Pyrazine reaction with phosphoryl chloride

Heating with phosphoryl chloride converted 1 -hydroxy-3-phenyl-2( 1H )-pyrazinone (52) into the 2,5-dichloro derivative (53) via the 5-monochIoro species. It had been expected that chlorination would take place at C-6, but this occurred only to a minor extent. The observed chloride attack /3 to the oxygen function might be accounted for in terms of the sequence illustrated in Scheme 46 (86JHC149). Reaction mechanisms have been proposed to explain the observed a- and /3-chlorination when 2- and 3-substituted pyrazine Af-oxides are subjected to the Meisenheimer reaction. /3-Chlorination was rationalized in terms of electron withdrawal by the unoxidized nitrogen atom [84JCR(S)318] (Scheme 46). 

The amides of pyrazine-2-carboxylic acids and -2,3-dicarboxylic acids undergo the Hofmann reaction. In the case of the conversion of pyrazinamide to aminopyrazine (Scheme 20), the intermediate sodium carbamate can be isolated.219 Pyrazinamides react with phosphoryl chloride to give the corresponding cyanopyra-... 

Pyrazine 1,4-dioxide reacts exothermically with phosphoryl chloride if, after the initial reaction has subsided, reaction is completed by heating under reflux, 2,6-dichloropyrazine is obtained.301,362 Elina and Musatova report that reaction of the dioxide with benzene sulfonyl chloride gives 2-chloropyrazine 1-oxide, m.p. 131°-132°, in low yield.406 A melting point of 140w—146° has been reported by previous workers for this compound.398... 

With the exception of those halogenopyrazines made by primary synthesis (see Chapters 1 and 2), most chloropyrazines have been made recently by the reaction of tautomeric pyrazinones with a phosphorus chloride or by the reaction of pyrazine iV-oxides with phosphoryl chloride in contrast, most other halogenopyrazines have been made by direct halogenation or by transhalogenation of chloropyrazines. A single interesting example of the conversion of a methoxy- into a chloropyrazine is included at the end of Section 4.1.1. 

Chloro-2,S-dimethylpyrazine was not isolated from the reaction of DL-alanine anhydride with a mixture of phosphoryl chloride and phosphorus pentachloride, but the reaction gives a poor yield of (48, X = Q) and a small quantity of (48, X = OH). Gallagher et al. (282) found that DL-phenylglycine with phosphoryl chloride gave 2,5-dichloro-3,6-diphenylpyrazine and 3-hydroxy-2,5-diphenyl-pyrazine (presumably formed by loss of the elements of hydrogen chloride from an intermediate 2-chloro-5-hydroxy-3,6-diphenyldihydropyrazine) and Dunn et al. (95) from DL-leucine anhydride and phosphoryl chloride prepared flavacol, 3-hydroxy-2,5-diisobutylpyrazine, and a mature of chloropyrazines, whereas Ohta (101) used phosphoryl chloride and phosphorus pentachloride and obtained flavacol and a little 2[Pg.26]

A series of monoalkylpyrazines has been chlorinated specifically at the 3-position with sulfuryl chloride in the presence of iV,V-dimethylformamide the nucleus of 2,6-dialkylpyrazines is also readily chlorinated (687,693). The reaction of isobutyl-pyrazine with phosphoryl chloride and phosphorus pentachloride gave 2-chloro-5-isobutylpyrazine in 25% yield (693). 2-Acetonylpyrazine and 2-phenacylpyrazine with aqueous potassium hypochlorite gave 2-dichloromethylpyrazine (694). 

Matsuura and co-workers (756) have reexamined the reactions of the A -oxides of 2,5-dimethylpyrazine and found that 2,5-dimethylpyrazine di-A -oxide (29) when heated with phosphoryl chloride at 160° gave 2,5-dichloro-3,6-dimethylpyrazine (6%) (30), 3-chloro-2,5-dimethylpyrazine 1-oxide (5%) (31), and 5-chloromethyl-2-methylpyrazine 1 -oxide (9%) (32). In addition small amounts of other chlorinated products, 3-chloro-2-chloromethyl-5-methylpyrazine (33) and 2,5-bischloromethyl-pyrazine (34), were identified. These authors also examined the action of p-tosyl chloride, methane sulfonyl chloride, and mixtures of phosphoryl chloride and concentrated sulfuric acid, but state that these did not give good results. Pyrazine 1-oxide and phosphoryl chloride have been shown to give 2reaction conditions it gave 2-chloropyrazine 1-oxide (757). Pyrazine 1,4-dioxide and benzenesulfonyl chloride also gave a low yield of 2-chloropyrazine 1-oxide (758). 

