Selective 1,4-reduction of unsaturated carbonyl compounds using Co2(CO)8-H2O

Article abstract of DOI:10.1016/S0040-4039(03)00462-3

α,β-Unsaturated ketones and aldehydes were selectively reduced to the corresponding saturated carbonyl compounds by Co₂(CO)₈-H₂O system. The current reducing system also offered a chemoselective reduction of less substituted unsaturated carbonyl groups.

Full text of DOI:10.1016/S0040-4039(03)00462-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2775–2778
Selective 1,4-reduction of unsaturated carbonyl compounds using
Co2(CO)8–H2O
Hee-Yoon Lee* and Mihyun An
Center for Molecular Design and Synthesis, Department of Chemistry & BK21 School of Molecular Science,
Korea Advanced Institute of Science and Technology, Daejon, 305-701, Republic of Korea
Received 22 January 2003; revised 18 February 2003; accepted 20 February 2003
Abstract—a,b-Unsaturated ketones and aldehydes were selectively reduced to the corresponding saturated carbonyl compounds
by Co2(CO)8–H2O system. The current reducing system also offered a chemoselective reduction of less substituted unsaturated
carbonyl groups. © 2003 Elsevier Science Ltd. All rights reserved.
Chemoselective reduction of conjugated carbonyl
compounds1 is a useful functional group transforma-
tion in organic synthesis. Many useful methodologies
for selective 1,2-reduction of a,b-unsaturated carbonyl
compounds have been developed through metal hydride
mediated reduction2 or hydrogenation reactions.3 On
the other hand, selective 1,4-reduction of a,b-unsatu-
rated carbonyl compounds has not been developed as
much.4 Especially, 1,4-reduction of a,b-unsaturated
aldehydes has been quite challenging and reduction of
a,b-unsaturated aldehydes to the corresponding satu-
rated aldehydes was achieved either through unusual
reducing agents4d,e or indirectly through hydrosilation.5
During the course of our investigation in the reductive
Pauson–Khand reaction (PKR) we found out that
Co2(CO)8 was capable of reducing a,b-unsaturated
ketones in presence of water as Co2(CO)8 with water
produced the saturated ketone from a bicyclooctenone
(Scheme 1).
addition of a proton source to Co2(CO)8 generated a
reducing species. Though the exact structure or nature
of the reducing species under these conditions is not
known, it is presumed that the reducing species would
possess the similar properties to that of CoH(CO)4 as
both of them showed selective reduction of olefins of
conjugated ketones. Though CoH(CO)4 was reported to
reduce unsaturated aldehydes as well as unsaturated
ketones selectively to the corresponding saturated car-
bonyl compounds,6 the reaction has not been developed
for practical use partly due to the lack of reliable
methodology for the preparation of CoH(CO)4. We
became interested in developing a synthetic methodol-
ogy of selective reduction of unsaturated carbonyl com-
pounds using Co2(CO)8.
A similar reductive PKR was reported under different
reaction conditions by Krafft7 and Periasamy.8 Krafft
used isopropanol as the solvent for the reductive PKR
and Periasamy added trifluoroacetic acid to promote
PKR as well as the reduction. It was speculated that
Herein we report a selective reduction of unsaturated
carbonyl compounds using Co2(CO)8 with water.
Reduction was tested on benzylideneacetone with all
three different additives that were known to promote
reductive PKR to select the best additive among them.
Though the selective 1,4-reduction was achieved with
all additives, isopropanol promoted the reduction with
low conversion and addition of trifluoroacetic acid
showed incomplete conversion and presence of
unknown products other than the saturated ketone.
When water was added as the additive, clean and
complete reduction was observed (Scheme 2). The reac-
tivity difference between Co2(CO)8–H2O and
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00462-3

