2 pyrazinone

Both and H NMR data are also available for a range of 2(l//)-pyrazinones which are structurally related to the aspergillic acids (76T655). 

Other reactions with their counterparts in the pyridine series are also well known. Thus, 2,3-dimethylpyrazine 1,4-dioxide reacts with acetic anhydride to yield 2,3-bis(acetoxy-methyl)pyrazine (S3) in good yield (72KGS1275). Pyrazine 1-oxide also reacts directly with acetic anhydride to yield 2(ljH)-pyrazinone by way of the intermediate acetate (Scheme 22). The corresponding reaction in the quinoxaline series is not so well defined and at least three products result (Scheme 23) (67YZ942). 

Ring substituents show enhanced reactivity towards nucleophilic substitution, relative to the unoxidized systems, with substituents a to the fV-oxide showing greater reactivity than those in the /3-position. In the case of quinoxalines and phenazines the degree of labilization of a given substituent is dependent on whether the intermediate addition complex is stabilized by mesomeric interactions and this is easily predicted from valence bond considerations. 2-Chloropyrazine 1-oxide is readily converted into 2-hydroxypyrazine 1-oxide (l-hydroxy-2(l//)-pyrazinone) (55) on treatment with dilute aqueous sodium hydroxide (63G339), whereas both 2,3-dichloropyrazine and 3-chloropyrazine 1-oxide are stable under these conditions. This reaction is of particular importance in the preparation of pyrazine-based hydroxamic acids which have antibiotic properties. 

Alkylation of pyrazinones and quinoxalinones may be carried out under a variety of conditions and it is usually observed that while O-alkylation may occur under conditions of kinetic control, to yield the corresponding alkoxypyrazines or alkoxyquinoxalines, under thermodynamic control the A-alkylated products are formed. Alkylation using trialkyl-oxonium fluoroborate results in exclusive O-alkylation, and silylation under a variety of conditions (75MI21400) yields specifically the O-silylated products. Alkylation with methyl iodide or dimethyl sulfate invariably leads to A-methylation. 

Pyrazinones and quinoxalinones both play important roles in the chemistry of pyrazines and quinoxalines respectively, in that they are usually available by direct synthesis and serve as important starting points for halo derivatives, which in turn lead to a range of substitution products (e.g. see Section 2.14.3.3). 

Other synthetic routes to pyrazinones and quinoxalinones are from the halo compounds, by dealkylation of ethers (8lJCS(Pl)3111> or by diazotization of the corresponding amines, but since the halo derivatives are normally derived from the hydroxy compounds, and the amines from the halo derivatives, direct synthesis seems to represent the most practical approach. 

Aminopyrazines and 2-aminoquinoxalines, like their pyridine analogs, react with nitrous acid under aqueous conditions to give the 2(l//)-pyrazinones and 2(l//)-quinoxalinones. 2-Aminoquinoxalines are more readily hydrolyzed than typical heterocyclic amines and 2-amino-3-methylquinoxaline, for example, undergoes hydrolysis on heating at 100 °C with dilute sodium hydroxide (59JCS1132). 

Following the discovery of penicillins, an extensive program for the screening of culture fluids and residual mycelial material commenced which resulted in the discovery of a large number of pyrazinones and related 1-hydroxy-2-pyrazinones with pronounced antibiotic character. Some examples are shown in Table 4. One of the earliest substances to be isolated, aspergillic acid (110 = OH, = Me, R = Et, R = R = H, R = Pr ), was found... 

Pyrido[2,3-b]pyrazin-8-one-7-carboxylic acids H NMR, 3, 249 Pyrido[2,3-b]pyrazinones alkylation, 3, 250... 

Greater para than ortho deactivation is seen in the hydrolysis (HCl in AcOH, 100°, 1 hr) of the nitro group in 5,6-diphenyl-2-nitro-3-pyrazinone (218) but not in 6-phenyl- or 3,6-diphenyl-2-nitro-5-pyrazinone (219). Similarly, acid hydrolysis of a 2-bfomo substituent in 3-pyrazinone, but not in 5-pyrazinone, is readily accomplished. All flve of these pyrazinones are stable in strong alkali or alkoxide as a result of complete anionization. Decreased reactivity of... 

Tlie expected lactam tautomers 155 and 156 were assigned by UV spectroscopic data for these pyrido[2,3-h]pyrazinones (92JHC129). 

Microwave-Promoted Route to Diverse 2(1H)-Pyrazinones and Pyridinones... 

Fig. 39 Microwave-assisted synthesis of pyridinones from resin-bonnd 2(iH)-pyrazinones. Reagents and conditions a dimethyl acetylenedicarboxylate, chlorobenzene, reflux (132 °C), 1-2 days or 1,2-dichlorobenzene, MW 220 °C, 20-40min b bromobenzene, reflux (156 °C), 2h or 1,2-dichlorobenzene, MW 220 °C, 10min R = OC2H4C2H c TFA, reflux (72 °C), 20-24 h or TFA/Ch2Cl2, MW 120 °C, 10-40min. R=OMe or Ph, R = methoxyphenyl. All microwave-assisted reactions were rim in sealed vessels...

The Cu(I)-catalyzed Huisgen [3 + 2] dipolar cycloaddition was also utilized by Van der Eycken and co-workers to obtain a new class of glycopep-tidomimetics based on the 1,2,3-triazole ring system 78 starting from glu-copyranosyl azide 75 and the pyrazinone compound 76 (Scheme 26) [58]. 

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