ZINC

1

Zinc

1

Zn

[7440-66-6]

Zn

(MW 65.39)

InChI = 1/Zn
InChIKey = HCHKCACWOHOZIP-UHFFFAOYAS

(reducing agent;

2

used for preparation of organozinc reagents,

1,3

Reformatsky reagents,

4

and the Simmons–Smith reagent

(cyclopropanation)

5

)

Physical Data:

mp 419

◦

C; bp 907

◦

C; d 7.14 g cm

−3

.

Solubility:

insol organic solvents; reacts with aqueous acidic

solutions.

Form Supplied in:

dust, foil, granular, wire, mossy, rod; widely

available at low cost.

Handling, Storage, and Precautions:

slowly oxidizes in air; no

toxic properties are associated with zinc and zinc organometal-
lics; in several cases the metal requires an activation procedure
before use.

6

Original Commentary

Paul Knochel
Philipps-Universität Marburg, Marburg, Germany

Reduction of Carbon–Carbon Multiple Bonds.

Whereas

isolated double bonds are rarely reduced by zinc, triple bonds
are cleanly converted to alkenes using either Zinc/Copper Cou-
ple or Zinc Amalgam.

7

A regio- as well as stereospecific reduc-

tion of a wide range of alkynic derivatives can be performed us-
ing zinc powder (eq 1).

8

The reduction of propargylic alcohols

proves to be especially efficient (eq 2).

9

Also, the selective cis re-

duction of conjugated dienynes and trienynes proceeds well with
Zn(Cu/Ag).

10

The presence of a leaving group at the propargylic

position leads to the formation of allenes.

11

The conjugation of a

double bond with an electron-withdrawing substituent consider-
ably facilitates the reduction of the double bond.

12

The reduction

of α,β-unsaturated ketones produces the corresponding saturated
ketones.

13

Nickel catalysis allows the reduction of unsaturated

aldehydes, ketones, and esters in an aqueous medium under ultra-
sonic irradiation (eq 3).

14

>95% (Z)

(1)

Zn, ethanol

Et

Et

OH

OH

reflux, 3 h

>95%

Reduction of Carbonyl Groups. Zinc reduces ketones to ei-

ther alcohols or to a methylene unit, depending on the reaction
conditions and the nature of the substrate. For example, con-
jugation is required if reduction to a hydroxy group is desired.
The reduction of aryl ketones provides benzylic alcohols (eq 4)

15

and α-diketones can be converted selectively to α-hydroxy ke-
tones (eq 5).

16

The reduction of the carbonyl group of noncon-

jugated ketones to a methylene unit with zinc and hydrochlo-
ric acid in organic solvents such as ether, acetic anhydride,
or benzene–ethanol proceeds in satisfactory yields with a wide

range of ketones (Clemmensen reaction) (eqs 6–8).

17

The Clem-

mensen reduction of aromatic α-hydroxy ketones gives conjugated
alkenes.

18

Finally, the Clemmensen reduction can also be per-

formed by using zinc and Chlorotrimethylsilane in an aprotic
medium, leading to alkenes (eq 9).

19

This variation has been ex-

ploited for the preparation of alkenes (eq 10)

19b

and has been

used in new cyclization reactions (eqs 11 and 12).

20

Trimethyl-

silyl ethers can be regioselectively prepared by the zinc reduction
of α-chloro ketones in the presence of TMSCl.

21

Mixed pinacol

products have been prepared by using Zn(Cu) as the reducing
agent (eq 13).

22

1. Zn, KCN

(2)

OTBDMS

OH

2. Bu

4

NF

Zn, NiCl

2

cat ))))

EtOH, H

2

O

O

O

(3)

30 °C, 2.5 h

97%

CO

2

H

Ph

O

O

Ph

O

Zn(Hg), HCl

(4)

reflux, toluene

79%

Zn, AcOH

(5)

+

48:52

O

O

O

O

OH

OH

reflux

Zn(Hg), HCl

(6)

H

O

H

Et

2

O

77%

Zn(Hg), HCl

(7)

Cl

Cl

Cl

Cl

O

EtOH, PhH

56%

Zn(Hg), HCl

(8)

CO

2

H

O

CO

2

H

O

O

50%

Zn(Hg), TMSCl

(9)

O

Et

2

O

72%

Avoid Skin Contact with All Reagents

2

ZINC

Si

Si

Cl

Cl

Me Me

Me

Me

Zn(Hg), THF

24 h

(10)

O

O

t

-Bu

t

-Bu

H

Zn, TMSCl

Zn, TMSCl

t

-Bu

H

HO

(11)

2,6-lutidine

66%

without

2,6-lutidine

71%

Zn, TMSCl

O

t

-Bu

t

-Bu

H

HO

(12)

THF
74%

(13)

+

Zn(Cu), H

2

O

O

O

OH

HO

))))
87%

Reduction of Carbon–Oxygen Bonds. Carbon–Oxygen

bonds situated α to an unsaturation are easily reduced with zinc in
an acidic medium. In the case of α-hydroxy ketones, ketones are
obtained in good yields (eq 14).

23

A wide range of allylic or

benzylic ethers, acetates, and alcohols are reduced with zinc
(eq 15).

24,25

The reduction of epoxides can lead to either alcohols

(eq 16)

26

or alkenes.

26b−e

In the presence of catalytic amounts of

Pd

0

and zinc dust, allylic acetates are coupled to give 1,5-dienes

(eq 17).

27

Under similar reaction conditions and in the presence

of an aldehyde, homoallylic alcohols are obtained in satisfactory
yields (eq 18).

27b−d

O

HO

(14)

( )

n

( )

n

O

Zn(Hg), HCl

AcOH

75–78%

(15)

Zn(Hg), HCl

OH

Et

2

O, –15 °C

68–75%

(16)

+

2:1

O

C

5

H

11

H

H

C

5

H

11

C

5

H

11

OH

OH

Zn, TMSCl

CH

2

Cl

2

97%

Zn, Pd

0

OAc

(17)

THF, 25 °C

70%

OAc

(18)

Ph

OH

Zn, Pd

0

+

PhCHO

syn

:anti = 1:1

THF, 25 °C

70%

Reduction of Carbon–Halide Bonds.

