Methylpyrazines alkylation

Methylpyrazine reacts with sodamide in liquid ammonia to generate the anion, which may be alkylated to give higher alkylpyrazines (Scheme 10) (61JOC3379). The alkylpyrazines have found extensive use as fiavouring and aroma agents (see Section 2.14.4). Condensation reactions with esters, aldehydes and ketones are common, e.g. methyl benzoate yields phenacylpyrazine in 95% yield, and reactions of this type are summarized in Scheme 11. 

The ease of oxidation varies considerably with the nature and number of ring substituents thus, although simple alkyl derivatives of pyrazine, quinoxaline and phenazine are easily oxidized by peracetic acid generated in situ from hydrogen peroxide and acetic acid, some difficulties are encountered. With unsymmetrical substrates there is inevitably the selectivity problem. Thus, methylpyrazine on oxidation with peracetic acid yields mixtures of the 1-and 4-oxides (42) and (43) (59YZ1275). In favourable circumstances, such product mixtures may be separated by fractional crystallization. Simple alkyl derivatives of quinoxalines are... 

Alkyl-2-methoxypyrazines exhibit a base peak at miz 124 in the mass spectrum. The peak corresponds to a molecular ion in 2-methoxy-3-methylpyrazine (24a) and to a fragment ion, resulting from a McLafferty rearrangement of an alkyl group, in 3-isopropyl-2-methoxypyrazine (24b) and 3-5cc-butyl-2-methoxy pyrazine (24d) (97). 

Optically pure or almost pure a-methyl a-amino acids (alanine derivatives) can be prepared by reacting 5-substituted 2,5-dihydro-3,6-dimethoxy-2-methylpyrazines 1, which are derived from alanine and various amino acids as the chiral auxiliary, with alkylating agents, followed by hydrolysis (see Table 2). 

The composition of the products from the alkylation of lithiated 3,6-dialkoxy-2,5-dihydropy-razines with bis-alkylating reagents depends on the equivalents of electrophile employed. For example, with three equivalents of bis-alkylating electrophiles, (25)-2,5-dihydro-2-isopropyi-3,6-dimethoxy-5-methylpyrazine (I) gives high yields of the 1 1 adducts 2 or 5 with > 97% de2. These products can be further converted to the bicyclic systems (3 and 6. respectively) which, upon hydrolysis, give optically pure cyclic amino acids (4 and 7). Methyloxirane is used as an acid scavenger in order to release the free amino acid zwitterion. 

The condensation of a,j8-diketones with 1,2-diamines is a classical route for the synthesis of alkyl- and arylpyrazines. For example, good yields of dihydropyrazines are obtained from reaction of 2,3-dioxo-alkanes andethylenediamine dehydrogenation over a copper chromite catalyst at 300° then gives 3-alkyl-2-methylpyrazines (Scheme 1). Attempts to carry out the dehydrogenation using a variety of milder and more convenient laboratory procedures were not successful.100,110... 

The methyl group of a methylpyrazine is activated similarly to the methyl group of 2- and 4-methylpyridines (the a- and y-picolines). Thus treatment with strong base (e.g., sodamide in liquid ammonia) generates a reactive anion which may undergo aldol-type addition, acylation, alkylation, and nitrosation. These and other features of the reactivity of inethylpyrazines are illustrated by reference particularly to the work of Levine and his co-workers. 

The reaction of the sodium derivative of methylpyrazine with alkyl halides in liquid ammonia gives good yields (44-81%) of mono-alkylated products phenylation has been achieved by reaction with benzyne (generated from bromobenzene and sodamide in liquid ammonia) and gives 53% benzylpyrazine.178 The alkylation of the sodio derivative of 2-methoxy-3-methylpyrazine with methyl iodide, and of the product with ethyl bromide, gives 2-methoxy-3-sec-butylpyrazine (25) a constituent of galbanum oil.31... 

