ZINC BOROHYDRIDE

Zinc Borohydride1

OH
Zn(BH4)2

(3)

DME, 78 C

Zn(BH4)2

(MW 95.09)
[17611-70-0]
B2 H8 Zn
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 agent2 )
Solubility: sol ether, DMF, CH2 Cl2 , 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 12 h
under argon and allowed to stand at 23 C. The supernatant sat.
solution of ZnCl2 (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 N2 or argon. However, it
is preferable to use freshly prepared reagent.

O
100% selectivity

Although Zn(BH4 )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 -Tetramethylethylenediamine (eq 7).14 Acetals are reductively cleaved to
ethers when Chlorotrimethylsilane is added (eq 8).15
CO2H

O
MeO
COSPh

NHCHO
6 CN

C5H11
AcO

6 CN

Zn(BH4)2

C5H11

diglyme
25 C

AcO

(1)

Ar

OH

(6)

( )16 OH

1 equiv Zn(BH4)2

(7)

1 equiv TMEDA
ether, 0 C
93%

OH

0.5 equiv Zn(BH4)2

(5)

ether, rt
99%

1 equiv TFAA
DME
92%

( )7

Zn(BH4)2

( )16 OH

(4)

2. Zn(BH4)2
DME, 20 C
>45%

1 equiv Zn(BH4)2

Cl

NHCHO

HO
1. Im2CO

Mild Reducing Agent. Zn(BH4 )2 is a mild reducing agent

and only aldehydes, ketones, and azomethines4 are reduced to
the corresponding alcohols and amines under normal conditions. 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 -lactone,7 aliphatic
nitro,8 and base-sensitive functional groups (eqs 1 and 2).5,9
Selective reduction of saturated ketones and conjugated aldehydes over conjugated enones can also be effected with Zn(BH4 )2
in DME (eq 3).10

O
OH
( )8 ( )2

1.2 equiv TMSCl

ether, rt
97%

(8)

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 unaffected under the normal conditions undergo reduction (eqs 9
and 10).16
O

CO2Me

OH

Zn(BH4)2
sonication
DME
100%

O
OH

(9)

a mixture of epimeric alcohols

O

CO2Me
O

Zn(BH4)2

OCO2CH2CCl3

ether, rt
73%

O
O

O
OCO2CH2CCl3

OH

(2)

Zn(BH4)2
sonication
DME
N,N-dimethylaniline
100%

OH
(10)

Unsymmetrical epoxides are reductively cleaved to the less

substituted alcohols by the use of silica gel-supported Zn(BH4 )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(BH4 )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

ZINC BOROHYDRIDE

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

P
O

Zn(BH4)2/SiO2

THF, rt
85%

(11)

Zn(BH4)2

ether
78 C
95%

OH

OH

cis:trans = 90:10

P
O

OH
Zn(BH4)2/SiO2

(12)

THF
5 to 10 C
80%

OH

Zn(BH4)2/XP4

(13)

EtOH
80%

OH

Zn(BH4)2/XP4

(14)

EtOH
0%

Br

ether, rt
81%

Br

Acylation of chiral N-propionyloxazolidinones gives chiral methyl--keto imides, whose Zn(BH4 )2 reduction affords optically active syn--methyl--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.

Zn(BH4)2

1. LDA

2. EtCOCl

CH2Cl2Et2O
0 C
>95%

O
Zn(BH4)2

(15)
O

Zn(BH4)2

OBn (16)

ether
0 C
85%

OH

syn:anti = >99:1

NHPh
O

Zn(BH4)2
ether
78 C
99%

NHPh
OH

syn:anti = 98:2
A list of General Abbreviations appears on the front Endpapers

(17)

OMOM

OMOM
Zn(BH4)2

*
O

OH O
OMOM
syn:anti = 99:1

OMOM

Ph
N
S
O2

(20)

96%

(19)

OH

Stereoselective Reductions. syn--Methyl--hydroxy esters

or their equivalents which repeatedly appear in the framework
of polyoxomacrolide antibiotics are synthesized stereoselectively
by the reduction of the corresponding -methyl--keto esters23,24
or -methyl--hydroxy ketones25 with Zn(BH4 )2 in ether. Excellent selectivities are obtained when the carbonyl group is conjugated with phenyl or vinyl groups (eq 16)2325 or the esters
in -methyl--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(BH4 )2 reduction, while
reduction with Lithium Triethylborohydride gives the anti isomer
stereoselectively (eq 18).27 The syn-directing reduction is presumed to proceed through a metal-mediated cyclic transition state
and thus the use of a complex hydride like Zn(BH4 )2 , whose metal
possesses a high coordinating ability, is advantageous for
producing excellent selectivity.
OBn

