VenPure

NaBH
4
for Ester Reductions
Enhancing Borohydrides Reductive Strength

Introduction:
Sodium borohydride is a water soluble reducing agent
exhibiting unique properties in organic synthesis. It is
established as the default reducing agent for aldehydes,
ketones, acid chlorides and anhydrides. Over the past 40
years, significant progress has been made to fine-tune
borohydrides chemoselectivity to make it either more
selective, or a stronger reductant. Hence, the Reductive
Strength of NaBH
4
could be increased to have it reduce
acid, ester, halide, amide, lacton and lactam functions.
Some of these reductions occur by virtue of the in-situ
generation of boranes from sodium borohydride.

Especially in the last 20 years, sodium borohydride has
become established as the reductant of choice in the large
scale synthesis of active ingredient in applications beyond
aldehyde/ketone reductions. Also its use as a reductant
with good diastereo-selectivity has become more and more
established, e.g. in the ketone reduction of the Statins
(Atorvastatin, Fluvastatin).

This data sheet focuses on enhancing borohydrides
reductive potential so that it may reduce esters. The
following systems are discussed :
1. neat borohydride ester reductions
2. assistance from Lewis acids
3. assistance from protic solvents

For reasons of confidentiality, public information only is
discussed. Reaction schemes are often amenable to
optimization for a higher-efficiency use of NaBH
4
.

For technical information regarding reductions other than
esters, please do not hesitate to contact Rohm and Haas.

Typical Properties
Mol. weight: 37.85
Form: White crystalline solid
Melting point: Decomposes above 400
o
C without melting
A comprehensive overview of the physical and chemical
properties of sodium borohydride can be found in Rohm
and Haas Companys Sodium Borohydride Digest.


Benefits of NaBH
4
for Reductive Chemistry :
Of the commercially available metal hydrides used for
synthetic organic reductions,, NaBH
4
enjoys the largest
industrial use, with a estimated (equivalent) market share
greater than 50%. Some of the benefits of using
borohydride chemistry :
the least expensive metal hydride commercially
available (on a hydride equivalent basis)
safe with regards to storage and use & handling
industrial implementation requires no or limited
equipment investment
ease of work-up (water soluble boron salts)
ubiquitous solvents such as water and methanol are
typically employed
unique and versatile as a hydride reducing agent for
both chemo- and diastereo-selectivity

Product Stewardship
Rohm and Haas offers metal hydride products as part of a
comprehensive Product & Services package, including :
the highest product quality
the broadest range of product grades
formulations stable under various transport conditions
the availability of a choice of package sizes
safety audits and training
technical advice with regards to both the safe handling
and the cost-efficient synthetic use

Availability
With its 50+years of manufacturing experience, Rohm and
Haas Company is unique as a borohydride supplier by
offering the most complete range of products :
- VenPure SF Powder
- VenPure AF granules, VenPure SF granules
- VenPure AF caplets
- VenPure solution, VenPure 20/20 solution
- VenPure Potassium Borohydride
- Organic NaBH
4
solutions available upon request

All products are available in an ample choice of packages,
such as metal pails and drums, mini-bulk containers, and
tank trucks or railway cars for bulk quantities.

Please feel free to contact us via hydride@rohmhaas.com
Updated information can be found at : http://www.hydridesolutions.com/
Find your local Rohm and Haas Representative : http://www.hydridesolutions.com/contact.html
1. Ester Reductions with Neat NaBH
4

A. High Temperature NaBH
4
Reductions
1
At room temperature, NaBH
4
without solvent or cationic
assistance is not capable of reducing esters. However, at
elevated temperatures, it can reduce ester groups in high
yields. At those temperatures, protic solvents cannot be
used, because the NaBH
4
decomposition would be swift.
Solvents like glymes are a valuable alternative.

OR
O X
OH X
NaBH
4
Diglyme
162
o
C


Whereas academic research typically uses mono- or di-
glyme solvents, we recommend to use tri- or tetra-glyme
for large-scale applications, because of their better
toxicological and solubility profile.

