2.5- Dimethoxy-3,6-dihydropyrazine

Dimethoxy-3,6-dihydropyrazine (109), prepared by methylation of 2,5-piperazinedione with trimethyloxonium tetrafluoroborate, is susceptible to lithiation because the protons at C-3 and C-6 are activated by adjacent imine moieties. The lithium salt of this bislactim ether reacts with the 2-chloro-l-phenylsulfonyl alkene (110) to give the 3-substituted pyrazine (111) (Scheme 25) <89JCS(P1)453>. The bislactim ether from piperazinedione cyclo(L-Val—Gly) is lithiated with butyl-lithium and then treated with ketones, alkyl halides, or others to form, nearly stereospecifically, ran5-3-isopropyl-6-substituted piperazinediones due to the steric influence of the isopropyl group <828866, 838673). Similar stereoselective syntheses have been achieved in reactions starting from cyclo(L-Val—D,L-Ala) <828864, 918939). Acid hydrolysis of these products affords chiral a-amino acids. 

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). 

Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (35, R = H) gave 2-isopropyl-3,6-dimethoxy-5-(2-methoxycarbonyl-l-phenylethyl)-2,5-dihydropyrazine (35, R = CHPhCH2C02Me) (LiBu, THF—C6H14, -70°C, 10 min then... 

Allyl-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (59) gave 2-allyl-2-(2-hydroxyethyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (60) (BuLi, THF—C6H14, -78°C, A, 45 min then (CH2)20 [, BF3.Et20 j, -78°C, 1 h 60%).1615... 

C, 3 h 62%) 49 the same substrate (53) gave 2-(4-ethoxycarbonyl-l-methylbut-2-enyl)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (62) (similarly, using MeCH=CHCH=CHC02Et >52%).218... 

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 (64) gave the complex (67) (BuLi, THF, -78°C then PhMn (CO)3.BF4 J, -78°C, 30 min 80%), and thence, by oxidative demetalation, 2-isopropyl-3,6-dimethoxy-5-phenyl-2,5-dihydropyrazine (68) [/V-bromosuc-cinimide (NBS), Et20, 20°C, 15 min 60%) also substituted-phenyl analogues likewise.169... 

Isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (71) and l,4-dioxaspiro[4.5]-decane-2-carbaldehyde (72) gave 2-(l,4-dioxaspiro[4.5]dec-2-yl)hydrox-ymethyl-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (73) [BuLi, THF, -70°C, 15 min then aldehyde (72) j, -70°C, 12 h 69%].521... 

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. 

The same substrate (71) gave the 2-(l-ethyl-l-mercaptopropyl) derivative (75), isolated as its more stable thioether, 2-[l-ethyl-l-(methylthio)propyl]-5-iso-propyl-3,6-dimethoxy-2,5- dihydropyrazine (76) (BuLi, THF—C6H14, -70°C, 10 min then Et2C=S j, -70°C, 12 h then Mel, 20°C, 40 h 76%).355... 

The foregoing chloro intermediate (80) gave a tin complex (83) that reacted with p-diethoxybenzene to afford 2-(2,5-diethoxyphenyl)-5-isopropyl-3, 6-dimethoxy-2,5-dihydropyrazine (84) (EtOC6H4OEt-p, SnCl4, CH2C12 then (80) i, —78°C, 6 h 65%).920... 

Allyl-5-isopropyl-3,6-dimethoxy-2-(prop-2-ynyl)-2,5-dihydropyrazine (315) gave a separable mixture of 8-isopropyl-7,10-dimethoxy-2,3-dimethylene-6, 9-diazaspiro[4.5]deca-6,9-diene (316) and 3-isopropyl-2,5-dimethoxy-10-methylene-l,4-diazaspiro[5.5]undeca-l,4,8-triene (317) [Pd(OAc)2, PPh3, PhH, A, 20°C, 24 h 32 and 24%, respectively, after separation] also analogous reactions.1610... 

Chloroethyl)- gave 2-(2-bromoethyl)- (NaBr, Me2NCHO, 70°C, 12 h 88%) or 2-(2-iodoethyl)-5-isopropyl-3,6-dimethoxy-2-methyl-2,5-dihydropyrazine (likewise but Nal 88%).1608... 

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... 

Allyl-2-(2-hydroxyethyl)- (137, R = CH2OH) gave 2-allyl-2-formylmethyl-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (137, R = CHO) [Me2SO, (COCl)2, CH2C12, 60°C, A, 5 min then substrate J, - 60 — - 15°C,... 

Although both types of pyrazine ethers are easily made, only the nuclear alkoxypyrazines can be used as substrates for nucleophilic displacement reactions. Some epoxides are included in the present discussion. Shape details of cis- and tra y-2,5-dimethoxy-3,6-diphenyl-3,6-dihydropyrazine have been elucidated by X-ray analysis.1243... 

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