Organocatalytic asymmetric synthesis of functionalized 4 H -chromenes via a one-pot Domino Michael-Hemiacetalization and dehydration sequence

Article abstract of DOI:10.1055/s-0030-1260017

A one-pot thiourea-catalyzed enantioselective synthesis of polyfunctionalized 4H-chromenes via a domino Michael-hemiacetalization reaction and subsequent dehydration is reported. Starting from 2-nitrovinylphenols and -keto esters, the new protocol affords the 4H-chromenes bearing a variety of functional groups with good to excellent yields (76-95%) and enantioselectivities ranging from 30-99%ee. Both enantiomers are available at will depending on the ephedrine or pseudoephedrine-based thiourea catalyst used. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260017

PAPER
1905
Organocatalytic Asymmetric Synthesis of Functionalized 4H-Chromenes via a
One-Pot Domino Michael-Hemiacetalization and Dehydration Sequence
A
symmetric Synth
i
esis of
e
4
H
-Chrom
t
enes er Enders,* Gregor Urbanietz, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 11 March 2011
troalkenes employing such ephedrine-derived thiourea
Abstract: A one-pot thiourea-catalyzed enantioselective synthesis
of polyfunctionalized 4H-chromenes via a domino Michael-hemi-
acetalization reaction and subsequent dehydration is reported. Start-
ing from 2-nitrovinylphenols and b-keto esters, the new protocol
affords the 4H-chromenes bearing a variety of functional groups
with good to excellent yields (76–95%) and enantioselectivities
ranging from 30–99% ee. Both enantiomers are available at will de-
pending on the ephedrine or pseudoephedrine-based thiourea cata-
lyst used.
catalysts, which had been synthesized earlier by Berkessel
et al.6d and applied in the enantioselective dynamic kinetic
resolution of azlactones.
Following our recently developed asymmetric synthesis
of chromans and dihydrocoumarins employing an organo-
catalytic simple domino reaction,8 we now wish to report
on the asymmetric synthesis of 4-nitromethyl-4H-
chromenes via a one-pot domino Michael-hemiacetaliza-
tion and dehydration sequence. As depicted in Scheme 1,
(E)-2-(2-nitrovinyl)phenols 19 were treated with b-keto
esters 2 in the presence of 10 mol% of thiourea catalysts
A–F to form the chroman-2-ols 3, which were directly de-
hydrated with p-toluenesulfonic acid to the title 4H-
chromenes 4.
Key words: organocatalysis, cascade reaction, thiourea, one-pot
reaction, 4H-chromene
Heterocycles such as chromans and chromenes are impor-
tant classes of benzopyran derivatives to be found in many
natural products and synthetic molecules exhibiting
unique biological and pharmacological activities.1 De-
spite the fact that the subclass of 4H-chromenes are im-
portant as core structures featured in a great number of
biologically active molecules, efficient catalytic asym-
metric methods allowing the rapid access to these hetero-
cycles are still rare.2 Therefore, the development of novel
catalytic asymmetric methods for the efficient construc-
tion of structurally diverse and densely functionalized 4H-
chromenes is an important task. Especially tandem/domi-
no/cascade and multicomponent strategies3 have recently
received increasing attention in asymmetric synthesis, of-
ten based on the concept of aminocatalysis. Another im-
portant activation mode is through hydrogen bonding4
employing thiourea catalysts. In organocatalytic asym-
metric syntheses of benzopyran derivates salicylic alde-
hydes are important starting materials based on the well-
developed enamine and iminium activation modes. On the
other hand thiourea-catalyzed enantioselective 4H-
chromene syntheses have not been reported so far, al-
though organocatalytic conjugate additions of 1,3-dicar-
bonyl compounds to nitroalkenes as a possible key step
are already well developed.5
We first performed the reaction between (E)-2-(2-
nitrovinyl)phenol (1a) and methyl 3-oxobutanoate (2a)
using 10 mol% of the bifunctional thiourea catalyst A.6a,d
Table 1 Catalyst Screening for the Synthesis of Methyl 2-Methyl-
4-(nitromethyl)-4H-chromene-3-carboxylate (4a)
O
CO2Me
NO2
O2N
+
2a
CO2Me
1. catalyst (10 mol%), toluene
2. PTSA (20 mol%), 2 h
OH
O
(one pot)
1a
4a
Entrya
Catalyst
Temp (°C) Time (h) Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
A
B
C
D
E
B
D
E
F
r.t.
r.t.
r.t.
r.t.
r.t.
0
3
3
84
77
86
90
87
91
93
92
82
55d
40d
71
3
3
98
3
98d
63d
99
The basic structural unit used in the majority of bifunc-
tional thiourea catalysts are enantiopure 1,2-diamines,
which can be obtained, for instance, from commercially
available ephedrine or pseudoephedrine precursors.6 Re-
cently Bolm et al.,6a reported on the efficient asymmetric
Michael addition7 of 1,3-dicarbonyl compounds to ni-
24
24
24
168
0
0
99d
0
r.t.
a All reactions were performed on a 1.0 mmol scale.
b Yield of isolated product 4a.
SYNTHESIS 2011, No. 12, pp 1905–1911
Advanced online publication: 21.04.2011
DOI: 10.1055/s-0030-1260017; Art ID: C26811SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1
c Determined by HPLC analysis on a chiral stationary phase.
d The opposite enantiomer ent-4a was obtained.

1906
D. Enders et al.
PAPER
O2N
O
R1
NO2
+
R1
O
O
catalyst (10 mol%)
toluene
OR4
R3
R3
OR4
OH
O
OH
R2
R2
1
2
3
bifunctional thiourea catalysts used
PTSA (20 mol%)
toluene
– H2O
S
S
Ph
S
O2N
Ar
Ar
Ar
O
N
H
N
N
H
N
H
H
R1
NMe2
NMe2
OR4
B
A
O
R3
R2
S
Ph
4
Ar
N
H
N
N
H
N
H
H
N
N
CF3
Ar =
D
C
F3C
S
Ph
S
Ar
Ar
N
H
N
N
H
N
H
H
HN
S
N
HN
Ar
E
F
Scheme 1 Organocatalytic asymmetric synthesis of functionalized 4-nitromethyl-4H-chromenes via a one-pot domino Michael-hemiacetali-
zation and dehydration sequence
The expected hemiacetal chroman-2-ol 3a was obtained (Table 1, entries 4, 5). The absolute configuration was de-
in high yield. No lactonization occurred, as might have termined by X-ray crystal structure analysis in the case of
been expected. After dehydration of the chroman-2-ol 3a, 4a (Figure 1), ent-4b, and 4f. In addition, it could be
the 4H-chromene 4a was isolated in good yield and mod- shown that racemic 4H-chromenes 4 are obtained with
erate ee value (Table 1, entry 1).
catalyst F,12 which does not bear a tertiary amine group. A
piperidinyl moiety seems to be crucial for the high asym-
metric inductions in our cases.
