Asymmetric synthesis of cis-3,4-disubstituted chromans and dihydrocoumarins via an organocatalytic Michael addition/ hemiacetalization reaction

Article abstract of DOI:10.1002/adsc.201000659

The organocatalytic domino Michael/hemiacetalization reaction between various aldehydes and ortho-nitrovinylphenols has been developed. Under the catalysis of diphenyl prolinol trimethylsilyl ether, cis-3,4-disubstituted chromanols are obtained in high to excellent yields (81-98%) and stereoselectivities (dr: 86:14 to >99:1, ee 96 to >99%). The corresponding disubstituted chromans are available by dehydroxylation of the domino products in good to excellent yields (58-95%). Furthermore, oxidation of the domino products with pyridinium chlorochromate provided 3,4-dihydrocoumarins in good yields (65-83%) without any epimerization. Copyright

Full text of DOI:10.1002/adsc.201000659

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DOI: 10.1002/adsc.201000659
Asymmetric Synthesis of cis-3,4-Disubstituted Chromans and
Dihydrocoumarins via an Organocatalytic Michael Addition/
Hemiacetalization Reaction
Dieter Enders,a,* Chuan Wang,a Xuena Yang,a and Gerhard Raabea
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2127; e-mail: enders@rwth-aachen.de
Received: August 23, 2010; Published online: November 17, 2010
Dedicated to Professor Carmen Nꢀjera on the occasion of her 60th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000659.
Abstract: The organocatalytic domino Michael/
hemiacetalization reaction between various alde-
hydes and ortho-nitrovinylphenols has been devel-
oped. Under the catalysis of diphenyl prolinol tri-
methylsilyl ether, cis-3,4-disubstituted chromanols
are obtained in high to excellent yields (81–98%)
and stereoselectivities (dr: 86:14 to >99:1, ee 96 to
>99%). The corresponding disubstituted chromans
are available by dehydroxylation of the domino
products in good to excellent yields (58–95%). Fur-
thermore, oxidation of the domino products with
pyridinium chlorochromate provided 3,4-dihydro-
coumarins in good yields (65–83%) without any epi-
merization.
The chroman core is the central structural skeleton
present in various biologically active compounds and
thus many reports on the asymmetric synthesis of this
moiety have been published.[8,9] The dihydrocoumarin
structure is also present as a subunit in diverse com-
pounds exhibiting biological activities.[10] Therefore,
numerous methods have been developed to approach
this moiety in an asymmetric manner.[11] To access
these two structural motifs we envisaged an organo-
AHCTUNGTRENNUNG
catalytic Michael/hemiacetalization reaction[12,13] using
aldehydes (A) and (E)-2-(2-nitrovinyl)phenols (B) as
substrates (Scheme 1). This cascade is initiated by an
enamine-mediated Michael addition, followed by an
intramolecular hemiacetalization. In this process 3,4-
disubstituted chroman-2-ols (C) are provided as the
domino product, which can be converted into 3,4-di-
Keywords: chromans; 3,4-dihydrocoumarins; hemi-
acetalization; Michael addition; organocatalysis
ACHTUNGTRENUNsNG ubstituted chromans (D) by removal of the OH
group or into 3,4-dihydrocoumarins (E) by oxidation
of the lactol moiety.
In the first instance we performed the reaction of
(E)-2-(2-nitrovinyl)phenol (2a) and 3 equivalents of
After first reports by List et al., Barbas et al. and our
group, organocatalyzed Michael additions to nitroal-
kenes were developed with breathtaking speed in the
last decade.[1–3] Much effort has been devoted to the
development of new organocatalysts to improve the
efficiency and the stereoselectivity of this Michael ad-
dition.[4] Furthermore, considerable attention has
been given to the expansion of the substrate spectrum
of both the donor and the acceptor structures with
known catalysts.[5] Moreover, domino or tandem reac-
tions involving Michael additions to nitroalkenes,
which provide direct access to structurally complex
cyclic compounds bearing the synthetically useful
nitro group, have also been intensively investigated in
the last years.[6,7]
Scheme 1. Asymmetric synthesis of substituted chromans (C,
D) and dihydrocoumarins (E) via an organocatalytic
Michael/hemiacetalization reaction – retrosynthetic analysis.
Adv. Synth. Catal. 2010, 352, 2869 – 2874
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Dieter Enders et al.