The reaction of simple hydroxypyrazines with phosphoryl chloride has been used extensively for the preparation of chloropyrazines. 2-Hydroxypyrazine with phosphoryl chloride alone (818) gave 2-chloropyrazine (819-821), and 2-chloro-[l- N]pyrazine (822) and 2-chloro(2- C)pyrazine (823) have been prepared by the method described by Karmas and Spoerri (362). 

Earlier results from the reactions of 2-methylpyrazine 1-oxide and 3-methyl-pyrazine 1-oxide with phosphoryl chloride (626, 735, 736) now appear to have been clarified (686) [see Section 1V.3C(1)]. 

TABLE V. 1 REACTIONS OF PYRAZINE W-OXIDES WITH PHOSPHORYL CHLORIDE (AND OTHER ACID CHLORIDES) ... 

D. By Reaction of Pyrazine 1,4-Dioxide with Phosphoryl Chloride (and Other Acid Chlorides)... 

The reactions of phosphoryl chloride and some hydroxypyrazine A-oxides with an unsubstituted position adjacent to the A-oxide function to give chlorohydroxy-pyrazines have been described in Section V.IG. In this way 3-hydroxy-2,5-diisobutylpyrazine 1-oxide was converted to 2-chloro-5-hydroxy-3,6-diisobutyl-pyrazine (101) and 2-hydroxy-3,5-diphenylpyrazine 1-oxide gave 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873). 

Reactions of C-alkoxypyrazine A-oxides with phosphoryl chloride have been described in Section V.IG (756, 817, 838, 872, 881). For example, 3-ethoxy-2,5-dimethylpyrazine 1-oxide refluxed with phosphoryl chloride for 10 minutes gave 2-chloro-5-ethoxy-3,6-dimethylpyrazine and 2-chloromethyl-3-ethoxy-5-methyl-pyrazine (872). 

Pyrazine N-oxides are commonly O-acylated and undergo addition followed by elimination (85JHC1291 86JHC149). Some examples of chlorination by the reaction of pyrazine N-oxides with phosphoryl chloride are given in Tables I and II (84JCR(S)318) (Scheme 5). 

Reaction of 3-Substituted Pyrazine I-Oxides (239) WITH Phosphoryl Chloride... 

The pyrazine mono-iV-oxides show close similarity in their reactions to the pyridine AT-oxides.402-404 In the latter compounds the electronreleasing ability of the iV-oxide function is demonstrated by the activation of the a- and y-ring carbon atoms to electrophilic attack. Pyrazine mono-AT-oxides are predictably less activated to electrophilic substitution, and thus there have been no reports of the successful nitration of pyrazine /V-oxides. The pyrazine ring is, however, activated by the A-oxide function to nucleophilic attack, especially if the positive charge of the N atom is enhanced by formation of an intermediate with an electron acceptor. Thus, phosphoryl chloride treatment of pyrazine 1-oxide yields chloropyrazine391 and similar... 

Many chloropyrazines have been prepared from hydroxypyrazines by reaction with mixed phosphorus pentachloride-phosphoryl chloride as follows 2-hydroxy-pyrazine to 2-chloropyrazine (818), 2-hydroxy-3-phenylpyrazine to 2-chloro-3-phenylpyrazine (535), 2-hydroxy-6-methyl- and 5-hydroxy-23-[Pg.102]

Okada et al. (838), from comprehensive studies of the reactions of 3-substituted pyrazine 1-oxides (12) with phosphoryl (thionyl and sulfutyl) chloride, concluded that when the substituent was an electron-withdrawing group (e.g., methoxy-carbonyl) the substitution would be at the 5-position to give the 2,6-disubstituted pyrazine (e.g., 13, R = COOMe), whereas the 2-chloro compound (e.g., 14, R = NHj) would be obtained when the substituent was electron-donating (e.g., amino). When a weak electron-donating group (e.g., methoxy) was present both types of pyrazines (e.g., 13 and 14, R = OMe) would be formed. 

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