RuHCl(CO)(PPh3)3-catalyzed chemoselective transfer-hydrogenation of enones leading to saturated ketones

Article abstract of DOI:10.1055/s-2006-933133

The highly chemoselective transfer-hydrogenation of α,β- unsaturated ketones to give saturated ketones was achieved using RuHCl(CO)(PPh₃)₃ as a catalyst. In addition to α,β-unsaturated ketones, other enones, containing a remote C=C bond, were also reduced to give saturated ketones in good to excellent yields with high selectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-933133

LETTER
721
RuHCl(CO)(PPh ) -Catalyzed Chemoselective Transfer-Hydrogenation of
3
3
Enones Leading to Saturated Ketones
R
T
uHCl(CO)(PP
a
h
)
-Cataly
k
zed Chemos
a
elective Tra
s
nsfer-Hyd
h
rogenation
o
i
f
Enone
s
Doi, Takahide Fukuyama, Jiro Horiguchi, Takahiro Okamura, Ilhyong Ryu*
3
3
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Fax +81(72)2549695; E-mail: ryu@c.s.osakafu-u.ac.jp
Received 17 January 2006
leaving the carbonyl group unaffected, under mild condi-
tions is a continuing challenge associated with ruthenium
catalysis. Herein we report that under mild reaction con-
Abstract: The highly chemoselective transfer-hydrogenation of
a,b-unsaturated ketones to give saturated ketones was achieved us-
ing RuHCl(CO)(PPh ) as a catalyst. In addition to a,b-unsaturated
4
3
3
ketones, other enones, containing a remote C=C bond, were also re- ditions RuHCl(CO)(PPh ) catalyzes a highly selective
3 3
duced to give saturated ketones in good to excellent yields with high transfer-hydrogenation from 2-propanol to, not only a,b-
selectivity.
unsaturated ketones, but also other enones giving in many
Key words: transfer-hydrogenation, enones, ruthenium hydride cases saturated ketones in good to high selectivity.5
complexes, ketones, chemoselective
When a benzene solution of 2-cyclohexen-1-one (1a) and
2
-propanol (2 equiv) was treated with RuHCl(CO)(PPh3)3
(
3 mol%) at reflux for 1 h, a 65:35 mixture of cyclohex-
The transition metal-catalyzed hydrogen-transfer reduc-
tion of unsaturated organic substrates are of both practical
and fundamental importance in organic synthesis. The
anone (2a) and cyclohexanol (3a) was obtained (Table 1,
entry 1). The allylic alcohol 4a was not detected in the
crude reaction mixture. When the amount of 2-propanol
used was decreased to 1.1 equivalents, the formation of 3a
was largely suppressed (entry 2). Furthermore, decreasing
the bath temperature to 70 °C completely suppressed the
formation of overreduction product 3a, affording 2a in
1
ability of ruthenium complexes to dehydrogenate alcohols
and deliver the resulting hydrides to a ketone or an a,b-un-
saturated ketone has made them potentially useful as
2
transfer-hydrogenation catalysts. However, the rutheni-
um-catalyzed transfer-hydrogenation of enones to ketones
reported thus far suffer from further overreduction with
saturated alcohols being produced as by-products.2 The
highly chemoselective reduction of the carbonyl group of
a,b-unsaturated ketones to allylic alcohols has been
8
9% yield (entry 3). The reduction of cyclohexanone (2a)
under similar conditions proceeded slowly to give the
saturated alcohol 3a in 15% yield.
d–g
The results for the transfer-hydrogenations of a series
of enones are summarized in Table 2. 4,4-Dimethyl-2-
cyclohexen-1-one (1b) also underwent a chemoselective
3
achieved using ruthenium complexes as catalysts. Ac-
cordingly, the problem of reducing only the C=C bond,
Table 1 Transfer-Hydrogenation of 2-Cyclohexen-1-one (1a) to Cyclohexanone (2a) Catalyzed by RuHCl(CO)(PPh ) under Selected
3
3
Conditions
O
O
OH
OH
3
mol% RuHCl(CO)(PPh3)3
2
-PrOH
+
+
C6H6, 1 h
1a
2a
3a
4a
Entry
Substrate
2-Propanol (equiv)
Temp
Yield (%)a
1
0
0
0
–
a
2a
49
82
89
71
3a
26
5
4a
0
1
2
3
1a
1a
1a
2a
2.0
1.1
1.1
1.1
Reflux
Reflux
70 °Cb
70 °Cb
0
0
0
4
15
0
a
GC yields.
