2.5- Dimethyl-3,6-dihydropyrazine

Ethylenediamine and diacetyl gave 2,3-dimethyl-5,6-dihydropyrazine (183) (Et20, 5 — 20°C, 15 h 67%) homologues likewise.1282, cf-473 However, when KOH was included in the condensation medium, the main product was the tricyclic spiro entity (184), formed by a rational mechanism and confirmed in structure by X-ray analysis.120... 

Dimethyl-5,6-dihydropyrazine (39) gave 2,3-dimethyl-5-propylidene-5,6-dihy-dropyrazine (40, Q = Et, R = H) and/or the tautomeric 2,3-dimethyl-5-propy-lpyrazine (41, Q = Et, R = H) (EtCHO, EtONa, EtOH, N2, reflux, 1 h 37%) 473 the same substrate (39) gave 2-.sec-butyl-5,6-dimethylpyrazine (41, Q = Me, R = Et) (AcEt, similarly 46%) 473 also many analogues likewise.473,849 1246... 

The photorearrangement of 2,3-dihydropyrazines to imidazoles has been described (1547, 1563, 1564). For example, 2,3-dimethyl-5,6-dihydropyrazine gave... 

When a solution of diacetyl or 2,3-pentanedione in diethyl ether is slowly added to a solution of ethylene diamine in diethyl ether while maintained at 0 C under an inert gas atmosphere, an extremely exothermic reaction results in 2,3-dimethyl-5,6-dihydropyrazine or... 

Ethyienediamine and diacetyl gave 2,3-dimethyl-5,6-dihydropyrazine (183) (Et2O, 5 20°C, 15 h 61%), homologues likewise.However, when... 

According to Sheldon et al. (1986), two molecules of the 2,3-dihydropyrazines can form a mixture of the corresponding pyrazine and 1,2,3,4-tetrahydropyrazine by disproportionation. It was also observed by Masuda et al. (1980) that dehydrogenation of 2,3-dimethyl-5,6-dihydropyrazine generated the disproportionation compounds 2,3-dimethyl-1,2,5,6-tetrahydropyrazine and 5-ethyl-2,3-dimethylpyrazine in addition to the desired 2,3-dimethylpyrazine in a sodium ethoxide/ethanol solution. It was then deduced that the carbanion of 2,3-dimethyl-5,6-dihydropyrazine was formed with the base and then reacted with acetaldehyde, present in ethanol in small quantities, to yield the 5-substituted pyrazine. On the basis of this result the authors prepared in high yield a series of nine, 5-substituted, 2,3-dimethylpyr-azines by reaction of 2,3-dimethyl-5,6-dihydropyrazines with six aldehydes and three ketones under the same basic conditions. 

Masuda H., Tanaka M., Akiyama T. and Shibamoto T. (1980) Preparation of 5-substituted 2,3-dimethyl-5,6-dihydropyrazine and aldehydes or ketones. J. Agric. Food Chem. 28, 244-6. 

The precursor of pyrazine IV, 3,6-dimethyl-dihydropyrazine, is formed by the condensation both of tv o molecules of aminoacetone as v ell as two molecules of 2-aminopropanal (cf. Formula 5.20). The nucleophilic attack by dihydropyrazine on the carbonyl group of acetaldehyde and water elimination yield pyrazine IV. This mechanism also explains the formation of pyrazine II if 3,5-dimethyldihydro-pyrazine, which is produced by the condensation... 

The dihydropyrazines 1 undergo ring expansion on treatment with potassium hydroxide in dimethyl sulfoxide to give 2//-1,4-diazcpines 3 via the unstable 5//-tautomers 2. No further details were reported.184... 

An alternative method of synthesizing the pyrazine compounds was described by Ghosh et al, and the synthesis is shown is Scheme 32 [78]. Reaction of a 1,2-dione (124) with a 1,2-diamine (125) to form an imine intermediate followed by spontaneous oxidation of the dihydropyrazine intermediate, formed the protected pyrazine compound 126. The free phenol 127 was obtained by removal of the methyl-protecting groups with a boron trifluoride-dimethyl sulfide complex. Similar compounds were prepared via the same method by Simoni et al. [79]. 

Since 1,4-dihydropyrazine itself is unknown, various substitutions of the ring system are required to produce stable isolable molecules. Carbonyl-stabilized 1,4-dihydropyrazines are synthesized by self-condensation of 3-chloromethyl-5,6-dihydro-l,5,5-trimethyl-2(l//)-pyrazinone <1998J(P1)289>. Another carbonyl-stabilized example is provided by WA -BOC-protected 1,4-dihydropyrazine 102, which can undergo Michael addition with nucleophiles such as 1,2,4-triazole, 3-formylindole, 4-bromothiophenol, benzylamine, or sodium methoxide to yield tetrahydropyrazines 103 (Scheme 26) <2004T8489>. Treatment of the di- and tetrahydropyrazines with trifluoroacetic acid leads to cleavage of BOC groups and/or elimination of the nucleophile to both afford dimethyl 2,5-pyrazinedicarboxylate 104. 

