Tetrahydropyrazines

Pratt (36) in 1957 published a comprehensive review which included reduced pyrazines (di- and tetrahydropyrazines, piperazines, and piperazinones), and the literature prior to 1957 is generally not further examined. 

Early publications in this area have been reviewed by Pratt (1957) (36) and Ramage and Landquist (1959) (37), and updated to about 1971 by Cheeseman and Werstiuk (39). Generally only significant publications since, or not mentioned in, these reviews are discussed below. 

Mason and Winder (26) reported that the base-catalyzed cyclodehydration of JV-phenacylbenzylamine hydrobromide (1) gave 1,4-dibenzyl-2,5-diphenyl-1,4-dihydropyrazine (2) but Chen and Fowler (1535) showed that the product was l,2-dibenzyl-3,6-diphenyl-l,2-dihydropyrazine (3) (20%). Further investigation by 

Author(s) (Total References Cited) Year Published Reduced Pyrazines Reviewed Refs. 

Pratt (170) 1957 1,2-, 2,3-, 2,5-, and 1,4-Dihydropyrazines, tetrahydropyrazines, piperazin-2-ones, piperazine-2,3-, 2,5-, and 2,6-diones, piperazinetetraones, piperazines 36 

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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 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). 

Praziquantel (9) was prepared by the cyclization of 4-cyclohexylcarbonyl-l-phenethyl-2-oxo-l,2,3,4-tetrahydropyrazine in cone. H2SO4 at room temperature in quantitative yield (98H(48)2279). 

QiiHioiNOioSij I286S4-97-9) see Tacrolimus Ar-(l,l-dimethylethyl)pyrazinecarboxamide (C,H jNjO 121885-10-7) see Indinavir sulfate (l,l-dimethylethyl)[[(3P E,7E,22 )-9,10-secoergosta-5,7,10(19),22-tetraen-3-yl]oxy]dimethylsilane (CMHjgOSi 104846-63-1) see Calcipotriol iV-(l,l-dimethylethyl)-l,4,5,6-tetrahydropyrazine-carboxamide... 

Reduction of amides 159 with LiAlH4 provides tetrahydropyrazines 160 <2004ARK286>. Further reduction of protected 160 (R1 = Cl, Rz = Me, R3 = BOC, X = C, Y = N) with NaCNBH3 furnishes compound 161 as a mixture of isomers in an 8 1 ratio (Scheme 2) <2006BML1207>. 

The reaction of pyrazine and quinoxaline with methyl chloroformate and bis-silyl enol ethers gave fused tetrahydropyrazine lactones 88, in an extension of previous work. There was little consistency with the variation of R in the stereochemistry of the products <06T12084>. 

DIPAMP-Rh complex to give the corresponding chiral a-amino acid derivative in over 98% ee. The chiral product has been used for the synthesis of (S)-(-)-ac-romelobic acid [88]. Hydrogenation of a tetrahydropyrazine derivative catalyzed by a PHANEPHOS-Rh complex at -40"C gives an intermediate for the synthesis of Crixivan in 86% ee [82a]. Hydrogenation of another tetrahydropyrazine carboxamide derivative catalyzed by an (R)-BINAP-Rh catalyst leads to the chiral product in 99% ee [89]. 

It should be noted that, as all carbon positions in pyrazine are identical, the locant 2- in a monosubstituted derivative is unnecessary. All possible reduced derivatives of pyrazine 1, and several of those of its benzo analogues quinoxaline 2 and phenazine 3, are known. There are four dihydropyrazines, the 1,2-, 2,3-, 1,4-, and 2,5-isomers, two tetrahydropyrazines, the 1,2,3,4- and 1,2,3,6-, and hexahydropyrazine or piperazine, the last of which is omitted in this chapter. The reduced quinoxalines are the 1,2- and 1,4-dihydro compounds and 1,2,3,4-tetrahydroquinoxaline. The only known reduced phenazine is 1,4-dihydrophenazine. Hydroxypyrazine 4 and hydroxyquinoxaline 6 have been shown to exist in the tautomeric amide form by spectral studies, and therefore they are formulated as 2(1//)-pyrazinone 5 and 2(l//)-quinoxalinone, respectively. In contrast, aminopyrazine and aminoquinoxaline exist as described in the amino rather than the imino forms (Figure 1). 

