Piperazines pyrazines

The final reduction product of pyrazine, piperazine (89), is a stable compound which behaves as a typical diamine. It has found extensive use in medicinal chemistry as a linking agent and as a medicine in its own right for the treatment of helminths both in human and veterinary medicine. 

Pyrazine, piperazine, and pyrazole are, like 4,4 -bipyridyl, suitable ligands for bridging pairs of Zn + ions to give a variety of polynuclear species, while multifunctional (bi)pyridine-pyrazine ligands give scope for the assembly... 

Procedures involving the reduction of oxirane and ammonia in the vapor phase over an Al203-Si02 catalyst have been patented for the preparation of pyrazine, piperazine, and morpholine. The formation of quinoxalines is illustrated in Eq. 225. ... 

Catalytic deamination of diethylenetriamine (86) over kaolin and alumina with some acidic admixtures at 280-400° to give pyrazine, piperazine, and other products has been examined (476). The conversion of a-amino acids, through piperazine-2,5-diones, with phosphoryl chloride to pyrazines has been discussed in Section IN. 

Classic A/-heterocychc ligands, eg, bipyridyl (bipy), terpyridyl, imidazole, pyrazine, phenanthroline, piperazine (including alkyl- and aryl-substituted derivatives), and polypyrazol-l-yl-borates (bis, tris, and tetra), have all been found to coordinate Th(IV) chlorides, perchlorates, and nitrates. The tripodal hydrotris(pyrazolyl)borates, HBPz, have been used to stabilize organometaHic complexes (31). Bis-porphyrin Th(IV) "sandwich" complexes have been... 

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). 

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. 

In the aliphatic series, hydrogenation of y-nitroketones gives pyrrolidines in good yields (52) and tx-nitroketones give a mixture of pyrazines and piperazines (i5). 

Die Dihydro-Derivate sind bei diesen Potentialen offenbar bestandig das 2,3-Diphcnyl-5,6-dihydro-pyrazin jedoch wird bei —1,4 V (vs. SCE) unter Ar%y>nzum2,3-Diphenyl-1,4,5,6-tetrahydro-pyrazin weiterreduziert (an Quecksilber in geteilter Zelle 70% d. Th. F 106°). 2,3-Diphenyl-pyrazin (-1,75 V 15% d. Th.) und 2,5-Di-phenyl-l,2-dihydro-pyrazin (- 1,55 V 59% d. Th.) wird im selben basischen Milieu dagegen za 2,3-Diphenyl-bzw. 2,5-Diphenyl-piperazin reduziert1 ... 

Diphenyl-1,2-dihydro-pyrazin wird dagegen unter analogen Bedingungen zum 2,5-Diphenyl-piperazin reduziert (s. S. 584) analog verhalten sich 2,3-Dihydro-l,4-diaz-epin-Derivate (S, 585). 

Maldotti (96) studied the kinetics of the formation of the pyrazine-bridged Fe(II) porphyrin shish-kebab polymer by means of flash kinetic experiments. Upon irradiation of a deaerated alkaline water/ethanol solution of Fe(III) protoporphyrin IX and pyrazine with a short intense flash of light, the 2 1 Fe(II) porphyrin (pyrazine)2 complex is formed, but it immediately polymerizes with second-order kinetics. This can be monitored in the UV-Vis absorption spectrum, with the disappearance of a band at 550 nm together with the emergence of a new band due to the polymer at 800 nm. The process is accelerated by the addition of LiCl, which augments hydrophobic interactions, and is diminished by the presence of a surfactant. A shish-kebab polymer is also formed upon photoreduction of Fe(III) porphyrins in presence of piperazine or 4,4 -bipyridine ligands (97). 

Amino-2-methoxyphenyl)perhydropyrido[l,2-tf]pyrazine was prepared from a 2-(5-nitro-2-methoxyphenyl)-3-one derivative by catalytic hydrogenation over Pd/C catalyst, followed by the reduction of the 3-oxo group by treatment with BH3-THF complex <1999WO99/042465>. A nitro group was reduced to an amino group in 2-[4-(3-nitrophenyl)piperazin-l-yl]butyl]perhydropyrido[l,2-tf]pyrazine-l,4-dione <2001JME186>, in 8-hydroxy-... 

Pyrazino[l,2-tf]pyrazines 245 (Y = NH) were prepared from [6+0] fragments by bond formation a to the ring junction nitrogen atom in the reductive cyclization of the N-protected piperazine derivative 244 (Scheme 44) <2002W0055518>. 

Acylation of the piperazine nitrogen atoms of 47/,87/-bis[l,2,5]oxadiazolo[3,4- 4 -< ]pyrazine 59 with acetyl bromide proceeds smoothly in the presence of pyridine in acetonitrile to give 60 (Equation 9) <1997CHE618>. 

Relevant examples of enantioselective hydrogenation of aromatic N-heterocycles are given below. Scheme 16.21 shows the hydrogenation of a 2-ester substituted piperazine to the corresponding 2-substituted pyrazine with a catalyst... 

PIPERAZINES AND PYRAZINES The classical synthetic method for constructing 2-aminopyrazines is illustrated by the synthesis of ampifzine (117), a CNS stimulant. Condensation of aminomalonamide and glyoxal leads to pyrazine 114. Hydrolysis to the acid and decarboxylation gives 2-hydroxypyrazine (115). Reaction with PCl produces chloride 116, and heating with dimethylamine completes... 

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). 

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