ZINC BOROHYDRIDE 1
O
OH
Zinc Borohydride1
Zn(BH4)2
(3)
DME,  78 °C
O
O
Zn(BH4)2
100% selectivity
[17611-70-0] B2H8Zn (MW 95.09)
Although Zn(BH4)2 is usually unreactive towards carboxylic
InChI = 1/2BH4.Zn/h2*1H4;/q2*-1;+2
acids and esters, activated esters (eq 4)11 and thiol esters (eq 5)12
InChIKey = PTJGRTOJBSRNJP-UHFFFAOYAM
undergo reduction, giving alcohols. Even carboxylic acids can
be reduced to alcohols with this reagent in the presence of
(mild reducing agent for carbonyl groups;1 can be used in the
Trifluoroacetic Anhydride (TFAA) (eq 6)13 and acid chlorides
presence of base-sensitive functional groups; stereoselective
undergo reduction by the addition of N,N,N ,N -Tetramethyl-
reducing agent2)
ethylenediamine (eq 7).14 Acetals are reductively cleaved to
ethers when Chlorotrimethylsilane is added (eq 8).15
Solubility: sol ether, DMF, CH2Cl2, toluene, THF.
CO2H
Preparative Method: commercially available anhydrous Zinc
HO
Chloride (ca. 10 g) in a 200 mL flask was fused three or
1. Im2CO
O (4)
four times under reduced pressure and then anhydrous ether
2. Zn(BH4)2
O
O
DME,  20 °C
(ca. 100 mL) was added. The mixture was refluxed for 1 2 h
O
>45%
ć%
Ar
MeO
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
Zn(BH4)2
added to a stirred suspension of Sodium Borohydride (4 g;
COSPh (5)
ether, rt
106 mmol) in anhydrous ether (300 mL). The mixture was OH
99%
stirred for 2 d and stored at rt under argon. The supernatant
O 1 equiv Zn(BH4)2
solution was used for reduction.3
(6)
( )16 OH
Handling, Storage, and Precautions: the solutions are sensitive
1 equiv TFAA
( )16 OH
DME
to moisture and must be flushed with N2 or argon. However, it
92%
is preferable to use freshly prepared reagent.
O
1 equiv Zn(BH4)2
(7)
1 equiv TMEDA
Cl OH
ether, 0 °C
93%
Mild Reducing Agent. Zn(BH4)2 is a mild reducing agent
and only aldehydes, ketones, and azomethines4 are reduced to
O
0.5 equiv Zn(BH4)2
O OH
the corresponding alcohols and amines under normal condi-
( )8 ( )2 (8)
1.2 equiv TMSCl
O
( )7
tions. Moreover, the ether solutions are almost neutral and thus
ether, rt
can be used for the chemoselective reduction of aldehydes and 97%
ketones in the presence of nitrile,5 ester,5,6 Å‚-lactone,7 aliphatic
nitro,8 and base-sensitive functional groups (eqs 1 and 2).5,9 Reduction of aliphatic carboxylic esters takes place under
ultrasonic activation to give alcohols.16 The reducing ability of
Selective reduction of saturated ketones and conjugated aldehy-
des over conjugated enones can also be effected with Zn(BH4)2 this system is enhanced by the addition of a catalytic amount
of N,N-dimethylaniline and thus aromatic esters which are un-
in DME (eq 3).10
affected under the normal conditions undergo reduction (eqs 9
and 10).16
NHCHO
NHCHO
CN CN
6 Zn(BH4)2 6
O O O O
Zn(BH4)2
(1)
(9)
C5H11 diglyme C5H11 CO2Me
OH
sonication
25 °C
DME
AcO AcO
O OH
100%
a mixture of epimeric alcohols
OH
Zn(BH4)2
(10)
CO2Me
sonication
O
O
DME
O N,N-dimethylaniline
Zn(BH4)2
OCO2CH2CCl3 100%
ether, rt
73%
Unsymmetrical epoxides are reductively cleaved to the less
O
substituted alcohols by the use of silica gel-supported Zn(BH4)2
O
O
(eq 11).17,18 The same reagent is effective for regioselective
O
1,2-reduction of conjugated ketones and aldehydes to give
OCO2CH2CCl3 (2)
allylic alcohols (eq 12).19 Zn(BH4)2 supported on cross-linked
Poly(4-vinylpyridine) (XP4) reduces aldehydes in the presence
OH
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.
