromatography and melting point. The products are also analysed by LC-MS and 1H-NMR techniques. The yields of the products have been found to be good and catalysts exhibited excellent recyclability. The effect of changing the reaction parameters such as temperature, reaction time, amount of the catalyst, nature of solvent and molar ratio of reactants on the yield of the product has been studied. The surface acidity of the catalysts plays an important role in activating the reaction.
A simple, highly efficient and green procedure for the preparation of quinoxaline in the presence of catalytic amount of ionic liquid of imidazolium salts is described. Using this method, quinoxaline derivatives as biologically interesting compounds are produced in high to excellent yields and short reaction times. Environmentally benign, simple methodologies, easy workup procedure, clean reaction, short reaction time, high yield and easy preparation of the catalysts are some advantages of this work.
A simple, highly efficient and green procedure for the condensation of aryl and alkyl 1,2-diamines with α-diketones in the presence of catalytic amount of sulfonic acid functionalized imidazolium salts (SAFIS) is described. Using this method, quinoxaline derivatives as biologically interesting compounds are produced in high to excellent yields and short reaction times. Environmentally benign, simple methodologies, easy workup procedure, clean reaction, short reaction time, high yield and easy preparation of the catalysts are some advantages of this work. In this work, some sulfonic acid functionalized imidazolium salts (SAFIS), as a new category of ionic liquids, are synthesized by eco-friendly and simple procedures, and used as highly efficient and reusable catalysts to promote the following one-pot organic transformations under solvent-free conditions.
Quinazoline derivatives are associated with broad spectrum of biological activities. In view of this, 4-substituted phenyl-3,4,5,6-tetrahydrobenzo[h]quinazoline-2(1H)-thiones were prepared under microwave irradiations through one-pot multicomponent reactions and these quinazolinethiones were then converted to S-alkyl/aryl quinazoline derivatives. The synthetic schemes of the prepared compounds are given.
TiO 2 SO 4 2¹ , prepared by solgel method has been used for the synthesis of quinoxaline and dipyridophenizine derivatives under microwave irradiation. High-resolution transmission electron microscope (HR-TEM) and atomic force microscope (AFM) images reveal the corrosion of TiO 2 particles by sulfuric acid, which causes an increase in the acidity of the catalyst. Sulfate loading by H 2 SO 4 increases catalytic activity of TiO 2 . This catalyst gives an excellent yield with less reaction time and is an inexpensive, easily recyclable and efficient catalyst for this reaction. Green chemistry is a rapidly developing new field since it provides a proactive avenue for the sustainable development of future science and technologies. 1 Green chemical synthesis uses highly efficient and environmentally benign synthetic protocols to deliver life saving medicines, accelerating lead optimization processes in drug discovery. For green synthesis it is desirable to avoid any organic solvents as a reaction medium and to use green catalysts. Quinoxaline and its derivatives are an important class of benzoheterocycles 2 displaying a broad spectrum of biological activities 3,4 which has made them privileged structures in combinatorial drug discovery libraries. 5 Dipyridophenazines have been used as a metal ligand for the formation of ligand complexes with attractive features. 6 A number of synthetic strategies have been developed for the preparation of substi-tuted quinoxalines and dipyridophenazines. 69
The structure of one of the blue pigments formed by the reaction of o-acetylbenzophenone [1] with phenylhydrazine was determined by comparison with l-(2,3-diphenyl-l-isoindolyl)-2-(4-phenyl-l-phthalazinyl) ethylene [3 a] and its methyl iodide adduct. [3 a] was prepared by the reaction of 1,2-diphenyl-3-(phenyliminomethyl)isoindole with l-methyl-4-phenylphthaIa-zine in the presence of potassium t-butoxide. [1] reacted with 2-aminoethanol to give blue pigment, C48H88N2O4 [5]. The mechanism for the formation of [5] is proposed as shown in Scheme 1.