Bath temperature.
b
SYNLETT 2006, No. 5, pp 0721–0724
1
7.
0
3.
2
0
0
6
Advanced online publication: 09.03.2006
DOI: 10.1055/s-2006-933133; Art ID: U00606ST
©
Georg Thieme Verlag Stuttgart · New York

7
22
T. Doi et al.
LETTER
Table 2 Transfer-Hydrogenation of Various Enones Catalyzed by RuHCl(CO)(PPh3)3a
Entry
1
Substrate
Time (h)
1
Conversion (%)
100
Products
Yield (%)b
89
O
O
2
a
1
a
O
O
2
3
5
100
93
1
b
O
2b
O
OH
22
47
1
c
2c 57
3c 32
(
cis:trans = 27:73c)
O
O
4
5
2.5
100
88
1
d
e
2d
O
O
16
2
1
23
100
100
83
97
99
d
6
7
e
1
2e
O
O
8
9
5
85f
(95)
1
1
1
f
2f
O
O
66
0
Not formedg
(97)
O
O
g
2g
O
O
1
0
6.5
100
Ph
Ph
h
2h
O
O
1
1
1
2
26
22
85
100
(79)
(81)
e
e
Ph
Ph
Ph
Ph
1
i
2i
O
O
44h
75
1
1
3
4
3
1
55
100
1
1
j
2j
O
O
1
1
5e
6
5
18
36
56
60
68
e
k
2k
a
b
c
d
e
f
General conditions: substrate (1 mmol), 2-propanol (1.1 mmol), RuHCl(CO)(PPh ) (3 mol%), C H (3.0 mL), 70 °C (bath temperature).
3
3
6
6
GC yields. Isolated yields in parentheses.
1
Determined by H NMR.
The amount of 5 mol% RuHCl(CO)(PPh ) was used.
3
3
The amount of 10 mol% RuHCl(CO)(PPh ) was used.
An isomeric mixture of enones remained in 15% (GC and H NMR).
Starting material was recovered.
3
3
1
g
h
1
A mixture of 3-hexen-2-one and 4-hexen-2-one remained in 30% and 15%, respectively (GC and H NMR).
Synlett 2006, No. 5, 721–724 © Thieme Stuttgart · New York

LETTER
RuHCl(CO)(PPh ) -Catalyzed Chemoselective Transfer-Hydrogenation of Enones
723
3
3
reduction, leading to the saturated ketone 2b (entry 2). On
the other hand, the reduction of 3-methyl-2-cyclohexen-1-
one (1c) was very sluggish. As a result, overreduction to
the saturated alcohol 3c occurred as a competing reaction
[Ru]-H
O
O
[
Ru]–H
[Ru]
O
isomerization
1i
OH
O
(
entry 3). Other cyclic unsaturated ketones, 2-cyclopent-
reduction
en-1-one (1d) and 2-cyclohepten-1-one (1e), were re-
duced at the C=C bond to give the saturated ketones, 2d
and 2e, respectively (entries 4 and 5). The reduction of
OH
H
2
-cyclohepten-1-one (1e) was sluggish under the standard
[Ru] H
O
O
conditions used, but when the amount of Ru-
HCl(CO)(PPh ) was increased to 5 mol% and 10 mol%,
3
3
reduction
the complete reduction of 1e resulted (entries 6 and 7).
The acyclic unsaturated ketone 1f was also reduced in
good yield (entry 8). On the other hand, 4-methoxy-3-
buten-2-one (1g), containing a methoxy group at the b-
position, was not reduced (entry 9). The reduction of
benzylideneacetone (1h) proceeded smoothly to give sat-
urated ketone 2h in 97% yield (entry 10). In contrast, the
reduction of 1i to 2i was very sluggish (entries 11 and 12).
