Amino chloropyrazines

Amino chloropyrazines may be prepared from amino hydroxypyrazines with phosphoryl chloride. 2-Amino-3-hydroxypyrazine with phosphoryl chloride gave... 

Dihaloquinoxalines are extremely reactive and both halogen atoms are replaceable, on occasions explosively (59RTC5), whereas in the case of dihalopyrazines, and tri- or tetra-halopyrazines, there is frequently a considerable difference in reactivity of the halogen atoms. When 2,3-dichloropyrazine is treated with ammonia at 130 °C, only one chlorine atom is displaced, giving 2-amino-3-chloropyrazine (66FES799). 

The progression from hydroxypyrazines/quinoxalines through the halo derivatives to the amines is a logical sequence in that, for practical purposes, this is the best method of synthesis of the amino compounds (see preceding Section). The ammonolysis proceeds most easily in the case of fluoro compounds. Fluoropyrazine reacts with aqueous ammonia at room temperature, whereas the reaction with chloropyrazine requires higher temperature and pressure. 

Besides furo[2,3-d]pyrimidines, 6-substituted 5H-pyrrolo[2,3-h]pyrazines have also been obtained in a microwave-promoted one-pot process starting from N-mesyl protected 2-amino-3-chloropyrazine (Scheme 60) [74]. The... 

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. 

The readily available 2-amino-3-chloropyrazine 247 has been coupled with phenylacetylene using palladium-catalyzed conditions to give 2-amino-3-phenylethynylpyrazine 248, which subsequently is cyclized to pyrrolo[2,3-. ]pytazine 249 (Scheme 23) <2004TL8087, 2004TL8631, 2005TL1845>. 

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. 

Palamidessi and Bernardi report the displacement of chloride ion from 2-carboxamido- and 2-amino-6-chloropyrazine with methanolic sodium methoxide.307 In the former case, reaction is carried out for... 

Only one halogen is frequently displaced in the reactions of dihalo-genopyrazines with nucleophiles. Thus, 2-amino-3-chloropyrazine is isolated in 85% yield from the reaction of 2,3-dichloropyrazine and aqueous ammonia in an autoclave at 130° for 14 hours.270 Similarly Cragoe and his colleagues report a series of displacements in which the chlorine para to the electron-attracting carbomethoxy group in the dichloropyrazine (96) is preferentially displaced.309,310 These are illustrated in Scheme 31. The reaction of 2,6-dichloropyrazine with... 

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... 

Ring substituents of pyrazine A-oxides show increased reactivity, and substituents in the a-position to the A7-oxide function are more reactive than those in the /3-position. Thus, 2-chloropyrazine 1-oxide is converted into the 2-hydroxy-1-oxide on mild alkali treatment,398 but attempts to carry out a similar reaction with the 2-chIoro-4-oxide were not successful.412 Ammonolysis of the 2-chloro-4-oxide has been achieved, and nitrous acid treatment of the resulting 2-amino-4-oxide gives 2-hydroxypyrazine 4-oxide (Scheme 46). The chlorine atom of both isomeric 2-chloropyrazine A-oxides is readily displaced with sulfanilamide to give the corresponding sulfanilamidopyrazine A-oxides.413,414... 

The marked activation of the iV-oxide function on the chlorine atom of 2-chloropyrazine 4-oxide and 2-ehloro-3,6-dimethylpyrazine 4-oxide is also demonstrated by the milder conditions under which these compounds react with ammonia and amines compared with chloro-pyrazine and 2-chloro-3,6-dimethyl pyrazine, respectively. Although 2-chloropyrazine 4-oxide undergoes the expected displacement reaction with ammonia on heating at 115°-120° for 2.5 hours, reaction at 140° for 16 hours gives 2,3-diaminopyrazine, possibly as a result of an addition-elimination reaction on the initially formed 2-amino-pyrazine 4-oxide (Scheme 47).417... 

The 3-amino-2-chloropyrazines (235) can be transformed into the thiols (236) by NaSH and cyclization with 2-chloroacetic acid or 2-chloropropionic acid gives 2,3-dihydro-(4//)-pyrazino[2,3-b][, 4]thiazin-3-ones (237) <71KGS230>. 

Amino-2-chloropyrazine upon treatment with sodium ethoxide in DMF saturated with H2S gave 3-amino-2-thiolpyrazine and cyclization to the pyrazino[2,3-6][ 1,4]thiazine was effected with phenacyl bromide in a similar way to that described above <70KGS1092>. 

A number of piperazine-2,5-diones (a-amino acid anhydrides ) has been converted to pyrazines by the action of phosphorus halides. Baxter and Spring (312) first described the conversion of isoleucine anhydride (45) with phosphoryl chloride to 2,5-di-s-butyl-3,6-dichloropyrazine (46, X = Cl) and 2,5-di-s-butyl-3-chloropyrazine (46, X = H), and of DL-alanine anhydride (47) similary to 2,5-dichloro-3,6-dimethylpyrazine (48, X = Q) and 3from alanine anhydride does not involve an oxidation step, whereas the formation of 2,5-dichloro-3,6-dimethylpyrazine involves the oxidation of an intermediate dihydropyrazine derivative. Treatment of DL-alanine anhydride with phosphoryl chloride in the presence of a tertiary base (dimethylaniline) gave only the monochloro derivative the intermediate dichlorodihydropyrazine presumably loses hydrogen chloride and gives the stable aromatic 3-chloro-2,5-dimethylpyrazine. 

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