(1; R = 1-pyrrolidino)

[1125-99-1]  · C10H17N  · 1-Pyrrolidino-1-cyclohexene  · (MW 151.28) (2; R = 4-morpholino)

[670-80-4]  · C10H17NO  · 4-Morpholino-1-cyclohexene  · (MW 167.28) (3; R = 1-piperidino)

[2981-10-4]  · C11H19N  · 1-Piperidino-1-cyclohexene  · (MW 165.31) (4; R = 1-perhydroazepino)

[23430-63-9]  · C12H21N  · 1-Perhydroazepino-1-cyclohexene  · (MW 179.34) (5; R = Me2N)

[13815-46-8]  · C8H15N  · Dimethylamino-1-cyclohexene  · (MW 125.24)

(both the enamine nitrogen and its b-carbon atom are nucleophilic, undergoing substitution or conjugate addition;1 can take part in 1,2- or 1,4-cycloadditions;1 iminium salts act as electrophiles1,2)

Physical Data: (1) bp 114-115 °C/15 mmHg; n20D 1.5217; IR (C=C) 1638 cm-1. (2) bp 118-120 °C/10 mmHg; n20D 1.5146; IR (C=C) 1641 cm-1. (3) bp 108-109 °C/12 mmHg; n20D 1.5144; IR (C=C) 1637 cm-1. (4) bp 122-126 °C/8 mmHg; n20D 1.5251; IR (C=C) 1632 cm-1. (5) bp 171-172 °C; n20D 1.4747.

Preparative Methods: the most commonly used method of preparation for these enamines is the acid-catalyzed condensation of a secondary amine with cyclohexanone.3 An example is the reaction of Pyrrolidine with cyclohexanone (eq 1).3a The use of a preformed Titanium(IV) Chloride-amine complex with cyclohexanone greatly decreases the reaction time while maintaining high yields.4

This technique is also is effective with functionalized cyclohexanones.5 When unsymmetrical tin(II) amides are allowed to react with cyclohexanone, good yields of enamines result.6,7

Handling, Storage, and Precautions: readily reacts with water or atmospheric oxygen; should be stored under dry nitrogen.


Alkylation at the carbon a to a carbonyl group can be accomplished by use of metal alkoxides to form an enolate anion. However, this may lead to poor results with ketones because of rapid proton exchange and incomplete conversion to the enolate. Although the introduction of lithium dialkylamide bases has solved this long-standing problem, enamine alkylation has certain other advantages. These advantages are the following: (1) strongly basic (or acidic) conditions are not required; (2) the major product is the monoalkylated derivative; (3) when dialkylation is observed (using excess of alkyl halide), it occurs at the least substituted carbon, in contrast to alkylation with base, where the a-disubstituted product is formed; hence 1-pyrrolidino-1-cyclohexene on treatment with 2 equiv of Allyl Bromide followed by hydrolysis gives 2,6-diallylcyclohexanone (eq 2);8 (4) the byproduct formed by alkylation at nitrogen is easily removed from the desired C-alkylation product.

The size of the heterocyclic amine rings is an important factor in determining the ratios of C-alkylation to N-alkylation. The pyrrolidine enamine gives some of the best yields whereas morpholine enamines give poorer yields. Since enamines are generally weaker nucleophiles than enolate anions, the list of generally useful alkylation agents is restricted to methyl-, allyl-, or benzyl-type halides (eq 3).9

Electrophilic radicals have been used to alkylate cyclic enamines (eq 4),10 and reductive alkylation of enamines via a radical pathway has been shown to be stereoselective (eq 5).11,12

A photoinduced electron transfer reaction with difluorodiiodomethane gives 2-(trifluoromethyl)cyclohexanone (eq 6).13 This reaction apparently involves elimination of iodide and addition of fluoride, either before or after the a-alkylation reaction.

The series of electrophilic alkenes that typically undergo Michael addition to cyclic enamines are a,b-unsaturated ketones (eq 7),14 a,b-unsaturated nitriles (eq 8),1a a,b-unsaturated esters,1a a,b-unsaturated sulfones,15 and nitroalkenes (eq 9).16 Electrophilic alkenes generally attack enamines of cycloalkanones in a stereospecific antiparallel manner.1,17,18


Acylation of cyclohexanone enamines using acyl halides takes place readily.19 The morpholine enamine gives the best yields (eq 10).1a An extra mole of enamine must be present to remove the liberated HCl. Alternatively, an organic base such as Triethylamine can be used for this purpose. Acylation using acid chlorides having a b-hydrogen in the presence of triethylamine usually proceeds via the ketene and subsequent cycloaddition. The intermediate cyclobutanone is then opened to give the enamino ketone, which is hydrolyzed to the 2-acylcyclohexanone.20


Aryl halides with a halogen activated by electron-withdrawing groups react with enamines (eq 11).21


Cycloadditions and annulation reactions take place when cyclohexanone enamines are allowed to react with 1-buten-3-one,1a 1,3-butadienephosphonate,22 acrolein,23-25 1,4-diacetoxy-2-butene with Palladium(II) Acetate,26 or 5-nitropyrimidine (Scheme 1).27

Further 2,3-(ethylenedisulfonyl)-1,3-butadiene acts as a diene in Diels-Alder reactions with enamines (eq 12).28

[2 + 2] Cycloaddition takes place with benzyne21 and Dimethyl Acetylenedicarboxylate (Scheme 2).29

Oxidation and Reduction.

