Quinoxalines, synthesis from

SCHEME 65 Quinoxaline synthesis from 1,2-aryl diamines and 2-bromomalonic ester at room temperature. 

SCHEME 68 Bismuth-catalyzed quinoxaline synthesis from epoxides. 

R2 = H. 4-MeC6H4. 4-COPh SCHEME 87 Quinoxaline synthesis from diketones and amines under metal-free conditions. 

Quinoxaline mono-N-oxides are also available by a direct synthesis from n-nitroaniline derivatives. Condensation of acetyl chloride derivatives with o-nitroaniline followed by treatment with sodium ethoxide in ethanol yields the mono-N-oxides in good yields (Scheme 20) (64JCS2666). 

This is by far the most used type of primary synthesis for quinoxalines. It usually involves the cyclocondensation of an o-phenylenediamine (or closely related substrate) with a synthon containing an oxalyl [—C(=0)—C(=0)—] or equivalent [e.g., HC(=0)—C=N] grouping. For convenience, discussion of this synthesis is subdivided according to the type of synthon used to produce formally aromatic quinoxalines the formation of similar ring-reduced quinoxalines (mostly from related synthons at a lower oxidation state) is included in each such category. 

Growing attention is directed to intramolecular reactions involving alkyls attached to position 5 of the tetrazole ring. The synthesis of 4,5-dihydrotetrazolo[l,5- ]quinoxalines 347 from 5-substituted tetrazoles 346 via the intramolecular. KNAr substitution of the halogen in the ortho-position of the iV1-aryl substituent is an example of such a reaction (Equation 64) <2006TL2041>. 

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. 

Catalysts and conditions for catalytic reduction were also carefully examined, as reduction of nitrated intermediates also posed dangers and required control strategies. These steps appear late in the quinoxaline synthesis therefore, full purging of anilines (e.g., 15) is essential for quality control. After a thorough analysis of all reaction steps, the team concluded that the direct and efficient discovery approach from benzazepine (8) to varenicline (1) could be safely and efficiently operated in a manufacturing setting with further development.34... 

Quinoxaline and phenazine bis-jV-oxides, synthesis from benzofuroxan M. J. Haddadin and C. H. Issidorides, Heterocycles 4, 767-816 (1976). 

Bis(bromomethyl)quinoxaline (41), prepared by direct synthesis from o-phenylenediamine and l,4-dibromo-2,3-butanedione (BrCH2COCOCH2Br), can be similarly converted into the bispyridinium bromide 42, and this on treatment with p-nitroso-iV,N-dimethylaniline and sodium cyanide yields the biscyanoanil 44. Reaction with secondary amines such as diethylamine yields pyrroline derivatives (e.g., 43, see chapter XXXV). 

Sulfuric acid dehydration of 2-polyhydroxyalkylquinoxalines is now known to yield 2-(2-furyl)quinoxalines rather than pyrido[l,2-a]-quinoxalines (glucazidones). " The structure of product 7 from 2-(d-arabinotetrahydroxybutyOquinoxaline follows from its independent synthesis from 2-furanglyoxylic acid (9). °... 

Quaternization of quinoxaline is neatly avoided by the synthesis of the azirino[l,2-a]quinoxalines 71 from o-phenylenediamine and the dibromo ketones 70. The azirino compound apparently acts as a 1,3 dipole and undergoes addition with a variety of dipolarophiles to give fused quinox-alines containing a bridgehead nitrogen atom. " Thus the acetylene derivatives 72 give the pyrrolo derivatives 73. The yields are much improved by the use of chloranil in situ to oxidize the presumed dihydro intermediates 74. 

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. 

HADDADIN ISSIDORIDES Ouinoxalinesynthesis Synthesis of quinoxaline dioxides from benzofurazan oxide and ketone enolates or enamines (also known as Beirut reaction). 

Sarodnick and Linker developed an onc-pot synthesis of quinoxaline 254 from 1,2-phenylenediamine (242) and 23-butancdione monoxime 252 via oxime intermediate 253 < 01JHC829>. Yields were only moderate. 

Antoniotti S, Dunaeh E (2002) Direct and catalytic synthesis of quinoxaline derivatives from epoxides and ene-1,2-diamines. Tetrahedron Lett 43 3971-3973... 

Instead of 1,2-diaminoarenes, 2-nitroanilines, 1,2-dinitroarenes, or benzofuroxanes (cf p. 253) can be reacted with 1,2-diketones to give quinoxalines in an SnCl2-promoted process, in which SnCh acts both as a reducing agent and as a catalyst for cydoconden-sation [311]. Instead of 1,2-dicarbonyl compounds, phenacyl bromides in the presence of DABCO and atmospheric oxygen have been used for 2-arylquinoxaline synthesis from 1,2-diaminoarene [312]. 

Scheme 2.71 Common strategies for the synthesis of quinoxalines starting from 2-fluoro-1 -nitrobenzenes...

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