Showing papers on "Piperidine published in 1996"

Redox and Acidity Properties of Alkyl- and Arylamine Radical Cations and the Corresponding Aminyl Radicals1

Abstract: In this work the pKas of six alkyl- and arylamine radical cations in aqueous solution have been determined by means of laser flash photolysis. The corresponding N-nitrosamines were used as precursors for the aminyl radicals which, upon protonation, formed the amine radical cations. The following pKas were obtained: 3.6 ± 0.2, 7.6 ± 0.3, 6.8 ± 0.5, 5.3 ± 0.5, 5.5 ± 0.5, and 5.8 ± 0.5 for the radical cations of diphenylamine, N-methylaniline, dimethylamine, diethylamine, pyrrolidine, and piperidine, respectively. In addition, the peak oxidation potentials of diphenylamine, N-methylaniline, aniline, diethylamine, pyrrolidine, and piperidine have been measured in aqueous solution and in acetonitrile using cyclic voltammetry. Furthermore, the one-electron reduction potentials of the diphenylaminyl radical and the N-methylanilinyl radical in acetonitrile were measured using photomodulation voltammetry. The results of this study and of previously published studies are discussed in terms of relative substituent ...

Exploratory Synthetic Studies of the α-Methoxylation of Amides via Cuprous Ion-Promoted Decomposition of o-Diazobenzamides†

Abstract: A convenient nonelectrochemical amide oxidation method has been developed. The process involves a cuprous ion-promoted decomposition of o-diazobenzamides like 4, generated in situ from the corresponding o-aminobenzamides, to give N-acyliminium ion intermediate 9 via a 1,5-H-atom transfer, followed by metal-catalyzed oxidation of the resulting α-amidyl radical. The transformation produces α-methoxybenzamides 15 in good yields. An attempt was made to apply this oxidation method to a total synthesis of the alkaloid (−)-anisomycin (16). Scalemic o-aminobenzamide pyrrolidine derivatives 18a/18b underwent oxidation to give α-methoxylated amide substrates 19a/19b, respectively, in good yields. However, alkylation of the N-acyliminium intermediate 20 with (p-methoxybenzyl)magnesium chloride gave the undesired anti-compounds 22a/22b as the major products. The amide oxidation exhibits good regioselectivity with many unsymmetrical 2-substituted piperidine and pyrrolidine systems. In general, it appears that the larg...

A new asymmetric entry to 2-substituted piperidines. A concise synthesis of (+)-coniine, (−)-pelletierine, (+)-δ-coniceine, and (+)-epidihydropinidine

Abstract: A new asymmetric route to 2-substituted piperidines involving the Sharpless asymmetric dihydroxylation (AD) of 5-hexenylazide 1 and an intramolecular aminocyclization as crucial steps and its application to the asymmetric synthesis of four piperidine alkaloids, (+)-coniine 2, (−)-pelletierine 3, (+)-δ-coniceine 4, and (+)-epidihydropinidine 5 is presented.

Systematic investigations on the reactivity of oxazolinium salts

Abstract: The termination reaction of the cationic polymerization of 2-phenyl- and 2-nonyl-2-oxazolines was examined by reacting the corresponding model oxazolinium salts having tosylate and trifluoromethansulfonate counterions with various nucleophiles. The reaction was monitored by 1 H NMR spectroscopy. Piperidine and KOH react with the oxazolinium salts very fast and quantitatively. In the case of piperidine, the use of a double molar amount of piperidine is necessary to achieve complete conversion. The addition of piperidine, pyridine, 4-dimethylaminopyridine and morpholine takes place in position 5 of the oxazolinium ring, whereas water and KOH add in position 2. The rate of the termination reaction depends on the electron density of the nucleophile which can be correlated with the pK a value. With CF 3 SO 3 - as counterion the addition of nucleophiles in position 5 is distinctly faster, whereas the addition of water in position 2 is much slower than with TsO - as counterion. The ring-opening of the nonyl oxazolinium ion is slower than that of the phenyl oxazolinium ion.

