Tetramethylpyrazine, reaction

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. 

Pyrazines form diquaternary salts on treatment with triethyloxonium fluoroborate. Using this reagent the 1,4-diethylpyrazinium difluoro-borates of pyrazine, 2,5-dimethyl-, and 2,6-dimethylpyrazines have been obtained in 96, 97, and 46% yield, respectively. The reaction is subject to considerable steric hindrance since the yield of diquaternary salt from tetramethylpyrazine is only 6%. The diquaternary salts are extremely reactive substances and that of the parent compound is shown by ESR measurements to be readily reducible to the radical cation [Eq. (7)].150... 

The reactions of the isomeric dimethylpyrazines and trimethyl-pyrazine with methyllithium have been studied in order to gain insight into the factors involved in the competition between ring methylation and side-chain metalation.189 The major product from the reaction of 2,5-dimethylpyrazine and ethereal methyllithium was shown to be trimethylpyrazine, thus confirming Klein and Spoerri s earlier observation.190,191 Tetramethylpyrazine was also formed as a by-product. Proof of side-chain metalation was obtained by treatment of the reaction mixture with methyl benzoate and isolation of 2-methyl-5-phenacylpyrazine. Evidence for the presence of dihydro-and tetrahydropyrazine intermediates is derived from the infrared spectrum of the crude product obtained on hydrolysis of the reaction mixture which shows C=N and N-H absorptions (see Scheme 17). 

Tetramethylpyrazine can be converted into its monoanion by the use of sodamide in liquid ammonia or phenyllithium in ether.192 Thus, when phenyllithium, tetramethylpyrazine, and methyl benzoate are reacted in 2 2 1 molar proportion, a 67% yield of the monoacylated product, phenacyltrimethylpyrazine, is formed. A lower yield of monoacylated product is obtained when sodamide and liquid ammonia is used as the condensing agent, but reaction of sodamide, tetramethylpyrazine, and methyl benzoate in 6 1 1 molar proportion gives the optimum yield of diacylated derivative, formulated as 2,6-diphenacyl-3,5-dimethylpyrazine (39), by UV spectral comparison with 2,6-dimethylpyrazine and by the formation of a dioxime. 

The reaction of tetramethylpyrazine with alkyl halides using either sodamide in liquid ammonia or phenyllithium in ether as condensing agent gives mixtures of alkyltrimethylpyrazines and 2,5-dialkyl-3,6-dimethylpyrazines. A number of carbinols were also prepared from... 

The addition reactions of methyl-, 2,5-dimethyl-, 2,6-dimethyl-, and tetramethylpyrazine with dimethyl acetylenedicarboxylate have... 

The most abundant pyrazine identified in cocoa butters was tetramethylpyrazine, which existed at an extremely high concentration in the unroasted cocoa butter but only a moderate level in the roasted cocoa butter. Tetramethylpyrazine accounted for over 90% of the pyrazine content of the unroasted cocoa butter. Besides thermal generation, tetramethylpyrzine could be formed in cocoa beans through biosynthetic reactions. Kosuge and Kamiya (38) identified tetramethylpyrazine as a metabolic product of a strain of Bacillus subtilis. Several species of this organism were identified in a fermenting mass of cocoa beans by Ostovar (39). 

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. 

Methylpyrazine is methylated with methyl iodide in dimethyl sulfoxide at room temperature to give l-methyl-3-methylpyrazinium iodide and i-methyl-2-methyl-pyrazinium iodide, in a ratio of 3.9 I. The rate of methylation relative to pyrazine was 2.06 (666). The reaction of 2,5-dimethylpyrazine with iodo- or bromoacetic acid to give the 1,2,5-trimethylpyrazinium salt has been investigated (3). A kinetic study of the reaction of sodium hydroxide on quaternary pyrazinium salts (667, 668) has been made using a conductivity method to follow the progress of the reaction (11=5 12). In the case of 1,2,5-trimethylpyrazinium hydroxide, equilibrium lies toward (11), which slowly disappears, presumably forming the ether (13) (668). When 1,2,5-trimethylpyrazinium bromide was heated in a sealed tube trimethyl- and tetramethylpyrazine were produced (660). 

A number of carbinols has been prepared by the reaction of tetramethylpyrazine with aldehydes and ketones using phenyllithium as the condensing agent (648). 