Next, the Takemoto bifunctional thiourea catalyst B was
tested, which has been reported to give very good results
in the enantioselective Michael addition of malonates to
nitroalkenes.10 In our one-pot protocol, 4a was formed in
good yield, but again with only a moderate ee value
(Table 1, entry 2). However, better enantioselectivities
could be achieved with the modified Takemoto catalyst
C
11 in which the dimethylamino group is substituted by a
piperidino function (Table 1, entry 3). This led us to the
idea to modify catalyst A with a piperidinyl group. In con-
trast to catalyst C, excellent enantioselectivities could be
achieved (Table 1, entry 4). Next, we wondered whether
switching the diamino moiety from anti to syn configura-
tion might have any influence on the stereochemical out-
come of the obtained 4H-chromenes. Indeed, by
employing catalyst E the opposite enantiomer was ob-
tained without loss of enantioselectivity (Table 1, entry
5). With these thiourea organocatalysts based on norpseu-
doephedrine D and its epimer E, the best enantioselectiv-
ities were achieved, even at 0 °C (Table 1, entries 7, 8).
Figure 1 X-ray crystal structure of (R)-4a13
Next, a range of typical solvents were screened. All reac-
tions were first performed in a two-step procedure. For the
domino Michael-hemiacetalization reaction, 10 mol% of
catalyst D at room temperature was used. After comple-
tion of this reaction as monitored by TLC, the correspond-
ing chroman-2-ol 3a was isolated by flash
chromatography and dehydrated by using 20 mol% PTSA
in toluene at 100 °C for two hours. The reaction time in
With both catalysts in hand, we had the option to synthe-
size the R-configured 4H-chromene 4a, whereas the
epimeric catalyst E produced the S-enantiomer in excess
Synthesis 2011, No. 12, 1905–1911 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4H-Chromenes
1907
Table 2 therefore corresponds to the domino Michael- 4e, 4f were formed with virtually complete asymmetric
hemiacetalization reaction. Among the solvents used, tol- induction, whereas in all other cases the (R)-nitromethyl
uene was the most suitable, in which an excellent yield of 4H-chromenes were obtained (Table 3, 4a–d). With the p-
4a was obtained with an ee value of 98% (Table 2, entry nitrophenol substrate a drastic decrease of the enantiose-
1).
lectivity was seen. This may be explained by the nitrophe-
nyl group that interferes with the catalyst by hydrogen
bonding and thus has a great influence on the asymmetric
induction in the transition state (Table 3, 4d). While the
Michael acceptor 1 had not such great influence on the
domino Michael-hemiacetalization reaction, a great de-
crease of enantioselectivity was observed by variation of
the b-keto ester substrates 2. As illustrated in Table 3,
good yields but poor enantioselectivities resulted with the
increasing bulkiness of the ester function (Table 3, 4g–i).
In the case of tert-butyl 3-oxobutanoate (2i), the domino
Michael-hemiacetalization to afford 3i occurs in good
yield, but the corresponding 4H-chromene could not be
isolated under the acidic conditions in the dehydration
step (Table 3, 4i). With ethyl 3-oxo-3-phenylpropanoate
(2k) a moderate enantiomeric excess could be achieved
(Table 3, 4k).
Table 2 Solvent Screening for the Synthesis of (R)-Methyl 2-Meth-
yl-4-(nitromethyl)-4H-chromene-3-carboxylate (4a)
Entrya
Solvent
toluene
CH2Cl2
Et2O
Time (h)
Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
3
3
90
66
42
72
76
57
73
65
n.r.
98
42
66
70
54
9
3
EtOAc
MeCN
DMF
2
2
1
MeOH
H2O
2
67
35
–
1
Table 3 Scope of the Asymmetric Synthesis of Chromenes via One-
Pot Domino Michael-Hemiacetalization and Dehydration
AcOH
168
a All reactions were performed on a 1.0 mmol scale in toluene using
10 mol % of catalyst D. After completion as monitored by TLC, the
chromanol 3a was isolated.
ProductaR1
R2
R3
R4
Time Yield ee
(h)
(%)b (%)c
b Yield of isolated product 4a.
4a
4b
4c
4d
4e
4f
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
3
90
95
90
78
92
93
92
82
98
98
88
49
99d
99d
62
30
c Determined by HPLC analysis on a chiral stationary phase.
Br
H
3
Dichloromethane and Et2O, usually good solvents for
thiourea-amine catalyzed reactions, led to relatively low
yields and stereoselectivities (Table 2, entries 2, 3). Apro-
tic polar solvents such as MeCN and EtOAc were suitable
for this reaction with respect to the reaction time, but only
poor enantioselectivities resulted (Table 2, entries 4, 5). In
the case of DMF a nearly racemic product was obtained,
after the reaction was finished after one hour (Table 2, en-
try 6). The reaction could also be performed in protic po-
lar solvents like MeOH or even H2O, but again poor
enantioselectivities were obtained (Table 2, entries 7, 8).
AcOH did not allow the reaction at all and no conversion
could be observed under these acidic conditions (Table 2,
entry 9). Thus, it turned out that toluene is the best solvent
for this type of reaction in order to get very good yields
and enantioselectivities.
CO2Me
H
2.5
4
NO2
H
H
Me
3
H
OMe Me
2
4g
4h
4i
H
H
H
H
H
H
Me
Me
Me
Me
Ph
3
H
i-Pr
t-Bu
4
H
4
79e n.d.
4j
H
(CH2)2OMe 3
Et 5
89
76
79
80
4k
H
a All reactions were performed on a 1.0 mmol scale with catalyst D.
b Yield of isolated products 4a–k.
c Determined by HPLC analysis on a chiral stationary phase.
d The opposite enantiomer was obtained.
Having established the optimal conditions for this one-pot
domino Michael-hemiacetalization and dehydration se-
quence, we then investigated the scope of the new proto-
col. As illustrated in Table 3, a series of substituted 2-(2-
nitrovinyl)phenols 1 were reacted with 1.1 equivalents of
different b-keto esters 2 in toluene catalyzed by 10 mol%
of D at room temperature followed by dehydration with
20 mol% PTSA for two hours at 100 °C in the same flask.
