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PubMed1985

Metabolism of phencyclidine. The role of the carbinolamine intermediate in the formation of lactam and amino acid metabolites of nitrogen heterocycles.

The transformation of phencyclidine in a mouse liver microsome preparation to several oxidative metabolites was studied. With use of GLC and HPLC methods with internal standards, phencyclidine and six metabolites were quantitated and the amino acid 12, resulting from the alpha-oxidation of the piperidine ring, was produced in 10-50 times greater amounts than the other metabolites. While most piperidines and pyrrolidines produce an amino acid and a corresponding lactam, it was found that phencyclidine was not converted to the lactam 11.

Amino Acids↗
PubMed1985

Analogues of aminoglutethimide: selective inhibition of aromatase.

In exploring further the structural features that influence the relative efficacy of analogues of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] as inhibitors of the cholesterol side-chain cleavage enzyme system desmolase and the estrogen forming system aromatase, analogues have been synthesized in which the aminophenyl substituent is replaced by pyridyl or substituted pyridyl. The 4-pyridyl analogue 5 [3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a strong competitive inhibitor of aromatase (Ki = 1.1 microM; value for 1, 0.60 microM), which exhibits a type II difference spectrum (Ks = 0.28 microM; value for 1, 0.13 microM) but is noninhibitory toward desmolase. The 2- and 3-pyridyl analogues (3 and 4) inhibit neither enzyme system. 1-Amino-3-ethyl-3-phenylpiperidine-2,6-dione (2) is a strong and selective inhibitor of desmolase but the 4-pyridyl analogue 10 [1-amino-3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a weak inhibitor of desmolase and aromatase. Analogues of 5 having a less basic aromatic substituent, namely, the N-oxide 11 and the 2,3,5,6-tetrafluoro derivative 13, were also prepared. The latter is a weak inhibitor of aromatase and the former inhibits neither enzyme system.

Aminoglutethimide↗
PubMed2001

5-(Tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based potent and selective CCK(1) receptor antagonists: structure-activity relationship studies on the central 1,3-dioxoperhydropyrido[1,2-c]pyrimidine scaffold.

To further define the pharmacophore of the potent and selective 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK(1) receptor antagonists the electronic and topographic properties of the central 1,3-dioxoperhydro-pyrido[1,2-c]pyrimidine scaffold have been modified. With this aim, the 1- and 3-oxo groups have been replaced by the thioxo- and deoxi-analogues, and the fused piperidine ring has been contracted to the corresponding pyrrolidine moiety. The results of the evaluation of the new analogues as CCK receptor ligands, in rat pancreas and cerebral cortex preparations, showed that, whereas replacement of oxygen with sulfur is allowed, reduction of the 1- or 3-oxo groups or the contraction of the fused piperidine ring lead to the complete loss of binding affinity at CCK(1) receptors. The thioxo-analogues 5a, 8a, 12a, and 12b showed functional CCK(1) antagonist activity, inhibiting the CCK-8-stimulated amylase release from pancreatic acinar cells. The 1-thioxo analogue 5a, with subnanomolar affinity (IC(50) = 0.09 x 10(-9) M), was found to be the most potent and selective compound within the family of 5-(tryptophyl)amino-1,3-dioxoperhydropyrido[1,2-c]pyrimidine-based CCK(1) antagonists.

Animals↗
PubMed2002

Novel soluble cationic trans-diaminedichloroplatinum(II) complexes that are active against cisplatin resistant ovarian cancer cell lines.

Positively charged, water soluble cis/trans-[PtCl(2)(piperazine)(Am1)] (where Am1 = NH(3), n-butylamine, isopropylamine, 4-picoline, piperidine, and piperazine) has significant cytotoxic activity against cisplatin resistant ovarian cancer cells. The charged complexes are taken up by cancer cells much more rapidly than cisplatin and bind to cellular DNA and to calf thymus DNA much faster than cisplatin or transplatin. The platinum-piperazine complexes bind proteins (ubiquitin and myoglobin) very slowly as compared to cisplatin and to their neutral piperidine analogues. Altogether, the results reported here suggest that combination of positively charged ligands with a trans-Pt(II)Cl(2) center may lead to the discovery of platinum complexes that are able to circumvent cisplatin resistance.

