[1121-89-7]  · C5H7NO2  · Glutarimide  · (MW 113.13)

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

Alternate Name: 2,6-piperidinedione.

Physical Data: mp 163-165 °C; d 1.393 g cm-3; dipole moment 2.58 D (dioxane, 30 °C); pKa 11.43 (H2O, 25 °C).

Solubility: sol H2O, hot EtOH, boiling benzene; insol ether.

Form Supplied in: white solid.

Reactions at the Nitrogen Atom.

The direct reaction of glutarimide with a primary3 or a secondary4 alcohol, mediated by Triphenylphosphine and dialkyl azodicarboxylate (Mitsunobu reaction5) is the most widely used method for the N-alkylation (eq 1).3 However, because of the tedious workup procedure (removal of Ph3PO and RO2CNHNHCO2R), alkylation of alkali metal salts of glutarimide with primary halides or sulfonates is usually more convenient (eq 2).6 The sodium salt is prepared by reaction with NaOMe in MeOH, followed by precipitation with ether. The alkali metal salts can also be generated from the metal hydride in DMF or HMPA, without isolation of the salt.

N-Alkylation of glutarimide in high yield is also possible by using primary chlorides, bromides, or tosylates under solid-liquid phase transfer conditions (Potassium Carbonate, 0.1 equiv 18-Crown-6, benzene or toluene, reflux).7 Addition of 0.1 equiv Potassium Iodide increases the reaction rate for less reactive halides.

N-Alkenyl or N-alkynyl glutarimides are important intermediates for the synthesis of other heterocyclic systems; upon partial reduction to the hydroxylactam and treatment with acid, an N-acyliminium cyclization occurs.2

Reactions at the Carbonyl Group.

Addition of Grignard reagents (>2 equiv) to glutarimide gives rise to t-hydroxylactams (in equilibrium with the ring-opened keto-amide). In the case of alkenyl derivatives, N-acyliminium cyclizations to the 1-azaspiran derivatives are possible (eq 3).8

Reaction of sodium glutarimide with [1-(Ethoxycarbonyl)cyclopropyl]triphenylphosphonium Tetrafluoroborate leads to an indolizidine derivative via nucleophilic opening of the cyclopropyl ring and a subsequent intramolecular Wittig reaction (eq 4).9

Reactions at the Carbon Atom next to the Carbonyl Group.

Disodium glutarimide in liquid ammonia can be alkylated or acylated with Benzyl Chloride, benzophenone, or methyl benzoate to give the 2-substituted glutarimides10 (e.g. eq 5).11

Related Reagents.

Diethyl Azodicarboxylate; [1-(Ethoxycarbonyl)cyclopropyl]triphenylphosphonium Tetrafluoroborate; 4-Phenylsulfonyl-3-buten-2-one; Phthalimide; Succinimide.

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. Schoemaker, H. E.; Boer-Terpstra, T.; Dijkink, J.; Speckamp, W. N. T 1980, 36, 143.
4. Ent, H.; De Koning, H.; Speckamp, W. N. H 1988, 27, 237.
5. Hughes, D. L. OR 1992, 42, 335.
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. Schoemaker, H. E.; Speckamp, W. N. T 1980, 36, 951.
9. Flitsch, W.; Russkamp, P. LA 1983, 521.
10. Kaiser, E. M.; Petty, J. D.; Knutson, P. L. A. S 1977, 509.
11. Goehring, R. R.; Greenwood, T. D.; Nwokogu, G. C.; Pisipati, J. S.; Rogers, T. G.; Wolfe, J. F. JMC 1990, 33, 926.

Henk de Koning & W. Nico Speckamp

University of Amsterdam, The Netherlands

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