ZINC BROMIDE

1

Zinc Bromide

1

ZnBr

2

[7699-45-8]

Br

2

Zn

(MW 225.19)

InChI = 1/2BrH.Zn/h2*1H;/q;;+2/p-2/f2Br.Zn/h2*1h;/q2*-1;m
InChIKey = VNDYJBBGRKZCSX-JCMKJQRZCM

(used in the preparation of organozinc reagents via trans-
metalation;

1

a mild Lewis acid useful for promoting addition

2

and substitution reactions

3

)

Physical Data:

mp 394

◦

C; bp 697

◦

C (dec); d 4.201 g cm

−3

.

Solubility:

sol Et

2

O, H

2

O (1 g/25 mL), 90% EtOH (1 g/0.5 mL).

Form Supplied in:

granular white powder; principal impurity is

H

2

O.

Analysis of Reagent Purity:

melting point.

Purification:

heat to 300

◦

C under vacuum (2 × 10

−2

mmHg) for

1 h, then sublime.

Handling, Storage, and Precautions:

very hygroscopic; store un-

der anhydrous conditions. Irritant.

Organozinc Reagents.

The transmetalation of organomag-

nesium, organolithium, and organocopper reagents by anhydrous
ZnBr

2

in ethereal solvents offers a convenient method of preparing

organozinc bromides and diorganozinc reagents.

1a

Alternatively,

anhydrous ZnBr

2

may be reduced by potassium metal to result in

highly activated Zn

0

, which is useful for the preparation of zinc

reagents through oxidative addition to organic halides.

4

Alkyl,

allylic, and propargylic zinc reagents derived by these methods
have shown considerable value in their stereoselective and regios-
elective addition reactions with aldehydes, ketones, imines, and
iminium salts.

1a,5

Zinc enolates used in the Reformatsky reac-

tion may also be prepared through transmetalation using ZnBr

2

.

1b

Organozinc species are especially useful in palladium-and nickel-
catalyzed coupling reactions of sp

2

carbon centers. In this fashion,

sp

2

–sp

3

(eq 1)

6

and sp

2

–sp

2

(eqs 2 and 3)

7,8

carbon–carbon bonds

are formed selectively in high yields. The enantioselective cross
coupling of secondary Grignard reagents with vinyl bromide is
strongly affected by the presence of ZnBr

2

, which accelerates the

reaction and inverts its enantioselectivity (eq 4).

9

(1)

CO

2

Me

I

CO

2

Me

Ph

1. ZnBr

2

, THF

2.

Ni(PPh

3

)

4

THF–Et

2

O, 25 °C

88%

PhCH

2

Li

Organozinc intermediates formed via transmetalation using

ZnBr

2

have been used to effect carbozincation of alkenes and

alkynes through metallo-ene and metallo-Claisen reactions. Both
intermolecular and intramolecular variants of these reactions have
been described, often proceeding with high levels of stereoselec-
tivity and affording organometallic products that may be used in
subsequent transformations (eqs 5 and 6),

10

including alkenation

(eq 6).

10b,c

Bimetallic zinc–zirconium reagents have also been

developed that offer a method for the alkenation of carbonyl com-
pounds (eq 7).

11

(2)

OCONEt

2

Ph

Li

OCONEt

2

Br

Ph

1. ZnBr

2

, THF

80%

Pd(PPh

3

)

4

2.

(3)

2

I

C

5

H

11

I

CO

2

Me

CuLi

Et

Et

C

5

H

11

Et

CO

2

Me

ZnBr

2

Pd(PPh

3

)

4

THF–Et

2

O

ZnBr

2

, THF

Pd(PPh

3

)

4

96%

81%

(4)

NiCl

2

, Et

2

O, 0 °C

MgCl

Br

MeS

PPh

2

NMe

2

R

1

R

2

without ZnBr

2

with ZnBr

2

R

1

= Me, R

2

= H; >95% (52% ee)

R

1

= H, R

2

= Me; >95% (49% ee)

(5)

OMe

TMS

TMS

OMe

X

1. BuLi, THF

2. ZnBr

2

X = ZnBr

X = H

80%

H

2

O

1. t-BuLi

2.
3. ZnBr

2

M

1

, M

2

= metal

M

1

, M

2

= H

1. PhCHO

2. H

3

O

+

Zn

O

Pr

t-

Bu

Pr

t-

BuO

I

Pr

O-t-Bu

O-t-Bu

Pr

Ph

M

2

M

1

MgBr

(6)

75%, 95% de

68%

95% de

H

3

O

+

Concerted Ring-forming Reactions.