Enzymatic Route to Chiral, Nonracemic cis-2,6- and cis,cis-2,4,6-Substituted Piperidines. Synthesis of (+)-Dihydropinidine and Dendrobate Alkaloid (+)-241D

Abstract: Piperidine-based compounds are an important class of natural alkaloids found in plants, insects, and amphibians. A general asymmetric synthesis of 2-alkyl-6-methylpiperidines is presented via the enzymatic desymmetrization of meso cis-2,6- and cis,cis-2,4,6-substituted piperidines with Aspergillus niger lipase (ANL). The enzymatic reaction proceeds in excellent chemical yield and high enantiotopic selectivity (ee ≥ 98%). The general method is used to effect the synthesis of (+)-dihydropinidine−HCl as well as the first asymmetric synthesis of dendrobate alkaloid (+)-241D.

Efficient Total Syntheses of Pumiliotoxins A and B. Applications of Iodide-Promoted Iminium Ion−Alkyne Cyclizations in Alkaloid Construction

Abstract: A practical route for the total synthesis of pumiliotoxin A alkaloids is described. The central step is formation of the piperidine ring and establishment of the (Z)-alkylidene side chain by an iodide-promoted iminium ion−alkyne cyclization. The total synthesis of (+)-15(S)-pumiliotoxin A (2) was realized in 5 steps and 32% overall yield from alkyne 36 and epoxide 7. This synthesis of 2 proceeded in 13 steps and 12% overall yield from (S)-2-methyl-1-penten-3-ol (25) and 8 steps and 9% overall yield from N-[(benzyloxy)carbonyl]-l-proline. The synthesis of (+)-pumiliotoxin B (3) was similarly achieved in four steps and 44% overall yield from alkyne 54 and epoxide 7. The overall yield of enantiopure 3 was 8% from N-[(benzyloxy)carbonyl]-l-proline and 10% from (4S,5R)-4-methyl-5-phenyl-2-oxazolidinone. These syntheses represent substantial improvement over previous routes to these important alkaloids.

Imino Diels-Alder-Based Construction of a Piperidine A-Ring Unit for Total Synthesis of the Marine Hepatotoxin Cylindrospermopsin.

Abstract: The synthesis of a piperidine A-ring precursor to the alkaloid cylindrospermopsin (1) is described. The initial approach to the A-ring precursor focused on the imino Diels−Alder reaction of diene 8 with ethyl (N-tosylimino)acetate (9) to form the cycloadduct 10 as a single stereoisomer. However, all attempts to convert ester 10 to a requisite diene such as 5 were unsuccessful. An alternative strategy involved the Diels−Alder cycloaddition of N-tosylimine 9 with oxygenated diene 19 under either thermal or Lewis acid-catalyzed conditions to produce a mixture of cis and trans enones 20 and 21. Although the undesired cis-enone 20 was the major product under all reaction conditions, it could be converted to the desired trans enone 21 by acid-catalyzed isomerization. Copper-mediated conjugate addition of vinylmagnesium bromide to cis-enone 20 followed by stereoselective ketone reduction with L-Selectride produced alcohol 23, whose structure was confirmed by X-ray crystallography. Similarly, trans-enone 21 was c...

Structure−Activity Relationship Studies of Novel 4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine Analogs: Synthesis and Biological Evaluation at the Dopamine and Serotonin Transporter Sites

Abstract: Several analogs of the potent dopamine (DA) transporter ligand 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-1-(3-phenylpropyl)piperidine, 1b, were made and biologically evaluated for their binding at the DA and serotonin (5HT) transporters in rat striatal membranes. Different alkyl chain lengths and substitutions were introduced in these molecules to generate an optimum activity and selectivity for the DA transporter. In general, unsubstituted and fluoro-substituted compounds were the most active and selective for the DA transporter. The compound 4-[2-(diphenylmethoxy)ethyl]-1-benzylpiperidine, 9a, showed high potency and was the most selective for the DA transporter (5HT/DA = 49) in this series of compounds. Some of these novel analogs were found to be more selective in binding at the DA transporter than the original GBR 12909 molecule, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperidine.

