Halogenopyrazines preparation

Although there have been few new developments in the period since 1993, halogenopyrazines 42 have been convenient precursors for a variety of pyrazine derivatives. For example, the halogenopyrazines 42 are cyanated by palladium-catalyzed cross-coupling with alkali cyanide or by treatment with copper cyanide in refluxing picoline, to yield cyanopyrazines 48. Alkoxypyrazines 49 are produced by treatment with alkoxide-alcohol, and aminopyrazines 50 are prepared by amination with ammonia or appropriate amines. The nucleophilic substitution of chloropyrazine with sodium alkoxide, phenoxide, alkyl- or arylthiolate is efficiently effected under focused microwave irradiation <2002T887>. 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides for example, 5-hydroxy-2-pyrazinecarboxylic acid, rather than 5(477)-pyrazinone-2-carboxylic acid, is chlorinated with phosphorus pentachloride/phosphoryl chloride to afford a 63% yield of 5-chloro-2-pyrazinecarbonyl chloride <1994SL814>. Sato and Narita provided an improved synthesis of various halogenopyrazines in which 2(l//)-pyrazinones were activated with chlorotrimethylsilane to give silyl ethers (Section 8.03.7.3). This procedure is most effective for synthesis of bromopyrazines whose overall yields are 62-81% <1999JHC783>. Bromopyrazine is directly prepared by treatment of 2-(l//)-pyrazinone with phosphoryl... 

Most halogenopyrazines undergo facile nucleophilic displacement of their halogeno substituent (s),1286 thus making them ideal substrates for the preparation of other pyrazines. 

Many such pyrazinones have been made by primary synthesis (see Chapters 1 and 2) or by hydrolysis of halogenopyrazines (Section 4.2.2). Other methods of preparation are illustrated in the following examples, classified according to the type of substrate ... 

Most alkoxy- or aryloxypyrazines have been made by primary synthesis (see Chapters 1 and 2), by addition of alcohols to alkynylpyrazines (see Section 3.2.4.9), by alcoholysis or phenolysis of halogenopyrazines (see Sections 4.2.3 and 4.4), by O-alkylation of tautomeric pyrazinones or extranuclear hydroxypyrazines (see Sections 5.1.2.2 and 5.2.2), or by epoxidation of alkenylpyrazines (see Section 3.2.4.1). Some of the few remaining routes (presently of minor preparative value) are illustrated briefly in the following recent examples ... 

The major and recently used preparative routes to azidopyrazines have been covered already by azidolysis of halogenopyrazines (Sections 4.2.6 and 4.4) and by treatment of hydrazinopyrazines with nitrous acid (Section 7.4). In addition, direct C-azidation of pyrazines has been used for example, the lithio intermediate (225), generated in THF by treatment of 2-methoxypyrazine (224) with lithium 2,2,6,6-tetramethylpiperidine, gave 2-azido-3-methoxypyrazine (226) (87%) on subsequent treatment with p-toluenesulfonyl azide.232... 

Examples have been given already of the preparation of isothiocyanatopyrazines from halogenopyrazines (Section 4.4) or from pyrazinamines (Section 7.3.2.4) also of the reaction of isothiocyanatopyrazines with amines to give thioureidopyrazines (Section 7.3.2.4). 

The primary syntheses of pyrazine JV-oxides from aliphatic components only are described in this chapter. The preparations of pyrazine JV-oxides by oxidation of pyrazines are dealt with under the reactions of the appropriately substituted pyrazines for example, those of pyrazine and alkylpyrazine TV-oxides are described in Chapter IV, and of halogenopyrazine JV-oxides in Chapter V. The cleavage of JV-oxides of pteridines and related systems to aminopyrazine JV-oxides is described in Section VIII.3A(2). 

Preparations of halogenopyrazines utilizing primary syntheses from a-(p-toluenesulfonyloxyimino)malononitrile have been discussed in Section II.7. a-Aminophenylacetonitrile with chloral (or bromal) were claimed to give 2,3-dichloro(or dibromo)-5-phenylpyrazine (830, 893), but this has now been shown to be in error (829). 

TABLE V.2 THE PREPARATION OF HALOGENOPYRAZINE A/-OXIDES BY OXIDATION OF HALOGENOPYRAZINES... 

The preparation of certain halogenopyrazine 7V-oxides from pyrazine 1,4-dioxide with phosphoryl chloride (and othe r acid chlorides) has been described in Section 1G. 

The reactivity of 2-fluoropyrazine with aqueous sodium hydroxide to give 2-hydroxypyrazine has been investigated (882, 884). In 1.07N sodium hydroxide at 26° the reaction followed pseudo-first-order kinetics with a half-life of 43 minutes, whereas under the same conditions 2-chloropyrazine had a half-life of 18 days, and 2-iodopyrazine and 2-fluoropyridine remained unchanged (882, 884). Thus, under the above conditions, 2-fluoropyrazine was 640 times more reactive than 2-chloropyrazine (882). Hydrolysis of 2-fluoropyrazine in 61V hydrochloric acid proceeded at a much slower rate with a half-life of 4 days at room temperature (884). Some literature preparations of hydroxypyrazines by hydrolysis of halogenopyrazines (chloropyrazines with aqueous sodium or potassium hydroxide unless otherwise specified) are as follows 2-hydroxy (150°) (818) 2-hydroxy-3-methyl (reflux) (680) 2-hydroxy-3,5-dimethyl (reflux) (978) 3-hydroxy-2,5-dimethyl (reflux) (98, 312, 680, 740) [at 120° (978)] 3-hydroxy-2,5-di- -butyl (powdered potassium... 

Halogenopyrazines react with alkylthiolate ions to give alkylthiopyrazines, by replacement of one or, in some cases, two halogeno substituents the reaction is usually carried out at reflux or at elevated temperatures in sealed tubes. The following pyrazines have been prepared by these methods from the chloropyrazines unless otherwise specified 2-ethylthio and 2-isopropylthio (668a) 2-methyl-3-methylthio (735, 844,977) 2-methyl-5(and 6)-methylthio (735) 2,5-dimethyl-3-methyl(ethyl,... 

The preparation of mercaptopyrazines (1) by the reaction of halogenopyrazines with sodium (or potassium) hydrogen sulfide or sodium polysulfide in various solvents (780, 790, 799, 805, 809, 821, 858, 890, 892, 993, 1006-1011), by reaction with phosphorus pentasulfide in pyridine (1013), and by reaction with thiourea in acid (905) and in alcohol followed by alkali (535) has been described in Section V.5G. 

Alkylthiopyrazines may be prepared from halogenopyrazines by reaction with the appropriate sodium (or potassium) alkylthioiate, usually at elevated temperatures. In this way 2-ethylthio- and 2-isopropylthiopyrazine were prepared from... 

The preparation of aminopyrazines and hydrazinopyrazines from halogenopyrazines has been described in Sections V.5B and V.5C, respectively. 

Some preparations of extranuclear aminopyrazines from extranuclear halogenopyrazines and amines have been described in Section V.6B (542, 679, 932,1029-1031). 2-Chloromethylpyrazine also reacted with sodium azide and gave 2-azidomethylpyrazine, which was hydrogenated in 95% ethanol over Adams catalyst to 2-aminomethylpyrazine (690). 

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

Preparations of cyanopyrazines from halogenopyrazines have been described in Section V.5I. 

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