Diastereoselective reductive aldol reaction of enones to ketones catalyzed by halogenotin hydride

Article abstract of DOI:10.1002/chem.201002108

It's in the tin: The reductive aldol reaction of enones has been established by the Bu₂SnClH (cat.)/Ph₂SiH₂/MeOH system (see scheme). The reaction of enones with α-ketoesters or α-alkoxyketones is highly diastereoselective through a chelation-controlled mechanism. Copyright

Full text of DOI:10.1002/chem.201002108

COMMUNICATION
DOI: 10.1002/chem.201002108
Diastereoselective Reductive Aldol Reaction of Enones to Ketones
Catalyzed by Halogenotin Hydride
[
a]
[a]
[a]
[a]
Ikuya Shibata,* Shinji Tsunoi, Kumiko Sakabe, Shinji Miyamoto,
[b]
[
b]
[b]
[b]
Hirofumi Kato, Hideto Nakajima, Makoto Yasuda, and Akio Baba
In memory of Professor Haruo Matsuda
The reductive aldol reaction promoted by metal hydrides
is a valuable method for obtaining b-hydroxycarbonyls in a
one-pot synthesis. The advantage of this reaction is that
there is no need to isolate metal enolates. To date, catalytic
Initially, we examined the reductive aldol reaction of 1-
phenyl-2-buten-1-one (1) with p-methoxybenzaldehyde (2)
in the presence of a catalytic amount of Bu SnIH and stoi-
2
chiometric Ph SiH (Table 1, entry 1). However, aldol prod-
2
2
[1]
[2a–d]
reductive aldol reaction of enones or unsaturated esters
to aldehydes have been reported. In particular, enantioselec-
tive reactions have been developed for the reaction using
Table 1. Optimization of reductive aldol reaction of enone 1 to aldehyde
2
.
[2]
unsaturated esters. However, the reductive aldol reaction
of enones to ketones instead of aldehydes is uncommon due
to the low reactivity of intermediate enolates and low elec-
[3]
trophilicity to ketones. We have previously reported that
[4]
use of dibutylhalogenotin hydride (Bu SnIH) as stoichio-
[a]
2
Entry
Bu
2
SnXH
Additive
none
t [h]
Yield [%] (syn/anti)
metric metal hydride promoted reductive aldol reaction of
enones to aldehydes. We investigated catalytic use of dibu-
tylhalogenotin hydride (Bu SnClH or Bu SnIH) for reduc-
1
2
3
4
5
Bu
Bu
2
SnIH
SnIH
24
3
3
4
4
4
4
24
15 (34:66)
[b]
2
H
2
O
51 (89:11)
2
2
Bu SnIH
2
MeOH
MeOH
MeOH
MeOH
MeOH
iPrOH
76 (91:9)
tive aldol reaction of enones, and found here that high reac-
tivity, high chemo- and diastereoselectivity of intermediate
tin enolates toward ketones. (Scheme 1).
Bu
2
Bu
2
Bu
2
Bu
2
Bu
2
SnClH
SnClH
SnClH
SnClH
SnClH
93 (89:11)
52 (93:7)
67 (86:14)
88 (44:56)
97 (66:34)
[c]
[
[
d]
e]
6
7
8
[
2
a] Conditions: Bu
a (1 mmol), Additive (1 mmol), THF (1 mL). [b] 1-Phenyl-butan-1-one
was obtained in 47% yield. [c] MeOH (3 mmol) was used. [d] PhSiH
1.1 mmol) was used instead.
2 2 2
SnClH (0.1 mmol), Ph SiH (1.1 mmol), 1a (1 mmol),
3
(
Scheme 1. Reductive aldol reaction of enones.
uct 3 was obtained in only 15% yield. In addition, the dia-
stereoselectivity of 3 was low. We previously reported on
the Bu SnClH complex-catalyzed reductive amination of
2
carbonyl compounds with primary amines by using hydrosi-
[5]
lanes as hydride sources. In this reaction, the presence of
water was critical for the catalytic reaction. Accordingly,
herein addition of water (1 equiv) promoted the reductive
aldol reaction to give 3 in 51% yield with high syn-selectivi-
ty (entry 2). A side reaction took place to give 1-phenyl-
butan-1-one, generated by conjugate reduction of 1, in 47%
yield. The yield of 3 was increased by using MeOH as an ad-
ditive and by-products such as 1-phenyl-butan-1-one were
not obtained in significant amounts (entry 3). Furthermore,
[
a] Prof. Dr. I. Shibata, Dr. S. Tsunoi, K. Sakabe, S. Miyamoto
Research Center for Environmental Preservation, Osaka University
2
-4 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-8978
E-mail: shibata@epc.osaka-u.ac.jp
[
b] Dr. H. Kato, H. Nakajima, Dr. M. Yasuda, Prof. Dr. A. Baba
Department of Applied Chemistry, Graduate School of Engineering
Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002108.
Chem. Eur. J. 2010, 16, 13335 – 13338
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13335

