Pyrazine-2,3-diones

An alternative approach to the use of a-aminoketones involves acetals (72JOC221) and pyrazine-2,3-diones have been synthesized by this route (Scheme 58). The acetals are readily available from the phthalimido derivatives via the a-chloroketones. Hemiacetals have also served as a starting point for pyrazine synthesis, although in most cases hemiacetals are too labile to be easily prepared examples are common in the 2-amino-2-deoxy sugar series 2-amino-2-deoxy-D-glucose for example dimerizes to the pyrazine (101) when generated in situ from the hydrochloride salt (68JAP6813469). 

Little work has been reported on pyrazine-2,3-diones, however spectral evidence has been advanced by HonzL to support the dioxo formulation 126. Dioxo structures have been assigned to quin-oxaline-2,3-dione (127) and its 1-methyl analog on the basis of ultraviolet and infrared spectral data, and according to... 

Pyrazine-2,3-diones are conveniently prepared from aminoacetalde-hyde diethyl- or dimethylacetal. The condensation product of the acetal and diethyl oxalate is treated with ammonia or a primary amine and the resulting intermediate cyclized in hot acetic acid containing a trace of hydrochloric acid (Scheme 4).120... 

This sequence comprises biacetyl (butane-2,3-dione) 41, cyclohexane-1,2-dione 42, and pyrazine-2,3-dione 43 with or without benzofusion to the corresponding quinoxalinedione 44. For the first two at least computation is probably the only way forward, while the third and fourth raise subtle problems of lone pair... 

Krasavin et al. described the synthesis of dihydropyrazol pyrazine diones via Ugi-4CR, employing ferf-butyl isocyanide as a convertible reagent [102], The authors reported that, under microwave irradiation, the ferf-butyl isocyanide behaves similar to Armstrong s isocyanide, furnishing the DKPs in good yields. It is noteworthy that the low priced isonitrile applied may be helpful for developing large-scale syntheses in the future (Scheme 6). 

Treatment of the /3-lactam, 3,3-dimethoxy-l-p-methoxyphenyl-4-p-methoxyphenyliminomethyl-2-azetidinone (3, R = H), with stannous chloride in dichloromethane for 20 h gave 1,4-bisf/ -methoxyphenyl)-2,3(l//,4//)-pyrazine-dione (5, R = H) in 95% yield by ring expansion via the acetal (4) 874 the 4-methy-lated substrate (3, R = Me) likewise gave 1,4-bisf p-methoxyphenyl)-5,6-dimcthyl-2,3(lH,4tf)-pyrazinedione (5, R = Me) (99%).874 cf-1740... 

Albonoursin, 3 -benzylidene-6-isobutylidene-3,6-dihydro-2,5 (l//,4//)-pyrazine-dione, antibacterial and antineoplastic [1222-90-8],1710... 

Flutamide, 1-hydroxy-3,5-diisobutyl-3,6-dihydro-2,6-dihydro-2,6(lH)-pyrazine-dione (or tautomer), antiandogenic for prostate cancer [162666-34-3],... 

Pyrazine dione 88 reacted with o-phenylenediamine to give the imidazodiazocine 89 (m.p. 206-208 °C) in moderate yield (Equation 16) <2003CHE250>. 

An improved dissymmetrization of imidazole-4,5-dicarboxylic acid 869 for the synthesis of Ar,AT -disubstituted dicarboxamides 872 involves the preparation of pyrazine-dione diphenyl ester 870. Selective amide formation at the pyrazine carbonyl at low temperatures affords the mixed amide ester 871, which is subsequently converted into 872 (Scheme 213) <2002JOC7151>. 

Radicals derived from l,4-di-tert-butyl-5,6-dihydro-2,3(lH, 4H)-pyrazine-dione (214), " 1,4-di -tert-butyl-5,6-dihydro-2,3,5,6(l/7,4//)-pyrazine-... 

Attempts to prepare imidazol-4(S)-carbonyl chloride give the tricyclic pyrazine-dione— a type of reaction which also occurs with other azolecarbonyl chlorides. 

Most pteridines are degraded to pyrazines and when they do yield pyrimidines, these may well be the ones from which they were made. However, some useful preparations of pyrimidines from pteridines are known. Thus, reduction of pteridin-7(8//)-one (732) and subsequent hydrolysis yields N-(4-aminopyrimidin-5-yl)glycine (733) (52JCS1620) and hydrolysis of 5,8-dimethylpteridine-6,7(5Ff,8Ff)-dione (734) gives dimethyl-... 