Dimethyl-188 and 2,6-dimethylpyrazine react very similarly to methylpyrazine. Thus, 2,6-dimethylpyrazine can be converted into a monoanion with sodamide in liquid ammonia which can be condensed with aldehydes and ketones,179 acylated with esters,181 and alkylated with alkyl halides181 to give the corresponding 2-methyl-6-substituted pyrazines. Acylation under suitable conditions also yields diacylated derivatives. Thus, when 2,6-dimethylpyrazine, sodamide, and ethyl benzoate are reacted in 1 3 2 molecular proportion, 38% 2,6-diphen-acylpyrazine (35) and 25% 2-methyl-6-phenacylpyrazine (36) is obtained. From the preparative point of view it is better to form the diacyl derivative by the further acylation of the monoacyl derivative rather than by direct diacylation.187... 

Oxidation of alkyl- or arylpyrazines with dichromate or permanganate yields pyrazinecarboxylic acids. Thus, Beck reported that on heating 2-methylpyrazine with aqueous dichromate and phosphoric acid in an autoclave at 225°-300°, pyrazinecarboxylic acid was obtained in 74% yield.216 Pyrazine-2,5- and -2,6-dicarboxylic acids... 

The mass spectral fragmentation pathways for a series of eight 2-(E- and Z-) alkenyl-3-alkyl-5-methylpyrazines (representing some of the most complex pyrazines isolated from the ant, Rhytidoponera metallica,961 or indeed any natural source) have been elucidated with the help of specifically placed deuterium labels within the alkenyl group these paths are influenced significantly by the stereochemistry of each alkenyl group.1407... 

Methyl-2(lH)-pyrazinone (57) underwent quatemization to l-benzyl-3-methyl-5-oxo-4,5-dihydropyrazinium bromide (58) (PhCH2Br, EtOH, reflux, N2, 24 h 80%) that then gave the zwitterionic base, l-benzyl-5-methylpyrazin-l-ium-3-olate (59) [H20—MeOH, (Amberlite IRA-400, HO ) column 97% this indirect route offers a procedure for N-alkylation on a ring-N that is not adjacent to the oxo substituent] 341 l,5-dimethylpyrazin-l-ium-3-olate was made somewhat similarly.1478... 

Ring aUylation and propenylation of methylpyrazine has been described (634) acetonylpyrazine with phenyllithium gives 2-acetonyl-6-phenylpyrazine (639) and 2,5-dimethylpyrazine with isopentylUthium gave 3-isopentyl-2,S-dimethylpyrazine (70). Aldehydes and ketones in the presence of a solution of an alkali or alkaline earth metal in liquid ammonia, or a suspension of these metals in other solvents, can be used to alkylate the pyrazine ring in moderate to good yields (614, 640, 641). This alkylation has been successfully applied to alkyl- and dialkyl(amino- and methoxy)pyrazines, and a mechanism has been proposed for the reaction (614). For example, the reaction of potassium with methylpyrazine and ethyl methyl ketone, catalyzed by sodamide (0.25 mol) gave 88% of 2 -butyl-6-methylpyrazine. 

The enhanced activity of alkyl groups attached to the pyrazine nucleus is illustrated by methylpyrazine, which undergoes aldol type condensations with aldehydes and ketones. Methylpyrazine (14) formed an adduct (IS) with chloral in pyridine solution (405) with paraformaldehyde at 165°, it gave 2-hydroxyethylpyrazine (470) (which was subsequently dehydrated with molten potassium hydroxide to 2-vinylpyrazine) and with benzophenone and sodamide it gave the corresponding carbinol (705). 