Kinetics and Mechanism of the Aminolysis of Phenyl and 4-Nitrophenyl Ethyl Thionocarbonates

Abstract: The reactions of the title substrates (PTOC and NPTOC, respectively) with secondary alicyclic amines are subjected to a kinetic study in aqueous solution at 25.0 °C, ionic strength 0.2 M (KCl). Under amine excess, pseudo-first-order rate coefficients (kobsd) are found throughout. The order in amine is one for the reactions of piperidine but is of intermediate order between 1 and 2 for the reactions of the other amines. The kinetic results can be accommodated by a reaction scheme with two hypothetical tetrahedral intermediates: a zwitterionic (T±) and an anionic (T-) one, whereby amine catalysis (deprotonation of T± to give T-) is kinetically important. Both the pKa of T± and the rate coefficient for proton transfer (k3 ca. 1010 s-1 M-1) are estimated. The values of the other rate microcoefficients of the scheme are found by a nonlinear least-squares fitting, and these values are compared with those exhibited in the aminolysis of phenyl thionoacetate (PTOA), and S-phenyl and S-(4-nitrophenyl) O-ethyl dith...

Solid-Phase Total Synthesis of Bacitracin A.

Abstract: An efficient solid-phase method for the total synthesis of bacitracin A is reported. This work was undertaken in order to provide a general means of probing the intriguing mode of action of the bacitracins and exploring their potential for use against emerging drug-resistant pathogens. The synthetic approach to bacitracin A involves three key features: (1) linkage to the solid support through the side chain of the L-asparaginyl residue at position 12 (L-Asn(12)), (2) cyclization through amide bond formation between the alpha-carboxyl of L-Asn(12) and the side chain amino group of L-Lys(8), and (3) postcyclization addition of the N-terminal thiazoline dipeptide as a single unit. To initiate the synthesis, Fmoc L-Asp(OH)-OAllyl was attached to a PAL resin. The chain of bacitracin A was elaborated in the C-to-N direction by sequential piperidine deprotection/HBTU-mediated coupling cycles with Fmoc D-Asp(OtBu)-OH, Fmoc L-His(Trt)-OH, Fmoc D-Phe-OH, Fmoc L-Ile-OH, Fmoc D-Orn(Boc)-OH, Fmoc L-Lys(Aloc)-OH, Fmoc L-Ile-OH, Fmoc D-Glu(OtBu)-OH, and Fmoc L-Leu-OH. The allyl ester and allyl carbamate protecting groups of L-Asn(12) and L-Lys(8), respectively, were simultaneously and selectively removed by treating the peptide-resin with palladium tetrakis(triphenylphosphine), acetic acid, and triethylamine. Cyclization was effected by PyBOP/HOBT under the pseudo high-dilution conditions afforded by attachment to the solid support. After removal of the N-terminal Fmoc group, the cyclized peptide was coupled with 2-[1'(S)-(tert-butyloxycarbonylamino)-2'(R)-methylbutyl]-4(R)-carboxy-Delta(2)-thiazoline (1). The synthetic peptide was deprotected and cleaved from the solid support under acidic conditions and then purified by reverse-phase HPLC. The synthetic material exhibited an ion in the FAB-MS at m/z 1422.7, consistent with the molecular weight calculated for the parent ion of bacitracin A (MH(+) = C(73)H(84)N(10)O(23)Cl(2), 1422.7 g/mol). It was also indistinguishable from authentic bacitracin A by high-field (1)H NMR and displayed antibacterial activity equal to that of the natural product, thus confirming its identity as bacitracin A. The overall yield for the solid-phase synthesis was 24%.

