BENZYL CHLORIDE 1
Ph
Benzyl Chloride
O O
1. K (2 equiv), NH3
(1)
Ph Ph Ph Ph
2. BnCl (1 equiv)
Et2O
Ph Cl
73%
[100-44-7] C7H7Cl (MW 126.59)
Reactions with Metals and Organometallics. Benzylmag-
InChI = 1/C7H7Cl/c8-6-7-4-2-1-3-5-7/h1-5H,6H2
nesium chloride can be prepared satisfactorily by rapid addi-
InChIKey = KCXMKQUNVWSEMD-UHFFFAOYAV
tion of benzyl chloride to magnesium in ether.26 Benzyl chlo-
(benzylating agent for a variety of heteroatom functional groups
ride is readily dimerized by lithium naphthalenide,27 sodium and
and carbon nucleophiles; precursor to benzyl organometallics)
tetraphenylethane,28 zinc in the presence of catalytic nickel(II)
ć% bromide,29 with titanocene dichloride and diiodomethane,30
Physical Data: bp 177 181 C; d 1.100 g cm-3.
(PPh3)3CoCl,31 and by electrolysis.32 The cross-coupling reac-
Solubility: freely miscible in ethereal, chlorinated, and dipolar
tions of benzyl chloride with other organometallics is demon-
aprotic solvents.
strated by the benzylation of organolithiums,33 as in the case
Form Supplied in: 99% pure liquid.
of a directed lithiation product (eq 2),32a Grignard reagents,34
Handling, Storage, and Precautions: the reagent is a mutagen
and organocuprates.35 Vinyl boranes, derived from the addition
and possibly a carcinogen. It should be used in a fume hood.
of boron tribromide to alkynes and subsequent alkylation with
organozincs (eq 3),35a couple with benzyl chloride under palla-
dium catalysis.36 Benzyl chloride will add to an ą-diketone in the
Benzylation of Heteroatom Functional Groups. Benzyl
presence of powdered nickel to give the ą-ketol (eq 4).37
chloride is a versatile benzylating agent for heteroatom func-
Li O Bn O
tional groups and is commonly used to introduce this protecting
group.1 Benzylation of alcohols with this reagent is achieved
N(i-Pr)2 BnCl, THF N(i-Pr)2
(2)
under strongly basic conditions such as KOH, either in an alco-
83%
holic solvent2 or under phase transfer conditions with n-Bu4-
SPh SPh
NHSO4.3 Silver oxide in DMF is also effective.4 A procedure
involving Ni(acac)2 has also been reported.5 Phenols may also be
1. BBr3, CH2Cl2
benzylated under basic conditions.6 2. PhZnCl, PdCl2(PPh3)2
Amino groups are readily benzylated when treated with benzyl
3. BnCl
77%
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 po-
(3)
Bn
lar solvents such as ethanol or DMF.8 Dibenzyl sulfide is produced
Ph
by reaction of benzyl chloride with elemental sulfur and sodium
triethylborohydride.9
O O
Amides can be N-benzylated with this reagent under the
BnCl
(4)
influence of strong bases such as metal hydrides.10 A benzyl car-
Ni0 powder
HO Bn
O
boxylate ester may be formed from benzyl chloride and the cor-
DME
responding sodium salt of the acid in DMSO.11
78%
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
1. (a) Greene, T. W.; Wuts, P. G. M., Protective Groups in Organic
Benzylation of Active Methylene Compounds. The an-
Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Protective Groups in
ions or dianions of �-ketoesters,14 substituted malonate esters,15
Organic Chemistry, McOmie, J. F. W., Ed.; Plenum: New York, 1973.
�-ketoaldehydes,16 �-diketones,17 �-ketoamides,18 and �-
2. Fletcher, H. G., Methods Carbohydr. Chem. 1963, 166.
ketonitriles19 all react effectively with benzyl chloride to afford
3. Freedman, H. H.; Dubois, R. A., Tetrahedron Lett. 1975, 3251.
C-benzylated products. When the dianion of a �-ketoamide,
4. Kuhn, R.; L�w, I.; Trischmann, H., Chem. Ber. 1957, 90, 203.
�-ketoester, or �-diketone is generated and treated with benzyl
5. Yamashita, M.; Takegami, Y., Synthesis 1977, 803.
chloride, benzylation is observed at the least acidic position.
6. Heer, J.; Billeter, J. R.; Miescher, K., Helv. Chim. Acta 1945, 28, 991.
Nitrile-stabilized carbanions are readily benzylated in ethereal
7. Velluz, L.; Amiard, G.; HeymŁs, R., Bull. Soc. Chem. Fr., Part 2 1954,
solvents, ammonia, or DMSO.15,20 Benzyl chloride also reacts
1012.
well with carbanions derived from ketones,21 esters,22 imines
8. (a) Frankel, M.; Gertner, D.; Jacobson, H.; Zilkha, A., J. Chem. Soc.
