Benzyl Chloride

[100-44-7]  · C7H7Cl  · Benzyl Chloride  · (MW 126.59)

(benzylating agent for a variety of heteroatom functional groups and carbon nucleophiles; precursor to benzyl organometallics)

Physical Data: bp 177-181 °C; d 1.100 g cm-3.

Solubility: freely miscible in ethereal, chlorinated, and dipolar aprotic solvents.

Form Supplied in: 99% pure liquid.

Handling, Storage, and Precautions: the reagent is a mutagen and possibly a carcinogen. It should be used in a fume hood.

Benzylation of Heteroatom Functional Groups.

Benzyl chloride is a versatile benzylating agent for heteroatom functional groups and is commonly used to introduce this protecting group.1 Benzylation of alcohols with this reagent is achieved under strongly basic conditions such as KOH, either in an alcoholic solvent2 or under phase transfer conditions with n-Bu4NHSO4.3 Silver oxide in DMF is also effective.4 A procedure involving Ni(acac)2 has also been reported.5 Phenols may also be benzylated under basic conditions.6

Amino groups are readily benzylated when treated with benzyl chloride in the presence of carbonate or hydroxide base,5 although dibenzylation of primary amines is a competing reaction.7 Thiols are benzylated with sodium hydroxide or cesium carbonate in polar solvents such as ethanol or DMF.8 Dibenzyl sulfide is produced by reaction of benzyl chloride with elemental sulfur and sodium triethylborohydride.9

Amides can be N-benzylated with this reagent under the influence of strong bases such as metal hydrides.10 A benzyl carboxylate ester may be formed from benzyl chloride and the corresponding sodium salt of the acid in DMSO.11

Benzyl cyanide can be prepared from benzyl chloride and KCN with an ion exchange resin.12 Benzyl azide is formed by reaction with trimethylsilyl azide in HMPA.13

Benzylation of Active Methylene Compounds.

The anions or dianions of b-ketoesters,14 substituted malonate esters,15 b-ketoaldehydes,16 b-diketones,17 b-ketoamides,18 and b-ketonitriles19 all react effectively with benzyl chloride to afford C-benzylated products. When the dianion of a b-ketoamide, b-ketoester, or b-diketone is generated and treated with benzyl chloride, benzylation is observed at the least acidic position. Nitrile-stabilized carbanions are readily benzylated in ethereal solvents, ammonia, or DMSO.15,20 Benzyl chloride also reacts well with carbanions derived from ketones,21 esters,22 imines (metalloenamines),23 oximes,24 and hydrazones.23 When benzalacetophenone is treated sequentially with 2 equiv of potassium in ammonia and then with benzyl chloride in ether, a formal conjugate addition of the benzyl group is observed (eq 1).25 If a second equivalent of benzyl chloride is added, benzylation occurs at both the a- and b-positions.

Reactions with Metals and Organometallics.

Benzylmagnesium chloride can be prepared satisfactorily by rapid addition of benzyl chloride to magnesium in ether.26 Benzyl chloride is readily dimerized by lithium naphthalenide,27 sodium and tetraphenylethane,28 zinc in the presence of catalytic nickel(II) bromide,29 with titanocene dichloride and diiodomethane,30 (PPh3)3CoCl,31 and by electrolysis.32 The cross-coupling reactions of benzyl chloride with other organometallics is demonstrated by the benzylation of organolithiums,33 as in the case of a directed lithiation product (eq 2),32a Grignard reagents,34 and organocuprates.35 Vinyl boranes, derived from the addition of boron tribromide to alkynes and subsequent alkylation with organozincs (eq 3),35a couple with benzyl chloride under palladium catalysis.36 Benzyl chloride will add to an a-diketone in the presence of powdered nickel to give the a-ketol (eq 4).37