Excellent yields and very good ee values were achieved
for the 4H-chromene products with nitroalkenephenols 1
(Table 3). In the case of ortho-substituted (E)-2-(2-nitro-
vinyl)phenols 1 (R2 = Me, OMe), a change in the config-
uration was observed and the S-configured 4H-chromenes
e Yield of isolated chroman-3-ol 3i.
In conclusion, we have developed an enantioselective
one-pot synthesis of polyfunctionalized 4H-chromenes
employing a thiourea-catalyzed domino Michael-hemi-
acetalization reaction and subsequent dehydration of the
intermediate chroman-2-ols. The title compounds are
important heterocycles, due to their widespread occur-
rence in nature and as privileged scaffolds in medicinal
chemistry. They were obtained in good to excellent yields
of 76–95% and enantiomeric excesses of 30–99%. In ad-
Synthesis 2011, No. 12, 1905–1911 © Thieme Stuttgart · New York

1908
D. Enders et al.
PAPER
MS (EI, 70 eV): m/z (%) = 218 (M+, 0.1), 174 (1), 132 (1), 126 (1),
113 (22), 112 (100).
dition, our protocol allows the introduction of several
functional groups, such as the 4-nitromethyl and 3-ester
groups as well as various substituents at the aromatic ring. HRMS: m/z calcd for C14H12N2: 218.1783; found: 218.1789.
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-1-phenyl-2-(pip-
eridin-1-yl)propyl]thiourea (D)
Unless otherwise noted, all commercially available compounds
were used without further purification. For preparative column
The diamine (vide supra) (2.18 g, 10 mmol) was dissolved in
chromatography SIL G-25 UV254 from Macherey-Nagel, particle
CH2Cl2 (20 mL) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate
size 0.040–0.063 mm (230–240 mesh, flash) was used. Visualiza-
(1.83 mL, 10 mmol) was added. The reaction was monitored by
tion of the developed TLC plates was performed with ultraviolet ir-
radiation (254 nm) or by staining with a p-anisaldehyde solution.
Microanalyses were performed with a Vario EL element analyzer.
TLC. After completion, the solvent was removed under reduced
pressure and the product was purified by column chromatography
(n-pentane–Et2O, 1:1, then Et2O) to afford the thiourea catalyst D in
Mass spectra were measured on a Finnigan SSQ7000 (EI 70 eV)
spectrometer and high-resolution mass spectra on a Thermo Fisher
Scientific Orbitrap XL. IR spectra were recorded on a Perkin-Elmer
FT-IR Spectrum 100 instrument. 1H and 13C NMR spectra were re-
corded at r.t. with Varian Mercury 300 or Gemini 300 spectrometers
with TMS as an internal standard. Melting points were determined
with Büchi Melting Point B-540 apparatus. Optical rotations were
measured with a Perkin-Elmer P241 polarimeter.
20
62% yield (3.04 g) as a colorless solid, mp 64 °C; [a]D +36.8 (c
1.03, CHCl3); Rf = 0.23 (Et2O + 5% Et3N).
IR (film): 3270, 2936, 1621, 1472, 1380, 1275, 1172, 1130 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.82 (d, J = 6 Hz, 3 H, CH3), 1.40
(m, 6 H, CH2), 2.25 (m, 2 H, CH2), 2.43 (m, 2H, CH2), 2.82 (m, 1
H, CH), 4.36 (br s, 1 H, CH), 7.32–7.46 (m, 5 H, C6H5), 7.63 (s, 1
H, CHarom), 7.69 (s, 2 H, CHarom).
13C NMR (75 MHz, CDCl3 ): d = 8.7 (CH3), 24.2 (CH2), 26.3 (2
CH2), 48.8 (2 CH2), 61.9 (CH), 65.0 (CH), 119.0 (CHarom), 123.5
(CHarom), 124.7 (2 CF3), 127.5 (CHarom), 127.8 (CHarom), 128.2 (2
CHarom), 128.6 (2 CHarom), 132.2 (Carom), 132.6 (Carom), 139.7
(Carom), 140.0 (Carom), 181.0 (C=S).
Preparation of 1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-1-
phenyl-2-(piperidin-1-yl)propyl]thiourea (D)
(1S,2S)-1-Phenyl-2-(piperidin-1-yl)propan-1-ol
A mixture of (+)-(1S,2S)-2-amino-1-phenylpropan-1-ol (7.55 g, 50
mmol), 1,5-dibromopentane (6.85 mL, 50 mmol), and K2CO3
(27.65 g, 200 mmol) in MeCN (300 mL) was refluxed for 18 h. Af-
ter cooling the reaction mixture to r.t., the solid was filtered off and
washed with EtOAc (3 × 100 mL). The combined filtrates were con-
centrated under reduced pressure and the crude amino alcohol was
purified by column chromatography on silica gel (n-pentane–
Et2O, 1:1, then Et2O) to afford the piperidinyl alcohol in 86% yield
(9.43 g) as a colorless solid.
1H NMR (300 MHz, CDCl3): d = 0.82 (d, J = 7 Hz, 3 H, CH3),
1.40–1.50 (m, 2 H, CH2), 1.53–1.64 (m, 4 H, CH2), 2.45–2.60 (m, 4
H, CH2), 2.71 (dq, J = 4 Hz, 7 Hz, 1 H, CH), 4.18 (br s, 1 H, OH),
4.83 (d, J = 4 Hz, 1 H, CH), 7.19–7.33 (m, 5 H, C6H5).
19F NMR (282 MHz, CDCl3): d = –63.5.
MS (EI, 70 eV): m/z (%) = 470 (1), 404 (1), 389 (5), 371 (2), 271
(1), 202 (2), 176 (2), 112 (100).
HRMS: m/z calcd for C23H25F6N3S: 489.1673; found: 489.1682.
(3R,4R)-Methyl 2-Hydroxy-2-methyl-4-(nitromethyl)chroman-
3-carboxylate (3a)
In an ordinary glass vial equipped with a magnetic stirring bar was
added catalyst D (49 mg, 10 mol%) to a mixture of methyl 3-oxo-
butanoate (2a; 0.13 mL, 1.1 mmol) and (E)-2-(2-nitrovinyl)phenol
(1a; 165 mg, 1 mmol) in toluene (1 mL) at r.t. The reaction was
monitored by TLC (n-pentane–EtOAc, 3:1). After completion, the
crude mixture was purified by column chromatography on silica gel
to afford 3a in 96% yield (270 mg) as a colorless solid; mp 88 °C;
[a]D20 +39.6 (c 1.04, CHCl3); Rf = 0.29 (n-pentane–EtOAc, 3:1).
