One-pot enantioselective synthesis of 3-nitro-2H-chromenes catalyzed by a simple 4-hydroxyprolinamide with 4-nitrophenol as cocatalyst

Article abstract of DOI:10.1002/ejoc.201300505

The asymmetric domino oxa-Michael-Henry reaction of salicylaldehyde derivatives with trans-β-nitro olefins catalyzed by a readily available trans-4-hydroxy-L-prolinamide with 4-nitrophenol as an effective cocatalyst is presented. The corresponding 3-nitro

Full text of DOI:10.1002/ejoc.201300505

FULL PAPER
DOI: 10.1002/ejoc.201300505
One-Pot Enantioselective Synthesis of 3-Nitro-2H-chromenes Catalyzed by a
Simple 4-Hydroxyprolinamide with 4-Nitrophenol as Cocatalyst
Guohui Yin,[a] Richeng Zhang,[a] Lei Li,[a] Jun Tian,[a] and Ligong Chen*[a]
Keywords: Asymmetric catalysis / Oxygen heterocycles / Michael addition / Henry reaction / Domino reactions
The asymmetric domino oxa-Michael–Henry reaction of sal-
icylaldehyde derivatives with trans-β-nitro olefins catalyzed
by a readily available trans-4-hydroxy-L-prolinamide with 4-
nitrophenol as an effective cocatalyst is presented. The corre-
sponding 3-nitro-2H-chromenes were obtained in moderate
to excellent yields (up to 99%) and with up to 90% ee under
mild conditions. In addition, a preliminary study shows that
this organocatalytic system is able to promote the domino
aza-Michael–Henry reaction of 2-formylpyrrole derivatives
with trans-β-nitro olefins to give chiral 2-nitro-3H-pyrroliz-
ines.
desulfonamidation of salicyl N-tosylimine with nitro olefins
promoted by a bifunctional thiourea.[11] Unfortunately,
these procedures suffer from poor to moderate enantio-
selectivities and/or low yields, and/or require commercially
unavailable starting materials. Therefore, it is desirable to
develop improved, efficient, catalytic methods for the syn-
thesis of chiral 3-nitro-2H-chromenes.
Introduction
Chiral 2H-chromenes are important structural motifs
frequently found in many natural products and synthetic
molecules with unique biological and pharmacological ac-
tivities. For example, Gaudichaudianic acid, a natural
chromene isolated from Piper gaudichaudianum, has been
described as a potent trypanocidal compound against the
Y-strain of Trypanosoma cruzi,[1] and EM-800 shows anties-
trogenic activity.[2] Moreover, this class of compounds could
readily be used for the synthesis of valuable chiral chromans
such as epigallocatechin gallate, a major constituent of
green tea extract with potent anticancer activity,[3] and myr-
istinin A, a DNA polymerase β inhibitor.[4] Consequently,
much attention has been paid to the construction of chiral
2H-chromene scaffolds.[5] 3-Nitro-2H-chromenes are one of
the most important subfamilies of 2H-chromenes, because
of their biological activities[6] and their potential to be used
as precursors in the synthesis of important targets.[3b,7]
However, only a few strategies for the synthesis of 3-nitro-
2H-chromenes in enantiomerically pure form have been ex-
plored to date, including: (i) tandem oxa-Michael–Henry
reactions of salicylaldehyde derivatives with nitro olefins,
catalyzed by chiral secondary amines;[8] (ii) organocatalytic
kinetic resolution of racemic 3-nitro-2H-chromene deriva-
tives;[9] (iii) intramolecular crossed Rauhut–Currier reac-
tions of nitro olefins with tethered α,β-unsaturated esters,
involving cooperative nucleophilic activation and hydrogen-
bonding catalysis;[10] (iv) tandem oxa-Michael–aza-Henry-
Despite the fact that a range of substrates gave chiral 3-
nitro-2H-chromenes with low ee values and in low yields,
the condensation between salicylaldehyde derivatives and
nitro olefins drew our attention, as it is a straightforward
process that uses readily available starting materials.[8] Imin-
ium-activated salicylaldehyde is a key intermediate in this
process that was proposed and then confirmed by Xu’s
group.[8a] Over the past decade, chiral secondary amines, in
particular, proline-based derivatives and MacMillan’s imid-
azolidinones, have shown an extraordinary capacity to par-
ticipate in asymmetric iminium activation with enals and
enones.[12] On the other hand, the use of bifunctional or-
ganocatalysts to promote enantioselective transformations
has recently emerged as a highly efficient tool for the con-
struction of optically active molecules.[13] Synergistic acti-
vation by the functional groups on the catalyst can lead to
control of the transition state structure, and so products
can be formed with high enantioselectivities. We anticipated
that a suitable bifunctional organocatalyst that could simul-
taneously activate both salicylaldehyde derivatives and nitro
olefins could overcome the low ee values that were a limita-
tion of this approach. In this paper, bifunctional organocat-
alysts I and II, based on the concepts of iminium catalysis
and hydrogen-bonding activation using hydroxy group as
hydrogen-bonding donor,[14] are reported to catalyze the
asymmetric synthesis of 3-nitro-2H-chromenes by a domino
oxa-Michael–Henry reaction. As shown in Scheme 1, hy-
drogen-bonding and electrostatic interactions were expected
to help to connect the electrophile to the iminium-activated
[a] School of Chemical Engineering and Technology, Tianjin
University,
Tianjin 300072, P. R. China
Fax: +86-22-27406314
E-mail: lgchen@tju.edu.cn
Homepage: http://chemeng.tju.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300505.