Photooxygenation using singlet oxygen leads to a-diketones.30 Use of N-sulfonyloxaziridines gives a-amino ketones (Scheme 3).31

Use of trimethylene dithiotosylate produces the dithiane of cyclohexanone (eq 13).3a

The enamine is readily converted to cyclohexene via hydroboration (Scheme 3).32

Related Reagents.

Acrolein; Dimethyl Acetylenedicarboxylate; 1-(N,N-Dimethylamino)-2-methyl-1-propene; Morpholine; Pivalaldehyde; Pyrrolidine; 1-Pyrrolidino-1-cyclopentene; Bis[N,N-bis(trimethylsilyl)amino]tin(II).

1. (a) Stork, G.; Birzzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. JACS 1963, 85, 207. (b) Szmuszkovicz, J. Advances in Organic Chemistry: Methods and Results; Interscience: New York, 1964; Vol. 4, p 1. (c) Kuehne, M. E. S 1970, 510. (d) Dyke, S. F. The Chemistry of Enamines; Cambridge: London, 1973. (e) Hickmott, P. W. T 1982, 38, 1975, 3363. (f) Pitacco, G.; Valentin, E. In The Chemistry of Amino, Nitroso, and Nitro Compounds and Their Derivatives; Wiley: New York, 1982; Part 1, p 623. (g) Granik, V. G. RCR 1984, 53, 383. (h) Enamines: Synthesis, Structure, and Reactions, 2nd ed.; Cook, A. G., Ed.; Dekker: New York, 1988.
2. Advances in Organic Chemistry: Iminium Salts in Organic Chemistry; Bohme, H.; Viehe, H. G., Eds.; Wiley: New York, 1976 and 1979; Vol. 9, Parts 1 and 2.
3. (a) Woodward, R. B.; Pachter, I. J.; Scheinbaum, M. L. OSC 1988 6, 1014. (b) Hünig, S.; Lücke, E.; Brenninger, W. OSC 1973, 5, 808.
4. Nilsson, A.; Carlson, R. ACS 1984, B38, 49.
5. Nilsson, A.; Carlson, R. ACS 1984, B38, 523.
6. Burnell-Curty, C.; Roskamp, E. J. SL 1993, 131.
7. Whitesell, J. K.; Whitesell, M. A. S 1983, 517.
8. Opitz, G.; Mildenberger, H., Suhr, H. LA 1961, 649, 47.
9. Harvey, R. G.; Pataki, J.; Cortez, C.; Di Raddo, P.; Yang, C. X. JOC 1991, 56, 1210.
10. Russell, G. A.; Wang, K. JOC 1991, 56, 3475.
11. Renaud, P.; Schubert, S. AG(E) 1990, 29, 433.
12. Renaud, P.; Schubert, S. SL 1990, 624.
13. Chen, Q.-Y.; Li, Z.-T. JCS(P1) 1993, 645.
14. Corcoran, R. C.; Ma, J. JACS 1992, 114, 4536.
15. Fabrissin, S.; Fatutta, S.; Risaliti, A. JCS(P1) 1981, 109.
16. Kuehne, M. E.; Foley, L. JOC 1965, 30, 4280.
17. Hashimoto, Y.; Machida, S.; Saigo, K.; Inoue, J.; Hasegawa, M. CL 1989, 943.
18. Machida, S.; Hashimoto, Y.; Saigo, K.; Inoue, J., Hasegawa, M. T 1991, 47, 3737.
19. Hünig, S.; Hoch, H. Fortschr. Chem. Forsch. 1970, 14, 235.
20. Hünig, S.; Hoch, H. CB 1972, 105, 2216.
21. Kuehne, M. E. JACS 1962, 84, 837.
22. Darling, S. D.; Subramanian, N. JOC 1975, 40, 2851.
23. Stork, G.; Landesman, H. K. JACS 1956, 78, 5129.
24. Schut, R. N.; Liu, T. M. H. JOC 1965, 30, 2845.
25. Appleton, R. A.; Baggaley, K. H.; Egan, C.; Davies, J. M.; Graham, S. H.; Lewis, D. O. JCS(C) 1968, 2032.
26. Onoue, H.; Moritani, I.; Murahashi, S.-I. TL 1973, 121.
27. Marcelis, K. A. T. M.; Van Der Plas, H. T 1989, 45, 2693.
28. Lee, S.-J.; Peng, M.-L.; Lee, J.-C.; Chou, T.-S. CB 1992, 125, 499.
29. Brannock, K. C.; Burpitt, R. D.; Goodlett, V. W.; Thweatt, J. G. JOC 1963, 28, 1464.
30. Wasserman, H. H.; Terao, S. TL 1975, 1735.
31. Davis, F. A.; Sheppard, A. C. TL 1988, 29, 4365.
32. Singaram, B.; Rangaishenvi, M. V.; Brown, H. C.; Goralski, C. T.; Hasha, D. L. JOC 1991, 56, 1543.

A. Gilbert Cook

Valparaiso University, IN, USA

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