13C NMR (75 MHz, CDCl3): d = 10.2 (CH3), 24.5 (CH2), 26.5 (2
CH2), 51.8 (2 CH2), 64.6 (CH), 72.2 (CH), 126.0 (2 CHarom), 126.7
(CHarom), 127.9 (2 CHarom), 142.2 (Carom).
(1S,2S)-1-Phenyl-2-(piperidin-1-yl)propan-1-amine
IR (film): 3440, 3011, 2959, 2919, 1727, 1552, 1533, 1491, 1442,
1377, 1292, 1250, 1226, 1168, 1092, 1020, 996, 943, 913, 873, 806,
756, 682 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.76 (s, 3 H, CH3), 3.24 (d, J = 14
Hz, 1 H, CH), 3.87 (s, 3 H, CO2CH3), 4.20 (dt, J = 4, 14 Hz, 1 H,
CH), 4.70 (dd, J = 4, 14 Hz, 1 H, CHH), 4.95 (dd, J = 14, 4 Hz, 1 H,
CHH), 6.90 (dd, J = 1, 7 Hz, 1 H, CHarom), 7.02 (dt, J = 1, 7 Hz, 1
H, CHarom), 7.19–7.26 (m, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 30.5 (CH3), 42.6 (CH), 52.8
(Cquart), 53.0 (CO2CH3), 61.4 (CH), 77.1 (CH2), 127.7 (CHarom),
127.9 (Carom), 128.4 (CHarom), 129.0 (CHarom), 129.2 (CHarom), 136.4
(Carom), 168.0 (C=O).
The amino alcohol (vide supra) (9.00 g, 41 mmol) was dissolved in
THF (120 mL) and Et3N (17.1 mL, 123 mmol) was added. The mix-
ture was cooled to 0 °C and MsCl (4.8 mL, 62 mmol) was added
slowly. The reaction mixture was stirred for 1 h, then warmed to r.t.,
and Et3N (11.4 mL, 82 mmol) and NH3 (16 mL, 25% solution in
H2O) were added successively. After stirring overnight, the phases
were separated and the organic layer was washed with sat. aq
NaHCO3 (100 mL). The aqueous layer was extracted with Et2O (3
× 100 mL), and the combined organic layers were then washed with
H2O (80 mL) and dried (MgSO4). The solvent was removed under
reduced pressure and the product was purified by column chroma-
tography (Et2O, then 5% Et3N and 5% MeOH in Et2O) to afford the
20
diamine in 78% yield (6.98 g) as a colorless solid; mp 73 °C; [a]D
+2.7 (c 1.01, CHCl3); Rf = 0.67 (Et2O + 5% Et3N).
MS (EI, 70 eV): m/z (%) = 281 (M+,22), 217 (19), 202 (23), 191
(86), 160 (89), 131 (100), 91 (99), 77 (42), 59 (15).
IR (film): 3373, 2930, 2851, 2793, 1601, 1449, 1383, 1109, 755,
700 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.61 (d, J = 7 Hz, 3 H, CH3),
1.33–1.53 (m, 2 H, CH2), 1.54–1.76 (m, 4 H, CH2), 2.48 (br s, 2 H,
NH2), 2.55–2.69 (m, 5 H, CH2, CH), 3.71 (d, J = 10 Hz, 1 H, CH),
7.17–7.32 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 8.6 (CH3), 24.5 (CH2), 26.8 (2
CH2), 49.6 (2 CH2), 58.5 (CH), 66.0 (CH), 127.1 (CHarom), 127.7 (2
CHarom), 128.5 (2 CHarom), 144.4 (Carom).
Anal. Calcd for C13H15NO6: C, 55.51; H, 5.38; N, 4.98. Found: C,
55.48; H, 5.16; N, 4.86.
One-Pot Domino Michael-Hemiacetalization and Dehydration
Reaction; General Procedure (GP)
In an ordinary glass vial equipped with a magnetic stirring bar was
added catalyst D (10 mol%) to a mixture of b-keto ester 2 (1.1
equiv) and (E)-2-(2-nitrovinyl)phenol 1 (1 equiv) in toluene (1.0
mL per mmol) at r.t. The reaction mixture was monitored by TLC.
After completion, toluene (5 mL per mmol) and PTSA monohy-
Synthesis 2011, No. 12, 1905–1911 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4H-Chromenes
1909
drate (20 mol%) were added. After heating the reaction mixture to
100 °C for 2 h, it was cooled to 25 °C, and the crude reaction mix-
ture was worked up with aq NaHCO3 (10 mL). The aqueous layer
was extracted with CH2Cl2 (3 × 10 mL) and the combined organic
layers were dried (Na2SO4), filtered, and concentrated. The 4H-
chromenes 4 were obtained by column chromatography (silica gel,
mixture of n-pentane–EtOAc) as colorless solids (in case 4k as a red
viscous oil).
mL/min, l = 254 nm]; tR = 8.75 min (major), tR = 10.43 min (mi-
nor).
IR (film): 3003, 2954, 2908, 1686, 1589, 1540, 1436, 1377, 1354,
1293, 1238, 1186, 1139, 1105, 1066, 991, 919, 876, 842, 816, 766
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.48 (s, 3 H, CH3), 3.82 (s, 3 H,
CO2CH3), 3.90 (s, 3 H, CO2CH3), 4.52–4.66 (m, 3 H, CH, CH2),
7.09 (d, J = 9 Hz, 1 H, CHarom), 7.82–7.98 (m, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 19.8 (CH3), 35.0 (CH), 52.0
(CO2CH3), 52.3 (CO2CH3), 80.5 (CH2), 101.1 (Colef), 116.7 (Carom),
120.3 (CHarom), 127.0 (Carom), 130.0 (CHarom), 130.7 (CHarom), 153.8
(Colef), 164.4 (C=O), 165.9 (Carom), 166.3 (C=O).
(R)-Methyl 2-Methyl-4-(nitromethyl)-4H-chromene-3-carbox-
ylate (4a)
Compound 4a was synthesized according to GP to yield 237 mg
(90%) of a colorless solid; mp 93 °C; [a]D20 +88.4 (c 1.01, CHCl3);
ee = 98%; Rf = 0.45 (n-pentane–EtOAc, 6:1). The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralpak IA column [n-heptane–EtOH (9:1), flow rate 1.0 mL/
min, l = 254 nm]; tR= 7.16 min (major), tR= 9.94 min (minor).