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. Fletcher, H. G., Methods Carbohydr. Chem. 1963, 166.
3. Freedman, H. H.; Dubois, R. A. TL 1975, 3251.
4. Kuhn, R.; Löw, I.; Trischmann, H. CB 1957, 90, 203.
5. Yamashita, M.; Takegami, Y. S 1977, 803.
6. Heer, J.; Billeter, J. R.; Miescher, K. HCA 1945, 28, 991.
7. Velluz, L.; Amiard, G.; Heymès, R. BSF(2) 1954, 1012.
8. (a) Frankel, M.; Gertner, D.; Jacobson, H.; Zilkha, A. JCS 1960, 1390. (b) Vogtle, F.; Klieser, B. S 1982, 294.
9. Gladysz, J. A.; Wong, V. K.; Jick, B. S. CC 1978, 838.
10. (a) Xia, Y.; Kozikowski, A. P. JACS 1989, 111, 4116. (b) Bryant, D. R.; Work, S. D.; Hauser, C. R. JOC 1964, 29, 235.
11. Shaw, J. E.; Kunerth, D. C.; Sherry, J. J. TL 1973, 689.
12. Sukata, K. JOC 1985, 50, 4388.
13. Nishiyama, K.; Karigomi, H. CL 1982, 9, 1477.
14. (a) Elsinger, F. OS 1973, 5, 76. (b) Stork, G.; McElvain, S. M. JACS 1946, 68, 1053.
15. Cope, A. C.; Holmes, H. L.; House, H. O. OR 1957, 9, 107.
16. Ravikumar, V. T.; Sathyamoorthi, G.; Thangaraj, K.; Rajagopalan, K. IJC(B) 1985, 24, 959.
17. Hauser, C. R.; Harris, T. M. JACS 1958, 80, 6360.
18. Hubbard, J. S.; Harris, T. M. TL 1978, 4601.
19. Baraldi, P. G.; Pollini, G. P.; Zanirato, V. S 1985, 969.
20. Arseniyadis, S.; Kyler, K. S.; Watt, D. S. OR 1984, 31, 1.
21. Bates, G. S.; Ramaswamy, S. CJC 1980, 58, 716.
22. Muller-Uri, C.; Singer, E. A.; Fleischacker, W. JMC 1986, 29, 125.
23. (a) Stork, G.; Dowd, S. R. JACS 1963, 85, 2178. (b) Hosomi, A.; Araki, Y.; Sakurai, H. JACS 1982, 104, 2081.
24. Henoch, F. E.; Hampton, K. G.; Hauser, C. R. JACS 1969, 91, 676.
25. Hamrick, P. J.; Hauser, C. R. JACS 1959, 81, 493.
26. Gilman, H.; Catlin, W. E. OS 1941, 1, 471.
27. (a) Ginah, F. O.; Donovan, T. A.; Suchan, S. D.; Pfennig, D. R.; Ebert, G. W. JOC 1990, 55, 584. (b) Boudjouk, P.; Thompson, D. P.; Ohrbom, W. H.; Han, B. H. OM 1986, 5, 1257.
28. Muller, E.; Roscheisen, G. CB 1957, 90, 543.
29. Iyoda, M.; Sakaitani, M.; Otsuka, H.; Oda, M. CL 1985, 127.
30. Eisch, J. J.; Piotrowski, A. TL 1983, 24, 2043.
31. Momose, D.; Iguchi, K.; Sugiyama, T.; Yamada, Y. CPB 1984, 32, 1840.
32. (a) Rollin, Y.; Troupel, M.; Tuck, D. G.; Perichon, J. JOM 1986, 303 (1), 131. (b) Bedioui, F.; Robin, Y.; Devynk, J.; Biedcharreton, C. JOM 1987, 326 (1), 117.
33. (a) Beak, P.; Kempf, D. J.; Wilson, K. D. JACS 1985, 107, 4745. (b) Aoyama, T.; Shioiri, T. TL 1986, 27, 2005.
34. Fuson, A. C.; Dewald, H. A.; Gaertner, R. JOC 1951, 16, 21.
35. Vig, O. P.; Sharma, S. D.; Kapur, J. C. JIC 1969, 46, 167.
36. (a) Satoh, Y.; Serizawa, H.; Miyaura, N.; Hara, S.; Suzuki, A. TL 1988, 29, 1811. (b) Hyuga, S.; Yamashina, N.; Hara, S.; Suzuki, A. CL 1988, 809. (c) Hyuga, S.; Yasumichi, C.; Yamashina, N.; Hara, S.; Suzuki, A. CL 1987, 1757.
37. Inaba, S.; Reike, R. D. S 1984, 10, 844.

William E. Bauta

Sandoz Research Institute, East Hanover, NJ, USA

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