Piperazine, resin-bound

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. 

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... 

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). 

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 ... 

A solution of 4-nitrophenyl chloroformate (43.0 g, 231 mmol, 5.5 equiv.) in DCM (200 mL) was added dropwise over a period of 0.5 h to a stirred suspension of Wang resin (45.0 g, 42.3 mmol) in DCM (600 mL) and pyridine (52.0 mL, 644 mmol, 15 equiv.). After completion of the addition, the mixture was stirred at room temperature for 3 h, and then filtered, lire resin was washed with DCM (5 x 300 mL) and then added portionwise to a stirred solution of piperazine (38.2 g, 444 mmol. 11 equiv.) in DMT1 (600 mL.). which led to an increase in the tempera-hue of the mixture and a color change to yellow-orange. The resulting mixture was shaken at room temperature for 13 h, then liltered, and the resin was extensively ashed w itli DMF. DCM, methanol, and finally with further DCM. After drying in aii, about 15 g of resin-bound pipera/ine was obtained. 

The 4500 MicroKans containing resin bound amines 8 were placed into a 12-liter three-necked round-bottom flask fitted with an overhead stirrer. Dimethylformamide (4.5 liters) was added to swell the resin in the MicroKans. l-Alloc-4-fmoc-piperazine-2-carboxylic acid scaffold 6 (78.6 g, 180.0 mmol) was dissolved into DMF (500 ml) and added to the MicroKans. HBTU (68.3 g, 180.0 mmol) and DIEA (62.7 ml, 360.0 mmol) were then added sequentially. The reaction was stirred at RT for 6.5 h. The solution was drained and the MicroKans were washed with DMF, DCM, and Et20. The MicroKans were dried overnight with a stream of nitrogen gas. 

An efficient, practical solid-phase synthesis of a variety of bis-hetero-cyclic compounds was developed starting from resin-bound orthogonally protected lysine (Fig. 10). Tetraamines 36 were synthesized by exhaustive reduction of resin-bound tetraamides 35. Cyclization with different commercially available bifunctional reagents such as cyanogen bromide, thio-carbonyldiimidazole, carbonyldiimidazole, and oxalyldiimidazole yielded the corresponding bis-heterocyclic compounds bis-cyclic guanidines 37,39 bis-cyclic thioureas 38, bis-cyclic ureas 39, and bis-diketopiperazines 40, respectively.40 Reduction of compounds 40 led to bis-piperazines 41. 

Another approach to the solid phase synthesis of thiazoles involves an interesting C-sulfanylation step. The starting material for this synthesis is a resin bound piperazine 55 which is converted into a thiourea and then treated with an a-bromoketone to give the thiazole 56. Treatment of 56 with either thiols or disulfides and iodine or sulfonyl chlorides with iodine and triphenylphosphine afforded 5-sulfanylthiazoles 57, which could be obtained in high yields and purity after cleavage from the resin <02EJOC2953>. 

In the laboratory of A. Golebiowski, the high throughput synthesis of diketopiperazines was accomplished. These compounds can serve as 3-turn mimetics. The key step in this approach was a Petasis boronic acld-Mannich reaction between the Merrifield resin-bound piperazine-2-carboxylic acid, glyoxylic acid, and a wide range of commercially available boronic acids to provide a 1 1 mixture of the products. A specific example is shown below. 

In addition to the linkers mentioned above, the chlorotrityl linker commonly applied for the binding of carboxylic acids can also be used for the attachment of secondary amines [37]. An example is the binding of piperazine as the amine component in a Mannich reaction on a solid support (Scheme 16). Reaction of an aldehyde with the resin-bound amine, followed by addition of acetyhde, led to solid-phase-bound intermediates of type 33, from which the final compounds 34 were obtained by acid-mediated cleavage. 

