Showing papers on "Piperidine published in 2010"

Asymmetric Deprotonation of N-Boc Piperidine: React IR Monitoring and Mechanistic Aspects

Abstract: The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.

N‐Sulfinyl Amines as a Nitrogen Source in the Asymmetric Intramolecular Aza‐Michael Reaction: Total Synthesis of (−)‐Pinidinol

Abstract: N-Sulfinyl amines have been successfully employed as nitrogen nucleophiles for the asymmetric intramolecular aza-Michael reaction. The synthetic strategy involves a cross-metathesis reaction followed by the Michael-type cyclization, either in a base-catalyzed two-step procedure or in a tandem fashion. The developed methodology allows access to chiral substituted pyrrolidines and piperidines bearing one or two stereocenters and it has been applied to the synthesis of the piperidine alkaloid (-)-pinidinol.

Pellitorine, a Potential Anti-Cancer Lead Compound against HL60 and MCT-7 Cell Lines and Microbial Transformation of Piperine from Piper Nigrum

Abstract: Pellitorine (1), which was isolated from the roots of Piper nigrum, showed strong cytotoxic activities against HL60 and MCT-7 cell lines. Microbial transformation of piperine (2) gave a new compound 5-[3,4-(methylenedioxy)phenyl]-pent-2-ene piperidine (3). Two other alkaloids were also found from Piper nigrum. They are (E)-1-[3',4'-(methylenedioxy)cinnamoyl]piperidine (4) and 2,4-tetradecadienoic acid isobutyl amide (5). These compounds were isolated using chromatographic methods and their structures were elucidated using MS, IR and NMR techniques.

Regioselective and stereoselective copper(I)-promoted allylation and conjugate addition of N-Boc-2-lithiopyrrolidine and N-Boc-2-lithiopiperidine.

Abstract: Copper salts have been screened for transmetalation and electrophilic quench of N-tert-butoxycarbonyl-2-lithiopyrrolidine (N-Boc-2-lithiopyrrolidine) and N-Boc-2-lithiopiperidine, formed by deprotonation of N-Boc-pyrrolidine and N-Boc-piperidine, respectively. Transmetalation with zinc chloride then (lithium chloride solubilized) copper cyanide followed by allylation typically gives mixtures of regioisomers (S(N)2 and S(N)2' products), whereas transmetalation with copper iodide.TMEDA then allylation occurs regioselectively (S(N)2 mechanism). Addition to an enone or alpha,beta-unsaturated ester occurs by 1,4-addition. Asymmetric deprotonation of N-Boc-pyrrolidine or dynamic resolution in the presence of a chiral ligand of N-Boc-2-lithiopiperidine followed by the zinc/copper chemistry was successful and gave the allylated pyrrolidine and piperidine products with good enantioselectivity, although use of the copper iodide chemistry resulted in some loss of enantiopurity. The chemistry provides formal syntheses of (+)-allosedridine, (+)-lasubine II, and (+)-pseudohygroline and has been used for the synthesis of (+)-coniine, (-)-pelletierine, (+)-coniceine, (-)-norhygrine, and the ant extract alkaloids cis- and trans-2-butyl-5-propylpyrrolidine.

A modular, efficient, and stereoselective synthesis of substituted piperidin-4-ols.