Alkyl and alkenyl

halides are readily reduced with zinc under various reaction condi-
tions. The reduction produces, as an intermediate, an organic rad-
ical which can undergo carbon–carbon bond formation (Barbier
reaction)

28

or can be further reduced, usually under acidic con-

ditions. Aliphatic iodides or bromides and benzylic chlorides re-
act readily with Zinc–Acetic Acid, providing the corresponding
hydrocarbon.

29

Although aromatic halides are reduced less eas-

ily, the tribromothiophene 1 is reduced selectively to the bro-
mide 2 (eq 19).

29e,g

Various β-chloro enones are cleanly reduced

to enones with Zinc/Silver Couple in methanol at rt (eq 20).

29f

α

-Dihalo ketones are reduced smoothly, allowing the preparation

of a variety of ketones (eqs 21 and 22).

30

The reductive couplings

of α-bromo ketones, tropylium, and 1,3-dithiolylium cations have
been observed.

31

In the case of 1,3-dihalides, cyclopropanes are

obtained in good yields.

32

If the reduction of the carbon–halide

bond is performed in the presence of an electrophile, a radical
addition often occurs. Thus phenacyl halides can be coupled with
methylenecyclohexanes (eq 23).

33a

Performing the reaction in the

presence of an unsaturated ketone provides the 1,4-adducts. In-
terestingly, the reduction proceeds well in an aqueous medium
supporting a radical mechanism, since zinc organometallics react
instantaneously with water but only very sluggishly with enones
(eq 24).

33b−h

The addition of Chloromethyl Methyl Ether to 1,2-

bis-silyl enol ethers in the presence of zinc leads to ring-enlarged
1,3-cycloalkanediones after acidic treatment.

34

An interesting

three-component reaction has been described (eq 25).

34b

A wide

range of allylic halides undergo Barbier-type addition to carbonyl
groups (eqs 26 and 27).

35,36

The reduction of α,α

′

-dihalo ketones

with a zinc–copper couple in the presence of a diene such as Iso-
prene provides cycloaddition products via a zinc oxyallyl cation.

37

(19)

Zn, AcOH

S

Br

Br

Br

S

Br

(1)

(2)

H

2

O, heat

89–90%

(20)

Zn(Ag), MeOH

O

Cl

O

H

20 °C

65%

(21)

Zn, AcOH

Cl

Cl

O

H

O

H

59%

(22)

Zn, EtOH

O

Cl

Cl

Bu

O

Bu

AcOH, TMEDA

84%

Ph

Br

O

Ph

O

Ph

O

(23)

Zn(Cu), DMSO

+

43%

5%

A list of General Abbreviations appears on the front Endpapers

ZINC

3

Zn(Cu), ))))

+

O

I

O

(24)

EtOH–H

2

O

95%

CN

I

OH

CN

(25)

Zn, heat

+

acetone

98%

(26)

aq NH

4

Cl, 25 °C

75%

+

OH

H

O

Br

OH

OH

Zn, THF

(27)

Br

Zn, THF

+

O

OHC

O

OH

aq NH

4

Cl, 25 °C

92%

Reduction of Carbon–Nitrogen and Carbon–Sulfur Bonds.

Aldimines and oximes are converted to amines, and various hete-
rocycles bearing carbon–nitrogen double bonds are reduced with
zinc under acidic conditions.

38

Cyanamides can be cleanly cleaved

leading to amines,

39a

and the zinc reduction of acylnitriles pro-

vides α-amino ketone derivatives (eq 28).

39b

Aromatic amides

can be reduced with zinc dust to aromatic aldehydes.

39c

Acti-

vated carbon–sulfur bonds α to a carbonyl group

40a,b

and sulfur

ylides

40c,d

can be reduced with zinc.

(28)

Zn, THF

MeO

2

C

CN

O

MeO

2

C

O

NHAc

Ac

2

O

83%

Reduction at Heteroatoms.

2

Nitrogen–oxygen bonds of

oximes,

41

nitro,

42

and nitroso

43

groups are readily reduced by

zinc in acidic medium. Zinc in acetic acid has often been used for
the workup procedure of alkene ozonolysis to afford aldehydes or
ketones.

2

Sulfinates and thiols can be obtained selectively by the

reduction of aromatic sulfonyl chlorides or disulfides.

44

Dehalogenation and Related Reactions.

6c

,

45

Zinc dust is

a very efficient reducing agent for the dehalogenation of 1,2-
dihalides or 1-halo-2-alkoxy derivatives, leading to alkenes.
The reaction allows an access to highly reactive ketenes,

46

alkenes,

47

or alkynes

48

not readily available by standard methods

(eqs 29–31). The reduction of β-alkoxy halides using Zinc–
Graphite proved to be especially interesting when applied to sugar
derivatives (eq 32).

6c,45e,49

The dehalogenation using zinc is such

a straightforward and chemoselective reaction that several pro-
tecting groups have been devised which use this reaction as a
deblocking step.

50

Cl

3

C

Cl

O

Cl

Cl

O

H

(29)

Zn(Cu), ether

+

77–83%

(30)

Zn(Cu), ether

CH

2

I

CH

2

I

>80%

F

3

C

CF

3

F

F

F

3

C

CF

3

(31)

Zn, EtOH

90%

(32)

THF, 10 min

93%

O

I

OMe

MeO

MeO

OMe

CHO

MeO

OMe

OMe

Zn(Ag)/graphite

The Reformatsky Reaction.

4

The insertion of zinc into

α

-halo esters produces zinc ester enolates which react readily

with aldehydes or ketones, leading to aldol products. Histori-
cally, this reaction has been important since it allowed the first
quantitative generation of an ester enolate. However, several mod-
ern synthetic methods for the stereoselective preparation of aldol
products using metal enolates compete favorably with the Refor-
matsky reaction.