Among the four isomers of dihydropyrazines, the 2,3-dihydro isomers are most explored because these reduced pyrazines have been easily prepared by condensation of 1,2-diamines and 1,2-dicarbonyl compounds. This class of compounds is unexpectedly unstable resulting in dimerization at room temperature. Thus, 2,3-dihydropyrazine 97 (R = = Me) gradually dimerizes to form tricyclic system 98, fused with two tetrahydropyrazine units... 

Since 1,4-dihydropyrazine itself is unknown, various substitutions of the ring system are required to produce stable isolable molecules. Carbonyl-stabilized 1,4-dihydropyrazines are synthesized by self-condensation of 3-chloromethyl-5,6-dihydro-l,5,5-trimethyl-2(l//)-pyrazinone <1998J(P1)289>. Another carbonyl-stabilized example is provided by WA -BOC-protected 1,4-dihydropyrazine 102, which can undergo Michael addition with nucleophiles such as 1,2,4-triazole, 3-formylindole, 4-bromothiophenol, benzylamine, or sodium methoxide to yield tetrahydropyrazines 103 (Scheme 26) <2004T8489>. Treatment of the di- and tetrahydropyrazines with trifluoroacetic acid leads to cleavage of BOC groups and/or elimination of the nucleophile to both afford dimethyl 2,5-pyrazinedicarboxylate 104. 

Acetyl-protected 1,2,3,4-tetrahydropyrazines 105, which are prepared by treatment of 2,3-dihydropyrazine with acetic anhydride and zinc (Scheme 27), undergo photooxidation to produce new dioxetanes 106 <1995JA9690>. Upon thermolysis, the dioxetanes 106 decompose quantitatively to tetraacyl ethylenediamines 107. Dimethyldioxirane oxidation of tetrahydropyrazine 105 affords novel epoxide 108, which is also generated by deoxygenation of dioxetane 106 with dimethyl sulfide. In 2,3,4,5-tetrahydropyrazine 1-oxide 109, which is prepared... 

D. Condensation of DAMN with Oxalyl Chloride 1. 2,3-Dioxo-5,6-dicyano-l,2,3.4-tetrahydropyrazine... 

Preparation of 2,3-dioxo-5,6-dicyano-l,2,3,4-tetrahydropyrazine (67) by condensation of DAMN with oxalyl cyanide or oxalyl chloride, and by reaction of DISN with oxalyl chloride, followed by the treatment of the intermediate with ethanethiol, was noted in Section V,B,1. 

DISN reacts with the electron-rich olefins 112 and 113 with complete retention of stereochemistry to give the 1,2,3,4-tetrahydropyrazines 114 and 115, respectively. Heat or acid converts either isomer to 2,3-dicyanopyrazine (116) (Scheme 40). 

Diaryl-5,6-dihydropyrazines 194 are analogous to benzil dianils311 and are reduced in aqueous solution in an analogous way a diimine-enediamine is analogous to a dione-enediol, and the products from 194 are the expected 2,3-diaryl-l,4,5,6-tetrahydropyrazines 195310 [Eq. (114)]. 

Absence of PG. When feeding an aq. solution of pure ED, only P (Fig. la) and tetrahydropyrazine (THP, Fig. If) were found in the reactor effluent. The selectivity to THP ) at very low values... 

Electrochemical reduction of imines (25 Schiff bases) in acidic media proceeds via the iminium species, i.e. the protonated imine (26) (Scheme 5)29. Since 26 bears a positive charge, it is very easily reduced, so much so that the resulting neutral radical (27) is formed at a potential positive of its reduction potential. The products are therefore derived from 27 rather than the corresponding carbanion (28). This stands in contrast with the electrochemical behavior of imines in neutral media, where 27 is immediately reduced to 2830. Thus, cathodic reduction of /u. s-irnincs of 1,2-diamines (29) in DMF containing methanesulfonic acid affords tetrahydropyrazines (equation 13)31. A similar reaction can... 

Different cyclization reactions of ort o-ami no-substituted benzothiazepinones 54 lead to tricyclic derivatives 55, containing imidazole (X = CR), 1,2,3-triazole (X = N), or tetrahydropyrazine (X = CH2CH2) rings (Equation 3). These compounds are structural analogues of the anti-HIV product thiobenzimidazolone (TIBO) <1999EJM701>. 