Abstract: Piperidine is a key structural motif in various alkaloids and a variety of compounds studied in medicinal chemistry. Though many methods have been developed for their construction, there is still a need for noval approaches, especially those with high efficiency, good modularity and excellent stereoselectivity. Recent intense research in gold catalysis[1] has provided several novel methods of piperidine synthesis.[2,3] For example, we reported earlier that piperidin-4-ones could be prepared in a two-step, [4+2] manner;[2a] however, the products are limited to those with ring nitrogen substituted with hard-to-remove aliphatic groups or benzyl groups suffering from low regioselectivities. To address this deficiency and develop a generally effective and modular synthesis of N-unsubstituted piperidines, we envisioned, as shown in Scheme 1, that a gold-catalyzed cyclization of N-homopropargyl amide 2 would offer cyclic imidate 3, which could be chemoselectively reduced to afford α-amino ether A. We anticipated that A would undergo spontaneous Ferrier rearrangement to furnish piperidin-4-one B, which might be further reduced in situ to the corresponding alcohol (i.e. 4). Several aspects of this design are noteworthy: 1) the sequence is highly modular and flexible; it is an overall {[2+3]+1} annulation from readily available imines, propargyl Grignard, and carboxylic acids or their derivatives; 2) enantiomeric synthesis is readily achievable as chiral amine 1 would be easily prepared from chiral sulfinyl imines;[4] 3) it constitutes an alternative to an aza-Petasis-Ferrier rearrangement, which has not been realized.[5,6] This is a surprising void as the Petasis-Ferrier rearrangement[7] has been applied with much success in total synthesis of complex natural products.[8] 4) the piperidine nitrogen is free and could be readily derivatized; 5) the gold catalysis is not the key transformation but instead employed to deliver requisite intermediates for subsequent processes. This sequential combination of gold catalysis and other distinctively different transformations in a one-pot process offer new opportunities to develop versatile synthetic methods with high efficiency. (1) Scheme 1 Modular synthesis of N-unsubstituted piperidines: design We began the implementation of the design by examining the feasibility of the gold catalysis[9] using amide 5 as the substrate. To our delight, the gold-catalyzed cyclization proceeded quantitatively in either CH2Cl2 or THF at ambient temperature (Eq 1). The keys to this reaction were the addition of MsOH (1.2 equiv) to prevent the nitrogen of imidate 6 from coordinating to and thus deactivating the gold catalyst[10] and the use of molecular sieves to minimize hydrolysis. Due to the sensitivity of imidate 6 to hydrolysis, we decided to study its reduction in a one-pot process. Hence, upon the complete consumption of amide 3 in the gold catalysis, various reductants were added. To our delight, with borane the all cis-isomer (i.e., 7) was indeed formed. Screening other reductants especially boron-based ones revealed that catecholborane (5 equiv) worked the best (entries 5-9), and an 80% isolated yield was achieved in CH2Cl2 and at -78 °C. Notable is that 7 was formed with excellent diastereoselectivity, and other potential diastereomers were formed in negligible amounts. The relative stereochemistry of 7 was initially established via NMR studies and later corroborated by the structure of 9p (vide infra) established by X-ray crystallography (see SI). We then tested a range of secondary amides as substrates following the optimized one-pot sequence with some fine tunings of reaction temperatures and the amount of the borane. As shown in Table 2, different acyl groups including aliphatic (entries 1-7) and aromatic ones (entries 8-11) were readily allowed. Steric bulk was well tolerated although the reduction was slower (entry 4). Different functional groups including a non-conjugated C-C double bond (entry 6), fluoro groups (entries 7 and 9), a carboxylate (entry 11) and a naphthyl group (entry 10) were tolerated. However, (2) (3) trifluoroacetamide 8 (R = CF3, R = Cy) was not a suitable substrate as its weakly nucleophilic carbonyl group failed to undergo gold-catalyzed cyclization. Notably, high to excellent diastereoselectivities were observed in the cases of aliphatic amides. However, the catecholborane reduction in the cases of aromatic amides (entries 8-11) was very slow at -40 °C, and the reactions were run at ambient temperature in order to achieve completion in 24 h; low diastereoselectivities were observed in most of these cases. To our delight, while the major isomers were the expected all-cis ones, the minor component in each case appeared to be the 4-OH epimer, which was confirmed via oxidation of the separated isomers of 9j to a common piperidin-4-one.[11] These results indicated that the piperidine ring-forming step was highly diastereoselective even at room temperature. In contrast to entry 6, the vinyl group in acrylamide 8l (entry 11) was reduced during the reaction, and piperidine 9l with an ethyl group instead was isolated in 47% yield. Substrates with an aryl group at the homopropargylic position worked equally well in this one-pot process (entries 13-18), and at -40 °C the diastereoselectivities were mostly excellent. Again, steric bulk (entries 15 and 17) were readily tolerated. Table 2 One-pot sequential gold catalysis, chemoselective reduction, and Ferrier rearrangement: scope study.[a] A key feature in these piperidin-4-ol products is that the ring nitrogen is free and could be readily derivatized. For example, subsequent one-pot intramolecular alkylations (Eq. 2 and 3) provided quick access to quinolizidine and indolizidine skeletons, respectively, which can be found in the structures of a range of alkaloids.[12] As a demonstration of the synthetic utility of this chemistry, an enantioselective synthesis of (+)-subcosine II[13,14] was achieved in 6 steps in an overall 22% yield (Scheme 2). Notably, homopropargyl amine 10 was easily prepared in >94% ee using Ellman's sulfinyl imine chemistry,[4a] and neither the gold catalysis nor the reduction/Ferrier rearrangement compromised the stereochemistry integrity of the original chiral carbon center. Scheme 2 Six-step, enantioselective total synthesis of (+)-subcosine II. In conclusion, we have developed a one-pot synthesis of piperidin-4-ols v i a sequential gold-catalyzed cyclization, chemoselective reduction and spontaneous Ferrier rearrangement. This reaction has a broad substrate scope and shows excellent diastereoselectivities in the ring formation step; in combination with a routine amide formation, it constitutes a highly flexible and diastereoselective [5+1] cycloaddition approach to piperidines. Since homopropargylic amines could be readily prepared with excellent e.e. from chiral sulfinyl imines and propargylmagnesium bromide, this overall {[2+3]+1} modular approach offers an ideal solution to enantioselective synthesis of various substituted piperidine. Importantly, the piperidine nitrogen is free and can be readily derivatized. By coupling with one-pot intramolecular alkylations, this chemistry provides a rapid access to quinolizidines and indolizidines and allows a succinct enantioselective synthesis of (+)-subcosine II.

