1.4- Dihydropyrazine

In a series of detailed studies, Armand and coworkers have examined the electrochemical reduction of pyrazines (72CR(C)(275)279). The first step results in the formation of 1,4-dihydropyrazines (85), but the reaction is not electrochemically reproducible. The 1,4-dihydropyrazine is pH sensitive and isomerizes at a pH dependent rate to the 1,2-dihydro compound (83). The 1,2-dihydropyrazine then appears to undergo further reduction to 1,2,3,4-tetrahydropyrazine (88) which is again not electrochemically reproducible. Compound (88) then appears to undergo isomerization to another tetrahydro derivative, presumably (8, prior to complete reduction to piperazine (89). These results have been confirmed (72JA7295). 

Dihydropyrazines, although the initial reduction product under electrochemical conditions, appear to be unstable, as might be predicted from the fact that they contain eight... 

Dihydropyrazines are relatively stable, although they are easily oxidized. They are usually formed via the addition of organometallic reagents to the pyrazine ring. Similarly, 2,3-dihydropyrazines are usually easily oxidized to pyrazines and are formed during type A synthesis (see Section 2.14.3.2). 

Dihydropyrazines are formed by the self-condensation of a-aminocarbonyl compounds and they are relatively stable, although again they are easily oxidized to the corresponding pyrazines. Tetrahydropyrazines are less well documented and structures such as (87) appear to be more stable than the enediamine (88). 

The fusion of a benzene ring to pyrazine results in a considerable increase in the resistance to reduction and it is usually difficult to reduce quinoxalines beyond the tetrahydroquinoxa-line state (91). Two possible dihydroquinoxalines, viz. the 1,2- (92) and the 1,4- (93), are known, and 1,4-dihydroquinoxaline appears to be appreciably more stable than 1,4-dihydropyrazine (63JOC2488). Electrochemical reduction appears to follow a course anzdogous to the reduction of pyrazine, giving the 1,4-dihydro derivative which isomerizes to the 1,2- or 3,4-dihydroquinoxaline before subsequent reduction to 1,2,3,4-tetra-hydroquinoxaline (91). Quinoxaline itself is reduced directly to (91) with LiAlH4 and direct synthesis of (91) is also possible. Tetrahydroquinoxalines in which the benzenoid ring is reduced are well known but these are usually prepared from cyclohexane derivatives (Scheme 30). 

In many instances the primary reaction product is a dihydropyrazine and aromatization may be required as a final step. In addition, many pyrazines are prepared by the structural modification of a preformed pyrazine ring and hence would be classified as a reaction of the ring rather than a ring synthesis such processes are discussed more fully in Section 2.14.2. 

Many variants of this procedure exist. Thus, Kano and coworkers have carried out the condensation of /3-keto sulfoxides with diaminomaleonitrile (Scheme 36) (78S372). This reaction probably yields an intermediate dihydropyrazine which is oxidized under the reaction conditions, and it seems likely that the condensation of the carbonyl group and the amine is the first step. 

Classically, type B pyrazine syntheses involve self-condensation of an a-aminoacyl compound to yield a 3,6-dihydropyrazine which is subsequently oxidized to the pyrazine (Scheme 54) (70CC25). The aromatization usually proceeds under very mild conditions. 

Treatment of a-hydroxy-ketones or -aldehydes with ammonium acetate (65BSF3476, 68BSF4970) results in the formation of dihydropyrazines, presumably by direct amination of the hydroxyketone followed by self-condensation (79AJC1281). Low yields of pyrazines have been noted in the electrolysis of ketones in admixture with KI and ammonia, and again it appears probable that the a-aminoketone derived by way of the a-iodoketone is the intermediate (69CI(L)237>. 

A number of reductive procedures have found general applicability. a-Azidoketones may be reduced catalytically to the dihydropyrazines (80OPP265) and a direct conversion of a-azidoketones to pyrazines by treatment with triphenylphosphine in benzene (Scheme 55) has been reported to proceed in moderate to good yields (69LA(727)23l). Similarly, a-nitroketones may be reduced to the a-aminoketones which dimerize spontaneously (69USP3453279). The products from this reaction are pyrazines and piperazines and an intermolecular redox reaction between the initially formed dihydropyrazines may explain their formation. Normally, if the reaction is carried out in aqueous acetic acid the pyrazine predominates, but in less polar solvents over-reduction results in extensive piperazine formation. 

Other methods of generating a-aminoketones in situ are common, if somewhat less general than the methods already described. 2-Nitrovinylpyrrolidine, which is readily available, yields 2,3-bis(3-aminopropyl)pyrazine on reduction and this almost certainly involves ring opening of the intermediate enamine to an a-aminoketone which then dimerizes under the reaction conditions (Scheme 59) (78TL2217). Nitroethylene derivatives have also served as a-aminoketone precursors via ammonolysis of the derived epoxides at elevated temperatures (Scheme 60) (76S53). Condensation of 1,1-disubstituted hydrazine derivatives with a-nitro-/3-ethoxyethylene derivatives has been used in the synthesis of l,4-dialkylamino-l,4-dihydropyrazines (Scheme 61) (77S136). 