The tetrahydropyrazine ring in the 5-methyluracil cation-radical is nonaromatic spin delocalization in the corresponding methylene radical is impossible. Correspondingly, this cation radical does not expel the proton at all (Rhodes et al. 1988). 

Rossen et al. [71a] has reported a synthesis of piperazine 113, a key intermediate in the synthesis of the HIV protease inhibitor Crixivan . The reaction between a preformed imine 110, f-butyl isocyanide, and formic acid afforded the Ugi product 111, which was dehydrohalogenated with triethylamine and cyclized with KO Bu to the tetrahydropyrazine 112. Catalytic hydrogenation in the presence of Rh-BINAP (97% ee) and deformylation with aqueous hydrazine gave the target piperazine 113 (Scheme 2.40). 

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. 

Rhodium and palladium catalysts that contain 4 display high enantioselectivities for the asymmetric hydrogenation of enamides, itaconates, P-keto esters, asymmetric hydroboration, and asymmetric allylic alkylation,80 82 but this ligand system distinguishes itself from other chiral bisphos-phines in the asymmetric reduction of tetrahydropyrazines and tetrasubstituted olefins (see also Chapter 15). The reduction of tetrahydropyrazines produces the piperazine-2-carboxylate core,... 

The reactions of the isomeric dimethylpyrazines and trimethyl-pyrazine with methyllithium have been studied in order to gain insight into the factors involved in the competition between ring methylation and side-chain metalation.189 The major product from the reaction of 2,5-dimethylpyrazine and ethereal methyllithium was shown to be trimethylpyrazine, thus confirming Klein and Spoerri s earlier observation.190,191 Tetramethylpyrazine was also formed as a by-product. Proof of side-chain metalation was obtained by treatment of the reaction mixture with methyl benzoate and isolation of 2-methyl-5-phenacylpyrazine. Evidence for the presence of dihydro-and tetrahydropyrazine intermediates is derived from the infrared spectrum of the crude product obtained on hydrolysis of the reaction mixture which shows C=N and N-H absorptions (see Scheme 17). 

Stevens and his co-workers report the preparation of 2-phenyl-3,3-dimethyl-3,4,5,6-tetrahydropyrazine (184) in 91% yield from the reaction of the epoxy ether (183) and ethylenediamine. The structural assignment is consistent with the observation of strong N-H and... 

The irans-benzylidene derivative (188), obtained as the major product of condensation of 3-methylpiperazine 2,5-dione and benzaldehyde in the presence of acetic anhydride, undergoes photoisomerization to the cis isomer (191) on irradiation in methanol. Both isomers have been converted into tetrahydropyrazine imino ethers (189) and (192) by treatment with triethyloxonium fluoroborate. The trans compound reacts more slowly and gives a lower yield of imino ether and this is attributed to steric hindrance. Compounds 188 and 191 are de-acetylated on treatment with methanolic 2 N potassium hydroxide. The trans and cis isomers (187) and (190), so produced are converted into 3-benzyl-2,5-dihydroxy-6-methylpyrazine (144) when heated at 100° with sodium hydroxide.384 Treatment of the dichloroacetyl derivative of phenylalanine with methylamine gives l-methyl-3-benzylidenepiperazine 2,5-dione with the stereochemistry shown.384a... 

Hydrogen peroxide is produced during the autoxidation of some 2,5-dihydropyrazines and 1,2,3,6-tetrahydropyrazines, e.g., compound 195. Hydrogen peroxide production is strongly catalyzed by manganese diphosphate complexes.387 388... 

Conformational studies in the pteridine series involve mainly the tetrahydro derivatives which adopt a half-chair orientation in the tetrahydropyrazine moiety, giving rise to some flexibility and special structural arrangements. 

Vicinal couplings 3J(H-a, H-fi) measured in the H-NMR spectra of tetrahydroquinoxalines condensed with six-membered heterocycles proved to be smaller (2-4 Hz) (86MI1) than those found for tetrahydroquinoxalines annelated with five-membered rings (6-9 Hz) (840MR775). It indicates that tetrahydroquinoxalines annelated to six-membered rings were found to have stereostructures different from those in which the tetrahydropyrazine ring is... 

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