Synthesis of Quinoxalines

The synthesis of quinoxalines has been intensively studied in the past, especially because of the diverse biological activities ascribed to many representatives of this class of compounds. Consequently, a large variety of synthetic methods for the synthesis of functionalized quinoxalines has been reported in literature. The first reports were published more than a century ago (Hinsberg 1884 Komer 1884), but even today chemists endeavor to create new and improved routes to these versatile compounds. 

A number of selected examples of biologically active quinoxalines chosen from an impressive list (Negwer and Schamow 2001) are depicted in Fig. 2.1. Note R indicates the salt form of the drug S indicates the synonyms under which the drug is known U indicates its medicinal use and P indicates the page in reference (Negwer and Schamow 2001). 

Caroverine, Oelirex, Espasmofibra, P20M, Spadon, Spasmium, Donau-Pharmazie , Tinnitin, U Spasmolitic (P.2293) 

S Bayo-Nox, Va9391 Celbar, Enterodox plus. Fedan, Neo-Iccadox. Olaquindox U Antibacterial growth stimulant (veterinary) (P.687) 

S Anticarb 100, Carbadiar 2, Carbadox, Carbamix, Enterodox, Enterosuis, Fortigro, Getroxel, 

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The classical synthesis of quinoxalines involves the condensation of an aromatic o-diamine and an -dicarbonyl compound. 

This method is widely applicable to the unambiguous synthesis of quinoxalin-2-ones." It involves the intermediate preparation of a l,2,3,4-tetrahydro-2-oxoquinoxaline by the reductive ring closure of the o-nitrophenyl derivative of an a-aminoacid. These derivatives are formed readily from the aminoacid and an o-nitrohalogenobenzene. The final step of oxidation of the tetrahydro- to the dihydro-quinoxa-line is carried out with potassium permanganate or hydrogen peroxide. The preparation of 7-nitroquinoxalin-2-one illustrates the application of this synthesis ... 

Each such category of synthon has potential for the synthesis of quinoxalines or hydroquinoxalines, but very few examples have been reported. 

Heteromonocyclic compounds other than pyrazines may be used as substrates or synthons for the primary synthesis of quinoxalines. All such syntheses are covered... 

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-... 

Heterobicyclic compounds are important substrates (or synthons) for the primary synthesis of quinoxalines. Such procedures are arranged alphabetically here according to the system name of each substrate/synthon so used. 

There is an extensive literature on the use of 2,1,3-benzoxadiazole 1-oxide [often called benzofuroxanie) (BFO) (462)] as a substrate for the primary synthesis of quinoxaline 1,4-dioxides and occasionally quinoxaline mono-A -oxides or even simple quinoxalines. Very few substituted derivatives of the parent substrate (462) have been employed in recent years. The general mechanism clearly involves a fission (usually amine-catalyzed) of the oxadiazole ring followed by reaction with an ancillary synthon. The following examples are divided according to the type of synthon employed. 

Many such substrates have been used for the primary synthesis of quinoxalines, but few such procedures are of general significance, although some have been decidedly useful in particular cases. Accordingly, the following subsections (arranged in alphabetical order according to the heterocyclic system involved) are each brief. 

Selective transformations Selective styrene ring opening [103] One-pot domino process for regioselective synthesis of a-carbonyl furans [104] Tandem process for synthesis of quinoxalines [105] Atmospheric oxidation of toluene [106] Cyclohexane oxidation [107] Synthesis of imines from alcohols [108] Synthesis of 2-aminodiphenylamine [109] 9H-Fluorene oxidation [110] Dehydrogenation of ethane in the presence of C02 [111] Decomposition of methane [112] Carbon monoxide oxidation [113]... 

Sithambaram, S., Ding, Y., Li, W., Shen, X., Gaenzler, F. and Suib, S.L. (2008) Manganese octahedral molecular sieves catalyzed tandem process for synthesis of quinoxalines. Green Chemistry, 10, 1029-1032. 

Scheme 6.260 Synthesis of quinoxalines and heterocycle-fused pyrazines.

Scheme 6.261 Synthesis of quinoxalines as allosteric Akt kinase inhibitors.

Scheme 7.69 Liquid-phase synthesis of quinoxalin-2-ones.

The formation of quinoxaline heterocyclic systems is a well-known transformation of benzofuroxanes, which occurs in the presence of /3-dicarbonyl compounds <2001RJ0891, 2003BMC2149, 2003EJM791, 2005JME2019>. For example, the synthesis of quinoxaline 1,4-di-jV-oxides was carried out by reaction of the appropriate benzofuroxane 69 with the corresponding /3-ketoester, using triethylamine as the catalyst (Scheme 15) <2005JME2019>. 

