Piperazines, 1,4-disubstituted

Aziridine is converted into piperazine on NH3 treatment 1-substituted aziridines give 1,4-disubstituted piperazines when reacted with Grignard reagents. Azirines (326) with Group VI metal carbonyls give pyrazines (327) and dihydropyrazines (328). 

Some unusual zwitterionic pyrazines have been prepared by dehydrogenation of 1,4-disubstituted piperazine-2,6-diones. Honzl et al. (476a) prepared theanhydro-2,6-dihydroxy-l, 4-diphenyl-3,5-bis(phenylthio)pyrazinium dihydroxide [s/c] (92) (which yields adducts by dipolar cycloaddition of maleic anhydride or formaldehyde) by the reaction of 1,4-diphenylpiperazine-2,6-dione with benzenesulfonyl chloride in pyridine. Tanaka et al. (476b), from I,4-diphenylpiperazine-2,6-dione with benzoyl chloride, and tosyl chloride in pyridine at reflux, obtained the anhydro - 3 - benzoyl - 2,6 -dihydroxy -1,4 -diphenyl - 5 - (p - toly lthio)pyrazinium dihydroxide [src] (93), together with some of the S-p-tolyl analogue of (92). 

Condensations of chloroacetyl chloride (and similar compounds) with substituted ethylenediamines to give 1,4-disubstituted piperazin-2-ones have been described, and a number of 4-alkyl(or aralkyl)- -arylpiperazin-2-ones has been prepared either by catalytic debenzylation or pyrolytic debenzylation (or demethylation) of I,l-dialkyl(or l,l-diaralkyl)-3-oxo-4-arylpiperazinium halides (1609). 3-Ethoxy-carbonylmethylene-6-methylpiperazin-2-one has been synthesized by the reaction of diethyl acetylenedicarboxylate with propylenediamine (1610), and treatment of diethyl fumarate with propylenediamine has been shown to give 3-ethoxycarbonyl-methyl-6-methylpiperazin-2-one, also prepared from the diethyl ester of N- 2 -hydroxyiminopropyl)aspartic acid (84) (1611). 

Dipole moments have been measured in the piperazine series in an attempt to correlate those of noncyclic nitramines and nitrosamines with the moments of some homologous dinitroso- and dinitropiperazines (1674), to examine the conformation of certain 1,4-disubstituted piperazines (1675), and to examine the effective size of the lone pair on nitrogen (1676). Infrared spectral measurements of the first overtone and electronic dipole moment measurements indicate that the N-H in a... 

Following the discovery of DEC, a series of 1,4-disubstituted piperazines (5) were synthesized, many of which showed moderate to good antifilarial activity. The noteworthy active analogues of DEC belonging to this class are 6 [13]. When tested against Litomosoides carinii infection in cotton rats, l-isobutoxycarbonyl-4-methylpiperazine (6) caused 91% reduction of microfilariae in blood at an intraperi-toneal dose of 3 mg/kg during 5 days and also killed 100% of the microfilariae and... 

Diethyl carbamazine (3, DEC) and related 1,4-disubstituted piperazines (Scheme 2)... 

The same group has also described the synthesis of 1,4-disubstituted polyfunctional piperazines 65 through a one-pot Ugi-5-MCR (Scheme 7.27) [60]. In this case, the authors used piperazine (62), which attacked the intermediate 63, and later, the formed intermediate 64 would attack to a second unit of the intermediate 63, forming the final 1,4-disubstituted piperazine 65. Thus, this reaction allowed the use of four points of diversity in the starting materials. 

Kung PP, Cook PD, Solution-phase simultaneous addition of functionalities (SPSAF) and chemical transformations to prepare N,N -disubstituted piperazine libraries, Biotechnol. Bioeng., 61 119-125, 1998. 

When 1-phenyl aziridine or 1 -(p-tolyl)aziridine is treated with sodium iodide in boiling ethanol-water solution the corresponding disubstituted piperazines are formed (62). In the absence of the salt only polymerization took place. The piperazines are most probably formed by the same mechanism as proposed by Dick. 

The benzyl group, easily removed by hydrogenolysis, is an ideal blocking group for the preparation of 1-monosubstituted, and of 1,4-unsymmetrically disubstituted, piperazines. 

Brouwer and Wilbrandt have applied resonance Raman spectroscopy and calculations to questions of structure of amine radical cations [73]. Well-resolved Raman spectra of trialkylamine radical cations that are so short-lived that their electrochemical oxidation waves are irreversible may be obtained at room temperature in solution by photoionization and time-resolved detection. Comparison of the observed spectrum with calculations for various isomers provides a powerful method of answering structural questions. Density-functional calculations prove much easier to apply to open-shell species than Hartree-Fock calculations, which require cumbersome and expensive corrections to introduce suffieient electron correlation to eonsider questions like the charge distribution of disubstituted piperazine (1,4-diazacyclohexane) radical cations. The dimethyl- and diphenyl-substituted piperazine radical cations are delocalized, but charge is localized on one ArN unit of the dianisyl-substituted compound [73dj. 

Disubstituted piperazin-2-ones (83) were first synthesized by the reaction of a-chloro oximes (81) with esters of amino acids, followed by reductive cyclization... 

Reductive alkylation. Alkylation of an amine simply involves treatment with an aldehyde in the presence of trimethyl orthoformate as a dehydrant and in situ reduction. An analogous method applying to a-amino esters with glyoxal results in optically active -disubstituted piperazines, and a convergent reductive amination of a ketodialdehyde to form an indolizidine skeleton in 53% yield makes possible a concise synthesis of castanospermine from a-D-glucopyranoside. ... 

Doss GA, Miller RR, Zhang Z, Teffera Y, Nargund RP, Palucki B, Park MK, Tang YS, Evans DC, Baillie TA, Steams RA (2005) Metabolic activation of a 1, 3-disubstituted piperazine derivative evidence for a novel ring contraction to an imidazoline. Chem Res Toxicol 18 271-276... 

N,N -unsymmetrically disubstituted piperazines are attainable by catalytic hydrogenation of the appropriate enamine of N-alkylpiperazine 9, Enamines oxidized with Tl(OAc)3 form a-acetoxyketones in yields generally superior to those obtained by oxidation of the free ketone O. Allylamines on treatment with KNH2 on alumina isomerize to form high yields of the enamine. ... 

Scheme 23 Synthesis of 3,6-disubstituted-piperazine-2,5-diones promoted by complex 28...

Nakhla and Wolfe reported on the synthesis of cis-2,6-disubstituted piperazines in enantiopure forms starting from a-amino acid using a Pd-catalyzed carboamination reaction... 

The reaction for the formation of 2,6-disubstituted piperazine followed the same carboamination mechanism described previously. 

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