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Table 1. Additive and solvent screening for the organocatalytic Michael/hemiacetalization reaction.[a]
Entry
Solvent
Additive
X [equiv.]
t [h]
Yield [%][b]
dr[c] cis:trans
ee [%][d] cis, trans
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
MeOH
MeCN
H2O
H2O
H2O
H2O
CH3CO2H
H2O
–
–
96
96
96
96
96
96
72
72
72
72
12
12
12
24
24
24
32
66
54
30
74
0
96
80
72
56
98
98
60:40
62:38
61:39
59:41
66:34
–
76:24
81:19
52:48
76:24
79:21
86:14
92:8
–
99, 83
99, 88
98, 85
98, 88
99, 87
–
99, 74
99, 69
97, 71
99, 64
>99, 63
99, 45
>99, 10
–
PhCO2H
4-NO2C6H4CO2H
CF3CO2H
CH3CO2H
NEt3
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
–
0.2
0.2
0.2
0.2
1.0
1.0
1.0
1.0
1.0
1.0
5.0
25.0
50.0
–
9
10
11
12
13
14
15
16[e]
98
traces
traces
98
–
92:8
–
CH3CO2H
25.0
>99, 19
[a]
Unless otherwise specified, reactions were performed on a 1.0-mmol scale of (E)-2-(2-nitrovinyl)phenol (2a) using
3.0 equivalents of pentanal (1a), 15 mol% catalyst 4 and X equivalents of additive at room temperature in 4.0 mL of sol-
vent.
[b]
[c]
[d]
[e]
Yield of the isolated product after flash chromatography.
1
Determined by H NMR spectroscopy on the corresponding dehydroxylated derivatives.
Determined by HPLC or GC analysis on a chiral stationary phase on the corresponding dehydroxylated derivatives.
Carried out at 48C.
pentanal (1a) in toluene at room temperature. The brief solvent screening was undertaken. Excellent
catalyst diphenylprolinol TMS-ether 4[14,15] (15 mol%) enantiomeric excesses were obtained in all solvents
was used because it shows good catalytic activity and used (Table 1, entries 8–11). The best outcome with
excellent asymmetric induction in enamine-mediated respect to yield and stereoselectivities was achieved
Michael additions to nitrostyrens.[4e,5c] The reaction af- when the reaction was conducted in water (Table 1,
forded the chromanol 3a after 96 h in a low yield entry 11). The obtained results indicated that both the
(32%) and diastereomeric ratio (cis:trans=60:40). efficiency and the diastereoselectivity of this reaction
However, an excellent enantiomeric excess was could be improved by increasing the quantity of the
achieved for the major enantiomer (ee 99%) (Table 1, acetic acid. Taking this into account we performed
entry 1). To improve both the yield and the diastereo- the reaction in water with 5.0, 25.0 and 50.0 equiv-
selectivity of this reaction, various acidic and basic ad- alents of acetic acid, respectively (Table 1, entries 12–
ditives were tested with toluene as solvent. In the 14). In the case of 25.0 equivalents of acetic acid the
cases of acidic co-catalysts similar or improved yields reaction was complete after 12 h furnishing the prod-
and diastereoselectivities were obtained and the best uct in excellent yield (98%), very good diastereomeric
result was achieved when acetic acid was used as ad- ratio (cis:trans=92:8) and perfect enantioselectivity
ditive (Table 1, entries 2–5). No product was formed (ee >99%) (Table 1, entry 13). Surprisingly, when the
in the case of triethylamine (Table 1, entry 6). When amount of added acetic acid was increased to
the amount of acetic acid was increased from 0.2 to 50.0 equivalents only a very low conversion of (E)-2-
1.0 equiv. the reaction was complete after 72 h to give (2-nitrovinyl)phenol (2a) was observed (Table 1,
3a in an excellent yield (96%), enantioselectivity (ee entry 14). A similar result was obtained when the re-
99%) and moderate diastereomeric ratio (cis:trans= action was carried out with acetic acid as solvent
76:24) (Table 1, entry 7). Based on these results, a (Table 1, entry 15). Finally, the reaction was per-
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Asymmetric Synthesis of cis-3,4-Disubstituted Chromans and Dihydrocoumarins