H,3H- Pyrrolo[l, 2-c]oxazole-l, 3-dione, 5,6,7,8-tetrahydro-IR spectra, 6, 978 [2.2](2,5)Pyrrolophane, N-aryl-rearrangements, 4, 209 Pyrrolophanes natural products, 7, 764 synthesis, 7, 771 Pyrrolophanes, N-aryl-synthesis, 7, 774 (2,4)Pyrrolophanes synthesis, 7, 771 Pyrrolo[3,4-c]pyran-4-ones synthesis, 4, 288 Pyrrolopyrans synthesis, 4, 525, 526 Pyrrolopyrazines synthesis, 4, 526 Pyrrolo[l, 2-a]pyrazines synthesis, 4, 516 Pyrrolo[2,3-6]pyrazines Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolo[3,4-c]pyrazole, 1,3a,6,6a-tetrahydro-structure, 6, 976 synthesis, 6, 1019 Pyrrolopyrazoles synthesis, 5, 164 Pyrrolo[l,2-6]pyrazoles synthesis, 6, 1002, 1006 Pyrrolo[3,4-c]pyrazoles reactions, 6, 1034 synthesis, 6, 989, 1043 Pyrrolo[3,4-c]pyrazolones synthesis, 6, 989 Pyrfolopyridazines synthesis, 4, 517 Pyrrolo[l, 2-6]pyridazines synthesis, 4, 297 6/7-Pyrrolo[2,3-d]pyridazines synthesis, 4, 291 2/f-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291 6/7-Pyrrolo[3,4-d]pyridazines synthesis, 4, 291... 

Structure of 4//-pyrido[l,2-a]pyrazines 348-350 was confirmed by X-ray investigations (99JPR332). The stereostructure of 1,3,4,6,1 l,lla-hexahydro-2/f-pyrazino[l,2-A]isoquinoline-l,4-dione 351 was determined by X-ray investigation (01TL543). 

Racemic or optically active perhydropyrido[l,2-a]pyrazines were obtained by reduction of 9a5-perhydropyrido[l,2-u]pyrazin-4-one with LAH in Et20 at room temperature (99H(51)2065) and by reduction of perhydropyr-ido[l,2-u]pyrazine-l,4-diones with LAH in boiling THF (97USP5703072, 00JAP(K)00/86659). Treatment of (9uS)-2-(fcrf-butoxycarbonyl)perhydro-pyrido[l,2-u]pyrazin-4-one with LAH in Lt20 afforded (9uS)-2-fcrf-butox-ycarbonyl-l,6,7,8,9,9a-hexahydro-2//-pyrido[l,2-a]pyrazine (99H(51)2065). 

Reduction of a 7-(2-oxoethyl) derivative with NaBH4 in EtOH at room temperature gave 7-(2-hydroxyethyl)-2-(2-pyrimidinyl)perhydropyrido[l, 2-u]pyrazine (99MIP6). Reduction of 7-formyl-8-[(4-cyanophenyl)methoxy]-1,3,4,6,11,1 lu-hexahydro-2//-pyrazino[l,2-A]isoquinoline-l,4-dione with NaBH4 yielded a 7-hydroxymethyl derivative (98MIP7). 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

Treatment of the appropriate pipecolic amide 396 with NEta afforded optically active or racemic perhydropyrido[l,2-a]pyrazine-l,4-dione (397) (97USP5703072). (9a5)-Perhydropyrido[l,2-a]pyrazin-3-one (400) was obtained by cyclization of piperidine 398, and the catalytic hydrogenation of quaternary salt 399 over Pd/C (99H(51)2065). 

Substituted perhydropyrido[l,2-a]pyrazine-l,4-diones were obtained when methyl A-[2-(benzyloxycarbonylamino)acetyl]-4-substituted pipecoli-nates were hydrogenated over 10% Pd/C catalyst in MeOH, and then the methanolic solutions were refluxed (00JAP(K)00/86659). 

Perhydropyrido[l, 2-a]pyrazine-1,6-diones and 6a,7,8,9-tetrahydro-5//-pyrido[l,2-a]quinoxaline-6,10-diones were formed when their precursors bond to a resin were cleaved by an acid (01MIP4). 

Cyclocondensation of 2-aminomethylpiperidine 422 and dimethyl oxalate yielded perhydropyrido[l,2-n]pyrazine-3,4-dione 423 (00T1005). 

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