Piperazine reactivity

Preparation of the substituted piperazine required for sul-falene (114) starts with bromination of 2-aminopiperazine to give the dihalide (150). Displacement of halogen by sodium methoxide proceeds regioselectively at the more reactive 3 position to give 151. Hydrogenolysis over palladium on charcoal gives the desired intermediate (152). 

These above equations suggest that amines with pKa In the range of 4-6 will be more rapidly nltrosated than those with pKa values In the range of 9-11. This has been borne out In practice many times. Amines such as N-methylanlllne with a pKa value of 4.84, piperazine (pKa value 5.9, 9.8), and amlno-pyrlne (pKa value 5.04) are much more rapidly nltrosated than plperdlne (pKa value 11.2), dlmethylamlne (pKa value 10.72), and pyrrolidine (pKa value 11.27). Under many of the conditions studied. It has been shown that the reactivity of ascorbic acid Is sufficiently rapid that It can successfully compete with most all amines when present In approximately 2 mole ratio excess of the nltrosatlng agent. 

Quaternary ammonium salts of 1-acryloy 1-4-methyl piperazine can be prepared by methylation with methyl chloride and dimethyl sulfate. These monomers can be polymerized by means of radical polymerization, either alone or with a comonomer [617]. A useful comonomer with appropriate monomer reactivity ratios is acrylamide. 

The initiating nucleophile in the vast majority of these studies is the hydroxide anion. However, in principle, any nucleophile can add to the keto or formyl group to give rise to an anionic intermediate, which then could act as an intramolecular nucleophile and effect hydrolysis of the ester. Their relative effectiveness will depend on two factors the relative extent of formation and the nucleophilicity of the adduct. The nucleophiles that have been investigated are hydroxide, cyanide, morpholine and piperazine. The only quantitative comparison available is that of hydroxide, morpholine and piperazine, which are effective in the order of ca. 102 10-3 1 (Bender et al., 1965 Dahlgren and Schell, 1967). For morpholine and piperazine this is as expected on the basis of their relative basicities. However, the expected order of increasing formation of the adducts would be cyanide > nitrogen bases > hydroxide (Hine, 1971). At this time, these results cannot be analysed further, but more work on the systems could enable the structural dependence and reactivity to be elucidated. 

The objective of the present review is to discuss all aspects of the chemistry of piperazine-2,5-diones and their synthesis, physical chracter-istics, chemical reactivity and applications. Earlier reviews had focused on certain specific topics thus the review by Sammes (75FOR51) is mainly oriented toward natural products containing the piperazine-2,5-dione ring, whereas the one by Anteunis (78BSB627) deals exhaustively with conformational aspects of the ring, as well as those of the side chains. 

The CO—NH units in piperazine-2,5-diones can be converted to lactim ethers. Such conversions and the reactivity of such lactim ethers are discussed separately in Section V. 

The methylene groups at positions 3 and 6 of piperazine-2,5-diones are known to undergo facile condensation with aldehydes to form the corresponding a,/3-unsaturated amides. Two earlier reviews have dealt with this subject. (75FOR51 80FOR251). The review by Sammes covers the literature to 1972 on the synthesis, stereochemistry, and reactivity of... 

The major impetus for the massive amount of research on the synthesis and reactivity of the 3-thia and 3,6-dithia derivatives of piperazine-2,5-dione has been the discovery of this moiety in several microbial metabolites of the gliotoxin group. 

The side chain on the fused five-membered ring can, interestingly, form part of a piperidine or piperazine ring. The scheme for preparing the first of these takes advantage of the reactivity of the indole 3 position. The relatively weak base, sodium hydroxide, thus catalyzes the addition of bromoindole (16-1) to the carbonyl group in 4-iV-methylpiperidone (16-2) to afford carbinol (16-3). This product dehydrates in the presence of acid catalytic reduction of the thus-produced olefin then affords the... 