MS (EI, 70 eV): m/z (%) = 290 (11), 275 (16), 274 (100), 262 (12),
261 (80), 259 (18), 229 (51), 216 (35), 128 (10).
Anal. Calcd for C15H15NO7: C, 56.08; H, 4.71; N, 4.36. Found: C,
56.12; H, 4.77; N, 4.31.
IR (film): 3003, 2951, 2848, 1730, 1544, 1489, 1488, 1376, 1289,
1256, 1161, 1099, 1041, 995, 955, 919, 884, 752 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.47 (s, 3 H, CH3), 3.82 (s, 3 H,
CO2CH3), 4.41 (dd, J = 4, 8 Hz, 1 H, CHH), 4.57 (dd, J = 4, 8 Hz,
1 H, CHH), 4.65 (dd, J = 4, 4 Hz, 1 H, CH), 7.02–7.32 (m, 4 H,
C6H5).
13C NMR (75 MHz, CDCl3): d = 20.0 (CH3), 35.2 (CH), 51.8
(CO2CH3), 80.7 (CH2), 100.7 (Colef), 116.5 (CHarom), 120.3 (Carom),
125.2 (CHarom), 128.0 (CHarom), 129.1 (CHarom), 150.5 (Colef), 165.0
(Carom), 166.6 (C=O).
(R)-Methyl 2-Methyl-6-nitro-4-(nitromethyl)-4H-chromene-3-
carboxylate (4d)
Compound 4d was synthesized according to GP to yield 240 mg
(78%) of a colorless solid; mp 138 °C; [a]D20 +47.4 (c 1.03, CHCl3);
ee = 49%; Rf = 0.28 (n-pentane–EtOAc, 4:1). The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralpak IA column [n-heptane–i-PrOH (4:1), flow rate 1.0 mL/
min, l = 254 nm]; tR = 10.79 min (major), tR = 12.70 min (minor).
IR (film): 3016, 2961, 2921, 2844, 1701, 1610, 1584, 1540, 1488,
1435, 1377, 1349, 1280, 1247, 1190, 1100, 1064, 990, 943, 894,
838, 769, 735, 671 cm–1.
MS (EI, 70 eV): m/z (%) = 295 (M + K, 36), 217 (34), 203 (100),
171 (41), 131 (25), 99 (43), 77 (16), 59 (26).
1H NMR (300 MHz, CDCl3): d = 2.51 (s, 3 H, CH3), 3.87 (s, 3 H,
CO2CH3), 4.54–4.72 (m, 3 H, CH, CH2), 7.06–7.37 (m, 1 H,
CHarom), 7.93–8.25 (m, 2 H, CHarom).
Anal. Calcd for C13H13NO5: C, 59.31; H, 4.98; N, 5.32. Found: C,
59.34; H, 4.83; N, 5.23.
13C NMR (75 MHz, CDCl3): d = 19.8 (CH3), 35.0 (CH), 52.3
(CO2CH3), 80.1 (CH2), 101.3 (Colef), 117.6 (CHarom), 121.4
(CHarom), 121.3 (Carom), 125.0 (CHarom), 128.1 (Carom), 155.0 (Colef),
164.3 (Carom), 166.0 (C=O).
(R)-Methyl 6-Bromo-2-methyl-4-(nitromethyl)-4H-chromene-
3-carboxylate (4b)
Compound 4b was synthesized according to GP to yield 325 mg
(95%) of a colorless solid; mp 113 °C; [a]D20 +61.2 (c 1.03, CHCl3);
ee = 98%; Rf = 0.21 (n-pentane–EtOAc, 6:1). The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralcel OD column [n-heptane–i-PrOH (9:1), flow rate 0.5 mL/
min, l = 254 nm]; tR = 15.63 min (major), tR = 18.10 min (minor).
MS (EI, 70 eV): m/z (%) = 261 (100), 248 (43), 170 (24), 128 (15),
115 (10), 114 (10), 59 (17), 46 (12).
Anal. Calcd for C13H12N2O7: C, 50.65; H, 3.92; N, 9.09. Found: C,
50.74; H, 3.80; N, 8.96.
IR (film): 2993, 2948, 2904, 1710, 1633, 1536, 1481, 1427, 1375,
1333, 1251, 1213, 1121, 1064, 989, 938, 883, 813, 770 cm–1.
(S)-Methyl 2,8-Dimethyl-4-(nitromethyl)-4H-chromene-3-car-
boxylate (4e)
1H NMR (300 MHz, CDCl3): d = 2.46 (s, 3 H, CH3), 3.82 (s, 3 H,
CO2CH3), 4.42–4.64 (m, 3 H, CH, CH2), 6.95 (d, J = 9 Hz, 1 H,
CHarom), 7.26–7.42 (m, 2 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 19.9 (CH3), 34.9 (CH), 52.0
(CO2CH3), 80.3 (CH2), 100.5 (Colef), 117.4 (Carom), 118.3 (CHarom),
122.4 (Carom), 130.7 (CHarom), 132.1 (CHarom), 149.7 (Colef), 164.8
(Carom), 166.3 (C=O).
Compound 4e was synthesized according to GP to yield 255 mg
(92%) of a colorless solid; mp 89 °C; [a]D20 –68.6 (c 1.02, CHCl3);
ee = 99%; Rf = 0.24 (n-pentane–EtOAc, 8:1). The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralcel OD column [n-heptane–i-PrOH (9:1), flow rate 1.0 mL/
min, l = 254 nm]; tR = 9.36 min (minor), tR = 10.35 min (major).
IR (film): 2995, 2949, 2905, 1711, 1635, 1538, 1482, 1429, 1375,
1334, 1255, 1217, 1119, 1065, 990, 938, 884, 839, 813, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.35 (s, 3 H, CH3), 2.50 (s, 3 H,
ArCH3), 3.84 (s, 3 H, CO2CH3), 4.42–4.84 (m, 3 H, CH, CH2),
6.90–7.15 (m, 3 H, CHarom).
MS (EI, 70 eV): m/z (%) = 296 (94), 293 (100), 282 (64), 280 (86),
250 (58), 248 (53), 236 (38), 156 (13), 155 (11), 142 (38), 77 (11),
51 (16).
HRMS: m/z calcd for C13H13BrNO5 + Na: 363.9791; found:
363.9792.
13C NMR (75 MHz, CDCl3): d = 20.0 (CH3), 20.8 (CH3), 35.2 (CH),
51.8 (CH3), 80.8 (CH2), 100.4 (Colef), 116.2 (CHarom), 120.0 (Carom),
128.1 (CHarom), 129.7 (CHarom), 134.9 (Carom), 148.5 (Colef), 165.1
(Carom), 166.8 (C=O).
