2-Amino-5-methoxypyrazine

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... 

The presence of an N-oxide function in pyrazine is not sufficient in itself to promote electrophilic halogenation, and even the presence of other weak donor groups may fail to promote reaction unless they can act in concert. Although 2-methoxypyrazine 1-oxide could not be bromi-nated, the 3-methoxy isomer [and 3-aminopyrazine 1-oxide (54)] was bro-minated in the 2- and 6-positions (ortho to oxide and ortho or para to the amino group cf. Scheme 47). Similarly, 2-aminopyrazine was brominated more readily than its Af-oxide (55 R = H) where the two groups are in opposition [83JOC1064 84H(22) 1195]. 

A new set of Mannich bases of 10//-indolo[3,2-6]quinoxaline was prepared <02IJH157>. A versatile synthetic route to /V-protected L-amino acid (3-benzylquinoxalin-2-yl)hydrazides was developed <02LPS49>. The properly substituted bis(indole) pyrazine 165 from the marine alkaloid dragmacidin D was prepared from 2,5-dibromo-3-methoxypyrazine (164) <02JOC9392>. 

Hydroxypropyl)-5-isobutyl-6-methoxypyrazine (157, R = Hu ) gave 2-isobutyl-3-methoxy-5-(3-phthalimidopropyl)pyrazine (158, R = Hu ) (phthal-imide, Et02CN=NC02Et, Ph3P, A, 20°C, 12 h 93%), and thence 2-(3-amino-propyl)-5-isobutyl-6-methoxypyrazine (159, R = Hu ) (H2NNH2.H20, EtOH, reflux, 4 h 83%) 295 2-(3-aminopropyl)-5-isopropyl-6-methoxypyrazine (159, R = Pfl)298 and other homologues295,298 were made similarly. 

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). 

Althou the amino aclci/sugar solutions were buffered in an effort to maintoin pH, a drop in pH was encountered with Increasing reaction times. Therefore, after heat treatment, each sample was adjusted to pH 9.0 with O.IN NaCH. One ml of a solution containing 2-methoxypyrazine in distilled water (2 ppm) was added as an internal standard. Firml sample volume was 15 ml. lyrazines were then isolated, s >arated and quantified using an... 

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). 

Q-(p-Toluenesulfonyloxyiinino)malononitrile (104), when treated with malono-nitrile in basic conditions, has been shown to give salts of l,l,3,3-tetracyano-2-azapropenide (105), which with concentrated sulfuric acid in methanol gave 2-amino-3,5-dicyano-6-methoxypyrazine (106) (484) and with hydrochloric acid in acetone gave 2-amino-6-chloro-3,5-dicyanopyrazine (485, 486). Catalytic cyclization of 2-(2 -aminobutylamino)butanol with Raney nickel has been found to give a mixture of 2,5-diethylpiperazine (25% yield) and 2,5-diethylpyrazine (8%) (487). 

Chloro-3-morpholinopyrazine treated with allyl alcohol followed by bromination in the presence of water has been shown to give 5-bromo-2-(3 -bromo-2-hydroxypropoxy)-3-morpholinopyrazine (813), and bromination of 2-amino[or 2-(p-toluenesulfonamido)]-3-methoxypyrazine with a mixture of potassium bromide and bromate in 6N sulfuric acid gave 2-amino-[or 2-(p-toluenesulfonamido)]-5-bromo-3-methoxypyrazine (814). The bromination (814) of 2-methoxy-3-sulfanilamidopyrazine in methanol was anomalous (815,816) [see Section 5D(2)]. 

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-... 

A number of alkoxypyrazines have been prepared from hydropyrazines. 5-(4 -Amino-3, 5 -dibromobenzenesulfonylimino)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetra-hydropyrazine (32) refluxed with 2N sodium hydroxide gave 2-(4 -amino-3, 5-dibromobenzenesulfonamido)-3-hydroxy-6-methoxypyrazine (881). Rperazine-2,5-dione (33) with an excess of triethyloxonium fluoroborate in dichloromethane gave... 