Zn(BH4)2
O
P
ether
O
O
Zn(BH4)2/SiO2
 78 °C
+
O (11)
95%
THF, rt O
OH OH
85%
cis:trans = 90:10
O
O (18)
P
OOH O
O
O
Zn(BH4)2/SiO2
(12)
OH
THF
syn:anti = 98:<2
 5 to  10 °C
80%
OOH
Zn(BH4)2/XP4 Acylation of chiral N-propionyloxazolidinones gives chiral Ä…-
(13)
methyl-²-keto imides, whose Zn(BH4)2 reduction affords opti-
EtOH
80%
cally active syn-Ä…-methyl-²-hydroxy derivatives with virtually
complete stereoselectivity (eq 19).28,29 In the same way, chiral
O OH
Zn(BH4)2/XP4
carboxamides (eq 20)30 and (R)-N-acylsultams (eq 21)31 also
(14)
EtOH afford chiral syn products with high selectivities.
0%
Tertiary and benzylic halides are reductively dehalogenated
with Zn(BH4)2 (eq 15).21 This process has been applied for the
Zn(BH4)2
1. LDA
O
selective reduction of the distant double bond(s) in geranyl farne-
2. EtCOCl O CH2Cl2 Et2O
N
N
0 °C
syl and geranyl geranyl derivatives.22 *
O O >95%
O O O
Br
Zn(BH4)2 Br
(15)
ether, rt
Br
81%
(19)
O
N
OH O O
Stereoselective Reductions. syn-Ä…-Methyl-²-hydroxy esters
or their equivalents which repeatedly appear in the framework
OMOM
of polyoxomacrolide antibiotics are synthesized stereoselectively OMOM
by the reduction of the corresponding Ä…-methyl-²-keto esters23,24
Zn(BH4)2
or Ä…-methyl-²-hydroxy ketones25 with Zn(BH4)2 in ether. Excel-
(20)
N N
96%
*
lent selectivities are obtained when the carbonyl group is con-
jugated with phenyl or vinyl groups (eq 16)23 25 or the esters O O OH O
OMOM OMOM
in Ä…-methyl-²-keto esters are replaced by the amides (eq 17).26
syn:anti = 99:1
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
Ph
Ph
stereoselectively (eq 18).27 The syn-directing reduction is pre-
Zn(BH4)2
*
(21)
sumed to proceed through a metal-mediated cyclic transition state N O
ether N OH
S
O
and thus the use of a complex hydride like Zn(BH4)2, whose metal
 10 °C S
O
O2
82% O2
possesses a high coordinating ability, is advantageous for
producing excellent selectivity. syn:anti = 99.1:0.9
Zn(BH4)2
OBn
OBn (16)
Selectivity of Zn(BH4)2 reductions of ²-hydroxy.32,33 or N-
ether
O O 0 °C
OH O aryl-²-amino34 ketones lacking Ä…-substituents is generally unsat-
85%
isfactory. A case where an excellent result is obtained is shown
syn:anti = >99:1
in eq 22.32 For the stereoselective preparation of syn- and anti-
1,3-diols the use of other reagents is recommended.35 However,
Zn(BH4)2 in the reduction of ²-keto esters, with chiral ester units, the syn
NHPh NHPh
(17)
selectivity is improved significantly (eq 23).36 Reduction of the
ether
O O  78 °C OH O
same keto ester with DIBAL-BHT (Diisobutylaluminum 2,6-
99%
Di-tert-butyl-4-methylphenoxide) affords the diastereomer with
syn:anti = 98:2
high selectivity (eq 24).36
A list of General Abbreviations appears on the front Endpapers
ZINC BOROHYDRIDE 3
OH O
Zn(BH4)2
ketone having two alkoxy groups on the Ä…- and ²-positions pro-
CO2Me
ether
duces the anti-2-alkoxy alcohol almost exclusively, showing that
 20 °C
a five-membered transition state involving the Ä…-alkoxy group is
69%
OH OH
contributing far more than six-membered one (eq 29).44 There is
CO2Me (22)
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 Et
Zn(BH4)2
S
S
(28)
O
O THF
O
OH
 78 °C
ZnCl2
>98%
O
O
(23)
R
anti:syn = 99:1
* R
Zn(BH4)2
Ar
Ar
toluene
O
O
O
OH
OMOM
 78 °C OMOM
Zn(BH4)2
94%
1
(29)
syn:anti = 92:8
2
BnO R
BnO R
91%
MOMO OH
MOMO O
Ar = , R = (CH2)2CH=CHMe2
1,2-anti:1,2-syn = >99:1
R = p-MeOC6H4
O
MeO OH
MeO
O
O
CO2Me
CO2Me
DIBAL-BHT
