ZINC BOROHYDRIDE

1

Zinc Borohydride

1

Zn(BH

4

)

2

[17611-70-0]

B

2

H

8

Zn

(MW 95.09)

InChI = 1/2BH4.Zn/h2*1H4;/q2*-1;+2
InChIKey = PTJGRTOJBSRNJP-UHFFFAOYAM

(mild reducing agent for carbonyl groups;

1

can be used in the

presence of base-sensitive functional groups; stereoselective

reducing agent

2

)

Solubility:

sol ether, DMF, CH

2

Cl

2

, toluene, THF.

Preparative Method:

commercially available anhydrous Zinc

Chloride (ca. 10 g) in a 200 mL flask was fused three or
four times under reduced pressure and then anhydrous ether
(ca. 100 mL) was added. The mixture was refluxed for 1–2 h
under argon and allowed to stand at 23

◦

C. The supernatant sat.

solution of ZnCl

2

(0.69 M) in ether (80 mL; 55 mmol) was

added to a stirred suspension of Sodium Borohydride (4 g;
106 mmol) in anhydrous ether (300 mL). The mixture was
stirred for 2 d and stored at rt under argon. The supernatant
solution was used for reduction.

3

Handling, Storage, and Precautions:

the solutions are sensitive

to moisture and must be flushed with N

2

or argon. However, it

is preferable to use freshly prepared reagent.

Mild Reducing Agent. Zn(BH

4

)

2

is a mild reducing agent

and only aldehydes, ketones, and azomethines

4

are reduced to

the corresponding alcohols and amines under normal condi-
tions. Moreover, the ether solutions are almost neutral and thus
can be used for the chemoselective reduction of aldehydes and
ketones in the presence of nitrile,

5

ester,

5,6

γ

-lactone,

7

aliphatic

nitro,

8

and base-sensitive functional groups (eqs 1 and 2).

5,9

Selective reduction of saturated ketones and conjugated aldehy-
des over conjugated enones can also be effected with Zn(BH

4

)

2

in DME (eq 3).

10

NHCHO

AcO

CN

C

5

H

11

O

Zn(BH

4

)

2

NHCHO

AcO

CN

C

5

H

11

OH

6

6

(1)

a mixture of epimeric alcohols

diglyme

25 °C

O

OCO

2

CH

2

CCl

3

O

O

O

Zn(BH

4

)

2

OH

OCO

2

CH

2

CCl

3

O

O

O

(2)

ether, rt

73%

(3)

O

O

O

OH

100% selectivity

Zn(BH

4

)

2

DME, –78 °C

Although Zn(BH

4

)

2

is usually unreactive towards carboxylic

acids and esters, activated esters (eq 4)

11

and thiol esters (eq 5)

12

undergo reduction, giving alcohols. Even carboxylic acids can
be reduced to alcohols with this reagent in the presence of
Trifluoroacetic Anhydride (TFAA) (eq 6)

13

and acid chlorides

undergo reduction by the addition of N,N,N

′

,N

′

-Tetramethyl-

ethylenediamine (eq 7).

14

Acetals are reductively cleaved to

ethers when Chlorotrimethylsilane is added (eq 8).

15

MeO

O

O

CO

2

H

O

Ar

O

HO

1. Im

2

CO

(4)

2. Zn(BH

4

)

2

DME, –20 °C
>45%

COSPh

Zn(BH

4

)

2

OH

(5)

ether, rt

99%

OH

O

( )

16

OH

1 equiv Zn(BH

4

)

2

( )

16

(6)

1 equiv TFAA

DME

92%

1 equiv Zn(BH

4

)

2

(7)

O

Cl

OH

1 equiv TMEDA

ether, 0 °C

93%

O

O

O

OH

( )

7

0.5 equiv Zn(BH

4

)

2

(8)

( )

8

( )

2

1.2 equiv TMSCl

ether, rt

97%

Reduction of aliphatic carboxylic esters takes place under

ultrasonic activation to give alcohols.

16

The reducing ability of

this system is enhanced by the addition of a catalytic amount
of N,N-dimethylaniline and thus aromatic esters which are un-
affected under the normal conditions undergo reduction (eqs 9
and 10).

16

O

O

CO

2

Me

Zn(BH

4

)

2

O

O

OH

(9)

sonication

DME

100%

CO

2

Me

Zn(BH

4

)

2

OH

(10)

sonication

DME

N,N

-dimethylaniline

100%

Unsymmetrical epoxides are reductively cleaved to the less

substituted alcohols by the use of silica gel-supported Zn(BH

4

)

2

(eq 11).