The cleavage of 6-methoxy-3-methyl4-oxo-3,4-dihydropteridine (37) to 2-amino-3-carboxy-5-methoxypyrazine (432) [with further data (783)] and of 6-methoxy-2-methyl4f/-pyrazino[2,3- /][l,3]oxazin-4-one (38) to 2-acetamido-3-amidinocarbamoyl-5-methoxypyrazine (432) has been discussed in Section II.5. 

Dicyano-3,6-dimethylpyrazine shaken with sodium ethoxide at room temperature for 10 hours produced 2-cyano-5-ethoxy-3,6-dimethylpyrazine (288). Bromination of 2-methoxy-3-sulfanilamidopyrazine (39) in methanol led to 5-(4 -amino-3, 5 -dibromobenzenesulfonimido)-6-hydroxy-2,3-dimethoxy-2,3,4,5-tetrahydropyrazine (32) which with 2 N sodium hydroxide gave 3-(4 -amino-3, 5 -dibromobenzenesulfonamido)-2-hydroxy-5 nethoxypyrazine (40) (816). The preparation of 2-amino-3,5-dicyano-6-methoxy(and ethoxy)pyrazine from a-(p-toluenesulfonyloxyiminomalononitrile and malononitrile has been described in Section II.7 (484). 2-Methoxycarbonyl(and cyano)-5-pyridiniopyrazine chloride (41) is reported (conditions not stated) to give 2-carboxy(and carbamoyl)-5-methoxypyrazine (765). 

Crystal structures of 3,5,6-tri-t-butyl-2-hydroxypyrazine (1093) 2,5-dichloro-3-methoxypyrazine (915) and 2,3-dichloro-5-ethylamino-6-methoxypyrazine (916) have been determined. The dipole moment of 2-amino-5-bromo-3-methoxypyrazine (2.94D in benzene) is consistent with the S-cis configuration (52) (749) and the polarographic behavior of 3-hydroxy(and methoxy)-2,5-dimethylpyrazine (and their A(-oxides) at various pH values has been investigated (588). 

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). 

Methoxy-2-methylthiazolo[4,5-h]pyrazine (2), when refluxed with aqueous methanolic sodium hydroxide, has been shown to give 2-amino-3-mercapto-5-methoxypyrazine (805, 1011). 

Methoxy-2-methylthiazolo[4,5-Z>]pyrazine (3) refluxed with IN sodium hydroxide in methanol gave 2-amino-3-mercapto-5-methoxypyrazine (4) (805, 1011), and 3,2 5,6-bis[(l, 3-diethyl-2,4-dioxo-l, 2,3,4-tetrahydro)- , 4-pyrimidino]-pyrazine refluxed in ethanol with N sodium hydroxide for 2.5 hours gave 2,6-bis(ethylamino)-3,5-bis-A -ethylcarbamoylpyrazine (1169). 

Methylation of 2-amino-34iydroxypyrazine with various reagents (832) have been described in Section VI.6D. The crystal structure of 23-dichloro-5-ethylamino-6-methoxypyrazine has been determined (916). 

Dimethoxycarbonylpyrazine heated with hydrazine hydrate in ethanol gave some 5,8-dihydroxypyrazino[2,3-with hydrazines (and amines) has been described in Section 2C(2)(a) (961,1330, 1331). An analogous active ester was prepared from 2-amino-3-carboxy-5-chloro-6-methoxypyrazine and with hydrazine in tetrahydrofuran gave 2-amino-5-chloro-... 

Reduction of 2-ethoxycarbonyl-3-methylpyrazine with lithium aluminum hydride in tetrahydrofuran at — 70° gave 2-formyl-3-methoxypyrazine (1185), and reduction of 2-amino-3-methoxycarbonylpyrazine with lithium aluminum hydride in tetrahydrofuran at room temperature (1074) and reflux gave 2-amino-3-hydroxymethylpyrazine (1075). 

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