Piperidines and Related Compounds

Under Pummerer rearrangement conditions, a-methylthio amide 248 affords a mixture of 2-piperidone 249 and pyridin-2-(3//)-one 250 (86CPB1061). 

A direct synthesis of cyclic quinone imine acetals has been accomplished by the treatment of substituted phenol ethers bearing an alkyl azido side chain with IBTA (Eq. 39) [96JCS(CC)1491]. The cyclization reaction proceeds smoothly in polar and low nucleophilic solvents such as CF3CH2OH and (CF3)2CH0H in the presence of 10% MeOH. 

On cyclization with IBTA, A-methoxyamides 254 are converted to N-methoxytetrahydroquinoline 256. The reaction proceeds via intermediate 255, which undergoes intramolecular cyclization to give 256 (90CL581). 

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Intermolecular cycloaddition reactions constitute an important and convergent route to piperidines and related compounds. The research group of Franklin Davis at Temple University published a novel route to optically active piperidines that proceeded through an imino Diels-Alder reaction with enantiomerically enriched compound 84 (Scheme 16) <02OL655>. On reaction with ftww-l,3-pentadiene, intermediate 85 was produced as a single diastereomer in 89% yield. Hydrogenation of this strained intermediate yielded the 2,6-disubstituted piperidine 86 in 75% yield. 

Piperidines and Related Compounds.—A simple synthesis of substituted N-arylpiperidines from hepta-1,6-diene is available (Scheme 83). ... 

Undoubtedly, the two main areas of interest and controversy in this general area are (i) tautomerism, particularly in the vinylogous amides 2- and 4-pyridinone and related compounds, and (ii) the question of conformation in piperidine structures. 

H. Sugimoto, Y. Iimura, Y. Yamanishi, K. Yamatsu, Synthesis and antiacetylcholinesterase activity of l-benzyl-4-[(5,6-dimethoxy-l-indanon-2-yl)methyl]piperidine hydrochloride (E2020) and related compounds, Bioorg. Med. Chem. Lett. 2 (1992) 871-876. 

Ring closure in the 4-position of the piperidine nucleus by an intramolecular Claisen condensation of di-(/3-carbethoxyethyl)-amines and related compounds leads to 4-pipetidones in excellent yields. ... 

In contrast to pyridine, isoquinoline, acridine and related compounds which fail to undergo ionic hydrogenation1, Hantzsch-type 1,4-dihydropyridines 1 are conveniently reduced by tri-ethylsilane/trifluoroacetic acid to yield the all-nww-isomers of 1,2,3,4-tetrahydropyridines 2 and piperidines 311. The steric course of the reduction is a function of the temperature and the amount of silane used. 

The IR-spectra of 41 tobacco alkaloids and related compounds have been tabulated (S5). Nornicotine, nicotine, myosmine, nicotyrine, anabasine, anatabine, and dihydronicotyrine were separated from an extract of tobacco alkaloids by countercurrent partition (86). Thin-layer chromatography has been used to separate nicotine, nornicotine, anabasine, and nicotyrine (57). The use of gas chromatography to separate tobacco alkaloids has been studied. The retention times of 11 tobacco alkaloids on polyethylene glycol columns has been reported (88) and the effect of the column packing on the retention times of pyridine bases has been described (89). Mixtures containing pyrrolidine, piperidine, pyridine, and various alkylated pyridines have been separated using programed temperature control (90). 

As37mmetric synthesis of hydroxylated piperidines and related bioactive compounds 06SL1133. 

Sugimoto, H., limura, Y., Yamanishi, Y, Yamatsu, K. Synthesis and structure-activity relationships of acetylchoUnesterase inhibitors l-benzyl-4-[(5,6-dimethoxy-l-oxoindan-2-yl)methyl]piperidine hydrochloride and related compounds. J. Med. ChertL 1996,38,4821—4829. 