Table 2. Organocatalytic Michael/hemiacetalization reactions between aldehydes 1 and (E)-2-(2-nitrovinyl)phenols (2)[a] to
form the hemiacetals 3 and dehydroxylation to the chromans 5.[b]
3/5
R1
R2
t [h]
Yield [%][c]
Yield [%][d]
dr[e] cis:trans
ee [%][f]
a
n-Pr (1a)
Et (1b)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
2-MeO (2b)
4-Br (2c)
4-Cl (2d)
5-Me (2e)
3-MeO (2f)
12
12
12
12
24
24
72
24
24
24
72
98
98
98
98
95
98
85
98
95
81
86
80
81
95
80
68
85
58
58
60
92
78
92:8
95:5
92:8
92:8
86:14
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99
À98
À99
98
b[g]
c[g]
d
n-Bu (1c)
allyl (1d)
Bn (1e)
i-Pr (1f)
i-Pr (1f)
i-Pr (1f)
i-Pr (1f)
i-Pr (1f)
i-Pr (1f)
e
f
g
98
>99
>99
À96
À99
>99
>99
h[g]
i[g]
j
k
[a]
Unless otherwise specified, reactions were performed on a 1.0 mmol scale of (E)-2-(2-nitrovinyl)phenols 2 using
3.0 equivalents of aldehydes (1), 15 mol% catalyst 4 and 25.0 equivalents of CH3CO2H at room temperature in 4.0 mL of
H2O.
[b]
Reactions were performed on a 0.75-mmol scale of 3,4-disubstituted chroman-2-ols 3 using 3.0 equivalents of triethyl-
ACHTUNGTRENNUNGsilane and 3.0 equivalents of boron trifluoride etherate in 3.0 mL of CH2Cl2.
[c]
[d]
[e]
[f]
Yield of the isolated product 3 after flash chromatography.
Yield of the isolated product 5 after flash chromatography.
1
Determined by H NMR spectroscopy on the isolated product 5.
Determined by HPLC or GC analysis on a chiral stationary phase on the isolated product 5.
(S)-4 was used as the catalyst.
[g]
formed at 48C, giving no better results than at room cellent results (dr: >99:1, ee 96 to >99%) were ob-
temperature (Table 1, entry 16). tained in all cases. The reactions employing (E)-5-
Based on the optimized conditions, we investigated methyl-2-(2-nitrovinyl)phenol (2e) and the halogen-
the scope of the reaction by variation of the structure substituted nitrovinylphenols 2c, d were complete
of both the aldehydes 1 and the nitrovinylphenols 2 within 24 h, affording the corresponding chromanols
(Table 2). In the cases of the linear aldehydes penta- 3h–j in good to excellent yields (81–98%). In the
nal (1a), butanal (1b), hexanal (1c) and 4-pentenal cases of the methoxy-substituted nitrovinylphenols 2b,
(1d) with (E)-2-(2-nitrovinyl)phenol (2), the reactions f a longer reaction time (72 h) was needed to provide
were complete after 12 h furnishing the products 3a–d the product in good yields (85–86%).
in excellent yields (98%), high diastereoselectivities
In order to obtain the 3,4-substituted chromans 5
(dr: 95:5–92:8) and excellent enantiomeric excesses the domino products 3 were dehydroxylated by treat-
(ee 98 to >99%). 3-Phenylpropanal (1e) reacted well, ment with triethylsilane and boron trifluoride ether-
too, providing the cascade product 3e in an outstand- ate using dichloromethane as solvent. The reaction
ing yield (95%) and enantiostereoselectivity (ee provided the desired products 5 in good to excellent
98%), but relatively low diastereomeric ratio (dr: yields (58–95%), diastereomeric ratios (dr: 86:14 to
86:14). When 3-methylbutanal (1f) was used as the >99:1) and excellent enantiomeric excesses (ee 96 to
donor, the product was obtained in a virtually diaster- >99%) (Table 2).
eo- and enantiomerically pure form (dr: >99:1, ee
Some chromanols 3a, f, j, k were oxidized with pyri-
>99%) with excellent yield (98%). Next, we reacted dinium chlorochromate (PCC) at room temperature
3-methylbutanal (1f) with several substituted (E)-2- in dichloromethane furnishing the cis-disubstituted
(2-nitrovinyl)phenols 2b–f. Generally, the electronic 3,4-dihydrocoumarins 5a, f, j, k in good to high yields
features and the position of the substituent on the (65–83%) and in a virtually diastereo- and enantio-
aromatic ring had no significant influence on the level merically pure form (dr: >99:1, ee >99%) (Table 3).