MS (EI, 70 eV): m/z (%) = 277 (M+, 1), 230 (85), 217 (100), 185
(71), 172 (50), 128 (45), 115 (21), 77 (10).
(R)-Dimethyl 2-Methyl-4-(nitromethyl)-4H-chromene-3,6-di-
carboxylate (4c)
Compound 4c was synthesized according to GP to yield 289 mg
20
(90%) of a colorless solid; mp 102 °C; [a]D +115.6 (c 1.03,
CHCl3); ee = 88%; Rf = 0.40 (n-pentane–EtOAc, 4:1). The enantio-
meric excess was determined by chiral stationary phase HPLC us-
ing a Chiralpak IA column [n-heptane–i-PrOH (4:1), flow rate 1.0
Anal. Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C,
60.76; H, 5.19; N, 5.01.
Synthesis 2011, No. 12, 1905–1911 © Thieme Stuttgart · New York

1910
D. Enders et al.
PAPER
(S)-Methyl 8-Methoxy-2-methyl-4-(nitromethyl)-4H-
chromene-3-carboxylate (4f)
H, CHH), 4.56 (dd, J = 4, 7 Hz, 1 H, CHH), 4.64 (dd, J = 4, 4 Hz, 1
H, CH), 5.14 (sept, J = 6 Hz, 1 H, CH), 7.01–7.30 (m, 4 H, CHarom).
Compound 4f was synthesized according to GP to yield 273 mg
(93%) of a colorless solid; mp 103 °C; [a]D –100.1 (c 1.01,
CHCl3); ee = 99%; Rf = 0.34 (n-pentane–EtOAc, 8:1). The enantio-
meric excess was determined by chiral stationary phase HPLC us-
ing a Chiralcel OD column [n-heptane–i-PrOH (9:1), flow rate 0.5
mL/min, l = 254 nm]; tR = 11.29 min (minor), tR = 12.35 min (ma-
jor).
13C NMR (75 MHz, CDCl3): d = 20.0 (CH3), 21.9 (CH3), 22.0
(CH3), 35.2 (CH), 68.4 (CH), 80.8 (CH2), 101.2 (Colef), 116.5
(CHarom), 120.5 (Carom), 125.1 (CHarom), 128.0 (CHarom), 129.0
(CHarom), 150.6 (Colef), 164.5 (Carom), 165.7 (C=O).
20
MS (EI, 70 eV): m/z (%) = 244 (44), 231 (28), 201 (64), 189 (100),
158 (25), 131 (10), 128 (15), 115 (34).
Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C,
61.87; H, 5.50; N, 4.71.
IR (film): 3015, 2961, 2843, 1701, 1610, 1584, 1540, 1488, 1435,
1377, 1351, 1278, 1248, 1188, 1100, 990, 943, 894, 839, 769, 733,
671 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.54 (s, 3 H, CH3), 3.82 (s, 3 H,
CO2CH3), 3.90 (s, 3 H, ArOCH3), 4.40 (dd, J = 4, 8 Hz, 1 H, CHH),
4.57 (dd, J = 4, 8 Hz, 1 H, CHH), 4.66 (dd, J = 4, 4 Hz, 1 H, CH),
6.76 (dd, J = 1, 8 Hz, 1 H, CHarom), 6.88 (dd, J = 1, 8 Hz, 1 H,
CHarom), 7.07 (t, J = 8 Hz, 1 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 19.9 (CH3), 35.2 (CH), 51.8 (CH3),
56.0 (CH), 80.6 (CH2), 100.7 (Colef), 111.3 (CHarom), 119.3 (CHarom),
121.3 (Carom), 125.1 (CHarom), 140.0 (Carom), 147.6 (Colef), 164.9
(Carom), 166.6 (C=O).
(R)-2-Methoxyethyl 2-Methyl-4-(nitromethyl)-4H-chromene-3-
carboxylate (4j)
Compound 4j was synthesized according to GP to yield 273 mg
(89%) of a colorless solid; mp 73 °C; [a]D20 +19.2 (c 1.04, CHCl3);
ee = 79%; Rf = 0.32 (n-pentane–EtOAc, 4:1). The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralcel OD column [n-heptane–EtOH (95:5), flow rate 0.5 mL/
min, l = 254 nm]; tR = 15.44 min (major), tR = 19.14 min (minor).
IR (film): 2992, 2934, 2892, 1706, 1636, 1585, 1545, 1490, 1452,
1377, 1291, 1254, 1209, 1108, 1067, 1028, 985, 947, 843, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.48 (s, 3 H, CH3), 3.41 (s, 3 H,
OCH3), 3.68 (t, J = 7 Hz, 2 H, CH2O), 4.36 (t, J = 7 Hz, 2 H, OCH2),
4.26–4.71 (m, 3 H, CH, CH2), 7.02–7.31 (m, 4 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 20.0 (CH3), 35.2 (OCH3), 58.9
(CH), 63.8 (CO2CH2), 70.4 (CH2O), 80.7 (CH2), 100.6 (Colef), 116.5
(CHarom), 120.3 (Carom), 125.2 (CHarom), 128.0 (CHarom), 129.0
(CHarom), 150.4 (Colef), 165.1 (Carom), 166.1 (C=O).
MS (EI, 70 eV): m/z (%) = 293 (M+), 246 (100), 233 (90), 201 (37),
188 (36), 115 (18), 77 (10).
Anal. Calcd for C14H15NO6: C, 57.34; H, 5.16; N, 4.78. Found: C,
57.27; H, 5.22; N, 4.74.
(R)-Ethyl 2-Methyl-4-(nitromethyl)-4H-chromene-3-carboxy-
late (4g)
Compound 4g was synthesized according to GP to yield 255 mg
(92%) of a colorless solid; mp 84 °C; [a]D20 +31.6 (c 1.01, CHCl3);
ee = 62%; Rf = 0.24 (n-pentane–EtOAc, 4:1). The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralcel OD column [n-heptane–EtOH (97:3), flow rate 0.7 mL/
min, l = 254 nm]; tR = 9.33 min (major), tR = 10.31 min (minor).
MS (EI, 70 eV): m/z (%) = 260 (80), 247 (98), 203 (54), 189 (95),
171 (100), 158 (97), 128 (30), 115 (68), 89 (13), 77 (13), 59 (39).
Anal. Calcd for C15H17NO6: C, 58.63; H, 5.58; N, 4.56. Found: C,
58.66; H, 5.52; N, 4.55.