The mild Lewis acid

character of ZnBr

2

sometime imparts a catalytic effect on ther-

mally allowed pericyclic reactions. The rate and stereoselectivity

Avoid Skin Contact with All Reagents

2

ZINC BROMIDE

of cycloaddition reactions (eq 8),

12

including dipolar cycloaddi-

tions (eq 9),

13

are significantly improved by the presence of this

zinc salt.

(7)

+

C

6

H

13

MgBr

ZnBr

Cl

Cp

2

Zr

CHO

C

7

H

15

1. ZnBr

2

C

7

H

15

83%, 100% (E)

2. H(Cl)ZrCp

2

(8)

CO

2

Me

CO

2

Me

+

CH

2

Cl

2

no catalyst, 5 h
with ZnBr

2

, 3 h

70%, 78% endo
80%, 95% endo

0 °C

+

Ph

N

Ph

OH

N

O

Ph

O

O

+

ZnBr

2

H

H

OH

O

Ph

(9)

single isomer

CH

2

Cl

2

65%

Some intramolecular ene reactions benefit from ZnBr

2

catalysis

to afford the cyclic products under milder conditions, in higher
yields and selectivities (eqs 10 and 11).

14,15

Generally, the use of

ZnBr

2

is preferred over Zinc Chloride or Zinc Iodide in this type

of reaction.

15

Activation of C=

=

=X Bonds. Lewis acid activation of carbonyl

compounds by ZnBr

2

promotes the addition of allylsilanes and

silyl ketene acetals.

16

Addition to imines has also been reported.

17

In general, other Lewis acids have been found to be more useful,
though in some instances ZnBr

2

has proven to be advantageous

(eq 12).

2

(10)

180 °C, o-dichlorobenzene
ZnBr

2

, CH

2

Cl

2

, 25 °C

66% (83% de)
79% (95% de)

MeO

2

C

MeO

2

C

MeO

2

C

MeO

2

C

reagent

(11)

ZnBr

2

(R

1

= CN, R

2

= H):(R

1

= H, R

2

= CN) = 88:12

S-p-Tol

CN

O

S-p-Tol

H

O

R

1

R

2

CH

2

Cl

2

82%

(12)

OTMS

Ph

CO

2

H

CO

2

H

OTMS

OH

OH

Ph

1. catalyst

+

ZnBr

2

, THF, 20 °C, 6 h

CsF, CH

2

Cl

2

. 20 °C, 14 h

100:0
5:95

+

PhCHO

2. H

3

O

+

Activation of C–X Bonds.

Even more important than car-

bonyl activation, ZnBr

2

promotes substitution reactions with suit-

ably active organic halides with a variety of nucleophiles. Alky-
lation of silyl enol ethers and silyl ketene acetals using benzyl
and allyl halides proceeds smoothly (eq 13).

3

Especially use-

ful electrophiles are α-thio halides which afford products that
may be desulfurized or oxidatively eliminated to result in α,β-
unsaturated ketones, esters, and lactones (eq 14).

18

Other elec-

trophiles that have been used with these alkenic nucleophiles
include Chloromethyl Methyl Ether, HC(OMe)

3

, and Acetyl

Chloride

.

3,19

(13)

ZnBr

2

CH

2

Cl

2

, rt

68%

ZnBr

2

CH

2

Cl

2

, rt

83%

Ph

Br

Ph

Ph

Ph

Ph

OTMS

Br

O

O

+

1. m-CPBA

90%

OTMS

OTMS

Cl

O

O

OTMS

SPh

H

H

H

H

O

O

SPh

(14)

1. ZnBr

2

92%

2. H

3

O

+

2. DBU

Enol ethers and allylic silanes and stannanes will engage

cyclic α-seleno sulfoxides,

20

ω

-acetoxy lactams,

21

and acyl

glycosides (eq 15)

22

in the presence of ZnBr

2

catalysis. Along

these lines, it has been found that ZnBr

2

is superior to Boron Tri-

fluoride Etherate

in promoting glycoside bond formation using

trichloroimidate-activated glycosides (eq 16).

