Malononitrile-assisted highly chemoselective bismuth triflate catalyzed conjugate reduction of α,β-unsaturated ketones

Article abstract of DOI:10.1002/ejoc.201200020

A very simple, direct, bismuth-catalyzed conjugate reduction protocol that allows for the catalytic regioselective formation of substituted ketones from enones under mild conditions has been developed. We have shown for the first time that the combined poly(methylhydro)siloxane-malononitrile system can serve as an efficient reductant/reagent in 1,4-conjugate reduction of enones. The regioselectivity, efficiencies, and experimental simplicity of the present method complements the more complex methods previously employed in copper or palladium-catalyzed reduction. This method should prove attractive because of its mild reaction conditions and the interesting chemistry of combining the use of poly(methylhydro)siloxane and malononitrile for selective reduction. Copyright

Full text of DOI:10.1002/ejoc.201200020

FULL PAPER
DOI: 10.1002/ejoc.201200020
Malononitrile-Assisted Highly Chemoselective Bismuth Triflate Catalyzed
Conjugate Reduction of α,β-Unsaturated Ketones
[a]
[a]
[a]
[a]
[a]
Jun-Yan Shang, Fei Li, Xing-Feng Bai, Jian-Xiong Jiang, Ke-Fang Yang,*
[a]
[a]
Guo-Qiao Lai, and Li-Wen Xu*
Keywords: Bismuth / Reduction / Lewis acids / Silanes / Reaction mechanisms
A very simple, direct, bismuth-catalyzed conjugate reduction
protocol that allows for the catalytic regioselective formation
of substituted ketones from enones under mild conditions has
been developed. We have shown for the first time that the
combined poly(methylhydro)siloxane-malononitrile system
can serve as an efficient reductant/reagent in 1,4-conjugate
reduction of enones. The regioselectivity, efficiencies, and
experimental simplicity of the present method complements
the more complex methods previously employed in copper
or palladium-catalyzed reduction. This method should prove
attractive because of its mild reaction conditions and the
interesting chemistry of combining the use of poly(methylhy-
dro)siloxane and malononitrile for selective reduction.
Introduction
promoted by malononitrile. In addition, this finding
prompted the development of an interesting strategy involv-
The chemoselective hydrogenation or conjugate re-
duction of α,β-unsaturated ketones is an attractive and im-
portant tactic in organic synthesis.[ Suitably substituted
ketones have been useful and important synthons, especially
for synthesis of complex molecules and natural products.
Therefore, it is not surprising that recent efforts have fo-
cused on the development of various transition-metal cata-
[8,9]
ing the use of bismuth catalysis,
and cooperative Lewis
[9]
acid and iminium catalysis in this hydrogenation.
1]
[
2]
Results and Discussion
Bismuth compounds and salts have recently attracted
lysts for the chemoselective 1,4-reduction of enones, and a much attention due to their low toxicity, low cost, good
number of significant advances have been made toward es- stability, and excellent catalytic activity in many organic
[
10]
tablishing economical protocols that achieve this transfor- transformations.
To expand the scope of bismuth-cata-
[
3]
mation. Especially in recent years, a number of metal salts lyzed organic reactions, we wanted to develop a new syn-
and complexes have been shown to facilitate the 1,4-conju- thetic method involving the use of environmentally-benign
[
3–7]
gate reduction of α,β-unsaturated ketones,
including bismuth salts in organic synthesis. During the course of our
[
4]
[5]
copper complexes (CuH-based precursor), palladium,
synthetic studies on bismuth catalysis, we were interested
[
6]
[7]
rhodium, and others. However, because of the difficult- in developing a chemoselective multicomponent reaction of
ies associated with selectively controlling and restraining chalcone, malononitrile, and poly(methylhydro)siloxane
the reactivity of the ketone group of the enone, there are (PMHS) that would generate a possible intermediate for the
still open challenges in the conjugate reduction of α,β-un- next transformation (Scheme 1). However, no Michael ad-
saturated ketones, such as the development of highly effec-
tive, chemoselective, and environmentally benign methodol-
ogies. To the best of our knowledge, there are no reports
on the bismuth-catalyzed conjugate reduction of α,β-unsat-
urated ketones. Herein, we describe a new chemistry and
approach to a highly chemoselective bismuth-catalyzed 1,4-
conjugate reduction of enones at room temperature that is
[
a] Key Laboratory of Organosilicon Chemistry and Material
Technology of Ministry of Education, Hangzhou Normal
University,
Hangzhou 310012, P. R. China
Fax: +86-571-28865135
E-mail: liwenxu@hznu.edu.cn and licpxulw@yahoo.com
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200020.
Scheme 1. Bismuth-catalyzed reaction of chalcone and malono-
nitrile in the presence of PMHS.
Eur. J. Org. Chem. 2012, 2809–2815
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2809

K.-F. Yang, L.-W. Xu et al.
FULL PAPER
duct or derivative was detected. Interestingly, to our sur-
prise, only 2a was obtained in promising yields through 1,4-
conjugate reduction. The unexpected results led us to inves-
tigate this catalysis in more detail.
An initial investigation into a simplification of the reac-
tion system revealed that malononitrile was essential in pro-
moting the 1,4-conjugate reduction in this model reaction.
As shown in Table 1, only bismuth triflate [Bi(OTf)3]
showed very poor catalytic activity in the absence of ma-
lononitrile (entry 2). Subsequent investigations showed that
the best ratio of bismuth triflate to malononitrile was 1:10;
in this case the reaction went to completion with excellent
chemoselectivity (Figure 1).
