Formation Of Piperidines Research Articles

Gold-Catalyzed Synthesis of Oxygen- and Nitrogen-Containing Heterocycles from Alkynyl Ethers: Application to the Total Synthesis of Andrachcinidine

In this paper we report that homopropargylic ethers containing pendent oxygen or nitrogen nucleophiles react with electrophilic gold catalysts in the presence of water to form saturated heterocyclic ketones. Mechanistic studies demonstrated that the reactions proceed through a sequence of alkyne hydration, alkoxy group elimination, and intramolecular conjugate addition. Diastereoselectivities for tetrahydropyran and piperidine formation are very good to excellent. This method has been applied to an efficient total synthesis of the natural product andrachcinidine. Utilizing propargylic ether substrates rather than homopropargylic ethers promotes regioselective hydration of internal alkynes, thereby expanding the scope of products that can be accessed through this protocol.

Pyrrolidine and Piperidine Formation via Copper(II) Carboxylate-Promoted Intramolecular Carboamination of Unactivated Olefins: Diastereoselectivity and Mechanism

An expanded substrate scope and in-depth analysis of the reaction mechanism of the copper(II) carboxylate-promoted intramolecular carboamination of unactivated alkenes is described. This method provides access to N-functionalized pyrrolidines and piperidines. Both aromatic and aliphatic gamma- and delta-alkenyl N-arylsulfonamides undergo the oxidative cyclization reaction efficiently. N-Benzoyl-2-allylaniline also underwent the oxidative cyclization. The terminal olefin substrates examined were more reactive than those with internal olefins, and the latter terminated in elimination rather than carbon-carbon bond formation. The efficiency of the reaction was enhanced by the use of more organic soluble copper(II) carboxylate salts, copper(II) neodecanoate in particular. The reaction times were reduced by the use of microwave heating. High levels of diastereoselectivity were observed in the synthesis of 2,5-disubstituted pyrrolidines, wherein the cis substitution pattern predominates. The mechanism of the reaction is discussed in the context of the observed reactivity and in comparison to analogous reactions promoted by other reagents and conditions. Our evidence supports a mechanism wherein the N-C bond is formed via intramolecular syn aminocupration and the C-C bond is formed via intramolecular addition of a primary carbon radical to an aromatic ring.

Synthesis of N‐Benzyl 3,5‐Disubstituted Piperidines via Double Michael Addition Strategy.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Development of a Flexible Approach to Nuphar Alkaloids via Two Enantiospecific Piperidine‐Forming Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of N-Benzyl 3,5-Disubstituted Piperidines via Double Michael Addition Strategy