Bu SnClH-catalyzed reaction quantitatively afforded 3 while
Table 2. Reductive aldol reaction of enones 1a with various ketones.
2
retaining the high syn-selectivity (entry 4). On the other
hand, addition of excess MeOH (3 equiv) resulted in a
lower yield (52%) (entry 5), and use of PhSiH as a hydride
3
source decreased the yield of 3 (entry 6). Using CH Cl also
2
2
afforded high yield although syn-selectivity was not so good
entry 7). Reaction rate and syn-selectivity were reduced in
the case using iPrOH as an additive (entry 8).
Entry Ketone 4
Conditions Product 5
Yield
%]
[
(
[
a]
(d.r.)
THF, RT,
[
b]
A plausible catalytic cycle is shown in Scheme 2. Initially,
1
2
37
80
3
h
Bu SnClH undergoes conjugate addition to enone 1 to give
2
CH
2
Cl
2
,
[6]
(
Z)-tin enolate A. In this step, Bu SnClH does not reduce
2
RT, 3 h
aldehyde 2. Next, generated (Z)-tin enolate A reacts with 2
CH
RT, 3 h
2
Cl
2
,
76
(80:20)
[
b]
3
4
5
6
THF, RT,
86
(>99:1)
4
h
[
d]
THF, RT,
74
4
h
(>99:1)
CH
RT, 24 h
2
Cl
2
,
80
(89:11)
[
c]
Scheme 2. Plausible catalytic cycle.
via Zimmerman–Traxler six-membered cyclic transition
THF, RT,
66
(>99:1)
[7]
[c]
state to form syn-tin aldolate B; B is protonated by
MeOH. We assume that this is the rate-determining step.
Thus, syn-aldol product 3 is obtained with generation of tin
methoxide C. In the final step, methoxide C reacts with
Ph SiH to regenerate Bu SnClH. In this system, the choice
7
8
2
4 h
[
d]
CH
2
Cl
2
,
66
2
2
2
RT, 3 h
(96:4)
of additive is important. Thus MeO group has effects on
both steps of trapping of tin aldolate B and of regeneration
of Bu SnClH. When water is used as an additive, tin enolate
2
THF,
reflux, 5 h
9
1
1
70 (92:8)
A is protonated to give saturated ketone as by-product. On
the other hand, iPrOH unlikely promotes protonation of tin
aldolate and regeneration of catalyst due to less acidity and
generation of sterically hindered tin alkoxide compared with
MeOH. syn-Selectivity would be reduced via retro-aldol re-
CH
2
Cl
2
,
,
80
(90:10)
0
1
RT, 3 h
[8]
action and reaction time increases.
It is noteworthy that this catalytic system was applicable
to the reductive aldol reaction of enone 1 with ketones
CH
2
Cl
2
79
(90:10)
(
Table 2). In the reaction of 1 with cyclohexanone (4a),
aldol product 5a was obtained in 37% yield in THF
entry 1) in which remaining product was 1-phenyl-butan-1-
RT, 3 h
(
[
a] Conditions: Bu
2
SnClH (0.1 mmol), Ph
1 mmol), Additive (1 mmol), THF (1 mL). [b] Ketone 4 (2 mmol) was
2
SiH
2
(1.1 mmol), 1 (1 mmol), 4
one by conjugate reduction of 1. Changing solvent to
(
CH Cl2 afforded 5a selectively in 80% yield (entry 2).
used. [c] iPrOH (1 mmol) was used instead of MeOH. [d] Stereochemis-
try was determined by X-ray analysis.
2
Table 2 shows the reaction using various ketones in which
indicated conditions are the result of optimization process.
Ketones bearing electron-withdrawing group 4b could be
employed to give product 5b in high yield without reduction
of 4b (entry 3). Furthermore, the reaction with a-ketoesters
stereogenic difference between methyl and methyl ester on
carbonyl moiety of methyl pyruvate (4e), considerably dia-
stereoselectivity was obtained (entry 6). These results could
be rationalized by chelated bicyclic transition state C as
shown in Scheme 3.
4
c–e also afforded aldol products 5c–e with high diastereo-
selectivities (entries 4–6). In particular, despite only small
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Diastereoselective Reductive Aldol Reaction
COMMUNICATION
Scheme 3. Plausible mechanism through chelated cyclic transition state.
