[123-56-8]  · C4H5NO2  · Succinimide  · (MW 99.10)

(building block for synthesis of other heterocyclic compounds, especially via N-acyliminium cyclizations2)

Physical Data: mp 126-127 °C; bp 287-288 °C (slight decomposition); d 1.418 g cm-3; dipole moment 1.54 D (dioxane, 20 °C); pKa 9.656 (H2O, 25 °C).

Solubility: sol H2O (1 g/3 mL at 20 °C; 1 g/0.7 mL at bp), ethanol (1 g/24 mL at 20 °C; 1 g/5 mL at 60 °C); insol ether, chloroform.

Form Supplied in: white solid.

Handling, Storage, and Precautions: may be harmful by inhalation, ingestion, or skin absorption; may cause irritation. Use in a fume hood.

Reactions at the Nitrogen Atom.

The most widely used method for direct N-alkylation of succinimide is the Mitsunobu condensation3 with primary4 or secondary5 alcohols under the influence of Triphenylphosphine and dialkyl azodicarboxylates (eq 1).4 The extraction and purification steps are often tedious, on account of Ph3PO and RO2CNHNHCO2R, formed in the reaction. Therefore, reaction of alkali metal salts of succinimide with primary halides or sulfonates is usually more convenient in cases where the electrophile does not give side reactions with the basic substrate (eq 2).6 The alkali metal salt can be prepared by reaction of Sodium Methoxide in MeOH, or Potassium t-Butoxide in t-BuOH, and can also be generated from the alkali metal hydride in DMF or HMPA, without isolation of the salt. Solid-liquid phase-transfer catalysis (Potassium Carbonate, 0.1 equiv 18-Crown-6, reflux in benzene or toluene)7 is also used for N-alkylation of succinimide in high yield. Addition of 0.1 equiv of Potassium Iodide increases the reaction rate for less reactive halides.

N-Alkenyl and N-alkynylsuccinimides are important intermediates in the synthesis of other heterocyclic compounds. Upon partial reduction (Sodium Borohydride, EtOH, H+) to the hydroxylactam and treatment with acid, an N-acyliminium cyclization occurs (eq 3).2

The Copper(I) Iodide promoted reaction of potassium succinimide with a vinyl bromide in an aprotic solvent affords the N-vinyl derivative (eq 4).8 N-Alkoxycarbonyl derivatives can be prepared with the corresponding alkyl chloroformate (eq 5).9

Reactions at the Carbonyl Group.

Addition of Grignard reagents (3 equiv; or first 1 equiv of MeMgCl and then 2 equiv of the more expensive reagent) provides hydroxylactams,10 which can be reduced with Sodium Cyanoborohydride at pH 3 to the 5-alkylpyrrolidinone (eq 6).10a

For intermolecular Wittig reactions of succinimide with stabilized phosphoranes, high temperatures are necessary and yields are poor.11 The intramolecular reaction proceeds somewhat better and can be applied to the synthesis of pyrrolizidine derivatives. N-Alkylation of sodium succinimide with bromophosphorane (1) and subsequent intramolecular Wittig reaction affords the pyrrolizidinedione (2) (eq 7).12 Another pyrrolizidine compound is obtained upon reaction of sodium succinimide with cyclopropyl derivative (3). The reaction presumably proceeds via nucleophilic opening of the activated cyclopropane ring, leading to a stabilized ylide which then undergoes an intramolecular Wittig reaction (eq 8).13

Reactions at the a-Methylene Position.

Upon reaction of the dipotassium or disodium salt of succinimide with electrophiles, such as Benzyl Chloride, benzophenone, or methyl benzoate, 2-substituted succinimide derivatives are obtained in moderate yields (eq 9).14

Related Reagents.

Glutarimide; Phthalimide.

1. Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. CRV 1970, 70, 439.
2. (a) Speckamp, W. N.; Hiemstra, H. T 1985, 41, 4367. (b) Hiemstra, H.; Speckamp, W. N. COS 1991, 2, 1047.
3. Hughes, D. L. OR 1992, 42, 335.
4. Schoemaker, H. E.; Boer-Terpstra, T.; Dijkink, J.; Speckamp, W. N. T 1980, 36, 143.
5. Hart, D. J. JOC 1981, 46, 367.
6. Hiemstra, H.; Sno, M. H. A. M.; Vijn, R. J.; Speckamp, W. N. JOC 1985, 50, 4014.
7. Gesson, J. P.; Jacquesy, J. C.; Rambaud, D. BSF 1992, 129, 227.
8. Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. CL 1991, 1443.
9. Gossauer, A.; Hirsch, W.; Kutschan, R. AG 1976, 88, 642.
10. (a) Melching, K. H.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. TL 1986, 27, 4799. (b) Esch, P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. H 1987, 26, 75.
11. Flitsch, W.; Schindler, S. R. S 1975, 685.
12. Flitsch, W.; Hampel, K. LA 1988, 387.
13. Flitsch, W.; Russkamp, P. LA 1983, 521.
14. Kaiser, E. M.; Petty, J. D.; Knutson, P. L. A. S 1977, 509.

Henk de Koning & W. Nico Speckamp

University of Amsterdam, The Netherlands

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.