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Scheme 1. Strategy to simplify the catalytic system, and the possible transition state.
salicylaldehyde in the transition state. In addition, to facili- ting trans-β-nitro olefins, as well as directing their ap-
tate the formation of iminium ions, an acid cocatalyst is proach, organocatalyst III was also prepared as shown in
generally needed in iminium catalysis.[12] We envisioned that Scheme 2.
the conjugate base of the acid cocatalyst might play an im-
portant role in promoting the nucleophilicity of iminium
intermediate’s phenolic hydroxy group by deprotonation or
hydrogen-bonding interactions. As a result, improved yields
could be achieved by using an appropriate acid cocatalyst.
Having synthesized the desired organocatalysts, we first
tested our hypothesis by treating salicylaldehyde (1a) with
trans-β-nitrostyrene (2a) in the presence of organocatalyst
Ia, together with benzoic acid as cocatalyst. Molecular
sieves were added to remove the water generated in the reac-
tion, and so push the equilibrium towards the formation of
the iminium intermediate.[16] After five days of stirring in
Cl(CH2)2Cl at ambient temperature, 3-nitro-2-phenyl-2H-
chromene (3a) was obtained in 28% yield and with 62%
ee (Table 1, entry 1). The improved enantioselectivity but
disappointing yield prompted us to search for an optimal
cocatalyst by screening a range of acids (Table 1).
Results and Discussion
Initially, organocatalysts Ia and Ib were synthesized from
Cbz-protected trans-4-hydroxy-l-proline (Scheme 2). Treat-
ment of Cbz-protected trans-4-hydroxy-l-proline with
amines under standard coupling conditions (ethyl chloro-
Similarly poor yields were observed with 4-toluenesulf-
formate and Et3N in THF) provided the corresponding onic acid, salicylic acid, or 4-nitrobenzoic acid as cocata-
amides, which were then transformed into Ia and Ib by lysts, regardless of the enantioselectivity (Table 1, entries 2–
catalytic hydrogenation (Pd/C) in 29% and 57% overall 4). These results appeared to show that a less acidic cocata-
yields, respectively. Starting from l-phenylalanine, imid- lyst gave the target compound in higher yield and with
azolidinone II was obtained according to the procedure de- higher enantioselectivity. Thus, we turned to phenols in-
scribed by Hansen.[15] To confirm whether the 4-hydroxy cluding 2,4-dinitrophenol, 4-nitrophenol, and hydro-
group in organocatalysts I plays an important role in activa- quinone. To our delight, 4-nitrophenol gave a relatively high
Scheme 2. Synthesis of organocatalysts Ia, Ib, and III. Cbz = benzyloxycarbonyl.
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One-Pot Enantioselective Synthesis of 3-Nitro-2H-chromenes
Table 1. Optimization of cocatalyst for the domino oxa-Michael–
Henry reaction.[a]
Table 2. Optimization of solvent for the domino oxa-Michael–
Henry reaction.[a]
Entry
Cocatalyst
Yield [%][b]
ee [%][c]
Entry
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
benzoic acid
4-toluenesulfonic acid
salicylic acid
4-nitrobenzoic acid
4-nitrophenol
2,4-dinitrophenol
hydroquinone
none
28
5
10
14
63
4
62
7
1
2
3
4
5
6
7
8
9
Cl(CH2)2Cl
CH2Cl2
CHCl3
toluene
CH3OH
THF
DMSO
DMF
CH3CN
63
87
93
62
29
7
6
31
42
72
72
80
62
30
44
26
34
45
56
62
72
54
53
36
14
26
[a] All reactions were carried out with salicylaldehyde (1a;
0.1 mmol, 1.0 equiv.), trans-β-nitrostyrene (2a; 0.2 mmol,
2.0 equiv.), organocatalyst Ia (20 mol-%), cocatalyst (20 mol-%),
[a] All reactions were carried out with salicylaldehyde (1a;
0.1 mmol, 1.0 equiv.), trans-β-nitrostyrene (2a; 0.2 mmol,
and molecular sieves (4 Å; 100 mg) in Cl(CH2)2Cl (0.5 mL) at room 2.0 equiv.), organocatalyst Ia (20 mol-%), 4-nitrophenol (20 mol-
temperature for 5 d. [b] Determined by 1H NMR spectroscopy
using 4-nitrotoluene as internal standard. [c] Determined by chiral
HPLC.
%), and molecular sieves (4 Å; 100 mg) in solvent (0.5 mL) at room
temperature for 5 d. [b] Determined by 1H NMR spectroscopy
using 4-nitrotoluene as internal standard. [c] Determined by chiral
HPLC.
yield and good enantioselectivity (63% yield, 72% ee;
Table 1, entry 5), whereas 2,4-dinitrophenol and hydro-
quinone were shown to be poor cocatalysts (Table 1, en-
tries 6 and 7).
