Benzyl Bromide

[100-39-0]  · C7H7Br  · Benzyl Bromide  · (MW 171.04)

(benzylating agent for a variety of heteroatomic functional groups as well as carbon nucleophiles)

Physical Data: mp -3 to -1 °C; bp 198-199 °C; d 1.438 g cm-3.

Solubility: sol ethereal, chlorinated, and dipolar aprotic solvents.

Form Supplied in: 98-99% pure liquid.

Handling, Storage, and Precautions: the reagent is a potent lachrymator and should be handled in a fume hood.

Benzylation of Heteroatomic Functional Groups.

Benzylation of various heteroatomic functional groups is readily achieved with this reagent under a variety of conditions and finds widespread application in organic synthesis, primarily as a protecting group.1

Alcohols and phenols are benzylated upon treatment with benzyl bromide under basic conditions. For example, treatment of alcohols with Sodium Hydride or Potassium Hydride in ethereal solvent2 or DMF3 generates alkoxides, which subsequently undergo Williamson reactions with benzyl bromide. Selective benzylation of a primary alcohol in the presence of a secondary alcohol has been accomplished in DMF at low temperature.4

Benzylation of alcohols using Potassium Fluoride-Alumina and benzyl bromide in acetonitrile at room temperature is effective.5 Silver oxide in DMF is yet another base system.6 Of particular interest in carbohydrate applications is the reaction of benzyl bromide with carbohydrate derivatives which have been pretreated with tin reagents. Thus it is possible to benzylate an equatorial alcohol in the presence of an axial alcohol (eq 1)7 and also to selectively benzylate an anomeric hydroxy through Di-n-butyltin Oxide.8

In some instances the sluggish reactivity of sterically hindered alcohols toward benzyl bromide may be overcome through addition of a catalytic iodide source such as Tetra-n-butylammonium Iodide, which generates the more reactive benzyl iodide in situ (see Benzyl Iodide). Benzylation of phenols proceeds well under the conditions described for aliphatic alcohols. Owing to the greater acidity of phenols it is possible to use weaker bases such as Potassium Carbonate for these reactions.9

Benzyl bromide will readily alkylate amino groups. Reactions are normally carried out in the presence of additional base and dibenzylation of primary amines is usually predominant.10 Selective quaternization of a less hindered tertiary amine in the presence of a more hindered tertiary amine has been described.11 Amide and lactam nitrogens can be benzylated under basic conditions,12 as can those of sulfonamides13 and nitrogen heterocycles.14

Thiols,15 silyl thioethers,16 and thiosaccharins17 may be benzylated with benzyl bromide under basic conditions. Thus L-cysteine is S-benzylated under basic conditions (eq 2).18 Benzylation of selenols is likewise possible.19 A synthesis of benzylic sulfones is possible using Benzenesulfonyl Chloride and Sodium O,O-Diethyl Phosphorotelluroate with benzyl bromide.20

Although the preparation of benzyl carboxylate esters from benzyl bromide and carboxylate anions is not the most common route to these compounds, the reaction is possible when carried out in DMF20 or using zinc carboxylates.21

Nucleophilic attack on benzyl bromide by cyanide and azide anions is feasible with ion-exchange resins or with the corresponding salts.22

Reactions with Active Methylene Compounds.

Enolates of ketones,23 esters,24 enediolates,25 1,3-dicarbonyl compounds,26 amides and lactams,27 as well as nitrile-stabilized carbanions,28 can be alkylated with benzyl bromide. Cyclohexanone may be benzylated in 92% ee using a chiral amide base.29 Amide bases as well as alkoxides have been employed in the case of nitrile alkylations.28b Benzylation of metalloenamines may be achieved30a and enantioselective reactions are possible using a chiral imine (eq 3).30b However, reactions between benzyl bromide and enamines proceed in low yield.31 The benzylation of a ketone via its enol silyl ether, promoted by fluoride, has been observed.32

Reactions with Metals and Organometallics.