Zn(BH4)2
O O
(24)
R R
* (30)
toluene
Ar Ar
ether
 78 °C
O O
O OH  78 °C
82%
S
100% S
S
S
syn:anti = 4:96
Ä…-OH:²-OH = 17:1
Ar = , R = (CH2)2CH=CHMe2
H
CO2Me
O
Zn
O S
Zn(BH4)2 reduction of Ä…-hydroxy ketones gives anti products
O
O
H
predominantly over syn products. The selectivity is dependent on S
S H O
CO2Me
Zn
H
Me
the substitution pattern of the Ä…-hydroxy ketones. When R1 is
S H O
Me
phenyl or R2 is a sterically demanding group, anti selectivity is
excellent (eq 25).37 This is reasonably explained by considering
Optically active Ä…-hydroxy imines are reduced with Zn(BH4)2
a zinc-chelated five-membered transition state.1,37 Other highly
to give anti-hydroxy amines (eq 31).46 Ä…,²-Epoxy ketones pro-
selective examples of Zn(BH4)2 reductions38 42 of Ä…-hydroxy
duce anti-epoxy alcohols with high selectivity, irrespective of the
ketones are shown in eqs 26 and 27.38,41
substitution pattern of the epoxide (eq 32).47,48 The correspond-
ing aziridino ketones and imines are also reduced with Zn(BH4)2
OH
OH OH
Zn(BH4)2
to the anti isomer with high selectivity (eqs 33 and 34).49
R1 R1
R1 +
R2
R2 R2 (25)
ether
0 °C
OH
O OH
OH OH
anti syn
Zn(BH4)2
(31)
Ph Ph
ether
R1 = Ph, R2 = Me 98:2
N HN
 76 °C
96:4
Me Me
R1 = Pr, R2 = i-Pr
>75%
Ephedrine
O
OH
anti:syn = 97:3
Zn(BH4)2
(26)
ether
R OBn
 30 °C
R OBn
Zn(BH4)2
(32)
ether
R = (CH2)2OTHP anti:syn = 95:5
O O
O OH
0 °C
86%
O Bu OH Bu
anti:syn = >99:1
Zn(BH4)2
(27)
ether
 50 °C
OH OH
Ph Zn(BH4)2 Ph
90%
Ph Ph
(33)
anti:syn = 98.5:1.5
ether
N N
O OH
100%
H H
In the cases where two functional groups are present on the Ä…-
or ²-position of the keto group, reduction proceeds through the
Ph Ph
Zn(BH4)2
more stable transition state. When alkoxy and alkylthio functions
(34)
N N
are present on the Ä…-position of the keto group, Zn(BH4)2 coor- ether
NH NH2
100%
t-Bu t-Bu
dinates preferentially with the former (eq 28).43 Reduction of a
Avoid Skin Contact with All Reagents
4 ZINC BOROHYDRIDE
1. Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic: London, 27. Elliott, J.; Warren, S., Tetrahedron Lett. 1986, 27, 645.
1988.
28. (a) Evans, A. D., Aldrichim. Acta 1982, 15, 23. (b) Evans, D. A.; Ennis,
2. Oishi, T.; Nakata, T., Acc. Chem. Res. 1984, 17, 338. M.; Le, T., J. Am. Chem. Soc. 1984, 106, 1154.
3. (a) Gensler, W. J.; Johnson, F.; Sloan, A. D., J. Am. Chem. Soc. 1960, 82, 29. Dipardo, R. M.; Bock, M., Tetrahedron Lett. 1983, 24, 4805.
6074. (b) Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T., Chem. Pharm.
30. Ito, Y.; Katsuki, T.; Yamaguchi, M., Tetrahedron Lett. 1984, 25,
Bull. 1984, 32, 1141. (c) Crabbe, P.; Garcia, G. A.; Rfus, C., J. Chem.
6015.
Soc., Perkin Trans. 1 1973, 810.
31. Oppolzer, W.; Rodriguez, I.; Starkemann, C.; Walther, E., Tetrahedron
4. Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M., Synthesis
Lett. 1990, 31, 5019.
1990, 401.
32. Kathawala, F. G.; Prager, B.; Prasad, K.; Repic, O.; Shapiro, M. J.;
5. Corey, E. J.; Andersen, N. H.; Carlson, R. M.; Paust, J.; Vedjs, E.; Vlattas,
Stabler, R. S.; Widler, L., Helv. Chim. Acta 1986, 69, 803.
I.; Winter, R. E. K., J. Am. Chem. Soc. 1968, 90, 3245.
33. Kashihara, H.; Suemune, H.; Fujimoto, K.; Sakai, K., Chem. Pharm.
6. (a) Guzman, A.; Crabbe, P., Chem. Lett. 1973, 1073. (b) Rozing, G. P.;
Bull. 1989, 37, 2610.
Moinat, T. J. H.; de Koning, H.; Huisman, H. O., Heteroatom Chem.
34. Pilli, R. A.; Russowsky, D.; Dias, L. C., J. Chem. Soc., Perkin Trans. 1
1976, 4, 719.