51

The nature of the zinc activation

6

has proved

to be important for fast and quantitative zinc insertion. Remark-
ably, the Zn(Ag) couple on graphite reacts with ethyl bromoac-
etate at −78

◦

C within 20 min,

52a

whereas Rieke zinc requires 1

h at 25

◦

C,

52b

as does zinc generated from the reaction of Zinc

Chloride with Lithium under ultrasound irradiation

52c

(eq 33).

52a

Interesting synthetic applications have been reported (eqs 34
and 35).

4,52

4-Bromocrotonate reacts with ketones and Zn(Cu)

with solvent-dependent regioselectivity.

52f

See also Ethyl Bromo-

zincacetate.

CO

2

Et

Br

OEt

O

HO

(33)

1. Zn(Ag)/graphite
THF, –78 °C, 20 min

92%

2. cyclohexenone

(34)

1. Rieke Zn
THF, 25 °C

O

O

O

Br

Br

O

O

O

64%

2. HMPA

Br

CO

2

Et

N

O

O

N

OH

CO

2

Et

O

(35)

Zn, THF

25 °C, ))))

70%

The Simmons–Smith Reaction.

5

,

53

Cut Zn foil readily in-

serts into Diiodomethane providing iodomethylzinc iodide,

53

which cyclopropanates a wide range of alkenes in good yields
(see Ethylzinc Iodide, Iodomethylzinc Iodide, Diethylzinc,
Ethyliodomethylzinc). The in situ generation of iodomethylzinc

Avoid Skin Contact with All Reagents

4

ZINC

iodide is often used. The Zn(Ag) couple has proved to be espe-
cially active for cyclopropanations (eq 36).

53d

40%

Zn(Ag)

OTMS

OTMS

OTMS

OTMS

O

(36)

CH

2

Cl

2

, py

Preparation of Organozinc Reagents.

1

,

3a

The insertion of

zinc into organic halides provides the most general synthesis
of organozinc halides. Primary and secondary organic iodides
react with zinc dust (2–3 equiv) in THF between 20

◦

C and

50

◦

C, leading to organozinc iodides in high yields.

3a,54a−c

Ben-

zylic chlorides and bromides react under even milder conditions,
providing the corresponding benzylic zinc halides without the for-
mation of significant amounts of Wurtz coupling products.

54d−f

Two remarkable properties characterize organozinc reagents:
(i) their high functional group compatibility, which allows the
preparation of polyfunctional organometallic zinc species bearing
almost all common functional groups with the exception of nitro,
azido, or hydroxy functions (see the reagents 3,

54b

4,

54g,h

5,

54i

6,

54j

7,

54k−o

8,

54p

9,

54n,o

10, 11,

54q

and 12–14,

54f

and eq 37); and

(ii) their ability to undergo transmetallation with other metallic
salts, such as copper salts, thus giving polyfunctional copper
reagents which react readily with a wide range of electrophiles
(enones,

54b,r

aldehydes,

54s

alkynes,

54t−v

nitro alkenes,

54w−y

allylic halides,

54b,z

alkynyl halides,

54g

acid chlorides,

54b,54aa

and

alkylidenemalonates

54ab

). Similarly, efficient transmetalations

with Pd

II

salts allow the coupling reactions to be performed

(eq 38).

55,56

Zinc insertion also proceeds well with various

polyfluorinated alkyl iodides

57

and with primary alkyl and benzyl

phosphates and mesylates.

58

Alkenyl and aromatic halides un-

dergo the zinc insertion far less readily and require the use of polar
solvents

59

or highly activated zinc.

60

The use of a sacrificial zinc

electrode offers an interesting alternative.

61

Allylic zinc halides

are formed under very mild conditions and, contrary to other
classes of organozinc reagents, display a high reactivity toward
organic

electrophiles

(comparable

to

organomagnesium

species).

36e−h54a,62

A wide range of synthetic applications of

zinc reagents for the formation of carbon–carbon bonds has been
reported (eqs 39–44).

56,60a,63−66

Diorganomercurials also react

with zinc dust, providing diorganozincs.

67,68

(3)

O

O

ZnI

NC

O

ZnI

(EtO)

2

P

ZnBr

O

(4)

(5)

(6)

(7)

(8)

B

O

O

BrZn

CO

2

Et

CN

ZnBr

Et
Et

OAc

N

O

O

IZn

IZn

SO

2

-t-Bu

N

H

ZnI

IZn

(9)

(10)

(11)

OAc

OAc

ZnCl

ZnBr

Cy

ZnBr

CN

O

(12)

(13)

(14)

(37)

5–45 °C

>85%

FG-RX

+

Zn

FG-RZnX

X = I, Br; R = alkyl, aryl, benzyl, allyl
FG = CO

2

R, enoate, CN, enone, halide, (RCO)

2

N,

(TMS)

2

Si, RNH, NH

2

, RCONH, (RO)

3

Si, (RO)

2

P(O), RS,

RS(O), RSO

2

, PhCOS

THF

(38)

R

2

X

FGR

1

R

2

FGR

1

ZnX

1. CuCN

·

2LiCl

FGR

1

E

2. E

+

Pd

0

(39)

I

I

O

H

1. Zn, THF
2. CuCN

·

2LiCl

74%

3. cyclohexenone, TMSCl

4. allyl bromide

I

CO

2

Et

COCl

CO

2

Et

O

(40)

1. Zn(Cu)
DMA–PhH

87–88%

Pd

0

cat

2.

Br

NC

I

CO

2

Et

NC

CO

2

Et (41)

1. Rieke Zn

Pd

0

cat

82%

2.

I

NHBoc

CO

2

Bn

I

NO

2

NHBoc

CO

2

Bn

O

2

N

(42)

1. Zn(Cu), DMA, PhH
)))), 20–35 °C, 0.5 h

Pd

0

cat

61%

2.

Br

CO

2

Et

(43)

Ph

N

CO

2

Me

Ph

N

O

Ph

Ph

CO

2

Me

1. Zn, THF

80%

2.

