Aryl piperazine

The n-BuLi-catalyzed hydroamination of styrene has been extended to 4-aryl-piperazines [157, 158]. For example, N-(4-fluorophenyl)piperazine reacts with styrene to afford the hydroamination product in 99% yield (Eq. 4.33). 

Indeed, palladium complexes ligated by P(/-Bu)3 catalyzed the formation of aryl piperazines from aryl halides and piperazine in high yields with turnover numbers of 7,000 at 120 °C.56 These complexes also catalyzed the formation of triarylamines from aryl halides and diarylamines with turnovers of 4,000. 

Multiple arylations of polybromobenzenes have been conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzene all react cleanly with A-aryl piperazines using either P(o-tolyl)3 or BINAP-ligated catalysts to form hexamine products [107]. Reactions of other polyhalogenated arenes have also been reported [108]. Competition between aryl bromides and iodides or aryl bromides and chlorides has been investigated for the formation of aryl ethers [109], and presumably similar selectivity is observed for the amination. In this case bro-mo, chloroarenes reacted preferentially at the aryl bromide position. This selectivity results from the faster oxidative addition of aryl bromides and is a common selectivity observed in cross-coupling. Sowa showed complete selectivity for amination of the aryl chloro, bromo, or iodo over aryl-fluoro linkages [110]. This chemistry produces fluoroanilines, whereas the uncatalyzed chemistry typically leads to substitution for fluoride. 

Multiple arylations of polybromobenzenes were also conducted to generate electron-rich arylamines. Tribromotriphenylamine and 1,3,5-tribromobenzene all react cleanly with iV-aryl piperazines using either P(o-tolyl)3 or BINAP-ligated catalysts to form hexamine products [107]. Reactions of other polyhalogenated arenes have also been reported [108]. 

Arylpiperazines can be prepared in a one-pot procedure by ipso SNAr of piperazine derivatives with //6-fluoroarene complexes la, 33a,b,d. Indeed, piperazine derivatives react with fluorobenzene derivatives in DMSO in the presence of K2CO3 at 80 °C to give, after 2.5 h, complexes 3m and 3k (Nu = piperazine) in good yields (Scheme 18) [34]. Piperazine itself may be used as a nucleophile and gives the monoarylpiperazine derivative uncontaminated by any symmetrical N,N -bis(aryl)piperazine, allowing the direct preparation of unprotected compounds. 

Scheme 14 Labelling of a serotonergic receptor ligand from the aryl-piperazine type, derivatized with a Schiff-base type bidentate chelator...

FlunarmneJ (aryl piperazine) Synthetic V-Na+ CH blocker (Cai+ channel blocker) [antinociceptive]... 

A series of compounds, illustrated by (137), was evaluated for in vitro affinity for a, and a,-adrenoceptors by radioligand-binding assays (83). All compounds showed good affinities for the a, adrenoceptor, with K- values in the low nanomolar range. The polymethylene chain spacer between furoylpiperazinylpyradiz-inone and aryl piperazine moieties was shown to influence the affinity and selectivity of these compounds. A gradual increase in affinity for the a, adrenoceptor was observed, by length-... 

Honzl (853) has described the preparation of alkyl(or aryl)-2-oxo-l, 2-dihydropyrazines by reaction of A,A -dialkyl(or aryl)piperazine-2,5-diones with phosphorus pentachloride. For example, 1,4-dicyclohexyl(or diethyl)piperazine-2,5-dione (85, R = cyclohexyl, Et) with phosphorus pentachloride in 1,2-dichloroethane gave... 

This class of compounds includes the BZDs like diazepam (Valium) and oxazepam (Serax), chlordiaz-epoxide (Librium), meprobamate (carbamate derivative), and related compounds, and buspirone (aryl piperazine derivative), which is an anxioselective drug. A miscellaneous group of drugs includes certain antihistaminic and anticholinergic drugs that are difficult to classify (e.g., hydroxyzine and buclizine). 

Aryl Piperazines/Piperidines. There are two major structural classes that confer concomitant 5-HT and Dg antagonism. These are the aiyl piperidines/piperazines and some tricyclic systems. One of the first clinical studies to assess the role of serotonergic blockade in antipsychotic therapy was conducted on se-toperone (129), a 5-HT2/D2 antagonist that showed promising results but was later discontinued because of bioavailability issues (588). 

Luo, G., Mattson, G. K., Bruce, M. A., Wong, H., Murphy, B. J., Longhi, D., Antal-Zimanyi, 1., Poindexter, G. S. Isosteric iV-aryl-piperazine replacements in a series of dihydropyridine NPYl receptor antagonists. Bioorg. Med. Chem. Lett. 2004, 74(24), 5975-5978. 

A similar acid/base washing strategy has been employed for the synthesis of an aryl piperazine hbrary [9]. The synthesis was based on a nucleophilic aromatic substitution of nitro-fluoro aromatic compounds with Boc-piperazine and subsequent Schotten-Baumann acylation with acid chlorides. The products were purified by extractive work-up after each step. 

Of the four conformationally locked analogues related to compound 59, only the isomer 64 with the benzamide and aryl piperazine functionalities both in an equatorial conformation had comparable binding and functional activity. This was consistent with the notion that 59 was bound to the DA D2 receptor in an extended conformation. Energy-minimized structures of 59 and 63-66 were modeled to determine the distance between the aryl centroid of the benzamide and the basic piperazine nitrogen atom (Figure 6). For 64 the distance was 11.8 A and corresponds to the distance observed in the extended conformation of compound 59,... 

N-substituted aryl piperazines on SiOj. (b) Schematic diagram of thin-layer chro-... 

During the discovery of a series of pyrrolidine-2,4-dicarboxylic acid amides, which have 1-(sulfur-containing hetero-aryl)piperazin -yl carbonyl as a substituent oftheL-prolylmoiety,and arenovelandstableDPP-IVinhibitors, the 1,2,4-thiadiazole 244 (Fig. 10) was found to be acceptable in the desired enzyme pocket, but its... 

Nakhla JS, Wolfe JP. A concise asymmetric synthesis of cis-2,6-disubstituted IV-aryl piperazines via Pd-catalyzed carboamination reactions. Org. Lett. 2007 9(17) 3279-3282. 

---