Stereoselective Synthesis and Antiviral Activity of (1E,2Z,3E)‐1‐(Piperidin‐1‐yl)‐1‐(arylhydrazono)‐2‐[(benzoyl/benzothiazol‐ 2‐oyl)hydrazono]‐4‐(aryl1)but‐3‐enes

Abstract: The reaction of benzoyl hydrazine 1a or benzothiazole-2-carbohydrazide 1b with 2-oxo-N-arylpropanehydrazonoyl chlorides 2a-d yielded (1Z,2E)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-N-(aryl)propanehydrazonoyl chlorides 3a-e. The reaction of 3a-c with sodium benzenesulphinate furnished sulphones 5a-c while the reaction of 5d, e with hydroxyl amine afforded hydroxomoyl derivatives 6a, b. The one-pot sterioselective reaction of N-(aryl)propanehydrazonoyl chlorides 3 with certain aromatic aldehydes in the presence of piperidine resulted in the formation of (1E,2Z,3E)-1-(piperidin-1-yl)-1-(arylhydrazono)-2-[(benzoyl/benzothiazol-2-oyl)hydrazono]-4-(aryl1)-but-3-enes 7a-g. X-ray analysis of piperidinyl amidrazone 7g showed a conversion of its geometrical structure with respect to that of compound 3 and confirmed the stereoselectivity of the latter reaction. The piperidinyl amidrazones 7a-g possessed a significant antiviral activity against herpes simplex viruses (HSV-1). Compound 7d reduced the number of viral plaques of herpes simplex type-1 (HSV-1) by 67%, with respect to the effect of reference drug Aphidicolin.

[Pd(Cl)2{P(NC5H10)(C6H11)2}2]--a highly effective and extremely versatile palladium-based Negishi catalyst that efficiently and reliably operates at low catalyst loadings.

Abstract: [Pd(Cl)(2){P(NC(5)H(10))(C(6)H(11))(2)}(2)] (1) has been prepared in quantitative yield by reacting commercially available [Pd(cod)(Cl)(2)] (cod=cyclooctadiene) with readily prepared 1-(dicyclohexylphosphanyl)piperidine in toluene under N(2) within a few minutes at room temperature. Complex 1 has proved to be an excellent Negishi catalyst, capable of quantitatively coupling a wide variety of electronically activated, non-activated, deactivated, sterically hindered, heterocyclic, and functionalized aryl bromides with various (also heterocyclic) arylzinc reagents, typically within a few minutes at 100 °C in the presence of just 0.01 mol% of catalyst. Aryl bromides containing nitro, nitrile, ether, ester, hydroxy, carbonyl, and carboxyl groups, as well as acetals, lactones, amides, anilines, alkenes, carboxylic acids, acetic acids, and pyridines and pyrimidines, have been successfully used as coupling partners. Furthermore, electronic and steric variations are tolerated in both reaction partners. Experimental observations strongly indicate that a molecular mechanism is operative.

Enantioselective construction of lactone[2,3-b]piperidine skeletons via organocatalytic tandem reactions

Abstract: A highly enantioselective construction of δ- and γ-lactone[2,3-b]piperidine skeletons was accomplished by tandem aza-Diels–Alder reaction–hemiacetal formation–oxidation from N-Tos-1-aza-1,3-butadienes and aliphatic dialdehydes.