Antineoplastic Agents↗
PubMed2002

Benzimidazole derivatives. 3. 3D-QSAR/CoMFA model and computational simulation for the recognition of 5-HT(4) receptor antagonists.

A three-dimensional quantitative structure-affinity relationship study (3D-QSAR), using the comparative molecular field analysis (CoMFA) method, and subsequent computational simulation of ligand recognition have been successfully applied to explain the binding affinities for the 5-HT(4) receptor (5-HT(4)R) of a series of benzimidazole-4-carboxamides and carboxylates derivatives 1-24. The K(i) values of these compounds are in the range from 0.11 to 10 000 nM. The derived 3D-QSAR model shows high predictive ability (q(2) = 0.789 and r(2) = 0.997). Steric (contribution of 43.5%) and electrostatic (50.3%) fields and solvation energy (6.1%) of this novel class of 5-HT(4)R antagonists are relevant descriptors for structure-activity relationships. Computational simulation of the complexes between the benzimidazole-4-carboxamide UCM-21195 (5) and the carboxylate UCM-26995 (21) and a 3D model of the transmembrane domain of the 5-HT(4)R, constructed using the reported crystal structure of rhodopsin, have allowed us to define the molecular details of the ligand-receptor interaction that includes (i) the ionic interaction between the NH group of the protonated piperidine of the ligand and the carboxylate group of Asp(3.32), (ii) the hydrogen bond between the carbonyl oxygen of the ligand and the hydroxyl group of Ser(5.43), (iii) the hydrogen bond between the NH group of Asn(6.55) and the aromatic ring of carboxamides or the ether oxygen of carboxylates, (iv) the interaction of the electron-rich clouds of the aromatic ring of Phe(6.51) and the electron-poor hydrogens of the carbon atoms adjacent to the protonated piperidine nitrogen of the ligand, and (v) the pi-sigma stacking interaction between the benzimidazole system of the ligand and the benzene ring of Tyr(5.38). Moreover, the noticeable increase in potency at the 5-HT(4)R sites, by the introduction of a chloro or bromo atom at the 6-position of the aromatic ring, is attributed to the additional electrostatic and van der Waals interaction of the halogen atom in a small cavity located between transmembrane domains 5 and 6.

Animals↗
PubMed2004

2-aminopyridines as highly selective inducible nitric oxide synthase inhibitors. Differential binding modes dependent on nitrogen substitution.

4-Methylaminopyridine (4-MAP) (5) is a potent but nonselective nitric oxide synthase (NOS) inhibitor. While simple N-methylation in this series results in poor activity, more elaborate N-substitution such as with 4-piperidine carbamate or amide results in potent and selective inducible NOS inhibition. Evidently, a flipping of the pyridine ring between these new inhibitors allows the piperidine to interact with different residues and confer excellent selectivity.

Aminopyridines↗
PubMed2004

Design and synthesis of novel biologically active thrombin receptor non-peptide mimetics based on the pharmacophoric cluster Phe/Arg/NH2 of the Ser42-Phe-Leu-Leu-Arg46 motif sequence: platelet aggregation and relaxant activities.