(R)-Ethyl 4-(Nitromethyl)-2-phenyl-4H-chromene-3-carboxy-
late (4k)
IR (film): 2982, 2936, 2902, 1710, 1635, 1532, 1487, 1435, 1377,
1288, 1250, 1213, 1106, 1058, 985, 945, 836, 769 cm–1.
Compound 4k was synthesized according to GP to yield 258 mg
(76%) of a red viscous oil; [a]D20 +113.2 (c 1.03, CHCl3); ee = 80%;
Rf = 0.35 (n-pentane–EtOAc, 6:1). The enantiomeric excess was
determined by chiral stationary phase HPLC using a Chiralpak IA
column [n-heptane–EtOH (9:1), flow rate 1.0 mL/min, l = 254
nm]; tR = 7.30 min (major), tR = 13.94 min (minor).
1H NMR (300 MHz, CDCl3): d = 1.36 (t, J = 7 Hz, 3 H, CH3), 2.47
(s, 3 H, CH3), 4.27 (q, J = 7 Hz, 2 H, CO2CH2), 4.41 (dd, J = 4, 8
Hz, 1 H, CHH), 4.56 (dd, J = 4, 8 Hz, 1 H, CHH), 4.66 (dd, J = 4, 4
Hz, 1 H, CH), 7.02–7.31 (m, 4 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 14.3 (CH3), 20.0 (CH2), 35.2 (CH),
60.8 (CO2CH3), 80.8 (CH2), 100.4 (Colef), 116.5 (CHarom), 120.4
(Carom), 125.2 (CHarom), 128.0 (CHarom), 129.0 (CHarom), 150.6
(Colef), 164.7 (Carom), 166.2 (C=O).
IR (film): 3057, 2979, 2919, 2853, 1692, 1640, 1549, 1457, 1375,
1308, 1231, 1194, 1077, 1035, 912, 834, 761, 698 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.94 (t, J = 7 Hz, 3 H, CH3), 4.00
(q, J = 7 Hz, 2 H, CH2), 4.60–4.82 (m, 3 H, CH, CH2), 7.10–7.34
(m, 4 H, CHarom), 7.37–7.51 (m, 5 H, C6H5).
13C NMR (75 MHz, CDCl3): d = 13.5 (CH3), 36.1 (CH2), 60.7 (CH),
80.6 (CH2), 101.5 (Colef), 116.7 (CHarom), 120.3 (Carom), 125.4
(CHarom), 127.9 (2 CHarom) 128.2 (CHarom), 128.9 (2 CHarom), 129.2
(CHarom), 130.2 (Carom), 134.2 (Carom), 151.1 (Colef), 163.0 (Carom),
166.6 (C=O).
MS (EI, 70 eV): m/z (%) = 230 (91), 201 (43), 189 (86), 171 (66),
158 (91), 129 (17), 128 (35), 127 (18), 116 (13), 115 (100), 89 (20),
77 (20), 51 (19).
Anal. Calcd for C14H15NO5: C, 60.64; H, 5.45; N, 5.05. Found: C,
60.59; H, 5.42; N, 4.98.
(R)-Isopropyl 2-Methyl-4-(nitromethyl)-4H-chromene-3-car-
boxylate (4h)
MS (EI, 70 eV): m/z (%) = 292 (100), 279 (85), 263 (42), 251 (44),
220 (28), 219 (11), 173 (14), 105 (31), 77 (19).
Compound 4h was synthesized according to GP to yield 239 mg
(82%) of a colorless solid; mp 78 °C; [a]D20 +9.4 (c 1.06, CHCl3);
ee = 30%; Rf = 0.37 (n-pentane–EtOAc, 10:1). The enantiomeric
excess was determined by chiral stationary phase HPLC using a
Chiralcel OD column [n-heptane–EtOH (9:1), flow rate 0.7 mL/
min, l = 254 nm]; tR = 9.80 min (major), tR = 12.35 min (minor).
Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13. Found: C,
67.49; H, 5.12; N, 4.05.
Acknowledgment
IR (film): 2986, 2936, 1702, 1634, 1538, 1490, 1462, 1427, 1378,
1292, 1222, 1106, 1054, 983, 945, 839, 766 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.33 (d, J = 6 Hz, 3 H, CH3), 1.34
(d, J = 6 Hz, 3 H, CH3), 2.46 (s, 3 H, CH3), 4.40 (dd, J = 4, 7 Hz, 1
This work was supported by the Fonds der Chemischen Industrie.
We thank BASF AG for the donation of chemicals.
Synthesis 2011, No. 12, 1905–1911 © Thieme Stuttgart · New York

PAPER
Asymmetric Synthesis of 4H-Chromenes
1911
Wang, R. J. Org. Chem. 2009, 74, 5562. (i) Oh, Y.; Kim, S.
M.; Kim, D. Y. Tetrahedron Lett. 2009, 50, 4674. (j) Pu,
X.-W.; Peng, F.-Z.; Zhang, H.-B.; Shao, Z.-H. Eur. J. Org.
Chem. 2009, 4622. (k) Ju, Y.-D.; Xu, L.-W.; Li, L.; Lai, G.-
Q.; Qiu, H.-Y.; Jiang, J.-X.; Lu, Y. Tetrahedron Lett. 2008,
49, 6773. (l) Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C.
Eur. J. Org. Chem. 2008, 4563. (m) Zhang, Z.-H.; Dong,
X.-Q.; Chen, D.; Wang, C.-J. Eur. J. Org. Chem. 2008,
8780. (n) Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-
J. Chem. Commun. 2008, 1431. (o) Peng, F.-Z.; Shao, Z.-
H.; Fan, B.-M.; Song, H.; Li, G.-P.; Zhang, H.-B. J. Org.
Chem. 2008, 73, 5202.
References
(1) (a) Shen, H. C. Tetrahedron 2009, 65, 3931. (b) Ferreira, S.
B.; da Silva, F. de C.; Pinto, A. C.; Gonzaga, D. T. G.;
Ferreira, V. F. J. Heterocycl. Chem. 2009, 46, 1080.
(c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(d) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao,
G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000,
122, 9939. (e) Keay, B. A. In Comprehensive Heterocyclic
Chemistry II, Vol. 2; Pergamon: Oxford, 1996.
(f) Schweizer, E. E.; Meeder-Nycz, O. In Chromenes,
Chromanes, Chromones; Ellis, G. P., Ed.; Wiley-
Interscience: New York, 1977.