Difficulties encountered in the preparation of benzylic metal compounds with active metals are due primarily to the tendency of these compounds to undergo Wurtz coupling (self condensation).33 Benzylmagnesium bromide may nevertheless be prepared from benzyl bromide and used under standard34 or Barbier conditions.35 Benzyllithium cannot be obtained practically from benzyl bromide. Benzylzinc bromide and the cyanocuprate BnCu(CN)ZnBr have both been prepared. The cuprate undergoes 1,2-additions with aldehydes and ketones.36

The propensity of benzyl bromide to undergo coupling with organometallic reagents may be used to advantage, as organolithiums,37 Grignard reagents,38 organocuprates,39 organocadmiums,40 organochromiums,41 and organoiron reagents42 are all known to give coupling products. An interesting coupling of benzyl bromide with N-methylphthalimide under dissolving metal conditions has been reported (eq 4).43

1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Protective Groups in Organic Chemistry; McOmie, J. F. W., Ed.; Plenum: New York, 1973.
2. Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P. JACS 1981, 103, 1224.
3. Hanessian, S.; Liak, T. J.; Dixit, D. M. Carbohydr. Res. 1981, 88, C14.
4. Fukuzawa, A.; Sato, H.; Masamune, T. TL 1987, 28, 4303.
5. Ando, T.; Yamawaki, J.; Kawate, T.; Sumi, S.; Hanafusa, T. BCJ 1982, 55, 2504.
6. Kuhn, R.; Low, I.; Trischmann, H. CB 1957, 90, 203.
7. (a) Nashed, M. A.; Anderson, L. TL 1976, 3503. (b) Cruzado, C.; Bernabe, M.; Martin-Lomas, M. JOC 1989, 54, 465.
8. Bliard, C.; Herczegh, P.; Olesker, A.; Lukacs, G. Carbohydr. Res. 1989, 8, 103.
9. Schmidhammer, H.; Brossi, A. JOC 1971, 93, 746.
10. (a) Yamazaki, N.; Kibayashi, C. JACS 1989, 111, 1396. (b) Gray, B. D.; Jeffs, P. W. CC 1987, 1329.
11. (a) Chung, B.-H.; Zymalkowski, F. AP 1984, 317, 307. (b) Chung, B.-H.; Zymalkowski, F. AP 1984, 317, 323.
12. (a) Landini, D.; Penso, M. SC 1988, 18, 791. (b) Staskun, B. JOC 1979, 44, 875. (c) Sato, R.; Senzaki, T.; Goto, T.; Saito, M. BCJ 1986, 59, 2950.
13. Bergeron, R. J.; Hoffman, P. G. JOC 1979, 44, 1835.
14. Chivikas, C. J.; Hodges, J. C. JOC 1987, 52, 3591.
15. Harpp, D. N.; Kobayashi, M. TL 1986, 27, 3975.
16. Ando, W.; Furuhata, T.; Tsumaki, H.; Sekiguchi, A. SC 1982, 12, 627.
17. Yamada, H.; Kinoshita, H.; Inomata, K.; Kotake, H. BCJ 1983, 56, 949.
18. Dymicky, M.; Byler, D. M. OPP 1991, 23, 93.
19. Mitchell, R. H. CC 1974, 990.
20. Huang, X.; Pi, J.-H. SC 1990, 20, 2291.
21. (a) Comber, M. F.; Sargent, M. V.; Skelton, B. W.; White, A. H. JCS(P1) 1989, 441. (b) Shono, T.; Ishige, O.; Uyama, H.; Kashimura, S. JOC 1986, 51, 546.
