Aminopyrazine A-Oxides

Preparations of aminopyrazine A oxides from halogenopyrazine 7V-oxides have been described in Sections V.7A(1) and V.7B(3). 

TABLE VIII.2 AMINOPYRAZINE A -OXIDES FROM CLEAVAGE OF V-OXIDES OF PTERIDINES AND RELATED RING SYSTEMS... 

A -Oxides of Ptcridines and Related Ring Systems Reagent (and Conditions) Aminopyrazine A -oxide Refs. 

The conversion of aminopyrazine A -oxides to hydroxypyrazine A -oxides has been described in Section VI.IOD. 

Acetamidopyrazine A -oxides have been prepared readily from acetic anhydride and aminopyrazine A -oxides as follows 2-acetamido-3,5-dimethylpyrazine 1-oxide... 

Some bicyclic heterocyclic 7V-oxides have been prepared from aminopyrazine A -oxides and some of these are listed together with the reagents in Table VIII3 (528-531,533,534,537,539-541,1039-1041,1222). 

The deoxygenation and chlorination of some aminopyrazine A -oxides by phosphoryl chloride has been described in Section V.IG (Table V.l). 

For the pyrazine A -oxides, there is a table for each substituent type, and compounds are listed (once only) at the first opportunity. For example, 2-amino-6-chloromethyl-3-cyanopyrazine 1-oxide is listed in Table A.31 (aminopyrazine A -oxides) and 2-hydroxy-5-methoxycarbonylpyrazine 1-oxide in Table A.32 (carboxypyrazine A -oxides). 

Amination of 2-fluoropyrazine 1-oxide with a variety of amines proceeds smoothly at 40-50°C to form excellent yields of the aminopyrazine A-oxides within 2 h <84H(22)il05>. This reactivity is in contrast to that in the amination of 2-chloropyrazine 1-oxide, where higher temperatures (100-110°C) are needed. An electron-withdrawing cyano substituent adjacent to a phenylsulfonyl group prompts its nucleophilic replacement by amines <92JHC1689>, for example, reaction of 3-phenyl-sulfonylpyrazinecarbonitrile (60) with ethylamine in the presence of triethylamine at room temperature for 2 hours produces 3-(A-ethylamino)pyrazinecarbonitrile (61) in 78% yield (Equation... 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides. A methoxy group is also displaced with phosphoryl chloride to yield chloropyrazine when the period of reaction is prolonged or the reaction is carried out at higher temperatures <78JHC665>. Chloro- and bromopyrazine N-oxides are obtained by diazotization of aminopyrazine A-oxides in concentrated hydrochloric acid and hydrobromic acid, respectively (see Section 6.03.5.4.2). 

Monooximes of a-diketones have found applicability in the synthesis of 2-aminopyrazine 1-oxides by condensation with a-aminonitriles, and this reaction was used by White and coworkers in an approach to the synthesis of Cypridina etioluciferamine (Scheme 66 R = 3-indoloyl) (73T3761). In this instance, the use of TiCU as a catalyst was essential, since the carbonyl group in 3-acylindoles is normally deactivated and the required amine/carbonyl condensation is impractically slow. Under normal circumstances the carbonyl group in simple alkyl-substituted monoximes of a-diketones is the more reactive site and the reaction is rapid, requiring no catalysis (69LA(726)loo). 

MesSiNs 19 (0.34 rtiL, 2.,4 mmol) and of Et2NCOCl (0.32 mL, 2.4 mmol) are added, in this sequence, under argon, to a solution of 3-aminopyrazine-l-oxide 934 (1 mmol) in abs. MeCN (8 mL) and the reaction mixture is heated under reflux for 18 h with exclusion of humidity. After evaporation in vacuo the residue is chromatographed with hexane-ethyl acetate (10 1 to 3 1) on a column of 20 g silica gel to give almost quantitative yield of microcrystalline 2-amino-3-azidopyrazine 935, m.p. 225 °C (dec.) [55] (Scheme 7.56). 

The synthetic strategy of preparing pyrazines by condensation of 2-keto aldoximes with a-amino nitriles is well represented by Taylor s pteridine synthesis, in which a variety of 2-amino-3-cyanopyrazine 1-oxides have been prepared by using aminomalononitrile <2002TL6747> as the amino nitriles. In the same fashion, some other a-amino nitriles, which are often the Strecker synthesis products, are converted into 2-aminopyrazine 1-oxides 160 (Scheme 44). The condensations are realized by treatment with iV-methylmorpholine <1993JOC7542>, and... 

Table 3 Synthesis of 2-aminopyrazine 1 -oxides by condensation of a-amino nitriies with 2-oximino ketones...

Construction of pyrazine rings from a-amino nitriles has been sometimes completed through multistep reactions. For example, 2-aminopyrazine 1-oxide 163 is synthesized via amide intermediate 162 formed by reaction of methyl a-aminocyanoacetate with a-oximino carboxylic acid (Scheme 45) <1994H(38)1581>. 