of the asymmetric induction of this reaction, while ex- In all the cases no racemization was observed. Nota-
Adv. Synth. Catal. 2010, 352, 2869 – 2874
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Table 3. Asymmetric synthesis of cis-3,4-disubstituted dihy-
drocoumarins 6.[a]
6
R1
R2
Yield [%][b]
dr[c]
ee [%][d]
a
f
i
j
k
n-Pr
i-Pr
i-Pr
i-Pr
i-Pr
H
H
4-Cl
5-Me
3-MeO
74
83
78
65
82
>99:1
>99:1
>99:1
>99:1
>99:1
>99
>99
>99
>99
>99
Figure 1. X-ray crystal structure of 5i.[16]
[a]
Unless otherwise specified, reactions were performed on
a 0.75 mmol scale of 3,4-disubstituted chroman-2-ols 3
using 2.0 equiv of PCC in 2.3 mL CH2Cl2 at rt.
Yield of the isolated product after flash chromatography.
Determined by 1H NMR-spectroscopy on the isolated
product.
been successfully converted to the corresponding cis-
3,4-disubstituted chromans by means of a dehydroxy-
lation reaching good to excellent yields and stereose-
lectivities. Furthermore, cis-3,4-disubstituted dihydro-
coumarins are available by pyridinium chlorochro-
mate oxidation of the domino products.
[b]
[c]
[d]
Determined by HPLC or GC analysis on a chiral station-
ary phase on the isolated product.
bly, when the chromanol 3a was employed as the sub-
strate, the corresponding dihydrocoumarin 6a was ob- Experimental Section
tained in a better diastereomeric ratio (dr: >99:1) in
comparison to its precursor 3a. This can be explained General Procedure of the Organocatalytic Domino
by the removal of the minor trans-isomer of 6a during Reaction
the chromatographic purification.
Furthermore, a cis-3,4-disubstituted chroman 5f
was readily converted into the corresponding amine
To a solution of diphenylprolinol TMS ether (4) (0.15 mmol,
15 mol%), acetic acid (25.0 mmol, 25.0 equiv.) and (E)-2-(2-
nitrovinyl)phenols 2 (1.0 mmol, 1.0 equiv.) in water (4.0 mL)
7f in excellent yield (90%) by treatment with zinc
powder in H2O/HOAc as a 1:1 mixture (Scheme 2).
The relative and absolute configurations of the title
compounds were unambiguously determined to be
3S,4R in the case of 5i by X-ray structure analysis
(Figure 1).
In summary, we have developed an organocatalytic
Michael/hemiacetalization reaction in water between
various aldehydes and ortho-nitrovinylphenols under
diphenylprolinol TMS ether catalysis providing the
cis-3,4-disubstituted chroman-2-ols in good to excel-
lent yields (81–98%) and stereoselectivities (dr: 86:14
to >99:1, ee 96 to >99%). The domino products have
was added aldehyde 1 (3.0 mmol, 3.0 equiv.) at room tem-
perature. After stirring for the time given in Table 2, the re-
action mixture was extracted with ethyl acetate or dichloro-
methane. The combined organic phases were washed with
saturated aqueous NaHCO3 and NaCl solution successively,
dried over MgSO4, filtered and evaporated under reduced
pressure. The crude product was purified by flash chroma-
tography on silica gel (pentane:ether mixture) affording the
corresponding chroman-2-ols 3 as a syrup or solid.
General Procedure for the Dehydroxylation
To a solution of chroman-2-ols 3 (0.75 mmol, 1.0 equiv.) in
dichoromethane (3.0 mL) was added triethylsilane
(2.25 mmol, 3.0 equiv.) and boron trifluoride etherate
(2.25 mmol, 3.0 equiv.) at 08C successively. After 15 min the
ice bath was removed and the mixture was stirred at room
temperature for the time given in the Supporting Informa-
tion. Then the reaction was quenched with saturated aque-
ous NaHCO3 solution and the mixture was extracted with
dichloromethane. The combined organic phases were
washed with saturated aqueous NaCl solution, dried over
MgSO4, filtered and evaporated under reduced pressure.