Acetyl-protected 1,2,3,4-tetrahydropyrazines 105, which are prepared by treatment of 2,3-dihydropyrazine with acetic anhydride and zinc (Scheme 27), undergo photooxidation to produce new dioxetanes 106 <1995JA9690>. Upon thermolysis, the dioxetanes 106 decompose quantitatively to tetraacyl ethylenediamines 107. Dimethyldioxirane oxidation of tetrahydropyrazine 105 affords novel epoxide 108, which is also generated by deoxygenation of dioxetane 106 with dimethyl sulfide. In 2,3,4,5-tetrahydropyrazine 1-oxide 109, which is prepared... 

It was also reported " that the reaction of 4,4-disubstituted-2-(trifluoromethyl)-5(4f/)-oxazolones 251 with 2,2-dimethyl-3-(dimethylamino)-2//-azirine afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(l//)-ones 252 (Scheme 7.81). In this case, the reaction only occurs when electron-withdrawing substituents are present at C-2 of the oxazolone. 

Instead of alanine and valine, several other chiral auxiliaries have been used, such as tert-leucine13, leucine14 and isoleucine15. In some cases diastereomeric excesses may be higher with the dihydropyrazines 5 and 6, derived from 0,0-dimethyl-alkylation with 3-bromo-propyne gives a de of 60% with (2S)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine (3), in contrast to 85% de with 516 and >95% de with 613. 

Methyl- and 2,6-dimethylpyrazines with DMAD in acetonitrile yield the corresponding azaindolizines (249),351 whereas 2,5-dimethyl-pyrazine gives a 1 3-molar adduct less the elements of acetonitrile. This adduct, originally described as an azepine,336 is probably the cyclo-butaindolizine 251,337 and could be formed via 250 by cycloaddition of DMAD across the dihydropyrazine ring and elimination of acetonitrile. 

Lipid-Protein-Carbohydrate Interactions. Evidence for such complex interaction was recently reported by Huang et al (36) who observed that the addition of corn lipids to zein and corn carbohydrates enhanced the formation of alkylpyrazines, indicating that lipid-derived free radicals may accelerate the rate of Maillard reactions. Two of the alkylpyrazines, identified in such mixtures after heating for 30 minutes at 180°C, have 5-carbon alkyl substitution at the pyrazine ring and could only be explained by interaction of lipid or lipid decomposition products. These authors suggested that condensation of amino ketones, formed by protein-carbohydrate interaction, may yield 3,6-dihydropyrazine which would in turn react with pentanal, a lipid oxidation product, to form 2,5-dimethyl-3-pentylpyrazine. 

An interesting photochemical approach to 4,5-disubstituted N-alkylimidazoles consists of the photolysis of 2,3-dihydro-5,6-disubstituted-pyrazines that can be easily prepared from 1,2-diketones and 1,2-diamino-alkanes. For example, the preparative-scale photolysis, in absolute EtOH with high-pressure Hg lamp (Pyrex filter), of 5,6-dimethyl- or 5,6-diphenyl-2,3-dihydropyrazines 54, yields the corresponding N-methyl-imidazoles 57 in high yields (Scheme 12.16). The reaction mechanism involves the formation of an enediimine intermediate 55, followed by cyclization and re-aromatization [41]. 

Polarographic studies on pyrazine and methylpyrazines indicate that 1 4-dihydropyrazines are the products of reduction. The reduction of pyrazine itself at the dropping mercury electrode proceeds reversibly. The substitution of methyl groups makes the reduction more difficult with an increased number of methyl groups an increased tendency toward irreversible reduction is noted.102-104 The half-wave reduction potentials for pyrazine, methylpyrazine, 2,6-dimethyl-pyrazine, and tetramethylpyrazine are 2.17, 2.23, 2.28, and 2.50 eV, respectively. Pyrazine is thus more easily reduced than pyridine which has a half-wave potential of 2.76 eV, and less easily reduced than quinoxaline which has a half-wave potential of 1.80 eV.105... 

Pyridazines (56) are reduced by treatment with a mixture of dimethyl sulfate (which forms the corresponding salts in situ) and sodium borohydride to yield 1,6-dihydropyridazines (57 R = Me), together with minor amounts of 1,4,5,6-tetrahydropyridazines (58 R = Me). Normally 1,6-dihydropyrazines are unstable and decompose in air, but N-acylated derivatives are more stable. Thus if methyl chloroformate replaces dimethyl sulfate in the reaction mixture both 1,4-dihydro- (59 R = C02Me) and 1,6-dihydro-pyridazines (57 R = COjMe) can be isolated, the latter predominating if there is an electron-withdraw-ing group at C-6 in the starting material (Scheme 2)f ... 

As in the research work of Vivet et al., new bicyclic sila-heterocycles were synthesized by Handmann et al. <2000ZNB133, 2000JOM19>. Compound rac-164 underwent a thermally induced cyclization reaction to give rac-7-ethoxy-2,2-dimethyl-2,3,5,7a-tetrahydro-177-3a,6,-sila-inden-4-one 9a (Equation 27). The crystal stmcture of 9a and kinetic studies of the cyclization reaction have also been reported. Starting from 3,6-ethoxy-2,5-dihydropyrazine 163, metallation with 1 molar equivalent of -butyllithium and subsequent treatment with 1 molar equivalent of the bis(chloromethyl)silane produced compound 164 in 50% yield. Pleating neat 164 at 120 °C gave the crystalline 9a in almost quantitative yield. 