Figure 1. The effect of the amount of malononitrile in the bismuth-
catalyzed 1,4-conjugate reduction of chalcone (1a) in the presence
Table 1. Screening of catalyst in the conjugate reduction of chalc-
one in the presence of PMHS.[
of PMHS. Reagents and conditions: manolonitrile, Bi(OTf)
3
(5 mol-
a]
%), chalcone (1.0 mmol), PMHS (7.0 mmol), CH
8 h.
2 2
Cl (1 mL), r.t.,
1
(
entries 1–11). With 10 mol-% of Cu(OTf) , BiI , NbCl ,
2 3 5
or ZrOCl , the reaction failed, whereas with FeCl , InCl ,
2
3
3
AgClO , or TMSOTf either a mixture of different reduced
4
products was obtained or staring material remained and the
reaction was incomplete. All these Lewis acids exhibited
poorer chemoselectivity than that of bismuth triflate. It
should be noted that TMSOTf and TfOH exhibited excel-
lent catalytic activity but resulted in a different product (4a
or 5a) with or without malononitrile (Table 1, entries 10–12).
However, both catalysts exhibited lower and different selec-
tivity in the regioselective 1,4-conjugate reduction in com-
parison to that of Bi(OTf) . When no malononitrile was
Entry
1
Cat.
Solvent Time Yield [%]
3
[h]
2a
3a
4a
5a
used in the TMSOTf-catalyzed reduction, the major prod-
uct of 1,4-conjugate reduction (2a) was obtained in good
yield but with poor selectivity (entry 10), whereas complete
reduction resulting in the formation of 5a was found in the
presence of malononitrile (entry 11). Given the moisture
sensitivity of strong Brønsted acid (TfOH) or TMSOTf,
Bi(OTf)
Bi(OTf)
3
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
18
18
36
40
36
36
36
17
36
15
15
13
18
82
trace
0
40
17
0
0
90
0
88
trace
trace
45
38
58
8
0
0
0
0
0
0
0
0
0
0
0
0
45
38
58
8
0
0
0
0
0
0
0
0
0
3
0
7
0
0
0
0
0
0
0
0
0
0
0
0
0
0
[
b]
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
3
Cu(OTf)
FeCl
InCl
BiI
NbCl
AgClO
ZrOCl
2
3
3
3
and the contrasting moisture stability of Bi(OTf) , we sug-
3
5
4
gest that bismuth triflate catalysis still offers an advantage
of operational simplicity and, because of the activation of
the enone, to selective reduction. In fact, similar phenom-
ena have been observed for other Lewis acids in the absence
of malononitrile. These findings led to an unprecedented
conclusion that malononitrile enhanced the catalytic ac-
tivity of the Lewis acid in the conjugate reduction of chalc-
one.
2
0
0
0[b]
1
TMSOTf
TMSOTf
TfOH
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
99
99
Ͻ 1
Ͻ 1
Ͻ 1
0
[
c]
2
3
4
5
6
7
8
3
3
3
3
3
3
DCE
toluene 18
EtOAc 18
THF
18
15
15
[
[
d]
e]
CH
CH
2
Cl
Cl
2
2
93
6
Ͻ 1
0
0
0
We then investigated the solvent effect in this reaction
and found that dramatic differences in yield were observed
in reactions using tetrahydrofuran (THF), 1,2-dichloro-
2
[
(
a] Reagents and conditions: chalcone (1.0 mmol), PMHS
7.0 mmol), MX or other catalyst (10 mol-%), malononitrile
n
(
0.5 mmol), solvent (1 mL), r.t. (unless otherwise stated). The yields ethane (DCE), dichloromethane, ethyl acetate, and toluene
1
were determined by GC/MS and H NMR spectroscopic analysis.
b] No addition of malononitrile. [c] 5 mol-% TfOH was used. [d]
mol-% Bi(OTf) was used. [e] 1 mol-% Bi(OTf) , and 10 mol-%
malonitrile was used.
as solvents (Table 1, entries 1 and 13–16). Therefore, dichlo-
romethane was the best choice for the bismuth-catalyzed
conjugate reduction (Table 1, entry 1). Gratifyingly, when
the catalytic amount of bismuth triflate was reduced to
[
5
3
3
5
mol-%, better conversion and good chemoselectivity was
A methodical and detailed study of the 1,4-conjugate re- obtained (Table 1, entry 17; 93% yield). Attempts to lower
duction focused on screening different Lewis acids as cata- the catalyst loading to 1 mol-% resulted in increased reac-
lysts for this reaction; the results are presented in Table 1 tion time and lower yields (Table 1, entry 18).
2810
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2809–2815

Conjugate Reduction of α,β-Unsaturated Ketones
Encouraged by these preliminary results, activated meth-
ylene compounds, such as malonic acid, dimethyl malonate,
diethyl malonate, and ethyl 2-nitroacetate, were examined in
place of malononitrile as additives in the bismuth-catalyzed
conjugate reduction (Table 2, entries 1–4). Interestingly, the
use of dimethyl malonate or malonic acid instead of mal-
ononitrile also resulted in promising yields for this conju-
gate reduction (Table 2, entries 1, 2). It was also found that
other activated methylene compounds were ineffective
(Table 2, entries 3 and 4). We then examined the effect of
nitrile-containing compounds (such as CH CN, PhCN, and
3
phthalonitrile), tertiary amine, and other amines (Table 2,
entries 5–7); however, all these additives exhibited either po-
orer or no activity in the bismuth-catalyzed reaction. These
results illustrated the superiority of malononitrile in the bis-
muth-catalyzed conjugate reduction of chalcone in the pres-
ence of PMHS.
