[53101-93-2]  · C4H3LiO  · 3-Lithiofuran  · (MW 74.007)

(nucleophilic organolithium reagent useful for alkylation; addition to ketones, acid chlorides, aldehydes, amides, lactones, carbon dioxide, nitrones, epoxides, sulfinate esters, boronic esters, metal carbonyls, borates, metal halides; affords intermediates for organometallic coupling reactions)

Alternate Name: b-furyllithium.

Preparative Methods: metalation of Furan at the 3-position requires a metal-halogen1-7 or metal-metal exchange8 since deprotonation of furan occurs preferentially at the 2-position. 3-Lithiofuran (1) (eq 1)1-3 is prepared by the treatment of 3-iodofuran (2a) with n-Butyllithium in ether or THF (-78 °C);4,5 by the treatment of 3-bromofuran (2b) with n-butyllithium in THF (-78 °C);6,7 or by the reaction of 3-tri-n-butylstannylfuran (2c) with n-butyllithium in THF (-78 °C).8

Handling, Storage, and Precautions: the reagent is generated in situ, under anhydrous conditions in an inert atmosphere at low temperatures (<=-40 °C), and used shortly after preparation. The ability to store the reagent is not clear. As n-BuLi is employed, the precautions for preparation and use would mirror those of n-BuLi and related organometallic reagents. It has been demonstrated that good temperature control is important to the regiochemical integrity of the reagent. Temperatures exceeding -40 °C during the course of reagent generation and use permit isomerization of 3-lithiofuran to the more thermodynamically stable 2-lithiofuran (eq 2).7


3-Lithiofuran (1) reacts readily with allylic halides and primary alkyl halides, in the presence of Hexamethylphosphoric Triamide, to give 3-substituted furans (eq 3).7

Addition to Carbonyl Compounds.

3-Lithiofuran (1) adds to acid chlorides to give furyl ketones (eq 4),5 to aldehydes (eq 5),7,9,10 and to ketones (eq 6)11 to give carbinols. The reaction of 3-lithiofuran (1) with lactones affords the related lactols (eq 7).12 Carbon Dioxide reacts with 3-lithiofuran (1) to provide 3-furoic acid.8,13 Although 3-lithiofuran is considered to be relatively unreactive, it will add to amides to give amines via the reduction of an intermediate enamine (eq 8).14,15

Reaction with Electrophiles.

Treatment of 3-lithiofuran (1) with CuBr.SMe2 (see Copper(I) Bromide) and 2-lithiofuran affords a higher order cuprate which adds to epoxides, giving carbinols (eq 9).16 3-Lithiofuran (1) affords branched hydroxylamines upon reaction with nitrones (eq 10).17 (-)-(S)-Menthyl p-toluenesulfinate,18 an optically pure boronic ester (see (-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate),19 and Hexacarbonylchromium20 also react with 3-lithiofuran (1) to provide an optically pure furyl sulfoxide (eq 11), an optically pure borinic ester (eq 12), and a furyl-substituted chromium carbene (eq 13), respectively.

Analogous Reagents.

A variety of substituted 3-lithiofurans has been prepared by metal halogen exchange [(3),21 (4),22 (5),23 (6)24]. However, when blocking [(7),25 (8)26] and/or coordinating groups at the 4-position (9)27 are present, metalation reactions provide an effective path to 3-lithiofurans. 3-Lithiofurans (8) and (9) have undergone metal-metal exchange to afford the bromozinc26 and tin reagents,28 respectively. These reagents, as well as a boronic acid produced from (9),27 have been employed in palladium-catalyzed carbon-carbon bond forming reactions.

1. Katritzky, A. R. Handbook of Heterocyclic Chemistry; Pergamon: Oxford, 1985, pp 261, 286.
2. Sargent, M. V.; Cresp, T. M. In Comprehensive Organic Chemistry; Barton, D. H. R., Ed.; Pergamon: Oxford, 1979; Vol. 4, pp 713, 742-725.
3. Gilchrist, T. L. Heterocyclic Chemistry, 2nd ed.; Wiley: New York, 1992; pp 208-209.
4. Gronowitz, S.; Sörlin, G. AK 1962, 19, 515.
5. Bell, R. A.; Gravestock, M. B.; Taguchi, V. Y. CJC 1972, 50, 3749.
6. Mangoni, L.; Adinolfi, M.; Laonigro, G.; Caputo, R. T 1972, 28, 611.
7. Bock, I.; Bornowski, H.; Ranft, A.; Theis, H. T 1990, 46, 1199.
8. Fleming, I.; Taddei, M. S 1985, 898.
9. Tokoroyama, T.; Fujimori, K.; Shimizu, T. Yamagiwa, Y.; Monden, M.; Iio, H. T 1988, 44, 6607.
10. Liu, H.-J.; Dieck-Abularach, T. H 1987, 25, 245.
11. Liebeskind, L. S.; Zhang, J. JOC 1991, 56, 6379.
12. Czernicki, S.; Ville, G. JOC 1989, 54, 610.
13. Fukuyama, Y.; Kawashima, Y.; Miwa, T.; Tokoroyama, T. S 1974, 443.
14. Aoyagi, S.; Shishido, Y.; Kibayashi, C. TL 1991, 32, 4325.
15. Hwang, Y. C.; Chu, M.; Fowler, F. W. JOC 1985, 50, 3885.
16. Kojima, Y.; Kato, N. T 1981, 37, 2527.
17. Basha, A.; Ratajczyk, J. D.; Brooks, D. W. TL 1991, 32, 3783.
18. Girodier, L.; Maignan, C.; Rouessac, F. TA 1992, 3, 857.
19. Brown, H. C.; Srebnik, M.; Bakshi, R. K.; Cole, T. E. JACS 1987, 109, 5420.
20. Peterson, G. A.; Kunng, F-A.; McCallum, J. S.; Wulff, W. D. TL 1987, 28, 1381.
21. Nolan, S. M.; Cohen, T. JOC 1981, 46, 2473.
22. Reich, H. J.; Olson, R. E. JOC 1987, 52, 2315.
23. Haarmann, H.; Eberbach, W. TL 1991, 32, 903.
24. Chiarello, J.; Joullie, M. M. T 1988, 44, 41.
25. Carpenter, A. J.; Chadwick, D. J. TL 1985, 26, 1777.
26. Ennis, D. S.; Gilchrist, T. L. T 1990, 46, 2623.
27. Christofoli, W. A.; Keay, B. A. TL 1991, 32, 5881.
28. Keay, B. A.; Bontront, J.-L. J. CJC 1991, 69, 1326.

Mark A. Collins & Steven P. Tanis

The Upjohn Company, Kalamazoo, MI, USA

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