Based on an aminoalkylurethane linker attached to the Wang resin 155, Zaragoza et al. developed a solid-phase synthesis of 1,2,3-triazoles. Thus, as shown in Scheme 4.1.30, Wang resin 84 was primarily treated with 4-nitrophenyl chloroformate 153 in the presence of pyridine to give 154 and then reacted with piperazine in DMF to produce 155. Subsequent reaction with a freshly prepared solution of 3-oxobutyric acid phenyl ester afforded resin-bound 3-oxobutyryl piperazine 156. In the presence of triethylorthoformate, the condensation of 156 with primary aliphatic amines readily produced the corresponding 3-amino-2-butenoic acid amides attached to the solid support (157). 

Thus, treatment of the resin bound (cyanoacetyl)piperazine 160 with aliphatic or aromatic isothiocyanates in the presence of DBU, followed by S-alkylation with a-haloketones under slightly acidic or neutral conditions resulted in the formation of the intermediates 161 and 162 (which one being the predominant form was determined by the electronic properties of the substituents R -R ). The treatment of these intermediates 161/162 with DBU in DMF following acidolytic cleavage of the resin with TFA yielded 3-aminothiophene derivatives 163 as trifluoroacetates. This synthetic sequence towards 163 encountered however some limitations. For instance, complex mixtures of products were obtained in those cases, where strongly electron-donating isothiocyanates or a-haloketones were used, and in general, no thiophenes resulted from aliphatic haloketones, except for 3-bromo-l,l,l-trifluoro-2-propanone. 

The first example of iron-activated nucleophilic aromatic substitution on solid phase has been presented by Ruhland et al. [141], who attached [(cyclopentadienyl)-benzene Fe(II)] PF6 to polymer-bound piperazine (Scheme 55). The complex 68 was subjected to a variety of nucleophiles using different protocols. The decomplexation was achieved by irradiation in the presence of phenanthroline, and in the final step the resin-bound products were cleaved with methyl chloroformate to give corresponding carbamates in good yields. 

Quinazolines are of great interest in the pharmaceutical industry as protein tyrosine kinase inhibitors. Dener et al 8 described a synthesis starting from 2-methoxybenzaldehyde, Wang, or Rink resins. With the aldehyde resin reductive aminations were undertaken to yield polymer-bound secondary amines (Fig. 7). The latter were subjected to 2,4-dichloro-6,7-dimethoxyquinazoline to give the 4-amino-substituted derivatives. These were then allowed to react with primary or secondary amines at 135-140° in the presence of DBU in DMA. As a result of a detailed scope and limitation study, Dener et al,28 note that some bifunctional amines, such as piperazine, give to some extent dimeric derivatives. 

Representative Reaction with Piperazine Bound to Polymeric Supports (Fig. 9)31. Piperazin-l-yl methyl polystyrene resin 51a (24 g, 24.2 mmol), 776-l,2-dichlorobenzene-i75-cyclopentadienyl iron(II) hexafluorophosphate (53) (25 g, 69.6 mmol), and potassium carbonate (13.4 g, 97 mmol) are suspended in dry THF (400 ml) at RT. (Caution Exothermic reaction ) The reaction mixture is agitated overnight. Resin 54 is washed with dry THF (2 x 100 ml), CH2C12 (3 x 100 ml), MeOH (2 x 100 ml), and CH2C12 (3 x 100 ml), and then dried in vacuo at 40° to afford a red resin. 

Release of compounds from polymer-bound carbamates has not to be performed via nucleophilic attack but can also be induced by the addition of acids like, for example, TFA in various concentrations. The released target compounds are either primary or secondary amines. The synthesis described in Scheme 34 has been recently published by DoUe et al. [183]. Synthesis of piperazines 227 has been conducted on a or-methylbenzyl resin 223 that has been activated with 4-NPCF and that has been fmther reacted with diethanolamine 224. After mesylation of the two resulting terminal hydroxy groups, reaction with a primary amine 226 and base gave immobilized piper-... 

---