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H.-Y. Lee, M. An / Tetrahedron Letters 44 (2003) 2775–2778
Co2(CO)8–isopropanol was further tested with cin-
namaldehyde. When isopropanol was used either as the
additive or the solvent, the reaction produced cinnam-
alcohol as the major product. Based on this preliminary
result, all the reactions for reduction study were carried
out using Co2(CO)8 with H2O in DME.
First, reduction of various a,b-unsaturated ketones was
examined under this reaction condition and the result
was summarized in Table 1.9 Both acyclic and cyclic
a,b-unsaturated ketones were reduced selectively to the
corresponding saturated ketones in good yield (entries
1–8). However, sterically encumbered enones were not
reactive under the reaction condition as evidenced by
the fact that tri- or tetra-substituted enones did not
react at all (entries 9–11). Only trisubstituted enones
with ring strain were reduced (entries 12 and 13). These
results prompted us to explore selective reduction
between conjugated olefins in the same molecule with
different substitution patterns. When there were two
a,b-unsaturated ketones present in a molecule, only the
disubstituted olefin was reduced while leaving the other
olefin intact (entries 14 and 15). Encouraged by this fine
selectivity for the enone reduction, we examined the
reduction of a,b-unsaturated aldehydes, esters and
nitriles (Table 2). A complete selectivity for the 1,4-
reduction was observed with acyclic unsaturated alde-
hydes (entries 1–4) as no allylic alcohols or saturated
alcohols were observed. 1,2-Reduction of unsaturated
aldehydes was observed only with a cinnamoyl com-
pound (entries 5 and 6). Contrary to unsaturated
ketones, trisubstituted unsaturated aldehydes were
reduced to the corresponding saturated aldehydes
(entries 2 and 6). However cyclic unsaturated aldehyde
was not reactive at all (entry 8). Unsaturated esters
were less reactive than ketones or aldehyes as only
unsaturated esters with extra activating groups were
reduced to the corresponding saturated esters (entries 9
and 10). Entries 12 and 13 indicated that unsaturated
lactones or unsaturated nitriles would not be reactive
toward the current reducing system. Lack of the reac-
tivity of unsaturated nitriles toward Co2(CO)8–water
system was quite contrast to the report of successful
reduction of unsaturated nitriles with HCo(CO)4.10
Scheme 2.
Table 1. Reduction of unsaturated ketones
Since this result also showed that the current reducing
system might offer selective reduction among various
conjugated functional groups, we next explored the
chemoselective reduction between two sets of unsatu-
rated carbonyls in the same molecule (Scheme 3). When
a substrate with an unsaturated ketone and an unsatu-
rated ester in the same molecule, 1 was treated with
Co2(CO)8–water system, only the olefin of the unsatu-
rated ketone of the molecule was reduced to afford 2 as
the sole product. When compound 3 was treated with
Co2(CO)8–water with anticipation of subsequent aldol
type cyclization reaction, only the reduction products
were obtained. In this case, over reduction product 4b
was also obtained as the minor product. On the other
hand, the reductive aldol reaction was realized in the
case of compound 5 that contained more reactive elec-
trophile for aldol reaction than 3. Reaction of 5 with
Co2(CO)8–water system produced cyclohexyl com-

H.-Y. Lee, M. An / Tetrahedron Letters 44 (2003) 2775–2778
2777
Table 2. Reduction of unsaturated aldehydes, esters,
nitriles
ity for syn-diastereomers. Currently, we are
investigating the scope of reductive aldol reaction using
Co2(CO)8–water system.
In summary, we have developed a reagent not only for
the selective 1,4-reduction of a,b-unsaturated carbonyl
compounds but also the selective reduction of less
substituted unsaturated carbonyl compounds. The
exact nature and properties of the reducing agent will
be the subject of future research since the understand-
ing of the exact reducing species could lead to the
catalytic use of Co2(CO)8.
Acknowledgements
We thank Dr. J. M. Nuss for helpful discussion and
Exelixis, Inc. for providing resources for the prepara-
tion of the manuscript.
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pounds 611 as a single diastereomer with syn stereo-
chemistry. This result indicated that the intermediate
from the reduction could react with electrophiles before
being quenched by water presented in the reaction. This
reductive aldol cyclization reaction produced the same
result as the Krische’s report of cobalt catalyzed reduc-
tive aldol reaction of 5.12 Krische reported that silane
mediated reductive aldol cyclization with a cobalt cata-
lyst produced b-hydroxyketones with complete selectiv-
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9. General reduction procedure: In a round bottom flask
charged with Ar atmosphere, 0.5 M solution of Co2(CO)8
(1 equiv.) in DME was prepared. A 1.0 M solution of an
unsaturated carbonyl compound (1 equiv.) in DME and
water (20 equiv.) were added, and the mixture was
refluxed for 2 h. Upon completion of the reaction, the

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H.-Y. Lee, M. An / Tetrahedron Letters 44 (2003) 2775–2778
mixture was cooled to room temperature and concen-
trated in vacuo. Direct purification by flash chromatogra-
phy (SiO2, EtOAc/hexane) afforded the saturated
carbonyl compound as a colorless oil.
1H), 7.45 (t, 2H, J=8 Hz), 7.56 (t, 1H, J=8 Hz), 7.90 (d,
2H, J=8 Hz); 13C NMR (100 MHz, CDCl3) l 19.6, 24.6,
25.6, 31.9, 48.1, 66.4, 128.4, 128.7, 133.4, 135.7, 205.9; IR
(CH2Cl2) 3487, 2935, 2861, 1665, 1447, 1251, 1213, 978,
701 cm−1; 300 MHz 1H and 13C NMR spectra of 6
overlaid exactly to the spectra reported in Ref. 12.
12. Baik, T.-G.; Luis, A. L.; Wang, L.-C.; Krische, M. J. J.
Am. Chem. Soc. 2001, 123, 5112.
10. Goetz, R. W.; Orchin, M. J. Org. Chem. 1962, 27, 3698.
1
11. Spectroscopic data of 6: H NMR (400 MHz, CDCl3) l
1.39–1.50 (m, 3H), 1.72–1.80 (m, 3H), 1.88–1.98 (m, 2H),
3.43 (ddd, 1H, J=2, 3.2, 9.2 Hz), 3.92 (brs, 1H), 4.26 (s,