Quinoxaline 2- -3-hydroxy

Quinoxaline hydroxy-JV-oxides (l-hydroxyquinoxalin-2-ones) have been prepared by alkaline hydrolysis of alloxazine N-oxides (Scheme... 

Conflicting reports on the nitration of phenazine have appeared, but the situation was clarified by Albert and Duewell (47MI21400). The early work suggested that 1,3-dinitroph-enazine could be prepared in 66% yield under standard nitration conditions however, this proved to be a mixture of 1-nitrophenazine and 1,9-dinitrophenazine (24). As with pyrazines and quinoxalines, activating substituents in the benzenoid rings confer reactivity which is in accord with valence bond predictions thus, nitration of 2-methoxy- or 2-hydroxy-phenazine results in substitution at the 1-position. 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Quinoxaline, 6-hydroxy-applications, 3, 195 tautomerism, 3, 173-174 Quinoxaline, isopropyl-oxidation, 3, 169 Quinoxaline, 2-methyl-bromination, 3, 167-168 oxidation, 3, 169 reactions... 

A number of quinoxalines carrying substituents in the benzene ring base have been quaternized, including 5-ethoxy,6-methyl, 6-chloro, and some 2-phenyl derivatives, but in none of these cases has the position of quatemization been ascertained. 5-Hydroxy-quinoxaline gives a methiodide which can still form metal complexes, indicating that salt formation occurred on N-1. ... 

E. Reactions of Quinoxalin-2-ones and Quinoxaline-2,3-diones (2-Hydroxy- and 2,3-Dihydroxy-quinoxalines) ... 

Quinoxalin-2 one (70) is in mobile tautomeric equilibrium with 2-hydroxyquinoxaline (71), but physical measurements fail to demonstrate the presence of the hydroxy form (see following). 

The ready conversion of quinoxalin-2-ones into 2-chloroquinoxalines is not chemical evidence for the existence of the hydroxy form. Phen-... 

Quinoxalin-2-ones are in tautomeric equilibrium with 2-hydroxy-quinoxalines, but physical measurements indicate that both in solution and in the solid state they exist as cyclic amides rather than as hydroxy compounds. Thus quinoxalin-2-one and its A -methyl derivative show practically identical ultraviolet absorption and are bases of similar strength. In contrast, the ultraviolet spectra of quinoxalin-2-one and its 0-methyl derivative (2-methoxyquinoxaIine) are dissimilar. The methoxy compound is also a significantly stronger base (Table II). Similar relationships also exist between the ultraviolet absorption and ionization properties of 3-methylquinoxalin-2-one and its N- and 0-methyl derivatives. The infrared spectrum of 3- (p-methoxy-benzyl)quinoxalin-2-one (77) in methylene chloride shows bands at 3375 and 1565 cm" which are absent in the spectrum of the deuterated... 

Ultraviolet and infrared spectroscopy indicate that quinoxaline-2,3-dione type structures are preferred to tlie tautomeric 3-hydroxy-quinoxalin-2 One or 2,3-dihydroxyquinoxaline forms. The light absorption properties (UV) of quinoxaline-2,3-dione have been compared with those of its NN -, ON-, and OO -dimethyl derivatives (79, 80, and 81), and also its N- and 0-monomethyl derivatives (43 and 82). The parent dicarbonyl compound and its mono- and di-A -methyl derivatives show very strong carbonyl absorption near to 1690 cm split into two peaks. 

The structure of glucazidone, obtained by treatment of 2-D-araho-tetrahydroxybutylquinoxaline with sulfuric acid, is shown to be 2- (2 -furyl)quinoxaline (110), and not (111) as originally proposed. This follows from the synthesis of (110) from o-phenylenediamine and 2-furanglyoxal (109) 3-hydroxyglucazidone, obtained as a by-product in the preparation of glucazidone, is reformulated as 2- (3 -hydroxy-2 -... 

The lipophilicity (7 m value) and specific hydrophobic surface area of pyrido[l,2-a]pyrazinium-l-olates 342 and -3-olate 343, and l-(4-chlorophe-nyl)-l-hydroxy-l,2-dihydropyrazino[2,l-a]isoquinolinium salt (344) has been measured by reversed-phase thin-layer chromatography (98MI13). Partition coefficient (log/ ) of 9-bromo-5-[(A-phenylaminocarbonyl)-methyl]-l,2,3,5,6,7-hexahydropyrido[l,2,3- fc]quinoxaline-2,3-dione was calculated to be 2.78 (97JMC4053). 

