5 -Chloro - 6- pyrazinone

The Suzuki-Miyaura and Heck reactions were recently also reported under conventional heating conditions [39,40]. A variety of 3-chloro pyrazinones were reacted with commercially available (hetero)aryl boronic acids or the alkyl-9-BBN derivatives under either classical or slightly modified Suzuki conditions to generate the 3-substituted analogues, however having the drawback of longer reaction times of up to 12 h of reflux. 

The cycloadducts formed from the Diels-Alder reaction of 3-amino-5-chloro-2(17/)-pyrazinones with methyl acrylate in toluene are subject to two alternative modes of ring transformation yielding either methyl 6-cyano-l,2-dihydro-2-oxo-4-pyridinecarboxylates or the corresponding 3-amino-6-cyano-l,2,5,6-tetrahydro-2-oxo-4-pyridinecarboxylates. From the latter compounds, 3-amino-2-pyridones can be generated through subsequent loss of HCN <96 JOC(61)304>. Synthesis of 3-spirocyclopropane-4-pyridone and furo[2,3-c]pyridine derivatives can be achieved by the thermal rearrangement of nitrone and nitrile oxide cycloadducts of bicyclopropylidene <96JCX (61)1665>. 

One more useful synthetic application of primary Michael adducts onto 2-chloro-2-cyclopropylideneacetates 1 is the recently reported new approach to oc-tahydrospirocyclopropanepyrazinopyrazines 182. In the first step, the adducts of primary amines onto 1-Me (or 1-fBu) were coupled with AT-Boc- or N-Vmoc-protected glycine derivatives and the resulting products 178, after deprotection, cyclized under mildly basic conditions to give the spirocyclopropanehexahydro-pyrazinones 179,180 and hexahydrodiazepinediones 181 (Scheme 53) [89]. 

A typical example of tautomerism is represented by the equilibrium between hydroxypyrazine 4 or 7 and 2(1//)-pyrazinone 5 or 8, in which the latter keto form predominates over the hydroxyl or enol form. A similar situation exists in hydroxylquinoxaline 6. The tautomeric equilibrium, however, is susceptible to the additional substituents. For example, 6-amino-2(l//)-pyrazinone 8 (R = Me, = Bn, R = NH2) has been shown to predominate over the hydroxyl form 7 <1993JOC7542>. On the contrary, 6-methoxy-2-hydroxypyrazines 7 (R = Me, R = Ph, R = OMe) exist in the hydroxyl form rather than as the tautomeric amide <1997J(P1)3167>, and these examples have a predominance of the hydroxyl form parallel the isomeric 5-methoxy-2-hydroxypyrazines as well as the chloro-hydroxypyrazine field <1996CHEG-II(6)233>. 

Ring nitrogens in pyrazines and the benzo derivatives react with electrophiles to form quaternary ammonium species such as iV-alkylpyrazinium salts and pyrazine iV-oxides. N-Alkylation has generally been performed by treatment with a reactive alkyl iodide. The N-1 nitrogen in 2(l//)-pyrazinone 5 is methylated using chloro(chloromethyl)dimethyl-silane followed by desilylation with cesium fluoride to yield l-methyl-2(l//)-pyrazinone <2000TL4933>. 

The most convenient synthesis of halogenopyrazines and -quinoxalines is by halogenation of pyrazinones and quinoxalinones with phosphoryl or other acid halides for example, 5-hydroxy-2-pyrazinecarboxylic acid, rather than 5(477)-pyrazinone-2-carboxylic acid, is chlorinated with phosphorus pentachloride/phosphoryl chloride to afford a 63% yield of 5-chloro-2-pyrazinecarbonyl chloride <1994SL814>. Sato and Narita provided an improved synthesis of various halogenopyrazines in which 2(l//)-pyrazinones were activated with chlorotrimethylsilane to give silyl ethers (Section 8.03.7.3). This procedure is most effective for synthesis of bromopyrazines whose overall yields are 62-81% <1999JHC783>. Bromopyrazine is directly prepared by treatment of 2-(l//)-pyrazinone with phosphoryl... 

Similarly, from 2-chloro(l//)-pyrazinone, the azides 498a-d were obtained and these underwent reversible cyclization to the fused tetrazoles 499a-d (Scheme 62) <2004OL4223, 2005JC0490>. 

Benzyl-6-[A -(but-3-ynyl)-A -propionylaminomethyl]-5-chloro-3-methoxy-2(l//)-pyrazinone (48) underwent thermolysis to afford l-benzyl-3-methoxy-7-propio-nyl-5,6,7,8-tetrahydro-l,7-naphthyridin-2(l/7)-one (49) (PhBr, reflux, 2 h 53%, after separation from a second product) the proposed intermediate was not isolated.602... 

Pyrazines with hydroxyl groups are generally in the oxo form however, substituents like chlorine may profoundly influence the position of the tautomeric equilibria. Ultraviolet measurements indicate that in ethanol solution 2-chloro-6-hydroxypyrazine (125a) exists predominantly in the hydroxy rather than in the oxo form (125b) 272 trifluorohydroxypyrazine also does not tautomerize appreciably to a pyrazinone.279... 

V-(l-Acetyl-l-methylethyl)-2-chloro-(V-hydroxyacetamide (69) gave 1-hydroxy-5,6,6-(rimc(hyl-3,6-dihydro-2( I //(-pyrazinone (70) (NH4OH—I (OH—dioxane, 20°C, 3 days 8%) likewise one homologue.424 Aldehydes gave better results under reductive conditions.1768... 