Synthesis and antimicrobial activity of schiff’s and n-mannich bases of isatin and its derivatives with 4-amino-n-carbamimidoyl benzene sulfonamide

Abstract: Isatin and substituted Isatin were reacted with 4-amino-N-carbamimidoyl benzene sulfonamide to form a series of Schiff’s bases. The Mannich bases of these compounds were synthesized by reacting them with formaldehyde and secondary amine (piperidine). All the compounds were characterized by means of their IR, 1H NMR spectroscopic data and elemental analysis. The antimicrobial activity of the synthesized compounds was evaluated by tube dilution method. The synthesized compounds showed better antibacterial activity than the reference drugs.

The influence of perhydroazepine and piperidine as further ancillary ligands on Ru-PPh3-based catalysts for ROMP of norbornene and norbornadiene

Abstract: Polynorbornadiene and polynorbornene were synthesized via ring opening metathesis polymerization (ROMP) with [RuCl 2 (PPh 3 ) 2 (amine)] as catalyst precursors, amine = piperidine ( 1 ) or perhydroazepine ( 2 ) in the presence of 5 μL of ethyl diazoacetate (EDA) ([monomer]/[Ru] = 5000; 40 °C with 1 ; 25 °C with 2 ). The effects of the solvent volume (2–8 mL of CHCl 3 ), reaction time (5–120 min) and atmosphere type (argon and air) on the yields were investigated to observe the behavior of the two different precursors. Quantitative yields were obtained for 60 or 120 min regardless of the starting volumes, either in argon or air, with both Ru species. However, low yields were obtained for short times (5–30 min) when the reactions are performed with large volumes (6–8 mL). In argon, the yields were larger with 2 , associated to a faster propagation reaction controlled by the Ru active species. In air, the yields were larger with 1 , associated to a higher resistance to O 2 of the starting and propagating Ru species. The different activities between 1 and 2 are discussed considering the steric hindrance and electronic characteristics of the amines such as ancillary ligands and their arrangements with PPh 3 and Cl − ions in the metal centers.

Piperidine and piperazine derivatives as autotaxin inhibitors

Abstract: The present invention relates to piperidine and pyrazine derivatives according to formulae (Ia), (Ib) and (II) as autotaxin inhibitors and the use of such compounds for the treatment and/or prophylaxis of physiological and/or pathophysiological conditions, which are caused, mediated and/or propagated by increased lysophosphatic acid levels and/or the activation of autotaxin, in particular of different cancers.

Piperidine inhibitors of janus kinase 3

Abstract: The present invention relates to new piperidine inhibitors of Janus kinase 3 activity, pharmaceutical compositions thereof, and methods of use thereof.

Configuration and conformation of all four cocaines from nmr spectra

Abstract: The configurations of (±)-allococaine and (±)-allopseudococaine have been determined, for the first time in an unambiguous way, by means of NMR spectroscopy. The known configurations of (±)-cocaine and (±)-pseudococaine receive independent confirmation. The preferential conformation of the piperidine ring of the tropane nucleus is found to be the chair form in all four isomers, and also in the methyl esters of the four corresponding isomers of ecgonine. The preparation of (±)-allococaine and (±)-allopseudococaine has been improved.

Electronic synergism in [RuCl2(PPh3)2(amine)] complexes differing the reactivity for ROMP of norbornene and norbornadiene

Abstract: The reactivity of the new complex [RuCl2(PPh3)2(3,5-Me2piperidine)], complex 1, was investigated for ring opening metathesis polymerization (ROMP) of norbornene (NBE) and norbornadiene (NBD) in the presence of ethyl diazoacetate (EDA) in CHCl3. The aim is to observe the combination of PPh3 and an amine as ancillary ligands concerning the steric hindrance and the electronic perturbation in the properties of the N-bound site when replacing the amines. Thus, the results with 1 were compared to the results obtained when the amine is piperidine (complex 2). Reaction with 1 provides 70% yield of isolated polyNBE (Mn = 8.3 × 104 g/mol; PDI = 2.03), whereas 2 provides quantitative reaction (Mn = 1.2 × 105 g/mol; PDI = 1.90) with [NBE]/[Ru] = 5000, [EDA]/[Ru] = 48 and 1.1 μmol of Ru for 5 min at 25 °C. The resulting polymers showed c.a. 62% of trans-polyNBE, determined by 1H NMR, and Tg = 32 °C, determined by DSC and DMTA. For ROMP of NBD, 1 showed quantitative yield with PDI = 2.62 when [NBD]/[Ru] = 5000 for 20 min at 25 °C, whereas the reaction with 2 reached 55% with PDI = 2.16 in the same conditions. It is concluded that the presence of the two methyl groups in the piperidine ring provides an increase in the induction period to produce the Ru-carbene species justifying better polyNBE results with 2, and a greater amine ⟶ σ Ru ⟶ π monomer synergism which contributed to the best activation of less tensioned olefin as NBD.