The identification of the thrombin receptor has promoted the interest for the development of new therapeutic agents capable of selectively inhibiting unwanted biological effects of thrombin on various cell types. In this study we have designed and synthesized two series of new thrombin receptor antagonists based on the thrombin receptor motif sequence S42FLLR46, one possessing two (Phe/Arg) pharmacophoric groups and the other possessing three (Phe/Arg/NH2). N-(6-Guanidohexanoyl)-N'-(phenylacetyl)piperazine (1), N-(phenylacetyl)-4-(6-guanidohexanoylamidomethyl)piperidine (2), and N-(phenylacetyl)-3-(6-guanidohexanoylamido)pyrrolidine (3) (group A) carry the two pharmacophoric side chains of Phe and Arg residues incorporated on three different templates (piperazine, 4-aminomethylpiperidine, and 3-aminopyrrolidine). Compounds with three pharmacophoric groups (group B) were built similarly to group A using the same templates with the addition of an extra methylamino group leading to (S)-N-(6-guanidohexanoyl)-N'-(2-amino-3-phenylpropionyl)piperazine (4), (S)-N-(2-amino-3-phenylpropionyl)-4-(6-guanidohexanoylamidomethyl)piperidine (5), and (S)-N-(2-amino-3-phenylpropionyl)-3-(6-guanidohexanoylamido)pyrrolidine (6). Compounds were able to inhibit thrombin-induced human platelet activation even at low concentrations. In particular, among compounds in group A, compound 3 was found to be the most powerful thrombin receptor activation inhibitor, showing an IC50 of approximately 0.11 mM on platelet aggregation assay. Among compounds in group B, compound 4 was the most powerful to inhibit thrombin-induced platelet aggregation, showing an IC50 of approximately 0.09 mM. All compounds were also found to act as agonists in the rat aorta relaxation assay. Interestingly, the order of potency of these compounds as agonists of the endothelial thrombin receptor was the inverse of the order of potency of the same compounds as antagonists of the platelet thrombin receptor. Such compounds that are causing vasodilation while simultaneously inhibiting platelet aggregation would be very useful in preventing the installation of atherosclerotic lesions and deserve further investigation as potential drugs for treating cardiovascular diseases. The above findings coupled with computational analysis molecular dynamics experiments support also our hypothesis that a cluster of phenyl, guanidino, and amino groups is responsible for thrombin receptor triggering and activation.

Amino Acid Motifs↗
PubMed2006

Synthesis and evaluation of novel macrocyclic and acyclic ligands as contrast enhancement agents for magnetic resonance imaging.

Novel chelates PIP-DTPA, AZEP-DTPA, NETA, NPTA, and PIP-DOTA were synthesized and evaluated as potential magnetic resonance imaging (MRI) contrast enhancement agents. The T1 and T2 relaxivities of their corresponding Gd(III) complexes are reported. At clinically relevant field strengths, the relaxivities of the complexes are comparable to that of the clinically used contrast agents Gd(DTPA) and Gd(DOTA). The serum stability of the 153Gd-labeled complexes, Gd(PIP-DTPA), Gd(AZEP-DTPA), Gd(PIP-DOTA), Gd(NETA), and Gd(NPTA), was assessed by measuring the release of 153Gd from the complexes. 153Gd(NETA), 153Gd(PIP-DTPA), and 153Gd(PIP-DOTA) were found to be stable in human serum for up to 14 days without any measurable loss of radioactivity. Significant release of 153Gd was observed with the 153Gd(III) radiolabled NPTA. In vivo biodistribution of the153Gd-labeled complexes was performed to evaluate their in vivo stability. While Gd(AZEP-DTPA) and Gd(NPTA) were found to be unstable in vivo, Gd(NETA), Gd(PIP-DTPA), and Gd(PIP-DOTA) were excreted without dissociation. These results suggest that the Gd(III) complexes of the novel chelates NETA, PIP-DTPA, and PIP-DOTA possess potential as MRI contrast enhancement agents. In particular, the piperidine backboned chelates Gd(PIP-DTPA) and Gd(PIP-DOTA) displayed reduced kidney retention as compared to the nonspecific MRI contrast agent Gd(DOTA) at all time points, although the observed effects were relatively small at 0.5 h postinjection. Incorporation of the lipophilic piperidine ring appears to confer a moderate effect on the liver uptake of these two chelates.

Animals↗
PubMed1996

7-[3-(1-piperidinyl)propoxy]chromenones as potential atypical antipsychotics.