The crude product was purified by flash chromatography on
silica gel (pentane:ether mixture) affording the correspond-
ing chromans 5 as a syrup or a solid.
Scheme 2. Synthesis of the amine 7f by reduction of the
chroman 5f.
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Asymmetric Synthesis of cis-3,4-Disubstituted Chromans and Dihydrocoumarins
Lett. 2001, 42, 4441–4444; e) D. Enders, A. Seki, Syn-
lett 2002, 26–28.
General Procedure for the Oxidation
To a solution of the chroman-2-ols 3 (0.75 mmol, 1.0 equiv.)
in dichloromethane (2.25 mL) were added silica gel (1.0
mass equiv.) and pyridinium chlorochromate (2.0 mmol,
2.0 equiv.) at room temperature successively. After stirring
for 2.5 d, the solvent was removed under reduced pressure
and the crude product was purified by flash chromatography
on silica gel (pentane:ether or pentane:dichloromethane
mixture) affording the corresponding 3,4-dihydrocoumarins
5 as a syrup or solid.
[4] a) A. Alexakis, O. Andrey, Org. Lett. 2002, 4, 3611–
3614; b) A. J. A. Cobb, D. A. Longbottom, D. M. Shaw,
S. V. Ley, Chem. Commun. 2004, 1808–1809; c) T. Ishii,
S. Fujioka, Y. Sekiguchi, H. Kotsuki, J. Am. Chem. Soc.
2004, 126, 9558–9559; d) W. Wang, J. Wang, H. Li,
Angew. Chem. 2005, 117, 1393–1395; Angew. Chem.
Int. Ed. 2005, 44, 1369–1371; e) Y. Hayashi, H. Gotoh,
T. Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284–
4287; Angew. Chem. Int. Ed. 2005, 44, 4212–4215;
f) S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9, 599–
602; g) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew.
Chem. 2006, 118, 6514–6518; Angew. Chem. Int. Ed.
2006, 45, 6366–6370; h) N. Mase, K. Watanabe, H.
Yoda, K. Takabe, F. Tanaka, C. F. Barbas III, J. Am.
Chem. Soc. 2006, 128, 4966–4967; i) S. B. Tsogoeva, W.
Wei, Chem. Commun. 2006, 1451–1453; j) M. Wiesner,
J. D. Revell, H. Wennemers, Angew. Chem. 2008, 120,
1897–1900; Angew. Chem. Int. Ed. 2008, 47, 1871–
1874; k) T. Mandal, C.-G. Zhao, Angew. Chem. 2008,
120, 7828–7831; Angew. Chem. Int. Ed. 2008, 47, 7714–
7717; l) B. Tan, X. Zeng, Y. Lu, P. J. Chua, G. Zhong,
Org. Lett. 2009, 11, 1927–1930.
Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (Priority Program Organocatalysis) and the Fonds der
Chemischen Industrie. We thank the former Degussa AG and
BASF AG for the donation of chemicals.
References
[1] For recent reviews on organocatalysis, see: a) A. Ber-
kessel, H. Grçger, Asymmetric Organocatalysis, Wiley-
VCH, Weinheim, 2005; b) P. I. Dalko, Enantioselective
Organocatalysis: Reactions and Experimental Proce-
dures, Wiley-VCH, Weinheim, 2007; c) H. Pellissier,
Tetrahedron 2007, 63, 9267–9331; d) B. List, (guest
editor), Chem. Rev. 2007, 107, 5413–5883, special issue
organocatalysis; e) R. M. De Figueiredo, M. Christ-
mann, Eur. J. Org. Chem. 2007, 2575–2600; f) A. Don-
doni, A. Massi, Angew. Chem. 2008, 120, 4716–4739.;
Angew. Chem. Int. Ed. 2008, 47, 4638–4660; g) D.
Enders, A. A. Narine, J. Org. Chem. 2008, 73, 7857–
7870; h) H. Kotsuki, H. Ikishima, A. Okuyama, Hetero-
cycles 2008, 75, 493–529; i) H. Kotsuki, H. Ikishima, A.
Okuyama, Heterocycles 2008, 75, 757–797; j) P. Mel-
chiorre, M. Marigo, A. Carlone, G. Bartoli, Angew.