Regioselectivity in the chlorination of pyrazine /V-oxides with phosphoryl chloride depends upon the substituent on the C-3 carbon. Thus, 3-aminopyrazine 1-oxide is chlorinated with loss of the /V-oxide oxygen to give 2-amino-3-chloropyrazine as the sole product whereas 3-methoxy and 3-chloropyrazine 1-oxides form approximately equal amounts of 3-chloro- and 6-chloro-2-substituted pyrazines along with a trace of the 5-chloro derivatives. 

Aminoacetonitrile (83) can be condensed with a-ketoximes such as 82 using a stoichiometric amount of FeCl3 (Scheme 8.35). The reaction presumably proceeds with initial imine formation (intermediate 85) followed by tautomerization to give ketenimine 86 and ring closure to 2-aminopyrazine N-oxide 87, which can be isolated. In a one-pot protocol this product 87 can be further reduced with Pd/C/H2 to give aminopyrazine 84 (80% over two steps) [105]. 

The 6-position in the oxide becomes less activated than the 3- and 5-positions with the result that mixtures of 3-bromo (3-8%) and 3,5-dibromo (56 R = H) (20-30%) products are formed (cf. bromination of 2-aminopyrazine). A sterically demanding substituent such as 2-morpholino gave rise to the 5-bromo derivative exclusively (83JOC1064) (Scheme 48). Annular bromination of 2,3-dimethylpyrazine 1,4-dioxide could not be achieved (72CHE1153). 

Palamidessi and Bernardi have obtained 2-chloropyrazine 1-oxide by mild treatment of pyrazine 1,4-dioxide with phosphoryl chloride. The structure of the 1-oxide was confirmed by hydrolysis to 2-hydroxy-pyrazine 1-oxide, which was also prepared by direct synthesis from glyoxal and glycine hydroxamic acid.398 This synthesis is illustrative of a general method for preparing 2-hydroxypyrazine 1-oxides by condensation of a,/3-dicarbonyl compounds with a-aminohydroxamic acids. An analogous synthesis of 2-aminopyrazine 1-oxides has already... 

Note This type of synthesis has been used extensively to furnish a variety of aminopyrazine N-oxides that may be deoxygenated to the corresponding aminopyrazines... 

AMINOPYRAZINE 1 -OXIDES FROM a-AMINO NITRILES AND a-HYDROXYIMINO CARBONYL COMPOUNDS... 

Marked activation of the chloro substituent by the A-oxide function to nucleophilic replacement by ammonia and amines has been demonstrated by comparison of the reactivities of chloropyrazine and 3-chloropyrazine 1-oxide. The preparation of 2-aminopyrazine in 87% yield from 2-chloropyrazine and aqueous ammonia required at least 16 hours at 140, but when 3-chloropyrazine 1-oxide was heated with an excess of aqueous ammonia at 115-120° for 2.5 hours (547a), 3-aminopyrazine 1-oxide was formed in good yield (921). [3-Chloropyrazine 1-oxide and aqueous ammonia, heated under the more usual amination conditions at 140° for 16 h, gave a mbcture of 2-aminopyrazine and 2,3-diaminopyrazine the latter product was the only one isolated when 3-aminopyrazine 1 -oxide was heated with aqueous ammonia at 140-145° for 16 h. This formation of 2,3-diaminopyrazine may involve an intermediate of the type (90) (921)]. 2-Butylaminopyrazine could not be prepared in reasonable yield by heating 2-chloropyrazine with butylamine under reflux for periods up to 16 hours, but it was prepared in 75% yield by heating the reactants in a sealed vessel at 120° for 8 hours, whereas 3-butylaminopyrazine 1-oxide was readily formed in 60% yield when 3-chloropyrazine 1-oxide was refluxed with an excess of butylamine for 30 minutes (921). 

Comparative A -oxide activation was likewise observed when other amines such as hexylamine, aniline, benzylamine, piperidine, and dimethylamine were used. It was also noted, in every example studied, that amination of the chloropyrazine A -oxide or alkylchloropyrazine 7V-oxide at elevated temperatures in a sealed vessel gave mixtures containing greater or lesser amounts of deoxygenated halogeno-pyrazine or aminopyrazine (921). Similar enhanced activation by theTV-oxide group was observed when 3-chloro-2,5-dimethylpyrazine and its 1-oxide in reaction with various amines were compared, although dialkyl substitution further retarded overall aminolysis (793,921). 

Preparations of pyrazine A -oxides containing extranuclear hydroxyl groups are also described in Qiapter III as follows Section III.l, 2-aminopyrazine 1-oxides from a-amino nitriles and a-hydroxyimino carbonyl compounds (540, 541) Section III.2, 3-substituted pyrazine 1-oxides from 2-amino-2-deoxy-D-glucose(or mannose) oxime with glyoxal (543, 544) and Section III.5, ring closure of the C-C-N-C-C-N-0 system (553). 

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