Piperazine catalysis

Kumar K, Michalik D, Garcia Castro I, Tillack A, Zapf A, Arlt M, Heinrich T, Bottcher H, Beller M (2004) Biologically active compounds through catalysis efficient synthesis of N-(heteroarylcarbonyl)-N -(arylalkyl)piperazines. Chem Eur J 10 746-757... 

In contrast, liquidiliquid phase-transfer catalysis is virtually ineffective for the conversion of a-bromoacetamides into aziridones (a-lactams). Maximum yields of only 17-23% have been reported [31, 32], using tetra-n-butylammonium hydrogen sulphate or benzyltriethylammonium bromide over a reaction time of 4-6 days. It is significant that a solidiliquid two-phase system, using solid potassium hydroxide in the presence of 18-crown-6 produces the aziridones in 50-94% yield [33], but there are no reports of the corresponding quaternary ammonium ion catalysed reaction. Under the liquidiliquid two-phase conditions, the major product of the reaction is the piperazine-2,5-dione, resulting from dimerization of the bromoacetamide [34, 38]. However, only moderate yields are isolated and a polymer-supported catalyst appears to provide the best results [34, 38], Significant side reactions result from nucleophilic displacement by the aqueous base to produce hydroxyamides and ethers. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

The efficiency of the catalysis would also depend on the binding of the substrate to the piperazine-2,5-dione by means of weak forces. Imanishi and his group (85BCJ497) have sought to achieve this by means of hydrophobic interactions. They have chosen as substrates p-nitrophenyl esters of long-chain fatty acids the hydrocarbon chain would enter into... 

Preparation of the C-labelled compound 65 was accomplished in a manner analogous to Scheme 14. Friedel-Crafts acylation of 44 was conducted with [2- C]-chloroacetyl chloride under aluminum trichloride catalysis to give the radiolabelled intermediate 64 (48 mCi/mmol). The carbonyl group of 64 was reduced with triethylsilane and the resulting alkyl chloride was reacted with piperazine 40 to provide C-labelled ziprasidone (65). The HCI salt of 65 was formed resulting m a final compound with a specific activity of 9.6 mCi/mmol. 

As in the case of dipeptide esters in solution, the rate of piperazine-2,5-dione formation in SPPS strongly depends on steric and chiral features of the original dipeptide structure.11501 The rate of the cyclization increases upon catalysis by weak carboxylic acids.11761 However, it was also reported that piperazine-2,5-diones are formed under basic conditions, e.g. removal of the Fmoc protecting group. Formation of piperazine-2,5-diones is generally overcome by... 

Clarke recently published the first microwave-accelerated Hiyama coupling [163,164]. It was noted that the availability and nontoxic attributes of the organosilicon reactants make them very attractive in synthesis, but their low nucleophilicity limits their potential. Microwave heating allowed aryl bromides and activated aryl chlorides to react under palladium catalysis using an electron-rich N-methyl piperazine/cyclohexyl phosphine ligand (Scheme 75). A vinylation reaction with vinyltrimethoxysilane was also reported [164],... 

Lopez-Rodriguez and co-workers prepared a number of serotonin 5-HTia receptor ligands using palladium catalysis [133]. The Spanish group used both DPPP- and BINAP-based systems to couple bromine-substituted benzimidazoles with piperazines. For example, the reaction of the protected heterocycle below with M-methylpiperazine proceeds in excellent yield, Eq. (166). 

Figure 5.10 Interactions of isofagomine-type and deox5mojirimycin-type inhibitors with retaining glucosidases. The piperazine can make either type of interaction and inhibits both a- and P-glucosidases comparably powerfully. The oxazine appears to be unprotonated and oxazine-based inhibitors have inhibition optima close to the optimum for catalysis.

For Suzuki coupling, amine ligands tested to support PdCl2 include polyaniline, 2-(2-pyridyl)-6-isopropylpiperidine, and piperazine The naphthidine 2 actually reduces PdCl2 to Pd(0) nanoparticles and stabilizes such to perform catalysis. ... 

After 3-chloropropylation of 330 (78%) under phase-transfer catalysis conditions compound 328 was prepared by refluxing a mixture of compound 331 with 1 -piperazine ethanol, KI, Na2C03, and MeCOEt for 20h °° (Scheme 12.87). 

We have already seen that p-bromophenol can be joined to an amine with palladium catalysis, so it should be easy to join it to piperazine. However, there is a potential problem of selectivity we want to add this benzene ring just once, and the way to do this is to protect one nitrogen atom by reductive amination with benzaldehyde. The remaining NH group can then be coupled to the aromatic ring and the benzyl group removed by hydrogenation. 

Two general classes are very well known. The first is composed of tertiary amines, of which DABCO, tertiary alkylamines, substituted morpholines, piperazines, guanidines, and substituted hydroxy amines are representative types. A wide range of activities is represented in this class, but stronger catalysts are sometimes needed to promote the reaction of secondary hydroxyl groups with isocyanates. Stronger catalysis is supplied by catalysts of the second class, organotin compounds like dibutyltin dilaurate... 

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