A list of General Abbreviations appears on the front Endpapers

ZINC

5

(44)

Br

MgBr

CO

2

Et

CO

2

Et

AcO

88%

AcO

1. Zn, THF
2.

( )

6

3.

First Update

Paul Knochel & Nathalie Grenouillat
Ludwig-Maximilians-Universität, München, Germany

During these last 10 years, the reductive behavior of zinc dust

has been widely used. The insertion of zinc dust into organic
halides is still a common method for the formation of organozinc
reagents. Organozincs have been used for cross-coupling reactions
under milder reaction conditions.

Reduction of Carbon–Oxygen Bonds. Activated C–O bonds

on functionalized compounds can be selectively reduced by zinc.
Thus, by using TiCl

4

, zinc dust leads to the deoxygenation of oxy-

genated derivatives of type (15), affording dibromonaphthalenes
(eq 45).

69

Reduction of functionalized α,β-unsaturated γ,δ-dioxy-

carboxylates with zinc dust in refluxing ethanol provides an
efficient route to substituted allylic alcohols (eq 46).

70

Under

ultrasonic irradiation, γ-enone-lactones are selectively cleaved
by zinc under acidic conditions.

71

A modification of this method

using zinc dust in the presence of ammonium chloride allows a
reductive deacetoxylation of 2-acyloxy-3-keto amides (eq 47).

72

Reduction of alkyl phenyl ketones by zinc and aluminium chloride
in acetonitrile results in a pinacol condensation followed by an in
situ rearrangement, with exclusive migration of the phenyl group
(eq 48).

73

These results contradict a previous report in which aryl

alkyl ketones are condensed to the corresponding alkenes.

74

O

Br

Br

Hex

Hex

15

Br

Br

Hex

Hex

Zn, TiCl

4

THF

reflux, 12 h

70%

(45)

CO

2

Et

O

O

O

O

CO

2

Et

O

O

HO

Zn, EtOH

reflux, 12 h

91%

(46)

N
H

O

O

O

O

N
H

O

O

Zn, ))))

NH

4

Cl, MeOH

20

°

C, 30 min

94%

(47)

O

Zn, AlCl

3

CH

3

CN

O

+

95%

5%

70

°C, 20 h

(48)

Reduction of Carbon–Nitrogen Bonds.

Zinc-mediated

reduction of imines proceeds under mild conditions. A reductive
dimerization leading to useful diamines can be realized (eq 49).

75

Symmetrical and unsymmetrical aromatic diimines undergo a
reductive intramolecular coupling, leading to substituted ethylene-
diamines (eqs 50 and 51).

76

Interestingly, reductive coupling of

aromatic aldoximes and azines to 1,2-diamines is achieved in
one-step using zinc in the presence of MsOH or TiCl

4

(eq 52).

77a

N

-Hydroxy-α-imino esters are reduced to α-amino esters with

Zn-MsOH in high yields (eq 53).

77b

Activation with TMSCl

allows the zinc reductive homocoupling of 2-aryl-2-oxazolinium
salts (eq 54).

78

N

-Bn, S-Bn, and O-Bn derivatives can be

hydrogenolyzed

using

zinc

dust

with

ammonium

for-

mate under microwave irradiation (eq 55).

79

Zinc dust in

refluxing methanol allows a selective monodeprotection of
di-Boc-protected amides, affording the corresponding mono-
Boc-protected amines (eq 56).

80

N

H

Me

Me

NH HN

Me

Me

Me

Me

NH

Me

Me

+

94%

dl

:meso = 1:1

5%

Zn, TMSCl

CH

3

CN

35

°C, 1 h

(49)

Avoid Skin Contact with All Reagents

6

ZINC

N

O

MeO

O

N

MeO

O

O

NH

NH

MeO

MeO

Zn, MsOH
DMF/THF

−

20

°

C

86%

(50)

trans

:cis = 90:10

N

SO

2

N

Me

HN

NH

SO

2

Me

Zn, TMSCl

DMF

20

°

C, 12 h

85%

trans

:cis = 1:2

(51)

N

H

OH

NH

2

H

2

N

N

N

Zn, MsOH

CH

3

CN

20

°

C

67%

Zn, TiCl

4

THF

20

°

C

73%

(52)

NHBoc

Me

CONH

CO

2

Me

Ph

85%

2. (Boc)

2

O, aq NaHCO

3

2

N

Me

CONH

HO

CO

2

Me

Ph

2

1. Zn, MsOH, THF, 25

°

C

(53)

N

O

Cl

I

N

O

Cl

N

O

Cl

Zn, TMSCl

DMF

20

°

C, 16 h

76%

(54)

H

3

C

CH

3

NHBn

H

3

C

CH

3

NH

2

7

7

Zn, HCO

2

NH

4

MeOH, ))))

20

°

C, 3 h

90%

(55)

TBDMSO

OMe

O

N(Boc)

2

TBDMSO

OMe

O

NHBoc

Zn, MeOH

reflux, 24 h

87%

(56)

Reduction of Carbon–Sulfur Bonds. 2-Thioxo-4-thiazolidi-

nones can be converted to 4-thiazolidinones by utilizing excess
zinc dust in acetic acid (eq 57).

81

Residual lead present in the

commercial source of zinc dust is essential for the success of the
reaction.

82

S

NH

O

S

HO

S

NH

O

HO

Zn, ε Pb

AcOH

(57)

reflux

90%

Reduction of Nitrogen–Nitrogen and Nitrogen–Oxygen

Bonds. In the presence of ammonium chloride and ammonium
formate, the reduction of N–O functions and N–N functions with
zinc dust proceeds with good yields under very mild conditions.
Many functional groups, which are known to be reducible moieties
(OH, OCH

3

, CH

3

, CO

2

H, COCH

3

, SO

3

Na, halogens, etc.) are

tolerated during this cleavage step. Thus, alkyl or aryl azides and
acyl azides are reduced to the corresponding amines and amides
(eqs 58–60).