Chem. 2008, 120, 6232–6265; Angew. Chem. Int. Ed.
2008, 47, 6138–6171; k) K. A. Jørgensen, S. Bertelsen,
Chem. Soc. Rev. 2009, 38, 2178–2189; l) M. Bella, T.
Gasperi, Synthesis 2009, 1583–1614.
[2] For a general review on asymmetric Michael additions
to nitroalkenes, see: a) O. M. Berner, L. Tedeschi, D.
Enders, Eur. J. Org. Chem. 2002, 1877–1894; for recent
reviews on organocatalyzed Michael-additions, see:
b) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701–1716;
c) S. Sulzer-Mossꢂ, A. Alexakis, Chem. Commun. 2007,
3123–3135; d) J. L. Vicario, D. Badꢃa, L. Carrillo, Syn-
thesis 2007, 2065–2092; e) D. Almas¸i, D. A. Alonso, C.
Nꢀjera, Tetrahedron: Asymmetry 2007, 18, 299–365;
f) D. Enders, C. Wang, J. X. Liebich, Chem. Eur. J.
2009, 15, 11058–11076.
[5] a) N. Mase, R. Thayumanavan, F. Tanaka, C. F. Barbas
III, Org. Lett. 2004, 6, 2527–2530; b) D. Enders, S.
Chow, Eur. J. Org. Chem. 2006, 4578–4584; c) S. Zhu,
S. Yu, D. Ma, Angew. Chem. 2008, 120, 555–558;
Angew. Chem. Int. Ed. 2008, 47, 545–548; d) Y. Chi, L.
Guo, N. A. Kopf, S. H. Gellman, J. Am. Chem. Soc.
2008, 130, 5608–5609; e) M. Wiesner, J. D. Revell, S.
Tonazzi, H. Wennemers, J. Am. Chem. Soc. 2008, 130,
5610–5611; f) P. Garcꢃa-Garcꢃa, A. LadꢂpÞche, R.
Hadler, B. List, Angew. Chem. 2008, 120, 4797–4799;
Angew. Chem. Int. Ed. 2008, 47, 4719–4721; g) Y. Hay-
ashi, T. Itoh, M. Ohkubo, H. Ishikawa, Angew. Chem.
2008, 120, 4800–4802; Angew. Chem. Int. Ed. 2008, 47,
4722–4724; h) N. Ruiz, E. Reyes, J. L. Vicario, D.
Badꢃa, L. Carrillo, U. Uria, Chem. Eur. J. 2008, 14,
9357–9367; i) S. Belot, A. Massaro, A. Tenti, A. Mor-
doni, A. Alexakis, Org. Lett. 2008, 10, 4557–4560; j) B.
Han, Y.-C. Xiao, Z.-Q. He, Y.-C. Chen, Org. Lett. 2009,
11, 4660–4663; k) L. Guo, Y. Chi, A. M. Almeida, I. A.
Guzei, B. K. Parker, S. H. Gellman, J. Am. Chem. Soc.
2009, 131, 16018–16020; l) H. Uehara, C. F. Barbas III,
Angew. Chem. 2009, 121, 10032–10036; Angew. Chem.
Int. Ed. 2009, 48, 9848–9852; m) D. Enders, C. Wang,
A. Greb, Adv. Synth. Catal. 2010, 352, 987–992.
[6] For selected examples of organocatalytic domino or
tandem reactions involving Michael addition to nitroal-
kenes via enamine intermediates, see: a) D. Enders,
M. R. M. Hꢄttl, C. Grondal, G. Raabe, Nature 2006,
441, 861–863; b) D. Enders, M. R. M. Hꢄttl, J. Runsink,
G. Raabe, B. Wendt, Angew. Chem. 2007, 119, 471–
473; Angew. Chem. Int. Ed. 2007, 46, 467–469; c) Y.
Hayashi, T. Okano, S. Aratake, D. Hazelard, Angew.
Chem. 2007, 119, 5010–5013; Angew. Chem. Int. Ed.
2007, 46, 4922–4925; d) D. Enders, M. R. M. Hꢄttl, G.
Raabe, J. W. Bats, Adv. Synth. Catal. 2008, 350, 267–
279; e) D. Enders, C. Wang, J. W. Bats, Angew. Chem.