In addition to the preparations listed in Table II.1, Gabriel and Colman (187) have obtained, from the reaction of aminoacetone hydrochloride with potassium hydroxide, a liquid base (188, 189) that has now been assigned the structure 2,5 -dimethyl-3,6-dihydropyrazine (190). 

Imidazolines on acid hydrolysis have been shown to give pyrazines (306). Thus 2,2-diethyl4-methylimidazoline-A with dilute hydrochloric acid at 60 gave diethyl ketone (62% of the theoretical) and 2,5-dimethylpyrazine (7%) 2,2-diethyl-4,5-dimethylimidazoline-A gave diethyl ketone (70.2%) and tetramethylpyrazine (20.4%) and 2,2,4-triethyl-5 methylimidazoline-A (41) gave diethyl ketone (84%) and 2,5-diethyl-3,6-dimethyl-3,6-dihydropyrazine (81%) (43). The pyrazines were formed presumably by self-condensation of the amino ketones (42) produced. 

Diniethylpiperazine-2,5-dione (34) on treatment with triethyloxonium fluoroborate in dichloromethane gave 5-ethoxy-l,3-dimethyl-2-oxo-l, 2,3.6-tetrahydropyrazine which was oxidized by DDQ in dry benzene to 5-ethoxy-l 3 dimethyl-2-oxo-l,2-dihydropyrazine (35) (1067). l,3,6-Trimethylpiperazine-2,5-dione similarly treated gave three products, one of which was assigned the structure 5-methoxy-l 3,6-trimethyl-2-oxo-l, 2-dihydropyrazine 3-benzyl-5-methoxy-l, 6-dimethyl-2-0X0-1,2-dihydropyrazine was also prepared similarly (1078). When 3,6-diethoxy-2,5"dimethyl-2,5-dihydropyrazine was refluxed with lead tetraacetate in dry benzene it gave a mixture of 2,5-diacetoxy-3,6-diethoxy-2,5-dimethyl-2,5-dihydropyrazine (36) (4 parts) and 2,5-diethoxy-3,6-dimethylpyrazine (1 part) (1068). 

Methylation of 2-amino-3-hydroxypyrazine (62) with methyl iodide and sodium methoxide afforded 3-amino-l-methyl-2-oxo-1,2-dihydropyrazine (63), and when an excess of methyl iodide was used, a mixture of compound (63) and its methio-dide (64) was isolated. Reaction with dimethyl sulfate and alkaU gave compound (63) and l,4-dimethyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine (66) the latter was presumed to be formed by hydrolysis of an intermediate quaternary salt since it was also obtained by treatment of the methiodide (64) with aqueous sodium hydroxide. Reaction of 2-amino-3-hydroxypyrazine with ethereal diazomethane produced a mixture of N- and 0-methyl derivatives, (63) and 2-amino-3-methoxy-pyrazine (65). With methyl toluene-p-sulfonate the quaternary salt 2-amino-3-hydroxy-1-methylpyrazinium toluenesulfonate (67) was obtained on alkaline hydrolysis it gave 3-hydroxy-l-methyl-2-oxo-l,2-dihydropyrazine (68) (832). Pulcherriminic acid with diazomethane gave a dimethyl derivative (99). 

Methylation of 2-hydroxy-3-7V-phenylcarbamoylpyrazine with dimethyl sulfate and potassium carbonate in boiling acetone gave l-methyl-2-oxo-3-A -phenylcarbamoyl-1,2-dihydropyrazine and the 3-(A -methyl-Af-phenylcarbamoyl) analogue was prepared likewise (1055). Similar methylation of 2-hydroxy-3-(o-methylaminophenyl)pyrazine produced 1 -methyl-3-(o-methylaminophenyl)-2-oxo-1,2-dihydropyrazine (1055). A series of 24iydroxy-3-(a-hydroxybenzyl)pyrazines has been methylated with dimethyl sulfate in aqueous sodium hydroxide to the 2-methoxy analogues (1045) and 2-benzyl-3,6-dihydroxy-5-methylpyrazine with diethyl sulfate and sodium ethoxide formed 2-benzyl-3,6-diethoxy-6-methylpyrazine (1066). 

Ethoxy-l,3-dimethyl-2-oxo-l,2-dihydropyrazine has been shown to undergo ready cycloaddition reactions even with nonactivated double bonds (1067), and also rapidly reacts with oxygen on exposure to air. 

Methylfluorosulfonate and 1 -methyl-2-oxo-l, 2-dihydropyrazine gave a quantitative yield of 1,4-dimethyl-2-oxo-l, 2-dihydropyrazinium fluorosulfonate, which reacted instantaneously and exothermically at room temperature and in high yields with hydroxide ion, hydrosulfide ion, and ammonia to give interesting new cage systems (1130). 

---