Bifunctional thiourea-promoted cascade aza-Michael-Henry-dehydration reactions: Asymmetric preparation of 3-nitro-1,2-dihydroquinolines

Article abstract of DOI:10.1039/c0ob00223b

A cascade aza-Michael-Henry-dehydration reaction catalyzed by quinidine-derived tertiary amine-thiourea catalyst was developed via installation of suitable electron withdrawing groups at the amino function of aniline. This strategy led to a one-step preparation of chiral 3-nitro-1,2-dihydroquinolines in high yields and with up to 90% enantiomeric excesses.

Full text of DOI:10.1039/c0ob00223b

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Bifunctional thiourea-promoted cascade aza-Michael-Henry-dehydration
reactions: asymmetric preparation of 3-nitro-1,2-dihydroquinolines†
Xiaoqian Liu and Yixin Lu*
Received 7th June 2010, Accepted 25th June 2010
First published as an Advance Article on the web 21st July 2010
DOI: 10.1039/c0ob00223b
A cascade aza-Michael-Henry-dehydration reaction cat-
alyzed by quinidine-derived tertiary amine-thiourea catalyst
was developed via installation of suitable electron with-
drawing groups at the amino function of aniline. This
strategy led to a one-step preparation of chiral 3-nitro-
1,2-dihydroquinolines in high yields and with up to 90%
enantiomeric excesses.
Hydroquinolines, which possess a broad spectrum of biolog-
Scheme
1
Synthesis of 3-nitro-1,2-dihydroquinoline via a cascade
ical activities, are of great importance in pharmaceutical in-
dustry and medicinal chemistry.1 In particular, functionalized
1,2-dihydroquinolines are useful structural motifs and synthetic
intermediates in natural product synthesis.1a,1d Methods for the
catalytic asymmetric synthesis of chiral 1,2-dihydroquinolines
are very limited.2 Shibasaki and co-workers developed an
asymmetric Reissert-type reaction promoted by a Lewis acid–
Lewis base bifunctional catalyst to access chiral 2-cyano-1,2-
dihydroquinolines.3 Wang et al. disclosed an asymmetric synthesis
of 3-formyl-1,2-dihydroquinolines employing a domino conjugate
addition-aldol-dehydration reaction promoted by prolinol silyl
ether via an iminium-enamine activation.4 A similar approach
for the dihydroquinoline synthesis was independently reported by
Co´rdova and co-workers.5 Given the importance of functionalized
1,2-dihydroquinoline compounds, and lack of efficient method for
the preparation of chiral 3-nitro-1,2-dihydroquinolines,6 we set out
to develop an organocatalytic approach to tackle this synthetic
challenge.
Bifunctional organic molecules containing a tertiary amino
group and a thiourea moiety have been established as remarkably
useful organic catalysts.7 We envisage that a cascade process8
mediated by tertiary amine-thiourea catalyst may lead to a one-
pot generation of chiral 3-nitro-1,2-dihydroquinoline (Scheme 1).
Installation of an electron-withdrawing group on the amino
moiety of 2-aminobenzaldehyde is anticipated to increase the
aniline N–H acidity, and the abstraction of which by the tertiary
amine leads to an aza-Michael reaction. The thiourea group in the
chiral catalyst is anticipated to have hydrogen bonding interactions
with the nitro group. The subsequent Henry reaction with the
aldehyde, followed by dehydration is expected to generate 3-nitro-
1,2-dihydroquinoline.
aza-Michael-Henry-dehydration reaction.