Table 2. Screening and evaluation of additives or silanes in the con-
jugate reduction of chalcone in the presence of bismuth triflate.[
a]
Scheme 2. Selective reduction of α,β-unsaturated ketones or alde-
hydes.
Entry Additives
Time [h]
Yield [%]
1
2
3
4
5
6
7
malonic acid
72
72
72
60
72
24
24
30
23
trace
trace
trace
trace
0
dimethyl malonate
diethyl malonate
ethyl 2-nitroacetate
[
[
c]
c]
[
b]
[c]
[c]
BPDM
[
d]
TMEDA
propane-1,3-diamine
[
(
a] Reagents and conditions: chalcone (1.0 mmol), PMHS
Scheme 3. Chemoselectivity in the bismuth-catalyzed conjugate re-
duction.
3 2 2
7.0 mmol), Bi(OTf) (5 mol-%), additive (0.5 mmol), CH Cl
(
1 mL), r.t. (unless otherwise stated). The yields were determined by
1
GC/MS and H NMR spectroscopic analysis. [b] (4-Bromophenyl)-
N,N-dimethylmethanamine. [c] Less than 5% yield. [d] Tetra-
methylethane-1,2-diamine.
Although we have no direct evidence for the involvement
of a bismuth intermediate derived from the reaction of bis-
muth triflate, substrates, and malononitrile, we assume that
With optimal conditions in hand, we next turned our the reaction proceeds in a similar manner to other bismuth
attention to evaluating the scope of the bismuth-catalyzed catalysts.[
8–10]
Because bismuth salts are known to readily
conjugate reductions of various α,β-unsaturated ketones or undergo hydrolysis to afford the corresponding Brønsted
[
11]
aldehydes. In general, it was found that the 1,4-conjugate acid and oxy-bismuth salt,
we hypothesized that the
reduction exhibited good to excellent selectivity in high Brønsted acid activates the Si–H bond of PMHS through
[
12,13]
yields for aryl chalcones. As shown in Scheme 2, products formation of a hypervalent silicon intermediate;
the
2a–g were obtained in good to excellent yields through se- oxy-bismuth salt or other bismuth intermediate then works
lective reduction, whereas substrates with a nitro group in as a Lewis acid to bind the carbonyl group of chalcone,
the aromatic ring gave poor yield (2h). In contrast to pre- thus synergistically promoting the conjugate reduction of
vious methods of 1,4-conjugate reduction,[
3–7]
unexpectedly, chalcone. On the basis of this hypothesis and on the above
the bismuth-based catalyst system was not effective in pro- experimental results, and inspired by the previous mecha-
moting the selective reduction of cinnamaldehyde (1i) or 4- nism of bismuth catalysis, a proposed catalytic cycle can be
phenylbut-3-en-2-one (1j). However, it is noteworthy that provided (Scheme 4). In this proposed mechanistic pro-
the bismuth/malononitrile/PMHS system exhibited excel- cedure, malonitrile promotes the formation of Brønsted
lent selectivity in the reduction of a mixture of cinnamal- acid (HOTf) and NCCH=C=N bismuth salt (ii), and poss-
dehyde and chalcone (Scheme 3), in which only chalcone ibly also acts as a buffer system. Therefore, in accordance
was reduced and cinnamaldehyde was recovered completely. with the experimental results, addition of malononitrile or
These results indicated that the reaction mechanism differs dimethyl malonate results in the decomposition of bismuth
from that of the conjugate reduction with silane.
triflate to form a dual catalyst system; the malononitrile
Eur. J. Org. Chem. 2012, 2809–2815
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2811

K.-F. Yang, L.-W. Xu et al.
FULL PAPER
could then stabilize the bismuth intermediate (iii) derived
from interaction of trifluoromethanesulfonic bismuth and
chalcone to facilitate the hydride-transfer and regeneration
of the dual catalyst system.
Scheme 5. Probing the mechanism with deuterium-labeled dimethyl
malonate.
position of Bi(OTf) in the presence of malononitrile (as
3
shown in Scheme 4).
Because 4-phenylbut-3-en-2-one (1j) was not a suitable
substrate for the conjugate reduction under the optimized
reaction conditions of Scheme 2, we continued to modify
the bismuth-based catalyst system to improve the catalytic
activity or change the possible mechanistic procedure. Be-
cause of the privileged catalytic activity of combined Lewis
acids and organocatalysts for many organic transforma-
[
15,16]
tions,
we assumed that the combination of iminium
catalysis and Lewis acid catalysis could promote the conju-
gate reduction of 4-phenylbut-3-en-2-one and its derivatives
Scheme 4. Plausible reaction mechanism of the bismuth-catalyzed
conjugate reduction.
[
17]
through
a
dual-activation pathway.
As shown in
Scheme 6, we hypothesized that the secondary amine or pri-
To elucidate the role of malononitrile in the bismuth- mary amine salts could react with 4-phenylbut-3-en-2-one
catalyzed conjugate reduction, a deuterium incorporation to form iminium intermediate (ii) or other possible interme-
experiment was carried out. Because the preparation of diate (i). The 4-phenylbut-3-en-2-one (1k) could then be ac-
pure deuterium-labeled malononitrile [CD (CN) ] was diffi- tivated by the bismuth-based Lewis acid according to above
2
2
cult, we used CD (COOMe) as a substitute in this reac- mechanistic procedure (Scheme 4 and Scheme 6), in which
2
2
tion. The deuterium-labeled dimethyl malonate was pre- the PMHS would also be activated by Brønsted acid
pared according to a previous report.[ When the deute- (HOTf) to deliver selective reduction in the presence of
rium-labeled dimethyl malonate was used as an additive in malononitrile.