Dimethyi-l-phenacylpyrazinium bromide (from 2,5-dimethylpyrazine and phenacyl bromide) and dimethyl acetylenedicarboxylate has been shown to give 6-benzoyl-7,8-bis(methoxycarbonyl)-1,4-dimethylpyrroIo[ 1,2-a] pyrazine (25) and 7,8-bis(methoxycarbonyl)-l,4-dimethylpyrrolo[l,2-fl]pyrazine (26) (723), and 1,2,5-trimethylpyrazinium iodide and dimethyl acetylenedicarboxylate also gave a 1% yield of (26). Addition reactions of 2-methyl- (724), 2,6-dimethyl- (724), 2,5-dimethyl- (725), and 2,3,5,6-tetramethylpyrazine (725), with dimethyl acetylenedicarboxylate have also been investigated. 

A patent (726) has described the preparation of 2methyl-pyrazine by reaction with ammonia and air at 350° over a catalyst containing vanadium pentoxide and potassium sulfate a series of cyanomethylpyrazines has been prepared from the corresponding methylpyrazines by reaction with sodium amide in liquid ammonia followed by Af-methyl-A -phenylcyanamide in dioxane (644). 2-Hydroxyiminomethylpyrazine has been prepared from 2-methylpyrazine, sodium amide, and liquid ammonia with butyl nitrite (727, 728), and 2-hydroxy-iminomethyl-3,6-dimethyI-5-pentylpyrazine similarly from 2,3,5-trimethyl-6-pentylpyrazine (648). Nitrones (28) have been prepared from 23-and 2,5-dimethyl-and tetramethylpyrazine through the substituted methylpyridinium (perchlorates) (27) by reaction with p-nitroso-A, fV-dimethylaniline (729). Dehydrogenation of ethylpyrazine at 600° over a calcium cobaltous phosphate catalyst gives 2-vinyl-pyrazine (658). 

Takken (2) identified thiazoles and 3-thiazolines from the reaction of 2,3-butanedione and 2,3-pentanedione with ammonia, acetaldehyde and hydrogen sulfide at 20 °C. Study of tetramethylpyrazine (5) also showed that it can be readily formed in 3-hydroxy-2-butanone and ammonia model reaction at 22 C. Recent study of the model reaction of 3-hydroxy-2-butanone and ammonium acetate at low temperature revealed an interesting intermediate compound, 2-(l-hydroxyethyl)-2,3,4-trimethyl-3-oxazoline, along with 2,4,5-trimethyloxazole, 2,4,5-trimethyl-3-oxazoline, and tetramethylpyrazine were isolated and identified 4,5). We hypothesized that with the introducing of H2S, replacement of oxygen by sulfur could happen and sulfur-containing heterocyclic compoimds such as thiazoles and thiazolines could be formed along with oxazoles, oxazolines and pyrazines. 

An interesting end product, tetramethylpyrazine was also presented in the reaction mixture (27.3% of peak area of the total volatiles). Previous study of the model reaction of 2,3-butanedione and ammonium acetate did not yield any tetramethylpyrazine. It is probably due to the reducing environment provided by H2S which reduced 2,3-butanedione to 3-hydroxy-2-butanone. This explained that both 3-hydroxy-2-butanone and 3-mercapto-2-butanone were found in the reaction mixture. This study also supported the mechanism proposed by Elmore and Mottram 10) who observed that, during the reactions of hydroxyketones with aldehydes and ammonium sulfide, the formation of thiazoles was discouraged due to reducing environment provided by H2S derived from ammonium sulfide. It is also interesting to note that con aring to previous a-hydroxyketone series tetramethylpyrazine was present at trace levels whereas in the a-dicarbonyl series it was the major product under comparable tenq)erature conditions. The reason for this observed phenomenon is not obvious. It is possible that in the reaction system of acetoin and ammonium sulfide, the... 

Attempts to liberate the diiminoamine ligand from the dysprosium complex by pyrolysis imder vacuum at 195 °C resulted in the isolation of 2,3/5,6-tetramethylpyrazine. A tetraphenylpyrazine was obtained together with 2,4,6-triphenyltriazine and 2,4,5-triphenylimidazole in the reaction of Tml2, Dyl2 and Ndl2 with benzonitrile followed by hydrolysis (Balashova et al., 2004). 

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... 

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