Please contact Rohm and Haas if you are interested in
purchasing NaBH
4
glyme solution (8% in Triglyme)

B. Neighboring Group Participation
2
Sodium borohydride can reduce hydroxy-esters in non-
polar solvents such as toluene in high yields. It is believed
that the hydroxy-function enhances borohydrides
reductive strength in much the same way as water or
methanol do as a solvent (see hereunder)

EtO
O
Cl
HO
1) 1NaBH
4
, Toluene, 55
o
C 3 h
2) 10
o
C, 1 mole Con HCl/water
Yield 92 %
HO
Cl
HO


This methodology has proven to be economically viable in
the synthesis of intermediates for both Pharmaceutical and
Agrochemical Active Ingredients.

E.g. in the synthesis of Lipoic acid, a vic-diol has to be
obtained in the presence of an ester function. This can be
achieved by the selective reduction of an hydroxy-ester to
the corresponding diol. The reaction proceeds by using 1
equivalent of NaBH
4
in THF, and results in less than 10%
of the over-reduction
3
. It should be noted that in
experiments where the hydroxy group was protected, no
ester reduction was observed.

MeO
O OH
OMe
O
H
OH OH
OMe
O NaBH
4
, THF
Reflux, 6h
H


Factors affecting the yields and reaction products include
solvent used, excess of sodium borohydride Used and
length of chain
4
.
I
n a recent patent it was described that the
solvent-free route affords yields up to 90 %
5
.



C. Esters to 2 Alcohols
6
An ester is the retro-synthetical synthon of the
corresponding primary alcohol. Recently it has been
demonstrated that esters can be converted into secondary
alcohols in a one-pot two-step synthesis. Following a
Grignard addition to an ester, the intermediate is
subsequently reduced by zinc borohydride


R O
R'
O
R R"
OH
THF, RT
0.25 Zn(BH
4
)
2
+4 R"MgBr
R"=Alkyl, Cyclic, Aryl, Allylic
R'=Me, Et
60-82 % yield


X R ratio time yield
Zn(BH
4
)
2
/ Substrate
H H 0.6 1h 82
Cl H 1 2h 87
Cl Me 0.6 1h 86
Cl i-Pr 0.6 2h 92
Cl t-Amyl 0.6 5h 95

Hallouis, S.; Saluzzo, C.; Amouroux, R. Synth. Commun. 2000, 30, 313


Zinc borohydride is often used in academic research for
chemo-selective reductions, such as the reduction of an
aldehyde in the presence of a ketone. Unfortunately,
Zn(BH
4
)
2
is not sufficiently stable to be commercialized
for large-scale usage. Therefore, it is recommended that it
be generated it in-house, from NaBH
4
and ZnCl
2
.

Feel free to contact Rohm and Haas Technical Support
Team for further details on in-situ generation of zinc
borohydride.
2. Assistance from Lewis Acids

The use of metal cations additives such as LiCl
7
, AlCl
3
8
,
ZnCl
2
9
and CaCl
2
10
to modify the reactivity of sodium
borohydride is well known. Examples of these systems are
shown below.

A. Sodium Borohydride and AlCl
3
8
H.C Brown and co-workers have demonstrated in the
1950s that the combination of aluminum trichloride with
sodium borohydride in tetrahydrofuran results in a
significant increase in Borohydrides Reductive Strength.
The combination NaBH
4
/ AlCl
3
is a cost-effective system
for the reduction of a myriad of functional groups. Esters
are reduced to alcohols in high yields under mild reaction
conditions.

B. Sodium Borohydride and ZrCl
4
11
More recently, zirconium borohydride has been recognized
as an economical reducing system for esters, even when
the Zr-salt cannot be recycled for re-use. Also Zr-
borohydride is a rather non-selective reducing system, that
will reduce a variety of functional groups.

