Recyclable tertiary amine modified diarylprolinol ether as aminocatalyst for the sequential asymmetric synthesis of functionalized cyclohexanes and chromenes

Article abstract of DOI:10.1002/ejoc.201100613

The one-pot, organocatalytic Hayashi sequential reaction (HSR) of β-nitroacrylate, aldehyde, toluenethiol, and ethyl 2-(diethoxyphosphoryl) acrylate allowed the synthesis of almost stereoisomerically pure, highly functionalized polysubstituted cyclohexane

Full text of DOI:10.1002/ejoc.201100613

FULL PAPER
DOI: 10.1002/ejoc.201100613
Recyclable Tertiary Amine Modified Diarylprolinol Ether as Aminocatalyst for
the Sequential Asymmetric Synthesis of Functionalized Cyclohexanes and
Chromenes
Hao Shen,[a] Ke-Fang Yang,*[a] Zi-Hui Shi,[a] Jian-Xiong Jiang,[a] Guo-Qiao Lai,*[a] and
Li-Wen Xu*[a,b]
Keywords: Asymmetric catalysis / Organocatalysis / Domino reactions / Multicomponent reactions / Silicon
The one-pot, organocatalytic Hayashi sequential reaction
(HSR) of β-nitroacrylate, aldehyde, toluenethiol, and ethyl 2-
(diethoxyphosphoryl)acrylate allowed the synthesis of almost
of salicyladehydes with α,β-unsaturated aldehydes with recy-
clable tertiary amine-modified diarylprolinol silyl ether 3d as
an effective organocatalyst, which results in the formation of
stereoisomerically pure, highly functionalized polysubsti- chiral chromenes with good enantioselectivities (up to
tuted cyclohexanes with very high diastereo- and enantio-
selectivity (up to Ͼ 99%ee). The one-pot synthesis consists
of the tertiary amine modified diarylprolinol silyl ether-medi-
ated asymmetric Michael reaction, a domino Michael reac-
94 %ee). UV/Vis and CD spectroscopy provide a cross-vali-
dation method to elucidate the slight difference between
electron-withdrawing 3d and diphenylprolinol silyl ether 3a,
which can give indirect evidence for the enhancement of
enantioselective induction with 3d in the above transforma-
tions.
tion/Horner–Wadsworth–Emmons reaction, and
a sulfa-
Michael reaction. In addition, we have also demonstrated an
improved protocol for the domino oxa-Michael/aldol reaction
Jørgensen[6] and Hayashi[7] in 2005, this class of silyl or-
ganocatalysts (Jørgensen–Hayashi catalysts) has emerged as
a powerful enamine organocatalyst in many organic trans-
formations,[8] including Michael reactions, cycloaddition,
domino reactions, and total syntheses, through the acti-
vation of aldehydes either by enamine formation (raising
the highest occupied molecular orbital)[9] or α, β-unsatu-
rated aldehydes by iminium ion formation (lowering the
lowest unoccupied molecular orbital).[10] Herein, we present
our recent results on the tertiary amine-modified diarylpro-
linol ether as a water soluble, recyclable organocatalyst to
promote one-pot sequential addition of aldehydes, β-nitro-
acrylate compounds, and ethyl 2-(diethoxyphosphoryl)-
acrylate, in which the sequential reaction affords function-
alized cyclohexanes, a similarly basic six-membered back-
bone or intermediate of (–)-oesltamivir phosphate (Tami-
flu), a neuraminidase inhibitor used in the treatment of
both type A and type B human influenza.[11] Furthermore,
we also report the one-pot, enantioselective domino oxa-
Michael/aldol reaction for the facile preparation of benzo-
pyranes in the presence of the same water soluble tertiary
amine or ammonium salt-modified diarylprolinol silyl
ether.
Introduction
The sequential reaction can be considered as one of the
most powerful and reliable tools for the one-pot construc-
tion of complicated molecules from simple and commer-
cially available substrates.[1] The development of sequential
one-pot enantioselective reactions is a new direction in or-
ganocatalysis.[2] Furthermore, asymmetric organocatalytic
sequential reactions catalyzed by chiral amines,[3] especially
secondary amines, have grown rapidly to become one of
the most exciting topics in asymmetric organocatalysis, as
secondary amines are capable of both enamine and iminium
catalysis.[4] In particular, the incorporation of silyl groups
in aminocatalysts, which allow steric and electronic modifi-
cations, has led to the enhancement in enantioselectivity
and reactivity.[5] Since the first example of the use of amino
alcohol derived silyl ethers (diarylprolinol silyl ethers) in
asymmetric synthesis was independently developed by
[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
licpxulw@yahoo.com
[b] State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences,
Results and Discussion
Lanzhou 730000, P. R. China
The asymmetric Michael reaction of aldehyde and β-ni-
troacrylate catalyzed by diphenylprolinol silyl ether is the
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100613.
