5.6- Dihydropyrazin-2 -ones

Rao, K.V.S., Srinivas, B., Subrahmanyam, M., and Prasad, A.R. (2000) A novel one step photocatalytic synthesis of dihydropyrazine from ethylenediamine and propylene glycol. Chemical Communications (16), 1533-1534. 

The electron-rich and cyclically conjugated 8 rr electron system of 1,4-dihydropyrazine can be stabilized in essentially planar conformation by organosilicon substitution at the enamine nitrogen centers [1], In addition to electron transfer [1] and triorganosilyl exchange reactions [2], we have explored the possibility of inserting heterocumulenes X=C = Y into one or both of the N-Si bonds of the compounds 1 in order to functionalize this unusual ring structure [3],... 

One of the most common approaches to pyrazine ring construction is the condensation of diaminoethane and 1,2-dicarbonyI compounds such as 206 to provide pyrazines 207 after aromatization. Aromatization was accomplished by treating the dihydropyrazines with manganese dioxide in the presence of potassium hydroxide <00JCS(P1)381>. The N-protected 1,2-dicarbonyl compounds 206 were prepared from L-amino acids by initial conversion into diazoketones followed by oxidation to the glyoxal. 

Shaabani et al. developed a one-pot MCR for the synthesis of 1,6 dihydropyrazine derivatives from condensation reactions among diketene 42, an isocyanide 40, and 2,3-diaminomaleonitrile 41 (Scheme 7) [27]. 

TABLE 7.13. 5-(DIMETHYLAMINO)-3,6-DIHYDROPYRAZIN-2(l//)-ONES FROM REACTION OF 5(2i7)-OXAZOLONES WITH 3-(DIMETHYLAMINO)-2i7-AZIRINES... 

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. 

Substituted 3,6-dialkoxy-2,5-dihydropyrazines are regioselectively metalated by strong alkyl-lithium bases, such as butyllithium, (l-methylpropyl)lithium, fcrf-butyllithium, or lithium diiso-propylamide, at the less substituted carbon atom (C5). Metalation proceeds at low temperatures (in general, below — 70 C) in THF as solvent. Electrophiles suitable for alkylation of the lithiated derivatives include alkyl iodides, bromides and chlorides, as well as alkyl methanesulfonates, 4-methylbenzenesulfonates and trifluoromethanesulfonates. The electrophile adds trans to the substituent at C2 in a highly stereoselective fashion, with typical diastereomeric excesses of greater than 90% (syn addition has been reported in only one case where a-methylphenyl alanine was used as chiral auxiliary and an alkyl trifluoromethanesulfonate as electrophile18). 

Treatment of lithiated 3,6-dialkoxy-2.5-dihydropyrazines 1. derived from L-valine/glycine (R1 = H), or L-valine/alanine (R1 = CH3), with oxiranes, followed by addition of one equiva-... 

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 earliest report on such lactim ether formation was from Sammes [72JCS(P1)2494], who converted piperazine-2,5-dione to 2,5-diethoxy-3,6-dihydropyrazine (173) with an excess of triethyloxonium fluoroborate. Subsequently, Rajappa and Advani (73T1299) converted proline-based piperazine-2,5-diones into the corresponding monolactim ethers. The starting material was a piperazinedione in which one of the amino acid units was the secondary amino acid proline, and the other a primary amino acid. This naturally led to the regiospecific formation of a monolactim ether (169) (on O-alkylation) from the secondary amide, whereas the tertiary amide remained intact. This was later extended to piperazine-2,5-diones in which the secondary amino acid was sarcosine [74JCS(P 1)2122], leading to the monolactim ethers (170). 

Pyrazine 192 is reduced in acidic solution in two one-electron steps through the protonated radical to 1,4-dihydropyrazine (193) 192 and 193 can react with formation of two PH- radicals.306,307 The 1,4-dihydro- (or... 

Enantiopure fused oxopiperazino-/3-lactams have been produced by application of the Staudinger reaction with 5,6-dihydropyrazin-2-(l/7)-ones and the /3-lactams were converted to the 2-oxopiperazine-3-acetic acid esters in good yield with no epimerization (Equation 86) <2006TL8911>. Fused /3-lactams have been formed from macrocyclic imines by use of the Staudinger reaction (see Section 2.04.9.7). When phenoxyacetyl chloride and triethylamine were used, the best yields (45-52%) of the fused /3-lactams were obtained with dry dichloromethane as solvent <2006TL8855>. 

