A simple borohydride-based method for selective 1,4-conjugate reduction of α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2011.10.056

Sodium borohydride is used in combination with a heterogeneous palladium catalyst and acetic acid to selectively reduce the carbon-carbon double bonds of various α,β-unsaturated ketones and related compounds. This simple method is most selective when non-polar solvents such as toluene are used. We observed nearly complete conversion and high selectivities using moderate catalyst loadings. The reactions were typically complete in less than 2 h.

Full text of DOI:10.1016/j.tetlet.2011.10.056

Tetrahedron Letters 52 (2011) 6823–6826
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A simple borohydride-based method for selective 1,4-conjugate reduction
of a,b-unsaturated carbonyl compounds
⇑
Alyssa T. Russo, Kerstin L. Amezcua, Vincent A. Huynh, Zach M. Rousslang, David B. Cordes
Pacific University, Department of Chemistry, 2043 College Way, Forest Grove, OR 97116, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Sodium borohydride is used in combination with a heterogeneous palladium catalyst and acetic acid to
selectively reduce the carbon–carbon double bonds of various ,b-unsaturated ketones and related com-
pounds. This simple method is most selective when non-polar solvents such as toluene are used. We
observed nearly complete conversion and high selectivities using moderate catalyst loadings. The reac-
tions were typically complete in less than 2 h.
Received 11 September 2011
Revised 8 October 2011
Accepted 10 October 2011
Available online 17 October 2011
a
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to the memory of Joseph Brendan
Cunningham (1968–2011)
Keywords:
Selective reduction
a,b-Unsaturated carbonyl
Sodium borohydride
Palladium catalyst
Conjugate reduction
Introduction
Selective synthetic transformations of multifunctional com-
pounds arguably constitute the most valuable category of organic
chemical methods. Of particular utility are the various selective
oxidation and reduction methods celebrated in sophomore organic
chemistry texts. The chemoselective reduction of a,b-unsaturated
carbonyl compounds is among the most studied of these families
of methods.1–6 Though a variety of products are possible, varying
ratios of three principal products are typically obtained under most
reductive conditions as shown in Scheme 1.
Catalytic hydrogenation using metals such as palladium, plati-
num, and rhodium can sometimes be used for selective reduction
of the carbon–carbon bond of these compounds to give product
A.4,7 Product A is often referred to as the 1,4-conjugate reduction
product. Good results for this selectivity often depend on careful
control of the amount of hydrogen being added and palladium is
generally perceived as providing the best results.6 In many cases,
however, the traditional combination of molecular hydrogen with
palladium catalysts results in overreduction of the compound to
produce saturated alcohol C. In other cases, it has been observed
that hydrogenation with a palladium catalyst will completely sat-
urate the compound through both reduction of the carbon–carbon
double bond and hydrogenolysis of the carbonyl function to give a
Scheme 1. Common reductive fates of a,b-unsaturated carbonyl compounds.
completely saturated hydrocarbon.8 Satisfactorily selective results
to obtain product A are also attained using palladium with molec-
ular hydrogen by modifying conditions for particular substrates,
often through adjustments in hydrogen pressure and/or catalyst
loading.5 Alternatively, deactivation of the palladium catalyst
through addition of various additives has been explored. Recently,
a highly selective 1,4-conjugate reduction was described in which
hydrogenation was carried out using diphenylsulfide as a palla-
dium catalyst poison to obtain product A.9
As an alternative to traditional palladium-catalyzed hydrogena-
tion, a range of other methods has been developed to obtain the
1,4-conjugate reduction product A.2–4 Many of these methods in-
⇑
Corresponding author. Tel.: +1 503 352 3021; fax: +1 503 352 2933.
E-mail address: cordes@pacificu.edu (D.B. Cordes).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.056