Compound 1 (1-benzyl-3-methyl-4-[4-(4-fluorophenyl)-4-oxobutyl]piperazine), a synthetic intermediate identified as a potential atypical antipsychotic, was selected as the starting point for pharmacological improvement. From 1, sequential structural variations were conducted in order to improve its potency and oral bioavailability. These variations included a series of piperazine, ethanediamine, and piperidine derivatives. The piperidine series afforded some orally potent compounds in the inhibition of apomorphine-induced climbing and hyperactivity in mice, which are regarded as behavioral models predictive of antipsychotic efficacy. Further optimization of these structures led to the highly potent 7-[3-(1-piperidinyl)propoxy]chromenones. Inhibition of stereotypies and induction of catalepsy in rats at doses substantially higher than required for inhibition of climbing suggest an atypical antipsychotic profile, which is assumed to predict a reduced induction of extrapyramidal side effects in humans.

Administration, Oral↗
PubMed1996

Synthesis and bioactivity of novel bis(heteroaryl)piperazine (BHAP) reverse transcriptase inhibitors: structure-activity relationships and increased metabolic stability of novel substituted pyridine analogs.

The major route of metabolism of the bis(heteroaryl)piperazine (BHAP) class of reverse transcriptase inhibitors (RTIs), atevirdine and delavirdine, is via oxidative N-dealkylation of the 3-ethyl- or 3-isopropylamino substituent on the pyridine ring. This metabolic pathway is also the predominant mode of metabolism of (alkylamino)piperidine BHAP analogs (AAP-BHAPs), compounds wherein a 4-(alkylamino)piperidine replaces the piperazine ring of the BHAPs. The novel AAP-BHAPs possess the ability to inhibit non-nucleoside reverse transcriptase inhibitor (NNRTI) resistant recombinant HIV-1 RT and NNRTI resistant variants of HIV-1. This report describes an approach to preventing this degradation which involves the replacement of the 3-ethyl- or 3-isopropylamino substituent with either a 3-tert-butylamino substituent or a 3-alkoxy substituent. The synthesis, bioactivity and metabolic stability of these analogs is described. The majority of analogs retain inhibitory activities in enzyme and cell culture assays. In general, a 3-ethoxy or 3-isopropoxy substituent on the pyridine ring, as in compounds 10, 20, or 21, resulted in enhanced stabilities. The 3-tert-butylamino substituent was somewhat beneficial in the AAP-BHAP series of analogs, but did not exert a significant effect in the BHAP series. Lastly, the nature of the indole substitution sometimes plays a significant role in metabolic stability, particularly in the BHAP series of analogs.

Anti-HIV Agents↗
PubMed1997

New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and antagonists for 5-HT4 receptors.

A number of benzoates derived from 4-amino-5-chloro-2-methoxybenzoic acid and substituted 1-piperidineethanol were synthesized and found to be potent 5-HT4 receptor agonists in the electrically-stimulated myenteric plexus and longitudinal muscle of the guinea pig ileum and the rat esophagus muscle. Monosubstitution of the piperidine ring with Me, OH, NH-Ac, or CONH2 groups gave compounds equipotent to 7a (ML 10302), a 5-HT4 receptor agonist previously reported to have nanomolar affinity. 7a,k were as potent as serotonin (5-HT) but had maximal responses which were only 60-80% of that of 5-HT, suggesting a partial agonist profile for these compounds. Binding assays were performed with [3H]GR 113808 in the rat striatum, and several of these compounds were found to have nanomolar affinity for 5-HT4 receptors (7a, Ki = 1.07 +/- 0.5 nM; 7k, Ki = 1.0 +/- 0.3 nM). The introduction of two methyl groups on the piperidine ring brought about a dramatic change in the pharmacological profile of 2-[(cis- and trans-3,5-dimethylpiperidinyl)ethyl]-4-amino-5-chloro-2- methoxybenzoate, 7g,h. 7g (Ki = 0.26 +/- 0.06 nM) inhibited the relaxant action of 5-HT in the rat esophagus muscle with a pA2 value of 8.6. The advantage of the ester function was demonstrated by comparing the activity of several such compounds at 5-HT4 receptors with those of the corresponding amidic derivatives. This difference was less marked when the basic moiety was sterically constrained as in the quinuclidine and tropane moieties. Structural analyses of 7a,g were performed by determining their X-ray crystal structures and by molecular modeling (SYBYL). A relatively limited number of minimum energy conformers was found for both compounds. They were characterized by the cis folded conformation of the ethyl chain and by the orientation of the lone pair of the nitrogen atom pointing out of the molecule as seen in conformationally-constrained benzamides such as zacopride and renzapride. A hypothetical model for the 5-HT4 receptor with two sites for the binding of agonist and antagonist molecules was proposed.