(6) For selected examples on ephedrine based catalysts and
ligands in asymmetric synthesis, see: (a) Flock, A. M.;
Krebs, A.; Bolm, C. Synlett 2010, 1219. (b) Paixao, M. W.;
de Godoi, M.; Rhoden, C. R. B.; Westermann, B.;
Wessjohann, L. A.; Lüdtke, D. S.; Braga, A. L. J. Mol. Catal.
A: Chem. 2007, 261, 120. (c) Garnier, J. M.; Robin, S.;
Rousseau, G. Eur. J. Org. Chem. 2007, 3281. (d)Berkessel,
A.; Mukherjee, S.; Müller, T. N.; Cleemann, F.; Roland, K.;
Brandenburg, M.; Neudörfl, J.-M.; Lex, J. Org. Biomol.
Chem. 2006, 4 , 4319. (e) Mlynarski, J.; Rakiel, B.;
Stodulski, M.; Agata Suszczyńska, A.; Frelek, J. Chem. Eur.
J. 2006, 12, 8158. (f) Enders, D.; Zhu, J.; Kramps, L. A.
Liebigs Ann./Recl. 1997, 1101. (g) Enders, D.; Zhu, J.;
Raabe, G. Angew. Chem., Int. End. Engl. 1996, 35 , 1725.
(h) Soai, K.; Okudo, M.; Okamoto, M. Tetrahedron Lett.
1991, 32, 95.
(7) For reviews on organocatalytic asymmetric Michael
additions, see: (a) Enders, D.; Wang, C.; Liebich, J. X.
Chem. Eur. J. 2009, 15, 11058. (b) Sulzer-Mossé, S.;
Alexakis, A. Chem. Commun. 2007, 3123. (c) Almaşi, D.;
Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18,
299. (d) Vicario, J. L.; Badía, D.; Carrillo, L. Synthesis 2007,
2065. (e) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
(f) For asymmetric Michael additions to nitroalkenes, see:
Enders, D.; Berner, O. M.; Tedeschi, L. Eur. J. Org. Chem.
2002, 1877. (g) For sulfa-Michael additions, see: Enders,
D.; Lüttgen, K.; Narine, A. A. Synthesis 2007, 959.
(8) Enders, D.; Wang, C.; Yang, X.; Raabe, G. Adv. Synth.
Catal. 2010, 352, 2869.
(2) For examples of catalytic asymmetric syntheses of 4H-
chromenes, see: (a) Zhang, X.; Zhang, S.; Wang, W. Angew.
Chem. Int. Ed. 2010, 49, 1481. (b) Alemán, J.; Nûńez, A.;
Marzo, L.; Marcos, V.; Alvarado, C.; Ruano, J. L. G. Eur. J.
Org. Chem. 2010, 9453. (c) Lu, D.; Li, Y.; Gong, Y. J. Org.
Chem. 2010, 75, 6900. (d) Ramachary, D. B.; Sakthidevi, R.
Org. Biomol. Chem. 2010, 8, 4259. (e) Nishikata, T.;
Yamamoto, Y.; Miyaura, N. Adv. Synth. Catal. 2007, 349,
1759.
(3) For general reviews on domino, tandem, or multicomponent
reactions, see for example: (a) Enders, D.; Jeanty, M.;
Grondal, C. Nat. Chem. 2010, 2, 167. (b) Yu, X.; Wang, W.
Org. Biomol. Chem. 2008, 6, 2037. (c) Enders, D.; Grondal,
C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570.
(d) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(e) Guo, H.-C.; Ma, J.-A. Angew. Chem. Int. Ed. 2006, 45,
354. (f) Pellissier, H. Tetrahedron 2006, 62, 1619.
(g) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C.
Chem. Rev. 2005, 105, 1001. (h) Ramón, D. J.; Yus, M.
Angew. Chem. Int. Ed. 2005, 44, 1602. (i) Zhu, J.;
Bienaymé, H. Multicomponent Reactions; Wiley-VCH:
Weinheim, 2005.
(4) For selected general reviews see: (a) Schreiner, P. R. Chem.
Soc. Rev. 2003, 32, 289. (b) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem. Int. Ed. 2006, 45, 1520. (c) Doyle, A. G.;
Jacobsen, E. N. Chem. Rev. 2007, 107, 5713. (d) Zhang, Z.;
Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187. (e) Kotke,
M.; Schreiner, P. R. In Hydrogen Bonding in Organic
Synthesis; Pihko, P. M., Ed.; Wiley-VCH: Weinheim, 2009,
141–352. (f) Takemoto, Y. Chem. Pharm. Bull. 2010, 58,
593. (g) Etzenbach-Effers, K.; Berkessel, A. Top. Curr.
Chem. 2009, 291, 1. (h) Knowles, R. R.; Jacobsen, E. N.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20678.
(9) The (E)-2-(2-nitrovinyl)phenols were synthesized from the
corresponding substituted salicylaldehydes and
nitromethane in the AcOH/NH4OAc system, according to:
Zhang, B.-L.; Wang, F.-D.; Yue, J.-M. Synlett 2006, 567.
(10) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672.
(5) For recent selected examples of organocatalytic asymmetric
Michael additions of 1,3-dicarbonyl compounds to
nitroalkenes, see: (a) Pu, X.-W.; Peng, F.-Z.; Zhang, H.-B.;
Shao, Z.-H. Tetrahedron 2010, 66, 3655. (b) Yu, Z.; Liu,
X.; Zhou, L.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2009,
48, 5195. (c) Li, H.; Zu, L.; Xie, H.; Wang, W. Synthesis
2009, 1525. (d) Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang,
W. Chem. Commun. 2009, 2136. (e) Luo, J.; Xu, L.-W.;
Hay, R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437.
(11) (a) Nie, S.-Z.; Hu, Z.-P.; Xuan, Y.-N.; Wang, J.-J.; Li,
X.-M.; Yan, M. Tetrahedron: Asymmetry 2010, 21, 2055.
(b) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron 2010, 66,
6349.
(12) Rampalakos, C.; Wulff, W. D. Adv. Synth. Catal. 2008, 350,
1785.
(13) CCDC 816422 (4a), 816423 (ent-4b), 816424 (4f) contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
(f) McGarraugh, P. G.; Brenner, S. E. Tetrahedron 2009, 65,
449. (g) Almaşi, D.; Alonso, D. A.; Gómez-Bengoa, E.;
Nájera, C. J. Org. Chem. 2009, 74, 6163. (h) Jiang, X.;
Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang, J.;
www.ccdc.cam.ac.uk/data_request/cif.
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