Pyrazino oxazin-4-ones

Of the possible 16 pyridazino-, pyrimido-, and pyrazino-oxazines, 10 are known with 19 benzo-fused derivatives. Literature over the past 10 years reports 10 bicyclic and 9 tricyclic systems and these are shown in Table 2. Of the possible 16 N-bridgehead pyridazino-, pyrimido-, and pyrazino-thiazines, 7 are known along with 13 benzo-fused derivatives. In this review five bicyclic and four tricyclic systems are discussed and these are shown in Table 3. One bicyclic system has been reported with a Se heteroatom and this is shown in Table 4. 

The oxazino ring of perhydropyrazino[2,l-c][l,4]oxazin-3-one was formed by cyclocondensation of 4-[(ethoxycar-bonyl)methyl]-3-hydroxymethylpiperazine in refluxing MeCN <2002W02002/018372>. The pyrazino[2,1 -tjbenzox-azine 352 was obtained by the strong base-promoted cyclization of the 3-hydroxymethyl-4-(2-fluorophenyl)piperazine 351 (Equation 37) <1997WO97/19089>. 

The principal method for preparation of pyrazino[2,3- [l,3]oxazines, as reported in CHEC-II(1996) <1996CHEC-II(7)737> involves cyclization of a 2-aminopyrazine-3-carboxylic acid ester with an aromatic acid chloride. Further applications of this three-step approach have been reported <19948405, 2000BMC2803>, but a one-pot approach has also been developed (Equation 157). This cyclization has also been carried out using acetic anhydride in place of an acid chloride <2005JMT(741)67>. 

The synthesis of pyrazino[2,3-d][l,3]oxazin-4-ones (169) starts with a 2-aminopyrazine ester (166) which is treated with two equivalents of an aromatic acid chloride. With a partial hydrazinolysis the diacylamino group (167) is transformed into the monoacylamino group (168). Finally, cyclization with dibromotriphenylphosphorane affords the 2-arylpyrazino[2,3-d][l,3]oxazin-4-one (169) (Scheme 29) <78JAP(K)53002499>. 

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)). 

Only one recent example of this synthesis has been reported. 2-Methyl-4//-pyrazino[2,3-<2][ 1,3]oxazin-4-one (123) and methylhydrazine at 5 —> 20°C during 1 h afforded 3-acetamido-/V-methyl-2-pyrazinccarbohydrazidc (124) in 45% yield.1265... 

Methyl-6-R-4//-pyrazino-(2,3-d] 11,3 ]oxazin-4-ones (where R = MeS, MeSO, PhCH,S,Me,N,MeO, Piperidino, Pi NH, PhCHjNH) Guanidine 2-Acetamido-3-amidino- carbamoyl-5-R 432... 

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. 

Dimethylamino-2-methyl-4/f-pyrazino 2,3-oxide Guanidine/NaOEt 2-Acetamido-5-dimethylamino-3-guanidinocarbonyl/ 1-oxide 1222... 

Guanidinocarbonylpyrazines (SS) have been prepared from 6-substituted 2-methyl4/f-pyrazino[2,3-J]oxazin-4-ones by ring opening reactions with guanidines as described in Section II.5 and references 778, 781, 783, 784, 786, 1058, 1158, 1159 and 1162 and guanidinocarbamoylpyrazines as described in Section II.5 and references 783 and 858. 

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. 

In the bicyclic system pyrazino[l,2-c][l,3]oxazine, only one compound has been described hexa-hydro-2 -methylspiro[cyclohexane-l,8 (6//)-oxazino[3,4-a]pyrazine], a convulsant, named COP <63MI 825-01,64MI 825-01 >. No information has been found in the literature, however, as concerns its chemistry and preparation. 

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