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FULL PAPER
first step that we have investigated. In 2008, Ma et al.[12] spectroscopy, we have demonstrated that the role of the sili-
reported the excellent asymmetric induction ability of di- con group in the diaryl prolinol silyl ethers (Jørgensen–
phenylprolinol silyl ether in the Michael reaction of alde- Hayashi catalyst) is not only as a bulky group to induce the
hydes to β-nitroacrylate. In 2009, Hayashi et al.[13] applied steric repulsion but also as a weak Lewis acidic promoter to
this key reaction in the three-step total synthesis of (–)-osel- facilitate the formation of the iminium intermediate derived
tamivir using alkoxyaldehyde, nitroalkene, and subsequent from the secondary amine and the substrate (α,β-unsatu-
treatment with diethyl vinylphosphonate. Although there rated aldehyde). According to 29Si NMR analysis, it was
are many important protocols for the synthesis of (–)-osel- expected that the presence of the tertiary amine on the aro-
tamivir,[14] one of the most efficient is that of Hayashi et matic ring of the diaryl prolinol silyl ether resulted in a
al.[13] with diphenylprolinol silyl ether as an organocatalyst higher level of stereoselectivity, perhaps due to the suppres-
(Scheme 1). In this procedure, the sequential reaction was sion of a possible intramolecular hypervalent conformer.
mainly composed of an asymmetric Michael reaction, Although we failed to observe the obvious differences be-
a Horner–Wadsworth–Emmons reaction, and a sulfa- tween the tertiary amine-modified diarylprolinol silyl ether
Michael reaction.
and the unmodified diphenylprolinol silyl ether with NMR
and other spectra analysis, the design and modification of
efficient chiral organocatalysts that lead to enhanced
enantioselectivity is not an easy task and could be one of
the major challenges in the growing field of asymmetric or-
ganocatalysis.
Scheme 1.
The HSR is valuable in the search for molecules effective
against Tamiflu-resistant viruses. However, major problems
associated with this organocatalytic system are high catalyst
loading (5–10 mol-%) and the difficulty of recovering the
catalyst from the reaction mixture. Therefore, it is impor-
tant to develop a convenient method to facilitate the recov-
Scheme 2. Catalytic asymmetric Friedel–Crafts alkylation of ind-
oles.
Previous findings led us to continue to hypothesize that
ery and reuse of the expensive organocatalysts. Ni et al.[15] the water soluble, recyclable tertiary amine-modified diaryl-
have provided a simple example of a modified organocata- prolinol silyl ether and some other chiral secondary amines
lyst using a tertiary amine-modified diarylprolinol silyl could act as effective organocatalysts in the important HSR
ether and its salt as efficient, water soluble, recyclable or- for the synthesis of functionalized cyclohexanes, a possible
ganocatalysts for asymmetric Michael addition. The hy- intermediate of (–)-oesltamivir phosphate. We started our
pothesis is based on the ability of the dimethylamine group investigation with a set of experiments to identify the most
of the catalyst to form water soluble ammonium salts with efficient secondary amine catalysts for the domino–tandem
a Brønsted acid. Their strategy proved to be efficient in the reaction as a model reaction (Scheme 3). Therefore, the se-
asymmetric Michael addition of aliphatic aldehydes to ni- arch for another excellent organocatalyst and optimal con-
troolefins in water, which provided the Michael adducts ditions for the domino–tandem addition of aldehydes, β-
with excellent diastereo- and enantioselectivities (Ͼ 98 %ee, nitroacrylate compounds, and ethyl 2-(diethoxyphosphor-
Ͼ 95:5 dr). Moreover, the catalytic system can be easily re- yl)acrylate to the enantioselective construction of optically
covered and reused at least six times without significant loss active functionalized cyclohexanes was performed using the
of catalytic activity.
well known diphenylprolinol silyl ether as the starting or-
We have recently reported the use of a tertiary amine- ganocatalyst.