Synthesis of quinoxaline-1,4-dioxides from benzofurazan oxide. 

A two-step synthesis of quinoxaline-l,2,3-dithiazolium chloride 119 utilized quinoxaline aminothiol 120 and a mixture of sulfur monochloride and chlorine with further treatment of intermediate 121 with S2CI2 (2001CJC1352 Scheme 60). 

A simple, efficient, one-step synthesis of quinoxaline 1,4-dioxides from the reaction of benzofurazan oxide 179 with activated alkenes such as enamines was named the Beirut reaction in honor of the city of its discovery. Developments up to 1993 were surveyed by Haddadin and Issidorides <1993H(35)1503>, who first demonstrated this reaction. The benzofurazan oxide 179 (Scheme 52) also condenses with 1,3-diketones <1995M1217, 1996JHC1057, 1999CHE459, 2003EJM791, 2005H(65)1589>, /3-keto acid derivatives <1995H(41)2203,... 

Our approach was based on the observation that it is possible to perform SwAr reactions on solid support with amino acids using a solvent system comprised, in equal parts, of acetone and an aqueous 0.5 M NaHC03 solution at temperatures around 70-75°C. Application of this solvent system to the synthesis of quinoxalin-2-ones 6 from la and a-amino acids is described in Section 3.3.2. With respect to the synthesis of 1,5-ben-zodiazepin-2-ones 4, more than 40 examples of aliphatic and aromatic P-amino acids 35 were found to furnish the desired o-nitro anilines 36, about 80% of which were successfully carried on to eventually afford the ben-zodiazepinone products 4 (Scheme 6). In general, the anthranilic acids required slightly harsher conditions to drive the fluorine displacement to completion (75-80°C, 72 h vs. 70-75°C, 24 h for aliphatic P-amino acids). 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

The synthesis of quinoxaline A-oxides from benzofurazan 1-oxides, and by N-oxidation of the corresponding substituted quinoxaline derivatives, has already been discussed (Sections II,D and III,C, respectively). 

Reactions proceeding more than once in the transformation of a substrate can be more effective than a single process If the reaction in question is a condensation of an N nucleophile with a carbonyl compound, the combination of the of two such reactions—allows for the synthesis of heterocycles like, the two depicted in Figure 9.27. The synthesis of quinoxaline (B) from glyoxal dihydrate (A) and orfho-phenylene diamine consists of two imine formations. Somewhat more complicated is the synthesis of dimethylpyrrole D from acetonyl acetone (C) and ammonia. After the formation of the first imine, an imine enamine isomerization occurs. A condensation followed by another imine — enamine isomerization leads to the product. 

Mohsenzadeh, R, Aghapoor, K., and Darabi, H.R. 2007. Benign approaches for the micro-wave-assisted synthesis of quinoxalines. Journal of the Brazilian Chemical Society, 18(2) 297-303. 

Condensation reactions using different fragments are very important for the synthesis of quinoxaline derivatives. Some of these condensation reactions lead, in the first step, to a partially saturated derivative of the heteroaromatic system which can be further oxidized with appropriate reagents. The most widely used method for the synthesis of the quinoxaline ring is the condensation of benzene-1,2-diamine with a two-carbon synthon. 

The synthesis of quinoxaline A-oxides by intramolecular cyclization was first reported by Tennant. ... 

The classical synthesis of quinoxalines involves the condensation of benzene-1,2-diamincs with different two-earbon synthons. The reaetion is also useful as a method of characterizing diketones. This reaction was first described by Korner and Hinsberg in 1884, and is still widely used for the synthesis of the parent system as well as for many derivatives bearing substituents in the hetero and/or in the benzenoid ring. 

With substituted unsymmetrical benzene-1,2-diamines and unsymmetrical reagents this type of reaction leads to isomeric products. Regioselective synthesis of quinoxaline derivatives and the effect of substituents at C3 in the aromatic ring on annulation has been studied for unsymmetrically substituted starting benzene-1,2-diamine derivatives. ... 

The synthesis of (quinoxaline-2,3-diyl)bis(aryldiazenes) 1 in high overall yields (77-84%) proceeds via reaction of benzene-1,2-diamine with l,2-dichloro-l,2-ethaiiebis(iV-arylhydra-zones) in the presence of tricthylamine and oxidation of the resultant 2,3-bis(arylhydrazono)-1,2,3,4-tetrahydroquinoxalines with iodobenzene bis(trinuoroacetate). ... 

The condensation of a,/3-diamino compounds with a,/3-dicarbonyl compounds has been extensively used for the synthesis of quinoxaline (59) and pteridines (61) from o-phenylenediamine (58) and 4,5-diaminopyrimidines (60), respectively. 

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