Benzo quinoxalines reactions

The reaction of benzene-1,2-diamines with nitromethyl phenyl ketone in the presence of sodium dithionite gives 2-phenylquinoxalines. In the same manner, naphthalene-1,2-diamine affords the corresponding benzo[/]quinoxalines. ... 

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). 

Reaction of 2-(D-araf //io-tetritol-l-yl)benzo /]quinoxaline (772) (Section XII,O) with three molar equivalents of phenylhydrazine gave the 3-(D-eryt/ira-l,2,3-hydroxypropyl)benzo[g]flavazole 773 (58CB113) (Scheme 201). 

The condensation of 1,2-diaminonaphthalene with an a-dicarbonyl compound to give a benzo[/]quinoxaline represents a simple extension of the classical quinoxaline synthesis. As a result of the unsymmetrical structure of the diamine, isomeric mixtures of benzo[/]quinoxalines can in principle be formed when the dicarbonyl compound is also unsymmetrical (Scheme 1). In practice only one isomer may be formed in appreciable quantities and be thus readily isolated. The orientation of a number of the products obtained from the condensation reactions of 1,2-diaminonaphthalene is uncertain, though, as discussed in the following sections, unambiguous syntheses of benzo[/]quinoxalines may be achieved using o-aminonitroso- and o-aminophenylazonaphthalenes. 

An interesting reaction sequence based on 1-tetralone (26) leads to an unambiguous synthesis of 2-amino-3-cyano-5,6-dihydro-benzo[/]-quinoxaline (27). The isomeric 3-amino-2-cyano compound is similarly obtained from 2-tetralone. ... 

Oxidation of the parent base with hydrogen peroxide in formic acid gives a high yield of mono-N-oxide and a little di-N-oxide N-Oxidation is assumed to proceed preferentially at the less hindered 4-nitrogen. A number of substituted benzo[/]quinoxaline 4-oxides have been prepared, the majority by oxidation of the appropriate benzo[/]quinoxaline with peracids. " Treatment of benzo[/]quinoxaline 4-oxide with phosphoryl chloride gives mainly 3-chlorobenzo[/]quinoxaline. An isomeric mono-chloride, m.p. 104-104.5°, is also isolated from this reaction which is shown by independent synthesis not to be the 2-chloro derivative. A dichloro derivative, m.p. 187-188°, of unknown structure is obtained by treatment of the parent base with chlorine in glacial acetic acid. A disubstitution product of unknown orientation and m.p. 288° is obtained by nitration of... 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

The diazines pyridazine, pyrimidine, pyrazine, and their benzo derivatives cinnoline, phthalazine, quinazoline, quinoxaline, and phenazine once again played a central role in many investigations. Progress was made on the syntheses and reactions of these heterocycles, and their use as intermediates toward broader goals. Some studies relied on solid-phase, microwave irradiation, or metal-assisted synthetic approaches, while others focused attention more on the X-ray, computational, spectroscopic, and natural product and other biological aspects of these heterocycles. Reports with a common flavor have been grouped together whenever possible. 

The second class of benzo-fused heterocycles accessible from benzofuroxans are benzimidazole oxides. In this case only one carbon from the co-reactant is incorporated in the product. With primary nitroalkanes 2-substituted l-hydroxybenzimidazole-3-oxides (46) are formed via displacement of nitrite, and / -sulfones behave similarly. The nitrile group of a-cyanoacetamides is likewise eliminated to alford 2-amide derivatives (46 R = CONRjX and the corresponding esters are formed in addition to the expected quinoxaline dioxides from acetoacetate esters. Under similar conditions secondary nitroalkyl compounds afford 2,2-disubstituted 2//-benzimidazole-1,3-dioxides (47). Benzimidazoles can also result from reaction of benzofuroxans with phosphorus ylides <86T3631>, nitrones (85H(23)1625>, and diazo compounds <75TL3577>. 

Reactivity dealt with in the following sections is limited only to that of the heteroaromatic ring of pyrazines, quinoxalines, and phenazines, but exceptionally the reactivity on the benzo moiety of quinoxaline and phenazine is described in the Section 8.03.5.3. In general, any type of substitution reaction on quinoxaline and phenazine should be more facile than with pyrazine because of the resonance stabilization effect of the additional benzenoid ring on the transition states leading to the products. 

The syntheses and reactions of pyridazino[3,4-3]quinoxalines, benzo derivatives of the pyrazino[2,3 dpytidazines, have been reviewed <1998JHC1101, 2005JHC387>. 

