2.3.5.6- Tetramethylpyrazine oxidation

Besides ruthenium porphyrins (vide supra), several other ruthenium complexes were used as catalysts for asymmetric epoxidation and showed unique features 114,115 though enantioselectivity is moderate, some reactions are stereospecific and treats-olefins are better substrates for the epoxidation than are m-olcfins (Scheme 20).115 Epoxidation of conjugated olefins with the Ru (salen) (37) as catalyst was also found to proceed stereospecifically, with high enantioselectivity under photo-irradiation, irrespective of the olefmic substitution pattern (Scheme 21).116-118 Complex (37) itself is coordinatively saturated and catalytically inactive, but photo-irradiation promotes the dissociation of the apical nitrosyl ligand and makes the complex catalytically active. The wide scope of this epoxidation has been attributed to the unique structure of (37). Its salen ligand adopts a deeply folded and distorted conformation that allows the approach of an olefin of any substitution pattern to the intermediary oxo-Ru species.118 2,6-Dichloropyridine IV-oxide (DCPO) and tetramethylpyrazine /V. V -dioxide68 (TMPO) are oxidants of choice for this epoxidation. 

Epoxidation of propene and oct-l-ene was effected with tran5-Ru(0)j(TMP)/ O ll atm)/water-CH2Cl2. After some 40 turnovers in a day, the deactivated form of the complex, Ru(C0)(TMP).H20 was detected (vide infra). Use of (l-( C)-oct-l-ene suggest that, in part at least, the carbon atom of the Ru(CO)(TMP) formed derives from the first C atom of the octene [591]. For styrene epoxidation by trans-Ru(0)2(TMP)/(LN0)/CgH (LNO=N-oxides of 2,3,5,6-tetramethylpyrazine, acridine, 2-methylquinoline and 3,6-dichloropyridazine) the mono- and bis-A-oxides of tetramethylpyrazine were the most effective co-oxidants [586]. 

Pyrazine 1-oxide, 2-methylpyrazine 4-oxide, and 2,6-dimethyl-pyrazine 4-oxide are unreactive toward acetic anhydride, but 2,5-dimethylpyrazine 1-oxide, 2,6-dimethylpyrazine 1-oxide, and 2,3,5,6-tetramethylpyrazine 1-oxide react to give 2-acetoxymethyl derivatives. The following mechanism (Scheme 44) is consistent with the observation that an acetoxymethyl derivative is only formed when a methyl group is adjacent to the AT-oxide function.407 However, in... 

Hydrogenation of 2,3,5,6-tetramethylpyrazine over platinum oxide was unsuccessful in alcohol or in ethyl acetate, and proceeded only to small extents in acetic acid. However, the anhydrous hydrochloride of the pyrazine was rapidly and quantitatively hydrogenated in absolute ethanol with the addition of acetic acid.162 The methiodide of the tetramethylpirazine was also successfully hydrogenated over platinum oxide in ethanol with the addition of a little water.163... 

Hydroxyamino-2-butanone oxime (185) and diacetyl (186) gave 2,3,5,6-tetramethylpyrazine 1,4-dioxide (187) (MeOH, 20°C, 8 h 72%).423 Variations in the substitution pattern of synthon (185) led to dihydro- or even tetrahy-dropyrazine oxides.414,437,1163... 

Proof of the structure of the pyrazines was established in 1893 by Wolff (22), who converted tetramethylpyrazine to piperazine (8) by the series of reactions shown. The conversion of a-amino ketones to pyrazines requires the loss of hydrogen as well as the loss of water. Gabriel and Pinkus (23) obtained considerably higher yields when oxidizing agents were added to the reaction mixture after the condensation had been allowed to take place. Snape and Brooke (14) in 1897 established that amarone was identical with benzoinimide, ditolanazotide, tetraphenylazine, and tetraphenylpyrazine. 

A. oryzae A21 grown in media containing 0.05 Af valine and 0.01 Af isoleucine gave 3-s-butyl-2-hydroxy-6-isopropylpyrazine 1-oxide (104a). Tetramethylpyrazine has been obtained from a strain of Bacillus subtilis (105) and fromfi. natto (106), and emimycin, 3-hydroxypyrazine I-oxide (19), has been isolated from the broth of Streptomyces No 2020-1 (107,108). 

The strong base-weakening effect of an A-oxide substituent upon a para-situated sp nitrogen atom is exemplified by a comparison of the of pyrazine [0.65 (122)] with that of pyrazine A-oxide [0.05 (745)]. The pKg of 3-methylpyrazine 1-oxide is 0.46 (745). Pyrazine A-oxides form salts thus 2,5-dimethylpyrazine A-oxide forms 1 1 addition products with hydrogen chloride, methyl iodide, and benzyl chloride (625). Thermodynamic parameters for the second protonation of tetramethylpyrazine 1,4-dioxide have been determined from measurements at 25, 40,60,80, and 90° (746). 

The polarographic behavior of the 1-oxides and 1,4-dioxides of pyrazine, 2,5-dimethylpyrazine, and tetramethylpyrazine at various pH values has been investigated. It was assumed that at lower pH values, the A -oxide group was reduced in its protonated form. In acid media the 1-oxides exhibited double waves, the first of which is attributable to the reduction of jV-oxide groups and the second to that of the pyrazine nucleus (production of 1,4-dihydro compounds). Reduction of both A -oxide groups of pyrazine-1,4-dioxide proceeded simultaneously (588). Half-wave potentials of the voltammetric oxidation and reduction of pyrazine mono- and di-A -oxides have been measured in dimethylformamide, and in acetonitrile by the technique of a rotating platinum electrode (750). 

Methylpyrazine 1-oxides react with benzaldehyde to give styrylpyrazine 1-oxides. Thus tetramethylpyrazine 1,4-dioxide, p-dimethylaminobenzaldehyde, and 37% hydrochloric acid at 140° for 15 hours gave 2,3,5,6-tetra(p-dimethyIaminostyryl)-pyrazine 1,4-dioxide (713) 2,5-dimethylpyrazine 1,4-dioxide, benzaldehyde, and sodium hydroxide gave 2,5-distyrylpyrazine 1,4-dioxide, and 2,5-dimethylpyrazine... 

Various methods of synthesis have been described by Marion (1967, 1971) ethylation of trimethylpyrazine (0.21), methylation of tetramethylpyrazine (0.31) or of an ethyldimethylpyrazine. The product can also be obtained by condensation of 2,3-diaminobutane with 2,3-pentanedione or from 2,3-diaminopen-tane with 2,3-butanedione, followed by oxidation of the corresponding dihydropyrazine. 

The compound tetramethylpyrazine, at concentrations of 50 to 200 fiM, stimulated nitric oxide production in human platelets (Sheu et al. 2000). 

The biosynthetic pathway of tetramethylpyrazine requires two pyruvate units, one of which is transferred to the thiamine diphosphate (TPP) cofactor under decarboxylation to give 2-(l-hydroxyethyl)thiamine diphosphate 55. The latter adds an acetyl group to the second pyruvate unit by acetolactate synthase (AS) to give (5)-2-acetolactate 56 (Figure 6.70). Subsequent decarboxylation converts (5)-2-acetolactate 56 to acetoin 57. Oxidation of the latter catalyzed by acetoin dehydrogenase (AD) forms butanedione 59. Transamination of butanedione 59 generates 3-aminobutanone 60. Alternatively, a transamination reaction of acetoin 57 proceeds... 

---