Pyrazino oxazines

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. 

Pyrimido]6,l-b]]l,3]oxazines and their benzo derivatives Pyrimido]2,1-b]]1,3]oxazines and their benzo derivatives Pyrimido]6,l-c]]l,4]oxazines and their benzo derivatives Pyrimido]2,Tc]]l,4]oxazines and their benzo derivatives Pyrazino-oxazines and their benzo derivatives Synthesis of Particular Classes of Compounds and Critical Comparison of the Various Routes Available... 

This group of compounds covers N-bridgehead pyridazino-, pyrimido- and pyrazino-oxazines and their benzo derivatives. Theoretically, 16 bicyclic systems are possible, and 10 of them are known, with 19 benzo-fused derivatives (see Table 4). 

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. 

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>. 

Libraries of the pyrazino[2,l-A [l,3]oxazines 373 with variable R1 and R2 substituents were synthesized on solid phase, the last step being the cyclative cleavage of 372 with formic acid (Equation 42) <2002W02002/092010>. 

Diaryl-octahydro-pyra/ino[2,1 -c 1,4]thiazines are useful as melanine concentrating hormone receptor ligands <2002W02002/094799>. Pyrazino[2,l-f][l,4]oxazines 245 (Y = 0) and pyrazino[2,1 -c][ 1,4]thiazines 245 (Y = S) exert a tachykinin antagonistic effect <2002W0055518>. 

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>. 

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 chemistry of the pyrido[2,1 -c][ 1,4]oxazines (1), pyrido[2,l-c][l,4]thi-azines (2), and pyrido[2,1 -a]pyrazines (3) (Scheme 1) and their benzologues (4)-(18) (Schemes 2-4) has not been systematically reviewed. Only Mosby s book in 1961 treated the early articles on pyrido[2,l-c][l,4]thi-azines (61CH1182), pyrido[2,1 -ajpyrazines (61CH1188), 5//-pyrido[l,2,3-de -, 4-benzoxazines (61CH1180), pyrazino[l,2-a]quinolines (61CH1192), pyrido[l,2-n]quinoxalines (61CH1191), and pyrido[ 1,2,3-de]quinoxalines (61CH1193). 

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. 

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)). 

Dichloro-3,4-dihydro-(2//)-pyrazino[2,3-7 ][l, 4]oxazines (174) and their A-alkyl derivatives possess insecticidal, fungicidal, and herbicidal activity. They can be easily prepared by the reaction of tetrachloropyrazine (173) with 2-aminoethanol or jY-alkyl-2-aminoethanols and sodium ethoxide (Equation (25)) <77USP4029657>. 

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