14]
the bismuth-catalyzed conjugate reduction (Scheme 5), a re-
To test the hypothesis, we screened various amine cata-
gioselective deuteration combined with conjugate reduction lysts combined with bismuth triflate in the conjugate re-
was detected in the product. Although the content of deute- duction of 4-phenylbut-3-en-2-one (1j). As shown in
rium incorporation was not high in this case, we speculated Table 3, the selective reduction of 4-phenylbut-3-en-2-one
that the dimethyl malonate or malononitrile enhanced the (1j) were conducted with different amine compounds, in-
reaction rate as a result of a dual activating effect of Lewis cluding l-proline (Table 3, entry 1), the combinational use
acid and Brønsted acid caused by the hydrolysis or decom- of secondary amines with acetic acid (Table 3, entries 2–5),
Scheme 6. Hypothesis of dual activation mechanism in the combined metal salt based Lewis acid and primary amine catalyzed conjugate
reduction of 4-phenylbut-3-en-2-one (1j).
2812
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2809–2815

Conjugate Reduction of α,β-Unsaturated Ketones
and ammonium salts (Table 3, entries 6–11), under a variety did not observed the formation of by-products in the selec-
of conditions, and found that commercially available and tive reduction of these α,β-unsaturated ketones.
inexpensive NH Cl was effective for the conjugate re-
The catalytic system described in this work has been
4
duction in the presence of malononitrile (Table 3, entry 11). shown to involve a novel cooperative strategy (in which a
Therefore, with the optimized reaction conditions on hand, primary amine salt is used to tune the reactivity of the
a catalytic amount of NH Cl (20 mol-%) was employed to metal complexes or Lewis acid catalyzed transformation of
4
evaluate the selective reduction of 4-phenylbut-3-en-2-one ketones) and is an efficient biomimetic catalytic process in
(1j) and its derivatives 1j–o having different substituents. As homogeneous catalysis.
shown in Scheme 7, α,β-unsaturated ketones substituted
with various groups (Me, OMe, or Cl) were cleanly reduced
in excellent yields and selectivities. It is noteworthy that we
Conclusions
We have developed a very simple, direct, bismuth-cata-
lyzed conjugate reduction protocol that allows for the cata-
lytic regioselective formation of substituted ketones from
enones under mild conditions. We have shown that the com-
bined poly(methylhydro)siloxane-malononitrile system can
serve as an efficient reductant/reagent in 1,4-conjugate re-
duction of enones. No hydrosilylation of ketones take place
with the bismuth catalyst system. The reaction conditions
are mild and environmentally friendly, and the process is
conducted under an atmosphere of air without the need for
dried solvents. In addition, the regioselectivity, efficiency,
and experimental simplicity of the present method are valu-
able in comparison with methods previously employed for
the copper or palladium-catalyzed reduction. This method
should prove to be an attractive method due to the mild
reaction conditions and the interesting chemistry of com-
bining the use of bismuth salts and malononitrile for or-
ganic transformations. Further investigations on the combi-
national use of PMHS/malononitrile and bismuth/ma-
lononitrile as interesting reagents or catalyst systems for
other chemical transformations are in progress.
Table 3. Screening and evaluation of additives in the conjugate re-
duction of chalcone in the presence of bismuth triflate.[
a]
Entry
Additives
Time [h]
Yield [%]
0
trace
trace
trace
trace
28
0
0
0
1
2
3
4
5
6
7
8
9
l-proline
96
96
96
96
96
14
14
14
96
96
50
[
b]
[c]
[d]
[d]
[d]
pyrrolidine
piperidine[
b]
diethylamine[
b]
diisopropylamine[
b]
NH
NH
NH
NH
NH
NH
4
4
4
4
4
4
Cl
OAc
PF
Cl + TMEDA
Cl + Et
Cl
6
[
e]
e]
1
0
1
3
N[
0
f]
1
Ͼ 99[
[
a] Reagents and conditions: 1j (1.0 mmol), PHMS (7.0 mmol),
Bi(OTf) (5 mol-%), malononitrile (0.5 mmol), additive (20 mol-%),
CH Cl (1 mL), r.t. (unless otherwise stated). The yields were deter-
mined by GC/MS and H NMR spectroscopic analysis. [b] 20 mol-
of AcOH was also used as co-additive. [c] Ͻ10% yield. [d] Ͻ5%
yield. [e] The malononitrile was replaced by an organic base
50 mol-%), such as TMEDA (N,N,NЈ,NЈ-tetramethylethane-1,2-di-
amine), or Et N (triethylamine). [f] 10 mol-% of Bi(OTf) was used.
3
2
2
1
Experimental Section
%
General: All reaction flasks and solvents were dried according to
standard methods prior to use. Flash column chromatography was
performed over silica (100–200 mesh). NMR spectra were recorded
(
3
3
1
3
with a 400 MHz spectrometer (Avance 400). C NMR spectra
were obtained with broadband proton decoupling. For spectra re-
3
corded in CDCl , unless noted otherwise, chemical shifts were re-
corded relative to an internal TMS (tetramethylsilane) reference
signal. GC/MS was performed with a TRACE DSQ instrument.