1-Phenyl, 1-methoxy, 1-phenoxy, 1-benzylphthalazine 3-oxides (Ia-d) reacted with dimethyl acetylenedicarboxylate (II) to afford four kinds of adducts : methyl 6-substituted pyrrolo [1, 2-α] phthalazine-1, 2, 3-tricarboxylate (IVa-d), dihydro derivative of IV (Va, c, d, VIa, d), 4-substituted 2-phthalazinium 3-methoxy-1-methoxycarbonyl-2, 3-dioxopropylide (VIIb, c, d). In the reaction of Ia with II, two products (VIII, IX), which showed the same molecular formula C20H16O5, were also obtained. It is considered that these products are formed by the liberation of nitrogen from the 1, 3-dipolar cycloadducts. The structures of VIII and IX have not been determined. Ia-d reacted with methyl propiolate (III) to afford methyl 6-substituted pyrrolo-[1, 2-α] phthalazine-1, 3-dicarboxylates (Xa-d). In the reaction of Ia with III, structure-unknown product (X, C18H14O3) was also obtained.
Irradiation of 2-thiopyridone (1), quinoline-2-thione (10), isoquinoline-l-thione (18h) and phthalazine-1-thione (18i) with vinyl ethers (7) gave two-fold addition products, by addition of theolefins to the C=S bond.
Acetic anhydride reacted with isoquinoline (IV) itself under reflux to give an addition product, whereas quinoline did not react with acetic anhydride under the same conditions. The structure of the product was determined to be 2-acetyl-1,2-dihydroisoquinoline-1-acetic acid (V) by means of chemical reactions. Active methylene (or methyl) compounds were observed to react with IV competitively to give the corresponding 1,2-dihydroisoquinolines when they were heated with IV in acetic anhydride. © 1981, The Pharmaceutical Society of Japan. All rights reserved.
Upon heating of the leuco triarylmethane dyes (2a) and (2b) with excess phosphoryl chloride under reflux, these compounds underwent a normal chlorination followed by a de-anilination process to give (3a) and (3b), respectively. Replacement of the p-dimethylamino substituent with a p-methoxy substituent on the 4, 4-diaryl groups had a marked effect on the reaction ; only the 1-chlorinated products, (4a) and (4b), were formed even upon heating under reflux for 10 hours. On heating of (2b) in TFA, only 1-trifluoroacetoxylation occurred. Thus, the driving force of this type of de-anilination could be ascribed to a combination of greater orbital interaction between phosphoryl chloride and the HOMO of dimethylaniline, and the aromaticity of the resulting phthalazine molecule, resulting in a special type of carbon-carbon bond cleavage.
A solution of dichloroethane containing crystal violet hydrazide (CVH) underwent a rapid photolytic coloration upon ultraviolet (UV) irradiation. When 5% ethanol-dichloroethane was used as a solvent, the dye formation was more efficient and the 620 nm band for triarylmethane dye continued to increase in intensity as the 270 nm band for CVH decreased. The solvent dependency of the fluorescence spectra clearly showed that raising the ratio of ethanol to dichloroethane accelerated the photoionization of CVH. However, the actual dye formation was not efficient due to substantial reversion to the leuco derivative, 5.
Grignard reaction of 5, 6, 7, 8-tetrahydro-2-methylphthalazinium iodide (IX) with 4-methoxybenzylmagnesium chloride afforded 1, 2, 5, 6, 7, 8-hexahydro-1-(4-methoxybenzyl)-2-methylphthalazine (X), which was further converted to several kinds of 1-benzylocta-hydrophthalazine derivatives (IV, XI, XII, XIII, XIV, XVII, and XIX). Grewe cyclization of IV to yield 16-azamorphinan (III) resulted in failure.
A new and convenient synthesis of 4-hydroxycinnoline-3-carboxylate derivatices was developed. Reactions of ethyl 2-diazo-3-(2, 4, 5-triflurophenyl- and 2, 3, 4, 5-tetrafluorophenyl)-3-oxopropionates (2a and 2c) with tri-n-butylphosphine afforded ethyl 6, 7-difluoro- and 6, 7, 8-trifluoro-4-hydroxycinnoline-3-carboxylates (5a and 5c) and ethyl 2-hydrazono-3-(2, 4, 5-trifluoro-phenyl- and 2, 3, 4, 5-tetrafluorophenyl)-3-oxopropionates (6a and 6c), respectively. When triphenylphosphine was used, the reaction of 2a-c afforded[[l-ethoxycarbonyl-2-oxo-2-(halogenated phenyl)ethylidene]hydrazono]triphenylphosphoranes (3a-c), which were hydrolyzed to give the corresponding hydrazones 6a-c. An alternate and efficient synthesis of 5a and 5c was accomplished by an intramolecular cyclization of 6a and 6c, respectively. A base-catalyzed cyclization of the methylhydrazone 7 gave ethyl 7-chloro-6-fluoro-1-methyl-1, 4-dihydro-4-oxocinnoline-3-carboxylate (8). Possible mechanisms for the reaction of 2 leading to 5 are discussed.