(metalloenamines),23 oximes,24 and hydrazones.23 When benza-
1960, 1390. (b) Vogtle, F.; Klieser, B., Synthesis 1982, 294.
lacetophenone is treated sequentially with 2 equiv of potassium in
9. Gladysz, J. A.; Wong, V. K.; Jick, B. S., J. Chem. Soc., Chem. Commun.
ammonia and then with benzyl chloride in ether, a formal conju-
1978, 838.
gate addition of the benzyl group is observed (eq 1).25 If a second
10. (a) Xia, Y.; Kozikowski, A. P., J. Am. Chem. Soc. 1989, 111, 4116.
equivalent of benzyl chloride is added, benzylation occurs at both
(b) Bryant, D. R.; Work, S. D.; Hauser, C. R., J. Org. Chem. 1964, 29,
the ą- and �-positions. 235.
Avoid Skin Contact with All Reagents
2 BENZYL CHLORIDE
11. Shaw, J. E.; Kunerth, D. C.; Sherry, J. J., Tetrahedron Lett. 1973, 689. 28. Muller, E.; Roscheisen, G., Chem. Ber. 1957, 90, 543.
12. Sukata, K., J. Org. Chem. 1985, 50, 4388. 29. Iyoda, M.; Sakaitani, M.; Otsuka, H.; Oda, M., Chem. Lett. 1985,
127.
13. Nishiyama, K.; Karigomi, H., Chem. Lett. 1982, 9, 1477.
30. Eisch, J. J.; Piotrowski, A., Tetrahedron Lett. 1983, 24, 2043.
14. (a) Elsinger, F., Org. Synth. 1973, 5, 76. (b) Stork, G.; McElvain, S. M.,
J. Am. Chem. Soc. 1946, 68, 1053. 31. Momose, D.; Iguchi, K.; Sugiyama, T.; Yamada, Y., Chem. Pharm. Bull.
1984, 32, 1840.
15. Cope, A. C.; Holmes, H. L.; House, H. O., Org. React. 1957, 9, 107.
32. (a) Rollin, Y.; Troupel, M.; Tuck, D. G.; Perichon, J., J. Organomet.
16. Ravikumar, V. T.; Sathyamoorthi, G.; Thangaraj, K.; Rajagopalan, K.,
Chem. 1986, 303(1), 131. (b) Bedioui, F.; Robin, Y.; Devynk, J.;
Indian J. Chem., Sect. B 1985, 24, 959.
Biedcharreton, C., J. Organomet. Chem. 1987, 326(1), 117.
17. Hauser, C. R.; Harris, T. M., J. Am. Chem. Soc. 1958, 80, 6360.
33. (a) Beak, P.; Kempf, D. J.; Wilson, K. D., J. Am. Chem. Soc. 1985, 107,
18. Hubbard, J. S.; Harris, T. M., Tetrahedron Lett. 1978, 4601.
4745. (b) Aoyama, T.; Shioiri, T., Tetrahedron Lett. 1986, 27, 2005.
19. Baraldi, P. G.; Pollini, G. P.; Zanirato, V., Synthesis 1985, 969.
34. Fuson, A. C.; Dewald, H. A.; Gaertner, R., J. Org. Chem. 1951, 16,
20. Arseniyadis, S.; Kyler, K. S.; Watt, D. S., Org. React. 1984, 31, 1.
21.
21. Bates, G. S.; Ramaswamy, S., Can. J. Chem. 1980, 58, 716.
35. Vig, O. P.; Sharma, S. D.; Kapur, J. C., J. Indian Chem. Soc. 1969, 46,
22. Muller-Uri, C.; Singer, E. A.; Fleischacker, W., J. Med. Chem. 1986, 29,
167.
125.
36. (a) Satoh, Y.; Serizawa, H.; Miyaura, N.; Hara, S.; Suzuki, A.,
23. (a) Stork, G.; Dowd, S. R., J. Am. Chem. Soc. 1963, 85, 2178. (b) Hosomi,
Tetrahedron Lett. 1988, 29, 1811. (b) Hyuga, S.; Yamashina, N.; Hara,
A.; Araki, Y.; Sakurai, H., J. Am. Chem. Soc. 1982, 104, 2081.
S.; Suzuki, A., Chem. Lett. 1988, 809. (c) Hyuga, S.; Yasumichi, C.;
24. Henoch, F. E.; Hampton, K. G.; Hauser, C. R., J. Am. Chem. Soc. 1969, Yamashina, N.; Hara, S.; Suzuki, A., Chem. Lett. 1987, 1757.
91, 676.
37. Inaba, S.; Reike, R. D., Synthesis 1984, 10, 844.
25. Hamrick, P. J.; Hauser, C. R., J. Am. Chem. Soc. 1959, 81, 493.
26. Gilman, H.; Catlin, W. E., Org. Synth. 1941, 1, 471.
William E. Bauta
27. (a) Ginah, F. O.; Donovan, T. A.; Suchan, S. D.; Pfennig, D. R.; Ebert,
Sandoz Research Institute, East Hanover, NJ, USA
G. W., J. Org. Chem. 1990, 55, 584. (b) Boudjouk, P.; Thompson, D. P.;
Ohrbom, W. H.; Han, B. H., Organometallics 1986, 5, 1257.
A list of General Abbreviations appears on the front Endpapers