R OR'
O
R OH
H H
0.125 [ZrCl
4
/ 4 NaBH
4
]
THF, 0-RT
2h


Yield (%)
Methyl 10-undeceneoate 93
Methyl Myristate 95
Methyl Laurate 90
Ethyl Benzoate 91
Dimethyl Brassylate 93
Dimethyl Terephthalate 92
Ethyl 2- Chlorobenozate 95
Methyl 4-Nitrobenzoate 95
Methyl 4-Hydroxybenzoate 96

Narasimhan, S.; Balakumar, R. Synth. Commun. 2000, 20, 4387


C. Ca(BH
4
)
2
: in-situ generation from NaBH
4
12
Calcium borohydride is a very cost-effective ester reducing
system, especially when methanol is the desired reaction
solvent. An example of this is the synthesis of a
intermediate for a anti-psychotic drug shown below.
13

N
O
Cl
O
O
N
O
Cl
OH 0.93 NaBH
4
, 1.23 CaCl
2
MeOH, Yield 92 %

Unfortunately, Ca-borohydride is not sufficiently stable to
be commercialized for large-scale usage. Therefore, we
recommend that it is generated in-house, from NaBH
4
and




CaCl
2
. Feel free to contact Rohm and Haas Technical
Support Team for further details.

D. LiBH
4
in THF : in-situ from NaBH
4
Lithium borohydride has two advantages over neat NaBH
4
:
1. it is soluble in THF (and glymes)
2. it reduces esters without any assistance

Lithium borohydride can be generated in-situ from sodium
borohydride and lithium chloride or bromide.
7
It is
typically used under reflux for the reduction of methyl
esters, however, for the more sterically hindered ethyl
ester, reduction can also proceed in acceptable yields

R O
R'
O
R O
H
LiBH
4
Et
2
O/toluene, reflux


Time(h) Yield
Ethyl caproate 0.25 86
Ethyl benzoate 1.0 90
Ethyl-p-chlorobenzoate 0.5 90
Ethyl-m-bromobenzoate 0.5 94
Ethyl-p-nitrobenzoate 0.25 70
Ethyl-p-methoxybenzoate 2.0 96
Diethyldimethylmalonate 0.25 83

Brown, H.C.; Narasimhan, S.; Choi, Y.M. J. Org. Chem. 1982, 47,
4702

Please contact Rohm and Haas Technical Support team
for recommendations on the in situ generation of LiBH
4
.

E. NaBH
4
with Li-salt Added as a Lewis Acid
The one pot reduction of ester groups using sodium
borohydride and lithium chloride in a polar aprotic
solvents is a popular methodology
14
..

However, it is worth noting that the one-pot chemistry
seems less kinetic than when LiBH
4
is generated in a
separate step, with subsequent removal of NaCl.

N
O
O
O
F
F
N
N
O
N
OH
OH
F
F
N
N
OH
2.1 NaBH
4
, 2.1 LiCl
EtOH, , 0 oC, 4h Yield 54 %
This hurdle may be overcome by using higher reaction
temperatures.
R
O
1 NaBH
4
, 1 LiCl
diglyme, 162
o
C
OH
H
H


R Time Yield
Me 5 85
i
Pr 5 83
t-Amyl 5 0




3. Assistance from Protic Solvents. 3. Assistance from Protic Solvents.

When sodium borohydride is dissolved in a protic solvent,
it will react with the solvent according to the equation
NaBH
4
+x HOR NaBH
x
(OR)
4-x
+x H
2

The resulting borohydride derivative, NaBH
x
(OR)
4-x
, is a
stronger reductant than neat NaBH
4
(this is due to
electron-donation from the oxygen ligands).

