Piperidine and pyrrolidine

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

Poupin P, Godon JJ, Zumstein E, Truffant N (1999) Degradation of morpholine, piperidine and pyrrolidine by microbacteria evidence for the involvement of a cytochrome P450. Can J Microbiol 45 209-216... 

Compound 642, obtained by condensation of glyoxal with benzotriazole and morpholine undergoes interesting [2+3] cyclocondensation with 2-aminopyridine to give imidazo[l,2- ]pyridine 643 (Equation 15) <2003JOC4935>. Similar derivatives of piperidine and pyrrolidine are also described. 2-Amino- and 6-aminopyrimidines react similarly to give imidazo[l,2- ]- and imidazoll - pyrimidines, respectively. 

For longer-chain or more bulky amines, yields and conversions are often significantly lower, possibly because the carbamate formed (Eq. (15)) is solid [99], but some successful syntheses have been reported. Siiss-Fink et al. were able to prepare the formamides of piperidine and pyrrolidine at 140 °C using... 

The chemistry of pepper has long been studied and the pungent principle of black pepper—a piperidine alkaloid, piperine 134—was isolated as early as 1877 (201). Its synthesis from the acid and piperidine was accomplished in 1882. (202). The corresponding pyrrolidine alkaloid trichostachyne (135) was isolated some 100 years later from several Piper species (see below). The cooccurence of piperidine and pyrrolidine alkaloids is a common feature of the chemistry of pepper. In many cases, the crude alkaloid extract is first cleaved with acids or bases and then each alkaloid is reconstituted by selective amidation. For the sake of unity, this chapter will be limited to comments on pyrrolidines, even in cases where they are minor alkaloids. 

Mannich reaction of 2-cyloalkyl(heteroaryl)-6-aryl-imidazo[2,l-A][l,3,4]thiadiazoles 161 with formaldehyde in the presence of cyclic bases (piperidine and pyrrolidine), in methanol with a catalytic amount of acetic acid, gives the corresponding C-alkylated derivatives 172 (Equation 8) <2006BMC3069>. 

The basicities of the simple heterocycles piperidine and pyrrolidine vary little from that of a secondary amine such as dimethylamine. pATa values for the conjugate bases of these three compounds are 11.1, 11.3, and 10.7 respectively. 

Reaction of Meldrum s acid derivative 25 with secondary alkylamines in dichloromethane at room temperature afforded a mixture of compounds, including furo[2,3- -l,2,3-dithiazoles 26, the novel Meldmm s acid derivatives 79a-g, and sulfur (Scheme 8 and Table 1). Usually the reaction time is less than 6h with yields of approximately 20%. Of note is the fact that cyclic amines such as piperidine and pyrrolidine do not produce furo[2,3- / -l,2,3-dithiazoles in this way <2000J(P1)3107>. 

By surveying 72 catalysts from the proline family, including piperidine- and pyrrolidine-derived catalysts, amino acids and diamines investigated over the past decade (Appendices 7.B-D), we may better understand both the structural features that are compatible with a successful catalyst and those which are detrimental and preferably avoided. 

RING REARRANGEMENT METATHESIS (RRM) - A NEW CONCEPT IN PIPERIDINE AND PYRROLIDINE SYNTHESIS... 

This chapter deals with applying ruthenium catalysed olefin metathesis to the synthesis of piperidine and pyrrolidine containing compounds. 

RRM has been implemented in the synthesis of fused carbocycles9 as well as a number of polycyclic ethers.10 This has been extended to the synthesis of piperidines and pyrrolidines via ROM-RCM or RCM-ROM-RCM combinations (Figure 3). 

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

Pandey, G., Devi Reddy, G., and Chakrabarti, D. (1996) Stereoselectivity in the photoinduced electron transfer (PET) promoted intramolecular cyclisations of l-alkenyl-2-silyl-piperidines and -pyrrolidines rapid construction of 1-azabicyclo [m.n.o] alkanes and stereoselective synthesis of ( )-isoretronecanol and ( )-epilupinine. Journal of the Chemical Society, Perkin Transactions 1, 219-224. 

