18-12-2012, 06:20 PM
Reduction of aromatic and aliphatic keto esters using sodium borohydride/MeOH at room temperature: a thorough investigation
[attachment=44319]
ABSTRACT
Reduction of keto esters is a valuable alternative to produce diols. Sodium borohydride/MeOH system at
room temperature and short reaction time efficiently reduced a, b, g, and d-keto esters having a-keto
esters as the most reactive. The ester functionality was reduced effectively due to the presence of oxo
group that somehow facilitates the formation of ring intermediate. As expected, the chemoselective
experiments showed that ester functionality was not reduced using this system. This study presents
a simple, easy, and benign reduction process of various keto esters to its corresponding diols.
Introduction
Reduction is one of the most important transformations in
organic synthesis and sodium borohydride as reducing agent is
the most common since its conception.1 It has been effective for
the selective reduction of aldehydes and ketones2 but it shows
lower reactivity for esters and other relatively difficult to reduce
functionalities. However, due to its relatively cheaper cost and
ease of handling, modification to augment its reducing power has
never stopped. This includes changing the reaction conditions
such as varying the solvent, increasing its amount, adding additives
or even using catalysts. For instance, sodium borohydride/
methanol system can reduce ester provided the reaction was
done under refluxing THF and/or used large excess of sodium
borohydride at a relatively longer time.3 Others used several
metal borohydrides4 while others used additive such as aluminum
chloride,5 magnesium bromohydride,6 zinc chloride,7 polyethylene
glycol,8 and a lot more. Refluxing in ethereal solvents
and inert conditions are commonly employed in the abovementioned
reactions. Furthermore, there have been reports also
that reduction of esters proceeded using sodium or potassium
borohydride provided a neighboring functional group such as
oxo, hydroxyl or carboxylic acid is present.9 However, there is no
detail investigation of this matter.
Experimental section
General procedure for the reduction of keto ester
In a flask, the starting material a-keto ester (1 mmol) was dissolved
in methanol (5 mL for a-keto ester and 2.5 mL for b-keto
ester). Then NaBH4 (3.0 equiv) was added portion wise. The
reaction mixture was stirred at room temperature until the
reaction was completed based on TLC monitoring. Upon completion
of the reaction, the mixture was acidified using 5.0 M HCl until
pH 6. The solvent was then evaporated using rotary evaporator. For
alkyl case: The residue was dissolved in methanol and column
filtered thru a short pad of silica using methanol/chloroform (1:4)
as eluent to obtain the crude product. This material was purified
with column chromatography using various hexane/EtOAc eluent
systems. For aromatic case: the residue was dissolved in brine
solution and the crude material was extracted using EtOAc as many
times necessary. The organic layer was dried using anhydrous
Na2SO4, filtered, and the solvent was evaporated. The residue was
purified via column chromatography using various hexane/EtOAc
eluent systems.
Conclusion
We have thoroughly investigated the reducing ability of sodium
borohydride/MeOH system at room temperature for various types
of keto esters. The protocol presented offers a mild reaction condition
for the formation of several diols that have widespread
application in synthetic chemistry.
[attachment=44319]
ABSTRACT
Reduction of keto esters is a valuable alternative to produce diols. Sodium borohydride/MeOH system at
room temperature and short reaction time efficiently reduced a, b, g, and d-keto esters having a-keto
esters as the most reactive. The ester functionality was reduced effectively due to the presence of oxo
group that somehow facilitates the formation of ring intermediate. As expected, the chemoselective
experiments showed that ester functionality was not reduced using this system. This study presents
a simple, easy, and benign reduction process of various keto esters to its corresponding diols.
Introduction
Reduction is one of the most important transformations in
organic synthesis and sodium borohydride as reducing agent is
the most common since its conception.1 It has been effective for
the selective reduction of aldehydes and ketones2 but it shows
lower reactivity for esters and other relatively difficult to reduce
functionalities. However, due to its relatively cheaper cost and
ease of handling, modification to augment its reducing power has
never stopped. This includes changing the reaction conditions
such as varying the solvent, increasing its amount, adding additives
or even using catalysts. For instance, sodium borohydride/
methanol system can reduce ester provided the reaction was
done under refluxing THF and/or used large excess of sodium
borohydride at a relatively longer time.3 Others used several
metal borohydrides4 while others used additive such as aluminum
chloride,5 magnesium bromohydride,6 zinc chloride,7 polyethylene
glycol,8 and a lot more. Refluxing in ethereal solvents
and inert conditions are commonly employed in the abovementioned
reactions. Furthermore, there have been reports also
that reduction of esters proceeded using sodium or potassium
borohydride provided a neighboring functional group such as
oxo, hydroxyl or carboxylic acid is present.9 However, there is no
detail investigation of this matter.
Experimental section
General procedure for the reduction of keto ester
In a flask, the starting material a-keto ester (1 mmol) was dissolved
in methanol (5 mL for a-keto ester and 2.5 mL for b-keto
ester). Then NaBH4 (3.0 equiv) was added portion wise. The
reaction mixture was stirred at room temperature until the
reaction was completed based on TLC monitoring. Upon completion
of the reaction, the mixture was acidified using 5.0 M HCl until
pH 6. The solvent was then evaporated using rotary evaporator. For
alkyl case: The residue was dissolved in methanol and column
filtered thru a short pad of silica using methanol/chloroform (1:4)
as eluent to obtain the crude product. This material was purified
with column chromatography using various hexane/EtOAc eluent
systems. For aromatic case: the residue was dissolved in brine
solution and the crude material was extracted using EtOAc as many
times necessary. The organic layer was dried using anhydrous
Na2SO4, filtered, and the solvent was evaporated. The residue was
purified via column chromatography using various hexane/EtOAc
eluent systems.
Conclusion
We have thoroughly investigated the reducing ability of sodium
borohydride/MeOH system at room temperature for various types
of keto esters. The protocol presented offers a mild reaction condition
for the formation of several diols that have widespread
application in synthetic chemistry.