modified diarylprolinol silyl ether in the catalytic, asymmet-
As shown in Scheme 3 and Table 1, we prepared several
ric Friedel–Crafts alkylation of indoles (Scheme 2),[16] secondary amine-based organocatalysts 3a–f, and the reac-
which resulted in the highly enantioselective Friedel–Crafts tion results under optimized conditions are shown in
alkylation of indoles with α,β-unsaturated aldehydes with Table 1. However, the diphenylprolinol silyl ether is not per-
excellent enantioselectivities (up to Ͼ 99 %ee). This im- fect for this example: the enantiomeric excess of this reac-
proved method offers substantial advantages over tradi- tion is only 87 %ee when (E)-ethyl 3-nitroacrylate was used
tional approaches, not only by avoiding the use of acids and a model substrate in this domino reaction. Although other
bases, but also the high level of stereoselectivity. In ad- aminocatalysts, such as 3b, 3c, 3e, and 3f, did not lead to a
dition, on the basis of experimental results and 29Si NMR significant improvement in enantioselectivity (up to
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Recyclable Modified Diarylprolinol Ether as Aminocatalyst
pensive organocatalyst (about 1200 RMB/1 g or 130 EUR/
1 g), this procedure demonstrates that 3d is recyclable and
would be beneficial for the large scale preparation of the
intermediate of (–)-oesltamivir phosphate.
Having established an optimal protocol for the domino
reaction, we examined the scope and limitations of the 3d
catalyzed sequential transformation with regard to different
aldehydes (Scheme 4). To our delight, in all cases, the dom-
ino–tandem reaction proceeded smoothly to furnish the de-
sired functionalized cyclohexanes in moderate overall yields
and with excellent enantioselectivities (up to Ͼ 99 %ee) un-
der the optimized conditions. Both linear and branched
apliphatic aldehydes, as well as aldehydes with an aryl or
silicon-based bulky groups, were found to be suitable sub-
strates in the domino–tandem reaction.
Scheme 3. Screening of organocatalysts for the asymmetric HSR of
β-nitroacrylate, aldehyde, toluenethiol, and ethyl 2-(diethoxyphos-
phoryl)acrylate.
65 %ee) and conversion (up to 32% yield), we found that
diarylprolinol silyl ether 3d containing a tertiary amine
moiety catalyzed the domino–tandem reaction very ef-
ficiently to afford the functionalized cyclohexane 10a with
five chiral centers in an acceptable yield as a single isomer
and with excellent enantioselectivity (95 %ee). This is in ac-
cordance with a previous report that the presence of a terti-
ary amine in diarylprolinol silyl ether is important for the
enhancement of enantioselectivities in different Michael re-
actions.[16] In addition, the HSR of β-nitroacrylate, alde-
hyde, toluenethiol, and ethyl 2-(diethoxyphosphoryl)acryl-
ate, was chosen as the model to examine the recyclability
of 3d. After the three-step sequential reaction was com-
pleted, 1 n HCl was added to the reaction solution. The
desired product, along with starting reagents and side-prod-
ucts of the reaction, was extracted into mixed solvent
(Et2O/hexane, 1:8).[15] The recovered aqueous phase con-
taining 3d-HCl was neutralized with aqueous K2CO3 and
the majority of 3d was obtained by simple extraction and
evaporation. Although diarylprolinol silyl ether is an ex-
Scheme 4. Direct organocatalytic asymmetric sequential reactions
of different aldehydes under optimized conditions.