formylphenyl)benzenesulfonamide and nitrooelfin was chosen for
initial exploration. As cinchona alkaloids are well-established or-
ganic catalysts,9 a number of cinchona alkaloid-based organocata-
lysts were examined in our study (Table 1). To our delight, quinine-
derived 4 and quinidine 5 effectively promoted the projected
cascade reactions, yielding the desired 3-nitro-1,2-quinolines in
excellent yields, albeit with poor enantioselectivities (entries 1 and
2). Quinidine-derived sulfonamide10 6 was completely ineffective
(entry 3). While quinidine-derived thiourea catalysts 7, 8 and
9 offered low enantioselectivities (entries 4–6), thiourea 10 was
found to be a good catalyst, affording the desired quinoline
in moderate enantioselectivity (entry 7). Enantioselectivity was
substantially improved when toluene was used as a solvent
(entry 8). Electron-withdrawing sulfone group in the sulfonamide
substrate is essential for the observed reactivity, as no reaction
was observed when 2-aminobenzaldehyde or its N-Cbz-protected
derivative was used.11 We reasoned that the sulfonamide moiety
in the substrate might play an important role in asymmetric
induction, thus various sulfonamides were prepared and their
influences on the reactions were investigated. Methanesulfonyl
group afforded the product in high yield, but the enantioselectivity
was significantly decreased, suggesting that the steric hindrance of
the sulfonamide may be important in the asymmetric induction
(entry 9). Sulfonamides containing various electron-withdrawing
groups on the phenyl rings or naphthylene gave results comparable
to those obtained with tosylsulfonamide (entries 10 to 13). By
employing sterically hindered 2,4,6-trimethylbenzenesulfonamide
substrate, very good enantioselectivity was attainable (entry 14).
Using more hindered 2,4,6-triisopropylbenzenesulfonamide led
to further improvement in the enantioselectivity of the reaction.
Under the optimized reaction conditions, the desired 3-nitro-1,2-
dihydroquinoline was obtained in 81% yield and with 90% ee
(entry 16).
To test the above hypothesis, a sulfonyl was used to ac-
tivate the amino group, and the reaction between N-(2-
Department of Chemistry and Medicinal Chemistry Program, Life Sci-
ences Institute, National University of Singapore, Singapore, Republic of
Singapore. E-mail: chmlyx@nus.edu.sg; Fax: +65-6779-1691; Tel: +65-
6516-1569
† Electronic supplementary information (ESI) available: Experimental
details, analytic data, HPLC chromatogram and NMR spectra of the
products. See DOI: 10.1039/c0ob00223b
This cascade aza-Michael-Henry-dehydration reaction is appli-
cable to different nitroolefins (Table 2). Various meta- or para-
substituted aryl nitroolefins were suitable substrates, and the
electronic nature of the aromatic rings can be varied. In addition,
aliphatic nitroolefin could be used. Moreover, employment of
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Table 1 Screening of organic catalysts for cascade aza-Michael-Henry-
Table 2 Asymmetric synthesis of various 3-nitro-1,2-dihydroquinolines
via 10-promoted cascade aza-Michael-Henry-dehydration reactiona
dehydration reactiona
Entry
1
Product
t/h
Yieldb (%)
81
eec (%)
90
72
2
36
77
82
Entry Cat.
R
Solvent
t/h Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4
pCH3–Ph
pCH3–Ph
pCH3–Ph
pCH3–Ph
pCH3–Ph
pCH3–Ph
pCH3–Ph
pCH3–Ph
CH3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene 72
Toluene 48
Toluene 72
Toluene 72
Toluene 18
Toluene 72
Toluene 60
Toluene 60
Toluene 72
12
48
73
24
48
50
50
95
95
—
95
70
80
95
95
95
43
79
> 95
> 95
80
13
12
—
23
15
9
48
70
40
63
58
55
72
86
90
90
65
86
0
3
4
5
36
36
48
91
92
83
85
87
81
5
6
7
8
9
10
10
10
10
10
10
10
10
10
10
10
10
10
9
10
11
12
13
14
15
16d
17
18
19
pCF3–Ph
pNO2–Ph
3,5-CF3–Ph
1-naphthyl
2,4,6-Me–Ph
2,4,6-iPr–Ph
2,4,6-iPr–Ph
2,4,6-iPr–Ph
2,4,6-iPr–Ph
2,4,6-iPr–Ph
57
81
60
70
95
CH2Cl2
Xylene
DMF
72
72
48
6
7
48
72
75
90
84
87
a The reactions were performed with 1 (0.025 mmol), 2a (0.075 mmol)
and the catalyst (0.0025 mmol) in anhydrous solvent (0.2 mL) at room
temperature, unless otherwise specified; b Isolated yield. c The ee value was
determined by chiral HPLC analysis. d 20 mol% catalyst was used.