It was suggested that a-amino carbonyls such as 3-amino-butane-2-one formed a dihydropyrazine which was subsequently oxidized to a pyrazine (30, 311. The conversion of dihydropyrazine to pyrazine occurs with or without oxygen. There are two possible ways to convert dihydropyrazine into pyrazine without oxygen. One is the disproportionation of dihydropyrazine to give pyrazine and tetrahydropyrazine or piperazine. The other is the dehydration of hydroxy dihydropyrazine (32). Recently, a dialkylpyrazine radical was reported as an intermediate of pyrazine formation (33). However, this simple step from dihydropyrazine to pyrazine is not yet thoroughly understood. 

Reactions of isoxazolotropone 90 with 1,2-diaminoethane or -propane afford, for instance, mixtures of isomeric dihydropyrazines 517a and isomeric pyrazines 517b in low yields [83H(20)1117], The latter structure is the result of double-bond migration from the seven-membered ring into the heterocyclic one. 

Ethoxycarbonylethyl-2-isopropyl-3-imidazoline (46) gave a separable mixture of 2,5-bis(2-ethoxycarbonylethyl)pyrazine (48, Q = H) and its 3-iso-propyl derivative (48, Q = IV) [trace TsOH, xylene, reflux, 1 h 21 and 38%, respectively postulated mechanism formation of dimer (47) and loss of FVC (=NH)H to give a dihydropyrazine that in part undergoes oxidation to product (48, R = H) and in part adds one of the foregoing fragments with subsequent oxidation to product (48, R = FV)].542... 

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... 

A theoretical/NMR study of keto-enol tautomerism in 2-(2-methoxycarbony-lacetyl)pyrazine (277/278) and other similarly substituted azines has been undertaken the foregoing pyrazine exists in its enolic form (278) to the extent of 35% in deuterochloroform.411 l,4-Diacetyl-l,4-dihydropyrazine (279) gave the persistent radical cation (279) + on one-electron oxidation (cyclic voltammetry in MeCN— Bu4NC104).167... 

Many other examples are known of acid-catalyzed intermolecular Schiff reactions18 to give cyclic dimers. Thus, condensation of two molecules of a-aminoketones gives 2,5-dihydropyrazines (e.g., 9 from l-aminopropan-2-one), most of which can be converted into pyrazines by oxidation with mercuric chloride (i.e., the Gutknecht pyrazine synthesis19). The same type of self-condensation occurs on heating... 

In summary, the insertion of 0=C=S into the Si-N bond of reactive 1 proceeds to give only one apparently rather stable primary product which owes its stability to the matching of thiocarbonyl n-acceptor and dihydropyrazine 7t-donor capacities. 

Some very clever syntheses of pyrazines were reported. Tandem Mn02-mediated oxidation followed by in situ trapping with aromatic or aliphatic 1,2-diamines was shown to give rise to quinoxalines, dihydropyrazines, pyrazines, and piperazines without the need to isolate highly reactive 1,2-dicarbonyl intermediates <03CC2286>. A new intramolecular cyclization route to highly substituted chiral 6,7-dihydro-5//-imidazo[l,5-a]pyrazin-8-ones like 157 from Meldrum s acid was developed <030L3907>, and 5-chloropyrido[3,4-6]pyrazines were prepared from 1,2-dicarbonyl compounds and 2-chloro-3,4-diaminopyridine <03H(60)925>. A synthesis of... 

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. 

Other chlorinations have been effected with phosphorus pentachloride alone as follows piperazine-2,5-dione in carbon tetrachloride to 2,5-dichloro-3,6-dihydropyrazine (847, 849) [but at 250°/24hours to tetrachloropyrazine (850, 851)] 2[Pg.102]

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). 

Ramage and Landquist 1959 1,2-, 2,3-, 2,5-, and 1,4-Dihydropyrazines, tetrahydropyrazines, piperazin-2-ones, piperazine-2,3- and 2,5-diones, piperazinetri- and tetraones, piperazines 37... 

