Piperidines and Pyridines

Piperidine and pyridine ring systems are the key structural elements in a vast array of natural products as well as in a large class of biologically active natural products. They are also often embedded within scaffolds as privileged structures by medicinal chemists. Indeed, over 12000 piperidine derivatives have been mentioned in clinical or preclinical studies during the last ten years. The development of new methods for the synthesis of multi-functionalized piperidines and pyridines is therefore of considerable importance.  

The Barbier reaction of y-cyanoesters 550 with allylindium reagent generated in situ from allyl bromide and indium powder in THF mainly afforded dia- 

Piperidines 564 could also be synthesized via palladium-mediated Heck-type reactions, which have been presented as an efficient synthetic method for the 

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It is now applied more widely to include malonic acid derivatives, such as diethyl monoethyl-malonate, ethyl cyanacetate, etc. Various amines may be used as catalysts, and usually the most effective is piperidine (hexahydro-pyridine) a mixture of piperidine and pyridine, or pyridine alone, is also often used. 

Bases, such as potassium or sodium hydroxide, piperidine, and pyridine, react with primary and secondary hydroperoxides to form aldehydes or ketones (28). In some cases, this reaction is slow or fails unless heating is employed. 

Blanco et al. (1994) reported measurements of the vapor pressure (P,at) for p-xylene, y-picoline, piperidine, pyridine and tetralin. The data for piperidine and pyridine are given in Table 3.4. A suitable equation to correlate these data is Antoine s relationship given next... 

Table 3.4 Vapor Pressure Data for Piperidine and Pyridine...

Blanco et al. (1994) presented VLE data at 26.66+0.03 kPa for binary systems of tetralin with p-xylene, g-picoline, piperidine, and pyridine. The data for the pyridine (1)—tetralin (2) binary are given in Table 15.7. 

From the pATa values shown, there is relatively little difference in basicities for diethylamine, pyrrolidine, or piperidine. Note, however, that morpholine and piperazine are weaker bases than piperidine. This is the result of an electron-withdrawing inductive effect from the second heteroatom, making the nitrogen atom both less basic and also less nucleophilic. This makes morpholine a useful base with basicity between that of piperidine and pyridine pK 5.2) (see Section 4.6). The second pK value for the diamine piperazine is substantially lower than the first, since the inductive effect from the protonated amine will withdraw electrons away from the unprotonated amine (see Section 4.7). 

Comparison with axial ligand complexes formed by Ni porphyrins in coordinating solvents (e. g. pyrrolidine, piperidine, and pyridine), however, shows a clear distinction between the frequencies of the "form 5" marker lines of the reconstituted proteins and those of the 6-coordinate models (9). The shifts of the 6-coordinate species relative to the 4-coordinate species are larger than for the form labeled 5 (Figure 1) of the proteins. The shifts for the 6-coordjnate models are about -41 cm ( iq)> i cm (i/g), and -41 cm (i/ ) for the core-size markers ana -12 cm... 

A number of elegant transient absorption studies have shown that nickel porphyrins possess a rich and complicated excited state photochemistry (3-5). In these studies it was concluded that in basic solvents such as piperidine and pyridine the state of... 

Tables I through VIII summarize the occurrences of alkaloids from ants and other insects. Each table presents chemical structures as well as specific sources of particular types of alkaloids e.g.. Table I covers piperidines and pyridines. Table II, pyrrolidines, pyrroles, and indolizidines.

Numerous UCNMR investigations on alkaloids have been reported in the literature [598, 599]. In Table 5.13 the 13C chemical shifts and structures of representative alkaloids of different types are collected Pyrrolidine, piperidine and pyridine [600-602], tropane [600, 603-605], izidine [606-612], indole [600, 603, 613-633], isoquinoline [599, 630, 634-647], quinolinic [648-656], imidazole [657], yuzurimine alkaloids [658], alkaloids with exocyclic nitrogen [659, 660], diterpenoid [661-663], steroid [664-666] and peptide alkaloids [667-671], The complete signal assignment for the alkaloids given in Table 5.13 was achieved using the correlations between 13C NMR spectral parameters and structural properties and the 13C chemical shift values of model compounds described in Chapters 3 and 4 of this monograph. 

Since that time, a general correlation between yield of extract and carbon content has been reported for ethylenediamine (Table 10.2). Various other amine solvents (e.g., monoethanolamine) show similar behavior insofar as the extract yield may decrease markedly with increase in rank for coals under 85% carbon. On the other hand, the yield of extract using solvents such as benzylamine, piperidine, and pyridine may show much less variation with rank, and the effectiveness of many solvents may decrease markedly for coal having more than 88% carbon (van Krevelen, 1965). 

A new monograph on alkaloid chemistry has been published parts of it are devoted to pyrrolidine, piperidine, and pyridine alkaloids.1 A review on the synthesis of alkaloids via nitrones has appeared,2 and another on the photochemistry of alkaloids, which includes a section on alkaloids of this group.3... 

The first extensive kinetic examination of the HDN reaction was published by Mcllvried.22a He studied the HDN of piperidine and pyridine diluted in xylene on a presulphided Co-Ni-Mo/Al203 catalyst in steady state conditions at 315°C, varying space velocity, amine feed rate, H2 flow, and pressure between 50 and 70 atm. Analysis of the reaction products did not however lead to identification of each of them. He assumed that the general reaction of pyridine HDN is stepwise and follows the general network ... 

Both piperidine and pyridine serve as structure-directing agents in the commercial production of Ferrierite zeolite. More recently, use of DMAP has allowed preparation of novel metallo-aluminophosphate molecular sieves with both small- <2006W02006037437> and large-pore architecture <2006USA074267>. 

The examples of substituted piperidines and pyridines show that ctbi depends on position and polarity of the substituents (Table XXI). Apolar groups seem to make the best fit with the receptor at position 3 or 4, while the negative influence of polar groups on the hydrophobic contact seems to be minimal at position 2. 

Chapter 2 Pyrrolidine, Piperidine, and Pyridine Alkaloids By A. R. Pinder... 

Two new monographs on alkaloid chemistry have appeared both contain sections on pyrrolidine, piperidine, and pyridine alkaloids.1,2... 

Ptnder AR (1992) Azetidine, pyrrole, pyrrolidine, piperidine, and pyridine alkaloids. Nat Prod Rep 9 491-504... 

The hybridization of the orbital that contains an amine s lone pair also affects its basicity. This is illustrated by comparing the basicity of piperidine and pyridine, two nitrogen heterocycles. The lone pair in piperidine resides in an sp hybrid orbital that has 25% s-character. The lone pair in pyridine resides in an sp hybrid orbital that has 33% s-character. 

Like the pyrrolidine ring, the piperidine and pyridine rings are found in a number of alkaloids, including nicotine, strychnine, cocaine, and reserpine (see p. 1004). 

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