BENZYL BROMIDE 1
Benzyl Bromide 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
Ph Br
as can those of sulfonamides13 and nitrogen heterocycles.14
Thiols,15 silyl thioethers,16 and thiosaccharins17 may be benzy-
lated with benzyl bromide under basic conditions. Thus L-cysteine
[100-39-0] C7H7Br (MW 171.04)
is S-benzylated under basic conditions (eq 2).18 Benzylation of
InChI = 1/C7H7Br/c8-6-7-4-2-1-3-5-7/h1-5H,6H2
selenols is likewise possible.19 A synthesis of benzylic sulfones
InChIKey = AGEZXYOZHKGVCM-UHFFFAOYAM
is possible using Benzenesulfonyl Chloride and Sodium O,O-
(benzylating agent for a variety of heteroatomic functional groups
Diethyl Phosphorotelluroate with benzyl bromide.20
as well as carbon nucleophiles)
O O
ć% ć%
PhCH2Br
Physical Data: mp -3to-1 C; bp 198 199 C; d 1.438 g cm-3.
(2)
HS OH Ph S OH
Solubility: sol ethereal, chlorinated, and dipolar aprotic solvents.
1N NaOH, rt
NH2 NH2
84%
Form Supplied in: 98 99% pure liquid.
Handling, Storage, and Precautions: the reagent is a potent
Although the preparation of benzyl carboxylate esters from ben-
lachrymator and should be handled in a fume hood.
zyl 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
Benzylation of Heteroatomic Functional Groups. Ben-
Nucleophilic attack on benzyl bromide by cyanide and azide an-
zylation of various heteroatomic functional groups is readily
ions is feasible with ion-exchange resins or with the corresponding
achieved with this reagent under a variety of conditions and finds
salts.22
widespread application in organic synthesis, primarily as a pro-
tecting group.1
Reactions with Active Methylene Compounds. Enolates of
Alcohols and phenols are benzylated upon treatment with ben-
ketones,23 esters,24 enediolates,25 1,3-dicarbonyl compounds,26
zyl bromide under basic conditions. For example, treatment of
amides and lactams,27 as well as nitrile-stabilized carbanions,28
alcohols with Sodium Hydride or Potassium Hydride in ethereal
can be alkylated with benzyl bromide. Cyclohexanone may be
solvent2 or DMF3 generates alkoxides, which subsequently un-
benzylated in 92% ee using a chiral amide base.29 Amide bases
dergo Williamson reactions with benzyl bromide. Selective benzy-
as well as alkoxides have been employed in the case of ni-
lation of a primary alcohol in the presence of a secondary alcohol
trile alkylations.28b Benzylation of metalloenamines may be
has been accomplished in DMF at low temperature.4
achieved30a and enantioselective reactions are possible using a
Benzylation of alcohols using Potassium Fluoride Alumina
chiral imine (eq 3).30b However, reactions between benzyl bro-
and benzyl bromide in acetonitrile at room temperature is
mide and enamines proceed in low yield.31 The benzylation of
effective.5 Silver oxide in DMF is yet another base system.6 Of
a ketone via its enol silyl ether, promoted by fluoride, has been
particular interest in carbohydrate applications is the reaction of
observed.32
benzyl bromide with carbohydrate derivatives which have been
pretreated with tin reagents. Thus it is possible to benzylate an
Ph
O
equatorial alcohol in the presence of an axial alcohol (eq 1)7
1. LDA
OMe
N 2. ZnBr2
and also to selectively benzylate an anomeric hydroxy through
Ph
(3)
Ph
Dibutyltin Oxide.8 3. PhCH2Br
4. H3O+
79% ee
OH 84%
BnO
n-Bu2SnO
BnO
OH
MeOH
BnO
OBn
Reactions with Metals and Organometallics. Difficulties
OH
O
Sn(n-Bu)2
encountered in the preparation of benzylic metal compounds with
BnO
BnO
PhCH2Br
BnO
BnO OBn (1) active metals are due primarily to the tendency of these compounds
O
BnO
BnO
OBn
OBn to undergo Wurtz coupling (self condensation).33 Benzylmagne-
60% sium bromide may nevertheless be prepared from benzyl bromide
and used under standard34 or Barbier conditions.35 Benzyllithium
In some instances the sluggish reactivity of sterically hindered cannot be obtained practically from benzyl bromide. Benzylzinc
alcohols toward benzyl bromide may be overcome through ad- bromide and the cyanocuprate BnCu(CN)ZnBr have both been
dition of a catalytic iodide source such as Tetrabutylammonium prepared. The cuprate undergoes 1,2-additions with aldehydes and
Iodide, which generates the more reactive benzyl iodide in situ ketones.36
(see Benzyl Iodide). Benzylation of phenols proceeds well un- The propensity of benzyl bromide to undergo coupling with
der the conditions described for aliphatic alcohols. Owing to the organometallic reagents may be used to advantage, as organo-
greater acidity of phenols it is possible to use weaker bases such lithiums,37 Grignard reagents,38 organocuprates,39 organocad-
as Potassium Carbonate for these reactions.9 miums,40 organochromiums,41 and organoiron reagents42 are all
Benzyl bromide will readily alkylate amino groups. Reactions known to give coupling products. An interesting coupling of ben-
are normally carried out in the presence of additional base and zyl bromide with N-methylphthalimide under dissolving metal
dibenzylation of primary amines is usually predominant.10 Selec- conditions has been reported (eq 4).43
Avoid Skin Contact with All Reagents
2 BENZYL BROMIDE
O O
23. (a) Gall, M.; House, H. O., Org. Synth., Coll. Vol. 1988, 6, 121. (b) Sato,
2.1 equiv Li, NH3
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(4)
N Me N Me
1989, 153.
PhCH2Br
96% Ph
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O HO
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Sandoz Research Institute, East Hanover, NJ, USA
A list of General Abbreviations appears on the front Endpapers