I -Benzyl-3,6-dichloro-2( l//)-pyrazinonc (127, R = Cl) gave l-benzyl-5-chloro-3-methyl-2(17/)-pyrazinone (127, R = Me) [Me4Sn, Pd(PPh3)4, PhMe, reflux, <5 days residue from evaporation, KF, AcOEt, 20°C, 12 h 81%) or its 3-ethyl ho-mologues (127, R = Et) (Et4Sn, likewise 95%) 391 analogues similarly.391... 

Note The paucity of examples in this category is surprising. l-Benzyl-3,5-dichloro-2(l//)-pyrazinone (131) gave l-benzyl-5-chloro-3-pheny 1-2(1//)-pyrazinone (132) [PhMgBr/Et20 (made in situ), THF, -30°C, 10 min 90%].374... 

Iodo-3,6-diisobutyl-2(l//)-pyrazinone (133) gave 3,6-diisobutyl-5-phenylethynyl-2 (1/0-pyrazinone (134) (Cu( =CPh, pyridine, reflux, 6 h 67% after separation from unchanged substrate (23%) the corresponding chloro and bromo substrates gave much lower yields under comparable conditions.321... 

Benzyl-5-chloro-3-ethy 1-2(1 //)-pyrazinone gave 1 -benzyl-3-(l-bromoethyl)-5-chloro-2( l//)-pyrazinonc (275) (NBS, Bz202, CCI4, reflux, <6 h 89%).391 Also other examples 29-395-431,513,547,550,676,957,1059,1094,1446, wsi... 

Mcthyl-5-phenyl-2(l//)-pyrazinone (4) gave 2-chloro-3-methyl-5-phenylpyra-zine (5) (P0C13,175°C, sealed, 18 h 92% beware of pressure within the tube even when cooled ) 57 such a sealed reaction also converted 5-chloro-3-phcnyl-2( l//)-pyrazinone into 2,5-dichloro-3-phenylpyrazine (6) (185°C, 5 h 92%).1382... 

Methylthioethyl)-5-phenyl-2(l//)-pyrazinone (20) gave 2-chloro-3-(2-methylthioethyl)-5-phenylpyrazine (21) (COCl2, PhMe—THF, reflux, 4 h >95%) 315 2-chloro-3-isobutyl-5-phenylpyrazine (>80%) similarly.632... 

Benzyl-3,5-dichloro-6-phenyl-2(l//)-pyrazinone (91, R = Cl) gave 1-benzyl-5-chloro-3-(o-iodoanilino)-6-phcnyl-2(l//)-pyrazinonc (91, R = NHC6H4I-o) (H2NC6H4I-o, NaH, THF, N2, 20°C, 30 min substrate J, reflux, <5 h 78%) 1607 analogues likewise.1607 Also other examples.481,1063... 

Chloro-3-isobutyl-6-isopropylpyrazine 1-oxide (109) gave l-hydroxy-3-isobutyl-6-isopropyl-2(l//)-pyrazinone (110) (KOH, H20—MeOH, reflux, 2 h 84%) 92 homologues likewise.1250... 

Chloro-3-isobutylpyrazine 4-oxide gave 3-isobutyl-2( I // )-pyrazinone 4-oxide (111, R = Hu ) (5 M NaOH, reflux, 2 h 39%) 86 2-chloro-3-phenylpyrazine 4-oxide gave 3-phenyl-2( I //(-pyrazinone 4-oxide (111, R = Ph) (KOH, H20—EtOH, reflux, 1 h 30%) 1290 also analogues likewise.1290... 

L-Benzyl-6-(l-bromo-2-methylpropyl)-5-chloro-3-phcnyl-2(l//)-pyrazinonc (256, R = Br) gave 6-(l-azido-2-methylpropyl)-l-benzyl-5-chloro-3-phenyl-2(l//)-pyrazinone (256, R = N3) (NaN3, Mc2NCIIO, 60°C, 5 h 62%).53... 

Chloro-1 -methyl-2,3(1//,4//)-pyrazinedione (63) gave a separable mixture of 5-chloro-3-methoxy-l-methyl-2(l//)-pyrazinone (64) and 5-chloro-l,4-di-methyl-2,3(l//,4Z/)-pyrazinedione (65) (H2CN2, Et20, h 47 and 34%, respectively).1309... 

Dichloro- l-phenyl-2(l//)-pyrazinone (207) and dimethyl acetylenedicarboxy-late gave an unisolated adduct (208) that immediately underwent competitive retro-Diels-Alder reactions to afford dimethyl 2,6-dichloro-3,4-pyridinedicar-boxylate (209) and dimethyl 5-chloro-6-oxo-l-phenyl-l,6-dihydro-2,... 

Hydroxy-5,6-diisopropyl-2(l//)-pyrazinone (264, R = H) gave 1-benzoyloxy-5,6-diisopropyl-2(l//)-pyrazinonc (264, R = Bz) (BzCl, pyridine, CH2C12, 5 20°C, 12 h 64%) 1515 several analogues like 5-chloro-1 -(p-chloroben-zoyloxy)-6-ethyl-2(l//)-pyrazinone (265), were made similarly.1011515... 

Chloro-1 -methyl-3-(hioxo-3,4-dihydro-2(l//)-pyrazinone gave 5-chloro-l-methyl-3- A,-[A,-phcnyl((hiocarbamoyl)]carbamoylmethylthio -2( I //)-pyrazi-none (26) [PhHNC(=S)NHC(=0)CH2Cl, K2C03, EtOH, reflux, 4 h ... 

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