Recently, Basavaiah and co-workers have reported the facile synthesis of functionalized 1,4-pentadienes from Baylis-Hillman type reaction from cinnamyl bromide derivatives (vide infra, Scheme 1). However, the usefulness of the 1,4-pentadienes has not been studied extensively. We thought that we could prepare 3,5disubstituted piperidine skeleton from these compounds via double Michael addition reaction strategy. 3,5-Disubstituted piperidines are important fundamental backbones for alkaloids, high affinity agonists of human GABA-A receptors, farnesyl-protein transferase inhibitors and continue to be basic moieties in pharmaceutical research. Due to their unique biological properties, the piperidines have been target molecules in organic synthesis. The starting materials 3a-e were synthesized according to the reported methods from the corresponding bromides or acetates 2a-c as shown in Scheme 1. With the 1,4-dienes in our hands, we first tried the reaction of 3a and benzylamine without solvent. As expected, 3,5-disubstituted piperidine 4a was obtained. As shown in Table 1 (entry 1), 4a-cis (28%) and 4a-trans (25%) were isolated. In the reaction, small amount of piperidone derivative 5a was also isolated (16%). The structures of piperidines 4a were easily assigned based on their H NMR spectra. As reported in a similar system, the benzylic protons appear as a singlet for 4a-cis whereas as a typical AB quartet for 4a-trans. However, long reaction time was required to complete the reaction at room temperature (5 days). When we elevated the temperature of the reaction mixture, somewhat complex mixtures were observed on TLC. Thus, we tried the same reaction in CH3CN at refluxing temperature. Long reaction time was required in this case also (entry 2, 60 h) to get similar yields of products. In order to reduce the reaction time we used LiClO4 (2 equiv) in refluxing CH3CN, and we obtained similar results (entry 3, 24 h) in relatively shorter reaction time. Similarly, the corresponding piperidines 4b-e were synthesized in moderate yields from 3b-e and the results are summarized in Table 1. The reaction mechanism for the formation of piperidine 4 and piperidone 5 is depicted in Scheme 2. Intermolecular Michael type addition of benzylamine to 1,4-pentadiene 3 gave the corresponding intermediate I. Intramolecular consecutive Michael type reaction (pathway a) gave the piperidine 4. Piperidone derivative 5 was formed by amide bond formation pathway (pathway b). As mentioned above, the benzylic protons of four cis-isomers (4a, 4c-e) appear as a singlet. The benzylic protons of all trans-isomers appear as AB quartets (∆δ/J = 2.4-5.3). Exceptionally, the benzylic protons of 4b-cis showed a typical AB quartet pattern with a relatively small ∆δ/J value (∆δ/J = 1.6). For the synthesis of 4c, the use of LiClO4 gave unsatisfactory results. Thus, in this case, we used the neat condition (entry 5). In summary, we disclosed the facile synthesis of 3,5disubstituted piperidines from the easily available 1,4pentadienes via double Michael addition reactions. Further studies on the selective formation of one-isomer and the chemical transformations of the synthesized piperidines are underway.

Development of a Flexible Approach to Nuphar Alkaloids via Two Enantiospecific Piperidine-Forming Reactions

In this paper we describe the stereoselective synthesis of functionalized lactam 7 via two enantiospecific piperidine-forming techniques and its employment in a general synthetic approach to Nuphar alkaloids. Specifically, the formation of piperidine 18 by formal [3 + 3] cycloaddition and stepwise annelation processes is described; the latter technique was found to be significantly more efficient than the Pd-catalyzed TMM addition process. Finally, exploitation of the exocyclic alkene installed in the piperidine-forming reaction in the transformation of 18 to (-)-deoxynupharidine ((-)-2), (-)-castoramine ((-)-3), and (-)-nupharolutine ((-)-4) via intermediate lactam 7 is delineated.

Efficient Asymmetric Hydrogenation of Pyridines.

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Efficient asymmetric hydrogenation of pyridines.