Condensation of diiminosuccinonitrile (10) with 3-methylbutan-2-one gave 5,6-dicyano-2,2,3-trimethyl-l,2-dihydropyrazine (II) (11%) and 4,5-dicyano-l-isopropyl-2-methylimidazole (7.6%) (383). Cyclization of a-cyanoalkyldiamino-maleonitiiles (12, e.g., R = Me) with phosphorus pentoxide in refluxing ethanol has been shown to give 5,6-dicyano-3-hydroxy(-2-substituted)-l, 2-dihydropyrazines(I3, e.g., R = Me) (489, 490) and the conversion of benzylidenediaminomaleonitrile to 5-carbamoyl-6-cyano- and 6-carbamoyl-5-cyano-2,3-diphenyl-l, 2-dihydropyrazines has been described in Section II.3 (395a). 

The method first described by Conant (1580) for preparing hexamethyl-2,5-dihydropyrazine from 3-methylbutanone with warm aqueous alkaline potassium ferricyanide has been expanded into a simple one-step selective way of preparing a-amino-a,Q -dialkyl ketones and/or their self-condensation products, hexaalkyl-... 

Treatment of 2-benzylideneamino-l-phenylvinyl benzoate (47) with sodium methoxide produced one major product which was assigned as 2,5-dibenzoyI-3,6-diphenyl-1,4-dihydropyrazine (48) (1585). Dimerization of a series of a-arylamino ketones (49) in toluene with p-toluenesulfonic acid gave the symmetrical 1,4-diaryl-1,4-dihydropyrazine (50), not the corresponding l,4-diaryl-l,4-dihydropyrazines (51) or l-aryl-l,2-dihydropyrazines (52). Thus w-(4-chloroanilino)acetophenone gave 1,4-bis(p-chlorophenyl)-2,6-diphenyl-1,4-dihydropyrazine (1546). 

Catalytic hydrogenation of 1,4-diacetyl-2,3-diphenyl-1,4-dihydropyrazine (46) over palladium-charcoal resulted in the rapid uptake of 1 mol of hydrogen with formation of 1,4-diacetyl-5,6-diphenyl-l, 2,3,4-tetrahydropyrazine (55) this addition of only one equivalent of hydrogen under these conditions is characteristic of a... 

Reduction of 2,2,3,3,5,6-hexamethyl-2,3-dihydropyrazine 1,4-dioxide (78) with sodium borohydride gave l,4-dihydroxy-2,2,3,3,5,6-hexamethylpiperazine (555) and attempted deoxygenation of (78) by zinc and hydrochloric acid gave the bishydroxylamine (79) (555). Compound (78) did not form benzylidene derivatives with benzaldehyde (555) and it was only slowly attacked by selenium dioxide one equivalent of selenium dioxide required 5 days boiling under reflux before the nitrone was completely reacted, and the product was thought to be 6-formyl-... 

The preparation of piperazin-2-ones by reduction of 2-oxo-l,2-dihydropyrazines has been described in Section V.5A(1) (853). 

Reactions of piperazine-2,5-diones with phosphorus pentachloride and phosphorus pentabromide have been described in Sections V.ID and V.IF, respectively. Aromatic aldehydes condense with 3-methylpiperazine-2,5-dione in the presence of acetic anhydride to form mainly mono-A -acetyl derivatives of trans-3-arylidene-6-methylpiperazine-2,5-diones (e.g., 96, R = Ac) (1066). In these products the acetyl group was shown to be attached to position 1 and the 4,5-amide group was found to be sterically hindered. Photolysis formed the cis isomers. Both isomers were deacetylated with methanolic potassium hydroxide (1066). Condensation of 1,4-diacetylpiperazine-2,5-diones with aldehydes has been applied to the synthesis of unsymmetrical 3,6-diarylidenepiperazine-2,5-diones and the reaction has been extended to l,4-diacetyl-3,6-dimethylpiperazine-2,5-diones (1624). Treatment of (96, R = H) with triethyloxonium tetrafluoroborate in dichloromethane gave the monoimino ether, 5-benzylidene-6-ethoxy-3-hydroxy-2-methyl-2,5-dihydropyrazine (97) (1066). l-Methylpiperazine-2,5-dione similarly treated gave 5-ethoxy-l-methyl-2-oxo-l,2,3,6-tetrahydropyrazine (which was condensed with anthranilic acid at 150° to 2-methyl-l,2-dihydropyrazino[2,l-fi]quinazoline-3(4/0.6-dione (98) (1625), and l,4-dimethylpiperazine-2,5-dione gave 5-ethoxy-l,4-dimethyl-2-oxo-1,2,3,4-tetrahydropyrazine and 5,5-diethoxy-l,4-dimethylpiperazin-2-one (1626). 

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