The synthesis of a wide variety of 9-substituted-3-oxo-3H-2,9-dihydropyridazino[3,4,5-de]phthalazines (11) was achieved by treatment of 3-substituted-3,4-dihydro-4-oxophthalazine-5-carboxylic esters (10) with hydrazine hydrate. These esters were prepared from 3-hydroxyphthalide-7-carboxylic acid (7) by two different routes. Under basic conditions, alkylation of 3-0~0-3H-2,9-dihydropyridazino[3,4,5-de]phthalazine (1) gave 9-substituted products. These undergo further alkylation at the 2-position. Some of them were converted to 3-chloro, 3-thiono, and 3-hydrazino compounds by standard methods. Dehalogenation of selected 3-chloro compounds or desulphurization of 3-thiono derivatives gave l-substituted-lH-pyridazino[3,4,5-de]phthalazines (22), some of which were also prepared by direct alkylation of the parent heterocycle 2 under basic conditions. However, treatment of 2 or its 1-methyl homologue with methyl iodide resulted in products in which nitrogen attached to carbon had been attacked rather than the 1- or 9-position. Treatment of the acid chloride of 3,4-dihydro-4-oxophthalazine-5-carboxylic acid with methyl hydrazine led to 2-methyl-3-0~0-3H-2,9-dihydropyridazino[3,4,5-de]phthalazine (21a) which was purified by cyanoethylation at the 9-position, recrystallization, and hydrazinolysis of the cyanoethyl group. Biological testing revealed that many of the compounds lowered blood pressure in animal models but none had a sufficient therapeutic ratio of activity vs. side effects to warrant clinical trial.
3,4-Dihydrophthalazin-1(2H)-one (II) was first prepared by H.Sund , by electrochemical reduction of phthalazin-1(2H)-one (I) (phthalazone). In the recent years we have described new syntheses of II, through easily hydrolyzable mono- or diacetyl- derivatives, namely condensation of 2-bromomethylbenzoylchloride with N,N'-diacetylhydrazine catalytic reduction of I in acetic acid or of 2-acetylphthalazone in acetic anhydride The reduction of I with zinc is known to proceed with ring contraction and formation of N-aminophthalimidine (III) (zinc and sodium hydroxide at about 100[ddot]C) or of phthalimidine (IV) (zinc and hydrochloric acid under unspecified conditions).Having observed that II is transformed into N-aminophthalimidine when heated with hydrazine hydrate or sodium hydroxide , the zinc reduction of I was reinvestigated with the aim to find out in which cases the intermediate formation of II can be dem-onstratedo
Chinolin (I) wird durch den Komplex Pyridin/Acetylboran (II) in Eisessig bei Raumtemperatur zu 1,2,3,4-Tetrahydrochinolin (III), in siedendem Eisessig zu einem Gemisch aus l-Ethyl-l ,2,3,4-tetrahydrochinolin (V) und 1-Acetyl-l ,2,3,4-tetrahydrochinolin (IV) reduziert.
Ethynylation of various azaaromatics was carried out using bis(tributylstannyl)acetylene 1 via N-alkoxycarbonyl quaternary salts of the substrates, followed by treatment with trifluoroacetic acid. The use of Grignard reagent was only available in the case of pyridine, and monostannylacetylene afforded poor results, thus the reaction was revealed to be generally feasible only by the use of 1. © 1994 Georg Thieme Verlag, Rudigerstr. 14, 70469 Stuttgart, Germany. All rights reserved.