Inspired by our work on diarylprolinol silyl ether cataly-
sis, and having established the 3d-catalyzed HSR of β-nitro-
acrylate, aldehyde, toluenethiol, and ethyl 2-(diethoxyphos-
phoryl)acrylate, we then considered improving the enantio-
selectivity of another sequential transformation with 3d as
the organocatalyst. Asymmetric domino oxa-Michael/aldol
sequences constitute a very effective and straightforward
entry to enantioenriched benzopyranes, also known as
chromenes, widespread constituents in natural products
with proven pharmacological activity. Since 2006, several
groups,[19] have reported their findings on pyrrolidine silyl
ether-catalyzed oxa-Michael initiated domino reactions. A
series of secondary amine organocatalysts and the combi-
nation of different organocatalysts have been tested for the
conjugate addition of salicylaldehyde to trans-cinnamal-
Table 1. Effect of chiral secondary amine-based organocatalysts in
the HSR (Scheme 3).[a]
Entry
Cat. (5 mol-%) Total yield [%][b]
ee[c]
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
46
Ͻ 10
18
51
trace
32
87
–
–59
95
–
–65
[a] Reaction conditions: aldehyde 1a (3 mmol), β-nitroacrylate 7
(2 mmol), (R) or (S)-diarylprolinol trimethylsilyl ether 3d (44 mg,
5 mol-%), 2-(diethoxyphosphoryl)acrylate 8 (708 mg, 3 mmol), and
toluenethiol (10 mmol). The reaction was carried out according to
ref.[13] [b] Total isolated yield for the one-pot domino operation. [c]
Enantiomeric excess (%) was determined by chiral HPLC analysis. dehyde. Most methods reported gave considerable turnover
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FULL PAPER
and promising levels of enantioselectivity (72–90 %ee) un-
der different conditions (Scheme 5). Despite the fact that 3a
was employed as an efficient organocatalyst in the domino
oxa-Michael/aldol condensation, enhanced enantio-
selectivity is still highly desired and there is much room for
improvement. Herein, we report an improved protocol for
the domino oxa-Michael/aldol reaction of salicyladehydes
with α,β-unsaturated aldehydes using 3d as an effective or-
ganocatalyst, resulting in the formation of chiral chromenes
with comparable and superior enantioselectivities (up to
94 %ee).
Scheme 5. Direct organocatalytic asymmetric domino oxa-Michael/
aldol reactions of salicylaldehyde and trans-cinnamaaldehyde re-
ported by different groups.[19]
Initially, we set out to investigate the catalytic activity of
(S)-3d in the sequential addition of salicylaldehyde and
trans-cinnamaldehyde under different conditions. An inves-
tigation on the effect of acid, base, and Lewis acidic addi-
tives on the reaction and extensive optimization of reaction
conditions determined that p-chlorobenzoic acid and mo-
lecular sieves provided the highest enantioselectivity
(83 %ee) and isolated yield (93%).
Scheme 6. Organocatalytic asymmetric oxa-Michael/aldol reac-
tions.
The optimized reaction conditions were applied to sev- to explain the slight steric difference between diphenylpro-
eral α,β-unsaturated aldehydes 11 and salicylaldehydes 12 linol silyl ether 3a and tertiary amine-modified diarylpro-
to probe the scope of the domino oxa-Michael/aldol pro- linol silyl ether 3d on enantioselective induction. However,
cess. As the data in Scheme 6 show, the reaction appears as the initial screening of catalysts showed the importance
to have a broad scope, but efficiencies (15–93% yield) and of the tertiary amine group, we believe that the electronic
enantioselectivities (58–94 %ee) varied with the electronic effect of the amine enhances the enantioselective activity of
and steric nature of 11 and 12. We found that the use of 5- the chiral seconary amine. Considering the small structural
methoxysalicyclaldehyde resulted in increased yields, and and electronic differences between 3a and 3d, the study of
the use of aliphatic α,β-unsaturated aldehydes led to good the enhanced enantioselectivity with 3d is surprising. In an
to excellent enantioselectivities (83–94 %ee). Notably, effort to demonstrate the structural discrepancies between
among the substrates investigated, the organocatalyst (S)- 3a and 3d, the electronic properties of 3a and 3d with dif-
or (R)-3d gave better efficiencies and enantioselectivities ferent groups (H and CH2NMe2, respectively) were investi-
compared to those of 3a in this reaction; for example, for gated by UV/Vis and CD spectroscopy. The structural in-
13b, 3d gave 94 %ee and 75% yield, and 3a resulted in formation obtained from these methods appear quite indi-
90 %ee and a poor yield (21%).[19a] The results showed that rect, but they present many advantages compared to more
relatively higher ee values and yields were consistently ob- conventional spectroscopy in the elucidation of electronic
served for 3d in this reaction.[20] Although the enantio- properties.
selectivities and yields for several structural motifs were un-
The electronic absorption spectra of 3a and 3d display
satisfactory, it is still one of the most efficient methods for several intense absorption bands between 220 and 300 nm
the preparation of chiral chromenes from readily available (Figure 1). The spectrum of 3d is redshifted compared to
starting materials and the results show that modifying that of 3a, which indicates the presence of a different π-
Jørgensen–Hayashi catalysts with an amino group on the conjugated system within the aryl ring that is though to
diaryl prolinol silyl ether enhances stereoselectivity in this arise from a p orbital conjugated, electron-withdrawing
transformation.
