2-Methoxypyrazine methylation

A cyano group produces practical reactivity (methanolic CH30, 66°, < 3hr) by its presence in 2-chloro-3-cyano-6-methylpyridine, opposing the deactivating effect of a methyl group, and on other 2-chloropyridines (see references 3-6 in ref. 140). The cyano group activates 3-cyano-6,6-diphenyl-2-methoxypyrazine (168) (pre-... 

Minuscule quantities of naturally-occurring pyrazines have been found in some foodstuffs and are largely responsible for their flavor and aroma. For example, 3-isopropyl-2-methoxypyrazine is isolated from green peas and wine and a seasoned wine connoisseur can identify a ppt quantity. In addition, 2-methyl-6-vinylpyrazine exists in coffee. 

The edible portion of broccoli Brassica oleracea var. italica) is the inflorescence, and it is normally eaten cooked, with the main meal. Over 40 volatile compounds have been identified from raw or cooked broccoli. The most influential aroma compounds found in broccoli are sulfides, isothiocyanates, aliphatic aldehydes, alcohols and aromatic compounds [35, 166-169]. Broccoli is mainly characterised by sulfurous aroma compounds, which are formed from gluco-sinolates and amino acid precursors (Sects. 7.2.2, 7.2.3) [170-173]. The strong off-odours produced by broccoli have mainly been associated with volatile sulfur compounds, such as methanethiol, hydrogen sulfide, dimethyl disulfide and trimethyl disulfide [169,171, 174, 175]. Other volatile compounds that also have been reported as important to broccoli aroma and odour are dimethyl sulfide, hexanal, (Z)-3-hexen-l-ol, nonanal, ethanol, methyl thiocyanate, butyl isothiocyanate, 2-methylbutyl isothiocyanate and 3-isopropyl-2-methoxypyrazine... 

Fig. 16.2 Flavour dilution (FD) chromatogram obtained by application of aroma extract dilution analysis on an extract prepared from parsley leaves. The odorants were identified as 1 methyl 2-methylbutanoate, 2 myrcene, 3 l-octen-3-one, 4 (2)-l,5-octadien-3-one, 5 2-isopropyl-3-me-thoxypyrazine, 6p-mentha-l,3,8-triene, 71inalool, 8 2-sec-butyl-3-methoxypyrazine, 9 (.Z)-6-dece-nal, 10 / -citronellol, 11 ( , )-2,4-decadienal, 12 / -ionone, 13 myristicin, 14 unknown. RI retention index. [30, 31]...

Trichloromethylpyrazine (109) reacts in a similar manner thus, with one equivalent of methoxide ion in methanol at 5°, 2-dichloro-methyl-5-methoxypyrazine (110) is formed treatment with three equivalents of methoxide ion in boiling methanol gives a mixture of compounds 111, 112, and 113, in 75, 15, and 10% yield, respectively. The mechanisms by which these products of abnormal substitution are formed is being further investigated.285-286... 

Other flavouring compounds found in reasonable quantities are 14(3098) pen-tanal, 21 l-methyl-l/f-pyrrole, 23(3584) 1-penten-3-ol, 26(2633) (B)-(+)-limonene, 36 cis-2-heplenal, 40(2782) nonanal, 42(2805) l-octen-3-ol and 44(2362) decanal. The compound described as the character-imparting compound in bell peppers is 2-isobutyl-3-methoxypyrazine. This very powerful odour-ant has a threshold in water of 1 part in 10A12 (Govindarajan and Sathyanarayana, 1986). 

Diisobutyl-3-methoxypyrazine 1-oxide (277) gave a separable mixture of 2-acetoxy-3,6-diisobutyl-5-methoxypyrazine (278) and 2-(l-acetoxy-2-methyl-propyl)-5-isobutyl-3-methoxypyrazine (279) (neat Ac20, reflux, 90 min 73 and 12%, respectively).310... 

Benzyloxy-6-hydroxymethyl-3-isobutylpyrazine 4-oxide 2-Benzyloxy-6-iodomethyl-3-isobutyl-5-methoxypyrazine 4-oxide 2-Benzyloxy-3-isobutyl-6-mesyloxy-methyl-5-methoxypyrazine-4-oxide 1 - Benzyloxy-3 - (2-methoxycarbonyl-ethyl)-5,6-dimethyl-2(l/7)-pyrazinone... 