The syntheses of dithiopyr (1), thiazopyr (2) and related compounds [4, 5] begin with a Hantzsch-type base-catalyzed intermolecular cyclization [22], which provides the dihydropyridines 4 (R = Me or Et). Two equivalents of methyl or ethyl trifiuoroacetoacetate (5, R = Me or Et) are allowed to react with one equivalent of isovaleraldehyde (6) in the presence of a base, like piperidine, in a suitable solvent at temperatures varying from room temperature to reflux. The intermediate dihydroxytetrahydropyran (structure not shown) is converted into the dihy-droxypiperidine 7 by reaction with a nitrogen source, such as ammonium hydroxide or ammonia gas. Reaction of 7 with a dehydrating agent, such as concentrated sulfuric acid, toluenesulfonic acid, or trifluoroacetic anhydride, gives a mixture... 

Also available are papers that deal with (i) the chemistry of 1,2-dichIorovinyl trifluoromethyl sulphone [dHCl CHCl + CFa SCI-Av-i-CFa S-CHCl CHQs- -(with CFs COsH) CF3 SO CHCI CHCI2 -> (with EtsN) CFrSO-CCl CHa (with CFs-COsH) CFs SOs-CChCHCl (with p-ClCaH -SH) CFs-SOa-CCl -CH-S-C6H4CI-P (with CFs-COsH) CF3SO2CCI CH-SOa-C0H4CI-p CFs SOa-CChCHCl + NaaS (CF3 S02-CCl CH)aS (with CFa-COsH) (CF3-SOa CCI CH)aSOa CFs SOa-CChCHCl + RH CFs-SOa-CCliCHR (R = piperidine)] (ii) yet more information on the conversion of perfluoro-olefins into /3-sultones and related compounds(iii) analysis of the F n.m.r. 

A rapid route to N-substituted trihydroxypiperidines (l,5-dideoxy-l,5-imino-pentitols) by nucleophilic opening of bis-epoxides derived from d- and L-ara-binitol, D-xylitol and related compounds has been reported. The 3-0-benzyl-Zn s-epoxides, generated by tosylation of the primary hydroxyl groups followed by treatment with sodium hydride and benzyl bromide, were treated with primary amines to yield piperidine/pyrrolidine mixtures, whose composition was found to be dependent on the nature of the alditol precursor, the amine and the reaction... 

Pinder, a. R., Pyrrole, pyrrolidine, pyridine, piperidine and related alkaloids, in Alkaloids and Sulphur Compounds (P. G. Waterman, ed.), Vol. 8 of Methods in Plant Biochemistry (P. M. Dey and J. B. Harborne, eds.), 241-269, Academic Press, London, 1993. 

Three-membered Ring Nitrogen Heterocycles Four-membered Ring Nitrogen Heterocycles Pyrrolidines and Related Compounds Piperidines and Related Heterocycles... 

While the benzylidine (or alkylidine) acetoacetates and related compounds are sometimes referred to as Knoevenagel products, it is important to note that Knoevenagel was by no means the first to produce these products by the condensation of ethylacetoacetate and aldehydes, as this had been done at least ten years earlier by Claisen and others. The important contribution of Knoevenagel was the discovery of a method that allowed for these condensations to take place under much milder conditions (i.e., catalytic piperidine at 0 °C) than was allowed by the previous methods (anhydrous HCl, sodium alkoxides etc.). 

Three syntheses of homopumiliotoxin alkaloids are compared below, and one more reaction leading to homo-pumiliotoxin-related compounds was mentioned in Section 12.01.9.3.7. The strategies involved for the ring-closure procedures leading to the quinolizidine system involved the formation of a- or 7-bonds from piperidine precursors and are summarized in Scheme 97. 

Rearangement of furoxans leads to the formation of new heterocyclic systems derivatives of triazoles, diazoles, isoxazoles, and pyrimidinones. For example, on the basis of the experimental results using labeled compound 52-15N , the formation of 8-phenyltheophylline 53, the 1,3-dimethylalloxazines (54 n = 0, 1), and l,3,7,9-tetramethyl-l//,9//-pyrimido[5,4-g]-pteridine-2,4,6,8-tetraone 55 in the thermal reaction of the iV-oxide 52 with benzylamine, aniline, or piperidine and the generation of NO or NO-related species in the reaction with iV-acetylcysteamine were reasonably explained by... 

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