22. (a) Gordon, M.; Griffin, C. E. CI(L) 1962, 1019. (b) Hassner, A.; Stern, M. AG 1986, 98, 479. (c) Bram, G.; Loupy, A.; Pedoussaut, M. BSF(2) 1986, 124. (d) Ravindranath, B.; Srinivas, P. T 1984, 40, 1623.
23. (a) Gall, M.; House, H. O. OSC 1988, 6, 121. (b) Sato, T.; Watanabe, T.; Hayata, T.; Tsukui, T. CC 1989, 153.
24. (a) Seebach, D.; Estermann, H. TL 1987, 28, 3103. (b) Lerner, L. M. JOC 1976, 41, 2228.
25. Duhamel, L.; Poirier, J.-M. BSF(2) 1982, 297.
26. (a) Berry, N. M.; Darey, M. C. P.; Harwood, L. M. S 1986, 476. (b) Bassetti, M.; Cerichelli, G.; Floris, B. G 1986, 116, 583. (c) Asaoka, M.; Miyake, K.; Takei, H. CL 1975, 1149. (d) Ogura, K.; Yahata, N.; Minoguchi, M.; Ohtsuki, K.; Takahashi, K.; lida, H. JOC 1986, 51, 508.
27. (a) Woodbury, R. P.; Rathke, M. W. JOC 1977, 42, 1688. (b) Klein, U.; Sucrow, W. CB 1977, 110, 1611. (c) Meyers, A. I.; Harre, M.; Garland, R. JACS 1984, 106, 1146.
28. (a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 31, 1. (b) Cope, A. C.; Holmes, H. L.; House, H. O. OR 1957, 9, 107.
29. Murakata, M.; Nakajima, M.; Koga, K. CC 1990, 1657.
30. (a) Stork, G.; Dowd, S. R. OSC 1988, 6, 526. (b) Saigo, K.; Kashahara, A.; Ogawa, S.; Nohira, H. TL 1983, 24, 511.
31. (a) Enamines: Synthesis, Structure, and Reactions, 2nd ed.; Cook, A. G., Ed.; Dekker: New York, 1988. (b) Brannock, K. C.; Burpitt, R. D. JOC 1961, 26, 3576. (c) Opitz, G.; Hellmann, H.; Mildenberger, M.; Suhr, H. LA 1961, 649, 36.
32. (a) Kuwajima, I.; Nakamura, E. JACS 1975, 97, 3257. (b) Binkley, E. S.; Heathcock, C. H. JOC 1975, 40, 2156.
33. Wakefield, B. J. Organolithium Methods; Academic: New York, 1988.
34. (a) Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic Substances; Constable: London, 1954. (b) Reuvers, A. J. M.; van Bekkum, H.; Wepster, B. M. T 1970, 26, 2683.
35. Blomberg, C.; Hartog, F. A. S 1977, 18.
36. Berk, S. C.; Knochel, P.; Yeh, M. C. P. JOC 1988, 53, 5789.
37. (a) Hirai, K.; Matsuda, H.; Kishida, Y. TL 1971, 4359. (b) Hirai, K.; Kishida, Y. TL 1972, 2743. (c) Villieras, J.; Rambaud, M; Kirschleger, B.; Tarhouni, R. BSF(2) 1985, 837.
38. Rahman, M. T.; Nahar, S. K. JOM 1987, 329, 133.
39. (a) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I. TL 1979, 4071. (b) Furber, M.; Taylor, R. J. K.; Burford, S. C. TL 1985, 26, 3285.
40. (a) Emptoz, G.; Huet, F. BSF(2) 1974, 1695.
41. Wellmann, J.; Steckhan, E. S 1978, 901.
42. (a) Sawa, Y.; Ryang, M.; Tsutsumi, S. JOC 1970, 35, 4183. (b) Cookson, R. C.; Farquharson, G. TL 1979, 1255. (c) Sawa, Y.; Ryang, M.; Tsutsumi, S. TL 1969, 5189.
43. Flynn, G. A. CC 1980, 862.

William E. Bauta

Sandoz Research Institute, East Hanover, NJ, USA

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