83,84

Azobenzenes are cleaved to their corresponding

anilines in a few minutes (eqs 61 and 62).

85

Heteroaromatic

N

-oxides are reduced to the corresponding pyridines through an

efficient deoxygenation (eq 63).

86

Reduction of γ-nitro carbonyl

compounds produces nitrones without isolation of the intermedi-
ate hydroxylamines (eq 64).

87

O

N

3

O

NH

2

Zn, NH

4

Cl

EtOH/H

2

O

reflux, 10 min

96%

(58)

A list of General Abbreviations appears on the front Endpapers

ZINC

7

N

3

O

NH

2

O

Zn, NH

4

Cl

EtOH/H

2

O

20

°C, 2 h

94%

(59)

N

3

N

O

CH(SEt)

2

NH

2

N

O

CH(SEt)

2

Zn, HCO

2

NH

4

MeOH

20

°

C, 25 min

90%

(60)

N N

H

3

C

H

2

N

H

3

C

NH

2

H

3

C

H

2

N

H

2

N

H

3

C

Zn, HCO

2

NH

4

MeOH

20

°

C, 12 min

90%

+

(61)

N N

N

HO

2

C

NH

2

N

H

2

N

HO

2

C

Zn, NH

4

Cl

MeOH

20

°

C, 20 min

80%

+

(62)

N

CO

2

Me

O

N

CO

2

Me

Zn, HCO

2

NH

4

MeOH

reflux, 4 h

78%

(63)

NO

2

EtO

2

C

EtO

2

C

O

NH

EtO

2

C

EtO

2

C

O

HO

N

EtO

2

C

EtO

2

C

O

(64)

Zn, aq NH

4

Cl

THF

0

°

C, 5 h

77%

Under acidic conditions, pyridazines are converted to pyrroles

through a ring contraction proceeding via a 1,4-dihydro-1,2-
diazine (eq 65).

88

Reduction with zinc of a nitroarene possessing a

cyano group leads to an interesting cyclization reaction (eq 66).

89

N N

MeO

2

C

CO

2

Me

OBn

N NH

MeO

2

C

CO

2

Me

OBn

N
H

MeO

2

C

CO

2

Me

OBn

Zn, TFA

25

°

C, 1 h

(65)

N

CN

O

2

N

N

NH

(66)

Zn, aq HCl

aq EtOH

78

°

C

65%

A zinc-mediated chemoselective reduction of nitroarenes to

amines and azobenzenes to hydrazobenzenes can be performed
in ionic liquids (eqs 67 and 68).

90

A selective reduction of

nitroarenes is also reported by using zinc in near-critical water
(250

◦

C).

91

Interestingly, under microwave irradiation, nitro and

azido arenes are reduced to N-arylformamides by using ammo-
nium formate (eq 69).

84

Zinc–hydrazinium monoformate is an

efficient system to reduce aliphatic and aromatic nitro compounds
to the corresponding amines (eq 70).

92

Zinc dust combined with

nickel chloride hexahydrate allows the selective reduction of
alkyl, aryl, aroyl and arylsulfonyl azides to amines (eq 71).

93

Interestingly, nitro substituted aromatic azides are selectively
reduced to their corresponding anilines without any further
reduction of the nitro group (eq 72).

NO

2

HO

NH

2

HO

20

°

C, 8 h

77%

(67)

Zn, NH

4

Cl

[bmim][PF

6

]/H

2

O

[bmim][PF

6

] = 1-butyl-3-methylimidazolium

hexafluorophosphate

N N

Me

Me

N
H

N
H

Me

Me

20

°

C, 35 min

94%

(68)

Zn, HCO

2

NH

4

[bmim][BF

4

]/H

2

O

[bmim][BF

4

] = 1-butyl-3-methylimidazolium tetrafluoroborate

Avoid Skin Contact with All Reagents

8

ZINC

NO

2

Cl

N

3

Cl

NHCHO

Cl

Zn, HCO

2

NH

4

)))), 300W

20

°

C, 3 min
80%

Zn, HCO

2

NH

4

)))), 300W

20

°

C, 2.5 min

90%

(69)

NO

2

NH

2

Zn, H

2

N-NH

2

·

HCO

2

H

MeOH

20

°

C, 2 min
94%

(70)

S

O

O

N

3

Zn-NiCl

2

·

6H

2

O

THF

S

O

O

NH

2

20

°

C, 2 h

85%

(71)

N

3

O

2

N

Zn-NiCl

2

⋅

6H

2

O

THF

NH

2

O

2

N

20

°

C, 2.5 h

80%

(72)

Reduction of Sulfur–Sulfur and Sulfur–Oxygen Bonds. A

Zn/AlCl

3

system in aqueous media is a convenient method for

the reduction of alkyl and aryl disulfides to zinc thiolates, which
react with alkyl or aryl halides and alkyl tosylates providing the
corresponding thioethers (eqs 73 and 74).

94

Unsymmetrical aryl

sulfides are also prepared by cleavage of the S–S bond by zinc and
nickel bromide/bipyridine (bpy) followed by trapping with an aryl
iodide (eq 75).

95

Zinc with dichlorodimethylsilane in dimethyl-

acetamide allows a nonaqueous reduction of aromatic sulfonyl
chlorides affording various thiols (eq 76).

96

S

S

Br

Bu

S Bu

(73)

+

Zn, AlCl

3

DMF/H

2

O

65

°

C, 17 h

95%

Bu

S

S Bu

OTs

S Bu

(74)

+

Zn, AlCl

3

CH

3

CN/H

2

O

65

°

C, 6 h

90%

Dehalogenation and Related Reactions. Zinc is well known

to promote dehalogenation reactions. Thus, olefins are obtained in

good yield by the reaction of β-((trimethylsilyl)oxy)alkyl iodides
with zinc dust in THF (eq 77).

97

Likewise, zinc-induced elimina-

tion of a bromomesylate thymidine derivative affords the desired
elimination product (eq 78).