Animals↗
PubMed2000

Neighboring group participation of the indole nucleus: An unusual DAST-mediated rearrangement reaction

A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of (3S, 4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S, 4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of the reaction.

Journal Article↗
PubMed2001

An improved and easy method for the preparation of 2,2-disubstituted 1-nitroalkenes.

Reactions of ketones 1, nitromethane 2, and catalytic amount of piperidine 3 in the presence of mercaptan 6 generate beta-nitroalkyl sulfides 7-9. At 0 degrees C and by the use of dichloromethane as solvent, beta-nitroalkyl sulfides 7-9 can be oxidized by m-chloroperoxybenzoic acid (m-CPBA) 10 to generate beta-nitroalkyl sulfoxides 11-13 and undergo elimination in carbon tetrachloride solution to produce medium to high yield of 2,2-disubstituted 1-nitroalkenes 5. The irreversibility of the synthetic mechanism not only can overcome the reversibility of the Henry reaction in the synthesis of 2,2-disubstituted 1-nitroalkenes 5 but also can generate the major products "exo-nitro olefins"5c-e when cyclic ketones 1c-e were used. Under similar conditions, medium to high yield of 5-substituted-2-nitromethyl-2-phenylthioadamantane 17 also can be prepared from the reaction of 5-substituted-2-adamantanones 15, nitromethane 2, piperidine 3, thiophenol 6a. The intermediate17 can be oxidized by m-CPBA 10 in dichloromethane solution and then undergo elimination at room temperature or can be dissolved in solvent, coated on silica gel, and then heated at 90-100 degrees C to generate 5-substituted-2-nitromethyleneadamantane 16.

Journal Article↗
PubMed2002

Kinetic and mechanistic investigation of the aminolysis of 3-methoxyphenyl 3-nitrophenyl thionocarbonate, 3-chlorophenyl 3-nitrophenyl thionocarbonate, and bis(3-nitrophenyl) thionocarbonate.

The reactions of the title thionocarbonates (6, 7, and 8, respectively) with a series of secondary alicyclic amines are subjected to a kinetic investigation in 44 wt % ethanol-water, 25.0 degrees C, ionic strength 0.2 M (KCl). Under excess amine, pseudo-first-order rate coefficients (k(obsd)) are obtained for all reactions. Reactions of substrates 6 and 7 with piperidine and of thionocarbonate 8 with the same amine and piperazine, 1-(2-hydroxyethyl)piperazine, and morpholine show linear k(obsd) vs [amine] plots, with slopes (k(1)) independent of pH. On the other hand, these plots are nonlinear upward for the reactions of substrates 6 and 7 with all the amines, except piperidine, and also for the reactions of compound 8 with 1-formylpiperazine and piperazinium ion. For all these reactions a mechanistic scheme is proposed with the formation of a zwitterionic tetrahedral intermediate (T(+/-)), which can transfer a proton to an amine to give an anionic intermediate (T(-)). Rate and equilibrium microcoefficients of this scheme, k(1), k(-)(1), K(1) (= k(1)/k(-)(1)), and k(2), are obtained by fitting the nonlinear plots through an equation derived from the scheme. The Brönsted-type plots for k(1) are linear with slopes beta(1) = 0.19, 0.21, and 0.26 for the aminolysis of 6, 7, and 8, respectively. This is consistent with the hypothesis that the formation of T(+/-) (k(1) step) is the rate-determining step. The k(1) values for these reactions follow the sequence 8 > 7 > 6, consistent with the sequence of the electron-withdrawing effects from the substituents on the "nonleaving" group of the substrates. The k(1) values for the aminolysis of 6, 7, and 8 are smaller than those for the same aminolysis of 3-methoxyphenyl, 3-chlorophenyl, and 4-cyanophenyl 4-nitrophenyl thionocarbonates (2, 3, and 4, respectively). The k(2) values (expulsion of the nucleofuge from T(+/-)) increase as the electron withdrawal from the nonleaving group increases. These values are smaller for the aminolysis of 6, 7, and 8 compared to those for the same aminolysis of 2, 3, and 4, respectively.