Subsequently, Tselinskii et al. found the dianion of Compound 2a to be stable and reacted it with a variety of electrophiles including picryl chloride, acetic anhydride, methyl iodide and vinyl ketone. They synthesized its dinitro derivative, dinitrodifurazano piperazine (2b) (DNDFP) [Structure (2.63)] by reacting the dianion (2a) with nitrogen oxide in CH3CN. The dinitro derivative which is quite reactive, was isolated by column chromatography and confirmed by mass spectroscopy [272]. 

Nucleic acids catalyze many different types of reactions. Some RNA-catalyzed transformations show stereoselectivity [10,34]. The potential scope of organic reactions is quite broad, with a commensurate variability in reaction conditions. The essential components present in successful nucleic acid-catalyzed reactions are divalent metal ions such as Mg2+, Ca2+, Cu2+, Zn2+, as well as K+ [7,10,21,35,36]. A buffer is also required but should not contain functional groups that are reactive under the reaction conditions. A commonly used buffer is HEPES (2-[4-(2-hydroxyethyl)-l-piperazine]ethanesulfonic acid). These essential components are present to maintain the RNA s tertiary structure and prevent its aggregation. Because these reactions are carried out in aqueous solution, the addition of a co-solvent (e. g., DM SO or EtOH) may be necessary, depending on the solubility of the substrates. 

Very recently, the combination of a reactive group at C-4 (an aldehyde or an imine) and a tu-haloalkyl group at nitrogen in different azetidin-2-ones enabled the synthesis of pharmaceuticaly relevant piperazine, morpholine, and 1,4-diazepane annulated /3-lactams upon reductive ring closure <2006JOC7083>. 

One approach utilizes Katritzky s route to tertiary amines to construct the benzhydrylpiperazine (Scheme 7) [42]. This method involves addition of an aryl Grignard reagent to a masked iminium, an adduct formed from the piperazine, an appropriate benzaldehyde, and benzotriazole. In solution, this adduct is in equilibrium with an iminium ion formed by elimination of the benzotriazole, and it is likely that the Grignard reagent adds to this species. Assuming that the iminium ion is the reactive entity, the stereoselectivity appears to rely on two separate events 1) preferential formation of one of the... 

Some very clever syntheses of pyrazines were reported. Tandem Mn02-mediated oxidation followed by in situ trapping with aromatic or aliphatic 1,2-diamines was shown to give rise to quinoxalines, dihydropyrazines, pyrazines, and piperazines without the need to isolate highly reactive 1,2-dicarbonyl intermediates <03CC2286>. A new intramolecular cyclization route to highly substituted chiral 6,7-dihydro-5//-imidazo[l,5-a]pyrazin-8-ones like 157 from Meldrum s acid was developed <030L3907>, and 5-chloropyrido[3,4-6]pyrazines were prepared from 1,2-dicarbonyl compounds and 2-chloro-3,4-diaminopyridine <03H(60)925>. A synthesis of... 

A comprehensive group of polyesters contains hindered piperidine or piperazine (HALS) moieties. Most of these stabilizers were prepared under transesterification conditions, using tetraalkyl titanates, lithium amide or sodium alkoxide as catalysts. Terminal HALS group was built in under these conditions into a polyether-polyester. Polyester 145 was prepared from a reactive diester derived from piperazinedione and fljco-alkylidenediol (n = 2-15) [188], A similar system contains 2,2,6,6-tetramethylpiperidine moiety [189]. 

The more reactive 2-chloro-3-fluoropyridine (89) is aminated readily by piperazine in boiling -butanol to give —60% of 90 (83JMC16%). The presence of a polar cyano group allows the 2-chloro-3-cyanopyridine (72) to be aminated already at I00°C by methylamine to 2-methylamino-3-cyanopyridine (91) in 63% yield (85SC10I3). An additional 6-chloro group, as in 92, leads, upon amination with ammonia to a mixture of the corresponding amino compounds 93 and 94. With the weakly basic aniline in the... 

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