2008, 120, 7649–7653; Angew. Chem. Int. Ed. 2008, 47,
7539–7542; f) S. Chadrasekhar, K. Mallikarjun, G. Pa-
[3] For first reports on organocatalyzed asymmetric Mi-
chael additions of aldehydes and ketones to nitroal-
kenes, see: a) B. List, P. Pojarliev, H. J. Martin, Org.
Lett. 2001, 3, 2423–2425; b) K. Sakthivel, W. Notz, T.
Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001, 123,
5260–5267; c) J. M. Betancort, C. F. Barbas III, Org.
Lett. 2001, 3, 3737–3740; d) J. M. Betancort, K. Sakthi-
vel, R. Thayumanavan, C. F. Barbas III, Tetrahedron
Adv. Synth. Catal. 2010, 352, 2869 – 2874
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2873

Dieter Enders et al.
COMMUNICATIONS
vankumarreddy, K. V. Rao, B. Jagadeesh, Chem.
Commun. 2009, 4985–4987; g) C.-L. Cao, Y.-Y. Zhou,
J. Zhou, X.-L. Sun, Y. Tang, Y.-X. Li, G.-Y. Li, J. Sun,
Chem. Eur. J. 2009, 15, 11384–11389; h) D. Zhu, M.
Lu, L. Dai, G. Zhong, Angew. Chem. 2009, 121, 6205–
6208; Angew. Chem. Int. Ed. 2009, 48, 6089–6092;
i) L.-Y. Wu, G. Bencivenni, M. Mancinelli, A. Mazzanti,
G. Bartoli, P. Melchiorre, Angew. Chem. 2009, 121,
7332–7335; Angew. Chem. Int. Ed. 2009, 48, 7196–
7199; j) S. Belot, K. A. Vogt, C. Besnard, N. Krause, A.
Alexakis, Angew. Chem. 2009, 121, 9085–9088; Angew.
Chem. Int. Ed. 2009, 48, 8923–8926; k) D. Enders, R.
Krꢄll, W. Bettray, Synthesis 2010, 567–572.
[12] For selected examples of organocatalytic domino reac-
tions involving hemiacetalization, acetalization or
hemiACTHNUTRGNEaNUG minalization steps, see: a) O. Andrey, A. Vi-
donne, A. Alexakis, Tetrahedron Lett. 2003, 44, 7901–
7904; b) I. Ibrahem, R. Rios, J. Veseley, G.-L. Zhao, A.
Cꢅrdova, Chem. Commun. 2007, 849–851; c) M. Ruep-
ing, E. Sugiono, E. Merino, Angew. Chem. 2008, 120,
3089–3092; Angew. Chem. Int. Ed. 2008, 47, 3046–
3049; d) T. Franke, B. Richter, K. A. Jørgensen, Chem.
Eur. J. 2008, 14, 6317–6321; e) D. Hazelard, H. Ishika-
wa, D. Hashizume, H. Koshino, Y. Hayashi, Org. Lett.
2008, 10, 1445–1448; f) Y. Hayashi, H. Gotoh, R.
Masui, H. Ishikawa, Angew. Chem. 2008, 120, 4076–
4079; Angew. Chem. Int. Ed. 2008, 47, 4012–4015; g) B.
Han, J.-L. Li, C. Ma, S.-J. Zhang, Y.-C. Chen, Angew.
Chem. 2008, 120, 10119–10122; Angew. Chem. Int. Ed.
2008, 47, 9971–9974; h) L. Zu, H. Xie, H. Li, J. Wang,
X. Yu, W. Wang, Chem. Eur. J. 2008, 14, 6333–6335;
i) H. Gotoh, D. Okamura, H. Ishikawa, Y. Hayashi,
Org. Lett. 2009, 11, 4056–4059; j) B. Han, Z.-Q. He, J.-
L. Li, R. Li, K. Jiang, T.-J. Liu, Y.-C. Chen, Angew.
Chem. 2009, 121, 5582–5585; Angew. Chem. Int. Ed.
2009, 48, 5474–5477; k) E. Reyes, G. Talavera, J. L. Vi-
cario, D. Badꢃa, L. Carrillo, Angew. Chem. 2009, 121,
5811–5814; Angew. Chem. Int. Ed. 2009, 48, 5701–
5704; l) Y. Wang, D.-F. Yu, Y.-Z. Liu, H. Wei, Y.-C.
