BENZYL BROMIDE

1

Benzyl Bromide

Ph

Br

[100-39-0]

C

7

H

7

Br

(MW 171.04)

InChI = 1/C7H7Br/c8-6-7-4-2-1-3-5-7/h1-5H,6H2
InChIKey = AGEZXYOZHKGVCM-UHFFFAOYAM

(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.

Ben-

zylation 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 pro-
tecting group.

1

Alcohols and phenols are benzylated upon treatment with ben-

zyl bromide under basic conditions. For example, treatment of
alcohols with Sodium Hydride or Potassium Hydride in ethereal
solvent

2

or DMF

3

generates alkoxides, which subsequently un-

dergo Williamson reactions with benzyl bromide. Selective benzy-
lation 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
Dibutyltin Oxide.

8

OH

OBn

BnO

BnO

BnO

OH

O

OBn

BnO

BnO

BnO

O

Sn(n-Bu)

2

OH

OBn

BnO

BnO

BnO

OBn

60%

(1)

n

-Bu

2

SnO

PhCH

2

Br

MeOH

In some instances the sluggish reactivity of sterically hindered

alcohols toward benzyl bromide may be overcome through ad-
dition of a catalytic iodide source such as Tetrabutylammonium
Iodide, which generates the more reactive benzyl iodide in situ
(see Benzyl Iodide). Benzylation of phenols proceeds well un-
der 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

Selec-

tive 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 sulfonamides

13

and nitrogen heterocycles.

14

Thiols,

15

silyl thioethers,

16

and thiosaccharins

17

may be benzy-

lated 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

(2)

HS

OH

O

NH

2

S

OH

O

NH

2

Ph

PhCH

2

Br

1N NaOH, rt

84%

Although the preparation of benzyl carboxylate esters from ben-

zyl bromide and carboxylate anions is not the most common route
to these compounds, the reaction is possible when carried out in
DMF

20

or using zinc carboxylates.

21

Nucleophilic attack on benzyl bromide by cyanide and azide an-

ions 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 ni-
trile alkylations.

28b

Benzylation of metalloenamines may be

achieved

30a

and enantioselective reactions are possible using a

chiral imine (eq 3).

30b

However, reactions between benzyl bro-

mide and enamines proceed in low yield.

31

The benzylation of

a ketone via its enol silyl ether, promoted by fluoride, has been
observed.

32

(3)

N

OMe

Ph

Ph

O

Ph

1. LDA
2. ZnBr

2

79% ee

3. PhCH

2

Br

4. H

3

O

+

84%

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

Benzylmagne-

sium bromide may nevertheless be prepared from benzyl bromide
and used under standard

34

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 organo-
lithiums,

37

Grignard reagents,

38

organocuprates,

39

organocad-

miums,

40

organochromiums,

41

and organoiron reagents

42

are all

known to give coupling products. An interesting coupling of ben-
zyl bromide with N-methylphthalimide under dissolving metal
conditions has been reported (eq 4).

43

Avoid Skin Contact with All Reagents

2

BENZYL BROMIDE

(4)

N

O

O

Me

N

O

Me

HO

Ph

2.1 equiv Li, NH

3

PhCH

2

Br

96%

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., J. Am. Chem. Soc. 1981, 103,
1224.

3.

Hanessian, S.; Liak, T. J.; Dixit, D. M., Carbohydr. Res. 1981, 88, C14.

4.

Fukuzawa, A.; Sato, H.; Masamune, T., Tetrahedron Lett. 1987, 28, 4303.

5.

Ando, T.; Yamawaki, J.; Kawate, T.; Sumi, S.; Hanafusa, T., Bull. Chem.
Soc. Jpn. 1982

, 55, 2504.

6.

Kuhn, R.; Low, I.; Trischmann, H., Chem. Ber. 1957, 90, 203.

7.

(a) Nashed, M. A.; Anderson, L., Tetrahedron Lett. 1976, 3503.
(b) Cruzado, C.; Bernabe, M.; Martin-Lomas, M., J. Org. Chem. 1989,
54

, 465.

8.

Bliard, C.; Herczegh, P.; Olesker, A.; Lukacs, G., Carbohydr. Res. 1989,
8

, 103.

9.

Schmidhammer, H.; Brossi, A., J. Org. Chem. 1971, 93, 746.

10.

(a) Yamazaki, N.; Kibayashi, C., J. Am. Chem. Soc. 1989, 111, 1396.
(b) Gray, B. D.; Jeffs, P. W., J. Chem. Soc., Chem. Commun. 1987, 1329.

11.

(a) Chung, B.-H.; Zymalkowski, F., Arch. Pharm. (Weinheim, Ger.) 1984,
317

, 307. (b) Chung, B.-H.; Zymalkowski, F., Arch. Pharm. (Weinheim,

Ger.) 1984

, 317, 323.

12.

(a) Landini, D.; Penso, M., Synth. Commun. 1988, 18, 791. (b) Staskun,
B., J. Org. Chem. 1979, 44, 875. (c) Sato, R.; Senzaki, T.; Goto, T.; Saito,
M., Bull. Chem. Soc. Jpn. 1986, 59, 2950.

13.

Bergeron, R. J.; Hoffman, P. G., J. Org. Chem. 1979, 44, 1835.

14.

Chivikas, C. J.; Hodges, J. C., J. Org. Chem. 1987, 52, 3591.

15.

Harpp, D. N.; Kobayashi, M., Tetrahedron Lett. 1986, 27, 3975.

16.

Ando, W.; Furuhata, T.; Tsumaki, H.; Sekiguchi, A., Synth. Commun.
1982, 12, 627.