1990, 1213.
7. Crabbe, P.; Guzman, A.; Vera, M., Tetrahedron Lett. 1973, 3021.
35. Oishi, T.; Nakata, T., Synthesis 1990, 635.
8. Ranu, B. C.; Das, A. R., Tetrahedron Lett. 1992, 33, 2361.
36. Taber, D. F.; Deker, P. B.; Gaul, M. D., J. Am. Chem. Soc. 1987, 109,
9. (a) Naito, T.; Nakata, T.; Akita, H.; Oishi, T., Chem. Lett. 1980, 445.
7488.
(b) Sierra, M. G.; Olivieri, A. C.; Colombo, M. I.; Ruveda, E. A., J.
37. Nakata, T.; Tanaka, T.; Oishi, T., Tetrahedron Lett. 1983, 24, 2653.
Chem. Soc. (C) 1985, 1045.
38. Takahashi, T.; Miyazawa, M.; Tsuji, J., Tetrahedron Lett. 1985, 26,
10. Sarkar, D. C.; Das, A. R.; Ranu, B. C., J. Org. Chem. 1990, 55,
5139.
5799.
39. Jarosz, S., Chem. Rev. 1988, 183, 201.
11. Yamada, K.; Kato, M.; Hirata, Y., Tetrahedron Lett. 1973, 29, 2745.
40. Pikul, S.; Raczko, J.; Ankner, K.; Jurczak, J., J. Am. Chem. Soc. 1987,
12. Kotsuki, H.; Yoshimura, N.; Ushio, Y., Chem. Lett. 1986, 1003.
109, 3981.
13. Ranu, B. C.; Das, A. R., J. Chem. Soc., Perkin Trans. 1 1992, 1561.
41. Fujisawa, T.; Kohama, H.; Tajima, K.; Sato, T., Tetrahedron Lett. 1984,
14. Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M., Bull. Chem. Soc. Jpn.
25, 5155.
1988, 61, 2684.
42. Sayo, N.; Nakai, E.; Nakai, T., Chem. Lett. 1985, 1723.
15. Kotsuki, H.; Ushio, Y.; Yoshimura, N.; Ochi, M., J. Org. Chem. 1987,
43. Matsubara, S.; Takahashi, H.; Utimoto, K., Chem. Lett. 1992, 2173.
52, 2594.
44. Iida, H.; Yamazaki, N.; Kibayashi, C., J. Org. Chem. 1986, 51,
16. Ranu, B. C.; Basu, M. K., Tetrahedron Lett. 1991, 32, 3243.
1069.
17. Ranu, B. C.; Das, A. R., J. Chem. Soc., Chem. Commun. 1990, 1334.
45. Nakata, T.; Nagao, S.; Oishi, T., Tetrahedron Lett. 1985, 26, 6465.
18. Ranu, B. C.; Das, A. R., J. Chem. Soc., Perkin Trans. 1 1992, 1881.
46. Jackson, W. R.; Jacobs, H. A.; Matthews, B. R.; Jayatilake, G. S.; Watson,
19. Ranu, B. C.; Das, A. R., J. Org. Chem. 1991, 56, 4796.
K. G., Tetrahedron Lett. 1990, 31, 1447.
20. Firouzabadi, H.; Tamami, B.; Goudarzian, N., Synth. Commun. 1991,
47. Nakata, T.; Tanaka, T.; Oishi, T., Tetrahedron Lett. 1981, 22, 4723.
21, 2275.
48. Banfi, S.; Colonna, S.; Molinari, H.; Julia, S., Synth. Commun. 1983, 13,
21. Kim S.; Hong C. Y.; Yang, S., Angew. Chem., Int. Ed. Engl. 1983, 22,
901.
562.
49. Bartnik, R.; Laurent, A.; Lesniak, S., J. Chem. Res. (S) 1982, 287.
22. Julia, M.; Roy, P., Tetrahedron 1986, 42, 4991.
23. Nakata, T.; Oishi, T., Tetrahedron Lett. 1980, 21, 1641.
Takeshi Oishi
24. Nakata, T.; Kuwabara, T.; Tani, Y.; Oishi, T., Tetrahedron Lett. 1982, 23,
Meiji College of Pharmacy, Tokyo, Japan
1015.
25. Nakata, T.; Tani, Y.; Hatozaki, M.; Oishi, T., Chem. Pharm. Bull. 1984, Tadashi Nakata
32, 1411.
The Institute of Physical and Chemical Research (RIKEN),
26. Ito, Y.; Yamaguchi, M., Tetrahedron Lett. 1983, 24, 5385.
Saitama, Japan
A list of General Abbreviations appears on the front Endpapers