PIPERIDINE 1
CHO
Piperidine1 H
NH
CHO HOAc
O O
R
N
(1)
H
CHO
H H
[110-89-4] C5H11N (MW 85.17)
(2)
+
InChI = 1/C5H11N/c1-2-4-6-5-3-1/h6H,1-5H2
CHO
InChIKey = NQRYJNQNLNOLGT-UHFFFAOYAY O O O O
R
R
(secondary amine base;1 condensation catalyst for aldol,4 Kno- (2) (3)
evenagel,3 and Michael condensations;20 thiophile for mediation
of sulfoxide sulfenate rearrangement;13 reagent for enamine for-
Piperidine in protonated form and accompanied by a carboxy-
mation and utilization22)
late counterion is, as noted, the reagent of choice for classical Kno-
ć% ć%
evenagel condensation.3 Typical among these are condensations
Physical Data: mp -9 C; bp 106 C; d 0.862 g cm-3; secondary
of malonic esters and acetoacetic esters with aromatic aldehydes
amine base of pKa 11.12.
(eq 3),7 aliphatic aldehydes (eq 4),8 and ketones (eq 5).9
Solubility: miscible with water; sol common organic solvents
(alcohol, benzene, chloroform).
CHO
NH
CO2Et
Form Supplied in: liquid (99%).
+
Drying: by treatment with standard drying agents, e.g. CaH2,
CO2Et
OH
NH2+  OCOMe
BaO, sodium metal, P2O5, or KOH.
Purification: distillation may be carried out directly from CaH2,
CO2Et
P2O5, or sodium.2
(3)
Handling, Storage, and Precautions: toxic either by absorption
O O
through the skin or by breathing. It is highly flammable, with a
ć%
flash point of 16 C. Use in a fume hood.
NH
CO2Me
+
CHO
AcOH
CO2Me
Condensation Catalyst. Piperidine has had wide usage as 82%
a catalyst for aldol condensations, particularly cyclization pro-
CO2Me
cesses. It is typically also the catalyst of choice, usually in
(4)
combination with a carboxylic acid, for condensations of rela-
CO2Me
tively acidic carbonyl compounds with aldehydes and ketones: the
Knoevenagel condensation.3 Michael addition of 2-methylcyclo-
hexane-1,3-dione to methyl vinyl ketone in the presence of potas-
O
sium hydroxide affords a triketone which upon treatment with NH
CN
CN
piperidine4 (or Pyrrolidine) cyclizes to produce the  Wieland + (5)
70%
CO2Et
CO2Et
Miescher ketone (eq 1).5
OH
O O The entire Robinson annulation sequence for preparing substi-
N
tuted cyclohexenones has also been carried out with piperidine
KOH H
+
itself as the catalyst for both the Michael and the aldol steps
O O O (eq 6).10 12 In these cases, only a catalytic quantity of piperi-
O dine is employed and deethoxycarbonylation of an intermediate
²-hydroxycyclohexanone is achieved by heating of the initial re-
ć%
(1)
action products to 100 C.
O
O
NH
O
The particular choice of secondary amine catalyst and acid
+ (6)
R CHO
CO2Et
copartner has been noted to affect the chemoselectivity, and by
EtOH
R
71 87%
extension the regioselectivity, of dialdehyde cyclization. Thus
CO2Et
piperidine Acetic Acid mediates the closure of dialdehyde (1) to
R = Me, Et, Pr, Bu, C5H11, C6H13
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 Piperidine also serves as an effective thiophile and has been
dialdehyde substrates. used as both the condensation catalyst and the oxygen sulfur
Avoid Skin Contact with All Reagents
2 PIPERIDINE
bond cleavage reagent in Knoevenagel/sulfoxide sulfenate rear- Enamine Formation. Piperidine forms enamines more slowly
rangement sequences,13 17 leading to Å‚-hydroxy-Ä…,²-unsaturated than does pyrrolidine. The enamines have no particular synthetic
nitriles (eq 7), esters, and sulfones. advantages over the corresponding pyrrolidine or morpholine
derivatives and have seen limited utilization. The piperidine enam-
ines of cycloalkyl carbaldehydes are useful for the preparation of
O NH
spiro bicyclic unsaturated ketones (eq 11).22
+ S CN
Ph 85%
O
CHO NH
(11)
CN O
(7)
O
OH
In many of these cases of piperidine catalysis, the amine pre-
1. Rubiralta, M.; Giralt, E.; Diez, A. Piperidine; Elsevier: New York, 1991.
sumably acts not only as a simple base for deprotonating relatively
acidic ²-dicarbonyl compounds but in two other critical and im- 2. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals,
3rd ed.; Pergamon: Oxford, 1988; p 542.
