N-arylpiperazine

N-Arylpiperazin-2-ones, N-arylpiperazin-2,5-diones and N-aryl-3,4-dihydro-quinolin-2(lff)-ones have been synthesized via a microwave-enhanced Goldberg reaction [105]. N-arylation reactions with 4-benzylpiperazin-2-one and 4-benzylpiperazin-2,5-dione performed in the microwave (reflux conditions) were tremendously accelerated in comparison with the same transformations performed under classical heating at reflux (Schemes 103 and 104). The phenylation of 3,4-dihydroquinolin-2(lH)-one under microwave irradiation was also faster but less pronounced. 

The N-arylpiperazine fragment shown in Table 12.4 represents an interesting structural motif with an expressed mixed type of receptor-specific activity. Compounds... 

Fig. 12.5 Dopamine D2 agonists having a distinct N-arylpiperazine privileged motif and structurally different peripheral fragments.

Among the most popular privileged structures, historical representatives are arylethylamines (including indolylethylamines), diphenylmethane derivatives, tricyclic psychotropics and sulfonamides. Dihydropyridines [5], benzodiazepines, [2, 5], N-arylpiperazines, biphenyls and pyridazines [6] are more recent contributions. 

N-Arylpiperazines are common substructures of molecules that influence various biological processes and, therefore, the arylation of monoprotected and the single arylation of unprotected piperazines has been studied. As discussed above, the monoarylation of piperazines... 

The initial catalyst systems described above were effective with aryl bromides and a relatively narrow array of amines, although these procedures found utility in the preparation of diaminofluorenes [22], poly(aryleneamines) [23], certain iV-aryl-aza-crown ethers [24], N -arylpiperazines [25], and diaminobenzenes [26] (Fig. 1). These original methods often proved reasonably effective in the coupling of cyclic amines. Presumably, cyclic amines are less challenging substrates for the palladium-catalyzed coupling because the cyclic palladium (II) amide intermediates are less prone to /1-H elimination compared to their acyclic counterparts. 

A series of novel neuroleptic agents derived from alpha-tetralone and N-arylpiperazine has been prepared. 38 Moderate activity in inhibiting amphetamine hypermobility and in producing hypothermia was found, with compound (26) being the most active. Another N-arylpiperazine analog (27) also had neuroleptic activity in antagonizing amphetamine and apomorphine stereotypy and production of catalepsy. 39... 

In this modeL prazosin, terazosin and conq>ound 12 proved devoid of selectivity, t hereas tamsulosin and 5-methylurapidil exhibited limited selectivity. SNAP 5089 showed some selectivity but its potency against the urethral contractile response was imexpectedly very low. On the contrary, the novel N-arylpiperazine derivatives (in particular conq>ounds 4 and 7) were endowed with very high potency and selectivity for the lower urinary tract. Interestingly, a good correlation between the in vitro potency on rabbit urethra and the in vivo potency in inhibiting the urethral contractions induced by La. injection of the agonist in the dog was found (R" = 0.925). 

Piperazines. Twofold (V-alkylation of N-arylamines with carbamates of bis(2-bromoethyl)amine on basic alumina at 150° forms N-arylpiperazines. The N-protecting group is also removed during the reaction. 

N-aryl-2-piperazmones are of great interest as famesyl-transferase inhibitors, and both N-aryl-2-piperazinones and N-aryl-2,5-piperazinediones are synthetic precursors of N-arylpiperazines which are key elements in monoamine receptor-active drugs. Lange et al. enhanced the Goldberg reaction with microwaves for synthesis of N-arylpiperazinones, N-arylpiperazinediones, and N-aryl-3,4-dihydroquinolines [88]. Microwave irradiation greatly accelerates the reaction when NMP is used as solvent. 

FIGURE 16.31 Hexahydr obenz[f]isoindole as a surrogate of the very frequently used ortAo-methoxy-N-arylpiperazine. 

Illescas BM, Martinez-Alvarez R, Femandez-Gadea J, Martin N (2003) Synthesis of water soluble fulleropyrrolidines bearing biologically active arylpiperazines. Tetrahedron 59 6569-6577. 

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. 

Condensations of chloroacetyl chloride (and similar compounds) with substituted ethylenediamines to give 1,4-disubstituted piperazin-2-ones have been described, and a number of 4-alkyl(or aralkyl)- -arylpiperazin-2-ones has been prepared either by catalytic debenzylation or pyrolytic debenzylation (or demethylation) of I,l-dialkyl(or l,l-diaralkyl)-3-oxo-4-arylpiperazinium halides (1609). 3-Ethoxy-carbonylmethylene-6-methylpiperazin-2-one has been synthesized by the reaction of diethyl acetylenedicarboxylate with propylenediamine (1610), and treatment of diethyl fumarate with propylenediamine has been shown to give 3-ethoxycarbonyl-methyl-6-methylpiperazin-2-one, also prepared from the diethyl ester of N- 2 -hydroxyiminopropyl)aspartic acid (84) (1611). 

Overall, the SAR data for the linker between N-4 and the imide group show that this region does not provide any interactions with the receptor and merely acts as a spacer. Some studies point to a role for this region in the modulation of the intrinsic activity of the arylpiperazines and of their selectivity for the 5HT-1A receptor. The general observation is that potency is optimized with a four carbon linker and drops off significantly as the chain is shortened, as exemplified by the phthaloyl derivatives (99) (434). This preference is fur-... 

The comparative ionization constant and lipophilicity, as determined by n-octanol aqueous buffer partition, of 14 1-arylpiperazines were investigated. The ionization constant varied little across the entire series.. 

In the series of N-4 unsubstituted arylpiperazines 7-methoxy-l-naphthylpiperazine is the most potent S-HTja ligand (Kj=1.8 nM). The 2-methoxy analogue is more than 2 decades less active. This result indicates that the N-1 phenyl ring of 1-naphthylpiperazine mimics the pyrrole ring of 5-HT. The benz-fused phenyl ring of 1-naphthylpiperazine corresponds to the phenyl ring of 5-HT... 

Preparation of aromatic amines by the reaction of aryl halides with aliphatic and aromatic amines has been regarded as a difficult reaction. Recently a facile synthetic method for aromatic amines by amination of aryl halides has been discovered, and rapid progress has occurred in the Pd-catalyzed reaction of amines with aryl halides [1]. One simple example which shows the usefulness of the new method is cited here. The commercially important arylpiperazines 1 have been synthesized by intramoleular N-alkylation of aniline derivatives with N,N-di-(2-chloroethyl)amine (2), which is highly carcinogenic. Now the amines 3 can be prepared efficiently by coupling aryl iodides, bromides or chlorides with N-substituted piperidines. This example provides a big contribution to synthetic chemistry by the new Pd-catalyzed efficient preparative method for arylamines, which are usefial in medicinal and material chemistry. 

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