Luo, D. J. Dixon, P.-F. Xu, Chem. Eur. J. 2010, 16,
3922–3925; m) W. Yao, L. Pan, Y. Wu, C. Ma, Org.
Lett. 2010, 12, 2422–2425.
[7] For reviews on organocatalytic domino reactions, see:
a) D. Enders, C. Grondal, M. R. M. Hꢄttl, Angew.
Chem. 2007, 119, 1590–1601; Angew. Chem. Int. Ed.
2007, 46, 1570–1581; b) X. Yu, W. Wang, Org. Biomol.
Chem. 2008, 6, 2037–2046; c) C. Grondal, M. Jeanty,
D. Enders, Nature Chemistry 2010, 2, 167–178.
[8] For a review on the asymmetric synthesis of chromans,
see: H. C. Shen, Tetrahedron 2009, 65, 3931–3952.
[9] For selected examples of organocatalytic asymmetric
syntheses of chromans, see: a) D. B. Ramachary, R.
Sakthidevi, Chem. Eur. J. 2009, 15, 4516–4522; b) P.
Kotame, B.-C. Hong, J.-H. Liao, Tetrahedron Lett. 2009,
50, 704–707; c) L. Zu, S. Zhang, H. Xie, W. Wang, Org.
Lett. 2009, 11, 1627–1630; d) A. E. Nibbs, A.-L. Baize,
R. M. Herter, K. A. Scheidt, Org. Lett. 2009, 11, 4010–
4013; e) B.-C. Hong, P. Kotame, C.-W. Tsai, J.-H. Liao,
Org. Lett. 2010, 12, 776–779; f) K.-S. Choi, S.-G. Kim,
Tetrahedron Lett. 2010, 51, 5203–5206.
[10] a) J. Posakony, M. Hirao, S. Stevens, J. A. Simon, A.
Bedalov, J. Med. Chem. 2004, 47, 2635–2644; b) A.
Kumar, B. K. Singh, R. Tyagi, S. K. Jain, S. K. Sharma,
A. K. Prasad, H. J. Raj, R. C. Rastogi, A. C. Watterson,
V. S. Parmar, Bioorg. Med. Chem. 2005, 13, 4300–4305;
c) X.-F. Zhang, H.-M. Wang, Y.-L. Song, L.-H. Nie, L.-
F. Wang, B. Liu, P.-P. Shen, Y. Liu, Bioorg. Med. Chem.
Lett. 2006, 16, 949–953.
[11] For recent selected examples of asymmetric syntheses
of 3,4-dihydrocoumarins, see: a) T. Matsuda, M. Shige-
no, M. Murakami, J. Am. Chem. Soc. 2007, 129, 12086–
12087; b) N. Alden-Danforth, M. T. Scerba, T. Lectka,
Org. Lett. 2008, 10, 4951–4953; c) B. D. Gallager, B. R.
Taft, B. H. Lipshutz, Org. Lett. 2009, 11, 5374–5377;
d) X. Han, X. Lu, Org. Lett. 2010, 12, 108–111; e) J.-L.
Li, S.-L. Zhou, B. Han, L. Wu, Y.-C. Chen, Chem.
Commun. 2010, 46, 2665–2667; f) H. Kim, J. Yun, Adv.
Synth. Catal. 2010, 352, 1881–1885.
[13] While our manuscript was in preparation a related
chroman synthesis was reported: D. B. Ramachary, R.
Sakthidevi, Org. Biomol. Chem. 2010, 8, 4259–4265.
[14] For first applications of diphenylprolinol TMS ether
catalysis, see ref.[4e] and M. Marigo, T. C. Wabnitz, D.
Fielenbach, K. A. Jørgensen, Angew. Chem. 2005, 117,
804–807; Angew. Chem. Int. Ed. 2005, 44, 794–797.
[15] For reviews on diphenylprolinol TMS ether catalysis,
see: a) C. Palomo, A. Mielgo, Angew. Chem. 2006, 118,
8042–8046; Angew. Chem. Int. Ed. 2006, 45, 7876–
7880; b) A. Mielgo, C. Palomo, Chem. Asian J. 2008, 3,
922–948.
[16] CCDC 789983 (5i) contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif or on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax.: (internat.) +44-1223/
336-033; e-mail: deposit@ccdc.cam.ac.uk].
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