RuCl2(PMe3)(C6Me6) and RuCl2(PMe3)(p-cymene) appear to be much more efficient catalysts than other mononuclear ruthenium complexes, or Ru3(CO)12, for a variety of secondary amines and terminal alkynes, such as diethylamine, morpholine, piperidine, and pyrrolidine (65,201), except for acetylene itself (202,203). The regioselective addition to the terminal carbon suggests that that the reaction proceeds via an arene ruthenium vinyl-idene intermediate that has been characterized (66) (Section II,A,3,d). 

Both of the racemic crystals of the piperidine and pyrrolidine complexes have chiral space groups before irradiation. The most important requirement for the racemic-to-chiral transformation is that the two molecules with R and S configurations crystallize in a chiral space group. Since the racemic compounds tend to make a pair around an inversion center in the process of crystallization, the racemic crystals, in general, have a center of symmetry. Otherwise, conglomerate crystals may be deposited from a racemic solution. Therefore, only several crystals with chiral space groups have been reported so far [38]. This may be a reason that such a racemic-to-chiral transformation has not been observed till now. 

The molecular structure of B after irradiation is shown in Fig. 21. Only the 1-cyanoethyl group was changed after irradiation. The inverted 1-cyanoethyl group takes a different conformation from those observed in the piperidine and pyrrolidine crystals the methyl group is replaced with the cyano group in the alaninate crystal, whereas the methyl group is replaced with the hydrogen atom in the piperidine and pyrrolidine crystals. Such an inversion mode has been found only in a crystal of (l-cyanoethyl)(3-hydroxypyridine)cobaloxime [42]. 

A wide variety of activities have been demonstrated for the alkaloids identified in myrmecine ant venoms, indicating that these small nitrogen heterocycles have been adapted to subserve multiple functions. Both the piperidines and pyrrolidines possess diverse pharmacological activities (reviewed in 1), and it seems likely that their roles in regulating both intra- and interspecific interactions are very significant. 

The monocyclic 2,6-disubstituted piperidines have been considered as possible precursors for dendrobatid alkaloids containing piperidine rings, such as the histrionicotoxins, decahydroquinolines, and gephyrotoxins (see Ref. J). Similarly, the monocyclic 2,5-disubstituted pyrrolidines have been considered as possible precursors for dendrobatid alkaloids containing pyrrolidine rings, such as the pumiliotoxins, the indolizidines, and now the pyrrolizidines (see Ref. 5). It should be noted that 2,6-disubstituted piperidines and 2,5-disubstituted pyrrolidines occur only rarely in dendrobatid frogs, while in ants they appear as major venom constituents, along with pyrrolizidines and indolizidines. It has been proposed that the monocyclic piperidines and pyrrolidines may serve as biosynthetic precursors of the bicyclic alkaloids in ants 125,134). 

Figure 19.6 Piperidine and pyrrolidine iminosugars obtained by catalysis with (a) RAMA, (b) RhuA and FucA, (c) RhuA and (d) FucA.

Direct N-nitration of secondary amines by nitric acid is possible only for weakly basic amines. The more basic amines can be nitrated under neutral conditions widi reagents such as dinitrogen pentoxide and nitronium tetrafluoroborate, but nitrosamines are significant by-products. The nitrate ester CF3CMe20N02 has been recommended as a nonacidic nitrating agent for secondary amines which avoids the problem of contamination of the products by A(-nitrosamines piperidine and pyrrolidine were nitrated in yields of 75% and 72%, respectively. Amides and imides are efficiendy N-nitrated using ammonium nitrate in trifluoroacetic anhydride. ... 

The intramolecular conjugate addition of in situ, chemoselectively generated amines 2 bearing an electrophilic double bond in the cu-position leads to functionalized pyrrolidines and piperidines 3 under very mild conditions34. The cyclization step occurs smoothly and the piperidine and pyrrolidine derivatives are obtained as a mixture of diastereomers with good diastereose-lection in most cases. The reactions are under kinetic control and the geometry of the starting alkene does not seem to have an influence on the stereochemical outcome of the cyclization step. 

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