Chloro-5-isobutylpyrazine 6-Chloro-5-isobutyl-2-pyrazinecarbothioamide 6-Chloro-5-isobutyl-2-pyrazinecarboxamide 2-Chloro-3-isobutylpyrazine 4-oxide 2-Chloro-5-isopentyl-3,6-dimethylpyrazine 2-Chloro-3-isopropenyl-6-isopropyl-5-methoxypyrazine 5-Chloro-6-isopropenyl-3-isopropyl-l-methyl-2(177)-pyrazinone... 

Isobutyl-5-isopropyl-6-methoxypyrazine 6-Isobutyl-3-isopropyl-5-methyl-20 //)-... 

In studies of methoxypyrazines, a stable isotope labeled internal standard has not always been used. Calo et al. (6) used 5ec-butylmethoxypyrazine as an internal standard to quantify isobutylmethoxypyrazine in a comparison of grape varieties. Recently, Hashizume and Umeda have used 2-methyl-3-Ai-propylpyrazine as an internal standard to quantify methoxypyiazines in Japanese red wine and grape samples (7). However, the increased potential for lack of precision and accuracy needs to be recognized, and the natural occurrence of 5gc-butylmethoxypyrazine is a drawback to its use as an internal standard. 

The co-occurrence of these three methoxypyrazines is consistent with a biosynthetic pathway (Figure 2) proposed over 20 years ago 14), The amino acid leucine is envisaged as the source of the C4 side chain of the methoxypyrazine, through condensation of its amino amide with an unspecified C2 component, and methylation of the initial pyrazinone condensation product. This proposed biosynthetic pathway readily accommodates all three methoxypyrazines through incorporation of either leucine, isoleucine or valine, all of which are commonly available amino acids in plants. Although the validity of this pathway in vines or other plant material is unknown, the major features of this proposed pathway have been shown to apply to the biosynthesis of isopropylmethoxypyrazine by certain bacteria (75, 16). 

A suitable tool for the quantitation of trace compounds in foods is a stable isotope dilution assay (IVA) 16, 17). Allen et al. (18) used the IVA for the quantification of two methoxypyrazines in red wines, Guth (77) quantified wine lactone in various red and white wines and Aubry et al. (7P) used the technique for the determination of four esters (ethyl dihydrocinnamate, ethyl cinnamate, methyl anthranilate and ethyl anthranilate) in Pinot Noir wines. 

The condensation of DAMN with 1,2-diimino-l, 2-dimethoxyethane (70) gives 2-amino-5,6-dicyano-3-methoxypyrazine (71) (385), but as in the condensation of DAMN with DISN the control of acid concentration is critical. The condensation of DAMN with chloroacetone or pyruvaldehyde has been shown to give 23-dicyano-5-methylpyrazine (385) and DAMN with methylsulfinylmethyl phenyl ketone refluxed in ethanol gave 23-dicyano-5-phenylpyrazine (386a). A, 7V -Dichlorodi-iminosuccinonitrile (a2DISN) (72) reacts with some olefins to give pyrazines. Thus with styrene (73, R = Ph, R = H) in benzene it gave 23-dicyano-5-phenyl-pyrazine (74, R = Ph, R = H). Similar reactions were observed with /J-methyl-styrene and 23-dihydropyran (387). 

Deuterolysis of 3-chloro-2-chloromethyl-5-methoxypyrazine over 5% palladium on alumina in the presence of sodium isopropoxide in 2-propanol afforded 3-deutero-2-monodeuteromethyl-5-methoxypyrazine (687) and methylation of the bromomagnesium derivative from 2-bromomethyl-3,5,6-trimethylpyrazine with methyl sulfate or methyl iodide gave 2-ethyl-3,5,6-trimethylpyrazine (330). 

Methoxypyrazines (31) have been prepared by diazomethane methylation of 2-hydroxy-3-isobutylpyrazine (60, 311, 367), 2-hydroxy-3-isopropylpyrazine (59, 367), 2-hydroxy-3-propyl(ethyl or hexyl)pyrazine (367), 3-hydroxy-2-isobutyl-5(and 6)methylpyrazine and 2-hydroxy-3-isobutyl-5,6-dimethylpyrazine (368), 2,3-dihydroxypyrazine (832), 2-hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenyl-pyrazine (832), 2-hydroxy-6-methoxy(and benzyloxy)pyrazine (832), 2,6-dihydroxy-3,5-diphenylpyrazine (873), 2,3,5-trifluoro-6-hydroxypyrazine (851), 2-chloro-6-hydroxy-3,5-diphenylpyrazine (873), 2-chloro-6-hydroxy-5-methyl-3-phenylpyrazine (873), 2-chloro-6-hydroxy-3-methyl-5-phenylpyrazine (873), 5,6-dichloro-1 -cyclohexyl-34iydroxy-2-oxo-l, 2-dihydropyrazine (853), 2-chloro-5-hydroxy-3-methoxy-6-methoxycarbonylpyrazine (881), 2-(4 -amino-3, 5 -dibromo-phenylsulfonamido)-3Tiydroxy-6-methoxypyrazine (881), 2-amino-3-hydroxy-... 

