[123-75-1]  · C4H9N  · Pyrrolidine  · (MW 71.14)

(secondary amine used for the formation and utilization of enamines;2 catalyst for aldol cyclization17 and Mannich condensation;23 formation of secondary amides28)

Physical Data: bp 88.5-89 °C; d 0.8618 g cm-3; pKa 11.1.

Solubility: miscible with water; sol alcohol, chloroform, and ether.

Form Supplied in: liquid, 99%; widely available.

Purification: distilled under nitrogen after drying with sodium or BaO.1

Handling, Storage, and Precautions: flammable; fumes in air; strong base; irritant. Use in a fume hood.

Enamine Preparation and Utilization.2

The principal use of pyrrolidine in synthesis is in the formation and utilization of ketone and aldehyde enamines. For preparation of the enamine a benzene or toluene solution of the carbonyl compound and pyrrolidine is heated at reflux with azeotropic removal of water. Acid catalysts or molecular sieves as water trapping agents are frequently employed. Cyclopentanone3-5 and cyclohexanone,3-6 for example, react in benzene to form enamines without added acid catalyst (eqs 1 and 2), as does b-tetralone (eq 3).7

In toluene solution, cyclododecanone is converted to the pyrrolidine enamine in the presence of Boron Trifluoride Etherate (eq 4).8

Acyclic ketones form pyrrolidine enamines sluggishly or with significant self-condensation. The enamine of diethyl ketone may be prepared in modest yield in the presence of 4 Å molecular sieves (eq 5).5

The pyrrolidine enamine of a relatively low-boiling aldehyde, isobutyraldehyde,9 may be prepared by heating the base and the carbonyl component without additional solvent (eq 6).

The reaction of ketones with pyrrolidine, Dimethyl Diazomethylphosphonate, and base yields the pyrrolidine enamine of the homologous aldehyde (eq 7).10

Enamino ketones have been prepared from b-chlorovinyl ketones (eq 8)11 or directly from the corresponding b-dicarbonyl compound (eq 9).12

The reaction of pyrrolidine with monoalkylated cyclohexanones results in the formation of the less substituted enamine as the major product (eq 10).5

Regioselectivity is also observed in the formation of an enamine from 3-tri-n-butylstannylcyclohexanone and pyrrolidine (eq 11).13

Pyrrolidine enamines react with both alkyl halides and electrophilic alkenes2-5,7,14 to provide a-alkylated ketones and aldehydes (eqs 12 and 13). The great advantage of enamines over simple enolates in these reactions is that they do not overalkylate. Monosubstitution products are generally obtained. Acylation at carbon to afford b-dicarbonyl compounds occurs upon exposure of pyrrolidine enamines to acyl halides, but less effectively than with the corresponding morpholine enamine.5

Pyrrolidine enamines also undergo [2 + 4] cycloaddition reactions with 1,2,4-Triazine to provide, following loss of dinitrogen and aromatization, substituted pyridines (eq 14) and isoquinolines.15,16

Condensation Reactions.

Pyrrolidine is a common catalyst for the aldol cyclization phase of the Robinson annulation process for both diketones14,17-20 and keto aldehydes (eqs 15 and 16).21

Spirocyclization has been shown to be favored over hydronaphthalenone closure in the reactions of substituted formylcyclohexanedione ethers (eq 17).22

In similar fashion to aldol cyclizations, Mannich-type condensations are frequently carried out with pyrrolidine as the secondary amine component. The enamine of cyclohexanone reacts with an o-hydroxyacetophenone to afford a spirochromanone product (eq 18).23

Phenols acting as the enol component of the Mannich process react with aldehydes in the presence of pyrrolidine (eq 19).24

Pyrrolidine is also the most effective catalyst for the condensation of both aldehydes and ketones with cyclopentadiene to provide fulvenes (eqs 20 and 21).25-27 In these cases the pyrrolidine has been shown to play the roles of both base catalyst and enamine-forming amine. The rates of such condensations are greater with pyrrolidine than with other secondary amine catalysts, a result attributable to the minimum steric hindrance exhibited by the cyclic amine.

Amide Formation.

Pyrrolidine is an effective reagent for the formation of secondary amides from esters (eq 22) and urethanes from thiocarbonates (eq 23).28,29

1. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988; p 542.
2. Cook, A. G. Enamines: Synthesis, Structure, and Reactions, 2nd ed.; Dekker: New York, 1988; p 717.
3. Stork, G.; Terrell, R.; Szmuszkovicz, J. JACS 1954, 76, 2029.
4. Stork, G.; Landesman, H. K. JACS 1956, 78, 5128.
5. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. JACS 1963, 85, 207.
6. Woodward, R. B.; Pachter, I. J.; Scheinbaum, M. L. OSC 1988, 6, 1014.
7. Stork, G.; Schulenberg, J. W. JACS 1962, 84, 284.
8. (a) Hamada, Y.; Shioiri, T. OS 1984, 62, 191. (b) Hamada, Y.; Shioiri, T. OSC 1990, 7, 135.
9. Chan, Y.; Epstein, W. W. OSC 1988, 6, 496.
10. Gilbert, J. C.; Weerasooriya, U. TL 1980, 21, 2041.
11. Leonard, N. J.; Adamcik, J. A. JACS 1959, 81, 595.
12. Greenhill, J. V.; Chaaban, I.; Steel, P. J. JHC 1992, 29, 1375.
13. Ahlbrecht, H.; Weber, P. S 1989, 117.
14. Tsuji, J. S 1984, 369.
15. Boger, D. L.; Schumacher, J.; Mullican, M. D.; Patel, M.; Panek, J. S. JOC 1982, 47, 2673.
16. Boger, D. T 1983, 39, 2869.
17. Ramachandran, S.; Newman, M. S. OSC 1973, 5, 486.
18. Spencer, T. A.; Schmiegel, K. K.; Williamson, K. L. JACS 1963, 85, 3785.
19. Scanio, C. J. V.; Hill, L. P. S 1970, 651.
20. Begbie, A. L.; Golding, B. T. JCS(P1) 1972, 602.
21. Martin, S. F.; Davidsen, S. K. JACS 1984, 106, 6431.
22. de Groot, A.; Jansen, B. J. M. TL 1976, 2709.
23. Kabbe, H. J. S 1978, 886.
24. Jurd, L. JHC 1988, 25, 89.
25. Stone, K. J.; Little, R. D. JOC 1984, 49, 1849.
26. Stone, K. J.; Little, R. D. JACS 1985, 107, 2495.
27. Griesbeck, A. G. JOC 1989, 54, 4981.
28. Matsumoto, K.; Hashimoto, S.; Otani, S. AG(E) 1986, 25, 565.
29. Matsumoto, K.; Hashimoto, S.; Uchida, T.; Okamoto, T.; Otani, S. CB 1989, 122, 1357.

David Goldsmith

Emory University, Atlanta, GA, USA

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