portant ways.18 First, piperidine, particularly when used in con-
3. Jones, G., Org. React. 1967, 15, 204.
junction with a carboxylic acid, serves to convert aldehydes and
4. Ramachandran, S.; Newman, M. S., Org. Synth., Coll. Vol. 1973, 5, 486.
ketones to their electrophilically more reactive iminium deriva-
5. Wieland, P.; Miescher, K., Helv. Chim. Acta 1950, 33, 2215.
tives, and second, through the formation of enamines from the
donor components of condensation reactions, it effects the conver- 6. Harayama, T.; Takatani, M.; Yamanaka, A.; Ikeda, H.; Ono, M.; Inubushi,
Y., Chem. Pharm. Bull. 1981, 29, 766.
sion of the initial carbonyl compound into a reactive nucleophilic
7. Horning, E. C.; Horning, M. G.; Dimmig, D. A., Org. Synth., Coll. Vol.
center. Illustrative of the role of piperidine as an imine/enamine-
1955, 3, 165.
forming agent rather than as a simple base is the selective cleavage
8. Tietze, L. F.; Beifuss, U., Tetrahedron Lett. 1986, 27, 1767.
of a bis-²-alkoxycarbonyl system (eq 8).19 Only the less-hindered
9. Farmer, E. H.; Ross, J., J. Chem. Soc. 1926, 1570.
carbonyl suffers ²-elimination, indicating that the cleavage is ini-
10. McCurry, P. M.; Singh, R. K., Synth. Commun. 1976, 6, 75.
tiated by enamine formation rather than by simple proton removal.
11. Horning, E. C.; Denekas, M. O.; Field, R. E., Org. Synth., Coll. Vol.
The product is stable to the reaction conditions.
1955, 3, 317.
12. Horning, E. C.; Denekas, M. O.; Field, R. E., J. Org. Chem. 1944, 9,
C9H19 t-Bu
547.
NH
O O 13. Ono, T.; Tamaoka, T.; Yuasa, Y.; Matsuda, T.; Nokami, J.; Wakabayashi,
C9H19 t-Bu
(8)
S., J. Am. Chem. Soc. 1984, 106, 7890.
AcOH
O
OH O
90%
14. Nokami, J.; Mandai, T.; Imakura, Y.; Nishiuchi, K.; Kawada, M.;
Wakabayashi, S., Tetrahedron Lett. 1981, 22, 4489.
15. Burgess, K.; Henderson, I., Tetrahedron Lett. 1989, 30, 4325.
16. Trost, B. M.; Grese, T. A., J. Org. Chem. 1991, 56, 3189.
Piperidine catalyzes Michael addition reactions by both
17. Dominguez, E.; Carretero, J. C., Tetrahedron Lett. 1990, 31, 2487.
carbon20 and heteroatom21 nucleophiles (eqs 9 and 10).
18. House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo
Park, CA, 1972; p 856.
Ph
19. Johnson, W. S.; Edington, C.; Elliott, J. D.; Silverman, I. R., J. Am. Chem.
O
NH
Soc. 1984, 106, 7588.
CN
O
+ (9)
Ph
20. Tyndall, D. V.; Nakib, T. A.; Meegan, M. J., Tetrahedron Lett. 1988, 29,
EtOH
CN Ph NH2
2703.
Ph
CN
21. Baraldi, P. G.; Barco, A.; Bennetti, S.; Pollini, G. P.; Zanirato, V.,
Tetrahedron Lett. 1984, 25, 4291.
22. Kane, V. V.; Jones, M., Org. Synth. 1983, 61, 129; Kane, V. V.; Jones,
O
M., Org. Synth., Coll. Vol. 1990, 7, 473.
NH
S
O
+
CO2Me
HS CO2Me
David Goldsmith
(10)
Emory University, Atlanta, GA, USA
A list of General Abbreviations appears on the front Endpapers