1 - piperazine reduction

The only reference to this ring system names the perhydro heterocycle as piperazino[l,2-a]piperazine. Reduction of the 2,4-dinitrophenyl-hydrazone 1 with Raney nickel gave the dioxo derivative 2 in 26% yield. This compound was reduced with lithium aluminum hydride to give the product 3. 

Aliphatic Alcohols and Alkylene Glycols. Simple aliphatic alcohols, such as methanol [67-56-1], can be used to alkylate alkyleneamines. For example, piperazine reacts with methanol over a reductive amination catalyst to yield a mixture of 1-methyl- [109-01 -3J and 1,4-dimethylpiperazine [106-58-1] (12). 

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). 

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. 

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. 

Acylation of the monosubstituted piperazine, 99 (obtainable by the protection-deprotection scheme outlined above), with cinnamoyl chloride gives the corresponding amide (100). Reduction of the carbonyl by means of lithium aluminum hydride affords cinnarizine (101). ... 

Alteration of the structural pattern produces a pair of adrenergic a-blocking agents which serve as anti hypertensives. These structures are reminiscent of prazoci n. Reaction of piperazine with 2-furoy1 chloride followed by catalytic reduction of the furan ring leads to synthon 69. This, when heated... 

Condensation of piperazine with 2-methoxytropone gives the addition-elimination product 12 [2]. Alkylation of the remaining secondary amino group with bromoketone 13, itself the product from acylation of dimethyl catechol, gives aminoketone 14. Reduction of the carbonyl group with sodium borohydride leads to secondaiy alcohols 15 and 16. Resolution of these two enantiomers was achieved by recrystallization of their tartrate salts to give ciladopa (16) [3],... 

Scheme 9 Synthesis of enantiopure piperazines by reductive coupling of chiral 2,5-diaza-1,5-dienes...

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>. 

The iV-( -nitrophcnyl)pipcrazinc-2-carbonitrilc 251 (Y = NBOC) was reductively cyclized to the tricyclic /V-oxides 252 (Y = NBOC) either by catalytic hydrogenation, or by electrochemical reduction. Electrochemical reduction gave lower yield. Compounds 251 were prepared by electrochemical cyanation of the iV-(o-nitrophenyl)piperazine 250. The jV-oxides 252 were further hydrogenated to the 2,3,4,4 ,5,6-hexahydro-l//-pyrazino[l,2- ]quinoxaline 253 (Y = NBOC) (Scheme 46) <2001EJ0987>. 

The syntheses of these three compounds share a common route as described by Brickner et al. [53] and Barbachyn et al. [54]. Namely, the coupling reaction of 3,4-difluoronitrobenzene (82) with piperazine, morpholine, or thiomorpholine to yield the corresponding 4-substituted 3-fluoro-nitrobenzene (83), which upon reduction gives rise to the aniline derivative (84). Carbobenzoxy protection of the active nitrogen of 84 using benzyloxy-carbonyl chloride (CbzCl) results in the formation of carbamates 85a and 85b. Treatment of 85a,b with n-BuLi and (i -glycidyl butyrate yields a 5-(R)-... 

The production of hydrazine and hydrazones by reduction of nitrosamines is another route for NOC production. Piperazine also leads to production of NOC and its use as an antihelminthic has decreased considerably in most developed countries, though not in the case of developing countries due to its low cost. 

Electrohydrodimerization is well known for its application in the preparation of adiponitrile [82]. The method was successfully used in the preparation of heterocycles from reductions of activated bis-alkenes (Scheme 60 and vide supra Scheme 6) [10, 83] or bis-imines affording substituted piperazines in good yields, in the presence of proton donors (Scheme 61) [84]. 

The bis-nitramine (155) has been prepared from the reaction of 1,5-diaminotetrazole (152) with glyoxal, followed by reduction of the resulting fused heterocycle (153) with sodium borohydride and subsequent A-nitration of the piperazine nitrogens of (154). ... 

Attachment of the basic side chain to the phenothiazine nucleus by means of a carbonyl function apparently abolishes the usual CNS or antihistamine effects shown by most compounds in this class. The product azaclorzine instead is described as an anti anginal agent. Reduction of proline derivative 106 with lithium aluminum hydride gives the corresponding fused piperazine 107. Use of that base to alkylate the chloroamide 109, obtained from acylation of phenothiazine with 3-chloropropionyl chloride, leads to azaclorzine (110). ... 

Meclizine Meclizine, l-[(4-chlorphenyl)methyl]-4-[(3-methylphenyl)phenyl]piperazine (16.1.16), is synthesized by reductive amination of a mixture of 3-methylbenzaldehyde with l-(4-chlorbenzhydryl)piperazine using hydrogen over Raney nickel [27-29]. 

Diethylcarbamazine is a derivative of piperazine. The mechanism of its action is not completely understood. However, it is highly likely that it causes a reduction in muscular activity, and even paralysis in hehninthes. It quickly gets rid of the parasites Brugia malayi, Loa loa, and Wuchereria bancrofti, and it is also used for diseases caused by Onchocerca volvulus and Mansonella strptocerca. Synonyms of this drug are hetrazan, notezine, banoside, and others. 

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