Piperazine resin

McCarthy and co-workers [275] prepared nitrile imines in situ by exposing two hydrazonyl chlorides (210) to basic conditions, and these underwent [2 -i- 3]-cy-cloaddition reaction -with solid-supported-enamines derived from a Merrifield-based piperazine resin and the selected phenylacetaldehyde (209) (Scheme 46). Pyrazoles (212) were then obtained after cleavage from the resin under mildly acidic conditions, the resin functioning as a traceless linker. 

Yi-Yong Ch., Xing-Zhong Y. S)mthesis and properties of l-(2-aminoethyl)piperazine resin used in the sorption of the platinum group and gold ions. Reactive Pol3tmers 1994 23 165-172. 

Traceless cleavage of products from the resin can be achieved through an elimination reaction. Aromatization of the product can be the driving force for the elimination. Piperazine resin-bound enamine reacted regioselectively in a 1,3-dipolar cycloaddition with nitrile imines generated in situ (Scheme 11.16). Elimination of the piperazine linker with highly diluted trifluoroacetic acid gave diverse 1,4-diarylpyrazoles in a traceless manner. 

A series of compounded flame retardants, based on finely divided insoluble ammonium polyphosphate together with char-forming nitrogenous resins, has been developed for thermoplastics (52—58). These compounds are particularly useful as iatumescent flame-retardant additives for polyolefins, ethylene—vinyl acetate, and urethane elastomers (qv). The char-forming resin can be, for example, an ethyleneurea—formaldehyde condensation polymer, a hydroxyethylisocyanurate, or a piperazine—triazine resin. 

Piperazine, I -diethyIcarbamyI-4-methyl-metabolism, 1, 227 Piperazine, N,JV-dimethyI-epoxy resin curative. 1, 406 Piperazine, 2,5-dioxo-occurrence, 3, 187 Piperazine-2,5-dione polymers, 1, 298... 

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

OS 11] [R 36] ]P 10] The feasibility of performing the acylating cleavage of T2-triazene resin (100 mg) in absolute tetrahydrofuran to give piperazine was demonstrated [75] 4 h of processing was required. 

Piperazine linker 77 was treated with propargyltriphenylphosphine bromide to provide a resin-bound Wittig reagent (Scheme 40) [89]. Base treatment followed by aldehyde addition produced a resin-bound 2-amino-butadiene which was implemented in [4 + 2] cycloadditions. Alternatively, treatment with 3% TFA in CH2CI2 released a,(J-unsaturated methylke-tones in high yields. 

The synthesis of azoniaspirocycles can also be carried out on solid support (Scheme 17) <2005JOC9622>. In the following example the resin-bound piperazine-tethered secondary amine 149 underwent an acylation to give amide 150. This was followed by a spontaneous intramolecular displacement of the bromide to yield the trisubstituted azoniaspiroundecane 151. 

To fully use the advantages afforded by multicomponent reaction systems in solid-phase organic synthesis, strategies in which each component is immobilized on the resin must be devised. In this way, individual components can be explored in terms of diversity without the restrictions imposed by immobilization. We have described solid-phase Mannich reactions1 of a resin-bound alkyne (see chapter 5), and we show here that the diversity of products using this chemistry can be enhanced when a different component of the reaction system is immobilized. Specifically, a secondary amine, piperazine, is bound to a resin and then treated with... 

To the Wang resin (100 mg, 0.070 mmol) in a 3-mL polypropylene filtration tube with polyethylene frit was added 1 mL 0.4 N CDI in anhydrous THF (note 1), capped with a yellow polyethylene cap, and shaken at room temperature for 6 h (note 2). The resin was thoroughly washed with CH2C12 (3x1 mL) and THF (3x1 mL) to remove the excess CDI and then treated with 1 mL 0.4 N piperazine in THF at room temperature for 15 h. The resulting resin was washed with DMF (3x1 mL), MeOH (4x1 mL),... 

Wang resin was purchased from Advanced ChemTech (1% DVB, 0.70mmol/g substitution, 100-200 mash, Cat. SA5009). Anhydrous tetrahydrofuran (THF), A/A-dimcthyl-formamide (DMF), methanol, dichloromethane, pyridine, 1,1 -carbonyldiimidazole (CDI), piperazine, homopiperazine, trans-1,4-diaminocyclohexane, 4-(dimethylamino)pyridine (DMAP), succinic anhydride, diglycolic anhydride, 3-methyl-glutaric anhydride, 2-aminophenol, 2-amino-p-cresol, 2-amino-4-tert-butyl phenol, /V-methylmorpholine (NMM), triphenylphosphine, diethyl azodicarboxylate (DEAD), and trifluoroacetic acid (TFA) were purchased from Aldrich Chemical Company, Inc. and used without further purification. PyBOP was purchased from Novabiochem. 

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). 

Peptides that contain amidated Pro or other Af-alkyl amino acids at their C-terminus are less prone to formation of piperazine-2,5-diones in SPPS. Apparently, the use of a benzhy-drylamine-type resin exerts enough steric hindrance to slow down piperazine-2,5-dione formation. In some cases, e.g., the synthesis of peptide amides that have -D-Pro-Pro-NH2 or -Aib-Pro-NH2 sequences, the use of the 4-benzyloxy-4 -4"-dimethoxytrityl amine resin (BDMTA resin, Scheme 34) 187 is recommended. 

In the synthesis of PMRI substance P, the slow, DCC/HOBt-mediated incorporation of the pseudodipeptide suffered from extensive formation of the Leu-Met piperazine-2,5-dione this led to about 20% loss of peptide from the resin. Two cycles of IBTFA-mediated (fourfold molar excess) rearrangement were carried out. The first one-hour cycle was followed by a second overnight cycle. 62 ... 

In the synthesis of PMRI-BPP9a, the incorporation of the pseudotripeptide amide was undertaken to overcome the enhanced generation of Ala-Pro piperazine-2,5-dione (ca. 50%) from the resin-bound Ala-Pro dipeptide. The overall yield of this synthesis was 25% J6 ... 

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