Synthesis of trans-3,4-Dimethyl-4-(3-hydroxyphenyl)piperidine Opioid Antagonists: Application of the Cis-Thermal Elimination of Carbonates to Alkaloid Synthesis

Abstract: Improved syntheses of twotrans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonists from 1,3-dimethyl-4-piperidinone are described. The 1,3-dimethyl-4-arylpiperidinol 23 was selectively dehydrated in a two step process to the 1,3-dimethyl-4-aryl-1,2,3,6-tetrahydropyridine 26 by the cis-thermal elimination of the corresponding alkyl carbonate derivative at 190 degrees C. In the presence of a basic nitrogen, the success of the elimination was found to be critically dependent upon the nature of the carbonate alkyl group, with Et, i-Bu, and i-Pr being preferred (90% yield). Alkylation of the metalloenamine, formed by deprotonation of 26 with n-BuLi, proceeded regio- and stereospecifically to give the trans-3,4-dimethyl-4-aryl-1,2,3,4-tetrahydropyridine 27, which was converted in three steps to the common intermediate, (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine. LY255582, a centrally-active opioid antagonist, and LY246736-dihydrate, a peripherally-active opioid antagonist, were prepared from 1,3-dimethyl-4-piperidinone in 11.8% yield (8 steps) and 6.2% yield (12 steps), respectively.

A process for preparing pyridine-2,6-diamines

Abstract: A process has been found for preparing pyridine-2,6-diamines, i.e., 2,6-diaminopyridine (DAP) and derivative compounds in which one of the amino groups is a substituted amine (secondary or tertiary). According to this process, 3-hydroxy pentane 1,5-dinitrile (3-hydroxyglutaronitrile) is reacted with an ammonium donor in the form of ammonia, a primary amine such as n-butylamine, or a secondary amine such as piperidine.

Enantioselective Total Synthesis of the Macrocyclic Spermidine Alkaloid (−)-Oncinotine

Abstract: The macrocyclic spermidine alkaloid (−)-oncinotine (1), isolated from Oncinotis nitida (Apocynaceae), was synthesized enantioselectively for the first time based on intramolecular iminium ion cyclization utilizing enantiomerically pure (2S)-N-[(benzyloxy)carbonyl]-2-piperidineacetaldehyde (8) as a chiral starting material. The required 8 was derived from the erythro adduct 16, which was obtained by diastereoselective 1,3-dipolar cycloaddition between 2,3,4,5-tetrahydropyridine 1-oxide (4) and (3S)-3-[(tert-butyldiphenylsilyl)oxy]-4-methyl-1-pentene (15). Wittig condensation of 8 with [8-(methoxycarbonyl)octyl]triphenylphosphonium iodide (21) followed by saponification provided the chiral piperidine moiety 23, which was coupled with the N-propyl-1,4-butanediamine segment 29 by using diethoxyphosphoryl cyanide in the presence of triethylamine to afford the tertiary amide 30. Conversion of 30 to the aldehyde 34 via desilylation and Swern oxidation, followed by hydrogenation over a palladium hydroxide catalys...

Piplaroxide, an ant-repellent piperidine epoxide from Piper tuberculatum

Abstract: Investigation of leaves from the shrub Piper tuberculatum for compounds that might serve as repellents to leafcutting ants has led to identification of three cinnamic acid derivatives. One has been characterized as a new piperidine epoxide, piplaroxide (1), while the other two were recognized as the known compounds piplartine (2) and demethoxypiplartine (3). Both piplaroxide and demethoxypiplartine demonstrated significant activity in a laboratory bioassay measuring repellency to the leafcutter ant Atta cephalotes.

Process for preparing 4-aryl-piperidine derivatives

Abstract: A process for the preparation of a compound of formula (VIII), wherein R1 is C?2-5?-alkyl, phenyl-C1-5-alkyl, or substituted phenyl-C1-5-alkyl.

