Asymmetrie organocatalytic four-component quadruple domino reaction initiated by oxa-michael addition of alcohols to acrolein

Article abstract of DOI:10.1002/chem.200900613

A four-component (ABC₂) quadruple cascade reaction through iminium-enamine-iminium-enamine sequential activation initiated by oxa-Michale addition of alcohol to acrolein was reported. The quadruple domino reaction of methanol, acrolein, and nit

Full text of DOI:10.1002/chem.200900613

COMMUNICATION
DOI: 10.1002/chem.200900613
Asymmetric Organocatalytic Four-Component Quadruple Domino Reaction
Initiated by Oxa-Michael Addition of Alcohols to Acrolein
Fang-Lin Zhang,[a] Ai-Wen Xu,[a] Yue-Fa Gong,*[a] Mo-Hui Wei,[a] and
Xiang-Liang Yang[b]
Asymmetric multicomponent cascade reaction (MCCR)
catalyzed by organocatalysts is an attractive strategy and re-
ceives considerable attention as the increasing economic
and ecological pressure.[1] This approach provides novel
chiral complex molecules in a fast reaction via a biomimetic
pathway and proceeds in a highly efficient and atom-eco-
nomical manner through the formation of multiple new
bonds and stereocenters in a one-pot system, which saves
time and energy by avoiding purification of intermediates
and the protection/deprotection of functional groups.[2] In
the field, not only most two-step[3] but also many three-step
MCCRs[4] have been successfully achieved using chiral sec-
ondary amines as the catalysts, which are capable of both
enamine (En) and iminium (Im) catalysis in tandem se-
quence.[5] Recently, Kotame and co-workers[6] developed an
elegant three-component quadruple domino reaction be-
tween 2-(E)-2-nitrovinyl)phenol and a,b-unsaturated alde-
hydes to produce tetrahydro-6H-benzo[c]chromenes with
excellent enantioselectivity through iminium–enamine–imi-
nium–enamine activation. However, control of more steps
with more components to achieve more bond formations
consecutively using chiral secondary amines through enam-
ine and iminium activation remains an unmet challenge, be-
cause the potential reactions will proceed in an exponential
amplification mode as the number of components and steps
increased.
phenols[6,9] to a,b-unsaturated aldehydes were investigated,
there are no examples available for the MCCRs initiated by
oxa-Michael addition of simple alcohol to a,b-unsaturated
aldehyde. In addition, b-alkoxy propanal, a commercially
unavailable intermediate, is usually prepared by a two-step
sequence involving monoalkylation of 1,3-propanediol and
subsequent Swern oxidation.[10] Few examples have been re-
ported that the oxa-Michael addition reaction of alcohol to
acrolein requires six days to provide b-alkoxy propanal in a
moderate yield; in addition this methodology is limited to
specific substrate alcohol such as p-methoxybenzyl alco-
hol.[11] To the best of our knowledge, one case about the
asymmetric intermolecular oxa-Michael addition of simple
alcohols to a,b-unsaturated aldehydes using chiral biphenyl
diamine catalyst has been reported thus far,[12] in which only
a moderate yield of the desired oxa-Michael adduct was ob-
tained, mainly due to the relative weakness of O-nucleo-
philes, the reversibility of reaction, the affinity for acetal for-
mation and self-aldol reaction of the oxa-Michael adduct.[13]
We assumed that the side-reactions mentioned above could
partially be circumvented by introducing high reactive Mi-
chael acceptors such as nitroalkenes to the reaction system
for their ease to react with b-alkoxy aldehyde generated in
situ by addition of simple alcohols to a,b-unsaturated alde-
hydes. Herein, we envisioned four-component (ABC2) quad-
ruple cascade reaction through iminium–enamine–iminium–
enamine sequential activation initiated by oxa-Michael addi-
tion of alcohol to acrolein, as outlined in Scheme 1, to pro-
vide a straightforward protocol for the synthesis of chiral
cyclic products with multiple substituents.
On the other hand, although the domino reactions involv-
ing the hetero-Michael addition of amines,[3i,7] thiols[3g,8] and
[a] Dr. F.-L. Zhang, A.-W. Xu, Prof. Dr. Y.-F. Gong, M.-H. Wei
Department of Chemistry
In this process, we found that a diphenylprolinol silyl
Huazhong University of Science and Technology
1037 Luoyu Road, Wuhan, Hubei 430074 (China)
Fax : (+86)27-87543632
ether[14] catalyzed the oxa-Michael/Michael/Michael/aldol
E-mail: gongyf@mail.hust.edu.cn
[b] Prof. Dr. X.-L. Yang
College of Life Science and Technology
Huazhong University of Science and Technology
1037 Luoyu Road, Wuhan, Hubei 430074 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900613.
Scheme 1. Four-component quadruple cascade organocatalysis.
Chem. Eur. J. 2009, 15, 6815 – 6818
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6815

