SUCCINIC ANHYDRIDE

1

Succinic Anhydride

O

O

O

[108-30-5]

C

4

H

4

O

3

(MW 100.08)

InChI = 1/C4H4O3/c5-3-1-2-4(6)7-3/h1-2H2
InChIKey = RINCXYDBBGOEEQ-UHFFFAOYAN

(acylation reactions,

1

–

8

lactone synthesis,

9

–

14

Reformatsky

reaction

15

)

Alternate Names:

succinic acid anhydride; butanedioic anhy-

dride; 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 acy-

lating agent and reacts rapidly with amines. For alcohols, proce-
dures 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

O

O

O

H

2

N

OH

Ph

N

Ph

O

OH

O

+

toluene

reflux

(1)

80%

O

O

O

Ph

OH

Ph

OH

Ph

O

O

HO

2

C

+

Pseudomonas

fluororescens

lipase

+

(2)

(S)-1-phenylethanol

97% ee

ether

41%

Acylation of Organometallic Agents.

γ

-Keto acids can be

obtained in good yield by reaction of organomanganese(II) com-
pounds 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

O

O

O

MnI

O

CO

2

H

+

ether

0 °C to rt, 8 h

(3)

72.5%

(4)

O

CO

2

H

O

CO

2

H

CO

2

H

O

O

O

O

OMe

OMe

1. 2 equiv LDA
THF
–78 °C

Khellin

2. (1)

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

(5)

Cl

O

Cl

O

O

CO

2

H

1. LDA, THF
–78 °C

2. (1)
–78 °C to rt

75%

Friedel–Crafts Acylation.

Alkenes

7

and aromatic

8

com-

pounds 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

(6)

O

O

O

O

O

OH

O

AlCl

3

ethylene chloride

+

reflux, 0.25 h

50–55%

O

O

O

Cl

Cl

Cl

Cl

CO

2

H

O

Cl

Cl

NHMe

AlCl

3

60 °C, 2.5 h

+

(7)

Sertraline

(antidepressant)

92%

Avoid Skin Contact with All Reagents

2

SUCCINIC ANHYDRIDE

Lactone Synthesis.

Reduction. Anhydride (1) can be reduced to give γ-butyrol-

actone by metal oxide catalysts

9a

by catalytic hydrogenation,

9b

and by Sodium Borohydride

10a

. Similar reductions of unsymmet-

rical succinic anhydrides by hydrogenation [Ru(PPh

3

)

3

Cl

2

],

10b

sodium borohydride,

10a,c

or Lithium Aluminum Hydride

10d

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

O

O

O

MgBr

MgBr

O

O

+

(8)

0 °C to rt, 3 h

THF

(9)

O

O

O

Cl

2

Ce

O

O

OCeCl

2

1. THF
–78 to –40 °C
2. H

+

O

+

72%

Condensation with Aldehydes and Ketones. The enolate of

(1) can be successfully prepared by treatment of (1) with a steri-
cally 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 γ-butyrolactones (eq 10).

13

(10)

O

O

O

LiO

TMS

TMS

+

PhCHO

1.

O

O

Ph

MeO

2

C

2. HCl
3. CH

2

N

2

84%

Wittig Reaction. Enol lactones can be prepared by the Wittig

reaction between stabilized phosphoranes and (1) (eq 11).

14

CHCl

3

O

O

O

CO

2

Et

PPh

3

+

(11)

O

O

CO

2

Et

55 °C, 17 h

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 elec-

trochemically assisted procedure circumvented both the problems
of zinc activation and the difficulty associated with the uncontrol-
lable exothermic course of the normal Reformatsky reaction of
cyclic carboxylic anhydrides.

DMF

zinc anode

O

O

O

+

Br

CO

2

Et

(12)

CO

2

Et

O

CO

2

H

65%

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

(13)

O

OMe

O

(1), py, diglyme

PhCO

2

H

110 to 120 °C

O

O

50%

Related Reagents. Acetic Anhydride; Acetic Formic Anhy-

dride; Benzoic Anhydride; Diethyl Succinate; Itaconic Anhy-
dride; Maleic Anhydride; Succindialdehyde; Succinimide.

1.