We also screened different organocatalysts and reaction
times for the domino oxa-Michael–Henry reaction. As
shown in Table 3, Ia was the most effective organocatalyst
in terms of yield and enantioselectivity. When structurally
similar Ib was used as the catalyst, 2H-chromene 3a was
obtained in only 20% yield and with 40% ee. To our sur-
prise, the use of MacMillan imidazolidinone II led to race-
mic product in 8% yield. The bulky chiral secondary amine
might not easily form iminium ions with salicylaldehydes.
With catalyst III, which doesn’t bear a hydroxy group, a
reduction in both the yield and the enantioselectivity was
observed compared to Ia. This result clearly indicates that
the hydroxy group in Ia plays an important role in activa-
The domino oxa-Michael–Henry reaction was also inves-
tigated without any cocatalyst, and unsurprisingly, this gave
the desired product in 26% yield and with 36% ee (Table 1,
entry 8). It is well known that the stronger the acidity of
the acid, the weaker the basicity of its conjugate base. The
remarkable performance of 4-nitrophenol as cocatalyst
could be rationalized by its having an acidity most appro-
priate for the formation of the iminium intermediate, and
also its conjugate base being relatively strongly basic, which
results in an enhancement of the nucleophilicity of the
phenolic hydroxy group of the iminium intermediate.
Subsequently, we surveyed a number of solvents in an
effort to further improve the yield and enantioselectivity
(Table 2). In the presence of Ia and 4-nitrophenol, 2H-
chromene product 3a was obtained in high yields and high
ee values in chlorinated solvents, of which CHCl3 gave the
best results (Table 2, entries 1–3). This is most likely to be
due to the ability of the polar CHCl3 to stabilize the
charged iminium intermediate. As expected, the competi-
tion for hydrogen bonding made polar CH3OH a poor me-
dium for this process (Table 2, entry 5). Surprisingly little
product was formed in both polar DMSO and less polar
THF (Table 2, entries 6 and 7). We suppose that the electro-
static interactions between the charged iminium ion and the
hydrogen-bond-acceptor solvents DMSO and THF, al-
though helping to stabilize the iminium intermediate (un-
like the polar, weak hydrogen-bond-donor solvent CHCl3),
hindered the facial approach of the trans-β-nitrostyrene to
the iminium species, thereby resulting in poor yields and
enantioselectivities.
Table 3. Optimization of organocatalyst and time for the domino
oxa-Michael–Henry reaction.[a]
Entry
Catalyst
Time [d]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
Ia
Ib
II
III
Ia
Ia
5
5
5
5
4
6
93
20
8
55
85
91
80
40
0
62
80
80
[a] All reactions were carried out with salicylaldehyde (1a;
0.1 mmol, 1.0 equiv.), trans-β-nitrostyrene (2a; 0.2 mmol,
2.0 equiv.), organocatalyst (20 mol-%), 4-nitrophenol (20 mol-%),
and molecular sieves (4 Å; 100 mg) in CHCl3 (0.5 mL) at room
temperature. [b] Determined by 1H NMR spectroscopy using 4-
nitrotoluene as internal standard. [c] Determined by chiral HPLC.
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G. Yin, R. Zhang, L. Li, J. Tian, L. Chen
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ting nitro olefins, as well as in directing their approach to Table 4. Domino oxa-Michael–Henry reactions between salicylal-
dehyde derivatives 1 and trans-β-nitro olefins 2.[a]
the iminium intermediate through a hydrogen-bonding in-
teraction. Next, the optimum reaction time for this process
in the presence of Ia, 4-nitrophenol, and molecular sieves
(4 Å) in CHCl3 was confirmed to be 5 d.
Having established the optimal conditions, we investi-
gated a range of salicylaldehyde derivatives and trans-β-
nitro olefins to evaluate the scope of the domino process.
The results are summarized in Table 4. It appears that the
electronic properties and the positions of the substituents
on the phenyl ring of the salicylaldehyde derivatives have a
significant influence on the yield and enantioselectivity of
the reaction (Table 4, entries 1–6). Relatively electron-rich
salicylaldehyde derivatives showed higher reactivity, pre-
sumably due to the formation of more stable positive-
charged iminium intermediates (Table 4, entries 1, 4, and 5).
When salicylaldehyde derivatives with an electron-donating
methoxy substituent at different positions were used in the
reaction with trans-β-nitrostyrene (2a), 4-methoxysalicylal-
dehyde gave the best result (99% yield, 89% ee; Table 4,
entry 3), whereas 3-methoxysalicylaldehyde and 5-methoxy-
salicylaldehyde led to 3b and 3d, respectively, with moderate
enantioselectivities (Table 4, entries 2 and 4). Generally,
trans-β-nitro olefins bearing electron-deficient or electron-
rich aryl groups underwent the domino oxa-Michael–Henry
reaction smoothly to give the corresponding 2H-chromenes
in high yields and with good ee values (Table 4, entries 7–
12). When a heteroaromatic β-furyl-substituted nitro olefin
was used, a moderate yield of the product was observed
(Table 4, entry 13). The aliphatic trans-β-nitro olefin de-
rived from n-butyraldehyde also proved to be a viable sub-
strate for this asymmetric transformation, resulting in the
desired product (i.e., 3n) in 78% yield and with 67% ee
(Table 4, entry 14).
