[110-89-4]  · C5H11N  · Piperidine  · (MW 85.17)

(secondary amine base;1 condensation catalyst for aldol,4 Knoevenagel,3 and Michael condensations;20 thiophile for mediation of sulfoxide-sulfenate rearrangement;13 reagent for enamine formation and utilization22)

Physical Data: mp -9 °C; bp 106 °C; d 0.862 g cm-3; secondary amine base of pKa 11.12.

Solubility: miscible with water; sol common organic solvents (alcohol, benzene, chloroform).

Form Supplied in: liquid (99%). Drying: by treatment with standard drying agents, e.g. CaH2, BaO, sodium metal, P2O5, or KOH.

Purification: distillation may be carried out directly from CaH2, P2O5, or sodium.2

Handling, Storage, and Precautions: toxic either by absorption through the skin or by breathing. It is highly flammable, with a flash point of 16 °C. Use in a fume hood.

Condensation Catalyst.

Piperidine has had wide usage as a catalyst for aldol condensations, particularly cyclization processes. It is typically also the catalyst of choice, usually in combination with a carboxylic acid, for condensations of relatively acidic carbonyl compounds with aldehydes and ketones: the Knoevenagel condensation.3 Michael addition of 2-methylcyclohexane-1,3-dione to methyl vinyl ketone in the presence of potassium hydroxide affords a triketone which upon treatment with piperidine4 (or Pyrrolidine) cyclizes to produce the Wieland-Miescher ketone (eq 1).5

The particular choice of secondary amine catalyst and acid copartner has been noted to affect the chemoselectivity, and by extension the regioselectivity, of dialdehyde cyclization. Thus piperidine-Acetic Acid mediates the closure of dialdehyde (1) to enals (2) and (3) in a ratio of 19:1 (eq 2).6 The combination of Morpholine and camphoric acid affords a 1:25 ratio of the two cyclization products. Similar ratios were observed with related dialdehyde substrates.

Piperidine in protonated form and accompanied by a carboxylate counterion is, as noted, the reagent of choice for classical Knoevenagel condensation.3 Typical among these are condensations of malonic esters and acetoacetic esters with aromatic aldehydes (eq 3),7 aliphatic aldehydes (eq 4),8 and ketones (eq 5).9

The entire Robinson annulation sequence for preparing substituted cyclohexenones has also been carried out with piperidine itself as the catalyst for both the Michael and the aldol steps (eq 6).10-12 In these cases, only a catalytic quantity of piperidine is employed and deethoxycarbonylation of an intermediate b-hydroxycyclohexanone is achieved by heating of the initial reaction products to 100 °C.

Piperidine also serves as an effective thiophile and has been used as both the condensation catalyst and the oxygen-sulfur bond cleavage reagent in Knoevenagel/sulfoxide-sulfenate rearrangement sequences,13-17 leading to g-hydroxy-a,b-unsaturated nitriles (eq 7), esters, and sulfones.

In many of these cases of piperidine catalysis, the amine presumably acts not only as a simple base for deprotonating relatively acidic b-dicarbonyl compounds but in two other critical and important ways.18 First, piperidine, particularly when used in conjunction with a carboxylic acid, serves to convert aldehydes and ketones to their electrophilically more reactive iminium derivatives, and second, through the formation of enamines from the donor components of condensation reactions, it effects the conversion of the initial carbonyl compound into a reactive nucleophilic center. Illustrative of the role of piperidine as an imine/enamine-forming agent rather than as a simple base is the selective cleavage of a bis-b-alkoxycarbonyl system (eq 8).19 Only the less-hindered carbonyl suffers b-elimination, indicating that the cleavage is initiated by enamine formation rather than by simple proton removal. The product is stable to the reaction conditions.

Piperidine catalyzes Michael addition reactions by both carbon20 and heteroatom21 nucleophiles (eqs 9 and 10).

Enamine Formation.

Piperidine forms enamines more slowly than does pyrrolidine. The enamines have no particular synthetic advantages over the corresponding pyrrolidine or morpholine derivatives and have seen limited utilization. The piperidine enamines of cycloalkyl carbaldehydes are useful for the preparation of spiro bicyclic unsaturated ketones (eq 11).22

1. Rubiralta, M.; Giralt, E.; Diez, A. Piperidine; Elsevier: New York, 1991.
2. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988; p 542.
3. Jones, G. OR 1967, 15, 204.
4. Ramachandran, S.; Newman, M. S. OSC 1973, 5, 486.
5. Wieland, P.; Miescher, K. HCA 1950, 33, 2215.
6. Harayama, T.; Takatani, M.; Yamanaka, A.; Ikeda, H.; Ono, M.; Inubushi, Y. CPB 1981, 29, 766.
7. Horning, E. C.; Horning, M. G.; Dimmig, D. A. OSC 1955, 3, 165.
8. Tietze, L. F.; Beifuss, U. TL 1986, 27, 1767.
9. Farmer, E. H.; Ross, J. JCS 1926, 1570.
10. McCurry, P. M.; Singh, R. K. SC 1976, 6, 75.
11. Horning, E. C.; Denekas, M. O.; Field, R. E. OSC 1955, 3, 317.
12. Horning, E. C.; Denekas, M. O.; Field, R. E. JOC 1944, 9, 547.
13. Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.; Wakabayashi, S. JACS 1984, 106, 7890.
14. Nokami, J.; Mandai, T.; Imakura, Y.; Nishiuchi, K.; Kawada, M.; Wakabayashi, S. TL 1981, 22, 4489.
15. Burgess, K.; Henderson, I. TL 1989, 30, 4325.
16. Trost, B. M.; Grese, T. A. JOC 1991, 56, 3189.
17. Dominguez, E.; Carretero, J. C. TL 1990, 31, 2487.
18. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park, CA, 1972; p 856.
19. Johnson, W. S.; Edington, C.; Elliott, J. D.; Silverman, I. R. JACS 1984, 106, 7588.
20. Tyndall, D. V.; Nakib, T. A.; Meegan, M. J. TL 1988, 29, 2703.
21. Baraldi, P. G.; Barco, A.; Bennetti, S.; Pollini, G. P.; Zanirato, V. TL 1984, 25, 4291.
22. Kane, V. V.; Jones, M. OS 1983, 61, 129; Kane, V. V.; Jones, M., OSC 1990, 7, 473.

David Goldsmith

Emory University, Atlanta, GA, USA

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