(a) Meyers, A. I.; Lefker, B. A.; Sowin, T. J.; Westrum, L. J., J. Org.
Chem. 1989

, 54, 4243. (b) Polniaszek, R. P.; Belmont, S. E., J. Org.

Chem. 1990

, 55, 4688.

2.

(a) Terao, Y.; Tsuji, K.; Murata, M.; Achiwa, K.; Nishio, T.; Watanabe,
N.; Seto, K.; Achiwa, K., Chem. Pharm. Bull. 1989, 37, 1653.
(b) Ottolina, G.; Carrea, G.; Riva, S., J. Org. Chem. 1990, 55, 2366.
(c) Nicotra, F.; Riva, S.; Secundo, F.; Zucchelli, L., Synth. Commun.
1990, 20, 679.

3.

Friour, G.; Cahiez, G.; Normant, J. F., Synthesis 1985, 50.

4.

Gammill, R. B.; Hyde, B. R., J. Org. Chem. 1983, 48, 3863.

5.

Bunce, R. A.; Dowdy, E. D., Synth. Commun. 1990, 20, 3007.

6.

(a) Murray, W. V.; Wachter, M. P., J. Org. Chem. 1990, 55, 3424.
(b) Fieser & Fieser 1981, 9, 82.

7.

(a) Merényi, F.; Nilsson, M., Org. Synth. 1972, 52, 1. (b) Naora, H.;
Ohnuki, T.; Nakamura, A., Chem. Lett. 1988, 143.

8.

(a) Quallich, G. J.; Williams, M. T.; Friedmann, R. C., J. Org. Chem.
1990, 55, 4971. (b) Murakami, Y.; Tani, M.; Ariyasu, T. Nishiyama, C.;
Watanabe, T.; Yokoyama, Y., Heterocycles 1988, 27, 1855. (c) Rao, Y.
S.; Kretchmer, R. A., Org. Prep. Proced. Int. 1971, 3, 177. (d) Zheng, G-
C; Kojima, T.; Kakisawa, H., Heterocycles 1988, 27, 1341. (e) Rahman,
U.; Torre, M. C., Justus Liebigs Ann. Chem. 1968, 718, 136.

9.

(a) Takahashi, K.; Shibagaki, M.; Matsushita, H., Bull. Chem. Soc. Jpn.
1992, 65, 262. (b) Hara, Y.; Wada, K., Chem. Lett. 1991, 553.

10.

(a) Bailey, D.; Johnson, R., J. Org. Chem. 1970, 35, 3574. (b) Morand,
P.; Kayser, M., J. Chem. Soc., Chem. Commun. 1976, 314. (c) Kayser,
M.; Morand, P., Can. J. Chem. 1980, 58, 2484. (d) Bloomfield, J. J.; Lee,
S. L., J. Org. Chem. 1967, 32, 3919. (e) Makhlouf, M. A.; Rickborn, B.,
J. Org. Chem.

, 1981, 46, 4810.

11.

(a) Murty, Y. V. S. N.; Pillai, C. N., Tetrahedron Lett. 1990, 31, 6067. (b)
Canonne, P.; Bélanger, D., J. Chem. Soc., Chem. Commun. 1980, 125.
(c) Canonne, P.; Boulanger, R.; Angers, P., Tetrahedron Lett. 1991, 32,
5861.

12.

Mudryk, B.; Shook, C. A.; Cohen, T., J. Am. Chem. Soc. 1990, 112,
6389.

13.

Minami, N.; Kuwajima, I., Tetrahedron Lett. 1977, 1423.

14.

Doyle, I. D.; Massy-Westropp, R. A.; Warren, R. F. O., Synthesis 1986,
845.

15.

Schwarz, K-H; Kleiner, K.; Lugwig, R.; Schick, H., J. Org. Chem. 1992,
57

, 4013.

16.

(a) Buchanan, G.; Gustafson, A., J. Org. Chem. 1973, 38, 2910. (b) Wang,
S.; Morrow, G. W.; Swenton, J. S., J. Org. Chem. 1989, 54, 5364.

Sompong Wattanasin

Sandoz Research Institute, East Hanover, NJ, USA

A list of General Abbreviations appears on the front Endpapers