To account for the stereochemical outcome of the dom-
ino reaction, a plausible transition-state model has been
proposed, and is shown in Figure 1. In this model, the
amide side-chain sterically hinders one face of the iminium
ion. Meanwhile, the 4-hydroxy group in catalyst Ia, together
with the iminium ion, are believed to activate trans-β-nitro
olefins and direct their approach from the opposite face
through cooperative hydrogen-bonding and electrostatic in-
teractions with the nitro group in substrate 2. The perform-
ance of the organocatalysts, especially Ia and III (Table 3,
entries 1 and 4), strongly support this proposed transition
state. Moreover, this model can also be used to explain the
moderate ee values of 2H-chromenes 3d–f (Table 4, en-
tries 4–6): the 5-substituents (-OMe, -Br) on the phenyl ring
[a] All reactions were carried out with salicylaldehyde derivatives
of the salicylaldehyde derivatives were close to the 4-hy-
droxy group in the iminium intermediates, which disturbed
the formation of the hydrogen-bonding interaction with
trans-β-nitro olefins 2.
Next, our attention focused on finding further applica-
tions of this organocatalytic system. Inspired by the struc-
tural similarity between the salicylaldehyde derivatives and
(1; 0.1 mmol, 1.0 equiv.), trans-β-nitro olefins (2; 0.2 mmol,
2.0 equiv.), organocatalyst Ia (20 mol-%), 4-nitrophenol (20 mol-
%), and molecular sieves (4 Å; 100 mg) in CHCl3 (0.5 mL) at room
temperature for 5 d. [b] Isolated yields. [c] Determined by 1H NMR
spectroscopy using 4-nitrotoluene as internal standard. [d] Deter-
mined by chiral HPLC.
2-formylpyrrole derivatives, we envisaged that an aza- ines could take place using the same organocatalytic sys-
Michael–Henry reaction between 2-formylpyrrole deriva- tem. To the best of our knowledge, the asymmetric synthe-
tives and trans-β-nitro olefins to give 2-nitro-3H-pyrroliz- sis of 2-nitro-3H-pyrrolizines has not been reported to date.
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One-Pot Enantioselective Synthesis of 3-Nitro-2H-chromenes
Experimental Section
General Remarks: All reagents were used as purchased from com-
mercial suppliers without further purification unless otherwise
noted. Solvents were dried and purified according to standard pro-
cedures before use. Flash column chromatography was performed
1
using 200–300 mesh silica gel. H and 13C NMR spectra were re-
corded with a Bruker Avance 400 spectrometer, and tetramethylsil-
ane was used as a reference. 1H NMR spectroscopic data are repre-
sented as follows: chemical shift (ppm), multiplicity (s = singlet, d
= doublet, t = triplet, dd = doublet of doublets, m = multiplet, br
= broad), integration, coupling constants in Hertz (Hz). 13C NMR
spectroscopic data are reported in ppm. IR spectra were recorded
with a Bruker Tensor 27 spectrometer and are reported in wave-
numbers (cm–1). High-resolution mass spectra were measured with
a Bruker Daltonics micrOTOF-Q II instrument (ESI). Elemental
analysis data were obtained with an Elementar Vario Micro cube
instrument. Melting points were determined with a commercially
available melting point apparatus. Optical rotations were measured
with an Autopol II automatic polarimeter. Analytical chiral HPLC
was performed using Daicel ChiralPak AS-H or Daicel Chiralcel
Figure 1. Proposed transition state in the asymmetric domino oxa-
Michael–Henry reaction.
A preliminary study showed that 1H-pyrrole-2-carbal-
dehyde reacted with trans-β-nitrostyrene to give 2-nitro-3-
phenyl-3H-pyrrolizine in 61% yield and with 18% ee
(Scheme 3). An initial concern was that 2-nitro-3H-pyrroliz-
ine 5 might undergo racemization under the reaction condi-
tions. Racemization would lead to a reduction in ee as time
went on.[17] Thus, a control experiment with a shortened
reaction time (1 d) was performed to test for this possibility.
Compound 5 was still formed with 18% ee, indicating that OD columns.
there was no racemization under the reaction conditions.
Synthesis of Organocatalysts Ia and Ib
Rather, a facile conformational switch between the two con-
formers (A and B), without a significant steric effect, ac-
counts for the low ee of product 5.
