(1; R = H)

[85-41-6]  · C8H5NO2  · Phthalimide  · (MW 147.14) (2; R = K)

[1074-82-4]  · C8H4KNO2  · Potassium Phthalimide  · (MW 185.23)

(reagent for preparation of primary amines and amino compounds via Gabriel synthesis;2 building block for synthesis of heterocyclic compounds)

Physical Data: (1) mp 238 °C; bp 366 °C; d 1.47 g cm-3; dipole moment 2.91 D (dioxane; 30 °C); pKa 9.90 (H2O; 25 °C). (2) mp >300 °C.

Solubility: (1) sol boiling AcOH, H2O (0.036 g/100 mL at 25 °C; 0.4 g/100 mL at bp), ethanol (5 g/100 mL at bp); insol benzene, ligroin. (2) sol H2O, DMF; insol ethanol, ether.

Form Supplied in: both are white solids.

Handling, Storage, and Precautions: (2) may be harmful by inhalation, ingestion, or skin absorption. May cause irritation. Moisture sensitive. Use in a fume hood.

Reactions at the Nitrogen Atom.

A widely used method for the preparation of primary amines comprises reaction of a halo compound with potassium phthalimide and subsequent hydrolysis of the N-substituted phthalimide; this method is commonly referred to as the Gabriel synthesis (eq 1).2

Gabriel Synthesis. First Step: Formation of N-Alkylphthalimide.

In the original method of conducting the reaction, potassium phthalimide and the alkyl halide are heated without solvent, or in the presence of a high-boiling, nonpolar solvent (e.g. xylene). Because potassium phthalimide is insoluble under these conditions, the long periods of heating required at relatively high temperatures (150-240 °C) result in lowered yields and impure products (eq 2).3 Alkyl sulfonates have been used as an alternative for organic halides.4 Later it was found that DMF, in which potassium phthalimide is appreciably soluble, is an excellent solvent for the alkylation, which often starts at rt and is completed within minutes for the more reactive halides (eq 3).5

Another convenient procedure for alkylation of the potassium salt with alkyl halides or methanesulfonates, in solvents like benzene or toluene, makes use of solid-liquid phase-transfer catalysis by quaternary phosphonium6 or ammonium7 salts or 18-Crown-68 (eqs 4 and 5).6,7b In the case of the phosphonium salt, even 2-octyl derivatives have been obtained in high yield.

The Gabriel synthesis can be extended to include aromatic and vinylic halides. Under appropriate conditions, the copper-catalyzed nucleophilic substitution with the potassium salt is effective with a wide range of aryl bromides or iodides, which may contain either electron-withdrawing or electron-donating substituents. The polar effect of the substituents is small, and the reaction is strongly subject to steric inhibition (eq 6).9 Similar reaction conditions have been used for vinylic bromides RCH=CHBr (R = H, alkyl, aryl).10 Copper(II) oxide has been used for condensing phthalimide with aryl or ferrocenyl halides.11

Gabriel Synthesis. Second Step: Formation of the Primary Amine.

Hydrolysis of the N-substituted phthalimides is usually carried out by refluxing in 20% hydrochloric acid2 (eq 7).2b In certain cases, concentrated hydrochloric acid at temperatures up to 200 °C (sealed tube) may be necessary. Other acids, such as HBr, HI, and H2SO4, have also been used. Alkaline hydrolysis of the N-substituted phthalimides (e.g. 10% KOH or NaOH) is not commonly used.

Mild cleavage with Hydrazine12 is the method of choice for N-substituted phthalimides not containing functional groups like halogen, aldehyde, or ketone that react with hydrazine. Usually the phthalimide compound is refluxed in ethanol with an equivalent amount of hydrazine hydrate. Upon removal of the ethanol, the residue is heated with hydrochloric acid. The phthalyl hydrazide is filtered off, leaving a solution of the amine hydrochloride (eq 8).

The primary amines may also be liberated by reactions with 40% aqueous methylamine,13a n-pentylamine,13b Sodium Borohydride-2-propanol followed by acetic acid,13c and Sodium Sulfide in aqueous THF or acetone.13d

Miscellaneous Alkylations.

A mild alternative for the above-described reaction of potassium phthalimide and alkyl halides is the direct coupling of phthalimide with alcohols under Mitsunobu's conditions.14a The advantage of this method is that a primary or secondary alcohol is activated in situ by using Triphenylphosphine and RO2CN=NCO2R, and then reacts (with inversion of configuration) with phthalimide under aprotic conditions at rt or below (eq 9).14b

N-Alkylations through base-catalyzed conjugate additions to acrylonitrile15 and acrolein or its methyl congeners16 are known. The smooth reaction of phthalimide and aqueous Formaldehyde leads to the N-hydroxymethylimide (eq 10),17 which can be used in the acid-catalyzed amidomethylation17 of aromatic compounds (Tscherniac-Einhorn reaction) or, upon conversion into the N-halomethyl derivative, in the amidomethylation of aliphatic nucleophiles. Unfortunately, higher aldehydes do not undergo this reaction with phthalimide. The a-haloalkyl derivatives can be prepared, however, via the a-chloroalkyl phenyl sulfide as an aldehyde equivalent (eq 11).18