Journal Article↗
PubMed2003

Stereospecific rearrangements during the synthesis of pyrrolidines and related heterocycles from cyclizations of amino alcohols with vinyl Sulfones.

Conjugate additions of amino alcohols derived from alpha-amino acids to vinyl sulfones, followed by N-benzylation, chlorination, and intramolecular alkylation, provide a convenient route to substituted pyrrolidines. The process is accompanied by the stereospecific rearrangement of substituents from the alpha-position of the amine to the beta-position of the product and takes place via the corresponding aziridinium ion intermediates. Another type of rearrangement was observed during the reaction of (2-piperidine)methanol or 2-(2-piperidine)ethanol with phenyl trans-1-propenyl sulfone, in which the methyl group appears to migrate from the beta- to the alpha-position of the sulfone moiety. This process involves the isomerization of phenyl trans-1-propenyl sulfone to phenyl 2-propenyl sulfone by the addition-elimination of catalytic benzenesulfinate anion to the former vinyl sulfone, followed by conjugate addition of the amino group to the latter sulfone. Chlorination and intramolecular alkylation then afford the corresponding rearranged indolizidine and quinolizidine derivatives, respectively.

Alkylation↗
PubMed2004

Organolanthanide-catalyzed intramolecular hydroamination/cyclization/bicyclization of sterically encumbered substrates. Scope, selectivity, and catalyst thermal stability for amine-tethered unactivated 1,2-disubstituted alkenes.

This paper reports the organolanthanide-catalyzed intramolecular hydroamination/cyclization of amine-tethered unactivated 1,2-disubstituted alkenes to afford the corresponding mono- and disubstituted pyrrolidines and piperidines using coordinatively unsaturated complexes of the type (eta(5)-Me(5)C(5))(2)LnCH(TMS)(2) (Ln = La, Sm), [Me(2)Si(eta(5)-Me(4)C(5))(2)]SmCH(TMS)(2), and [Me(2)Si(eta(5)-Me(4)C(5))((t)BuN)]LnE(TMS)(2) (Ln = Sm, Y, Yb, Lu; E = N, CH) as precatalysts. [Me(2)Si(eta(5)-Me(4)C(5))((t)BuN)]LnE(TMS)(2) mediates intramolecular hydroamination/cyclization of sterically demanding amino-olefins to afford disubstituted pyrrolidines in high diastereoselectivity (trans/cis = 16/1) and good to excellent yield. In addition, chiral C(1)-symmetric organolanthanide catalysts of the type [Me(2)Si(OHF)(CpR*)]LnN(TMS)(2) (OHF = eta(5)-octahydrofluorenyl; Cp = eta(5)-C(5)H(3); R* = (-)-menthyl; Ln = Sm, Y), and [Me(2)Si(eta(5)-Me(4)C(5))(CpR*)]SmN(TMS)(2) (Cp = eta(5)-H(3)C(5); R* = (-)-menthyl) mediate asymmetric intramolecular hydroamination/cyclization of amines bearing internal olefins and afford chiral 2-substituted piperidine and pyrrolidine in enantioselectivities as high as 84:16 er at 60 degrees C. The substrate of the structure NH(2)CH(2)CMe(2)CH(2)CH=CH(CH(2))(2)CH=CH(2) is regiospecifically bicyclized by [Me(2)Si(eta(5)-Me(4)C(5))((t)BuN)]LnE(TMS)(2) to the corresponding indolizidine skeleton in good yield and high diastereoselectivity. Thermolysis of (eta(5)-Me(5)C(5))(2)LaCH(TMS)(2) in cyclohexane-d(12) at 120 degrees C rapidly releases CH(2)(SiMe(3))(2) and leads to possible formation of fulvene (eta(6)-Me(4)C(5)CH(2)-) species. The thermolysis product readily reverts to active catalysts upon protonolysis by substrate and exhibits the same catalytic activity as the (eta(5),eta(1)-Me(5)C(5))(2)LaCH(TMS)(2) precatalyst at 120 degrees C in the cyclization of cis-2,2-dimethylhept-5-enylamine. Catalytically-active lanthanide-amido complexes (eta(5)-Me(5)C(5))(2)La(NHR)(NH(2)R)(n) and [Me(2)Si(eta(5)-Me(4)C(5))((t)BuN)]Sm(NHR)(NH(2)R)(n) are shown to be thermally robust species.

