Pyrazino-

The double cyclisation of (422) to give the pyrazino[2,3-f ]quinoline (423) must also involve a [6+0( )] cyclization step (B-79MI21505), although it might also be viewed as a [5 +1] reaction. 

Most syntheses of this type have followed the classical Gould-Jacobs pattern (Section 2.15.5.4.2) in which 2-aminopyrazines bearing a 6-substituent give esters of 8-oxopyrido[2,3-f ]pyrazine-7-carboxylic acids (424) via the usual intermediate ethoxy-methylenemalonate adducts. In some cases the isomeric pyrazino[l,2-a]pyrimidines are formed in addition (e.g. 74CPB1864). 

The one report of a true [3-1-3] cyclization occurs in the only reported synthesis of the pyrazino[2,3-c]isoquinoline ring system. The isoquinolino fused derivative (451) was isolated from dimerization of an intermediate iminoquinone formed by air oxidation of the unstable 4-amino-2-methyltetrahydroisoquinolin-l-one (450) 75JOC1760). 

Examination of the pyrazino[2,3-rf]pyrimidine structure of pteridines reveals two principal pathways for the synthesis of this ring system, namely fusion of a pyrazine ring to a pyrimidine derivative, and annelation of a pyrimidine ring to a suitably substituted pyrazine derivative (equation 76). Since pyrimidines are more easily accessible the former pathway is of major importance. Less important methods include degradations of more complex substances and ring transformations of structurally related bicyclic nitrogen heterocycles. 

Glutamic acid, p-aminobenzoyl-2-amino-8-methyl-4,9-dioxo-6,7,8,9-tetrahydro-4H-pyrazino[l,2-u][l,3,5]tria2in-7-ylmethyl ester, 3, 308... 

Pyrazino[l,2-a]pyrazine, octahydro-spectra, 3, 340 Py razino[2,3- h]pyrazine applications, 3, 368 cations... 

Pyrazino[2,3-fc]pyrazine, decahydro-as vulcanization accelerator, 3, 368 Pyrazino[2,3-fc]pyrazine, 2,3-dimethyl-cations... 

Pyrazino[2,3-d]pyridazine, 3,4-dihydro-dehydrogenation, 3, 348 Pyrazino[2,3-d]pyridazine, 5,8-dimorpholino-reactions... 

Pyrazino[2,3-d]pyridazine-5,8-dione chlorination, 3, 347 lithiation, 3, 347 synthesis, 3, 359 Pyrazino[2,3- d]pyridazin-5-one reactivity, 3, 347 synthesis, 3, 360... 

Pyrazino[2,3-d]pyridazin-8-one, 5-chloro-synthesis, 3, 347 Pyrazino[l, 2-a]pyrimidine reactions, 3, 350 structure, 3, 339-340 synthesis, 3, 256, 365 Pyrazino[ 1,2-a]pyrimidine, 2-hydroxy-alkylation, 3, 351... 

Pyrazino[2,3-d]pyrimidine — see Pteridines 4//-Pyrazino[l,2-a]pyrimidin-4-one, 3-ethoxycarbonyl-synthesis, 3, 366... 

Pyrazino[l, 2-c]pyrimidin-6-one, 7-ethyl-2-methyl-1,2,3,6,7,8,9a-octahydro-spectra, 3, 340... 

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