17.

Yamada, H.; Kinoshita, H.; Inomata, K.; Kotake, H., Bull. Chem. Soc.
Jpn. 1983

, 56, 949.

18.

Dymicky, M.; Byler, D. M., Org. Prep. Proced. Int. 1991, 23, 93.

19.

Mitchell, R. H., J. Chem. Soc., Chem. Commun. 1974, 990.

20.

Huang, X.; Pi, J.-H., Synth. Commun. 1990, 20, 2291.

21.

(a) Comber, M. F.; Sargent, M. V.; Skelton, B. W.; White, A. H., J. Chem.
Soc., Perkin Trans. 1 1989

, 441. (b) Shono, T.; Ishige, O.; Uyama, H.;

Kashimura, S., J. Org. Chem. 1986, 51, 546.

22.

(a) Gordon, M.; Griffin, C. E., Chem. Ind. (London) 1962, 1019.
(b) Hassner, A.; Stern, M., Angew. Chem. 1986, 98, 479. (c) Bram,
G.; Loupy, A.; Pedoussaut, M., Bull. Soc. Chem. Fr., Part 2 1986, 124.
(d) Ravindranath, B.; Srinivas, P., Tetrahedron 1984, 40, 1623.

23.

(a) Gall, M.; House, H. O., Org. Synth., Coll. Vol. 1988, 6, 121. (b) Sato,
T.; Watanabe, T.; Hayata, T.; Tsukui, T., J. Chem. Soc., Chem. Commun.
1989, 153.

24.

(a) Seebach, D.; Estermann, H., Tetrahedron Lett. 1987, 28, 3103.
(b) Lerner, L. M., J. Org. Chem. 1976, 41, 2228.

25.

Duhamel, L.; Poirier, J.-M., Bull. Soc. Chem. Fr., Part 2 1982, 297.

26.

(a) Berry, N. M.; Darey, M. C. P.; Harwood, L. M., Synthesis 1986, 476.
(b) Bassetti, M.; Cerichelli, G.; Floris, B., Gazz. Chim. Ital. 1986, 116,
583. (c) Asaoka, M.; Miyake, K.; Takei, H., Chem. Lett. 1975, 1149.
(d) Ogura, K.; Yahata, N.; Minoguchi, M.; Ohtsuki, K.; Takahashi, K.;
lida, H., J. Org. Chem. 1986, 51, 508.

27.

(a) Woodbury, R. P.; Rathke, M. W., J. Org. Chem. 1977, 42, 1688.
(b) Klein, U.; Sucrow, W., Chem. Ber. 1977, 110, 1611. (c) Meyers, A.
I.; Harre, M.; Garland, R., J. Am. Chem. Soc. 1984, 106, 1146.

28.

(a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S., Org. React. 1984, 31, 1.
(b) Cope, A. C.; Holmes, H. L.; House, H. O., Org. React. 1957, 9, 107.

29.

Murakata, M.; Nakajima, M.; Koga, K., J. Chem. Soc., Chem. Commun.
1990, 1657.

30.

(a) Stork, G.; Dowd, S. R., Org. Synth., Coll. Vol. 1988, 6, 526. (b) Saigo,
K.; Kashahara, A.; Ogawa, S.; Nohira, H., Tetrahedron Lett. 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., J.
Org. Chem. 1961

, 26, 3576. (c) Opitz, G.; Hellmann, H.; Mildenberger,

M.; Suhr, H., Justus Liebigs Ann. Chem. 1961, 649, 36.

32.

(a) Kuwajima, I.; Nakamura, E., J. Am. Chem. Soc. 1975, 97, 3257.
(b) Binkley, E. S.; Heathcock, C. H., J. Org. Chem. 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., Tetrahedron 1970, 26, 2683.

35.

Blomberg, C.; Hartog, F. A., Synthesis 1977, 18.

36.

Berk, S. C.; Knochel, P.; Yeh, M. C. P., J. Org. Chem. 1988, 53, 5789.

37.

(a) Hirai, K.; Matsuda, H.; Kishida, Y., Tetrahedron Lett. 1971, 4359.
(b) Hirai, K.; Kishida, Y., Tetrahedron Lett. 1972, 2743. (c) Villieras, J.;
Rambaud, M.; Kirschleger, B.; Tarhouni, R., Bull. Soc. Chem. Fr., Part
2 1985

, 837.

38.

Rahman, M. T.; Nahar, S. K., J. Organomet. Chem. 1987, 329, 133.

39.

(a) Kobayashi, Y.; Yamamoto, K.; Kumadaki, I., Tetrahedron Lett. 1979,
4071. (b) Furber, M.; Taylor, R. J. K.; Burford, S. C., Tetrahedron Lett.
1985, 26, 3285.

40.

(a) Emptoz, G.; Huet, F., Bull. Soc. Chem. Fr. Part 2 1974, 1695.

41.

Wellmann, J.; Steckhan, E., Synthesis 1978, 901.

42.

(a) Sawa, Y.; Ryang, M.; Tsutsumi, S., J. Org. Chem. 1970, 35, 4183.
(b) Cookson, R. C.; Farquharson, G., Tetrahedron Lett. 1979, 1255.
(c) Sawa, Y.; Ryang, M.; Tsutsumi, S., Tetrahedron Lett. 1969, 5189.

43.

Flynn, G. A., J. Chem. Soc., Chem. Commun. 1980, 862.

William E. Bauta

Sandoz Research Institute, East Hanover, NJ, USA

A list of General Abbreviations appears on the front Endpapers