Table 1. Representative screening results of the MCCR.[a]
condensation reaction between simple alcohol 1, acrolein
and nitroalkene 2; the reaction afforded highly functional-
ized trisubstituted cyclohexene carbaldehyde 4 with excel-
lent stereoselectivity. As outlined in Scheme 2, in the first
step, the catalyst 3 reacts with acrolein to give the iminium
ion intermediate A. Alcohol 1, as a hard oxygen nucleo-
phile, selectively reacts with A to give enamine intermediate
B, which then prefers to react with nitroalkene 2 to give Mi-
chael product C. In the third step, the nitroalkane C subse-
quently reacts with A to generate enamine intermediate D,
which is unstable and easily reacts through an intramolecu-
lar aldol condensation under the reaction conditions, provid-
ing the desired trisubstituted cyclohexene carbaldehyde 4
and regenerating catalyst 3.
Entry
Cat. ([%])
Additive
([%])
t [h]
Yield[b]
[%]
d.r.[c]
n.d.
ee[d] [%]
1[e]
2
3 (10)
3 (10)
I (30)
II (30)
III (30)
3 (10)
3 (5)
none
84
84
84
84
84
24
48
24
<2
52
n.d.
>99
n.d.
n.d.
n.d.
>99
>99
>99
none
none
none
none
IV (10)
IV (5)
IV (25)
>20:1
n.d.
3
4
5
6
<5
<5
<5
50
51
54
n.d.
n.d.
>20:1
>20:1
>20:1
7
8
3 (5)
[a] Reactions performed with methanol (1 mmol), nitrostyrene
(0.25 mmol), acrolein (1 mmol) and solvent (0.5 mL) at 48C. [b] Isolated
yield of main diastereomer. [c] Determined by 1H NMR spectroscopy of
the crude mixture. [d] The ee value for the major diastereomer deter-
mined by HPLC. [e] Methanol as the solvent.
the MCCR has broad applicability. Simple aliphatic alcohols
such as ethanol, n-butanol, and benzyl alcohol are also reac-
tive enough to participate, to yield the corresponding ad-
ducts in moderated to good yields (entry 1–4). Furthermore,
this reaction system was also suitable for secondary alcohol
(isopropanol) and for functional alcohols such as allyl alco-
hol, 2-chloroethanol, propargyl alcohol and 2-furanmethanol
(entry 5–9). Besides alcohols, phenols can also act as O-nu-
cleophiles. In the case of p-methoxyphenol, good yields of
the product were obtained without addition of benzoic acid
(entry 10). On the other hand, the reaction proceeds effi-
ciently for different nitroalkenes not only with electron-rich
aromatic substituents such as 3,4-methylenedioxyphenyl, but
also with electron-deficient substituents such as p-chloro-
phenyl (entry 11–12). Heteroaromatic groups such as furyl
are also suitable substituents (entry 13). In addition, it
should be emphasized that this MCCR was also applicable
to produce 4 on a larger scale. For example, the reaction be-
tween methanol, acrolein and nitrostyrene on a 10 mmol
scale gave 1.49 g (54% yield) of 3-(methoxymethyl)-5-nitro-
4-phenylcyclohex-1-ene carbaldehyde (4a) (entry 3). Fore-
most, in all cases, the cyclohexene carbaldehydes 4 were ob-
tained with excellent diastereomeric and complete enantio-
meric control.
Scheme 2. Proposed mechanism for the organocatalyzed asymmetric
four-component quadruple cascade reaction.
The quadruple domino reaction of methanol, acrolein and
nitrostyrene was investigated first in the presence of
10 mol% of catalyst 3 in methanol at 48C. The desired
product 4a was detected in low yield by GC-MS (Table 1,
entry 1). By screening the solvents, an encouraging result
was observed in that 52% yield of the adduct 4a was isolat-
ed with excellent diastereoselectivity and an enantiopure
form[15] (entry 2) after reacting methanol (4 equiv), acrolein
(4 equiv) and nitrostyrene (1 equiv) in chloroform. To opti-
mize the reaction conditions of this MCCR, other different
amine catalysts such as pyrrolidine, proline and diphenylpro-
linol (entry 3–5) were also estimated, but no 4a could be ob-
tained in all cases. As expected, the reaction was significant-
ly accelerated by adding benzoic acid, which probably pro-
moted the formation of the iminium ion (entry 6–8). When
25 mol% of benzoic acid was used, loading of catalyst 3
could be reduced to 5 mol% and a good yield (54%) of 4a
was obtained without compromising the enantio- and diaste-
reoselectivity (entry 8).
In summary, we have described a novel organocatalytic
four-component domino oxa-Michael/Michael/Michael/aldol
condensation reaction, which can be explained as an imini-
um–enamine–iminium–enamine sequence, by treating alco-
hol, acrolein and nitroalkene. Through three intermolecular
Michael and one intramolecular aldol condensation step,
this quadruple cascade reaction enables the consecutive for-
mation of four new bonds and provides an atom economic
The generality of the MCCR initiated by oxa-Michael ad-
dition was assessed next under the reaction conditions de-
scribed above. The results summarized in Table 2 show that
6816
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Chem. Eur. J. 2009, 15, 6815 – 6818