23

Imidazole car-

bamates are also effective activating groups for ZnBr

2

-mediated

glycosylation (eq 17).

24

Cyclic acetals also undergo highly selective, Lewis acid-

dependent ring opening substitution with Cyanotrimethylsilane
(eq 18).

25

Reduction.

Complexation with ZnBr

2

has been shown to

markedly improve stereoselectivity in the reduction of certain
heteroatom-substituted ketones (eqs 19 and 20).

26,27

Furthermore,

the anti selectivity observed in BF

3

·OEt

2

-mediated intramolecular

hydrosilylation of ketones is reversed when ZnBr

2

is used instead

(eq 21).

28

A list of General Abbreviations appears on the front Endpapers

ZINC BROMIDE

3

(15)

O

H

OBz

BzO

BzO

OBz

OBz

BzO

OBz

O

TMS

+

ZnBr

2

α:β = 1:1

110 °C, 3 h

100%

(16)

+

ZnBr

2

, CH

2

Cl

2

3

Å mol sieves,

∆

60%

OAc

O

O

H

AcO

H

AcO

AcO

AcO

H

H

OAc

OAc

O

O

HO

H

H

H

H

H

H

H

H

H

H

H

H

O

O

O

O

O

OC(NH)CCl

3

OAc

O

OAc

H

H

AcO

AcO

AcO

H

AcO

H

O

OAc

(17)

O

OBn

OBn

BnO

OBn

H

O

Ph

Ph

MeO

2

C

CO

2

Me

OH

H

OBn

BnO

OBn

OBn

O

O

O

N

N

ZnBr

2

THF, Et

2

O,

∆

88%

10:1 de

(18)

O

O

MeO

Ph

H

MeO

OH

O

OH

O

MeO

CN

NC

Ph

Ph

+

ZnBr

2

, CH

2

Cl

2

, 25 °C, 20 h

TiCl

4

, CH

2

Cl

2

, 25 °C, 20 h

1:250

250:1

TMSCN

(19)

Ph

Ph

N

O

OH

N

Ph

Ph

1. ZnBr

2

, MeOH

2. NaBH

4

100%

H

H

(20)

ZnBr

2

, THF

91%

+

66:34

S

p-

Tol

O

O

OH

S

O

p-

Tol

S

p-

Tol

O

OH

DIBAL

i-

Pr

i-

Pr

OSiMe

2

H

O

O

O

Me

2

Si

i-

Pr

i-

Pr

i-

Pr

i-

Pr

O

Me

2

Si

O

(21)

+

BF

3

· OEt

2

, CH

2

Cl

2

, –80 °C, 2 h

ZnBr

2

, CH

2

Cl

2

, –80 °C, 8 h

23:1
1:6

Deprotection.

ZnBr

2

is a very mild reagent for sev-

eral deprotection protocols, including the detritylation of
nucleotides

29

and deoxynucleotides,

30

N

-deacylation of N,O-

peracylated nucleotides,

31

and the selective removal of Boc groups

from secondary amines in the presence of Boc-protected primary
amines.

32

Perhaps the most widespread use of ZnBr

2

for deprotec-

tion is in the mild removal of MEM ethers to afford free alcohols
(eq 22).

33

(22)

H

O

O

OMe

OH

H

ZnBr

2

CH

2

Cl

2

25 °C, 10 h

93%

Miscellaneous.

An important method for the synthesis of

stereodefined trisubstituted double bonds involves the treatment
of cyclopropyl bromides with ZnBr

2

. The (E) isomer is obtained

almost exclusively by this method (eq 23).

34

(23)

1. PBr

3

, LiBr

collidine, Et

2

O

2. ZnBr

2

, Et

2

O

>95%

(E)

CO

2

Me

OH

Br

CO

2

Me

The rearrangement of a variety of terpene oxides has been

examined (eq 24).

