ZINC–ACETIC ACID

1

Zinc–Acetic Acid

1

Zn–AcOH

(Zn)
[7440-66-6]

Zn

(MW 65.39)

InChI = 1/Zn
InChIKey = HCHKCACWOHOZIP-UHFFFAOYAS
(AcOH)
[64-19-7]

C

2

H

4

O

2

(MW 60.06)

InChI = 1/C2H4O2/c1-2(3)4/h1H3,(H,3,4)/f/h3H
InChIKey = QTBSBXVTEAMEQO-TULZNQERCK

(reducing agent; causes reductive elimination of vicinal hetero-
atoms;

2

–

15

cleaves heteroatom–heteroatom bonds;

16

–

27

reduces

allylic, benzylic, or α-carbonyl-substituted heteroatoms,

28

–

34

activated carbonyls,

35

–

37

and alkenes

38

–

40

)

Physical Data:

see entries for Zinc and Acetic Acid.

Form Supplied in:

although zinc is available in a variety of forms,

the overwhelming majority of zinc–acetic acid reductions use
zinc powder.

Purification:

acid washing is not uncommon, but not always vital.

Introduction. Zinc in acetic acid is capable of a wide range of

reduction reactions. Although many of these can also be performed
by a great number of other reagents, this reagent is of particular
value in that good chemoselectivities can often be achieved. Some
such instances are noted in the text and equations below; many
of the references have also been chosen to demonstrate selective
reduction in sensitive, polyfunctional molecules.

Reductive Elimination of Vicinal Heteroatoms.

2

–

15

A great

variety of combinations of heteroatom substituents has been suc-
cessfully reductively eliminated by Zn/AcOH (eq 1 and Table 1).
Cosolvents such as ether, THF, CH

2

Cl

2

, i-PrOH, or water have

all been used. Reaction temperatures vary from case to case, but
yields reported are typically good to excellent.

X

Y

(1)

Zn

AcOH

A set of protecting groups, based upon Zn/AcOH elimination

of the 2,2,2-trichloroethoxy group, has been developed, and is
discussed below as a special case. Table 1 records several of the
combinations of heteroatoms successfully eliminated under these

Table 1

Reductive eliminations of vicinal heterosubstituents (eq 1)

X

Y

Yield (%)

Cl

OR

see next section

Cl

Cl

96

2

Cl

SO

2

R

87

3

Cl

NO

2

79

4

Br

OR

88

5

Br

Br

94

6

OR

OR

92

7

conditions. Perhaps surprisingly, the relative stereochemistry of
the two carbon centers does not have to permit trans coplanarity
of the heteroatoms.

4,7

Heterocyclic rings may be cleaved by these reactions. Thus,

effective reversal of iodolactonization (eq 2)

8

or of epoxidation

(after iodide ring opening) (eq 3)

9

may be achieved.

I

CO

2

Me

O

O

CO

2

Me

CO

2

H

(2)

Zn, AcOH

reflux, 0.5 h

100%

O

R

(3)

R

NaI, NaOAc

Zn, AcOH, 0 °C

67%

Halogenated oximes (1) eliminate to give the nitrile in variable,

but often good to excellent, yields (eq 4).

10

N

R

Hal

OMe

(4)

Zn, AcOH, DMF

(1)

RCN

150 °C, 0.5–8 h

23–95%

2,2,2-Trichloroethoxy-based

Protecting

Groups.

11

–

15

Valuable protecting groups for alcohols,

11

phenols,

11c

amines,

11c

and carboxylic acids,

12

and an introduction/protection reagent

for thiols,

13

all dependent upon the lability of this group to

Zn/AcOH reductive elimination, have been developed. They are
summarized in Table 2.

Table 2

Protecting groups based on OCH

2

CCl

3

elimination

Functionality

Protected form

ROH

11a

ROCH

2

CCl

3

ROH

11b

ROCH

2

OCH

2

CCl

3

ROH

11c,d

ROC(O)OCH

2

CCl

3

ROH

11e

ROC(O)OCMe

2

CCl

3

ArOH

11c

ArOC(O)OCH

2

CCl

3

R

2

NH

11c

R

2

NC(O)OCH

2

CCl

3

RCO

2

H

12

RC(O)OCH

2

CCl

3

RSH

13

RSC(O)OCH

2

CCl

3

The trichloroacetylidene acetal has also been proposed as a po-

tential protection for diols, similarly deprotectable.

14

Also, along

similar lines, the 2-iodoethyl carbamate protection for amines, de-
protectable by Zn dust alone in MeOH, has been proposed,

15

but

has found relatively little use.

Heteroatom–Heteroatom Cleavage.

16

–

27

N=N double

bonds can be cleaved

16

by Zn/AcOH; less frequently, hydrazines

17

may be obtained from the reduction (eqs 5 and 6).

17

Hydrazones

may also be reduced to amines,

18

as used

18b

in a variant of the

classical Knorr pyrrole synthesis. Diazo ketone (2) has been suc-
cessfully reduced, despite the apparent potential for adverse side
reactions (eq 7).

19

(5)

Zn, AcOH

PhN=NAr

PhNH-NHAr

90–100%

Avoid Skin Contact with All Reagents

2

ZINC–ACETIC ACID

N

NAr

2

Ar

1

O

–

(6)

Zn, AcOH

Ar

1

NH-NHAr

2

+

89%

O

O

(7)

N

2

Zn, AcOH

(2)

0 °C, THF

50%

Aromatic nitro groups

20a

(aliphatic nitro groups can yield

oximes,

20b

even though not all such would be stable under all

reaction conditions), hydroxylamines,

21

oximes

22

(once again,

finding use

22b

in a Knorr pyrrole synthesis), N-nitro-

23a

and

N

-nitrosoamines,

23b

aromatic N-oxides,

24

and aromatic N–S

bonds

25

have all been reduced to amines with Zn/AcOH. These

references include ample evidence of the ability of this reagent to
perform the desired reaction, while leaving intact, for example,
bromides,

22

carbon-bonded sulfur atoms,

20,23b

and isolated C=C

double bonds.

