To pyrazino-oxazine

Another method for the preparation of these pyrazino[2,3-d][l,3]oxazines (169) is the alkylation-cyclization of an appropriate aminocarboxylic acid (170) and an acetanhydride <90JMC464,93UP 719-01). This one-step reaction is an extremely simple way to pyrazino[2,3-d][l,3]oxazines (Equation (23)). 

The methods most frequently used to synthesize these compounds are [6 + 0(a)] cyclizations. Ring closures may take place via intramolecular alkylation, condensation, or nucleophilic substitution. The starting materials for the cyclizations in the case of pyrazino-oxazines are always pyrazine derivatives. Only a few representatives of these systems have been prepared. Pyrimido-oxazines are the most explored group of compounds. In the bicyclic series, cyclizations have been carried out in most cases from pyrimidine intermediates and only rarely from morpholino intermediates. For the preparation of benzo-fused derivatives, both benzoxazine and quinazoline intermediates have been used. Pyrazino-oxazines represent a small group of compounds. For cyclizations, both pyrazino and oxazino intermediates have been used. There are many lactone structures among these compounds. For their preparation, the usual methods of lactone formation have been applied. 

Little information on the reactivity of pyrazinooxazines was available for inclusion in CHEC-II(1996) <1996CHEC-II(7)737> and little has been published since. Ring opening of pyrazino[2,3-t/][l,3]oxazines by amines to form amides (Equation 155) has been reported, but is rather inefficient <2005W02005/115986>. As shown in Equation (156), oxidation of a benzannulated pyrazino[2,3- ][l,4]oxazine, catalyzed by iV,A -bis(salicyliden)ethylenediiminecobalt(ii) (salcomine), gives a quinonoid product, of interest for its antineoplastic activity <2001H(54)619>. 

Only H NMR, 13C NMR, IR, and MS measurements have been reported for characterization of pyrazino[2,3-d ][l,3]oxazines. The literature relating to their preparations contains these spectro-scopical data. Neither x-ray analysis nor theoretical calculations have been reported. 

Tetrachloropyrazine with 2-hydroxyethylamines gave 2,3,5-trichloro-6-(2 -hydroxyethylamino)pyrazine, which cyclized with sodium ethoxide to 6,7-dichloro-3,4-dihydro-2//-pyrazino[23- ][l, 4]oxazines (42) (967). 

The cleavage of 6-methoxy-3-methyl4-oxo-3,4-dihydropteridine (37) to 2-amino-3-carboxy-5-methoxypyrazine (432) [with further data (783)] and of 6-methoxy-2-methyl4f/-pyrazino[2,3- /][l,3]oxazin-4-one (38) to 2-acetamido-3-amidinocarbamoyl-5-methoxypyrazine (432) has been discussed in Section II.5. 

Pyrimidines fused to other six-membered rings, most frequently in the form of bicyclic structures, can be degraded to corresponding substituted monocyclic pyrimidines. Fused pyrimidine structures described are benzo- (quinazolines), pyrano[2,3-tf]-, pyrazino[2,3-i/j- (pteridines), pyrimido[l,2-u]-, pyrimido[4,5-i/]pyrimidines, and pyrimido[5,4-e]-a -triazines, pyrimido[5,4- f]-v-triazine, pyrim-ido[4,5-i/][l,3]oxazines, pyrimido[5,4-i/][l,3]oxazine, pyrimido[4,5- ][l,4]thiazines, pyrimido[5,4- ][l,4]thiazines, and pyrimido[4,5-e][l,2,4]thiadiazines. References to these reactions can be found in . 

None of the above groups of compounds was considered in CHEC-I, and therefore the whole of the literature has been surveyed. The only previous review of this field is that by Mosby , who lists one reference <53ACS1017> on the preparation of a pyrimido[6,l-c][l,4]oxazine and/or pyrazino[2,l-c][l,4]oxazine derivative. No further indication has been found in the literature as to which structure was formed. 

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