available and the reaction has the potential for the simultaneous creation of multiple stereocenters. Here we describe an efficient and unprecedented auxiliary-based method for the asymmetric hydrogenation of substituted pyridines (YR= N), which enables the stereoselective formation of piperidines with up to four new chiral centers in a single operation (Scheme 2a). The heterogeneous catalytic hydrogenation of pyridines is usually performed in acidic media. Protonation not only activates the pyridines for hydrogenation, it also suppresses catalyst poisoning by the resulting piperidines. We reasoned that single-point attachment of chiral oxazolidinones 4 for ease of introduction of the auxiliary in the 2-position of the pyridine would be ideal (Scheme 2a). Moreover, it occurred to us that whereas conformation 2 should be strongly preferred for unprotonated pyridines due to dipole-moment minimization, upon protonation hydrogen bonding between the pyridinium and the oxazolidinone moiety would favor conformation 5, in which the auxiliary is oriented coplanar with the pyridine ring but rotated by 1808. Indeed, on hydrogenation the iPr substituent shields one of the diastereotopic p-faces and selective hydrogen transfer to the opposite side leads to aminal 6 (Scheme 2b). Substrates 2 can be readily synthesized from oxazolidinones and the corresponding 2-bromoor chloropyridines 1 by copper catalysis (Scheme 2a). Gratifyingly, hydrogenation of pyridine 2d in acetic acid under a hydrogen atmosphere of 100 bar with PtO2 as the catalyst led to the formation of (S)-3-methyl piperidine (3d) in 85% ee. Different catalysts were screened, and Pd(OH)2/C was identified as the optimum catalyst, providing 3d in 98% ee (Table 1, entry 4). Importantly, the reaction does not stop at aminal 6d, but leads directly to piperidine 3d and oxazolidinone 4. Evidently traceless cleavage of the auxiliary occurs under the reaction conditions, thereby combining chirality transfer from and release of the auxiliary into a single operation. We were pleased to find that after treatment of the crude reaction mixture with hydrochloric acid, separation and purification of the less soluble piperidine hydrochloride 3d and the more soluble auxiliary could be achieved efficiently by simple extraction with ether/hexanes mixtures. The piperidinium hydrochloride 3d was obtained in 90% yield (98% ee) and 4 was recovered unchanged (93% yield, > 99% ee), allowing the recycling of the auxiliary. This method for the stereoselective synthesis of piperidines has been applied successfully to a large number of substrates, whereby the oxazolidinone with a tBu group often resulted in slightly improved ee values relative to those obtained with the iPr group (Table 1). Substituents in the 4, 5or 6-position of the 2-oxazolidinone-substituted pyridine can be used to create stereocenters at the corresponding positions (entries 1–7). Even multiple stereocenters can be generated, as exemplified by the stereoselective formation of diand trisubstituted piperidines in near-quantitative yield and excellent enantioselectivities (entries 9, 10). As far as we know this is the first highly asymmetric hydrogenation of an aromatic compound that selectively generates three stereocenters. Under milder conditions we even succeeded in the stereoselective synthesis (> 95:5) of aminal 6j, which bears four new chiral centers (entry 11). Furthermore, functional groups on the pyridine ring are well tolerated (entries 3, 5–6). The versatility of the process can be increased still further, since hydrogenation of 2d in the presence of acetaldehyde or acetic anhydride results in the formation of the corresponding (S)-N-ethylpiperidine 7 (entries 12, 13). The only present limitation concerns 3-substitution of the pyridine ring. A methyl substituent in the 3-position leads to a less reactive substrate, presumably because the oxazolidinone is rotated out of the plane of the pyridine ring thereby shielding both pfaces. Hydrogenation of 2h results in a nearly racemic product (entry 8). Finally, we were pleased to find that our method gives easy access to coniine (3b), the poisonous hemlock alkaloid, in excellent yield and enantiomeric excess (entry 2). Scheme 1. Stereoselective hydrogenation of (hetero)aromatic compounds (YR=CR, N).

Synthesis of (+)-1-Deoxy- galactonojirimycin

A total synthesis of (+)-1-deoxygalactonojirimycin has been accomplished using stereoselective dihydroxylation and piperidine formation by catalytic hydrogenation.

ChemInform Abstract: An Unusual Carbon—Carbon Bond Scission Reaction with Molecular Oxygen under Mild Conditions; Formation of Piperidines from 1‐Azabicyclo[2.2.2]octanes.

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An unusual carbon–carbon bond scission reaction with molecular oxygen under mild conditions; formation of piperidines from 1-azabicyclo[2.2.2]octanes

Molecular oxygen reacts with 2-(1-phenylethyl)- and 2-benzhydryl-3-alkylimino-1-azabicyclo[2.2.2]octanes 1–7 in neutral solution at room temperature to form 1-acylpiperidine-4-carboxylic acid N-alkylamides 8–14. During the transformation two new carbonyl bonds are formed and a carbon–carbon bond is cleaved. The transformation is quite general provided the 2-substituent of the imine is of sufficient steric bulk, such as the 2-(1-phenylethyl) or 2-benzhydryl groups. No reaction is observed in the absence of a 2-substituent, as in the case of imine 15.

