Dicarbonyl Compounds with a-Amino Acids

Pyrazines have been prepared by heating 1,2-dicarbonyl compounds with a-amino acids. Thus Rizzi (308) observed that under the conditions of the Strecker degradation, equimolar amounts of DL-valine (44) and butane-2,3-dione in refluxing bis(2-methoxyethyl) ether, diglyme, gave isobutyraldehyde, tetra-methylpyrazine (9%), and a mixture of cis- and trans-2-isopropyl-4,5-dimethyl-3-oxazoline (4%). He proposed a reductive amination mechanism in which butane-23-dione was converted to 2-aminobutan-3-one which underwent self-condensation to the pyrazine. Tetramethylpyrazine was also prepared when the same reactants were heated in dimethylformamide at 123° for 5 hours (and other pyrazines prepared similarly) (308a). 

Other workers (309) have extended this reaction and found that mixtures of a-amino acids (glycine, alanine, phenylalanine, tyrosine, tryptophan, leucine, methionine, cysteine) and benzil when heated to 180-220° gave good yields of 2,3,5,6-tetraphenylpyrazine, and a mechanism also involving an a-amino ketone was proposed. Benzoin with glycine, alanine, phenylalanine, or tyrosine at elevated temperatures similarly gave tetraphenylpyrazine. 

An equimolar glyoxal-glycine mixture heated under reflux for 4 hours has been shown to give pyrazine and various methylpyrazines (310), but L-leucine and glyoxal sodium bisulfite gave 2-hydroxy-3-isobutylpyrazine (311). 

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 3 hloro-2,5-dimethylpyrazine (48, X = H). The formation of the monochloro compound (48, X = H) from 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. 

3-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 hloro-5-hydroxy-3,6-diisobutylpyrazine. 

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The preparations of hydroxypyrazines by primary syntheses have been described in Chapter II, and are summarized briefly, together with further data, as follows Section II.IG, from the reaction of a, 3-dicarbonyl compounds with ammonia [282 (cf. 281, 280), 283, 285] with additional information (1042, 1043) Section II.IM, from 1,2-dicarbonyl compounds with a-amino acids (311) Section II.IN, from a-amino acids through piperazine-2,5-diones (93,95,101,282,312,313)with additional data (843) Section 11.10, from aldehyde cyanohydrins ( ) [317-319 (cf. 282)1 and Section II.IP, from o-nitromandelonitrile and ethereal hydrogen cyanide (325). The preparations from a,iJ-dicarbonyl compounds with a,/ -diamino compounds are described in Section 11.2 (60, 80, 358, 359, 361-365b, 365d, 366-375) additional data have also been reported (824, 825, 827,845,846,971, 1044, 1045) and some reaction products have been isolated as the dihydro-pyrazines (340,341,357). 

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