Furo[3,4-J]pyridazines have also been used in Diels-Alder reactions (331a with maleic anhydride, acrylic acid, 1,4-naphthoquinone, dibenzoyl-ethylene, 1,4-benzoquinone, benzo[c]furandione ° 331c with maleic anhydride) 331a has been shown to be more reactive than 331c. 1,3-Diphenylfuro[3,4-b]quinoxaline (335) has been obtained from phthalide 334 (Eq. 17) as a green crystalline, quite stable solid (mp 244-246°C). In DMSO (deep blue solution), 335 reacts instantaneously with such dienophiles... 

The same type of synthesis affords pyrazino[2,3-e]-1,2,4-triazines (329) and (330) from the diamino precursor (328), by reaction of the latter with glyoxal or phenylglyoxal, respectively. Product (329) is a dihydrate. The fully aromatic intermediate could not be isolated. Formation of (330) involves not only covalent solvation, but also an unusual TV-methylation of the presumed first-formed intermediate, and the suggested mechanism is outlined in Scheme 24 <86JHC33,93H(36)2577>. Reversing the order of polarities of the components allows [4 + 2] cyclization of pyrimidine (331) with orr/io-phenylenediamine (332), giving the benzo fused pyrazino[2,3-c][l,2,6]thiadiazine (333) (a [l,2,6]thiadiazino[3,4-6]quinoxaline]) (Equation (52)) <72ZN(B)1471>. 

Benzofuroxan reacts with benzo[6]furan-3(2//)-oncs to give a product at an oxidation level lower than the expected di-lV-oxide in a process where benzo[A]furan-3(2//)-one plays the dual role of substrate as well as reductant during the reaction, and redox processes determine the structure of the products,This is a general, one-step synthesis of 2-(2-hydroxyaryl)-quinoxaline 4-oxidcs, c.g. formation of 3. ... 

Reaction of 1-arylamino-l-deoxyketoses (764) with 1,2-diaminonaphtha-lene (765) in the presence of hydrazine hydrate gave a mixture of the 2-and 3-(alditol-l-yl)benzo[f]quinoxalines 766 and 767, respectively, in the ratio of 2.5 1 (58CB101) (Scheme 198). 

Applying the just-mentioned reaction to the benzo[g]quinoxalin-2-yl acyclo C-nucleoside 774 (Section II,P) gave 775 (58CB113) (Scheme 202). 

Compound 777 of this type of acyclo C-nucleoside was prepared from the benzo[g]quinoxalin-3-yl precursor 776 (Section XII,O) by reaction with phenylhydrazine (58CB113) (Scheme 203). 

The reaction of benzene-1,2-diamines with 3,4,6-trichloropyridazine leads to 3-chloro-5,10-di-hydropyridazino[3,4- >]quinoxalines (6,7-benzo-annulated pyiazino[2,3-c]pyridazines) which can be oxidized to the fully conjugated system using potassium dichromate.74... 

Halogenation reactions are known for quinoxalino[2,3-c]cinnolines (3,4- and 6,7-bisbenzo-an-nulatcd pyrazino[2,3-c]pyridazines)69 and for pyridazino[3,4-6]quinoxalines (6,7-benzo-annu-lated pyrazino[2,3-c]pyridazines).77... 

The reaction of ethyl 3-formylquinoxaline-2-carboxylate Af/V -dioxide (9) with hydrazine results in the formation ofpyridazino[4,5-h]quinoxalin-l-ol 5,10-dioxide (10) (2,3-benzo-annulat-ed pyrazino[2,3-<7]pyridazin-5-ol).92... 

The reaction of pyridazino[4,5- >]quinoxaline-l-thiol (2,3-benzo-annulated pyrazino[2,3-r/]-pyridazine) with anhydrous hydrazine in anhydrous ethanol (reflux, 4 h) affords pyridazi-no[4,5-A]quinoxaline-l-hydrazine in a yield of ca. 80% (mp 271 -273 °C).92... 

The reactivity of substituents dealt with in this section is limited to those on the heteroaromatic ring in pyrazines and quinoxalines. In Section 6.03.9 the reactions of the benzo-fused rings (regarded as a special type of ring-carbon substituent for the purposes of this review) are covered. 

A simple, efficient, one-step synthesis of quinoxaline 1,4-dioxides from the reaction of benzo-furazan oxide (171) with activated alkenes such as enamines was named the Beirut reaction in honor of the city of its discovery. Earlier developments to 1981 were surveyed by Porter <84CHEC-I(3)157>, and later progress has been reviewed by Haddadin and Issidorides <93H(35)1503> who first demonstrated this reaction. Dienamines and azadienes (172) also react with benzofurazan oxide to yield... 

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