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A. T. Russo et al. / Tetrahedron Letters 52 (2011) 6823–6826
clude the use of external hydrogen with various monometallic and
mixed metal catalysts other than palladium.7 Some of the best re-
sults using external hydrogen were demonstrated by Singaram and
coworkers who used a nickel boride catalyst to hydrogenate the
however, using common borohydride reagents. Hutchins et al. re-
ported that sodium cyanoborohydride could be used for the selec-
tive 1,4-conjugate reduction of very highly activated
a,b-
unsaturated esters and nitriles.25 More recently, limited examples
of selective 1,4-conjugate reduction using sodium borohydride
with CoCl2 in aqueous micellar solutions were reported.26 While
all of the aforementioned methods provide good to excellent re-
sults for selective reduction of certain compounds, they are, to
varying degrees, limited by the requirements of complex catalyst
preparation, long reaction times, experimental complexity, and
limited substrates.
olefinic bond of a number of
a,b-unsaturated compounds with a
high degree of selectivity.10 Other interesting systems for selective
1,4-conjugate reduction using external hydrogen have been de-
scribed such as copper hydride-mediated catalysis11 and a recycla-
ble water-soluble iron(II)/EDTA catalytic system.12
Unfortunately, all of the aforementioned systems require the
use of molecular hydrogen from an external source, often at extre-
mely elevated pressures and for long reaction times. Accordingly, a
diverse group of methods has been developed that allows for selec-
tive 1,4-conjugate reduction without the use of an external hydro-
gen gas source. These include methods based on selenium,13,14
indium,15 nickel,16 and a complex palladium catalyst.17 Another
variation achieved good results using a palladium catalyst under
microwave radiation.18 These methods rely variously on in situ for-
mation of hydrogen gas or on catalytic transfer hydrogenation. A
number of remarkable specialized methods have also been de-
scribed for enantioselective 1,4-conjugate reduction of carbonyl
compounds.3
Results and discussion
We have developed a palladium-catalyzed reduction system of
exceptional simplicity that uses gentle and inexpensive sodium
borohydride and acetic acid to selectively reduce the olefinic bonds
of several a,b-unsaturated ketones and related compounds. Signif-
icantly, the observed 1,4-selectivity reverses that ordinarily ob-
served for sodium borohydride. Additionally, the reactions tend
to be very rapid, with quantitative yields of the desired product ob-
tained in as little as 1 h even with fairly low catalyst loadings. The
method provides results that are as good or better than those ob-
tained with available methods.
In contrast to the systems described above, several groups have
also examined the use of hydride-based systems for selective
reduction of the carbon–carbon bond of a,b-unsaturated carbonyl
systems. Ordinarily, hydride reagents are used to reduce the more
polar carbonyl function rather than the unsaturated carbon–car-
bon bond to give product B. Nevertheless, the chemoselectivity
for this 1,2-addition is far from steady and shows great variation
depending on the type of hydride reagent, the solvent, the sub-
strate, and the specific conditions employed.19 For example, lith-
ium aluminum hydride tends to show slightly better selectivity
for the reduction of the carbonyl than its milder cousin, sodium
borohydride, sometimes producing fairly good yields of the allylic
alcohol product. Sodium borohydride more commonly reacts by
way of a conjugate, 1,4-addition mechanism, eventually resulting
in a fully reduced product. When alcoholic solvents are used, a
higher degree of 1,2-reduction is usually observed. It has been sug-
gested that this might be due to the formation of sterically
demanding alkoxyborohydrides as the active reducing species that
Solvent study
We had originally developed this system for the reduction of
monofunctional alkenes and alkynes using isopropyl alcohol as
the solvent of choice.27 When we first applied the system to the
reduction of
a,b-unsaturated carbonyl compounds using this sol-
vent we found rather poor selectivity with the fully reduced com-
pound as the main product. We considered the solubility of active
species and decided to conduct a solvent study. We were delighted
to observe that the selectivity for a number of substrates improved
dramatically as solvent polarity decreased, with toluene generally
giving best results. Representative solvent effects on selectivity are
shown for the reduction of 4-phenyl-3-buten-2-one in Table 1.
Selectivity shows a strong solvent dependence, with 1,4-conju-
gate reduction of the olefinic bond favored in non-polar solvents
such as toluene, while 1,2-reduction of carbonyl functions is
increasingly favored as solvent polarity increases. We suspect that
the non-polar solvent disfavors the solubility of borohydride spe-
cies and instead favors catalytic decomposition of NaBH4 on the
palladium metal surface to produce hydrogen through the forma-
tion and reaction of intermediate palladium hydride surface spe-
cies. Such a catalytic mechanism for hydrogen formation via
react with the carbonyl system through
a push–pull type
interaction.20,21
Luche explored this mechanistic hypothesis and demonstrated
that a cerium catalyst could be used with sodium borohydride in
methanolic solvent to effect highly selective reductions of the car-
bonyl while leaving the olefinic bond unaffected.22 This was a sig-
nificant innovation because it meant that expensive and highly
flammable lithium aluminum hydride could be replaced with mild
and inexpensive sodium borohydride to obtain the 1,2-reduction
product. In many ways, the sodium borohydride-based Luche
Table 1
reduction of a,b-unsaturated carbonyl systems solved the problem
Solvent effects on selective reduction of 4-phenyl-3-buten-2-one to 4-phenyl-2-
butanone
of selective reduction in these compounds since it is usually the
allylic alcohol, product B, which is desired. Sometimes, however,
the other product of selective reduction is desired—product A, in
which case the olefinic bond is reduced and the carbonyl remains
unaffected.
Surprisingly, there have only been a small number of reports on
general hydride-based methods for selective 1,4-reduction of the
olefinic bond of a,b-unsaturated carbonyl compounds. Such meth-
Conditions
% Yield 30 min
% Yield 1 h
Acetonitrile
IPA
<1/99
4/96
<1/99
2/98
ods can serve as convenient alternatives to existing catalytic meth-
ods that use molecular hydrogen and require gas tanks, long
reaction times, and, often, elevated pressures. A number of hy-
dride-based methods for conjugate reduction of unsaturated car-
bonyl systems have been described, including several using
unusual but fairly effective hydrides of indium23 and silicon.24,2
Only limited success with conjugate reduction has been achieved,
Ethyl lactate
DCM
THF
27/9
25/12
64/36
4/96
71/29
16/84
99/0
Toluene
98/2
Yield determined by GC/MS. Difference from 100% represents unconverted starting
material. Reactions performed using 1:4:2 ratio of substrate/NaBH4/CH3COOH with
2.5 mol % Pd/C in 5 mL solvent in open air at room temperature.

