Quinoxaline-2,3-dione preparation

Depending on the reaction temperature and reaction time, tetrahydroisoquinoline 357 afforded different mixtures of 1,2,3,4,11,11 a-hcxahydro-6//-pyrazino[ 1,2-3]isoquinolines 358-361 and tetracyclic compound 362 (Scheme 30) <2005JA16796>. Each of the individual diastereoisomers 358-361 could be transformed into the compound 362. z7r-3//,4a//-3-Phcnylpcrhydropyra/ino[ 1,2-7]isoquinoline-l,4-dione was prepared via automated parallel solid-phase synthesis on Kaiser oxime resin <1998BML2369>. l,2,3,5,6,7-Hexahydropyrido[l,2,3-r/f ]quinoxaline-2,5-dionc was obtained by catalytic hydrogenation of ethyl 3-(2-oxo-l,2,3,4-tetrahydro-5-quinoxalinyl)acrylate in the presence of TsOH over 5% Pd/C catalyst under 40 psi of hydrogen <1996JME4654>. 

It is of primary interest to avoid corrosive mineral acids in synthetic processes. This can easily be achieved by use of acidic solid supports coupled with microwave irradiation. This has been applied to the preparation of quinolines [53] (Scheme 8.35). This procedure is a safe, green alternative to the use of H2S04 at more than 150 °C. In the same way, quinoxaline-2,3-diones were prepared [54] by use of single-mode irradiation. Previous attempts in solution led to explosions, but the authors successfully used solvent-free conditions with acidic supports or catalysts (the best being p-toluenesulfonic acid) and irradiation times of 3 min (Scheme 8.36). 

Bis(bromomethyl)quinoxaline (126) is better prepared by the condensation of o-phenylenediamine and l,4-dibromobutane-2,3-dione than by side-chain bromination of 2,3-dimethylquinoxaline. It reacts with secondary amines, forming quinoxalino[2,3-c]pyrrolidine salts, e.g. (127).134 Reaction with thiols yields 2,3-bis(thiomethyl)quinoxalines,135... 

Disubstituted and unsubstituted l,2,5-thiadiazolo[3,4- ]quinoxaline-4,9-diones (110) have been prepared in good yield by condensation of 5,6-diaminobenzo[c][l,2,5]thiadiazole with a-dicarbonyl reagents (Equation (62)) <92H(33)337>. These quinones were then converted into 1,2,5-thiadiazolo-, pyrazino-fused TCNQ analogues by condensation with malononitrile in the presence of TiCl4 in dry pyridine. The x-ray crystal structure determination of the product derived from compound (110 R1 = R2 = H) has been accomplished. 

Another Step 5 analogue, 9-[(4-chlorophenyl)acetyl]-1,4,7,8,9,lO-hexahydro-6-nitropyrido[(3,4-f]quinoxaline-2,3-dione, (II), has also been prepared and is discussed (3). 

Quinoxaline-2,3-dithione has been prepared fromquinoxaline-2,3-dione by treatment with phosphorus pentasulfide in pyridine. 

The chemistry of quinoxalin-2-ones and quinoxaline-2,3-diones (2-hydroxy- and 2,3-dihydroxyquinoxalines) has been previously reviewed by Simpson. Quinoxalin-2-ones are very easily prepared from condensation of o-phenylenediamines and a-keto acids and because of their ease of preparation, they have been used as characterizing derivatives for a-keto acids. There are widespread references in the patent literature to the preparation of quinoxalinones for potential pharmaceutical and horticultural applications and also for the formation of polymers. 

Quinoxaline-2,3-diones are conveniently prepared by boiling a mixture of the o-phenylenediamine with oxalic acid dihydrate in 4 M hydrochloric acid. Alternatively a mixture of the diamine is refluxed with excess diethyl oxalate under an air condenser so that the ethyl alcohol formed by intermolecular condensation is allowed to escape (Scheme 19). 6-Nitroquinoxaline-2,3-dione has been prepared by fusion of 4-nitro-o-phenylenediamine with oxalic acid at 160° in this preparation diethyl... 

Electrophilic substitution of quinoxaline-2,3-dione and its 1,4-dimethyl derivative occxu at positions 6 and 7. For example, treatment of a solution of quinoxaline-2,3-dione in concentrated sulfuric acid with one equivalent of potassium nitrate yields the 6-nitro derivative, whereas with two equivalents of potassium nitrate 6,7-dinitroquinoxaline-2,3-dione is formed. 6-Bromo and 6,7-dibromoquinoxaline-2,3-dione have been prepared by bromination of the 2,3-dione in sulfuric acid with bromine and silver sulfate, and chlorination is found to occur under similar conditions. Treatment of quinoxaline-2,3-dione with fuming sulfuric acid yields the... 

Quinoxaline-2-thione is readily converted into 2-hydrazinoqmnoxaline on treatment with hydrazine hydrate, and 3-hydrazinoquinoxaline-2-thione is readily hydrolyzed (2.5 M HCl at 70°) to quinoxaline-2,3-dione. The sodium salt of quinoxaline-2-thione has been S-alkylated with a wide range of alkyl halides to give 2-quinoxalinyl sulfides,but attempts to carry out a parallel reaction with p-nitrochlorobenzene failed. p-Nitrophenyl-2-quinoxalinyl sulfide (5) can however be prepared by reaction of 2-chloroquinoxaline with the sodium salt of p-nitro-benzenethiol. ... 

Many quinoxaline-2,3-dithiones have been prepared from the corresponding 2,3-dichloroquinoxalines by heating under reflux with excess of aqueous potassium hydrogen sulfide solution. The alkali-soluble product on acidification with acetic acid yields the quinoxaline-2,3-dithione. When 2,3-dichloroquinoxaline is treated with two molecular proportions of thiourea in ethanolic solution, S-2-(3-mercaptoquinoxalinyl)-isothiouronium chloride is formed in almost quantitative yield. This on treatment with boiling aqueous sodium hydroxide solution yields quinoxaline-2,3-dithione (15). Substituted quinoxaline-2,3-dithiones have also been prepared by this method. Quinoxaline-2,3-dithione has also been prepared from quinoxaline-2,3-dione by treatment with phosphorus pentasulfide in pyridine, thus avoiding the necessity of first forming the dichloroquinoxaline from the dione. ... 

Compounds of this type are usually prepared from the corresponding quinoxaline-2,3-diones. A variety of chlorinating reagents have been used, including phosphoryl chloride," phosgene," thionyl chloride, and mixtures of phosphoryl chloride with N,N-dimethylaniline or N,N-diethylaniline" " or phosphorus pentachloride." The reactions are normally carried out under reflux in an open vessel for periods of about... 

Quinoxaline-2,3-diones have been prepared by use of single-mode irradiation [214]. Previous attempts in solution led to explosions, but the authors successfully used solvent-free conditions with acidic supports or catalysts (the best being p-toluenesulfonic acid) and irradiation times of 3 min (Scheme 10.108). 

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