CH2NMe2 group and nǞπ* transition.
Although the origin of the enantioselectivity in the di-
CD spectroscopy has been shown to be a sensitive and
arylprolinol silyl ether-catalysed transformation through powerful tool for analytical applications.[22] To elucidate the
enamine or iminium catalysis has been investigated spectro- difference between 3a and 3d, we have investigated and
scopically and with DFT calculations,[21] it is still difficult compared the chiroptical properties of the chiral 3a and 3d
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Recyclable Modified Diarylprolinol Ether as Aminocatalyst
can conclude that the enantioselective induction and the
rate of diarylprolinol silyl ether-catalyzed transformations
are largely dependent on the electronic effect of the aryl
substitutents.
Conclusions
We have shown that the tertiary amine-modified diaryl-
prolinol silyl ether 3d can be successfully used as an efficient
organocatalyst in the sequential reaction of β-nitroacrylate,
aldehydes, toluenethiol, and ethyl 2-(diethoxyphosphoryl)-
acrylate. Notably, this strategy improved the enantio-
selectivity from 87–95 %ee without affecting the conver-
sion. The reaction proceeds with superior and complete re-
gioselectivity with a very high enantioselectivity to furnish
almost stereoisomerically pure, highly functionalized, pol-
ysubstituted cyclohexanes. In addition, we have demon-
strated an improved protocol for the domino oxa-Michael/
aldol reaction of salicyladehydes with α,β-unsaturated alde-
hydes in which recyclable 3d was used as an effective organo-
catalyst. This protocol resulted in the formation of chiral
chromenes with comparably good enantioselectivities (up to
94 %ee). Finally, UV/Vis and CD spectroscopy provide a
cross-validation method, which elucidates the slight differ-
ence between electron-withdrawing tertiary amine-modified
diarylprolinol silyl ether 3d and diphenylprolinol silyl ether
3a. This gives indirect evidence for the enhancement of
enantioselective induction with 3d in these transformations.
Although the current organocatalytic route has some
limitations in terms of yields and enantioselectivities, the
oxa-Michael/aldol reaction constitutes a direct catalytic
asymmetric route to chiral chromenes, and modifying
Jørgensen–Hayashi catalysts with the introduction of an
amino group on the diarylprolinol silyl ether enhances ster-
eoselectivity in certain asymmetric transformations setting
the benchmark for further development.
Figure 1. UV/Vis spectra of (S)-3d and (S)-3a in CH2Cl2.
by CD in CH2Cl2. As shown in Figure 2, we can see that the
chiroptical properties of diarylprolinol silyl ethers appear to
be dominated by the two geminal aryl rings that reflect n–
π* and π–π* transitions due to the existence of the H and
CH2NMe2 groups, respectively. Moreover, the differences
between 3a and 3d reflect the electronic nature of the
CH2NMe2 group in 3d. UV/Vis and CD spectroscopy pro-
vide a cross-validation method to elucidate the slight differ-
ence between the electron-withdrawing 3d and 3a, which
gives indirect evidence for the enhancement of enantioselec-
tive induction with catalyst 3d in the above transformations.
Very recently, Zeitler and Gschwind et al.[23] demonstrated
that the electronic contributions of electron-donating
groups and electron-withdrawing groups should have the
opposite effect on the enamine amounts and the stability of
enamine intermediates. Therefore, in analogy to this new
investigation and on the basis of experimental results, we
Experimental Section
General Remarks: All reagents and solvents were used directly with-
out purification. Flash column chromatography was performed
1
with silica (200–300 mesh). H NMR and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively with an Advance
(Bruker) 400 MHz Nuclear Magnetic Resonance Spectrometer, and
were referenced to internal solvent signals. TLC was performed
using silica gel F254 TLC plates and visualized with ultraviolet
light. HPLC was carried out with a Waters 2695 Millennium system
equipped with a photodiode array detector. EI and CI mass spectra
were performed with a Trace DSQ GC/MS spectrometer. The dom-
1
ino reaction products were confirmed by GC–MS, H NMR, and
13C NMR spectroscopy. The ESI-MS analysis of the samples was
performed with an LCQ advantage mass spectrometer (Thermo-
Fisher Company, USA), equipped with an ESI ion source in the
positive ionization mode, with data acquisition using the Xcalibur
software (Version 1.4). The diarylprolinol silyl ethers were synthe-
sized according to reported procedures.[6–8,15–17]
Typical Procedure for One-Pot Asymmetric Domino-Tandem Reac-
Figure 2. CD spectra of (R)-3d and (S)-3d (top) and (S)-3d and
(S)-3a (bottom) in CH2Cl2.