Epoxides can be used to alkylate phthalimide. Ethyl glycidate, for instance, reacts with phthalimide in the presence of a catalytic amount of base to give exclusively the b-substitution product (eq 12).19

A highly stereoselective route to (E)-allylamines has been developed via N-alkylation of sodium phthalimide with vinyltri-n-butylphosphonium bromide in the presence of an aldehyde, leading to the allylic phthalimide with high (E) stereoselectivity (71-100%), which upon subsequent hydrazinolysis gives the desired amine (eq 13).20 Use of the vinyltriphenylphosphonium salt (Schweizer reaction) gives predominantly the (Z)-isomer.

Reactions at the Carbonyl Group.

Though intermolecular Wittig reactions of phthalimide are known, yields are usually poor and rather severe conditions (refluxing xylene for 20 h) are required.21 Certain tandem reactions, consisting of an N-alkylation followed by an intramolecular Wittig-type condensation, lead to fused heterocyclic compounds in high yield. Ring opening of an activated cyclopropane derivative with potassium phthalimide, and Wittig reaction of the intermediary stabilized ylide at the imide carbonyl function, affords the pyrrolo[2,1-a]isoindole derivative (eq 14).22

Reaction of sodium phthalimide with 2 equiv of triethyl 2-phosphonoacrylate provides the pyrido[2,1-a]isoindole derivative (eq 15).23 Apparently the carbanion formed upon addition of the first equivalent of the vinylphosphonate does not undergo the intramolecular Wittig-Horner type reaction to the strained four-membered ring. Upon addition of the intermediary carbanion to a second molecule of the vinylphosphonate, formation of the six-membered ring readily occurs.

Related Reagents.

Benzophenone Imine; Isocyanic Acid; Glutarimide; Hexamethylenetetramine; Sodium Azide; Succinimide.

1. Hargreaves, M. K.; Pritchard, J. G.; Dave, H. R. CRV 1970, 70, 439.
2. (a) Gibson, M. S.; Bradshaw, R. W. AG 1968, 80, 986. (b) Spielberger, G. MOC 1957, 11/1, 79.
3. Salzberg, P. L.; Supnievski, J. V. OSC 1961, 1, 119.
4. Sakellarios, E. J. HCA 1946, 29, 1675.
5. Sheehan, J. C.; Bolhofer, W. A. JACS 1950, 72, 2786.
6. Landini, D.; Rolla, F. S 1976, 389.
7. (a) Santaniello, E.; Ponti, F. SC 1980, 10, 611. (b) Arrad, O.; Sasson, Y. JOC 1989, 54, 4993.
8. Soai, K.; Ookawa, A.; Kato, K. BCJ 1982, 55, 1671.
9. Bacon, R. G. R.; Karim, A. JCS(P1) 1973, 272.
10. (a) Bacon, R. G. R.; Karim, A. JCS(P1) 1973, 278. (b) Ogawa, T.; Kiji, T.; Hayami, K.; Suzuki, H. CL 1991, 1443.
11. Sato, M.; Ebine, S. S 1981, 472.
12. (a) Ing, H. R.; Manske, R. F. H. JCS 1926, 2348. (b) Smith, L. I.; Emerson, O. H. OSC 1955, 3, 151.
13. (a) Wolfe, S.; Hasan, S. K. CJC 1970, 48, 3572. (b) Kasztreiner, E.; Szilágyi, G.; Kośáry, J.; Huszti, Z. Acta Chim. Acad. Sci. Hung. 1975, 84, 167 (CA 1975, 83, 113 804). (c) Osby, J. O.; Martin, M. G.; Ganem, B. TL 1984, 25, 2093. (d) Kukolja, S.; Lammert, S. R. JACS 1975, 97, 5582.
14. (a) Hughes, D. L. OR 1992, 42, 335. (b) Hegedus, L. S.; Holden, M. S.; McKearin, J. M. OSC 1990, 7, 501.
15. (a) Galat, A. JACS 1945, 67, 1414. (b) Birkofer, H. MOC 1958, 11/2, 495.
16. Moe, O. A.; Warner, D. T. JACS 1949, 71, 1251.
17. Zaugg, H. E.; Martin, W. B. OR 1965, 14, 52.
18. Worley, J. W. JOC 1979, 44, 1178.
19. Williams, T. M.; Crumbie, R.; Mosher, H. S. JOC 1985, 50, 91.
20. Meyers, A. I.; Lawson, J. P.; Carver, D. R. JOC 1981, 46, 3119.
21. Flitsch, W.; Schindler, S. R. S 1975, 685.
22. Muchowski, J. M.; Nelson, P. H. TL 1980, 21, 4585.
23. Minami, T.; Watanabe, K.; Hirakawa, K. CL 1986, 2027.

Henk de Koning & W. Nico Speckamp

University of Amsterdam, The Netherlands

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