98

p

-Toluenesulfonates of chiral 2,

3-epoxy alcohols are converted into allylic alcohols by a two-step
reaction (iodination and reduction) (eq 79).

99

A rearrangement

of the iodomesylate derivative (16) produces an interesting inter-
mediate of (+)-8-deoxyvernolepin (eq 80).

100

The reductive ring

opening of bromopyranose sugars, first developed by Vasella,

101

allows a zinc dust reduction of iodoglycosides under sonication

102

and furnishes highly functionalized unsaturated carbohydrates
(eq 81).

102d,e,f

A chemoselective deprotection of prenyl carba-

mates was performed in a one-pot procedure (iodoetherification
and reduction) (eq 82).

103

A mild cleavage of allyl protection is af-

forded using perfluoroalkylation and subsequent elimination with
zinc dust (eq 83).

104

Me

S

S Me

I

S

Me

(75)

+

NiBr

2

-bpy (10 mol

%)

Zn, DMF

110

°

C, 48 h

81%

SO

2

Cl

H

3

CS

SH

H

3

CS

(76)

Zn, Me

2

SiCl

2

1,2-DCE, DMA

75

°

C, 1.5 h

97 %

Me

3

SiO

I

PhO

PhO

Zn, THF

reflux, 1 h

93%

(77)

O

N

Br

MsO

HN

O

O

BzO

O

N

HN

O

O

BzO

Zn, AcOH cat.

EtOAc, MeOH

20

°

C, 3.5 h

97%

(78)

OTs

O

O

O

H

H

H

O

O

H

OH

H

1. KI, DMF, 55

°

C, 1.5 h

2. Zn. NH

4

Cl, 0

°

C, 20 min

86%

96% de

(79)

A list of General Abbreviations appears on the front Endpapers

ZINC

9

O

O

O

H

O

MsO

I

16

O

O

O

H

O

MsO

O

O

O

H

O

O

O

O

H

Zn, NaI, aq DME

(80)

reflux

78%

O

OBn

BnO

OBn

OMe

I

Br

BnO

BnO

BnO

NH Bn

(81)

1. Zn dust (excess), ))))

THF, BnNH

2

73%

2.

85:15

83%

2. Zn, 30 min

MeS

CO

2

Me

HN

O

MeS

CO

2

Me

NH

2

1. I

2

, MeOH, rt, 7 h

(82)

O

O

O

SPh

AllO

O

O

O

SPh

O

I

F(F

2

C)

6

O

O

O

SPh

HO

I(CF

2

)

6

F, Na

2

SO

4

NaHCO

3

CH

3

CN/H

2

O

20

°

C, 30 min

98%

(83)

Zn, NH

4

Cl

EtOH

reflux, 15 min

90%

1,1-Dibromo-1-alkenes are reduced to the corresponding

monobromoalkenes with zinc in the presence of NH

4

Cl,

105

but

are efficiently converted to methyl ketones by using zinc metal
in near-critical water.

106

This reductive process was applied to

homologation of aldehydes (eq 84). Oxyallyl cations are easily
generated by zinc reduction of α,α

′

-diiodoketones under sono-

chemical conditions. Their reaction with dienes leads to the
cycloadducts in high yields (eq 85).

107

A synthesis of octaflu-

oro[2.2]paracyclophane (AF4) based on the generation of a
p

-xylylene intermediate with zinc in DMA at 100

◦

C has been

reported (eq 86).

108

Reductive defluorination of pentafluorobenzoic acid proceeds

with high regioselectivity para to the carboxy group using zinc in
ammonia (eq 87).

109

O

Cl

Cl

Br

Br

CH

2

Cl

2

Cl

O

Zn, H

2

O

CBr

4

, PPh

3

78%

(84)

275

°

C, 4 h

I

O

I

O

O

Zn

II

I

, I

O

Zn

O

O

+

Zn, )))), CH

3

CN

−

44

°

C, 15 min
90%

reduction

[4+3]

oxyallyl cation

(85)

cis

:trans = 100:0

endo

:exo = 91:1

ClF

2

C

CF

2

Cl

F

F

F

F

F

F

F

F

F
F

F

F

F

F

Zn, DMA

AF4 : 60%

6%

(86)

100

°

C, 3 h

+

CO

2

H

F

F

F

F

F

CO

2

H

F

F

H

F

F

Zn, NH

3

−

45

°

C, 3.5 h

90%

(87)

Zinc-mediated Cross-coupling Reactions.

Zinc dust pro-

motes, under mild conditions, the acylation of alcohols,

110

amines,

111

thiols,

112

ylides,

113

the synthesis of carbamates,

114

and

Friedel-Crafts acylation of electron rich arenes (eqs 88–92).

115

Under microwave irradiation, the Friedel-Crafts acylation can be
performed in solvent-free conditions and not only on activated
arenes but also on benzene, toluene, or chlorobenzene.

116

It is

presumed that the electrophilic character of the acyl chloride is
enhanced by the zinc which undergoes nucleophilic displacement.
The recovery of zinc and its reuse make these general meth-
ods more economic. Zinc metal allows also acylation and sul-
fonation of pyrrole and its derivatives in high regioselectivity

Avoid Skin Contact with All Reagents

10

ZINC

(no N-acylated products were obtained under these conditions)
(eq 93).

117

Symmetrical thiosulfonic S-esters are obtained in good

yield by the reduction of sulfonyl chlorides in the presence of
acetyl chloride (eq 94).

118

N

O

O

Cl

OH

N

O

O

O

+

Zn, benzene

20

°

C, 15 min

94%

(88)

FmocHN

Cl

O

Ph

−

Cl

+

H

3

N

OMe

O

FmocHN

N
H

O

Ph

OMe

O

+

Zn, THF

20

°

C, 10 min

90%

(89)

Cl

O

Ph

SH

S

O

Ph

+

Zn, toluene

20

°

C, 15 min

91%

(90)

BnO

Cl

O

S

N

H

2

N

S

N

N
H

BnO

O

+

Zn, benzene

20

°

C, 8 min
93%

(91)

OMe

Me

Cl

Cl

COCl

Cl

Cl

O

OMe

Me

+

Zn, toluene

70

°

C, 8 h

89%

(92)

N
H

Cl

SO

2

Cl

N
H

S
O

2

Cl

+

Zn, toluene

20

°

C, 1 h

85%

(93)

(94)

S

O

Cl

O

Zn, TMSCl

1,2-diobromoethane

CH

3

COCl, EtOAc, 20

°

C

90%

S

O

S

O

Wittig Reaction and Simmons–Smith Reactions.