[(2S,4R)-4-Hydroxypyrrolidin-2-yl](morpholino)methanone
(Ia):
Ethyl chloroformate (3.61 g, 33.3 mmol) was added to a stirred
solution of (2S,4R)-1-benzyloxycarbonyl-4-hydroxyproline (8.73 g,
32.9 mmol) and triethylamine (3.35 g, 33.1 mmol) in anhydrous
THF (50 mL) at 0 °C. After 30 min of stirring, morpholine (4.08 g,
46.8 mmol) was added, and the mixture was stirred further over-
night. The resulting solid was removed by filtration and washed
with EtOAc. The filtrate was concentrated under vacuum, and the
residue was purified by silica gel flash column chromatography. The
resulting product was dissolved in CH3OH (10 mL), and Pd/C
(20 wt-%) was added. The mixture was stirred at room temperature
under an H2 atmosphere (p = 1 atm) overnight. Then, the mixture
was filtered through Celite, and the solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography to give title product Ia (1.91 g, 29% yield) as a
white solid, m.p. 104–106 °C. [α]rD.t. = –63.7 (c = 0.5 in CH2Cl2). 1H
NMR (400 MHz, CDCl3): δ = 4.46 (s, 1 H), 4.18 (t, J = 7.6 Hz, 1
H), 3.65–3.70 (m, 6 H), 3.47–3.57 (m, 2 H), 3.36 (s, 2 H), 3.27 (dd,
J = 11.2, J = 4.0 Hz, 1 H), 2.93 (d, J = 11.2 Hz, 1 H), 2.15 (dd, J
= 12.8, J = 7.2 Hz, 1 H), 1.82–1.89 (m, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 172.2, 72.4, 66.8, 66.5, 56.4, 55.3, 45.5,
42.6, 40.0 ppm. HRMS (ESI): calcd. for C9H18N2O3 201.1239 [M
+ H]+; found 201.1230.
Scheme 3. Domino aza-Michael–Henry reaction of 1H-pyrrole-2-
carbaldehyde with trans-β-nitrostyrene.
(2S,4R)-N-Cyclohexyl-4-hydroxypyrrolidine-2-carboxamide (Ib):[14e]
White solid (57% yield), m.p. 160–162 °C; ref.[14e] 159–161.5 °C.
[α]rD.t. = –40.0 (c = 0.5 in CH2Cl2); ref.[14e] [α]2D8 = –40.5 (c = 0.2 in
Conclusions
In summary, we have developed an efficient organocata-
lytic system, including a simple trans-4-hydroxyprolinamide
catalyst and 4-nitrophenol as cocatalyst, for the synthesis
of synthetically and biologically useful chiral 3-nitro-2H-
chromenes. The domino oxa-Michael–Henry reaction be-
tween salicylaldehyde derivatives and trans-β-nitro olefins
gave significantly better yields (up to 99%) and ee values
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.0 Hz, 1
H), 4.42 (s, 1 H), 3.96 (t, J = 8.4 Hz, 1 H), 3.66–3.75 (m, 1 H), 3.02
(d, J = 12.4 Hz, 1 H), 2.78 (dd, J = 12.4, J = 3.2 Hz, 1 H), 2.64 (s,
2 H), 2.27 (dd, J = 14.0, J = 8.4 Hz, 1 H), 1.82–1.95 (m, 3 H), 1.69
(s, 2 H), 1.60–1.62 (m, 1 H), 1.32–1.42 (m, 2 H), 1.11–1.23 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 174.0, 73.0, 59.7, 55.3,
47.4, 40.1, 33.1, 33.0, 25.5, 24.8 ppm. HRMS (ESI): calcd. for
(up to 90%) than those reported previously. The asymmet- C11H22N2O2 213.1603 [M + H]+; found 213.1595.
ric synthesis of 2-nitro-3H-pyrrolizines has also been ac-
complished, albeit with poor enantioselectivity. Further in-
General Procedure for the Asymmetric Domino Oxa-Michael–Henry
Reaction: trans-β-Nitro olefin 2 (0.2 mmol, 2.0 equiv.) was added
vestigations into applications of this organocatalytic system
in domino aza-Michael–Henry reactions and other enantio-
selective domino reactions are ongoing in our laboratory.
to a stirred mixture of molecular sieves (4 Å; 0.1 g), catalyst Ia
(20 mol-%), 4-nitrophenol (20 mol-%), and salicylic aldehyde 1
(0.1 mmol, 1.0 equiv.) in chloroform (0.5 mL) at room temperature.
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After stirring for 5 d, the solvent was removed in vacuo, and the
residue was purified by flash column chromatography (petroleum
ether/ethyl acetate, 500:1–3000:1) on silica gel to give the corre-
sponding 3-nitro-2H-chromene (i.e., 3).
(R)-2-(2-Chlorophenyl)-7-methoxy-3-nitro-2H-chromene (3g): Yel-
low solid (95% yield, 82% ee), m.p. 110 °C. H NMR (400 MHz,
1
CDCl3): δ = 8.17 (s, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.26–7.32 (m,
2 H), 7.22 (dd, J = 7.6, J = 1.6 Hz, 1 H), 7.16 (t, J = 7.2 Hz, 1 H),
7.08 (s, 1 H), 6.59 (dd, J = 8.4, J = 2.4 Hz, 1 H), 6.38 (d, J =
1.6 Hz, 1 H), 3.79 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 165.3, 155.2, 137.2, 134.2, 133.5, 131.7, 130.8, 130.8, 130.6, 128.0,
(R)-3-Nitro-2-phenyl-2H-chromene (3a):[8a,9a] Yellow solid (93%
1
yield, 80% ee), m.p. 93 °C. H NMR (400 MHz, CDCl3): δ = 8.08
(s, 1 H), 7.32–7.41 (m, 7 H), 7.02 (t, J = 7.6 Hz, 1 H), 6.89 (d, J =
8.4 Hz, 1 H), 6.61 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 153.6, 141.2, 136.9, 134.3, 130.4, 129.5, 129.2, 128.9, 127.0, 122.5,
118.0, 117.3, 74.3 ppm. The enantiomeric excess was determined
by HPLC with a Chiralpak AS-H column (hexane/2-propanol,
90:10; flow rate = 1.0 mL/min; λ = 380 nm): tR (major) = 8.8 min,
tR (minor) = 15.0 min.