A series of 1,4-dihydro-4-oxo-1-phenylcinnoline-3-carboxylic acids were prepared, and their pollen suppression activity on wheat (Triticum aestivum L.) was evaluated. The substituents and substitution pattern on the cinnoline ring were varied systematically with particular interest shown to the substituent at C-5. Significant pollen suppressant activity is described for analogues bearing a heteroatom substituent, such as fluorine or alkoxy, at C-5 of the cinnoline ring. Compounds bearing an amino substituent showed little or no activity, and compounds with methyl substitution at C-5 were inactive. Variation in the substituents on the phenyl ring was carried out in parallel and was found to modulate the activity of the compounds. In addition to the pollen suppression activity measurement, the phytotoxic effect of the compounds on wheat was observed as chlorosis, plant height reduction, or necrosis. However, no effect on seed quality was seen. The leading compounds for use as chemical hybridization agents are members of the alkoxy series containing less than four carbon atoms, which have the best balance of high sterility and low phytotoxicity.
1‐(Phenylthio)‐ and 1‐(hydroxycarbonylmethylthio)‐4‐methylphthalazines were prepared from 1‐chloro‐4‐methylphthalazines ( 1 ). A series of 2‐benzyl‐ and benzenesulphonyl derivatives was prepared from the corresponding halides and 4‐methyl‐1(2 H )‐phthalazinone ( 4 ). 4‐Methyl‐1(2 H )‐phthalazinthione ( 6 ) was substituted at SH group to give 1‐(benzylthio)‐ and 1‐(ethoxycarbonylmethylthio)‐4‐methylphthalazines, 7 and 8 respectively. Treatment of hydrazine hydrate with 8 produced 1‐hydrazino‐4‐methylphthalazine ( 10 ). However, when the latter compound was treated with 1 it gave 1,2‐bis‐(4‐methylphthalazinyl)hydrazine.
Treatment of 10 with aromatic aldehydes in glacial acetic acid gave the corresponding 3‐phenyl‐ s ‐triazolo‐[3,4‐ a ]‐6‐methylphthalazines 13 . 1‐Hydrazino‐4‐methylphthalazine ( 10 ) underwent cyclization reactions with acetic anhydride, ethyl chloroformate, carbon disulphide, ethylformate, ethyl oxalate and with nitrous acid to give the corresponding triazolo‐, triazino‐ and tetrazolophthalazine compounds.
Reaction with 1-phthalazinecarboniteile (I) was attempted with active methy1ene compounds and ketones as the compounds forming a carbanion, in benzene, in the presence of sodium amide. Active methylene compounds used were pheny1acetonitri1e (IIa), ethyl cyanoacetate (IIb), ethyl malonate (IIc), and ethyl acetoacetate (IId), and ketones used were diethyl ketone (IIIa), acetophenone (IIIb), and cyclopentanone (IIIc). From the types of reaction products formed, two types of the reaction was assumed ; one (A-type reaction) in which the carbanion attacks the ring-carbon at 1-position in I to form 1-substituted phthalazine and the other (B-type reaction) in which the carbanion attacks the ring-carbon at 4-position to form 3, 4-dihydro-1-phthalazinecarbonitrile derivatives (Chart 1). In addition, products correspondnig to secondary reactions (B1, B2, and B3 types) were obtained indicating that the reaction progressed after attack of the ring-carbon at 4-position. Product from A-type reaction was a-phenyl-1-phthalazineacetonitrile (IV) from IIa and that from B-type reaction was 3, 4-dihydro-4-(1-methyl-2-oxobutyl)-1-1-phthalazinecarbonitrile (V) from IIIa. In the case of B1-type reaction, ethyl α, 4-dicyano-1-phthalazineacetate (VI) was obtained from IIb and 4-phenacyl-1-phthalazinecarbonitrile (VII) from IIIb (Chart 3). In the case of B2-type reaction, 4, 4'-methylene-bis-(1-phthalazinecarbonitrile) (VIII) was obtained from both IIc and IId (Chart 4), and as B3-type reaction product, 2, 3-dihydro-1H-benz[f]indene-4-carbonitrile (IX) was obtained from IIIc (Chart 5).
Pyridine, pyridazine and phthalazine derivatives were synthesised for evaluation of their anticancer activity against HeLa cells in vitro and against transplantable mouse tumors.