2-Methyl-3- 5,6-dihydropyrazine

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]. 

The first 3,6-dialkoxy-2,5-dihydropyrazine used in asymmetric synthesis of amino acids 7 10 was the symmetrical derivative 2, derived from cyclo(L-Ala, L-Ala) (1). This dihydropyrazine can be prepared by direct condensation of the methyl ester of L-alanine and subsequent alkylation with trialkyloxonium tetrafluoroborate7. Although the condensation process results in partial racemization of the alanine moiety, recrystallization yields almost optically pure cyclo(L-Ala, L-Ala) (1). 

The unsymmetrical 3,6-dialkoxy-2,5-dihydropyrazines are prepared via the jV-carboxyanhy-drides of the particular amino acid (e.g., 7) and subsequent reaction with the methyl ester of glycine or alanine to give the corresponding cyclodipeptides (e.g., 8). These hexahydrodioxopy-razines are converted to the 2,5-dialkoxy-3,6-dihydropyrazines by alkylation using Meerwein salts, such as trimethyloxonium tetrafluoroborate or triethyloxonium tetrafluoroborate n lb. 

The alkylated 3,6-dialkoxy-2,5-dihydropyrazines are hydrolyzed by treatment with 0.25 N hydrochloric acid (2 equivalents of H+) at room temperature to give the hydrochlorides of the corresponding alkylglycine methyl ester 3 and the chiral auxiliary amino acid methyl ester 2. Hydrolysis of the dihydropyrazines 1 under more drastic conditions (10-30 equivalents of 6 N hydrochloric acid) yields the corresponding diketopiperazines which are very stable to further hydrolysis. Basification of the hydrochlorides with aqueous ammonia liberates the free a-amino esters. In general, the chiral auxiliary amino ester is separated by distillation. 

Alkylglycine Methyl Esters 2 General Procedure for the Hydrolysis of rra/is-2,5-Disubstituted 3,6-Dialkoxy-2,5-dihydropyrazines l7,8 ... 

With chiral racemic oxiranes one enantiomer reacts faster than the other the degree of kinetic resolution is very high for L-valine/alanine-based dialkoxydihydropyrazines. For example, in the reaction of one equivalent of (2.S )-2,5-dihydro-2-isopropyl-3,6-dimethoxy-5-methyl-pyrazine (1, R1 = CH3) with two equivalents of fW-(//,/ )-2,3-dimethyloxirane (R2,R4 = CH3 R = H) virtually only the (2//,3/ )-oxirane enantiomer reacts with the lithiated dihydropyrazine to give exclusively the (l /, 2/, 2 / )-configuratcd adduct i.e., (2/ ,5S)-2,5-dihydro-5-isopropyl-3,6-dimethoxy-2-[(l/ ,2/ )-2-(2-methoxyethoxymethoxy)-l-methylpropyl]-2-methylpyrazine, entry 7. Likewise, kinetic resolution (intramolecular) occurs upon reaction with rac-7-oxabicy-clo[4.1.0]heptane (entry 8). 

The 5-[2-(2-methoxyethoxymethoxy)ethylated] 2,5-dihydro-2-isopropyl-3,6-dimethoxypy-razines 2 can be hydrolyzed with 2 equivalents of 0.1 N hydrochloric acid to give the (2-melh-oxyethoxymethyl)-protected homoserine methyl ester 3 in 49-73% yield. In some cases (entries 1 and 2) enrichment of the dominant (2/f)-diastereomer is observed, indicating that the / -configurated dihydropyrazine 2 is hydrolyzed faster than the S -epimer. Further hydrolysis... 

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. 

The Schollkopf nucleophile was also used in the enantioselective synthesis of -methyl-tryptophan. In this case the dihydropyrazine nucleophile undergoes conjugate addition to the sulfone 35a, which yields afl -methyltryptophan after reductive desulfonylation and hydrolysis <95JOC4978>... 

Hofmann and Schieberle509 also carried out model experiments employing synthetic 1,4-diethyl diquatemary pyrazinium ions with, for example, 2-furfurylthiol, showing that the primary products were 2-(2-furyl)methylthio-l,4-dihydropy-razine, bis[2-(2-furyl)methylthio-l,4-dihydropyrazine], and 2-(2-furyl)methyl-thiohydroxy-l,4-dihydropyrazine. This supports the interpretation of the binding of the thiols as being covalent to pyrazinium intermediates. 

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... 

The reaction of acetonylpyrazine with phenyllithium in the absence, and in the presence, of methyl benzoate has been studied in some detail by Chakrabartty and Levine.188 With phenyllithium alone, 2-phenyl-6-acetonylpyrazine (37) is formed, whereas in the presence of ester, a mixture of compound 37 and 3-(2-phenyl-6-pyrazyl)-4-phenylbutane-2,4-dione (38a) is obtained. Spectroscopic data indicate that compound 38a exists predominantly as the dihydropyrazine... 