Comparison of carbon- and alumina-supported Mo, CoMo and NiMo catalysts in parallel hydrodenitrogenation and hydrodesulphurization

The effect of support (alumina, active carbon) and promoter (Co, Ni) on activity and selectivity of Mo catalysts was compared in parallel hydrodenitrogenation-hydrodesulphurization (HDNHDS) of pyridine and thiophene at 320 °C and 2 MPa of hydrogen pressure. Two commercial CoMo/alumina and NiMo/alumina catalysts were included for comparison. The undesirable formation of piperidine was much lower on carbon-supported and unpromoted Mo catalyst than on alumina-supported and Co- or Ni-promoted Mo catalyst. Irrespective of the type of support, the presence of Co or Ni accelerated mainly the HDS reaction; the unpromoted Mo catalysts had therefore better HDN/HDS selectivity than the CoMo and NiMo catalysts.

Intramolecular photochemical reactions of N-alkyl-5-phenyl-4-penten-1-amines

Irradiation of N-alkyl-5-phenyl-4-penten-1-amines results in the formation of intramolecular styrene-amine adducts and disproportionation products. Increasing the bulk of the N-alkyl group increases the regioselectivity of N-H transfer favoring the formation of piperidine vs. pyrrolidine products and favors disproportionation vs. cyclization.

A study of hydrodenitrogenation of pyridine catalyzed by sulfided Ni-Mo/γ-Al2O3

The hydroprocessing of fuels containing relatively large amounts of organonitrogen compounds becomes increasingly important in the upgrading of hydrocarbon fuels. Therefore, to investigate the removal of organonitrogen compounds, the hydrodenitrogenation of pyridine dissolved in n-heplane was studied over sulfided Ni-Mo/u-Al2O3 catalysts in the range of lemperature between 513 K and 633 K and pressure between 30 bar and 50 bar in a fixed bed flow reactor. Pyridine conversion increased with the increased temperature and pressure, and the piperidine formation was found to be irreversible. Pyridine concentration reached a maximum at about 573 K and the apparent reaction order was found to be one with respect to pyridine.

<i>In vitro </i>Formation of Piperidine, Cadaverine and Pipecolic Acid in Chick and Mouse Brain during Development

We have demonstrated for the first time in vitro formation of cadaverine and pipecolid acid from L-lysine in (a) chick embryos and chick embryo heads at 3–7 days of incubation (d.i.) and 5–7 d.i., respectively; (b) brain of chick embryos from 11 d.i. to 30 days after hatching (d.a.h.) for cadaverine and from 20 d.i. to 30 d.a.h. for pipecolic acid; (c) mouse brain from 2 days after birth up to 3 months after birth; and (d) mouse embryos at days 17–20 of gestation for cadaverine and at days 13 and 17 of gestation for pipecolic acid. No in vitro formation of piperidine from L-lysine could be found in either chick or mouse embryos. Only the large intestine of the chick with its contents was able to form piperidine from L-lysine at 30 d.a.h. Neither chick nor mouse embryos were able to form piperidine from cadaverine at any stage of development investigated. Piperidine was formed in very small amounts from D,L-pipecolic acid only in the brain of chick at 16 d.a.h. and in the large intestine with its contents at 30 d.a.h. The first demonstration of cadaverine and pipecolic acid biosynthesis in the avian and mammalian brain adds further support to a possible neural role of these two substances.

固体酸触媒による１，５‐ペンタンジオールの気相アンモノリシス

The vapor-phase ammonolysis of 1, 5-pentanediol was carried out over solid-acid catalysts such as γ-alumina at atmospheric pressure in the temperature range from 270°C to 400°C. Piperidine and tetrahydropyran were detected as main products. Among the solid-acid catalysts tested, γ-alumina was the best for the production of piperidine. The reaction conditions were investigated from the view-point of the yield of piperidine, and the maximum yield of 38.5 % was obtained at 360°C. From the relation between activity and acidity of the catalysts, it is suggested that Lewis acid may play an important role in the formation of piperidine.