The art of using this technology resides in finding the
optimum reaction conditions that allow for the formation
of the strongly reducing borohydride derivative, without
loosing all of the hydrides to solvolysis. Indeed, if all 4
hydrides react with the protic solvent, then NaB(OR)
4
is
formed, which has ZERO reducing strength :
NaBH
4
+4 HOR NaB(OR)
4
+4 H
2

Methanol is by far the most efficient solvent in enhancing
borohydrides reductive strength. Water and ethanol are
second best, however, water is typically not a good solvent
for (longer chain) esters.
Ethanol would be a good solvent, however NaBH
4
only
dissolves up to 4% in it. If one wants to use e.g. a 10%
NaBH
4
dispersion in ethanol, then we recommend the use
of Rohm and Haas VenPure SF powder, which has a
small particle size (increased active surface).
The solubility of NaBH
4
in water and methanol is higher
than 15%. Hence, for making large quantities of a NaBH
4

solution in these 2 solvents, we recommend to use an
easier-to-handle, larger particle size, such as provided by
VenPure SF granules or VenPure AF caplets.
VenPure SF powder VenPure SF granules Venpure AF caplets

Hereunder are some examples of the use of protic solvents
for enhancing Borohydrides Reducing Strength.

A. Mixture : Water / Dioxane
15


R O
O
Me
R O
H
7-10 hydride eq NaBH
4

Water or Water/Dioxane,
RT, 2-24 h


Substrate Time(h) Yield
PhCO
2
Me 12 80
2-ClPhCO
2
Me 6 100
2-NO
2
PhCO
2
Me 2 100
2-MePhCO
2
Me 12 80
2-MeOPhCO
2
Me 24 60
Bianco, A.; Passacantilli, P.; Righi, G. Synth. Commun. 1988, 18, 1765

Mita, N.; Nagase, H.; Iizuka, H.; Oguchi, T.; Sakai, K.;
Horikomi, K.; Miwa, T.; Takahashi, S. EP 0839805; 1998

B. Mixture : an organic solvent / methanol
16









Solvent Temp Time Ratio Yield
(C) Sub /NaBH
4
%

THF/MeOH 65 1h 1 / 3.5 99
THF/MeOH 68 2.5 1 / 1.8 95
Spirits/MeOH 0 22h 1 / 1.79 100
THF/
i
PrOH 50 6h 1 / 1.8 85
iPrOH 50 7h 1 / 1.80 85
THF 25 17h 1 / 1.80 90
MeO
O
O
OMe
OH OH
OH
OH
NaBH
4
Solvent, MeOH
RT
US 6,479,714 B1, Nov 12, 2002
.
This technique is often used on larger-scale, as it is a
compromise between using the solubility characteristics of
THF, and the Reductive Strength Enhancing capability of
methanol.

C. Ethanol
In the above two examples the reactive protic solvent,
methanol or water, is diluted with a non-reactive solvent
This is done in order to minimize the amount of sodium
borohydride that is lost due to solvolysis decomposition. In
some instances, a 2-solvent system may not be optimal. It
is then possible to replace it by one protic solvent that
decomposes NaBH
4
less rapidly. Ethanol
17
and
polyethylene glycol
18
are such solvents. They have the
advantage that borohydrides solvolysis rate is
substantially slower then in methanol. On the other hand,
their enhancing effect will be less pronounced.
D. Methanol

Another way to minimize the rate of solvolysis of NaBH
4

in protic solvent is to increase the solvents alkalinity. An
example of this is to add sodium methoxide to a sodium
borohydride solution in methanol. The rate of solvolysis is
then reduced by more then 90 %.

0
20
40
60
80
100
0 10 20 30 40
T i m e ( m i n u t es )
%

N
a
B
H
4

c
o
n
s
u
m
e
d
No NaOMe
added
0.010 N
NaOMe


5. Overview

As a summary, please find hereunder a table with proven
Reductive Technologies for reduction of Ethyl Benzoate.