The use of a-alkoxyketone 4 f also afforded highly diaste-
reoselective reaction in which OMe acts as the coordinating
group to tin (entry 7). Surprisingly, the reaction of with ben-
zoin methyl ether (4g) afforded diastereoseolective product
Scheme 6. Chelation-controlled reductive aldol reaction of enone 1a with
a-haloketone 4j. Int. V-70 = initiatior, see ref. [9] and Supporting Infor-
mation.
5
g with three contiguous stereogenic centers (entry 8). In
this reaction, among possible chelated cyclic transition
states, an excellent stereocontrol was achieved through D as
sterically least hindered Cramꢁs cyclic transition state
In conclusion, we have established that Ph SiH and alco-
2
2
(
Scheme 4).
hol promoted reductive aldol reaction of enones in the pres-
ence of a catalytic amount of dibutylhalogenotin hydride
(
Bu SnClH). Highly chemo- and diastereoselective aldol
2
products were obtained in the case using a-ketoester, a-al-
koxyketone and a-haloketones. We are now enlarging the
scope of substrates.
Scheme 4. Control of diastereoselectivity of three contiguous streogenic
centers.
Experimental Section
A typical experimental procedure for reductive aldol reaction of enone
with ketone: To a dry nitrogen-filled 10 mL round-bottomed flask con-
We were able to perform the one-pot synthesis of hetero-
cyclic compounds starting from thiocarbonate 4h (entry 9).
Thus, heating of 1 with 4h gave cyclic thionocarbonate 5h in
taining Bu
0.05 mmol) at RT. The mixture was stirred at RT for 5 min. To the solu-
tion were added enone 1 (1 mmol), ketone 4 (1 mmol), MeOH (1 mmol)
and Ph SiH (1.1 mmol), and the resulting mixture was stirred at RT for
h. After quenching with H O (5 mL), the reaction mixture was extract-
ed with diethyl ether (2ꢂ10 mL). The combined organic layers were
dried over MgSO and concentrated. The residue was subjected to
2 2 2 2
SnH (0.05 mmol) in THF (1 mL) was added Bu SnCl
(
70% yield with high diastereoselectivity. The reaction pro-
2
2
4
2
ceeds through cyclic transition state E, followed by intramo-
lecular esterification (Scheme 5).
4
column chromatography eluting with hexane/EtOAc. Tin and silane resi-
dues were removed by this treatment. Further purification was per-
2
formed by TLC eluting with hexane/Et O. Product was determined by
1
H NMR. For products 5d, 5g, and 5h, further purification was per-
formed by recrystallization. The structures of crystalline products were
determined by X-ray analysis. CCDC 777382 (5d), 777388 (5g) and
7
77384 (5h) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
Scheme 5. One-pot and diastereoselective synthesis of heterocycle.
This research was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Science, Sports, and Culture and the
Naito Foundation.
The highly diastereoselective reaction was also applicable
to a-haloketones 4i and 4j (entries 10 and 11). In this case
Keywords: aldol reaction · diastereoselectivity · enones ·
ketones · reduction
the reactions proceeded through transition state
F
(
Scheme 6). The presented reductive aldol reaction has lim-
ited application for simple ketone such as acetophenone.
However, dehalogenation of product 5j afforded adduct 5k
which corresponds with the reaction product using aceto-
phenone.
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Chem. Eur. J. 2010, 16, 13335 – 13338
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13337

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Received: July 23, 2010
Zhao, K. Oisaki, M. Kanai, M. Shibasaki, Tetrahedron Lett. 2006, 47,
Published online: October 29, 2010
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