IR spectra were recorded with an FTIR apparatus (Nicolot 5700).
Thin layer chromatography was performed using Silica.
General Procedure for Conjugate Reduction of Enones: Bismuth
triflate (0.05 mmol) and malononitrile (0.5 mmol) were added into
a solution of chalcone (1.0 mmol) and PMHS (7.0 mmol) in
CH
mixture was diluted with H
3ϫ 15 mL). The combined organic layers were dried (Na
2
Cl
2
(1 mL). After stirring at room temperature for 15 h, the
O (10 mL) and extracted with EtOAc
SO ),
2
(
2
4
concentrated in vacuo, and purified by column chromatography on
silica gel (EtOAc/petroleum, 1:50) to obtain the pure product. All
the products are known compounds[ and their identities were
confirmed by GC/MS, NMR, and IR analyses; the characterization
data for 2 are listed in the Supporting Information. Data for 2g
are provided as a typical example.
18]
1
,3-Bis(4-fluorophenyl)propan-1-one (2g): 1H NMR(400 MHz,
CDCl ): δ = 7.95–7.99 (m, 2 H), 7.18–7.21 (m, 2 H), 7.09–7.14 (m,
Scheme 7. Selective reduction of α,β-unsaturated ketones.
3
Eur. J. Org. Chem. 2012, 2809–2815
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2813

K.-F. Yang, L.-W. Xu et al.
FULL PAPER
2
7
1
H), 6.95–6.99 (m, 2 H), 3.25 (t, J = 7.2 Hz, 2 H), 3.03 (t, J =
Int. Ed. 2007, 46, 3329; r) A. Pelss, E. T. T. Kumpulainen,
A. M. P. Koskinen, J. Org. Chem. 2009, 74, 7598.
5] a) A. Haskel, E. Keinan, Palladium-Catalyzed 1,4-Reduction
13
.6 Hz, 2 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 197.4, 167.0,
[
62.7, 136.8, 133.3, 130.7 (2 C), 129.9 (2 C), 115.8 (2 C), 115.4 (2
(Conjugate Reduction), in: Handbook of Organopalladium
C), 40.3, 29.2 ppm. IR (film): ν˜ max = 3341, 3062, 2953, 2936, 2901,
Chemistry for Organic Synthesis (Eds.: E.-i. Negishi, A. de Mei-
jere), Wiley, New York, 2002, vol. 2, p. 2767; b) B. P. S. Chau-
han, J. S. Rathore, T. Bandoo, J. Am. Chem. Soc. 2004, 126,
8493; c) H. Otsuka, E. Shirakawa, T. Hayashi, Chem. Commun.
2007, 1819; d) Y. Tsuchiya, Y. Hamashima, M. Sodeoka, Org.
Lett. 2006, 8, 4851; e) D. Monguchi, C. Beemelmanns, D.
Hashizume, Y. Hamashima, M. Sodeoka, J. Organomet. Chem.
2
1
872, 1922, 1885, 1680, 1594, 1512, 1450, 1408, 1360, 1296, 1204,
158, 1097, 1011, 981, 848, 780, 722 cm .
–1
Supporting Information (see footnote on the first page of this arti-
cle): General remarks, NMR and IR spectroscopic data for the
products.
2
008, 693, 867; f) D. B. Bagal, Z. S. Qureshi, K. P. Dhake, S. R.
Acknowledgments
Khan, B. M. Bhanage, Green Chem. 2011, 13, 1490; g) D. Mon-
guchi, C. Beemelmanns, D. Hashizume, Y. Hamashima, M.
Mikiko, J. Organomet. Chem. 2008, 693, 867.
Financial support by the National Natural Science Foundation of
China (NSFC) (grant numbers 20973051 and 21173064), Zhejiang
Provincial Natural Science Foundation of China (ZPNSFC) (grant
Y4090139), and the Program for Excellent Young Teachers in
Hangzhou Normal University (HNUEYT) (grant JTAS 2011-01-
[
6] a) D. A. Evans, G. C. Fu, J. Org. Chem. 1990, 55, 5678; b)
Z. Wang, G. Zou, J. Tang, Chem. Commun. 2004, 1192; c) Y.
Kanazawa, H. Nishiyama, Synlett 2006, 3343; d) X. Li, L. Li,
Y. Tang, L. Zhong, L. Cun, J. Zhu, J. Liao, J. Deng, J. Org.
Chem. 2010, 75, 2981; e) Y. Kanazawa, Y. Tsuchiya, K. Kobay-
ashi, T. Shiomi, J.-I. Itoh, M. Kikuchi, Y. Yamamoto, H. Nishi-
yama, Chem. Eur. J. 2006, 12, 63.
014), is appreciated. X. L. W. is greatly indebted to Prof. Shibasaki
Masakatsu, Graduate School of Pharmaceutical Sciences, The Uni-
versity of Tokyo, and Prof. Chun-Gu Xia, Lanzhou Institute of
Chemical Physics, Chinese Academy of Sciences, for their help.
[7]
a) I. K. Youn, G. H. Yon, C. S. Pak, Tetrahedron Lett. 1986,
27, 2409; b) T. Hudlicky, G. Sinai-Zingde, M. G. Natchus, Tet-
rahedron Lett. 1987, 28, 5287; c) E. Keinan, D. Perez, J. Org.
Chem. 1987, 52, 2576; d) D. S. Hays, M. Scholl, G. C. Fu, J.
Org. Chem. 1996, 61, 6751; e) P. Magnus, M. J. Waring, D. A.
