2-Amino-3- pyrazine hydrolysis

The diazotization of aminopyrazines has been described in earlier sections. Section V.IH records the preparation of 2-fluoropyrazine from 2-aminopyrazine in fluoroboric acid containing copper powder with sodium nitrite (882, 884) and Section V.ll the preparation of iodopyrazines from some aminopyrazines via isodiazotate salts (30) (887). These salts were assigned the isodiazotate structure, on the basis of their inability to couple with 0-naphthol in alkaline solution (887) and they were characterized by hydrolysis in cold 40% aqueous sulfuric acid to the hydroxypyrazine (887). Section V.I K describes the conversion of aminopyrazines to bromopyrazines (798, 800, 807, 890-892) for example, 2-amino-3-methoxy-carbonylpyrazine with hydrobromic acid, bromine, and sodium nitrite in water gave 2-bromo-3-methoxycarbonylpyrazine (798, 890). The diazotization of aminopyrazines to hydroxypyrazines has been described in Section VI. 1C, to alkoxy-pyrazines in Section V1.3C, and to oxopyrazines in Section V1.9A(5). 2-Amino-pyrazine with isopentyl nitrite in benzene gave 2-phenylpyrazine (45%) and some 2-isopentoxypyrazine and 2,2 -dipyrazinyl amino isomers (1211). 

Nitro groups have been reduced to amino groups, whilst amino groups in the 3- and 6-positions of pyrido[2,3-f ]pyrazines and in the 5-position of the [3,4-f ] isomers have been hydrolyzed to the corresponding hydroxy derivatives with alkali. Protected amino groups have been liberated by hydrolysis or reduction in deazapteridine syntheses. 

Strecker aldehyde are generated by rearrangement, decarboxylation and hydrolysis. Thus the Strecker degradation is the oxidative de-amination and de-carboxylation of an a-amino acid in the presence of a dicarbonyl compound. An aldehyde with one fewer carbon atoms than the original amino acid is produced. The other class of product is an a-aminoketone. These are important as they are intermediates in the formation of heterocyclic compounds such as pyrazines, oxazoles and thiazoles, which are important in flavours. 

The vinyl triflate of Komfeld s ketone has been subjected to Heck reactions with methyl acrylate, methyl methacrylate, and methyl 3-(Af-rerf-butoxycarbonyl-lV-methyl)amino-2-methylenepropionate leading to a formal synthesis of lysergic acid [259]. A similar Heck reaction between l-(phenylsulfonyl)indol-5-yl triflate and dehydroalanine methyl ester was described by this research group [260]. Chloropyrazines undergo Heck couplings with both indole and 1-tosylindole, and these reactions are discussed in the pyrazine Chapter [261], Rajeswaran and Srinivasan described an interesting arylation of bromomethyl indole 229 with arenes [262]. Subsequent desulfurization and hydrolysis furnishes 2-arylmethylindoles 230. Bis-indole 231 was also prepared in this study. 

An unequivocal synthesis of (637), protected as its A-2 -acetyl derivative (643), was successfully accomplished as shown in Scheme 3.140 [40]. Pyruval-dehyde dimethylacetal was first converted into its enamine (108). Condensation of (108) with the O-tosyl derivative of oximinomalononitrile gave the azadiene (638), which was converted to 2-amino-3-cyano-6-dimethoxymethyl-pyrazine (639) with ammonia. This latter compound was condensed with guanidine and the product (640) hydrolyzed first with base (to remove the 4-amino group) and then with acid to give pterin-7-carboxaldehyde (641). Acetylation of (641) followed by condensation with di-t-butyl p-aminobenzoyl-glutamate (235), reduction and hydrolysis gave (643). 