Methylated 1,4-dihydropyrazines (1,2,4-tri-, 1,2,4,5-tetra-, and 1,2,4,6-tetramethyl) as well as imidazolines have been isolated from the reaction of sucrose with methylamine at high temperatures (120°-260°), for prolonged reaction periods (18 hours) and in the presence of ammonium phosphate as catalyst. 1,4-Dihydropyrazines are also isolated from the reaction of sucrose and ethanolamine sucrose-ammonia interaction yields a wide range of pyrazines and imidazoles.369-372... 

For aromatic aldehydes or ketones, the (3R)-configuration can be derived from the1 H-nmr-spectrum. Like the benzyl-substituted dihydropyrazines 8a-e the hydroxy-benzyl-substituted compounds 13 c-f adopt the folded conformation. Hence, in the minor isomer with (3S)-configuration and conformation 14 the C-6-methyl signal suffers an upfield shift. 

Table 3. Dihydropyrazines 23 by Alkylation of 20 a and a-Methyl Amino Acid Methyl Esters 11...

The only reported example of this synthesis involved the treatment of 1,5-di-methyl-2,4-diazabicyclo[3.1.0]hexan-3-one (84) with aqueous barium hydroxide at 140°C (sealed) for 60 h, followed by an acidic work up, to give 2,2,3,5,5,6-hexam-ethyl-2,5-dihydropyrazine (85) in 42% yield, presumably via the cyclopropane derivative shown.1190... 

Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (64) gave 2-(2-acetyl-l-pheny-lethyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (63) (BuLi, THF, -78°C CuBr.SMe2j, SMe2 J, -30°C, 2 h then PhCH=CHAc, 70°C, >4 h 62%)921 or 2-isopropyl-3,6-dimethoxy-5-[(4-oxocyclohex-l-enyl)methyl]-2,5-dihydropyrazine (65) (likewise, using 4-methylenecyclo-hex-2-enone 48% after separation from an isomeric byproduct).892,924... 

The same substrate (64) gave 2-isopropyl-3,6-dimethoxy-5-(l-methyl-2-ni-troethyl)-2,5-dihydropyrazine (66) [BuLi, THF—C6H14, 78°C, 15 min then ClTi(NEt2)3 J, 1 h then MeCH=CHN02 J, 12 h 51% this yield was lower than that (81%) obtained without titanation but the stereoselectivity was much better] also analogues.377,919... 

The same substrate (71) gave 2-(l-hydroxy-l-methylethyl)-5-isopropyl-3, 6-dimethoxy-2,5-dihydropyrazine (74) (BuLi, THF—C6H14, — 70°C, 10 min the AcMe, -70°C, 1 h 98%) 196 2-(l-hydroxy-l-methylethyl)-5-isopropyl-3,6-dimethoxy-2- methyl-2,5-dihydropyrazine194 and other homologues517,905, 911 were made similarly. 

Dibromovinyl)- (158) gave 2-ethynyl-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydropyrazine (159) (BuLi, THF—C6H14, -78°C, 90 min 83% mechanism ).528... 

Bromobutyl)-(257, R = Br) gave 2-(4-azidobutyl)-3,6-diethoxy-5-iso-propyl-2-methyl-2,5-dihydropyrazine (257, R = N3) (NaN3, Me2NCHO, 90°C, 13 h 78%) 1609 homologues likewise.1609 Also other examples.152 228 1106 1348... 

Bromomethyl-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydropyrazine (272) gave 2-isopropyl-3,7-dimethoxy-6-methyl-2//-diazepine (273) and/or the isomeric 2-isopropylidcnc-3,7-diincthoxy-6-methyl-5,6-dihydro-2//-diazcpinc (274) [Bu OK, Mc2SO, 50°C, 1 h 0 and 75%, respectively KOH, Me2SO, 25°C, 24 h 73% and 6%, respectively KOH, Mc2SO, 50°C, 5 h 93% and trace, respectively the kinetics and mechanism have been studied].923... 

Aspergillic acid (H 65, 195), 6-,vet-butyl-l-hydroxy-3-isobutyl-2( l//)-pyrazi-none, a mycotoxic Aspergillus sp metabolite [490-02-8],1024 Astechrome, 3-(l-hydroxy-3-methoxy-5-methyl-6-oxo-l,6-dihydropyrazin-2-yl-methyl)-7-(3-methylbut-2-enyl)indole Fe complex, an Aspergillus sp metabolite [75310-10-0]90... 

OPC-15161, 3-[(5-isobutyl-3-methoxy-4-oxido-6-oxo-l,6-dihydropyrazine-2-yl)methyl]indole (X-ray confirmation), a Thielavia sp fungus metabolite inhibitor of superoxide anion generation [121071-92-9],1166... 

Acetyl-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine (20) gave potassium 3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydro-2-pyrazinecarboxylate (21, R = K) (KOC1, dioxane—H20,4 — 20°C, 1 h cmde) that was characterized as the corresponding ester, methyl 3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydro-2-pyrazinecarboxylate (21, R = Me) (Mel, THF, 0°C, 48 h 46% overall).170,371... 

Diethoxy-3-isopropyl-6-methyl-3,6-dihydropyrazine (289) gave 2-acetyl-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine (290) (BuLi, THF, -80°C, 20 min then AcCl, 80°C, 2 h 87%).371... 

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