Quinoxaline-2-carboxylic acids preparations

This chapter covers not only nuclear and extranuclear quinoxahnecarboxylic acids (and anhydrides) but also the carboxylic esters, acyl halides, carboxamides, carbohydrazides, carbonitriles, carbaldehydes, and (ketonic) acyl derivatives of quinoxaline a few related speceis are also included. To avoid repetition, the interconversions of these quinoxaline derivatives are discussed only at the first opportunity thus the esterification of quinoxalinecarboxylic acids in covered as a reaction of carboxylic acids rather than as a preparative route to carboxylic esters, simply because the section on carboxylic acids precedes that on carboxylic esters. To minimize any confusion, appropriate cross-references have been inserted. 

Reactions of 2,3-dioxo-l,2,3,5,6,7-hexahydropyrido[l,2,3-carboxylic acids and the homologous acetic and propionic acids, prepared by basic hydrolysis of the corresponding ester, with amines, 28% NH4OH, and hydroxylamine derivatives in the presence of l-ethyl-3-[3-(dimethylamino)propyl]carbodiimide and hydroxybenztria-zole <1995BML1527>, 1995BML1533>, and in the presence of NEt3 and A, A -bis(2-oxo-3-oxazolidinyl)phosphinic... 

The pyrazine ring is stable toward permanganate oxidation, and this explains a variety of pyrazinecarboxylic acids that have been prepared from quinoxalines or benzo-fused quinoxalines. In contrast, alkyl side chains on pyrazines are effectively oxidized by permanganate, selenious acid, selenium dioxide, or dichromate to afford the corresponding carboxylic acids (Section 8.03.7.1). Oxidation of pyrazines with hydrogen peroxide or percarboxylic acids gives pyrazine A -oxides and/or A, A -dioxides (Section 8.03.5.2). 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides for example, 5-hydroxy-2-pyrazinecarboxylic acid, rather than 5(477)-pyrazinone-2-carboxylic acid, is chlorinated with phosphorus pentachloride/phosphoryl chloride to afford a 63% yield of 5-chloro-2-pyrazinecarbonyl chloride <1994SL814>. Sato and Narita provided an improved synthesis of various halogenopyrazines in which 2(l//)-pyrazinones were activated with chlorotrimethylsilane to give silyl ethers (Section 8.03.7.3). This procedure is most effective for synthesis of bromopyrazines whose overall yields are 62-81% <1999JHC783>. Bromopyrazine is directly prepared by treatment of 2-(l//)-pyrazinone with phosphoryl... 

Substituted quinoxaline-2-carboxylic acids can be prepared by reaction of benzene-1,2-diamines with oxopropanedioic acid or with its monocthyl or diethyl ester.The synthesis of quinoxalinccarboxamides has been achieved by condensation reactions involving a,/l-dioxo-carboxamides. The reaction is limited to the oxo carbonyl groups because of the reduced reactivity of the amide carbonyl function. 

The pyrazine ring is relatively stable to oxidation, and many pyrazine-carboxylic acids have been prepared from quinoxalines, phenazines, and other fused pyrazines by oxidation with potassium permanganate. This reaction has been most used for the oxidation of quinoxalines, for example, 77 -> 78. The oxidations are usually carried out with potassium permanganate in alkali (397), but may also be effected without added base (398). Crippa and Perroncito (399) have also used chromic oxide in acetic acid-acetic anhydride to oxidize benzo(/]quinoxalines (79). Pyrazines prepared by this method are summarized in Table 11.9 (397-419). 

Quinoxaline mono-iV-oxides result from the partial reduction of the di-N-oxides. Among reagents that have been used for this purpose are hydrogen and a metal catalyst, phosphorus trichloride, and sodium dithionite. Thus 2-methylquinoxaline 1-oxide has been prepared by partial hydrogenation of the di-JV-oxide quinoxaline-2-carboxyanilide 1-oxide has been prepared from the partial deoxygenation of the 1,4-dioxide with phosphorus trichloride and quinoxaline-2-carboxylic acid... 

Quinoxaline-2-carboxaldehyde has been converted into the 2-carboxylic acid by oxidation with potassium permanganate in acetone and reduced to the 2-hydroxymethyl compound by treatment with formalin and potassium hydroxide. It also undergoes other typical reactions of aromatic aldehydes such as benzoin formation on reaction with potassium cyanide - and condensation reactions with malonic acid and its diethyl ester and Schiff base formation. Acid-catalyzed reaction of quinoxaline-2-carboxaldehyde with ethylene glycol gives the cyclic acetal the diethylacetal has been prepared by reaction of 2-dibromomethylquinoxaline with sodium ethoxide. " An indirect preparation of the oxime 11 is achieved by treatment of 2-nitromethyl-quinoxaline (10) with diazomethane followed by thermolysis of the resulting nitronic ester. 

