Succinic Anhydride

[108-30-5]  · C4H4O3  · Succinic Anhydride  · (MW 100.08)

(acylation reactions,1-8 lactone synthesis,9-14 Reformatsky reaction15)

Alternate Names: succinic acid anhydride; butanedioic anhydride; dihydro-2,5-furandione; succinyl anhydride.

Physical Data: mp 119-120 °C; bp 261 °C; vapor density 3.5; vapor pressure 1 mmHg (92 °C).

Form Supplied in: colorless needles or white flakes.

Solubility: slightly sol water; sol toluene (10.0 g L-1 at 30 °C).

Handling, Storage, and Precautions: use only in a chemical fume hood; severe eye irritant; moisture sensitive; store in cool dry place.

Acylation Reactions.

N- and O-Acylation.

Succinic anhydride (1) is a reactive acylating agent and reacts rapidly with amines. For alcohols, procedures often call for use of Pyridine or 4-Dimethylaminopyridine as catalyst. The N-acylation reaction has been extensively used for the synthesis of chiral succinimides (eq 1),1a which are important intermediates in asymmetric synthesis.1 The O-acylation has been widely employed as a facile method for enzymatic resolution of racemic alcohols (eq 2).2

Acylation of Organometallic Agents.

g-Keto acids can be obtained in good yield by reaction of organomanganese(II) compounds with (1) (eq 3).3

The keto acid intermediate in the khellin total synthesis was readily prepared by addition of (1) to the dianion of 3-furoic acid (eq 4).4 The anion derived from diphenylmethane reacts with (1) to form the diphenylmethyl ketone in 63% yield.5

Acylation of Ketone Enolates.

Aryl 1,3-diketones have been prepared in good yields by quenching the enolate of an aryl methyl ketone with (1) (eq 5).6

Friedel-Crafts Acylation.

Alkenes7 and aromatic8 compounds react with (1) in the presence of Lewis acid catalysts to give various succinoylation products,8c which are useful synthetic intermediates. Selected examples are shown in eqs 6 and 7.7a,8a

Lactone Synthesis.


Anhydride (1) can be reduced to give g-butyrolactone by metal oxide catalysts9a by catalytic hydrogenation,9b and by Sodium Borohydride.10a Similar reductions of unsymmetrical succinic anhydrides by hydrogenation [Ru(PPh3)3Cl2],10b sodium borohydride,10a,c or Lithium Aluminum Hydride10d often occur selectively at the more hindered carbonyl group, although some exceptions have been reported.10e

Spirolactone Synthesis.

Diaddition of Grignard reagents to (1) gives spirolactones in good yield.11 The reaction has been applied to the preparation of a key intermediate in the synthesis of cubebene (eq 8).11c Monoaddition of cerium 3-ceriopropoxide to (1) gives the oxaspirolactone (eq 9).12

Condensation with Aldehydes and Ketones.

The enolate of (1) can be successfully prepared by treatment of (1) with a sterically hindered alkoxide, lithium 1,1-bis(trimethylsilyl)-3-methyl-1-butoxide, in THF at -78 °C. The enolate readily reacts with aldehydes and ketones to give g-butyrolactones (eq 10).13

Wittig Reaction.

Enol lactones can be prepared by the Wittig reaction between stabilized phosphoranes and (1) (eq 11).14

Reformatsky Reaction.

Electrolysis of ethyl 2-bromo-2-methylpropanoate in the presence of (1) in DMF gave 1-ethyl 3-oxo-2,2-dimethylhexanedioate in 65% yield (eq 12).15 This electrochemically assisted procedure circumvented both the problems of zinc activation and the difficulty associated with the uncontrollable exothermic course of the normal Reformatsky reaction of cyclic carboxylic anhydrides.

Vinyl Ether Synthesis.

Use of (1) as a methanol scavenger, provides an improved procedure for the preparation of vinyl ethers.16 The method has been used for the synthesis of spiro vinyl ethers (eq 13).16b

Related Reagents.

Acetic Anhydride; Acetic Formic Anhydride; Benzoic Anhydride; Diethyl Succinate; Itaconic Anhydride; Maleic Anhydride; Succindialdehyde; Succinimide.

1. (a) Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J. JOC 1989, 54, 4243. (b) Polniaszek, R. P.; Belmont, S. E. JOC 1990, 55, 4688.
2. (a) Terao, Y.; Tsuji, K.; Murata, M.; Achiwa, K.; Nishio, T.; Watanabe, N.; Seto, K.; Achiwa, K. CPB 1989, 37, 1653. (b) Ottolina, G.; Carrea, G.; Riva, S. JOC 1990, 55, 2366. (c) Nicotra, F.; Riva, S.; Secundo, F.; Zucchelli, L. SC 1990, 20, 679.
3. Friour, G.; Cahiez, G.; Normant, J. F. S 1985, 50.
4. Gammill, R. B.; Hyde, B. R. JOC 1983, 48, 3863.
5. Bunce, R. A.; Dowdy, E. D. SC 1990, 20, 3007.
6. (a) Murray, W. V.; Wachter, M. P. JOC 1990, 55, 3424. (b) FF 1981, 9, 82.
7. (a) Merényi, F.; Nilsson, M. OS 1972, 52, 1. (b) Naora, H.; Ohnuki, T.; Nakamura, A. CL 1988, 143.
8. (a) Quallich, G. J.; Williams, M. T.; Friedmann, R. C. JOC 1990, 55, 4971. (b) Murakami, Y.; Tani, M.; Ariyasu, T. Nishiyama, C.; Watanabe, T.; Yokoyama, Y. H 1988, 27, 1855. (c) Rao, Y. S.; Kretchmer, R. A. OPP 1971, 3, 177. (d) Zheng, G-C; Kojima, T.; Kakisawa, H. H 1988, 27, 1341. (e) Rahman, U.; Torre, M. C. LA 1968, 718, 136.
9. (a) Takahashi, K.; Shibagaki, M.; Matsushita, H. BCJ 1992, 65, 262. (b) Hara, Y.; Wada, K. CL 1991, 553.
10. (a) Bailey, D.; Johnson, R. JOC 1970, 35, 3574. (b) Morand, P.; Kayser, M. CC 1976, 314. (c) Kayser, M.; Morand, P. CJC 1980, 58, 2484. (d) Bloomfield, J. J.; Lee, S. L. JOC 1967, 32, 3919. (e) Makhlouf, M. A.; Rickborn, B. JOC, 1981, 46, 4810.
11. (a) Murty, Y. V. S. N.; Pillai, C. N. TL 1990, 31, 6067. (b) Canonne, P.; Bélanger, D. CC 1980, 125. (c) Canonne, P.; Boulanger, R.; Angers, P. TL 1991, 32, 5861.
12. Mudryk, B.; Shook, C. A.; Cohen, T. JACS 1990, 112, 6389.
13. Minami, N.; Kuwajima, I. TL 1977, 1423.
14. Doyle, I. D.; Massy-Westropp, R. A.; Warren, R. F. O. S 1986, 845.
15. Schwarz, K-H; Kleiner, K.; Lugwig, R.; Schick, H. JOC 1992, 57, 4013.
16. (a) Buchanan, G.; Gustafson, A. JOC 1973, 38, 2910. (b) Wang, S.; Morrow, G. W.; Swenton, J. S. JOC 1989, 54, 5364.

Sompong Wattanasin

Sandoz Research Institute, East Hanover, NJ, USA

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