Scott, Tetrahedron Lett. 2000, 41, 9731; f) A. D. Kosal, B. L.
Ashfeld, Org. Lett. 2010, 12, 44; g) M. Sugiura, N. Sato, S.
Kotani, M. Nakajima, Chem. Commun. 2008, 4309; h) F.
Alonso, I. Osante, M. Yus, Synlett 2006, 3017.
[
1] a) W. S. Mahoney, D. M. Brestensky, J. M. Stryker, J. Am.
Chem. Soc. 1988, 110, 291; b) V. Jurkauskas, J. P. Sadighi, S. L.
Buchwald, Org. Lett. 2003, 5, 2417; c) C. L. Oswald, J. A. Pe-
terson, H. W. Lam, Org. Lett. 2009, 11, 4504; d) E. K. Marie,
V. V. Dinesh, W. C. John, Synlett 2011, 2355.
2] For selected examples, see: a) K. D. Schwartz, J. D. White, Org.
Lett. 2011, 13, 248; b) B. Gourdet, H. W. Lam, Angew. Chem.
Int. Ed. 2010, 49, 8733; c) C. K. Savile, J. M. Janey, E. C. Mun-
dorff, J. C. Moore, S. Tam, W. R. Jarvis, J. C. Colbeck, A.
Krebber, F. J. Fleitz, J. Brands, P. N. Devine, G. W. Huisman,
G. J. Hughes, Science 2010, 329, 305; d) P. Webber, M. J. Kris-
che, J. Org. Chem. 2008, 73, 9379; e) D. M. Skytte, S. F. Niel-
sen, M. Chen, L. Zhai, C. E. Olsen, S. B. Christensen, J. Med.
Chem. 2006, 49, 436; f) M. P. Rainka, J. E. Milne, S. L. Buch-
wald, Angew. Chem. 2005, 117, 6333; Angew. Chem. Int. Ed.
[
[
8] For selected examples, see: a) H. Qin, N. Yamagiwa, S. Mat-
sunaga, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 1611; b)
T. Ollevier, E. Nadeau, J. C. Eguillon, Adv. Synth. Catal. 2006,
3
2
48, 2080; c) F. M. Koch, R. Peters, Angew. Chem. 2007, 119,
739; Angew. Chem. Int. Ed. 2007, 46, 2685; d) H. Qin, N.
Yamagiwa, S. Matsunaga, M. Shibasaki, Angew. Chem. 2007,
1
19, 413; Angew. Chem. Int. Ed. 2007, 46, 409; e) T. Ollevier,
Z. Li, Adv. Synth. Catal. 2009, 351, 3251; f) H. Li, H. Y. Zeng,
H. W. Shao, Tetrahedron Lett. 2009, 50, 6858; g) S. T. Kadam,
P. Thirupathi, S. S. Kim, Tetrahedron 2010, 66, 1684; h) S. T. C.
Eey, M. J. Lear, Org. Lett. 2010, 12, 5510; i) H. Kamisaki, T.
Nanjo, C. Tsukano, Y. Takemoto, Chem. Eur. J. 2011, 17, 626;
j) B. Cacciuttolo, S. Poulain-Martini, E. Duñach, Eur. J. Org.
Chem. 2011, 3710; k) B. Barnych, J. M. Vatèle, Synlett 2011,
2
005, 44, 6177; g) H. Tanaka, T. Zenkoh, H. Setoi, T. Takah-
ashi, Synlett 2002, 1427.
[
3] a) S. Kotani, K. Osakama, M. Sugiura, M. Nakajima, Org.
Lett. 2011, 13, 3968; b) S. Chandrasekhar, G. Chandrashekar,
M. S. Reddy, P. Srihari, Org. Biomol. Chem. 2006, 4, 1650; c)
W. M. Clark, A. J. Andrew, M. A. Plotkin, A. M. Eldridge, I.
Lantos, Org. Lett. 1999, 1, 1839.
2048; l) J. M. Bothwell, S. W. Krabbe, R. S. Mohan, Chem. Soc.
Rev. 2011, 40, 4649.
[
9] a) T. Ollevier, E. Nadeau, V. Desyroy, Bismuth(III) Trifluoro-
methanesulfonate, in: e-EROS Encyclopedia of Reagents for Or-
ganic Synthesis 2009; b) Bismuth-Mediated Organic Reactions,
Topics in Current Chemistry (Ed.: T. Ollevier), Springer, Berlin,
2012.
[
4] a) T. Tsuda, T. Fujii, K. Kawasaki, T. Saegusa, J. Chem. Soc.,
Chem. Commun. 1980, 1013; b) W. S. Mahoney, J. M. Stryker,
J. Am. Chem. Soc. 1989, 111, 8818; c) B. H. Lipshutz, J. Keith,
P. Papa, R. Vivian, Tetrahedron Lett. 1998, 39, 4627; d) A.
Mori, A. Fujita, H. Kajiro, Y. Nishihara, T. Hiyama, Tetrahe-
dron 1999, 55, 4573; e) D. H. Appella, Y. Moritani, R. Shintani,
E. M. Ferreira, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121,
[10] a) Organobismuth Chemistry (Eds.: H. Suzuki, Y. Matano), El-
sevier, Amsterdam, 2001; b) S. Vidal, Synlett 2001, 1194; c)
N. M. Leonard, L. C. Wieland, R. S. Mohan, Tetrahedron
2002, 58, 8373; d) S. Antoniotti, Synlett 2003, 1566; e) H. Gas-
pard-Iloughmane, C. Le Roux, Eur. J. Org. Chem. 2004, 2517;
f) T. Ollevier, E. Nadeau, J. Org. Chem. 2004, 69, 9292; g) T.