Normal nucleophilic substitution reactions of alkyl and aryl chloropyrazines have been examined as follows 2-chloro-3-methyl- and 3-chloro-2,5-dimethyl(and diethyl)pyrazine with ammonia and various amines (535, 679, 680) 2-chloro-3(and 6)-methylpyrazine with methylamine and dimethylamine (681, 844), piperidine and other amines (681, 921) 2-chloro-5(and 6)-methylpyrazine with aqueous ammonia (362) alkyl (and phenyl) chloropyrazines with ammonium hydroxide at 200° (887) 2-chloro-3-methylpyrazine with aniline and substituted anilines (929), and piperazine at 140° (759) 2-chloro-3-methyl(and ethyl)pyrazine with piperidine (aqueous potassium hydroxide at reflux) (930,931) [cf. the formation of the 2,6-isomer( ) (932)] 2-chloro-3,6-dimethylpyrazine with benzylamine at 184-250° (benzaldehyde and 2-amino-3,6-dimethylpyrazine were also produced) (921) 2-chloro-3,5,6-trimethylpyrazine with aqueous ammonia and copper powder at 140-150° (933) and with dimethylamine at 180° for 3 days (934,935) 2-chloro-6-trifluoromethylpyrazine with piperazine in acetonitrile at reflux (759) 2-chloro-3-phenylpyrazine with aqueous ammonia at 200° (535) 2-chloro-5-phenylpyrazine with liquid ammonia in an autoclave at 170° (377) 2-chloro-5-phenylpyrazine with piperazine in refluxing butanol (759) but the 6-isomer in acetonitrile (759) 5-chloro-2,3-diphenylpyrazine and piperidine at reflux (741) and 5-chloro-23-diphenylpyrazine with 2-hydroxyethylamine in a sealed tube at 125° for 40 hours (834). 

Alkylations of halogenopyrazines have been effected as follows tetrafluoro-pyrazine with ethereal methyllithium at — 70° gave 2,3,5-trifluoro-6-methylpyrazine (851, 965), and with butyllithium in ether-hexane gave 2-butyl-3,5,6-trifluoro-, 2,5-dibutyl-3,6-difluoro-, and 2,3,5-tributyl-6-fluoropyrazines (851) tetrachloro-... 

A large number of 2-alkyl-3-methoxypyrazines has been isolated from raw vegetables (59, 60, 64, 65, 69, 80, 1099), bell peppers (60,61) and gambanum oil (49). 2-Isobutyl-3-methoxypyrazine is already finding commercial use as a flavoring material (368) and 2-ethoxy-3-methylpyrazine may be used for pineapple flavor (981). The odor characteristics (367, 368, 976, 977) and structure (977) of some alkoxy alkylpyrazines have been examined. 3-Guanidino-6-hydroxymethyl-l-methyl-2-oxo-l,2-dihydropyrazine has been isolated from seeds of Stizolobium hassjoo and on mild alkaline hydrolysis gave 3-hydroxy-6-hydroxymethyl-l -methyl-2-oxo-l, 2-dihydropyrazine (1060). 

Aminopyrazine was alkylated with ethyl methyl ketone and sodium in liquid ammonia (in the absence of a catalyst) to 2-amino-6-butylpyrazine, and a similar reaction occurred with isobutyraldehyde (614) and 2-cyano-3-(A, A -dimethylamino-methyleneamino)-5-methylpyrazine was deprotonated with lithium diisopropyl-amide (from butyllithium and diisopropylamine) and alkylated with ethyl iodide followed by removal of the protecting group by acid hydrolysis to give 3-amino-2-cyano-5-propylpyrazine (1031). 

Preparations of acylpyrazines from methylpyrazines have been described in Sections IV.2A(2) (635) and IV.2A(3) (634, 642, 645-647, 650-651). Recently it has been shown that 2-hydroxy(or mercapto)-3-methylpyrazine with two equivalents of butyllithium in dry tetrahydrofuran gave the colored dilithium salt (71, X = 0 or S), which reacted with alkyl benzoates and gave 2-benzoylmethyl-3-hydroxy(or mercapto)pyrazines (72, X = O or S, Y = 0). Similar reactions occurred with thio esters to give the thiocarbonyl compounds (72, X = O or S, Y = S)(1446). 

Benzylic coupling in substituted methylpyrazines (687) and the influence of side chain alkyl substitution on benzylic coupling constants (1500) have been examined. On the basis of the methyl replacement technique, within its inherent limitations, the para-benzylic coupling appeared to be rr-electron transmitted. 

All tables include relevant C-alkyl derivatives of the type of pyrazine listed. For example, Table A.2 (aminopyrazines) contains aminopyrazines and A -substituted analogues, as well as C-alkyl derivatives and Table A.21 (carboxy halogenopyrazines) lists 2,6-dichloro-3 -cyano-5 -methylpyrazine. 

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