Examination of the basic ionization constants (820) and ultraviolet spectra (821, 1081) of 2-hydroxypyrazine and its TV- and D-methyl derivatives (Table VI.1) (820, 821,1082) has revealed that the neutral species of2-hydroxypyrazine exists in aqueous solution as the amide form (46) but, in the absence of a common cation, tautomeric ratios could not be determined (821, 1083). The infrared spectra of 2-hydroxypyrazine in the solid state and in chloroform solution led to a similar conclusion (1084, 1085). Infrared spectra (680) for 2-hydroxy-3-methyIpyrazine and pjn.r. spectra (979,1086) of 2-hydroxy-and 2-methoxypyrazines also indicate that the hydroxy compounds exist in the amide form, and are further supported by MO[Pg.172]

Methylation (666, 912) of 2-methoxypyrazine with methyl iodide in dimethyl sulfoxide at room temperature gave 3-methoxy-l-methylpyrazinium iodide with a rate of methylation relative to pyrazine of 1.05 (666). 2-Methoxypyrazine with tetracyanoethylene oxide gave a small yield of 3 ethoxypyrazinium dicyano-methylide (53) (1094). Alkylation of 2-methoxypyrazine with ethyl methyl ketone in the presence of sodium in liquid ammonia to give 2-s-butyl-6-methoxypyrazine (17%) has been described (614). The reactions of 3-hydroxy-2,5-dimethylpyrazine and alkylhalides have been examined (1095). 

Pyrolyses and thermal stabilities of 2-hydroxy-, 2-ethoxy-, and 2-isopropoxy-pyrazines have been studied. 2-Hydroxypyrazine was very stable, but the alkoxy-pyrazines underwent thermal elimination of olefin to yield 2-hydroxypyrazine (668a). Electrochemical reductions of l-methyl-2-oxo-5,6-diphenyl-l,2-dihydro-pyrazine and 54iydroxy(and 5-methoxy)-2,3-diphenylpyrazine are reported to involve the intermediate enamine, for example, 6-hydroxy-1-methyl-2,3-diphenyl-1,4-dihydropyrazine (54) (1096, cf. 1097). When tested on mice 2-carbamoyl-5-methoxypyrazine had less anti tubercular activity than did pyrazinamide (1098). 

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). 

Khydroxypyrazine (which was converted into its jV -dimethyl derivative by treatment with dimethyl sulfate and alkali) gave, on reaction with an excess of ethereal diazomethane a mixture of its N,N-, 0,N-, and 0,0-dimethyl derivatives (58-60) (832). 2-Hydroxy-5-methoxy- and 2,5-dihydroxy-3,6-diphenylpyrazine with ethereal diazomethane gave predominantly 2,5-dimethoxy-3,6-diphenyl-pyrazine and only minor amounts of A -methylated products (832). Methylation of 2-hydroxy-6-methoxypyrazine with ethereal diazomethane produced a mixture of 0- and A -methyl derivatives in which the 0-methyl derivative predominated but the corresponding reaction of 2-benzyloxy-6-hydroxypyrazine gave almost exclusively the 0-methyl derivative (832) [the results of these methylations were correlated with the carbonyl stretching frequency (1103) in the parent lactam (832)]. 

Diazomethane methylation of 3-hydroxy-2,5-diisobutylpyrazine 1,4-dioxide has been shown to give the 4-methoxypyrazine 1-oxide, 2,5-diisobutyl4-methoxy-3-0X0-3,4-dihydropyrazine 1-oxide (96) (843, 980) [and some 3-methoxy-2,5-diisobutylpyrazine 1,4-dioxide (4 l)(980)] 5-s-butyl-3-hydroxy-2-isobutylpyrazine... 

Diisobutyl-3miethoxypyrazine 1,4-dioxide (107) with phosphorus trichloride in ethyl acetate at 40° gave 2,5-diisobutyl-3-methoxypyrazine (980). 2-Amino-5-[(/7-chlorophenoxy)methyl]-3-cyanopyrazine 1-oxide was deoxygenated with triethyl phosphite in dimethylformamide at 120° (1041). 

---