Metal
Hydride
moles Time
h
Temp
o
C
Additive Solvent Yield
(<%)
LiBH
4
1 8h RT B(OMe)
3
Et
2
O 100
LiBH
4
1 8h reflux none THF 100
NaBH
4
5 2h reflux MeOH THF 83
NaBH
4
2h RT ZrCl
4
THF 91
LiBH
4
0.5 1h 100 Toluene Et
2
O 100
LiBH
4
0.5 1h 100 Toluene THF 98
LiBH
4
1.5 0.75 reflux MeOH EtOH 93
NaBH
4
1 8h reflux CaCl
2
THF/tol 98
NaBH
4
1 3h 80 AlCl
3
THF/DG 97

6. References

1) Zhu, H.J ., Piittman, C.U. Synthetic
Commun. 2003, 33, 1733
2) US 6,359,155 B1 Mar 19, 2002
3) US 5,530,143 B2 J une 25,1996
4) Private communications with Dr. Martin
J . Klatt of the BASF Corporation
5) US 6,620,964 B2 Sep 16, 2003
6) Hallouis, S., Saluzzo, C., Amouroux, R.
Synth. Commun. 2000, 30, 313
7) Brown, H.C.; Narasimhan, S.; Choi,
Y.M. J. Org. Chem. 1982, 47, 4702
8) Brown, H.C.; Subba Rao, B.C. J. Am.
Chem. Soc. 1956, 78, 2582
9) Yamakawa, T.; Masaki, M.; Nohira, H.
Bull. Chem. Soc. Japan 1991, 64, 2730
10) Narasimhan , S.; Ganeshwar Prasad, K.;
Madhaven, S. Synth. Commun. 1995, 25,
1689
11) Narasimhan, S.; Balakumar, R. Synth.
Commun. 2000, 20, 4387


12) Ikunaka, M.; I.; Matsumoto, J .; Fujima,
Y.; Hirayama, Y. Org. Proc. Res. Dev.
2002 6, 49
13) Saksena, A.K.; Girijavallabhan, V.M.;
Lovey, R.G.; Pike, R.E.; Wang, H.; Liu,
Y.-T.; Ganguly, A.K.; Bennett, F. EP
0773941 B1 2003
14) Mita, N.; Nagase, H.; Iizuka, H.; Oguchi,
T.; Sakai, K.; Horikomi, K.; Miwa, T.;
Takahashi, S. EP 0839805; 1998
15) Bianco, A.; Passacantilli, P.; Righi, G.
Synth. Commun. 1988, 18, 1765
16) Soai, K.; Oyamada, H.; Takase, M.;
Ookawa, A. Bull. Chem. Soc. Jpn. 1984,
57, 1948
17) US 2003/0045759 Mar 6, 2003
18) Itsuno, S.; Sukurai, Y.; Ito, K. Synthesis
1988, 995
19) Brown, H.C.; Narasimhan, S. J. Org.
Chem. 1982, 47, 1606
20). Gurjar, M.K., Murugaiah, A. M. S.,
Reddy, D.S.; Chorghade M.S. Org.
Proc. Res. Dev. 2003, 7, 309


t rademark of Rohm and Haas Company or i t s subsi di ari es or af f i l i at es 09/ 03

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used wi t h caut i on. Al t hough cert ai n hazards are descri bed herei n, we cannot guarant ee t hat t hese are t he onl y hazards whi ch exi st . Fi nal
det ermi nat i on of sui t abi l i t y of t he product i s t he sol e responsi bi l i t y of t he user. Users of t he product shoul d sat i sf y t hemsel ves t hat t he
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RESPECT TO THE I NFORMATI ON CONTAI NED HEREI N OR THE PRODUCT TO WHI CH THE I NFORMATI ON REFERS. Not hi ng herei n i s
i nt ended as a recommendat i on t o use our product s so as t o i nf ri nge any pat ent . We assume no l i abi l i t y f or cust omer s vi ol at i on of pat ent or
ot her ri ght s. The cust omer shoul d make hi s own pat ent i nvest i gat i on rel at i ve t o hi s proposed use.