Lithium 3-Lithiopropionate

[117951-86-7]  · C3H4Li2O2  · Lithium 3-Lithiopropionate  · (MW 85.95)

(useful for the synthesis of g-lactones from aldehydes and ketones1)

Form Supplied in: 3-bromopropionic acid, mp 61-63 °C, is commercially available; hexane solutions of n-butyllithium are commercially available in several concentrations; naphthalene, mp 80-82 °C, is commercially available.

Preparative Method: for the in situ preparation of the reagent, n-Butyllithium (10.40 mL of a 1.73 M solution in hexane) is added dropwise with stirring under nitrogen over ca. 30 min to a solution of 2.75 g (18 mmol) of 3-bromopropionic acid in 75.0 mL anhydrous THF at -70 °C. The resulting solution of lithium 3-bromopropionate is held at -70 °C and added dropwise with rapid stirring to a solution containing 30 mmol of Lithium Naphthalenide in 100 mL of anhydrous THF at -70 °C until the dark green color of the solution changed to dark brown.

Handling, Storage, and Precautions: n-butyllithium is pyrophoric and moisture sensitive; 3-bromopropionic acid is corrosive; lithium naphthalenide is air and moisture sensitive. Avoid contact of all ingredients and the reagent itself with the eyes, skin, and clothing. Prepare and handle the reagent under an inert nitrogen or argon atmosphere. It is recommended that the reagent be prepared immediately prior to use.

In recent years there has been a great deal of interest in the preparation and reactions of metal homoenolates and homoenolate equivalents.2,3 The conversion of 3-bromopropionic acid into its lithium salt provides protection of the carboxyl group so that bromine-lithium exchange can occur with lithium naphthalenide to give the parent lithium homoenolate system. Under the reaction conditions the homoenolate system does not rearrange into the more thermodynamically stable lithium enolate of the carboxylate. Treatment of 3-bromopropionic acid with 2.2 equiv of n-butyllithium at -70 to -100 °C provides a very low yield of the reagent.1 Instead, heptanoic acid, which results from an unusually facile Wurtz coupling of the lithium 3-bromocarboxylate and n-butyllithium, is obtained.

The addition of carbonyl compounds to solutions of the reagent at -70 °C followed by warming to rt and neutralization of the reaction mixture produces g-hydroxy acids, which produce g-lactones in moderate yields upon mild acid treatment. Saturated aliphatic and aromatic aldehydes (eq 1) yield the corresponding g-monosubstituted g-lactones.1 Unconjugated unsaturated aldehydes also react similarly (eq 2).4

Acyclic and cyclic saturated ketones yield g,g-disubstituted or spirocyclic g-lactones upon treatment with the reagent. The reagent adds to 4-t-butylcyclohexanone from the equatorial direction with low stereoselectivity to produce the syn spirolactone as the major product (eq 3).1 Interestingly, the anti spirolactone is produced with high stereoselectivity in the SmI2-induced coupling of 4-t-butylcyclohexanone with ethyl acrylate.5

The reagent also reacts with a,b-unsaturated ketones, e.g. isophorone, to provide a direct route to allylic spirolactones (eq 4).6 A more lengthy synthesis of the allylic spirolactone shown in eq 4 was reported recently.7

A variety of other metal homoenolate reagents are capable of converting carbonyl compounds into g-lactones in a straightforward manner. Some of these include the dilithium dianion prepared from treating 3-tri-n-butylstannylpropionamide with 2.0 equiv n-BuLi at low temperature,8a,b trichlorotitanium homoenolates of propionate esters prepared from treatment of 1-alkoxy-1-trimethylsilylcyclopropanes with Titanium(IV) Chloride,8c,d esters of zinc homoenolates mediated by titanium(IV) reagents,8e and esters of lanthanoid homoenolates.8f Samarium(II) Iodide-promoted couplings of carbonyl compounds with a,b-unsaturated5 and 3-halopropionate esters9 also provide useful direct routes to g-lactones.

See also 1-Ethoxy-1-(trimethylsilyloxy)cyclopropane.


1. Caine, D.; Frobese, A. S. TL 1978, 883.
2. (a) Kuwajima, I.; Nakamura, E. COS 1991, 2, Chapter 1.14. (b) Hoppe, D. AG(E) 1984, 23, 932. (c) Stowell, J. C. CRV 1984, 84, 409. (d) Werstiuk, N. H. T 1983, 39, 205.
3. Seebach, D. AG(E) 1979, 18, 239.
4. Chattopadhyay, A.; Mamdapur, V. R. IJC 1988, 27B, 169.
5. Fukuzawa, J.; Nakanishi, A.; Fujinami, T.; Sakai, S. JCS(P1) 1988, 1669.
6. Caine, D.; Lin, C.-Y. SC 1994, 24, 2473.
7. Constantino, M. G.; Beltrame, M., Jr.; deMedeiros, E. F.; da Silva, G.-V. SC 1992, 22, 2859.
8. (a) Goswami, R.; Corcoran, D. E. TL 1982, 23, 1463. (b) Goswami, R.; Corcoran, D. E. JACS 1983, 105, 7182. (c) Nakamura, E.; Kuwajima, I. JACS 1983, 105, 651. (d) Nakamura, E.; Oshino, H.; Kuwajima, I. JACS 1986, 108, 3745. (e) Ochiai, H.; Nishihara, T.; Tamaru, Y.; Yoshida, Z. JOC 1988, 53, 1344. (f) Fukuzawa, S.; Sumimoto, N.; Fujinami, T.; Sakai, S. JOC 1990, 55, 1628.
9. Otsubo, K.; Kawamura, K.; Inanaga, J.; Yamaguchi, M. CL 1987, 1487. Csuk, R.; Hu, Z.; Abdou, M.; Kratky, C. T 1991, 47, 7037.

Drury Caine

The University of Alabama, Tuscaloosa, AL, USA



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