[110-52-1]  · C4H8Br2  · 1,4-Dibromobutane  · (MW 215.92)

(useful for annulation as bis-electrophile1 or as precursor to organobis(metallics)2)

Alternate Name: tetramethylene dibromide.

Physical Data: bp 194-196 °C, 63-65 °C/6 mmHg; d 1.808 g cm-3.

Solubility: sol THF, toluene, HMPA, benzene, DMF, Et2O.

Form Supplied in: colorless liquid, 99%.

Analysis of Reagent Purity: 1H NMR: d 3.48 (m), 2.05 (m).

Handling, Storage, and Precautions: store in a cool dry place. Lachrymator; this reagent should be handled in a fume hood.

Uses as a Bis-Electrophile.

1,4-Dibromobutane reacts with a wide variety of nucleophiles to give displacement of one or both bromine atoms, depending upon the stoichiometry of the reaction. When 1 equiv of nucleophile is present, monoalkylation occurs. In general, subsequent functionalization of the remaining bromide is performed in the course of the synthesis. In this way the reagent is a precursor to many 1,4-difunctionalized butanes. When 2 equiv of nucleophile are used, symmetrically substituted butanes are the result. Many different nucleophiles have been utilized in these reactions. Carbon nucleophiles include alkynyl,3 alkenyl,4 allyl,5 aryl,6 benzyl,7 and cyclopentadienyl anions.8 In addition, a number of enolate anions have been alkylated including those derived from dissolving metal reductions of carbonyl-substituted arenes.9 Heteroatom nucleophiles include halides,10 alkoxides,11 phenoxides,12 and N-deprotonated amides.13

Electrophilic Annulation.

When two nucleophilic sites exist in the same molecule, 1,4-dibromobutane can react to form a ring. Typically these reagents are carboxylic acid derivatives having two geminal a-hydrogens. When 2 equiv of base are added, the dibromide reacts twice at the same carbon center to give a cyclopentane. If the acidic carbon is part of a pre-existing ring, then a spirocycle is formed.1 Esters,14 ketones,15 and nitriles16 all work well for these annulation reactions, but any compound with two geminal acidic hydrogens can exhibit similar reactivity.17 The iminonitrile (1) was annulated by this method in a route to cycloleucine (eq 1).16 a,b-Unsaturated carbonyl compounds can react via their extended enolates at the a-position to give deconjugated annulated products18 or, if the structure permits, at the a-position.19 If the nucleophilic moieties are vicinally related, fused-ring compounds are obtained.20 This is the case for the isoquinoline formamidine (2), which is alkylated at its benzylic position with the aid of lithium chelation and then directly cleaved with Hydrazine to give a benzo[a]quinolizidine (eq 2).21 Metallacyclopentenes, prepared by the reaction of 1,3-dienes with activated Magnesium, react with 1,4-dibromobutane and lead to spiroannulated products.22

Formation and Uses of Organobis(metallics).

The electrophilic nature of 1,4-dibromobutane can be inverted by the formation of organobis(metallics). These compounds can be used with substrates bearing two electrophilic sites to form new rings. The bis-Grignard reagents have been used extensively. Reaction with esters and lactones gives cyclopentanols23 and cyclic dicarboxylic acid anhydrides lead to spirolactones.24 The bis-cuprate has been utilized in a novel class of spiroannulations via 1,4-addition to 3-halocycloalk-2-enones followed by elimination of the halide atom and a second 1,4-addition (eq 3).25