21

It will, of course, be understood that the newly

liberated amines often undergo spontaneous intramolecular reac-
tions. Sulfonamides

26

can also be reduced to the thiols.

Zn/AcOH can act as a useful alternative reagent for reductive

workup of ozonolysis reactions,

27

which can be considered, at

least formally, to involve O–O bond cleavage (see Ozone).

Curiously, the vigor of the conditions reported to have been

employed for these disparate reactions does not seem to follow
any consistent pattern; reaction conditions, therefore, may need
individual determination in many cases.

Carbon–Heteroatom Cleavage.

28

–

34

Substitution of N,

28

O,

29

S,

30

or halogen,

31

for example, at an allylic, benzylic, or

α

-carbonyl-substituted carbon atom renders the heteroatom liable

to cleavage with Zn/AcOH. In allylic systems, double bond migra-
tion usually occurs. If conjugated to a carbonyl group, migration
still occurs, giving the β,γ-product (eq 8),

32a

but these can be eas-

ily reconjugated (eq 9).

32b

Homoallylic reduction

33

has also been

reported in a constrained system (eq 10).

CO

2

Et

Br

(8)

CO

2

Et

Zn, AcOH

83%

O

O

OAc

OAc

O

O

OAc

92%

1. Zn, AcOH

(9)

2. Et

3

N

O

OTs

(10)

O

Zn, AcOH, H

2

O

reflux, 1.5 h

Cleavage α to a carbonyl group has been exploited in the use of

phenacyl protecting groups.

34

The reduction of compounds such

as (3) (for their formation, via Dichloroketene see Trichloroacetyl
Chloride) retains the strained four-membered ring, and often gives
excellent yields (eq 11).

31c

Bu

O

Bu

O

Cl

Cl

(11)

Zn, AcOH

TMEDA, EtOH

(3)

rt, 2.5 h

72–86%

Carbonyl Reduction.

35

–

37

Quinones are reduced to hydro-

quinones by Zn/AcOH at reflux.

35a

Incorporation of Ac

2

O into the

reaction mixture gives the respective diacetate.

35a

Under milder

conditions (rt), the intermediate γ-hydroxycyclohexenone may be
intercepted in surprisingly high yield (72–90%).

35b

Diaryl ketones may be reduced to the alcohols,

36a

but a com-

peting dimerization has also been reported

36b

in some unusual

cases. Reduction of phthalimide (4) proceeds well and, notably,
with regiospecificity (eq 12).

37

N

O

O

Me

N

O

Me

(12)

Zn, AcOH

(4)

reflux, 12 h

79%

Reduction of Activated Alkenes.

38

–

40

Carbonyl (mono-

38a

or di-

38b

) substitution renders a C=C double bond liable to re-

duction by Zn/AcOH. α,β,γ,δ-Dienones may yield either α,β-

38a

or β,γ-enones

38c

in equally high yields. A recent modification,

39

at lower temperature (rt), and with much shorter reaction times,
uses ultrasonication; excellent yields were achieved.

α

,β-Unsaturated nitro compounds can also be reduced.

40

Under

mild conditions an oxime can be obtained (eq 13)

40a

(cf. Sodium

Borohydride, which reduces the C=C double bond); more vigor-
ous reaction leads to the corresponding ketone.

40b

O

O

O

Ph

NO

2

OMe

O

O

O

Ph

NOH

OMe

(13)

Zn, AcOH, Et

2

O

reflux, 1 h

87%

Aza-heterocycle Ring Contraction.

A variety of polyaza

six-ring heterocycles undergo contraction with formal excision
of N, e.g. eq 14.

41a

Further heteroatoms in the ring are toler-

ated: 1,2,3-triazines yield pyrazoles

41b

and 1,2,4-triazines yield

imidazoles,

41c

with the latter usually requiring reflux tempera-

ture. The utility of indole syntheses from cinnolines

41d

by this

method should be noted. Adjacency of heteroatoms is not required:
conversions of pyrimidine to pyrrole

42a,b

and 1,3,5-triazine to

imidazole

42c

have been recorded. The mechanism of these con-

versions is unclear, but ring dihydro derivatives

41a,42b

are thought

to be involved.

N

N

MeO

2

C

CO

2

Me

N
H

MeO

2

C

CO

2

Me

(14)

Zn, AcOH

25 °C, 24 h

63%

Reduction of Aryl Substituents.

Although, as mentioned

above, many potentially labile functionalities are stable to

A list of General Abbreviations appears on the front Endpapers

ZINC–ACETIC ACID

3

Zn/AcOH, aryl iodides may be dehalogenated.

43

Substitution of

Cl or Br at the 2-position of heteroaromatics also renders them
liable to reduction, often with superb selectivity (eqs 15 and 16).

44

N

Cl

Cl

N

Cl

Zn, AcOH, H

2

O

(15)

70 °C, 6 h

90%

S

Br

Br

Br

S

Br

Zn, AcOH, H

2

O

(16)

reflux, 4 h

89%

Related Reagents. Iron; Tin; Zinc Amalgam; Zinc–Zinc

Chloride.

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Peter Ham

SmithKline Beecham Pharmaceuticals, Harlow, UK

Avoid Skin Contact with All Reagents