Aryl-5-oxo-1,2,3,5-tetrahydropyrido[ 1,2,3-i/e]quinoxaline-6-carboxy-mides were prepared from 7-chloro derivatives and arylboronic acids in the presence of Na2C03, diphenylphosphinated divinylbenzene-crosslinked polystyrene and Pd(PPh3)4 catalyst. 7-Chloro derivatives were obtained from 7-hydroxy derivatives by heating in POCI3 at 50°C for 3 h (01MIP12). 

Some impurities may be found under these GC conditions quinoxaline, phenazine, tetrahydrophenazine, nitroanilines, hydroxy anilines, chloronitrobenzenes, hydroquinone, diami-nophenazine, aminohydroxyphenazine 30 m DB-17 column, 100-275° at 6°/min. 

At least two derivatives of pyran have been used for the primary synthesis of quinoxalines. Thus o-phenylenediamine (390) and 6-(p-methoxyphenyl)-6-methyl-5,6-dihydro-2//-pyran-2,5-dione (391) in methylene chloride at 20°C open to the air for 48 h gave 3-[2-hydroxy-2-(p-methoxyphenyl)propionyl]methyl-3,4-dihydro-... 

Quinoxaline with allyltributyltin and 2,2,2-trichloroethyl chloroformate (CICO2-CH2CCI3) gave bis(2,2,2-trichloroethyl) 2,3-diallyl-l,2,3,4-tetrahydro-l,4-quinoxalinedicarboxylate (17) (CH2CI2, 0°C, 3 h 30%) and a separable byproduct, bis(2,2,2-trichloroethyl) 2-aUyl-3-hydroxy-l,2,3,4-tetrahydro-l,4-quinoxalinedicarboxylate (18) (18%). ... 

Quinoxalinecarbaldehyde (64) gave 2-(p-cyanostyryl)qumoxaline (65) [Ph CH2CN, trace of HN(CH2)5 or Na0H-H20, EtOH, 20°C, briefly 60%] other well-activated methylene synthons likewise gave products such as 2-(2,2-diacetylvinyl)- (66, Q = R = Ac) (66%), 2-(2-acetyl-2-benzoylvinyl)-(66, Q = Ac, R = Bz) (94%), or 2-(2,2-dimethoxycarbonylvinyl)quinoxaline (66, Q = R = C02Me) (58%) but some such synthons produced only the intermediate secondary alcohols, such as 2-(l-hydroxy-2-nitroethyl)quinoxa-line (67) (36%), without final dehydration under these conditions. ... 

Dimethylquinoxaline (147) gave 2-ethoxycarbonyl-2-hydroxy -methyl-2,3-dihydro-[l/ ]-pyrrolo[l,2-u]quinoxalin-10-ium bromide (148) (BrCH2CO-C02Et, AcEt, reflux, 3h, then 20°C, 12 h 72%) and thence successively ethyl 4-methylpyrrolo[l,2-fl]quinoxaline-2-carboxylate (149) (EtONa, EtOH, 20°C, 4h 93% note oxidation by loss of H2O), the uncharacterized quaternary salt (150) (as the first step but 6h 50%), and diethyl dipyr-rolo[l,2-fl 2, l -c]quinoxaline-2,ll-dicarboxylate (151) (KOH, H2O, reflux, 1 h 56%). ° " - ... 

The same substrate (25) aud ethyl 2-chloroacetoacetate gave an analogous product, ethyl 3-hydroxy-3-methyl-3,4-dihydro-2//-1,4-thiazino[2,3-h]qui-noxahne-2-carboxylate (27) (KOH, EtOH, 20°C, 3 h 58%), which underwent dehydration to ethyl 3-methyl-2H-1,4-thiazino[2,3-h]quinoxaline-2-carboxy-late (28) (HCl gas, EtOH, 20°C, 15 h 60% analogs likewise). ... 

Chloro-2-[A -methyl-Af -(thien-2-ylmethylene)hydrazino]quinoxaline 4-oxide (288, R = H) with 2-chloroacrylonitrile gave 8-chloro-4-hydroxy-l-methyl-... 

Abbreviations N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), L(+)-2 amino-3-phosphonopropionic acid (L-AP3), 6-cyano-7-nitroqninoxaline (CNQ5Q, 2,3-dihydroxy-6-nitro-7-sulfamyl-benzo-f-quinoxaline (NBQX), 3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP), 7 Chlorokynnreic... 

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