We also examined the reaction of 5-hexen-2-one (1j),
containing an olefin portion at the 4-position (entry 13).
After three hours, the saturated ketone 2j was obtained in
moderate yield along with unsaturated isomers, 3-hexen-
[
Ru]–H
[
Ru]–H
O
OH
isomerization
2i
Scheme 1 Possible mechanism of transfer-hydrogenations
References and Notes
(1) For reviews on transfer-hydrogenation, see: (a) Brieger, G.;
Nestrick, T. J. Chem. Rev. 1974, 74, 567. (b) Johnstone, R.
A.; Wilby, A. H.; Entwistle, I. D. Chem. Rev. 1985, 85, 129.
(c) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. Rev.
2
-one (30%) and 4-hexen-2-one (15%). Increasing the
amount of catalyst used to 10 mol% resulted in the smooth
6
alkene-isomerization and transfer-hydrogenation to give
1
992, 92, 1051. (d) Noyori, R.; Hashiguchi, S. Acc. Chem.
Res. 1997, 30, 97. (e) Bäckvall, J.-E. J. Organomet. Chem.
002, 652, 105.
2
j in 75% yield (entry 14). In the case of 6-methyl-5-hep-
ten-2-one (1k), containing a trisubstituted olefin, the re-
duction was sluggish presumably due to steric congestion
2
(
2) (a) Comprehensive Organic Synthesis, Vol. 8; Trost, B. M.,
(
entries 15 and 16).
Ed.; Pergamon Press: Oxford, 1991, 551–553; and
references cited therein. (b) Sasson, Y.; Blum, J.
A possible mechanism for the reaction is shown in
Scheme 1, in which hydrogen-transfer reductions of a,b-
unsaturated ketones have been proposed to proceed via
Tetrahedron Lett. 1971, 12, 2167. (c) Sasson, Y.; Blum, J. J.
Org. Chem. 1975, 40, 1887. (d) Bianchini, C.; Farnetti, E.;
Graziani, M.; Peruzzini, M.; Polo, A. Organometallics 1993,
12, 3753. (e) Bhaduri, S.; Sharma, K. J. Chem. Soc., Chem.
Commun. 1988, 173. (f) Bhaduri, S.; Sharma, K.; Mukesh,
D. J. Chem. Soc., Dalton Trans. 1993, 1191.
2
c,d
ruthenium p-oxaallyl intermediates: (i) isomerization
to the a,b-unsaturated ketones, (ii) coordination and acti-
vation of the hydrogen acceptor, (iii) coordination of the
hydrogen donor, (iv) hydrogen transfer, and (v) the
release of the product. Another path via the formation of
unsaturated alcohols followed by alkene isomerization to
the saturated ketones is also possible, although the forma-
tion of unsaturated alcohols as a by-product was not
observed in this study.
(
g) Chowdhury, R. L.; Bäckvall, J.-E. J. Chem. Soc., Chem.
Commun. 1991, 1063. For transfer-hydrogenation of
ketones to alcohols, see: (h) Leadbeater, N. E. J. Org. Chem.
2001, 66, 2168. (i) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim,
S. C. J. Org. Chem. 2001, 66, 9020. (j) Haack, K.-J.;
Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R. Angew.
Chem., Int. Ed. Engl. 1997, 36, 285. (k)Yamakawa,M.;Ito,
H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466.
In conclusion, the highly chemoselective transfer-hydro-
genation of a,b-unsaturated ketones to the saturated
ketones catalyzed by RuHCl(CO)(PPh ) under mild con-
ditions is reported. This method is also effective for the
selective reduction of other enones, having a remote C=C
bond.
(
2
l) Santosh Laxmi, Y. R.; Bäckvall, J.-E. Chem. Commun.
000, 611. (m) Ma, Y.; Liu, H.; Chen, L.; Cui, X.; Zhu, J.;
Deng, J. Org. Lett. 2003, 5, 2103. (n) Guo, R.; Chen, X.;
Elpelt, C.; Song, D.; Morris, R. H. Org. Lett. 2005, 7, 1757.