Resid-

ual lead found in commercial zinc dust has a dramatic ef-
fect on the Simmons–Smith reaction (addition of TMSCl is
necessary to suppress this negative effect), whereas it has a
positive catalytic effect on Wittig-type olefination with the
CH

2

I

2

, Zn, TiCl

4

system.

119

The reaction of aldoses with di-

bromomethyltriphenylphosphonium bromide, in the presence
of zinc, gives the corresponding unsaturated olefination prod-
ucts with good yields (eq 95).

120

A variety of organoz-

inc carbenoids can be generated by the reaction of acetals,
ketals,

121a

ortho

formates,

121b

carbonyl compounds,

121c,d

or

N

-diethoxymethyl amides

121e

with metallic zinc in the pres-

ence of a triorganosilyl chloride. Organozinc carbenoids undergo
several useful reactions including direct deoxygenation to alkenes,
cyclopropanation, and dicarbonyl coupling (eqs 96 and 97).

121

O

HO

OH

TrO

OH

HO

TrO

Br

Br

(95)

Ph

3

PCHBr

2

, Br

Zn, dioxane

reflux, 40 min

90%

O

O

13

reflux

86%

13

(96)

Zn(Hg), Me

3

SiCl

ZnCl

2

, Et

2

O

MeO

CHO

OAc

Si

Si

Cl

Cl

OAc

MeO

H

Zn, Et

2

O, reflux

69%

cis:trans

= 6.4:1

+

(97)

Preparation of Organozinc Reagents.

A broad range of

functionalized zinc organometallics have been prepared by us-

A list of General Abbreviations appears on the front Endpapers

ZINC

11

ing the direct insertion of zinc into organic halides.

122

In most

cases, activation of zinc dust is necessary, and the most com-
mon method remains the activation with 1,2-dibromoethane and
TMSCl in THF.

54b

In some cases, only trimethylsilyl chloride

has been used to prepare activated zinc. For solubility reasons,
it is sometimes necessary to use a dipolar aprotic solvent such
as DMF, DMSO, or DMAC instead of THF. Thus, chiral
β

-carbamate- and amido-alkylzincs bearing an acidic N–H group

are prepared under mild conditions (17,

123a

18,

123b

and 19,

123c

).

This activation allows the preparation of serine-derived organo-
zinc reagents as developed by Jackson (20,

124a,b

21,

124c

22,

124d

23,

124d

24,

124e,f

25,

124g,h,i

26,

124g,h,i

27,

124j

28,

124k

29,

124k

).

Various nitrogen-containing iodo- or bromo-substituted hetero-
cycles were converted to their corresponding zincated hetero-
cycles derivatives (30–33).

125,126

This reaction was extended to

the preparation of zinc organometallics derived from nucleosides
and nucleic bases (34 and 35).

126,127

The reaction of these new

zinc reagents with various electrophiles under palladium(0) or
copper(I) catalysis allows the preparation of a broad range of poly-
functional nitrogen-containing heterocycles.

Me

ZnI

NHBoc

17

X

NH

ZnI

O

18, X = O
19, X = C

IZn

NHBoc

CO

2

R

20, n = 1, R = Bn
21, n = 1, R = Me
22, n = 2, R = Bn
23, n = 3, R = Bn

n

Z
N

O

O

IZn

24

IZn

NHR

2

CO

2

R

1

25, n = 1, R

1

= Me, R

2

= Boc

26, n = 2, R

1

= Me, R

2

= Boc

27, n = 1, R

1

= Me, R

2

= TFA

28, n = 1, R

1

= Bn, R

2

= TFA

29, n = 1, R

1

= Bn, R

2

= Boc

n

N

ZnI

30

N

N

NC

NC

ZnBr

Me

31

N

S

ZnBr

32

N

Cl

ZnI

33

N

N

O

O

Bn

Bn

ZnI

34

N

N

N

N

O

OAc

OAc

AcO

ZnI

35

An efficient procedure using a catalytic amount of I

2

in a

polar aprotic solvent for activation of zinc allows the preparation
of alkylzinc compounds starting from unactivated alkyl bromides
and chlorides (eq 98).

128

The use of a sacrificial zinc anode

offers an interesting alternative. Hence, in the presence of cat-
alytic amounts of NiBr

2

bpy catalyst, 2,5-dibromo-3-substituted

thiophenes are electrochemically converted to their correspond-
ing thienylzinc species with good regioselectivity (eq 99).

129

Aryl-

zinc compounds are also efficiently prepared by electroreduction
of aryl chlorides and bromides with a zinc anode in the pres-
ence of cobalt bromide or a cobalt chloride—pyridine complex
in DMF or acetonitrile (eqs 100 and 101).

130

Arylzincs undergo

cross-couplings with aromatic halides or activated olefins.

131

An

alternative to this electrochemical process uses allyl chloride and
zinc dust activated by traces of an acid as a reducing agent.

132

Various aromatic ketones are obtained by trapping these organo-
zinc derivatives with carboxylic acid anhydrides (eq 102).