17,18

The same reagent is effective for regioselective

1,2-reduction of conjugated ketones and aldehydes to give
allylic alcohols (eq 12).

19

Zn(BH

4

)

2

supported on cross-linked

Poly(4-vinylpyridine) (XP4) reduces aldehydes in the presence
of ketones with high chemoselectivity (eqs 13 and 14).

20

This

Avoid Skin Contact with All Reagents

2

ZINC BOROHYDRIDE

polymer-supported reagent can be stored at rt without appre-
ciable change in its reactivity.

O

OH

OH

+

Zn(BH

4

)

2

/SiO

2

cis

:trans = 90:10

(11)

THF, rt

85%

(12)

O

OH

Zn(BH

4

)

2

/SiO

2

THF

–5 to –10 °C

80%

(13)

Zn(BH

4

)

2

/XP

4

O

OH

EtOH

80%

(14)

Zn(BH

4

)

2

/XP

4

O

OH

EtOH

0%

Tertiary and benzylic halides are reductively dehalogenated

with Zn(BH

4

)

2

(eq 15).

21

This process has been applied for the

selective reduction of the distant double bond(s) in geranyl farne-
syl and geranyl geranyl derivatives.

22

(15)

Br

Br

Br

Zn(BH

4

)

2

ether, rt

81%

Stereoselective Reductions. syn-α-Methyl-β-hydroxy esters

or their equivalents which repeatedly appear in the framework
of polyoxomacrolide antibiotics are synthesized stereoselectively
by the reduction of the corresponding α-methyl-β-keto esters

23,24

or α-methyl-β-hydroxy ketones

25

with Zn(BH

4

)

2

in ether. Excel-

lent selectivities are obtained when the carbonyl group is con-
jugated with phenyl or vinyl groups (eq 16)

23

–

25

or the esters

in α-methyl-β-keto esters are replaced by the amides (eq 17).

26

Ketones having a phosphine oxide group in place of esters or
amides produce syn products by the Zn(BH

4

)

2

reduction, while

reduction with Lithium Triethylborohydride gives the anti isomer
stereoselectively (eq 18).

27

The syn-directing reduction is pre-

sumed to proceed through a metal-mediated cyclic transition state
and thus the use of a complex hydride like Zn(BH

4

)

2

, whose metal

possesses a high coordinating ability, is advantageous for
producing excellent selectivity.

OBn

O

O

Zn(BH

4

)

2

OBn

OH

O

(16)

syn

:anti = >99:1

ether

0 °C
85%

NHPh

O

O

Zn(BH

4

)

2

NHPh

OH

O

(17)

syn

:anti = 98:2

ether

–78 °C

99%

P

O

O

O

O

P

O

OH

O

O

O

O

(18)

syn

:anti = 98:<2

Zn(BH

4

)

2

ether

–78 °C

95%

Acylation of chiral N-propionyloxazolidinones gives chiral α-

methyl-β-keto imides, whose Zn(BH

4

)

2

reduction affords opti-

cally active syn-α-methyl-β-hydroxy derivatives with virtually
complete stereoselectivity (eq 19).

28,29

In the same way, chiral

carboxamides (eq 20)

30

and (R)-N-acylsultams (eq 21)

31

also

afford chiral syn products with high selectivities.

N

O

O

O

N

O

O

O

O

N

O

O

O

OH

1. LDA

*

(19)

Zn(BH

4

)

2

2. EtCOCl

CH

2

Cl

2

–Et

2

O

0 °C

>95%

N

O

O

OMOM

OMOM

Zn(BH

4

)

2

N

OH

O

OMOM

OMOM

syn

:anti = 99:1

(20)

*

96%

S
O

2

N

Ph

O

O

Zn(BH

4

)

2

S
O

2

N

Ph

O

OH

syn

:anti = 99.1:0.9

(21)

*

ether

–10 °C

82%

Selectivity of Zn(BH

4

)

2

reductions of β-hydroxy.

32,33

or N-

aryl-β-amino

34

ketones lacking α-substituents is generally unsat-

isfactory. A case where an excellent result is obtained is shown
in eq 22.

32

For the stereoselective preparation of syn- and anti-

1,3-diols the use of other reagents is recommended.

35

However,

in the reduction of β-keto esters, with chiral ester units, the syn
selectivity is improved significantly (eq 23).

36

Reduction of the

same keto ester with DIBAL-BHT (Diisobutylaluminum 2,6-
Di-tert-butyl-4-methylphenoxide) affords the diastereomer with
high selectivity (eq 24).