A. T. Russo et al. / Tetrahedron Letters 52 (2011) 6823–6826
6825
Table 2
Table 3
Results of selective reduction of cinnamyl type compounds
Results of selective reduction of various a,b-unsaturated carbonyl compounds
% Yielda
98b
Substrate
Product
% Yielda
Substrate
Product
100
100
99
100
88c
87b
99
100c
100d
100
100
a
b
c
a
b
c
Yield determined by GC/MS using an internal standard.
12.5% cyclohexanol obtained as a side product.
Reaction performed using 5 mol % Pd/C and run for 6 h.
Yield determined by GC/MS using an internal standard.
Reaction stopped after 30 min.
12% propylbenzene obtained as a side product.
d
Reaction performed in isopropyl alcohol due to insolubility in toluene.
borohydride hydrolysis has already been proposed.28,29 In our sys-
tem, we suppose that these surface palladium hydride species form
hydrogen gas both through reaction with each other and with pro-
tons from the acetic acid co-reagent. We hypothesize that the thus-
generated molecular hydrogen then adds catalytically at the metal
surface to reduce the carbon–carbon double bond of the adsorbed
alkene function. Conversely, in more polar solvents, such as alco-
hols, the hydride is more soluble and tends to react directly with
the carbonyl moiety via a 1,2-mechanism. As indicated by the data
in Table 1, the exclusive product of 1,2-carbonyl reduction was not
observed. The data also suggests that in non-polar solvents, the
olefinic bond is reduced first, but that over extended reaction times
reduction of the carbonyl becomes competitive to give the fully re-
duced product. In our general method, we were able to obtain
excellent results in short reaction times using toluene as the sol-
vent.30 We also found that addition of two equivalents of acetic
acid tended to improve the rate of reaction without adversely
affecting selectivity. Besides quenching surface hydrides to pro-
duce hydrogen, we suspect that acetic acid also forms additional
hydrogen gas through direct reaction of borohydride with the acid
(HÀ + H+ = H2). Additionally, there is some speculation that acidic
conditions may assist the selectivity by protonation of the carbonyl
function and associated preferential adsorption of the olefinic bond
to the catalyst.18
related compounds from the cinnamyl family using catalyst load-
ings between 1% and 2.5%. Significantly, these cinnamyl type com-
pounds ordinarily show a preference to undergo 1,2-reduction in
the presence of a palladium catalyst. Cinnamaldehyde gave a mix-
ture of products, mainly the saturated alcohol. Selected results for
the reduction of cinnamyl type compounds under standard condi-
tions are shown in Table 2.
While best results are generally obtained with cinnamyl type
unsaturated systems, this method is also generally applicable to
a variety of
a,b-unsaturated carbonyl compounds. In most cases
good to complete conversion to the desired product was observed
along with excellent selectivity. In certain cases, as with the pule-
gone substrate, conversion could be improved by raising the cata-
lyst loading to 5%. In the case of simple cyclohexanone,
overreduction to the completely saturated alcohol product could
not be avoided, even by lowering the catalyst loading to 1% and
using reduced reaction times. Representative results are shown
in Table 3.
Conclusion
We have described a simple borohydride-based method for the
selective reduction of
a,b-unsaturated carbonyl compounds. This
method is a convenient alternative to traditional catalytic hydroge-
nation and allows for the application easily handled sodium boro-
Selective reduction of various
compounds
a,b-unsaturated carbonyl
hydride to selectively reduce the olefinic bond of a,b-unsaturated
ketones and other carbonyl compounds. Future work will be direc-
ted toward exploring the mechanism of this selective reduction
and broadening the range of substrates. Additional work will in-
volve the application of this method using deuterated reagents to
We found that we could obtain excellent results for 1,4-conju-
gate reduction with a number of ,b-unsaturated ketones and
a

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Institute for Science and Mathematics (PRISM) for funding.
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