Most preparations of quinoxaline-2-carboxylic acids and their derivatives are based on the reaction of an o-phenylenediamine with a suitable... 

Quinoxaline-2-carboxylic acids substituted in the 3-position have been widely prepared by reaction of an o-phenylenediamine with mesoxalic acid or its diethyl ester. Mesoxalic acid ester condensation proceeds as shown in Scheme 1. The resulting quinoxalinone carboxylate can be... 

The ready availability of alloxazines from reaction of 0-phenylenediamine hydrochlorides and alloxan makes them attractive starting materials for the preparation of quinoxaline-2-carboxylic acids. When the pyrimidine ring of the alloxazine is cleaved with ammonia, a 3-... 

Methylquinoxalines are converted into the corresponding carboxylic acids by condensation with an aromatic aldehyde and oxidation of the resulting styryl derivative with potassium permanganate. Quinoxaline-2-carboxylic acids are also conveniently prepared by oxidation of the readily available D-arabinotetrahydroxybutylquinoxalines with sodium peroxide in water or in a heterogeneous benzene-water system. ... 

Alkylquinoxalines have also been prepared by homolytic substitution. Thus reaction of quinoxaline with a mixture of the appropriate carboxylic acid and its sodium salt in the presence of aqueous ammonium perox-idisulfate gives the 2-alkylated quinoxaline. Alkylation can also be achieved by the use of the acid and salt in the presence of trifluoroacetic acid and lead(IV) acetate in benzene (Scheme 2-... 

Diarylquinoxalines have been prepared in the search for antimalarial and antifertility" agents. They have been incorporated into light-sensitive copying compositions, and 2,3-diphenylquinoxaline has been used as a photosensitizer for the decarboxylation of carboxylic acids. Various phenylated quinoxaline polymers have been prepared, and polymers have also been obtained from 6-acryloylamino-2,3-diphenylquinoxaline... 

The base-promoted reaction of 2-amino-1-nitrosonaphthalene with cyanoacetic acid gives an unambiguous synthesis of 3-aminobenzo-[/]quinoxaline-2-carboxylic acid (13), ° a compound previously prepared... 

Another straightforward procedure is described to prepare substituted isoindolo [2,l-a]quinoxalin-6(5//)-ones, which involved the transformation of a substituted 2//-isoindole-l-carboxylic acid into an acid chloride (Scheme 3.90) followed by a coupling reaction with a substituted 2-iodophenylamine and a copper-catalyzed C-N coupling reaction (Table 3.11). 

Pyrazinecarboxylic acid has been obtained by selenious acid oxidation in pyridine of methylpyrazine or aqueous permanganate oxidation of ethylpyrazine, in yields of 64 and 48%, respectively.171,218 It has also been obtained in 70% yield by partial decarboxylation of pyrazine-2,3-dicarboxylic acid on heating in vacuo at 210°.219 Aqueous permanganate oxidation of 2,5-distyrylpyrazine gives the 2,5-dicarboxylic acid.220 Pyrazine-2,5-dicarboxylic acid has also been prepared in 45% yield by direct carboxylation of pyrazine with carbon dioxide at 50 atm pressure at 250° for 3 hours in the presence of a potassium carbonate and calcium fluoride catalyst.221 Pyrazine-tricarboxylic acid (57), obtainable in only very poor yields by oxidation of 2,5-dimethyl-3-ethylpyrazine, is prepared in 87% yield by alkaline permanganate oxidation of 2-(D-arabo)tetrahydroxybutyl-quinoxaline (56).222 Decarboxylation of the tricarboxylic acid by... 

Pyrazinyl ketones have been prepared by treatment of pyrazinecarboxylic esters with an organo-metallic (alkyllithium or Grignard) reagent <84MI 603-01 >. Homolytic acylation of pyrazines and quinoxalines with a-keto acids is an important method for preparation of the acyl compounds (Section 6.03.5.6.1), but the procedure for monosubstitution needs care because the electron-withdrawing effect of the first-formed monoacyl compounds facilitates further substitution. An additional synthesis of pyrazinyl ketones is the lithiation of halogenopyrazines followed by treatment with carboxylic esters or carboxamides (Equation (8) and Scheme 24). Reaction of 2-chloropyrazine... 

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