127.1, 110.8, 110.1, 102.2, 71.1, 55.7 ppm. IR (KBr): ν = 1649,
˜
1607, 1558, 1509, 1498, 1336, 1304, 1271, 1244 cm–1. HRMS (ESI):
calcd. for C16H12ClNO4Na 340.0353 [M + Na]+; found 340.0343.
The enantiomeric excess was determined by HPLC with a Chi-
ralpak AS-H column (hexane/2-propanol, 99:1; flow rate = 0.9 mL/
min; λ = 380 nm): tR (minor) = 48.7 min, tR (major) = 53.0 min.
(R)-8-Methoxy-3-nitro-2-phenyl-2H-chromene (3b):[8a] Yellow solid
(99% yield, 75% ee), m.p. 125 °C. H NMR (400 MHz, CDCl3): δ
(R)-2-(3-Chlorophenyl)-7-methoxy-3-nitro-2H-chromene (3h): Yel-
low solid (98% yield, 84% ee), m.p. 139–140 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.37 (s, 1 H), 7.30–7.35 (m,
1 H), 7.26–7.28 (m, 3 H), 6.60 (dd, J = 8.8, J = 2.4 Hz, 1 H), 6.56
(s, 1 H), 6.43 (d, J = 1.6 Hz, 1 H), 3.82 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.3, 155.3, 139.0, 137.6, 134.8, 131.9,
130.2, 130.2, 129.6, 127.3, 125.2, 110.9, 110.1, 102.3, 73.8,
1
= 8.04 (s, 1 H), 7.39–7.41 (m, 2 H), 7.30–7.32 (m, 3 H), 6.95 (s, 3
H), 6.67 (s, 1 H), 3.81 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 148.7, 142.8, 141.4, 136.7, 129.4, 129.3, 128.8, 126.9, 122.5,
122.1, 118.8, 116.8, 74.2, 56.3 ppm. The enantiomeric excess was
determined by HPLC with a Chiralpak OD column (hexane/2-
propanol, 99:1; flow rate = 1.0 mL/min; λ = 380 nm): tR (major) =
15.7 min, tR (minor) = 37.6 min.
(R)-7-Methoxy-3-nitro-2-phenyl-2H-chromene (3c):[8a,9a] Yellow so-
lid (99% yield, 89% ee), m.p. 147 °C. 1H NMR (400 MHz, CDCl3):
δ = 8.08 (s, 1 H), 7.34–7.41 (m, 5 H), 7.26 (d, J = 8.4 Hz, 1 H),
6.57–6.59 (m, 2 H), 6.42 (d, J = 1.6 Hz, 1 H), 3.80 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 165.1, 155.6, 138.4, 137.1, 131.7,
129.8, 129.4, 128.9, 127.1, 111.1, 109.8, 102.2, 74.5, 55.7 ppm. The
enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (hexane/2-propanol, 85:15; flow rate = 1.0 mL/min;
λ = 380 nm): tR (major) = 15.4 min, tR (minor) = 25.9 min.
55.7 ppm. IR (KBr): ν = 1645, 1611, 1556, 1491, 1332, 1314, 1279,
˜
1243 cm–1. HRMS (ESI): calcd. for C16H12ClNO4Na 340.0353 [M
+ Na]+; found 340.0347. The enantiomeric excess was determined
by HPLC with a Chiralpak AS-H column (hexane/2-propanol,
85:15; flow rate = 1.0 mL/min; λ = 380 nm): tR (major) = 15.7 min,
tR (minor) = 25.8 min.
(R)-2-(4-Chlorophenyl)-7-methoxy-3-nitro-2H-chromene (3i):[8a,9a]
Yellow solid (97% yield, 90% ee), m.p. 96 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.07 (s, 1 H), 7.30–7.35 (m, 4 H), 7.26 (d, J = 8.4 Hz,
1 H), 6.60 (dd, J = 8.8, J = 2.4 Hz, 1 H), 6.55 (s, 1 H), 6.42 (d, J
= 1.6 Hz, 1 H), 3.81 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 165.3, 155.4, 138.0, 135.6, 135.4, 131.8, 129.9, 129.1, 128.4,
111.0, 110.0, 102.3, 73.8, 55.7 ppm. The enantiomeric excess was
determined by HPLC with a Chiralpak AS-H column (hexane/2-
propanol, 85:15; flow rate = 1.0 mL/min; λ = 380 nm): tR (major)
= 14.7 min, tR (minor) = 25.4 min.