different ortho-formyl anilines led to the ready formation of
different quinolines. However, ortho-substituted aryl nitroolefins
were poor substrates,12 likely due to the steric repulsion resulted
from the nearby bulky sulfonamide group.
The sulfonyl group could be easily removed by reductive cleav-
age. When 3j was treated with magnesium in methanol under re-
fluxing condition, 2-aryl-substituted 3-nitro-1,2-dihydroquinoline
4j was obtained in good yield. It should be noted that the
enantioselectivity was maintained and the bromine atom on the
benzene ring was not affected (Scheme 2).
8
9
72
72
86
83
89
81
10
72
86
70
Scheme 2 Reductive removal of the sulfonyl group
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Table 2 (Contd.)
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Malinakova, J. Org. Chem., 2004, 69, 4701.
Entry
11d
Product
t/h
Yieldb(%)
75
eec(%)
82
72
3 M. Takamura, K. Funabashi, M. Kanai and M. Shibasaki, J. Am.
Chem. Soc., 2000, 122, 6327.
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12
72
78
88
6 (a) For synthesis of racemic 3-nitro-1,2-dihydroquinolines, see: M.-C.
Yan, Z. Tu, C. Lin, S. Ko, J. Hsu and C.-F. Yao, J. Org. Chem., 2004,
69, 1565; (b) While our work was in progress, Xu et al. reported an
elegant asymmetric synthesis of 3-nitro-1,2-dihydroquinolines using a
dual-activation protocol, see Y.-F. Wang, W. Zhang, S.-P. Luo, B.-L. Li,
A.-B. Xia, A.-G. Zhong and D.-Q. Xu, Chem. Asian J., 2009, 4, 1834.
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a The reactions were performed with 1 (0.025 mmol), 2 (0.075 mmol) and
10 (0.0025 mmol) in anhydrous toluene (0.5 mL) at room temperature;
b Isolated yield. c The ee value was determined by chiral HPLC analysis.
d 50 mol% catalyst was used.
In conclusion, we have developed a new catalytic cascade
aza-Michael-Henry-dehydration process for the efficient prepa-
ration of chiral 3-nitro-1,2-quinolines. Installing an electron-
withdrawing sulfone group on anilines allows for their activation
by well-established tertiary amine-thiourea catalysts, and this
strategy may find wide applications in the preparation of nitrogen-
containing heterocycles. Mechanistic understanding of this cas-
cade reaction, development of other organocatalytic cascade
processes and their applications to the asymmetric synthesis of
flavonoids and their structural analogues are currently under
investigation in our laboratory.
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Pellissier, Tetrahedron, 2006, 62, 2143.
Acknowledgements
9 (a) For recent reviews and selective examples, see: C. E. Song,
Cinchona Alkaloids in Synthesis & Catalysis: Ligands, Immobilization
and Organocatalysis, Wiley-VCH, Weinheim, 2009; (b) Y. Chen, P.
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10 J. Luo, L.-W. Xu, A. S. R. Hay and Y. Lu, Org. Lett., 2009, 11, 437.
11 2-Aminobenzaldehyde or benzyl 2-formylphenylcarbamate was mixed
with catalyst 10 in toluene for 72 h, no reaction occurred.
12 When (E)-1-chloro-2-(2-nitrovinyl)benzene was subjected to the same
reaction conditions, the corresponding quinoline was obtained in 60%
yield and with 17% ee.
We wish to thank the National University of Singapore and the
Ministry of Education (MOE) of Singapore (R-143-000-362-112)
for generous financial support.
Notes and references
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The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 4063–4065 | 4065
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