36

A list of General Abbreviations appears on the front Endpapers

ZINC BOROHYDRIDE

3

CO

2

Me

OH

O

Zn(BH

4

)

2

CO

2

Me

OH

OH

syn

:anti = 91:9

(22)

ether

–20 °C

69%

O

Ar

R

O

O

ZnCl

2

Zn(BH

4

)

2

toluene

–78 °C

94%

O

Ar

R

OH

O

Ar =

*

syn

:anti = 92:8

(23)

, R = (CH

2

)

2

CH=CHMe

2

O

Ar

R

O

O

O

Ar

R

OH

O

DIBAL-BHT

Ar =

*

syn

:anti = 4:96

(24)

, R = (CH

2

)

2

CH=CHMe

2

toluene

–78 °C

82%

Zn(BH

4

)

2

reduction of α-hydroxy ketones gives anti products

predominantly over syn products. The selectivity is dependent on
the substitution pattern of the α-hydroxy ketones. When R

1

is

phenyl or R

2

is a sterically demanding group, anti selectivity is

excellent (eq 25).

37

This is reasonably explained by considering

a zinc-chelated five-membered transition state.

1,37

Other highly

selective examples of Zn(BH

4

)

2

reductions

38

–

42

of α-hydroxy

ketones are shown in eqs 26 and 27.

38,41

R

1

R

2

OH

O

R

1

R

2

OH

OH

R

1

R

2

OH

OH

+

(25)

R

1

= Ph, R

2

= Me

R

1

= Pr, R

2

= i-Pr

98:2
96:4

anti

syn

Zn(BH

4

)

2

ether
0 °C

OBn

O

R

Zn(BH

4

)

2

OBn

OH

R

(26)

R = (CH

2

)

2

OTHP

anti

:syn = 95:5

ether

–30 °C

OH

O

Bu

Zn(BH

4

)

2

OH

OH

Bu

(27)

anti

:syn = 98.5:1.5

ether

–50 °C

90%

In the cases where two functional groups are present on the α-

or β-position of the keto group, reduction proceeds through the
more stable transition state. When alkoxy and alkylthio functions
are present on the α-position of the keto group, Zn(BH

4

)

2

coor-

dinates preferentially with the former (eq 28).

43

Reduction of a

ketone having two alkoxy groups on the α- and β-positions pro-
duces the anti-2-alkoxy alcohol almost exclusively, showing that
a five-membered transition state involving the α-alkoxy group is
contributing far more than six-membered one (eq 29).

44

There is

also a case where the three-dimensional structure of the ketone
governs the selection of the transition state (eq 30).

45

O

S

Et

O

Zn(BH

4

)

2

O

S

Et

OH

(28)

anti

:syn = 99:1

THF

–78 °C

>98%

BnO

R

MOMO

OMOM

O

Zn(BH

4

)

2

BnO

R

MOMO

OMOM

OH

1

2

R = p-MeOC

6

H

4

(29)

1,2-anti:1,2-syn = >99:1

91%

O

CO

2

Me

O

MeO

S

S

Zn(BH

4

)

2

O

H

H

O

CO

2

Me

O

Zn

S

S

Me

O

H

H

O

O

CO

2

Me

Me

S

S

Zn

O

CO

2

Me

OH

MeO

S

S

α-OH:β-OH = 17:1

(30)

ether
–78 °C
100%

H

–

Optically active α-hydroxy imines are reduced with Zn(BH

4

)

2

to give anti-hydroxy amines (eq 31).

46

α

,β-Epoxy ketones pro-

duce anti-epoxy alcohols with high selectivity, irrespective of the
substitution pattern of the epoxide (eq 32).

47,48

The correspond-

ing aziridino ketones and imines are also reduced with Zn(BH

4

)

2

to the anti isomer with high selectivity (eqs 33 and 34).

49

Ph

OH

N

Me

Zn(BH

4

)

2

Ph

OH

HN

Me

(31)

Ephedrine

anti

:syn = 97:3

ether

–76 °C

>75%

(32)

anti

:syn = >99:1

O

O

O

OH

Zn(BH

4

)

2

ether

0 °C
86%

N
H

Ph

Ph

O

Zn(BH

4

)

2

N
H

Ph

Ph

OH

(33)

ether
100%

N

Ph

t

-Bu

NH

Zn(BH

4

)

2

N

Ph

t

-Bu

NH

2

(34)

ether

100%

Avoid Skin Contact with All Reagents

4

ZINC BOROHYDRIDE

1.

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2.

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Takeshi Oishi

Meiji College of Pharmacy, Tokyo, Japan

Tadashi Nakata

The Institute of Physical and Chemical Research (RIKEN),

Saitama, Japan

A list of General Abbreviations appears on the front Endpapers