tions: o-Nitrobenzoic acid (66.8 mg, 20 mol-%)[18] was added to a
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H. Shen, K.-F. Yang, Z.-H. Shi, J.-X. Jiang, G.-Q. Lai, L.-W. Xu
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solution of aldehyde 1 (3 mmol), β-nitroacrylate 7 (2 mmol), and
(R)-diarylprolinol trimethylsilyl ether 3d (44 mg, 5 mol-%) in
CH2Cl2 (4 mL) at room temperature. The reaction mixture was
stirred overnight at room temperature followed by addition of ethyl
2-(diethoxyphosphoryl)acrylate 8 (708 mg, 3 mmol), and Cs2CO3
(6 mmol) at 0 °C. After the resulting suspension was stirred for
additional 3 h at 0 °C, the solvent was removed under reduced pres-
sure. EtOH (6 mL) was added, and the resulting mixture was stirred
for 15 min at room temperature before addition of toluenethiol
(10 mmol) at –15 °C. The resulting mixture was stirred for 36 h at
room temperature before being quenched with cold 2 n HCl. The
products in the aqueous layer were extracted three times into
CHCl3. The combined organic layers were washed with saturated
aqueous NaHCO3, dried with MgSO4, and concentrated under re-
duced pressure. Flash chromatography (silica gel) provided 10a–f.
7.6 Hz, 2 H), 6.84–6.86 (t, J = 3.2 Hz, 2 H), 4.73–4.80 (m, 1 H),
4.13–4.22 (m, 4 H), 3.84–3.92 (m, 1 H), 3.69 (m, 1 H), 3.18–3.19
(d, J = 3.2 Hz, 1 H), 2.98–3.00 (m, 1 H), 2.68–2.74 (m, 2 H), 2.42–
2.49 (m, 2 H), 2.30 (s, 3 H), 1.26–1.27 (m, 3 H), 1.00–1.03 (t, J =
7.2 Hz, 3 H) ppm. 13C NMR(100 MHz, CDCl3): δ = 172.3, 170.1,
137.8, 137.3, 131.8, 130.9, 129.7, 129.3, 129.1, 128.8, 128.5, 126.5,
85.0, 61.7, 61.1, 50.2, 48.2, 46.1, 45.8, 36.3, 27.4, 21.1, 14.2, 13.9
ppm. IR (film): ν
= 3028, 2980, 2932, 2870, 1730, 1552, 1494,
˜
max
1455, 1370, 1371, 1290, 1257, 1213, 1163, 1116, 1094, 1029, 952,
866, 810, 739, 700 cm–1. ESI-MS: m/z = 992.73 (dimer + Na). The
ee value of the product was determined by HPLC with a Daicel
AD-H column (hexane/iPrOH = 95:5), flow rate 1.0 mLmin–1,
tmajor = 9.926 min; tminor = 11.895 min.