Journal Article↗
PubMed2004

Theoretical analysis of Lewis basicity based on local electron-donating ability. Origin of basic strength of cyclic amines.

It has been experimentally established that the proton affinities (PA), as well as the solution basicities (pK(BH)(+)), of aziridine derivatives are much smaller than those of the corresponding pyrrolidines and piperidines, though the basic strength of azetidines is close to those of pyrrolidines and piperidines. A simple idea of dependence of the basic strength on bond angles seems to be invalid. Because the basicity of cyclic amines is a fundamental property in organic chemistry, we revisited this topic in order to clarify quantitatively the intrinsic origin of the strength of Lewis basicity of the relevant amines, in particular, based on the local electron-donating ability of the amine nitrogen atoms evaluated in terms of the localized reactive hybrid orbital (RHO) concept. In the cases of representative N-substituents such as hydrogen, methyl, and phenyl groups, the electron-donating energy level of the nitrogen center, obtained by maximizing a kind of superdelocalizability, was shown to be correlated with the magnitudes of experimental and calculated gas-phase proton affinities. The present results strongly support the view that the C-N-C bond angle, i.e., angle strain, in the cyclic amines is not the major source of the difference in strength of basicity of these amines, but rather, the degree of pyramidalization around the nitrogen atom has a significant impact on the electron-donating ability of the nitrogen lone-pair orbital.

Journal Article↗
PubMed2004

On the dichotomic behavior of the Z-2,4-dinitrophenylhydrazone of 5-amino-3-benzoyl-1,2,4-oxadiazole with acids in toluene and in dioxane/water: rearrangement versus hydrolysis.

The mononuclear rearrangement (MRH) of the Z-2,4-dinitrophenylhydrazone (4a) and of the Z-phenylhydrazone (4b) of 5-amino-3-benzoyl-1,2,4-oxadiazole into the relevant triazoles 5a and 5b in toluene has been quantitatively investigated in the presence of trichloroacetic acid (TCA) and of piperidine at 313.1 K. While the behavior in the presence of piperidine recalls the one previously evidenced for some Z-hydrazones of 3-benzoyl-5-phenyl-1,2,4-oxadiazole, the study of the reactivity in the presence of TCA has most interestingly evidenced a general-acid-catalyzed rearrangement for "both" 4a and 4b. Thus, 4a offers the first example of a solvent-dependent dichotomic behavior in MRH processes on 1,2,4-oxadiazole derivatives as far as it undergoes an "acidic hydrolysis" in dioxane/water and a "rearrangement" in toluene.

Journal Article↗