(18)

OH
syn:anti = 98:<2

Tertiary and benzylic halides are reductively dehalogenated

with Zn(BH4 )2 (eq 15).21 This process has been applied for the
selective reduction of the distant double bond(s) in geranyl farnesyl and geranyl geranyl derivatives.22
Br

Ph
Zn(BH4)2

ether
10 C
82%

N
S
O2

OH

(21)

syn:anti = 99.1:0.9

Selectivity of Zn(BH4 )2 reductions of -hydroxy.32,33 or Naryl--amino34 ketones lacking -substituents is generally unsatisfactory. A case where an excellent result is obtained is shown
in eq 22.32 For the stereoselective preparation of syn- and anti1,3-diols the use of other reagents is recommended.35 However,
in the reduction of -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 2,6Di-tert-butyl-4-methylphenoxide) affords the diastereomer with
high selectivity (eq 24).36

ZINC BOROHYDRIDE
OH

Zn(BH4)2

CO2Me

ether
20 C
69%

OH

OH
CO2Me (22)

ketone having two alkoxy groups on the - and -positions produces the anti-2-alkoxy alcohol almost exclusively, showing that
a five-membered transition state involving the -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

syn:anti = 91:9

Et
S
O

ZnCl2

O
Ar

R
O

Ar =

O
Ar

Zn(BH4)2
toluene
78 C
94%

OH

syn:anti = 92:8

BnO
MOMO

O
Ar

toluene
78 C
82%

OH

(29)

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

CO2Me

MeO OH
O
CO2Me

Zn(BH4)2

(30)

ether
78 C
100%

syn:anti = 4:96

2
BnO
MOMO
OH

91%

* R (24)

anti:syn = 99:1
OMOM

R = p-MeOC6H4

DIBAL-BHT

(28)
OH

Zn(BH4)2

MeO O
O

Et

S
O

THF
78 C
>98%

OMOM

, R = (CH2)2CH=CHMe2

O
Ar

Zn(BH4)2

* R (23)
O

-OH:-OH = 17:1
, R = (CH2)2CH=CHMe2

Ar =

Zn(BH4 )2 reduction of -hydroxy ketones gives anti products

predominantly over syn products. The selectivity is dependent on
the substitution pattern of the -hydroxy ketones. When R1 is
phenyl or R2 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(BH4 )2 reductions3842 of -hydroxy
ketones are shown in eqs 26 and 27.38,41
OH
R1

R2
O

Zn(BH4)2

OH
R1

ether
0 C

OH

R2

+ R1

OH
anti

R = (CH2)2OTHP
O

Bu

OH

ether
50 C
90%

H
S H
O
Zn
Me

Me

OH
Zn(BH4)2

Ph
N

ether
76 C
>75%

Me

(31)

Ph
HN

Me

Ephedrine
anti:syn = 97:3
(26)

OBn

Zn(BH4)2

anti:syn = 95:5
Zn(BH4)2

H
S H

OH

Zn(BH4)2
ether
30 C

CO2Me

CO2Me

OH

98:2
96:4

R1 = Pr, R2 = i-Pr

OBn

(25)

Optically active -hydroxy imines are reduced with Zn(BH4 )2

to give anti-hydroxy amines (eq 31).46 ,-Epoxy ketones produce anti-epoxy alcohols with high selectivity, irrespective of the
substitution pattern of the epoxide (eq 32).47,48 The corresponding aziridino ketones and imines are also reduced with Zn(BH4 )2
to the anti isomer with high selectivity (eqs 33 and 34).49

OH
syn

R1 = Ph, R2 = Me

R2

Zn O
O

OH

ether
0 C
86%

Bu

(32)
O

OH

anti:syn = >99:1

(27)
OH
anti:syn = 98.5:1.5

In the cases where two functional groups are present on the or -position of the keto group, reduction proceeds through the
more stable transition state. When alkoxy and alkylthio functions
are present on the -position of the keto group, Zn(BH4 )2 coordinates preferentially with the former (eq 28).43 Reduction of a

Ph

Ph
N
H

Ph
N
NH
t-Bu

Zn(BH4)2
ether
100%

Zn(BH4)2
ether
100%

Ph

Ph
N
H

(33)

OH

Ph
N
NH2
t-Bu

(34)

Avoid Skin Contact with All Reagents

4
1.
2.
3.

4.
5.
6.

7.
8.
9.

10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.

ZINC BOROHYDRIDE
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Takeshi Oishi
Meiji College of Pharmacy, Tokyo, Japan
Tadashi Nakata
The Institute of Physical and Chemical Research (RIKEN),
Saitama, Japan