[110-91-8]  · C4H9NO  · Morpholine  · (MW 87.14)

(secondary amine base; reagent for enamine formation and utilization; condensation catalyst for Mannich condensations)

Physical Data: bp 128.9 °C; d 1.007 g cm-3; pKa 8.8.

Solubility: miscible with water, acetone, diethyl ether.

Form Supplied in: liquid, >99%.

Purification: dried with KOH, fractionally distilled, dried for a second time over sodium metal, then redistilled.1

Handling, Storage, and Precautions: eye and skin irritant; flammable liquid; use in a fume hood.

Willgerodt Reaction.2

Morpholine is employed as the amine component of the Kindler modification of the Willgerodt reaction. The process effects the rearrangement of aryl alkyl ketones to carboxylic acid derivatives (eqs 1 and 2).3,4 Morpholine is particularly useful in the reaction as its high boiling point makes the use of sealed tubes unnecessary.

Willgerodt-like processes are effected by treatment of benzylphosphonates5 and chlorides6 with morpholine and Sulfur (eqs 3 and 4).

Enamine Formation and Utilization.

Morpholine is one of the three principal secondary amines used in the formation of enamines.7-10 A weaker base than either Piperidine or Pyrrolidine, it forms enamines more slowly than the other two bases. The regioselectivity of morpholine enamine formation is significantly less than with pyrrolidine.11

The lower reactivity of morpholine has been used as a method for the separation of monoalkylated cyclohexanones from unalkylated material (eq 5).12

Morpholine enamines of saturated ketones and aldehydes are prepared by heating the base and the carbonyl compound alone in benzene solution (eq 6),10 by catalysis with p-Toluenesulfonic Acid in toluene (eq 7),13 and by catalysis with Titanium(IV) Chloride (eq 8).14 Aldehyde enamines may also be prepared by decarboxylation of the morpholine enamines of substituted pyruvic acids (eq 9).15

Enaminones may be prepared by conjugate addition of morpholine to an alkynic ketone (eq 10),16 and the morpholine enamine of pyruvaldehyde has been prepared by conjugate addition and rearrangement of 2-chloroacrolein (eq 11).17

Utilization of Morpholine Enamines.

The less reactive morpholine enamines have been shown to acylate in better yield than the corresponding pyrrolidine derivatives.10 A typical example is the acylation of the morpholine enamine of cyclopentanone (eq 12).18

Miscellaneous Reactions.

Morpholine is used as a base for dehydrobromination (eq 13)19 and in conjunction with molecular Iodine for the iodination of alkynic alcohols (eq 14).20

Treatment of benzyl phenyl ketone with Thionyl Chloride and morpholine results in the formation of benzil, a reaction which presumably occurs through the intermediacy of the ketone enamine (eq 15).21

Under high pressure, p-nitrophenyl triflate undergoes addition-elimination with morpholine (eq 16).22

Morpholine, like other secondary amines, may be used for Mannich-type condensations (eq 17).23

Related Reagents.

N-Chloromorpholine; 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide; 1-Cyclohexyl-3-(2-morpholinoethyl)carbodiimide Metho-p-toluenesulfonate; N,N-Dicyclohexyl-4-morpholinecarboximidamide; Diethyl Morpholinomethylphosphonate; Lithium Morpholide; N-Methylmorpholine N-Oxide; 2-Morpholinoethyl Isocyanide; N-Morpholinomethyldiphenylphosphine Oxide; Osmium Tetroxide-N-Methylmorpholine N-Oxide.

1. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.; Pergamon: Oxford, 1988; p 233.
2. Carmack, M.; Spielman, M. A. OR 1946, 3, 83.
3. Newman, M. S.; Lowrie, H. S. JACS 1954, 76, 6196.
4. Mayer, R.; Wehl, J. AG(E) 1964, 3, 705.
5. Okuma, K.; Ikari, K.; Ohta, H. CL 1992, 131.
6. Obayashi, M.; Kuzuna, S.; Noguchi, S. CPB 1979, 27, 1352.
7. Stork, G.; Terrell, R.; Szmuszkovicz, J. JACS 1954, 76, 2029.
8. Stork, G.; Landesman, H. K. JACS 1956, 78, 5128.
9. Stork, G.; Schulenberg, J. JACS 1962, 84, 284.
10. Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. JACS 1963, 85, 207.
11. Cook, A. G. Enamines: Synthesis, Structure, and Reactions, 2nd ed.; Dekker: New York, 1988; p 717.
12. Hickmott, P. W. T 1982, 38, 1975.
13. Hünig, S.; Lücke, E.; Brenninger, W. OSC 1973, 5, 808.
14. Carlson, R.; Nilsson, A.; Strömqvist, M. ACS 1983, B37, 7.
15. Stamos, I. K. TL 1982, 23, 459.
16. Vereshchagin, L. I.; Tikhonova, L. G.; Titova, E. I.; Latyshev, V. P.; Gavrilov, L. D. ZOR 1973, 9, 1355 (CA 1973, 79, 91 899v).
17. Keiko, N. A.; Rulev, A. Y.; Kalikhman, I. D.; Voronkov, M. G. S 1989, 446.
18. Pattenden, G.; Robertson, G. M. TL 1986, 27, 399.
19. Bandodakar, B. S.; Nagendrappa, G. S 1990, 843.
20. Southwick, P. L.; Kirchner, J. R. JOC 1962, 27, 3305.
21. Oka, K.; Hara, S. TL 1977, 695.
22. Kotsuki, H.; Kobayashi, S.; Suenaga, H.; Nishizawa, H. S 1990, 1145.
23. Raines, S.; Chai, S. Y.; Palopoli, F. P. JOC 1971, 36, 3992.

David Goldsmith

Emory University, Atlanta, GA, USA

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