Process for production of piperidine derivatives

Abstract: The present invention discloses processes for preparing piperidine derivative compounds of formulae (I) or (II) wherein n is 0 or 1; R1 is hydrogen or hydroxy; R2 is hydrogen; or, when n is 0, R?1 and R2? taken together form a second bond between the carbon atoms bearing R?1 and R2?, provided that when n is 1, R?1 and R2? are each hydrogen; R3 is -COOH or -COOR4; R4 is an alkyl or aryl moiety; A, B, and D are the substituents of their rings, each of which may be different or the same, and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy, and other substituents. One process comprises providing a regioisomer of formula (III) wherein Z is -CG1G2G3, (IV) or (V), m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR?5; G1, G2, and G3? are the same or different and are selected from the group consisting of OR8, SR8, and NR8R9; X3 is halogen, OR?15, SR15, NR15R16, OSO?2R15, or NHSO?2?R?15; R6 and R7? are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, an aryl moiety, OR8, SR8, and NR?8R9; and R5, R8, R9, R15, and R16? are the same or different and are selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety; and converting the regioisomer to the piperidine derivative compound with a piperidine compound. Another process for producing piperidine derivative compounds comprises providing an α,α-disubstituted-methylbenzene derivative having formula (VI) wherein X1 is a halogen, trialkyl or triaryl tin, trialkyl or triaryl borate, trialkyl silicon, alkylhalo silicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions and converting the α,α-disubstituted-methylbenzene derivative to the piperidine derivative compound with a piperidine compound. In yet another process, a 4-(α,α-disubstituted)-toluic acid derivative having formula (VII) wherein X2 is a halogen; an alkali metal oxide; a moiety having formula -OR10; a moiety having formula -SR10; or an amine; and R10 is selected from the group consisting of hydrogen, an alkyl moiety, and an aryl moiety, is provided and converted to the piperidine derivative compound with a piperidine compound.

Synthesis of β-hydroxypiperidine alkaloids by anodic oxidation of carbamates and hydroboration

Abstract: The β-hydroxypiperidine alkaloids (±)-pseudoconhydrine, (±)-N-methylpseudoconhydrine, (−)-5-hydroxysedamine, and (+)-sedacryptine were synthesized. Successive functionalization of the piperidine ring via anodic methoxylation allowed the regio- and stereoselective introduction of the substituents. The α and α′ substituents were introduced by application of the sequence elimination–nucleophilic addition from 2- or 2,5-substituted 6-methoxycarbamates. Hydroboration – oxidation of enecarbamates, obtained by elimination of methanol from α-methoxycarbamates, allowed the introduction of the β-hydroxy function. Key words: alkaloid, Sedum, N-acyliminium, enecarbamate.

1-(1,2-disubstituted piperidinyl)-4-(fused imidazole)-piperidine derivatives

Abstract: This invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; m is 1 or 2, provided that if m is 2, then n is 1; =Q is =O or =NR3; X is a covalent bond or -O-, -S-, -NR?3-; R1 is Ar1, Ar1C?1-6alkyl or di(Ar1)C1-6alkyl, wherein each C1-6alkyl group is optionally substituted; R?2 is Ar2, Ar2C?1-6alkyl, Het or HetC1-6 alkyl; R3 is hydrogen or C?1-6?alkyl; L is a piperidine derivative of formula (a-1) or a spiro piperidine derivative of formula (a-2); Ar?1? is phenyl or substituted phenyl; Ar2 is naphtalenyl; phenyl or substituted phenyl; and Het is a monocyclic or bicyclic heterocycle; each monocyclic and bicyclic heterocycle may optionally be substituted on a carbon atom; as substance P antagonists; their preparation, compositions containing them and their use as a medicine.

Di-substituted 1,4-piperidine esters and amides having 5-ht4 antagonistic activity

Abstract: Pharmacologically active novel esters and amides of di-substituted 1,4-piperidine as 5-HT4 antagonists of general formula (I), wherein A, X, Y and R have the meanings specified in the description, processes for their preparation and pharmaceutical compositions containing them, are disclosed.

A revised structure for the piperidine alkaloid andrachamine

Abstract: A new method for the synthesis of trans-2,6-disubstituted piperidine derivatives is described. The transformation of cyclic α-methoxycarbamates 5 and 6 affords trans ketones 17 and 18. The synthesis of diols 1–4 from 17 and 18 has shown that the structure proposed in the literature for the piperidine alkaloid andrachamine is incorrect. A reexamination of the original spectral data of this alkaloid suggested that it is a meso 2,6-disubstituted piperidine derivative. Unambiguous syntheses of 23 and 24 and comparison with a sample of andrachamine have established that this alkaloid possesses structure 23. Key words: N-acyliminium, piperidine, alkaloid, andrachamine.