Piperidines with Fused Rings

The conformational properties of a range of iV-nitrosodecahydroquino-lines have been based on 13C- and H-NMR spectral data. The Af-ni-troso-2/J-methyl-tran.s-decahydroquinoline (151), for example, in which the unfavorable interaction between substituents cannot be relieved by inversion as in yV-nitroso-2,6-cis-dimethylpiperidine (Section III,C,l,c) adopts conformations with the piperidine ring in a boat or twist form.204 

The 220 MHz NMR spectrum of N-methyl-cis-decahydroquinoline recorded at -30°C shows two iV-Me singlets in the ratio 2 1 and the 13C-NMR spectrum at — 50°C enables the equilibrium to be estimated as 70% N-inside (160) 30% N-outside (161). Replacement of N-Me by N-Et shifts the equilibrium 162 163 in favor of the N-outside conformation (86% 163).80 

Because of the relatively short C—N bond length, the most unfavorable interaction in the N-outside207a conformation involves C-2—N—C-8a— C-8, whereas the N-inside conformation is destabilized by the R—N—C-8a—C-8 interaction. This latter interaction increases with increasing size of 

On changing from 8/1-tm-butyl-ct.s-decahydroquinoline (156 157 R = H) to 8/ -tm-butyl-N-methyl-cis-decahydroquinoline (156 157 R = Me) the equilibrium shifts from 97% 156 (R = H) (at — 75°C in CDC13) to 62% 156 (R = Me) and 38% 157 (R = Me) with an axial IV-Me (at — 80°C in CDC13). Explanations have been offered in terms of deformations caused by the ferf-butyl group, altering the magnitudes of interactions from those in N-methylpiperidine.206 

Positive value indicates preference for first conformer drawn. 

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Other examples include CAN oxidation of silylmethyl amines and amides with the synthesis of aryl-fused piperidine and pyrrolidine ring derivatives.360... 

Reaction of arylhydrazones 216 of piperidin-2-ones with methyl chloro-formate, phosgene, or thiophosgene yielded (80USP4213773) the fused-ring system 217. Reaction of 2,2 -azopyridine (218) with diazoalkanes afforded [66JCS(C)78 73LA2088] the 2-(pyrid-2-yl)-l,2,4-triazolo[4,3-a]-... 

The H-NMR spectra of salts of morphine and its congeners are complicated by the existence of protonated epimers, evident from signal duplication and first reported in a 600 MHz study carried out at low pH to slow the interconversion rate Figure 5.10 and [44]). The usual pronounced preference of N-methyl for the equatorial conformation in piperidine derivatives is reduced in the fused-ring system of morphine by non-bonded interactions with the fi-lO-... 

We observe another structural variation for a piperidine alkaloid in the compound lupinine (3.16), which is isolated from seeds of Lupinus and Anabasis plants. Here, nitrogen is found at the junction of two fused rings. There are two chiral carbon atoms, so there will be four possible stereoisomers. Natural lupinine has only one of these isomeric stmctures, with the attached H atoms cis to each other. Nitrogen is not chiral because of the phenomenon of pyramidal inversion. This will be discussed in Chapter 10. 

More interest has been shown in ionic liquids derived from the 5- and 6-membered saturated nitrogen heterocycles, pyrrolidine and piperidine. iV,lV-dialkyl salts from these secondary amines display polymorphism f Section 11.2.31 as well as a propensity to frustrate attenpts to crystallise them Related materials (with some ring unsaturation, two heteroatoms or wiA fused ring structures) are discussed in Section 11.19.S. 

In spite of the diverse nature of alkaloid structures, two structural units, i.e. fused pyrrolidine and piperidine rings in different oxidation states, appear as rather common denominators. We therefore chose to give several examples for four types of synthetic reactions which have frequently been used in alkaloid total synthesis and which provide generally useful routes to polycyclic compounds with five- or six-membered rings containing one nitrogen atom. These are ... 

Aldoximes can be oxidatively dehydrogenated to nitrile oxides using a variety of oxidants such as lead tetraacetate [16a], alkali hypohalites [lla],NBS in DMF followed by base treatment [16b], chloramine-T [11b], 1-chlorobenzotriazole [16c], mercuric acetate [ 16 d], etc. However, we employed either NaOCl or chloramine-T for most of our INOC reactions. For instance, a piperidine ring fused to an isoxazoline as in 14 was constructed using the INOC methodology (Scheme 3) [17]. Monoalkylation of N-tosylallylamine 10 with the bromoacetal... 

X-Ray diffraction analyses of vincristine methiodide (39) and vinzoli-dine 1-naphthalene sulfonate (40) provide atomic coordinates of compounds that are either modified in the velbanamine portion (alkylation at N-6, Fig. 3) or in the vindoline portion (a spiro-fused oxazolidinedione at C-3 and C-23, Fig. 4). These structures show a chair-boat conformation for ring C with C-8 exhibiting an endo pucker. Ring D is clearly in a chair conformation, but, in contrast to the conclusions drawn from C-NMR studies, the N-6 -C-7 bond is axial relative to the piperidine ring. 

In a Ni-couple reaction, the benzo ring of tetrahydroisoquinolines is formed by reaction of acetylenes with piperidine-fused zirconocyclopentadienes (Scheme 76) <1999JA11093>. 

Mirtazapine 105, a polycyclic pyridine derivative containing a pyridine ring fused with an azepine ring system, is an antidepressant <2006W02006/008302>. The piperidine derivatives paroxetine 106, alnespirone 107, and Azaloxan... 

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