3
3
7
(
o) Yamaguchi, K.; Koike, T.; Kotani, M.; Matsushita, M.;
Shinachi, S.; Mizuno, N. Chem. Eur. J. 2005, 11, 6574.
3) (a) Bianchini, C.; Farnetti, E.; Frediani, P.; Graziani, M.;
Peruzzini, M.; Polo, A. J. Chem. Soc., Chem. Commun.
(
1
991, 1336. (b) Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-
Acknowledgment
W.; Zhu, J.; Deng, J.-G. J. Org. Chem. 2005, 70, 3584.
(c) For Zr-catalyzed transfer-hydrogenation of enones to
allylic alcohols, see: Nakano, T.; Umano, S.; Kino, Y.; Ishii,
Y.; Ogawa, M. J. Org. Chem. 1988, 53, 3752. (d) Ir:
Bianchini, C.; Farnetti, E.; Graziani, M.; Nardin, G.; Vacca,
A.; Zanobini, F. J. Am. Chem. Soc. 1990, 112, 9190.
I.R. acknowledges a Grant-in-Aid for Scientific Research on Priori-
ty Areas (A) ‘Reaction Control of Dynamic Complexes’ from
MEXT, Japan for financial support. T.F. also acknowledges a
Grant-in-Aid for Young Scientists (B) from MEXT Japan for finan-
cial support.
Synlett 2006, No. 5, 721–724 © Thieme Stuttgart · New York

7
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T. Doi et al.
LETTER
(6) For recent examples of RuHCl(CO)(PPh ) -catalyzed
(4) For Ir-catalyzed reactions, see: (a) Sakaguchi, S.; Yamaga,
T.; Ishii, Y. J. Org. Chem. 2001, 66, 4710. For Pd-
3
3
isomerization reactions of C=C bonds, see: (a) Wakamatsu,
H.; Nishida, M.; Adachi, N.; Mori, M. J. Org. Chem. 2000,
65, 3966. (b) Krompiec, S.; Pigulla, M.; Szczepankiewicz,
W.; Bieg, T.; Kuznik, N.; Leszczynska-Sejda, K.; Kubicki,
M.; Borowiak, T. Tetrahedron Lett. 2001, 42, 7095.
(c) Kuznik, N.; Krompiec, S.; Bieg, T.; Baj, S.; Skutil, K.;
Chrobok, A. J. Organomet. Chem. 2003, 665, 167.
catalyzed reactions, see: (b) von Holleben, M. L. A.;
Zucolotto, M.; Zini, C. A.; Oliveira, E. R. Tetrahedron 1994,
0, 973. (c) Rao, H. S. P.; Reddy, K. S. Tetrahedron Lett.
5
1
994, 35, 171.
(
5) RuHCl(CO)(PPh ) is rarely used in transfer-hydrogenation
3
3
reactions. To the best of our knowledge, only two examples
of the low-yield reduction of acetophenone and
benzaldehyde have been reported which used formic acid as
a hydrogen source: (a) Watanabe, Y.; Ohta, T.; Tsuji, Y.
Bull. Chem. Soc. Jpn. 1982, 55, 2441. (b) Gordon, E. M.;
Gaba, D. C.; Jebber, K. A.; Zacharias, D. M.
(7) General Procedure for the Transfer-Hydrogenation of
Enones Catalyzed by RuHCl(CO)(PPh ) .
3
3
Benzene (3 mL), 1h (146 mg, 1 mmol), 2-propanol (65.4 mg,
1.09 mmol) and RuHCl(CO)(PPh ) (28.7 mg, 0.03 mmol)
3
3
were placed in a 30-mL two-necked flask equipped with a
reflux condenser and a magnetic stirring bar under an
Organometallics 1993, 12, 5020.
atmosphere of N . The mixture was stirred at 70 °C (bath
2
temperature) for 6.5 h. After removing the solvent, the
residue was purified by column chromatography on silica
gel (20% EtOAc–hexane as eluent). The eluent contained 2h
(144 mg, 97%).
Synlett 2006, No. 5, 721–724 © Thieme Stuttgart · New York