Ollevier, Z. Y. Li, Org. Biomol. Chem. 2006, 4, 4440; h) T. Ol-
levier, E. Nadeau, J. C. Eguillon, Adv. Synth. Catal. 2006, 348,
2080; i) T. Ollevier, V. Desyroy, E. Nadeau, ARKIVOC
(Gainesville, FL, U.S.) 2007, 10, 10; j) B. D. Kelly, J. M. Allen,
E. E. Tundel, T. H. Lambert, Org. Lett. 2009, 11, 1381; k) R. J.
Hinkle, Y. Lian, L. C. Speight, H. E. Stevenson, M. M. Sprach-
man, L. A. Katkish, M. C. Mattern, Tetrahedron 2009, 65,
6834; l) W. J. Zhou, K. H. Wang, J. X. Wang, D. F. Huang, Eur.
J. Org. Chem. 2010, 416; m) B. N. Harris, P. P. Patel, C. P. Gob-
ble, M. J. Stark, C. De Meo, Eur. J. Org. Chem. 2011, 4023; n)
S. Wan, F. Wu, J. C. Rech, M. E. Green, R. Balachandran,
W. S. Horne, B. W. Day, P. E. Floreancig, J. Am. Chem. Soc.
9473; f) Y. Moritani, D. H. Appella, V. Jurkauskas, S. L. Buch-
wald, J. Am. Chem. Soc. 2000, 122, 6797; g) V. Jurkauskas,
S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 2892; h) C. Czek-
elius, E. M. Carreira, Angew. Chem. 2003, 115, 4941; Angew.
Chem. Int. Ed. 2003, 42, 4793; i) G. Hughes, M. Kimura, S. L.
Buchwald, J. Am. Chem. Soc. 2003, 125, 11253; j) B. H. Lip-
shutz, J. M. Servesko, Angew. Chem. 2003, 115, 4937; Angew.
Chem. Int. Ed. 2003, 42, 4789; k) C. Czekelius, E. M. Carreira,
Org. Lett. 2004, 6, 4575; l) B. H. Lipshutz, J. M. Servesko, T. B.
Petersen, P. P. Papa, A. A. Lover, Org. Lett. 2004, 6, 1273; m)
P. Chiu, Synthesis 2004, 2210; n) D. Kim, B.-M. Park, J. Yun,
Chem. Commun. 2005, 1755; o) M. P. Rainka, J. E. Milne, S. L.
Buchwald, Angew. Chem. 2005, 117, 6333; Angew. Chem. Int.
Ed. 2005, 44, 6177; p) B. H. Lipshutz, N. Tanaka, B. R. Taft,
C.-T. Lee, Org. Lett. 2006, 8, 1963; q) T. Llamas, R. G. Arrayás,
J. C. Carretero, Angew. Chem. 2007, 119, 3393; Angew. Chem.
2814
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2809–2815

Conjugate Reduction of α,β-Unsaturated Ketones
011, 133, 16668; o) X. Li, X. Q. Yang, H. H. Chang, Y. W. Li,
2
T. Okino, Y. Takemoto, Org. Lett. 2001, 3, 3329; c) S. France,
H. Wack, A. M. Hafez, A. E. Taggi, D. R. Witsil, T. Lectka,
Org. Lett. 2002, 4, 1603; d) S. France, M. H. Shah, A. Weather-
wax, H. Wack, J. P. Roth, T. Lectka, J. Am. Chem. Soc. 2005,
127, 1206; e) L. Yang, L. W. Xu, C. G. Xia, Tetrahedron Lett.
2007, 48, 1599; f) Z. Xu, P. Daka, H. Wang, Chem. Commun.
2009, 6825; g) D. E. A. Raup, B. Cardinal-David, D. Holte,
K. A. Scheidt, Nature Chem. 2010, 2, 766; h) P. Daka, Z. H.
Xu, A. Alexa, H. Wang, Chem. Commun. 2011, 47, 224; i) G.
Maiti, R. Karmakar, R. N. Bhattacharya, U. Kayal, Tetrahe-
dron Lett. 2011, 52, 5610; j) K. Motoyama, M. Ikeda, Y. Mi-
yake, Y. Nishibayashi, Eur. J. Org. Chem. 2011, 2239; k) Z. H.
Xu, L. Liu, K. Wheeler, H. Wang, Angew. Chem. Int. Ed. 2011,
50, 3484.
B. Ni, W. L. Wei, Eur. J. Org. Chem. 2011, 3122; p) V. André,
A. Hardeman, I. Halasz, R. S. Stein, G. J. Jackson, D. G. Reid,
M. J. Duer, C. Curfs, M. T. Duarte, T. Fri sˇ cˇ i c´ , Angew. Chem.
Int. Ed. 2011, 50, 7858.
[
11] a) P. A. Evans, J. Cui, S. J. Gharpure, R. J. Hinkle, J. Am.
Chem. Soc. 2003, 125, 11456; b) T. Ollevier, E. Nadeau, J. Org.
Chem. 2004, 69, 9292; c) R. F. Lambert, R. J. Hinkle, S. E. Am-
mann, Y. Lian, J. Liu, S. E. Lewis, R. D. Pike, J. Org. Chem.
2
011, 76, 9269; d) P. A. Evans, A. Grisin, M. J. Lawler, J. Am.
Chem. Soc. 2012, 134, 2856.