10e: 45% yield, 98 %ee, 1H NMR (400 MHz, CDCl3): δ = 7.38–
7.40 (d, J = 8.0 Hz, 2 H), 7.06–7.08 (d, J = 8.0 Hz, 2 H), 4.65–4.72
(m, 1 H), 4.12–4.23 (m, 4 H), 3.94–3.99 (m, 1 H), 3.91 (m, 1 H),
10a: 51% yield, 95 %ee, 1H NMR (400 MHz, CDCl3): δ = 7.38 (d,
J = 8.0 Hz, 2 H), 7.06 (d, J = 8.0 Hz, 2 H), 4.61–4.68 (m, 1 H),
4.20–4.28 (m, 1 H), 4.06–4.17 (m, 2 H), 3.98–4.00 (t, J = 7.2 Hz, 1
H), 3.84–3.90 (m, 1 H), 3.77–3.81 (dd, J1 = 3.6, J2 = 10.8 Hz, 1
H), 3.38–3.44 (t, J = 10.8 Hz, 1 H), 3.12–3.18 (m, 1 H), 2.74–2.79
3.07–3.13 (t, J = 11.2 Hz, 1 H), 2.78–2.83 (dt, J1 = 3.2, J2
=
13.2 Hz, 1 H), 2.68–2.72 (dt, J1 = 3.6, J2 = 13.6 Hz, 1 H), 2.30–
2.32 (m, 4 H), 1.21–1.29 (m, 14 H), 0.83–0.87 (m, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 172.5, 170.6, 137.7, 132.6, 131.3,
129.8, 85.0, 61.5, 61.4, 51.7, 48.2, 46.4, 45.0, 31.9, 30.5, 29.5, 29.4,
(dt, J1 = 3.2, J2 = 13.2 Hz, 1 H), 2.60–2.65 (dt, J1 = 3.6, J2
=
29.2, 27.7, 26.9, 22.7, 21.1, 14.2, 14.1 ppm. IR (film): νmax = 2926,
˜
13.6 Hz, 1 H), 2.30–2.36 (m, 4 H), 1.25–1.30 (m, 6 H), 1.16–1.20
(t, J = 7.2 Hz, 4 H), 0.72–0.76 (t, J = 7.2 Hz, 3 H), 0.62–0.65 (t, J
= 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.0,
170.1, 137.7, 133.0, 131.4, 129.6, 83.4, 80.4, 76.8, 61.8, 61.6, 52.8,
2852, 1732, 1558, 1493, 1439, 1378, 1366, 1319, 1290, 1261, 1200,
1158, 1135, 1034, 886, 812, 560 cm–1. ESI-MS: m/z = 1036.89 (di-
mer + Na). The ee value of the product was determined by HPLC
with a Daicel IB column (hexane/iPrOH = 97:3), flow rate
0.5 mLmin–1, tmajor = 13.148 min; tminor = 16.596 min.
49.2, 43.5, 27.0, 25.1, 23.7, 21.2, 14.2, 9.0, 8.5 ppm. IR (film): ν
˜
max
= 2965, 2937, 2878, 1733, 1557, 1493, 1463, 1376, 1290, 1260, 1197,
1033, 953, 810 cm–1. ESI-MS: m/z = 481.83. The ee value of the
product was determined by HPLC with a Daicel IA column (hex-
ane/iPrOH = 90:10), flow rate 1.0 mLmin–1, tmajor = 5.704 min;
tminor = 8.542 min.
1
10f: 45% yield, 90 %ee, H NMR (400 MHz, CDCl3): δ = 7.37 (d,
J = 8.0 Hz, 2 H), 7.06 (d, J = 8.0 Hz, 2 H), 4.61–4.68 (m, 1 H),
4.23–4.31 (m, 1 H), 4.03–4.11 (m, 3 H), 3.81–3.87 (m, 2 H), 3.38–
3.43 (t, J = 10.8 Hz, 1 H), 2.78–2.83 (dt, J1 = 3.2, J2 = 13.2 Hz, 1
H), 2.60–2.65 (dt, J1 = 3.6, J2 = 13.6 Hz, 1 H), 2.29 (s, 3 H), 1.25–
1.29 (t, J = 7.2 Hz, 4 H), 1.15–1.19 (t, J = 6.8 Hz, 3 H), 0.75 (s, 9
H), –0.04 (s, 3 H), –0.24 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 171.7, 169.9, 137.5, 132.7, 131.1, 129.6, 83.1, 73.1,
61.7, 61.5, 61.6, 55.5, 50.4, 43.5, 26.7, 25.5, 21.1, 17.8, 14.0, 13.9,
10b: 45% yield, Ͼ 99 %ee, 1H NMR (400 MHz, CDCl3): δ = 7.36–
7.38 (d, J = 8.0 Hz, 2 H), 7.05–7.07 (d, J = 8.0 Hz, 2 H), 4.65–4.72
(m, 1 H), 4.07–4.22 (m, 4 H), 3.91 (m, 1 H), 3.80–3.84 (m, 1 H),
3.03–3.09 (t, J = 11.2 Hz, 1 H), 2.77–2.82 (dt, J1 = 3.2, J2
=
12.0 Hz, 1 H), 2.65–2.70 (dt, J1 = 3.2, J2 = 13.6 Hz, 1 H), 2.28–
2.32 (m, 4 H), 1.72–1.87 (m, 2 H), 1.24–1.27 (t, J = 7.2 Hz, 3 H),
1.13–1.67 (t, J = 7.2 Hz, 3 H), 0.59–0.63 (t, J = 7.2 Hz, 3 H)
ppm.13C NMR (100 MHz, CDCl3): δ = 172.4, 170.5, 137.7, 132.6,
131.0, 129.8, 84.9, 61.5, 61.3, 51.0, 48.2, 46.4, 27.6, 23.4, 21.1, 14.1,
–4.3, –5.6 ppm. IR (film): ν
= 2960, 2934, 2858, 1737, 1727,
˜
max
1554, 1490, 1473, 1448, 1380, 1366, 1329, 1290, 1279, 1252, 1196,
1156, 1126, 1138, 1034, 930, 887, 840, 815, 780, 673 cm–1. ESI-
MS: m/z = 1072.71 (dimer + Na). The ee value of the product was
determined by HPLC with a Daicel IA column (hexane/iPrOH =
14.0, 11.4 ppm. IR (film): ν
= 2975, 2940, 1730, 1552, 1491,
˜
max
90:10), flow rate 1.0 mLmin–1, tmajor
= 4.929 min; tminor =
1474, 1374, 1320, 1297, 1266, 1201, 1164, 1138, 1103, 1037, 957,
866, 808 cm–1. ESI-MS: m/z = 868.76 (dimer + Na). The ee value
of the product was determined by HPLC with a Daicel IA column
(hexane/iPrOH = 90:10), flow rate 1.0 mLmin–1, tmajor = 6.147 min;
tminor = 6.553 min.