Asymmetric Organocatalytic Domino Reactions
Table 2. Scope of the MCCR.[a]
COMMUNICATION
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Entry R1
R2
4
Yield[b] [%] d.r.[c] [%] ee[d] [%]
1
2
nBu
Et
Me
Bn
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4b 49
4c 54
4a 54
4d 49
4e 57
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
3[e]
4
5
6
7
8
iPr
Allyl
2-Cl-Et
propargyl
2-furan-Me Ph
p-MeO-Ph Ph
Me
Me
Me
4 f
56
4g 46
4h 41
9
4i
4j
54
51
10[f]
11
12
13
p-Cl-Ph
V[g]
2-furanyl 4m 54
4k 49
4l 55
[a] Reactions performed using catalyst (S)-3 (0.05 mmol), benzoic acid
(0.25 mmol), alcohol (4 mmol), nitroalkene (1 mmol), acrolein
1
2
(4 mmol) in chloroform (2 mL) at 48C. [b] Isolated yield of main diaste-
reomer. [c] Determined by 1H NMR spectroscopy of the crude mixture.
[d] The ee value for the major diastereomer determined by HPLC.
[e] The reaction carried out on a 10 mmol scale. [f] The reaction per-
formed with p-methoxy-phenol (1.5 mmol), catalyst (S)-3 (10%) without
PhCO2H. [g] V=3,4-(Methylenedioxy)-Ph.
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Experimental Section
Typical procedure: Methanol (0.162 mL, 4.0 mmol) and acrolein (224 mg,
4.0 mmol) were added to nitrostyrene (149 mg, 1.0 mmol) in choroform
(2 mL). The mixture was cooled to 48C. Catalyst (S)-3 (16 mg, 5 mol%)
and benzoic acid (30 mg, 25 mol%), were added and the solution was
stirred until complete conversion of the starting materials (monitored by
TLC). The crude reaction mixture was directly loaded on a silica gel
column, and column chromatography (ethyl acetate/petroleum ether 1:6)
afford the pure product 4a as colorless oil (149 mg, 54%, 99% ee). The
enantiomers were determined by HPLC (Daicel Chirapak OD-H, flow
rate 0.5 mLminÀ1, n-heptane/isopropanol 90:10, 254 nm, Retention time:
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Acknowledgements
This work was supported by National Natural Science Foundation of
China (20572028, 20872041). The Center of Analysis and Testing of
Huazhong University of Science and Technology is thanked for charac-
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Keywords: domino reactions
multicomponent reactions · organocatalysis
·
Michael addition
·
Chem. Eur. J. 2009, 15, 6815 – 6818
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6817

Y.-F. Fong et al.
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[15] Relative stereochemical configuration assigned by NOE experi-
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was deduced based on the results reported by Enders (see ref. [4b]).
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Received: March 8, 2009
Published online: June 19, 2009
6818
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Chem. Eur. J. 2009, 15, 6815 – 6818