Dialkyl-1,4-dihydropyrazines are generally unstable and are reported to undergo rearrangement to 1,2-dialkylpyrazines (Scheme 62) (74TL179). 

An interesting reaction occurs when the dihydropyrazine (102 R = CHaPh) is pyrolyzed under vacuum. Toluene is liberated to give the monobenzylpyrazine (103) in high yield, presumably by a radical mechanism. 

The thermal chemistry of a number of aryl-substituted azirines often results in the formation of indole derivatives (68TL3499). Thus, heating a sample of azirine (152) gave 3-phenylindole (155) and dihydropyrazine (156). The formation of (155) was suggested to... 

Four possible tautomeric forms, e.g., 1,2- (62), 2,3- (63), 1,4- (64), and 2,5- (65), exist for unsubstituted dihydropyrazines however, information on the tautomeric interconversions and stabilities of these forms is sparse. It was demonstrated that, of the four tautomers, 1,4-dihydropyrazine 64 is the least stable (unsubstituted... 

Armand and coworkers have shown that, while 1,4-dihydropyrazines are the initial products of the electrochemical reduction of pyrazines, they could not be isolated and readily isomerize in solution into 1,2- or 1,6-dihydropyrazines depending on the substitution pattern in the heterocyclic ring (74CJC3971 84MI1). The rate of the isomerization depends on the type of pyrazine as well as the pH and the nature and amount of the cosolvent. 

The dihydropyrazines 1 undergo ring expansion on treatment with potassium hydroxide in dimethyl sulfoxide to give 2//-1,4-diazcpines 3 via the unstable 5//-tautomers 2. No further details were reported.184... 

Addition of Azaenolates from 3,6-Dialkoxy-2,5-dihydropyrazines (Bis-Imidate Anions)... 

The titaniated (25)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazines derived from cyclo(L-Val, Gly) or cyclo(L-Val, Ala) (1, R1 = H, CH3) react with a,/I-unsaturatcd aldehydes exclusively by 1.2-addition (cf. nearly exclusive 1,4-addition of ,//-unsaturated ketones with cuprate complexes of 2,5-dialkoxy-3,6-dihydropyrazines, see Section D. 1.5.2.3.1.4.) in a highly diastereoselective mode to give virtually only the (l S,2R)-diastereoniers 2 ". In reactions with the corresponding lithiated pyrazines both regioselectivity and diastereofacial differentiation at C-2 are also remarkably high (dc 95 %), but the diastereomeric excess at C-l is substantially smaller (30 50%) ... 

Another chiral cuprate that shows high diastereoselectivity on addition to cycloalkcnones is the dihydropyrazine derivative 12. The adducts 13 were obtained in good chemical yield with diastereoselectivities exceeding 90% A Lower diastereoselectivities resulted on addition of 12 to /(-substituted cycloalkenones or to acyclic ( )-enones. 

Ail extremely useful method for the asymmetric synthesis of substituted amino acids, in particular glutamic acids, is based on optically active bislactim ethers of cyclodipeptides. The lithium etiolates of bislactim ethers (which are prepared easily from amino acids) undergo 1,4-addition to various a,/ -unsaturated esters to give -substituted 2,5-dihydropyrazine-propanoates203-205 with high diastereofacial selectivity, ratio (R/S) > 140-200 1. 

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],... 

A more complicated type of reaction leading to 2-styrylindoles is observed when 2-arylazirines are treated with the rhodium complexes,70 [(Ph3P)2 Rh(CO)Cl] or [Rh(CO)2Cl]2, or with dicobalt octacarbonyl71 (Scheme 42). In contrast, 2-arylazirines with molybdenum hexacarbonyl give pyrazines and dihydropyrazines, and with diiron enneacarbonyl give pyrroles (see Sections V,C,2 and IV,A,1, respectively). The use of relatively low molar ratios of 2-arylazirine to rhodium catalyst (2 1) causes the formation of 2,5-diarylpyrroles. 

The ring cleavage of 3-aryl-2-substituted-2//-azirines by molybdenum hexacarbonyl has been described earlier in regard to the synthesis of pyrroles, pyrazoles and isoxazoles. In contrast to this behavior, analogous reactions of 2-unsubstituted derivatives lead to the formation of mixtures of 2,5-diarylpyrazines (139) and isomeric 3,6- and 1,6-dihydropyrazine derivatives (140,141) (Scheme 163).47,53 It is possible that the pyrazine products are formed by an intermolecular nitrene mechanism akin to the intramolecular processes described earlier (see Scheme 22 in Section IV,A,1). 

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