1. Krapcho, A. P. S 1974, 383 and references therein.
2. (a) Wender, P. A.; White, A. W. JACS 1988, 110, 2218 and references therein. (b) Cannone, P.; Belley, M.; Fytas, G.; Plamondon, J. CJC 1988, 66, 168 and references therein. (c) McDermott, J. X.; Wilson, M. E.; Whitesides, G. M. JACS 1976, 98, 6529.
3. (a) Clive, D. L. J.; Bergstra, R. J. JOC 1990, 55, 1786. (b) Nicolaou, K. C.; Zuccarello, G.; Riemer, C.; Estevez, V. A.; Dai, W.-M. JACS 1992, 114, 7360. (c) Canceill, J.; Collet, A. CC 1988, 582.
4. Lautens, M.; Tam, W.; Edwards, L. G. JOC 1992, 57, 8.
5. Macdonald, T. L.; Narayanan, B. A.; O'Dell, D. E. JOC 1981, 46, 1504.
6. (a) Takeuchi, M.; Nishimura, J. TL 1992, 33, 5563. (b) Nishimura, J.; Yamada, N.; Horiuchi, Y.; Ueda, E.; Ohbayashi, A.; Oku, A. BCJ 1986, 59, 2035. (c) Kadkhodayan, M.; Singleton, T.; Heldrich, F. J. SC 1984, 14, 707.
7. (a) Gilliatt, V. J.; Sultany, C. M.; Butcher, J. A., Jr. TL 1992, 33, 6255. (b) Bunce, R. A.; Sullivan, J. P. SC 1990, 20, 865.
8. Alexander, J.; Baumgarten, M.; Klabunde, K-U.; Müllen, K. TL 1991, 32, 735.
9. (a) Yamashita, M.; Matsumiya, K.; Morimoto, H.; Suemitsu, R. BCJ 1989, 62, 1668. (b) Beckwith, A. L. J.; Roberts, D. H. JACS 1986, 108, 5893. (c) Liepa, A. J.; Wilkie, J. S.; Winkler, D. A.; Winzenberg, K. N. AJC 1992, 45, 759.
10. Hahn, R. C. JOC 1988, 53, 1331.
11. Motoi, M.; Suda, H.; Shimamura, K.; Nagahara, S.; Takei, M.; Kanoh, S. BCJ 1988, 61, 1653.
12. (a) Cole, K. L.; Farran, M. A.; Deshayes, K. TL 1992, 33, 599.
13. (a) Flouzat, C.; Blanchet, M.; Guillaumet, G. TL 1992, 33, 4571. (b) Storey, J. M. D.; McCarthy, C.; Jones, K. CC 1991, 892. (c) Beckwith, A. L. J.; Westwood, S. W. T 1989, 45, 5269. (d) Crombie, L.; Jones, R. C. F.; Mat-Zin, A. R.; Osborne, S. CC 1983, 960.
14. (a) Tomioka, K.; Koga, K. T 1988, 44, 4351. (b) Kotha, S.; Kuki, A. TL 1992, 33, 1565.
15. Hori, K.; Takaishi, N.; Inamoto, Y. BCJ 1988, 61, 2669.
16. O'Donnell, M. J.; Bruder, W. A.; Eckrich, T. M.; Shullenberger, D. F.; Staten, G. S. S 1984, 127.
17. (a) Padwa, A.; Bullock, W. H.; Dyszlewski, A. D.; McCombie, S. W.; Shankar, B. B.; Ganguly, A. K. JOC 1991, 56, 3556. (b) Paquette, L. A.; Charumilind, P.; Kravetz, T. M.; Böhm, M. C.; Gleiter, R. JACS 1983, 105, 3126.
18. (a) Brocksom, T. J.; Constantino, M. G.; Ferraz, H. M. C. SC 1977, 7, 483. (b) Greene, A. E.; Coelho, F.; Deprés, J.-P. JOC 1985, 50, 1973. (c) Jones, R. C. F.; Hirst, S. C.; Turner, I. JCS(P1) 1991, 953.
19. Stork, G.; Danheiser, R. L.; Ganem, B. JACS 1973, 95, 3414.
20. Mahalanabis, K. K.; Mumtaz, M.; Sniekus, V. TL 1982, 23, 3971.
21. Meyers, A. I.; Du, B.; Gonzalez, M. A. JOC 1990, 55, 4218.
22. Rieke, R. D.; Xiong, H. JOC 1992, 57, 6560 and references therein.
23. (a) Canonne, P.; Foscolos, G. B.; Bélanger, D. JOC 1980, 45, 1828. (b) Canonne, P.; Caron, H.; Foscolos, G. T 1984, 40, 865. (c) Barluenga, J.; Yus, M.; Concellon, J. M.; Bernad, P.; Alvarez, F. JCR(S) 1984, 122. (d) Ref. 2b.
24. (a) Canonne, P.; Bélanger, D. CC 1980, 125. (b) Canonne, P.; Bélanger, D.; Lemay, G.; Foscolos, G. B. JOC 1981, 46, 3091.
25. (a) Wender, P. A.; Eck, S. L. TL 1977, 1245. (b) Wender, P. A.; White, A. W.; McDonald, F. E. OS 1992, 70, 204.

Paul A. Wender & Thomas E. Smith

Stanford University, CA, USA

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