132c

CN

Cl

EtO

O

CN

Cl

2

Ni(PPh

3

)

2

3

EtO

Br

O

EtO

ZnBr

O

Zn, I

2

DMA

3

3

20

°

C, 1 h

97% overall

(98)

80

°

C, 3 h

S

Hex

Br

Br

S

Hex

Br

BrZn

I

2

S

Hex

Br

I

(99)

Zn anode

e, NiBr

2

bpy

ZnBr

2

76%

100% 5-substitued

DMF, −10

°

C

Cl

H

3

CO

2

S

ZnCl

H

3

CO

2

S

I

2

I

H

3

CO

2

S

(100)

Zn anode

e, CoCl

2

ZnBr

2

90%

DMF/pyridine

20

°

C

Avoid Skin Contact with All Reagents

12

ZINC

Br

F

3

C

ZnCl

F

3

C

I

2

I

F

3

C

(101)

Zn anode

e, CoBr

2

ZnBr

2

90%

Acetonitrile, 20

°

C

Br

MeO

CoBr

2

Zn

ZnBr

MeO

O

Me

O

MeO

Me

O

1. Allyl chloride
acetonitrile, TFA, 20 °C

2.

+

71%

(102)

2

83%

Reformatsky Reaction and Barbier-type Reactions.

The

Reformatsky reaction can be carried out in aqueous media by addi-
tion of salts (NH

4

Cl, CaCl

2

, Mg(ClO

4

)

2

, BF

3

·OEt

2

) (eq 103).

133

Barbier-type zinc-mediated reactions have been widely devel-

oped, particularly the allylation and propargylation of carbonyl
compounds.

134

Such reactions proceed well in saturated aque-

ous ammonium chloride solution with or without addition of or-
ganic solvent and also in liquid ammonia.

135

Thus, intramolecular

carbonyl allylations of cyclic β-keto ester derivatives in aqueous
media allows a ring expansion of one or two carbons (eqs 104
and 105).

136

The same ring expansion of various α-halomethyl

cyclic β-keto esters was performed in a mixture of tert-amyl
alcohol and water with good yield (eq 106).

137

With chiral alde-

hydes or with the enantiopure 2-sulfinylallyl chloride the addition
is highly stereoselective (eqs 107–109).

138,139

Similar alkylation

on sulfonamines provides the corresponding homoallylic sulfon-
amides (eq 110)

140

and difluoroacetyltrialkylsilane reacts with

various allyl bromides affording homoallylic alcohols (eq 111).

141

Aldimines and ketimines are efficiently allylated by commercial
zinc dust without any activation (eq 112).

142

H

O

CO

2

Et

Br

OH

CO

2

Et

(103)

Zn, BF

3

·OEt

2

H

2

O /THF

+

20

°

C, 2 h

92%

O

CO

2

Et

Br

O

CO

2

Et

(104)

1. Zn, aq HCl/THF
20

°

C, 20 h

2. DBU, THF, 2 h, rt

50%

O

CO

2

Et

Br

O

CO

2

Et

O

CO

2

Et

Zn, aq NH

4

Cl

60%

overall

(105)

20

°

C, 5 h

DBU

THF, 20

°

C

O

I

CO

2

Me

O

CO

2

Me

Zn

tert

-amyl alcohol/H

2

O

20

°

C, 3 h

87%

(106)

O

O

CHO

Br

O

O

OH

(107)

+

Zn, aq NH

4

Cl

20

°

C, 8 h

75%

syn

:anti = 3:97

H

O

NBn

2

Br

OH

NBn

2

(108)

+

Zn, THF/NH

4

Cl

0

°

C, 30 min

95%

dr = 7:1

Cl

S

p

-Tol

O

CHO

S

p

-Tol

O

OH

(109)

+

Zn, NaI

aq NH

4

I/THF

0

°

C

80%

dr = 6:1

A list of General Abbreviations appears on the front Endpapers

ZINC

13

Ph

N

SO

2

Ph

H

Ph

Br

Ph

NHSO

2

Ph

Ph

+

20

°

C, 2 h

87%

Zn, aq NH

4

Cl

(110)

Br

HF

2

C

SiEt

3

O

Et

3

Si

OH

CF

2

H

(111)

+

Zn, aq NH

4

Cl

THF

20

°

C, 30 min

88%

Br

N

Me

Ph

Bn

BnHN

Me

Ph

(112)

+

1. Zn, THF
20

°

C, 2 h

2. aq NaHCO

3

98%

Allylic zinc halides add easily to acid chlorides providing β,γ-

unsaturated alcohols, or in the presence of TMSCl promoting
a gem-bisallylation (eq 113).

143

Likewise, allylic or benzylic

bromides add to alkyl and aryl sulfonyl chlorides providing
β

,γ

-unsaturated sulfones in ether or aqueous media (eq 114).

144

An efficient addition to α-amidoalkylphenyl sulfones is also
reported (eq 115).

145

Cl

Cl

O

HO

Ph

(113)

+

Zn, TMSCl

THF

50

°

C, 3 h

92%

Br

(114)

+

Zn, Et

2

O

20

°

C, 3 h

81%

S

O

O

Cl

S

O

O

Br

Bn

O

N
H

Ph

O

SO

2

Ph

Bn

O

N
H

Ph

O

(115)

+

Zn, THF

20

°

C, 1.5 h

99%

Related

Reagents.

Dibromomethane–Zinc–Titanium(IV)

Chloride; Dichlorobis(cyclopentadienyl)zirconium–Zinc–Dibro-

momethane;

Diiodomethane–Zinc–Titanium(IV)

Chloride;

Molybdenum(V) Chloride–Zinc; Niobium(V) Chloride–Zinc;
Phosphorus(III) Bromide–Copper(I) Bromide–Zinc; Potassium
Hexachloroosmate(IV)–Zinc;

Titanium(IV)

Chloride–Zinc;

Zinc–Acetic Acid; Zinc Amalgam; Zinc–Copper(II) Acetate–
Silver Nitrate; Zinc–Copper(I) Chloride; Zinc/Copper Couple;
Zinc–1,2-Dibromoethane;

Zinc–Dimethylformamide;

Zinc–

Graphite; Zinc/Nickel Couple; Zinc/Silver Couple; Zinc–
Zinc Chloride.

1.

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Avoid Skin Contact with All Reagents

14

ZINC

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A list of General Abbreviations appears on the front Endpapers

ZINC

15

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Avoid Skin Contact with All Reagents