(R)-2-(4-Bromophenyl)-7-methoxy-3-nitro-2H-chromene (3j):[8a,9a]
Yellow solid (99% yield, 88% ee), m.p. 94–95 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.47 (d, J = 8.4 Hz, 2 H),
7.25–7.28 (m, 3 H), 6.59 (dd, J = 8.4, J = 2.4 Hz, 1 H), 6.54 (s, 1
H), 6.41 (d, J = 2.0 Hz, 1 H), 3.81 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 165.3, 155.4, 137.9, 136.1, 132.0, 131.8,
130.0, 128.7, 123.6, 111.0, 110.0, 102.3, 73.8, 55.7 ppm. The enan-
tiomeric excess was determined by HPLC with a Chiralpak AS-H
column (hexane/2-propanol, 85:15; flow rate = 1.0 mL/min; λ =
380 nm): tR (major) = 15.5 min, tR (minor) = 26.4 min.
(R)-6-Methoxy-3-nitro-2-phenyl-2H-chromene (3d):[8a] Yellow solid
1
(97% yield, 54% ee), m.p. 128 °C. H NMR (400 MHz, CDCl3): δ
= 8.02 (s, 1 H), 7.31–7.36 (m, 5 H), 6.89 (dd, J = 8.8, J = 2.8 Hz,
1 H), 6.82 (d, J = 2.8 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.54 (s,
1 H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8,
147.5, 141.8, 136.6, 129.4, 128.8, 127.0, 120.7, 118.5, 118.1, 113.7,
74.0, 55.8 ppm. The enantiomeric excess was determined by HPLC
with a Chiralpak AS-H column (hexane/2-propanol, 85:15; flow
rate = 1.0 mL/min; λ = 380 nm): tR (major) = 12.0 min, tR (minor)
= 27.7 min.
(R)-6-Bromo-3-nitro-2-phenyl-2H-chromene (3e):[8c] Yellow solid
(68% yield, 67% ee), m.p. 127–128 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.99 (s, 1 H), 7.47 (d, J = 2.0 Hz, 1 H), 7.41 (dd, J =
8.8, J = 2.0 Hz, 1 H), 7.36 (s, 5 H), 6.78 (d, J = 8.8 Hz, 1 H), 6.60
(s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.5, 142.0,
136.7, 136.2, 132.4, 129.8, 129.0, 127.8, 127.0, 119.8, 119.1, 114.5,
74.4 ppm. The enantiomeric excess was determined by HPLC with
a Chiralpak AS-H column (hexane/2-propanol, 90:10; flow rate =
1.0 mL/min; λ = 380 nm): tR (major) = 9.5 min, tR (minor) =
16.5 min.
(R)-7-Methoxy-3-nitro-2-p-tolyl-2H-chromene (3k):[9a] Yellow solid
1
(92% yield, 86% ee), m.p. 123 °C. H NMR (400 MHz, CDCl3): δ
= 8.06 (s, 1 H), 7.24–7.29 (m, 3 H), 7.14 (d, J = 7.6 Hz, 2 H), 6.57
(dd, J = 8.4, J = 2.4 Hz, 1 H), 6.55 (s, 1 H), 6.40 (d, J = 1.6 Hz, 1
H), 3.80 (s, 3 H), 2.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 165.1, 155.6, 139.4, 138.5, 134.1, 131.6, 129.6, 129.5, 127.0,
111.2, 109.7, 102.2, 74.4, 55.6, 21.2 ppm. The enantiomeric excess
was determined by HPLC with a Chiralpak AS-H column (hexane/
2-propanol, 85:15; flow rate = 1.0 mL/min; λ = 380 nm): tR (major)
= 12.0 min, tR (minor) = 19.3 min.
(R)-7-Methoxy-2-(4-methoxyphenyl)-3-nitro-2H-chromene (3l):[8a,9a]
Yellow solid (99% yield, 86% ee), m.p. 110–111 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.32 (d, J = 8.4 Hz, 2 H),
(R)-6,8-Dibromo-7-methoxy-3-nitro-2-phenyl-2H-chromene
(3f):
Yellow solid (37% yield, 65% ee), m.p. 146 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.51 (s, 1 H), 7.36–7.41 (m,
5 H), 6.76 (s, 1 H), 3.91 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 158.5, 151.2, 141.5, 135.8, 132.3, 129.7, 128.9, 127.4,
126.8, 116.5, 110.6, 108.5, 74.7, 60.9 ppm. IR (KBr): ν = 1649,
˜
1589, 1510, 1334, 1297, 1273 cm–1. HRMS (ESI): calcd. for
C16H11Br2NO4Na 463.8932 [M + Na]+; found 463.8929. The enan-
tiomeric excess was determined by HPLC with a Chiralpak AS-H 7.25 (d, J = 8.4 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 2 H), 6.57 (d, J =
column (hexane/2-propanol, 90:10; flow rate = 1.0 mL/min; λ =
380 nm): tR (major) = 11.0 min, tR (minor) = 16.0 min.
8.4 Hz, 1 H), 6.53 (s, 1 H), 6.39 (s, 1 H), 3.80 (s, 3 H), 3.79 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.1, 160.4, 155.6,
5436
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 5431–5438

One-Pot Enantioselective Synthesis of 3-Nitro-2H-chromenes
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138.5, 131.6, 129.6, 129.2, 128.6, 114.2, 111.2, 109.7, 102.2, 74.2,
55.6, 55.3 ppm. The enantiomeric excess was determined by HPLC
with a Chiralpak AS-H column (hexane/2-propanol, 85:15; flow
rate = 1.0 mL/min; λ = 380 nm): tR (major) = 26.1 min, tR (minor)
= 40.3 min.
