Quinoxaline formation, glyoxal

Cyclodehydration of m-phenylglyoxal-2-phenylhydrazone with anhydrous AlCl3-NaCl, at 150°-160° yields some 2-phenyl-quinoxaline, together with 4-phenylcinnoline.38 The same workers prepared 2-(o-hydroxyphenyl)quinoxaline (34) from o-hydroxyphenyl-glyoxal-2-phenylhydrazone (33) under similar conditions. Quinoxaline formation is thought to proceed through a diazetine intermediate as shown.39... 

Many pyrazine and quinoxaline syntheses yield mono- or di-N-oxides (76H(4)769). The condensation of a-aminooximes with 1,2-diketones results in the direct formation of pyrazine mono-N-oxides. The a-aminooximes themselves are not easily prepared but 2-amino-2-deoxy sugars readily form the oximes, which have been condensed with glyoxal to yield the pyrazine 4-oxides (Scheme 18) (72JOC2635, 80JOC1693). 

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. 

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>. 

Early lots of varenicline were routinely generated through reduction of 8 to the corresponding diaminobenzazepine 9 and condensation of 9 with glyoxal (sodium bisulfite addition adduct) to afford crystalline quinoxaline trifluoroacetamide 10 (Scheme 3.8). Deprotection, salt formation, and crystallization completed the synthesis of 1 tartrate in 44% overall yield from 6 in early... 

First example Ogg and Bergstrom (1931) published a series of papers designed to demonstrate possible analogies between heterocyclic systems and their acyclic and alicyclic counterparts. Quinoxaline, for example, was described as an ammono glyoxal and 2,3-diphenylquinoxaline 1 was considered to be the heterocyclic equivalent of benzyl. In an attempt to justify this hypothesis, the authors carried out the reaction of 2,3-diphenylquinoxaline 1 with potassium amide in liquid ammonia, anticipating a reaction similar to the benzyl —> benzilic rearrangement, which would lead to the formation of 2,2-diphenyl-3-aminoquinoxaline 2 (Scheme 6.1). The reaction did, in fact, lead to a new product-2-phenylbenzimidazole 3 in an approximately 30 % yield and the recovery of about 60 % of unchanged 2,3-diphenylquinoxaline 1 (Taylor and McKillop 1965). 

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