6.415 min.
General Procedure for the Addition of 2-Hydroxybenzaldehydes to
Cinnamaldehyde: To a solution of trans-cinnamaldehyde (0.5 mmol)
in the presence of catalyst (20 mol-%), acid, and 4 Å molecular
sieves (250 mg) in CH2Cl2 (2.5 mL) was added salicylaldehyde
(1.0 mmol) and the resulting solution was stirred at room tempera-
ture for the specified time. The reaction mixture was directly puri-
fied by silica gel chromatography and fractions were collected and
concentrated in vacuo to give the pure product. This is a known
compound with spectroscopic properties in accordance with those
reported.[19]
10c: 45% yield, Ͼ 99 %ee, 1H NMR (400 MHz, CDCl3): δ = 7.34–
7.36 (d, J = 8.0 Hz, 2 H), 7.07–7.09 (d, J = 8.0 Hz, 2 H), 4.67–4.74
(m, 1 H), 4.08–4.23 (m, 4 H), 3.84–3.90 (m, 1 H), 3.73 (m, 1 H),
3.00–3.05 (t, J = 11.2 Hz, 1 H), 2.84–2.89 (dt, J1 = 3.2, J2
=
13.2 Hz, 1 H), 2.68–2.73 (dt, J1 = 3.6, J2 = 13.6 Hz, 1 H), 2.28–
2.34 (m, 4 H), 1.26–1.29 (t, J = 7.2 Hz, 3 H), 1.03–1.12 (m, 6 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 172.2, 170.2, 137.5, 133.4,
132.2, 129.8, 84.6, 61.5, 61.3, 55.5, 48.5, 46.4, 39.5, 27.4, 21.1, 17.8,
Supporting Information (see footnote on the first page of this arti-
cle): General remarks and the procedure of the organocatalytic
domino reaction, spectroscopic data and HPLC diagrams for the
domino adducts 10a–f and 13a–i.
14.2, 13.9 ppm. IR (film): ν
= 2982, 2906, 1730, 1551, 1492,
˜
max
1483, 1453, 1379, 1366, 1283, 1260, 1203, 1143, 1085, 1035, 939,
866, 809 cm–1. ESI-MS: m/z = 840.76 (dimer + Na). The ee value
of the product was determined by HPLC with a Daicel IA column
(hexane/iPrOH = 90:10), flow rate 1.0 mLmin–1, tmajor = 7.062 min;
tminor = 9.660 min.
Acknowledgments
10d: 43% yield, 92 %ee, 1H NMR (400 MHz, CDCl3): δ = 7.17– This Project was supported by the National Natural Science Foun-
7.18 (m, 3 H), 7.09–7.11 (d, J = 8.4 Hz, 2 H), 7.00–7.01 (d, J = dation of China (NSFC, No. 20973051), Program for Excellent
5036
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5031–5038

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5037

H. Shen, K.-F. Yang, Z.-H. Shi, J.-X. Jiang, G.-Q. Lai, L.-W. Xu
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Received: May 3, 2011
Published Online: July 28, 2011
Minor changes have been made since publication in Early View.
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Eur. J. Org. Chem. 2011, 5031–5038