(S)-2-(Furan-2-yl)-7-methoxy-3-nitro-2H-chromene (3m): Yellow so-
lid (51% yield, 90% ee), m.p. 95–96 °C. 1H NMR (400 MHz,
CDCl3): δ = 8.05 (s, 1 H), 7.40 (s, 1 H), 7.28 (d, J = 8.4 Hz, 1 H),
6.64 (s, 1 H), 6.61 (dd, J = 8.4, J = 2.4 Hz, 1 H), 6.46 (d, J =
1.6 Hz, 1 H), 6.34 (d, J = 3.2 Hz, 1 H), 6.31 (s, 1 H), 3.82 (s, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 165.1, 155.4, 149.7, 143.9,
136.1, 131.8, 130.5, 111.2, 110.6, 110.1, 110.0, 102.3, 67.4,
[2]
55.7 ppm. IR (KBr): ν = 1639, 1609, 1557, 1493, 1325, 1275,
˜
1247 cm–1. HRMS (ESI): calcd. for C14H11NO5Na 296.0535 [M +
Na]+; found 296.0529. The enantiomeric excess was determined by
HPLC with a Chiralpak AS-H column (hexane/2-propanol, 85:15;
flow rate = 1.0 mL/min; λ = 380 nm): tR (major) = 15.9 min, tR
(minor) = 27.8 min.
[3]
[4]
[5]
(R)-7-Methoxy-3-nitro-2-propyl-2H-chromene (3n): Yellow oil (78%
yield, 67% ee). 1H NMR (400 MHz, CDCl3): δ = 7.78 (s, 1 H),
7.18 (d, J = 8.8 Hz, 1 H), 6.57 (dd, J = 8.4, J = 2.4 Hz, 1 H), 6.47
(d, J = 1.6 Hz, 1 H), 5.54 (dd, J = 9.2, J = 2.4 Hz, 1 H), 3.84 (s, 3
H), 1.78–1.89 (m, 1 H), 1.43–1.66 (m, 3 H), 0.95 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 164.9, 155.5, 140.0,
131.6, 128.8, 111.6, 109.4, 102.4, 73.2, 55.6, 34.5, 18.1, 13.5 ppm.
IR (KBr): ν = 2962, 1643, 1617, 1558, 1505, 1330, 1305, 1274,
˜
1246 cm–1. HRMS (ESI): calcd. for C13H15NO4Na 272.0899 [M +
Na]+; found 272.0893. The enantiomeric excess was determined by
HPLC with a Chiralpak AS-H column (hexane/2-propanol, 90:10;
flow rate = 1.0 mL/min; λ = 380 nm): tR (major) = 7.5 min, tR
(minor) = 12.0 min.
Procedure for the Asymmetric Domino Aza-Michael–Henry Reac-
tion: trans-β-Nitrostyrene 2a (0.4 mmol, 2.0 equiv.) was added to a
stirred mixture of molecular sieves (4 Å; 0.2 g), catalyst Ia (20 mol-
%), 4-nitrophenol (20 mol-%), and 1H-pyrrole-2-carbaldehyde 4
(0.2 mmol, 1.0 equiv.) in chloroform (1.0 mL) at room temperature.
After stirring for 5 d, the solvent was removed in vacuo, and the
residue was purified by flash column chromatography (petroleum
ether/ethyl acetate, 1000:1) on silica gel to give the corresponding
2-nitro-3-phenyl-3H-pyrrolizine (i.e., 5). Yellow solid (61% yield,
18% ee), m.p. 99–100 °C. 1H NMR (400 MHz, [D6]DMSO): δ =
8.27 (s, 1 H), 7.35–7.42 (m, 3 H), 7.17 (dd, J = 7.6, J = 2.0 Hz, 2
H), 7.12 (s, 1 H), 6.67 (d, J = 4.0 Hz, 1 H), 6.45 (t, J = 4.0 Hz, 1
H), 6.37 (s, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
149.6, 137.6, 133.8, 130.2, 129.5, 129.3, 127.9, 122.3, 116.4, 110.6,
[6]
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63.9 ppm. IR (KBr): ν = 1548, 1534, 1465, 1364, 1306, 1266,
˜
1238 cm–1. C13H10N2O2 (226.23): calcd. C 69.02, H 4.46, N 12.38;
found C 68.81, H 4.56, N 12.38. The enantiomeric excess was deter-
mined by HPLC with a Chiralpak OD column (hexane/2-propanol,
99:1; flow rate = 1.0 mL/min; λ = 380 nm): tR (minor) = 16.3 min,
tR (major) = 33.6 min.
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra of Ia, Ib, 3a–3n, and
5, and the HPLC spectra of 3a–3n and 5.
Acknowledgments
The authors are grateful to Prof. Wan and his group for their sup-
port in our research.
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Eur. J. Org. Chem. 2013, 5431–5438
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5437

G. Yin, R. Zhang, L. Li, J. Tian, L. Chen
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Received: April 8, 2013
Published Online: July 8, 2013
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