[
12] a) X. H. Chen, Y. Deng, K. Jiang, G. Q. Lai, Y. Ni, K. F. Yang,
J. X. Jiang, L. W. Xu, Eur. J. Org. Chem. 2011, 1736; b) Z. H.
Shi, H. Sheng, K. F. Yang, J. X. Jiang, G. Q. Lai, Y. Lu, L. W.
Xu, Eur. J. Org. Chem. 2011, 66.
[17]
a) J. A. Ma, D. Cahard, Angew. Chem. 2004, 116, 4666; Angew.
Chem. Int. Ed. 2004, 43, 4566; b) D. H. Paull, C. J. Abraham,
M. T. Scerba, E. Alden-Danforth, T. Lectka, Acc. Chem. Res.
[
13] For selected reviews, see: a) C. Chuit, R. J. P. Corriu, C. Reye,
J. C. Young, Chem. Rev. 1993, 93, 1371; b) R. R. Holmes,
Chem. Rev. 1996, 96, 927; c) C. Chuit, R. J. P. Corriu, C. Reye,
In Chemistry of Hypervalent Compounds (Ed.: K.-y. Akiba),
Wiley-VCH, Weinheim, Germany, 1999, chapter 4, pp. 81–146;
d) M. A. Brook, Silicon in Organic, Organometallic, and Poly-
mer Chemistry, Wiley-Interscience, New York, 1999; e) A. D.
Dilman, S. L. Ioffe, Chem. Rev. 2003, 103, 733; f) S. Rendler,
M. Oestreich, Synthesis 2005, 1727.
2
008, 41, 655; c) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38,
2
745; d) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010, 2999; e) J.
Zhou, Chem. Asian J. 2010, 5, 422.
18] a) S. Condon, D. Dupre, G. Falgayrac, J. Y. Nedelec, Eur. J.
[
Org. Chem. 2002, 105; b) D. A. Powell, G. C. Fu, J. Am. Chem.
Soc. 2004, 126, 7788; c) X. Huang, H. Z. Zhang, Synth. Com-
mun. 2006, 36, 97; d) C. S. Cho, S. C. Shim, Appl. Organomet.
Chem. 2006, 20, 4329; e) M. J. Climent, A. Corma, S. Iborra,
M. Mifsud, Adv. Synth. Catal. 2007, 349, 1949; f) C. Lucchesi,
T. Inasaki, H. Miyamura, R. Matsubara, S. Kobayashi, Adv.
Synth. Catal. 2008, 350, 1996; g) J. C. Conrad, J. Kong, B. N.
Laforteza, D. W. C. MacMillan, J. Am. Chem. Soc. 2009, 131,
[14] J. S. Dickschat, C. A. Citron, N. L. Brock, R. Riclea, H. Kuhz,
Eur. J. Org. Chem. 2011, 3339. General procedure for prepara-
tion of CD
(
(
2
(COOMe)
0.8 g, 5 mmol) in D O (10 mL) was added anhydrous K
0.068 g, 0.5 mmol, 0.10 equiv.). The reaction mixture was
2
: To a solution of dimethyl malonate
2
2
CO
3
stirred for 24 h at room temperature and afterwards extracted
with diethyl ether. The combined organic layers were dried with
MgSO , and the solvent was removed under reduced pressure
4
1
1640; h) B. Zoltán, F. Zoltán, K. György, H. István, Green
Chem. 2009, 11, 1937; i) A. Stroba, F. Schaeffer, V. Hindie,
L. L. Garcia, I. Adrian, W. F. Hner, R. W. Hartmann, R. M.
Biondi, M. Engel, J. Med. Chem. 2009, 52, 4683; j) M. Sauthier,
N. Lamotte, J. Dheur, Y. Castanet, A. Mortreux, New J. Chem.
to yield (7.98 g, 4.92 mmol, 86%) deuterated product as a col-
orless liquid.
[
15] a) H. M. Yang, Y. H. Gao, L. Li, Z. Y. Jiang, G. Q. Lai, C. G.
Xia, L. W. Xu, Tetrahedron Lett. 2010, 51, 3836; b) H. M.
Yang, L. Li, K. Z. Jiang, J. X. Jiang, G. Q. Lai, L. W. Xu, Tet-
rahedron 2010, 66, 9708; c) Y. F. Cai, H. M. Yang, L. Li, K. Z.
Jiang, G. Q. Lai, J. X. Jiang, L. W. Xu, Eur. J. Org. Chem. 2010,
2
009, 33, 969; k) L. J. Allen, R. H. Crabtree, Green Chem. 2010,
1
2, 1362; l) A. D. Kosal, B. L. Ashfeld, Org. Lett. 2010, 12, 44;
m) A. Boffi, S. Cacchi, P. Ceci, R. Cirilli, G. Fabrizi, A. Pras-
taro, S. Niembro, A. Shafir, A. Vallribera, ChemCatChem 2011,
3
, 347; n) C. S. Choa, B. T. Kima, N. S. Yoonb, Appl. Or-
4986.
ganomet. Chem. 2011, 25, 695.
[
16] For selected examples, see: a) G. Chen, Y. Deng, L. Gong, A.
Mi, X. Cui, Y. Jiang, M. C. K. Choi, A. S. C. Chan, Tetrahe-
dron: Asymmetry 2001, 12, 1567; b) M. Nakoji, T. Kanayama,
Received: January 9, 2012
Published Online: March 28, 2012
Eur. J. Org. Chem. 2012, 2809–2815
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2815