The greater stability of the pyrazine ring to oxidation compared with that of benzene enables pyrazinecarboxylic acids to be prepared by permanganate oxidation of either quinoxalines or phenazines. The pyrazine ring is more stable than the pyrimidine ring to acid and alkaline hydrolysis. Thus, pteridine is converted into 2-amino-3-formylpyrazine on treatment with dilute sulfuric acid and N-(3-formyl-2-pyrazinyl)formamidine oxime on treatment with sodium carbonate and hydroxylamine (Scheme 11).136 Aminopyrazines and... 

Aminopyrazines are conveniently prepared from carboxamido-pyrazines by application of the Hofmann reaction (see Section V,B). Thus, Camerino and Palamidessi prepared aminopyrazine in 80% yield from carboxamidopyrazine.312 Aminopyrazine may also be prepared from the reaction of pyrazine with sodamide in liquid ammonia,313 and 3-amino-2,5-dimethylpyrazine is the product of amination of 2,5-dimethylpyrazine with sodamide in dimethyl-aniline.311 The ammonolysis of halopyrazines also represents a useful preparative procedure for aminopyrazines (see Section V,C). This reaction proceeds most easily in the case of fluoro compounds for example, fluoropyrazine is converted into aminopyrazine in 70% yield by treatment with concentrated aqueous ammonia at room temperature for 3 days,299 whereas the corresponding reaction with chloropyrazine has been carried out in a sealed tube at 150°.147 Alkaline hydrolysis of 2,4-dihydroxypteridines followed by decarboxylation yields aminopyrazines 315 thus, high-temperature alkaline hydrolysis of 7-methyl-2,4-dihydroxypteridine (7-methyIlumazine) gives, after decarboxylation of the intermediate pyrazinecarboxylic... 

Pyrazinecarbaldehydes can of course be recovered from their derivatives for example, the acetal, methyl 6-amino-5-cyano-3-diethoxymethyl- (249), gave methyl 6-amino-5-cyano-3-formyl-2-pyrazinecarboxylate (250) in 85% yield by selective hydrolysis in dilute hydrochloric acid at 20°C during 12 h 773 likewise, the extranu-clear acetal, 2-(3,3-diethoxypropyl)-3-ethoxycarbonylmethylpyrazine, gave 2-ethoxycarbonylmethyl-3-(2-formylethyl)pyrazine in 92% yield on hydrolysis in aqueous alcoholic hydrochloric acid at 35°C during 2 h.1249... 

TABLE 11.5 PYRAZINES PREPARED FROM AMINO ACIDS BY THE AimON OF ACETIC ANHYDRIDE AND PYRIDINE FOLLOWED BY HYDROLYSIS... 

Imidazolines on acid hydrolysis have been shown to give pyrazines (306). Thus 2,2-diethyl4-methylimidazoline-A with dilute hydrochloric acid at 60 gave diethyl ketone (62% of the theoretical) and 2,5-dimethylpyrazine (7%) 2,2-diethyl-4,5-dimethylimidazoline-A gave diethyl ketone (70.2%) and tetramethylpyrazine (20.4%) and 2,2,4-triethyl-5 methylimidazoline-A (41) gave diethyl ketone (84%) and 2,5-diethyl-3,6-dimethyl-3,6-dihydropyrazine (81%) (43). The pyrazines were formed presumably by self-condensation of the amino ketones (42) produced. 

Amino-5-chloromethyl-3-cyanopyrazine 1-oxide with triphenylphosphine in dimethylformamide at 80-90° gave 2-amino-3-cyano-5-(triphenylphosphonio)-methylpyrazine 1-oxide chloride (97) (520) and the 5-bromomethyl analogue reacted similarly with triphenylphosphine in propan-2-ol (542). Compound (97) on hydrolysis with 30% aqueous ethanol containing a small amount of triethylamine gave 2-amino-3-cyano-5-methylpyrazine 1-oxide and thus enabled removal of the chloro substituent from the chloromethylpyrazine (529) compound (97) with triethylamine and acetaldehyde (and other aldehydes) in chloroform at room temperature gave 2-amino-3-cyano-5-(prop-l -enyl)pyrazine 1-oxide (and other alkenyl analogues) (529). 

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