35

While ZnBr

2

is generally a satisfactory cat-

alyst for this purpose, other Lewis acids, including ZnCl

2

36

and

Magnesium Bromide

,

37

are advantageous in some instances.

(–)-

α-Pinene

ZnBr

2

88%

O

CHO

H

(24)

PhH, 80 °C

In the presence of ZnBr

2

/48% Hydrobromic Acid, suitably

functionalized cyclopropanes undergo ring expansion to afford
cyclobutane (eq 25)

38

and α-methylene butyrolactone products

(eq 26).

39

One-carbon ring expansion has been reported when

certain trimethylsilyl dimethyl acetals are exposed to ZnBr

2

with

warming (eq 27).

40

Et

SPh

OH

SPh

SPh

Et

SPh

Et

(25)

48% HBr

1. Cu(OTf)

2

i-Pr

2

NEt

81%

ZnBr

2

, PhSH

95%

2. 450 °C

Avoid Skin Contact with All Reagents

4

ZINC BROMIDE

EtOH, 100 °C, 6 h

50%

(26)

O

H

H

OH

CO

2

Et

O

H

H

48% HBr, ZnBr

2

(27)

40 °C, 30 min

100%

TMS

OMe

OMe

OMe

ZnBr

2

, CH

2

Cl

2

1.

(a) Knochel, P., Comprehensive Organic Synthesis 1991, 1, Chapter 1.7.
(b) Rathke, M. W.; Weipert, P., Comprehensive Organic Synthesis 1991,
2

, Chapter 1.8.

2.

For an example: Bellassoued, M.; Ennigrou, R.; Gaudemar, M., J.
Organomet. Chem. 1988

, 338, 149.

3.

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Engl. 1978

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Lett. 1979

, 1519.

4.

Riecke, R. D.; Uhm, S. J.; Hudnall, P. M., J. Chem. Soc., Chem. Commun.
1973

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5.

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1988

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1975

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6.

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7.

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8.

(a) Jabri, N.; Alexakis, A.; Normant, J. F., Bull. Soc. Chem. Fr., Part
2 1983

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Tetrahedron Lett. 1981

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9.

Cross, G.; Vriesema, B. K.; Boven, G.; Kellogg, R. M.; van Bolhuis, F.,
J. Organomet. Chem. 1989

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10.

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Marek, I.; Lefrançois, J.-M.; Normant, J.-F., Synlett 1992, 633.

11.

Tucker, C. E.; Knochel, P., J. Am. Chem. Soc. 1991, 113, 9888.

12.

Narayana Murthy, Y. V. S.; Pillai, C. N., Synth. Commun. 1991, 21, 783.
See also: López, R.; Carretero, J. C., Tetrahedron: Asymmetry 1991, 2,
93.

13.

Kanemasa, S.; Tsuruoka, T.; Wada, E., Tetrahedron Lett. 1993, 34,
87.

14.

Tietze, L. F.; Biefuss, U.; Ruther, M., J. Org. Chem. 1989, 54,
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123

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147.

15.

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16.

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Chem. Commun. 1990

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17.

Gaudemar, M.; Bellassoued, M., Tetrahedron Lett. 1990, 31,
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18.

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19.

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20.

Ren, P.; Ribezzo, M., J. Am. Chem. Soc. 1991, 113, 7803.

21.

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22.

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23.

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24.

Ford, M. J.; Ley, S. V., Synlett 1990, 255.

25.

Corcoran, R. C., Tetrahedron Lett. 1990, 31, 2101.

26.

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27.

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28.

Anwar, S.; Davis, A. P., Tetrahedron 1988, 44, 3761.

29.

Waldemeier, F.; De Bernardini, S.; Leach, C. A.; Tamm, C., Helv. Chim.
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30.

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31.

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32.

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33.

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34.

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35.

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29

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36.

Kaminski, J.; Schwegler, M. A.; Hoefnagel, A. J.; van Bekkum, H., Recl.
Trav. Chim. Pays-Bas 1992

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37.

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38.

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39.

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1973

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40.

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29

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1989

, 30, 6551.

Glenn J. McGarvey

University of Virginia, Charlottesville, VA, USA

A list of General Abbreviations appears on the front Endpapers