Alcaloïdes Pipéridiniques III. Nouveaux Alcaloïdes du Prosopis Africana (Guill. et Perr.) Taub.: Isoprosopinines A et B, Prosophylline, Prosafrine Et Prosafrinine [1]

Abstract: The structures of five new alkaloids have been established: the isoprosopinines A and B, 1 and 2 are homogeneous mixture: isoprosopinine A is (2R, 3S, 6R) 2-hydroxymethyl 3-hydroxy 6-dodecyl 7°-keto piperidine and isoprosopinine B is (2R, 3S, 6R) 2-hydroxymethyl 3-hydroxy 6-dodecyl 8°-keto piperidine. Prosophylline 4 is d 2-hydroxymethyl 3-hydroxyl 6-dodecyl 10°-keto piperidine, prosafrine 9 is (2R, 3R, 6S) 2-methyl 3-hydroxy 6-dodecyl 10°-hydroxy piperidine and prosafrinine 11, is (2R, 3R, 6S) 2-methyl 3-hydroxy 6-dodecyl 10°-keto piperidine.

Oligo(4-aminopiperidine-4-carboxylic acid): an unusual basic oligopeptide with an acid-induced helical conformation.

Abstract: In sharp contrast with helical polypeptides carrying basic side chains, Api8, a basic oligopeptide containing the non-natural achiral amino acid 4-aminopiperidine-4-carboxylic acid (Api), adopts a helical conformation only in acidic media. Alkaline titration of a protonated Api8 oligomer appended with a leucine derivative at its N-terminus showed that disruption of its helical conformation occurs in a pH range of 7−10. NMR studies indicated that the piperidine groups in Api8, when nonprotonated, possibly interact with the proximal amide protons in the peptide backbone and hamper the formation of the H-bonding network responsible for the helical conformation. The helical structure is induced not only by protonation but also by acylation of the piperidine groups.

Synthesis and Chemical Reactivityof New Azaenamines Incorporated the 4,5,6,7-Tetrahydrobenzo[b]thiophene Moiety: 3+3Atom Combination

Abstract: Novel azaenamines incorporating a tetrahydrothiophene moiety were prepared. Michael addition of an azaenamine with α,β-unsaturated nitriles took place to give [1]benzothieno[3',2':5,6]pyrimido[1,2-b]pyridazine (thia-triaza-benzo[a]fluorene) derivatives. The condensation with malononitrile resulted in the formation of a [1]benzothieno[3',2':5,6]pyrimido[1,2-b]pyridazine-4-carbonitrile. The azaenamine also reacted with aldehydes and piperidine to give Mannich products.

Association Constants of Pyridine and Piperidine Alkaloids to Amyloid ß Peptide Determined by Electrochemical Impedance Spectroscopy

Abstract: Amyloid β(1-40) peptide was immobilized on an Au-colloid modified gold electrode and an electrochemical impedance spectroscopy (EIS) system was elaborated for determining the association constants, Ka, between small molecular ligands and the peptide. The changes in the resistance of the modified electrode layer with deposited Aβ(1-40) peptide were measured with EIS in relation to a series of concentrations of the ligands studied. The association constants were calculated from Langmuir isotherms. The method is sensitive, reproducible and consumes only very little amounts of interacting species. The method was applied to determine the affinity of a series of pyridine and piperidine derivatives, mainly alkaloids of a known ability, to cross the blood-brain barrier. Along with nicotine and its main metabolite cotinine, the following agents were taken for the study: anabasine, arecoline, coniine, lobeline, pseudopelletierine, trigonelline, as well as pyridine and piperidine themselves. For the sake of comparison, two vitamins were also subjected to the study: ascorbic acid and pyridoxine. There was no association of these vitamins, which were tested as a negative control. For the compounds studied, a strong association with Aβ(1-40) was determined with Ka ranging from 1.7 x 107 M-1 for (±)- anabasine to 2.3 x 108 M-1 for arecoline hydrobromide. As a positive control, a well known amyloid specific binder, Congo Red, was tested, displaying Ka equal to 3.7 x 108 M-1.