3- Amino-2,5-dimethoxy pyrazine

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

Formylpyrazines have been isolated from acetals by hydrolysis. Thus 2-acetamido-3-dimethoxymethylpyrazine refluxed with aqueous pyridine hydrochloride gave 2-acetamido-3-formylpyrazine (1075), and 2-dimethoxymethyl-3-ethoxycarbonyl-aminopyrazine was hydrolyzed similarly (1075) 2-dimethoxymethyI-3-formamido-pyrazine with toluene-j9-sulfonic acid monohydrate and sodium sulfate in acetone at room temperature gave 2-formamido-3-formylpyrazine (1075), and 2-dimethoxy-methyl-3-ethoxalylaminopyrazine refluxed with the same reagents gave 2-ethoxalyl-amino-3-formylpyrazine (1075). 

Diiminosuccinonitrile (DISN) (10) reacts exothermically with ds-l,2-dimethoxy-ethylene (62) in acetonitrile to give 5,6-dicyano-2,3-dimethoxy-l,2,3,4-tetrahydro-pyrazine (63) (386, 1596). Styrene and p-halogenostyrenes reacted with DISN in acetonitrile at room temperature to form 2-amino-3-(2 -arylaziridin-r-yl)maleonitrile (64) (50-80%), whereas the more electron-rich p-methoxystyrene and 2-vinylfuran gave 5-aryl-2,3-dicyano-l,4,5,6-tetrahydropyrazine(65)(60-80%).p-Methylstyrene gave both types of products (1597). 

AMINO ACIDS r-Butylisonitrile. Diiso-propylethylamine. (3S,6SH+)-2,5-Dimethoxy-3,6-dimethyl-3,6-dihydro-pyrazine. (S>l-(Dimethoxymethyl-2-methoxymethylpyrrolidine. Phenyl iso cyanide. 

A variety of methods exists for the synthesis of optically active amino acids, including asymmetric synthesis [85-93] and classic and enzymatic resolutions [94-97], However, most of these methods are not applicable to the preparation of a,a-disubstituted amino acids due to poor stereoselectivity and lower activity at the a-carbon. Attempts to resolve the racemic 2-amino-2-ethylhexanoic acid and its ester through classic resolution failed. Several approaches for the asymmetric synthesis of the amino acid were evaluated, including alkylation of 2-aminobutyric acid using a camphor-based chiral auxiliary and chiral phase-transfer catalyst. A process based on Schollkopf s asymmetric synthesis was developed (Scheme 12) [98]. Formation of piperazinone 24 through dimerization of methyl (5 )-(+)-2-aminobutyrate (25) was followed by enolization and methylation to give (35.6S)-2,5-dimethoxy-3,6-diethyl-3.6-dihydropyrazine (26) (Scheme 12). This dihydropyrazine intermediate is unstable in air and can be oxidized by oxygen to pyrazine 27, which has been isolated as a major impurity. 

Dimethoxy-3,6-dihydropyrazine (109), prepared by methylation of 2,5-piperazinedione with trimethyloxonium tetrafluoroborate, is susceptible to lithiation because the protons at C-3 and C-6 are activated by adjacent imine moieties. The lithium salt of this bislactim ether reacts with the 2-chloro-l-phenylsulfonyl alkene (110) to give the 3-substituted pyrazine (111) (Scheme 25) <89JCS(P1)453>. The bislactim ether from piperazinedione cyclo(L-Val—Gly) is lithiated with butyl-lithium and then treated with ketones, alkyl halides, or others to form, nearly stereospecifically, ran5-3-isopropyl-6-substituted piperazinediones due to the steric influence of the isopropyl group <828866, 838673). Similar stereoselective syntheses have been achieved in reactions starting from cyclo(L-Val—D,L-Ala) <828864, 918939). Acid hydrolysis of these products affords chiral a-amino acids. 

Dimethoxy-2-pyrrolidinopropene (196) has been shown to be a useful synthon for the synthesis of formylpterins and related compounds. Thus treatment of (196) with nitrosyl chloride, followed by hydrolysis, yields 1,1-dimethoxy-3-oximino-2-propanone (197), which on treatment with amino-malononitrile gives a pyrazine (198) that is suitable for elaboration to a formylpterin (Scheme 89). Two nine-step syntheses, from pyrazine intermediates, of deoxyurothione (199) have been announced. A practical synthesis of the urinary thienopterin urothione (200) still remains a synthetic challenge. ... 

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