Asymmetric synthesis of 2-Aryl-2,3-dihydro-4-quinolones via bifunctional thiourea-mediated intramolecular cyclization

Article abstract of DOI:10.1021/ol102519z

A novel asymmetric preparation of optically enriched 2-aryl-2,3- dihydroquinolin-4(1H)-ones has been developed. By installing a sulfonyl group on the nitrogen of the anilines and an ester function on the unsaturated ketones, an intramolecular organocataly

Full text of DOI:10.1021/ol102519z

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5592-5595
Asymmetric Synthesis of
2-Aryl-2,3-dihydro-4-quinolones via
Bifunctional Thiourea-Mediated
Intramolecular Cyclization
Xiaoqian Liu and Yixin Lu*
Department of Chemistry & Medicinal Chemistry Program, Life Sciences Institute,
National UniVersity of Singapore, 3 Science DriVe 3, Republic of Singapore, 117543
chmlyx@nus.edu.sg
Received October 18, 2010
ABSTRACT
A novel asymmetric preparation of optically enriched 2-aryl-2,3-dihydroquinolin-4(1H)-ones has been developed. By installing a sulfonyl group
on the nitrogen of the anilines and an ester function on the unsaturated ketones, an intramolecular organocatalytic cyclization took place
readily in a stereoselective manner, resulting in the formation of dihydroquinolones with high enantioselectivity.
The quinolones are a family of compounds with broad-
spectrum antibiotic properties.1 In particular, 2-aryl-2,3-
dihydro-4-quinolones represent a new class of antitumor
agents.2 Since individual stereoisomers of quinolones dis-
played different biological acitivities, it is highly desirable
to develop enantioselective routes to access this class of
important antibiotics. To the best of our knowledge, only
two examples have been reported in the literature, both
making use of transition metal-mediated catalytic processes.
Hayashi and co-workers reported an asymmetric synthesis
of 2-aryl-2,3-dihydro-4-quinolones via a rhodium-catalyzed
1,4-addition of arylzinc reagent to 4-quinolones.3 Recently,
Hou et al. disclosed a kinetic resolution of 2,3-dihydro-2-
substituted 4-quinolones by a palladium-catalyzed asym-
metric allylic alkylation, affording chiral 2,3-disubstituted
2,3-dihydro-4-quinolones in excellent enantioselectivity.4
Given the biological importance of 2-aryl-2,3-dihydro-4-
quinolones, we were interested in developing organocatalytic
synthetic methods for the practical preparation of these
valuable molecules.
For a stereoselective synthesis of 2-aryl-2,3-dihydro-4-
quinolones, an intramolecular conjugate addition of aniline
to a properly activated alkene moiety appears to be an
attractive strategy (Figure 1). The key issue here is how to
effect the cyclization in an efficient and stereocontrolled
manner. We recently reported a bifunctional thiourea-
promoted cascade aza-Michael-Henry-dehydration reaction
for the asymmetric preparation of 3-nitro-1,2-dihydroquino-
lines,5 in which the nitrogen nucleophiles were activatived
by installing a sulfonyl group. Thus, we envisioned that a
sufonyl substituted aniline could be used as the nucleophilic
component; in the presence of bifunctional tertiary amine-
(1) Wagman, A. S.; Wentland, M. P. In ComprehensiVe Medicinal
Chemistry II; Taylor, J. B., Triggle, D. J., Eds.; Elsevier: Amsterdam, 2006;
Vol. 7, pp 567-596.
(2) (a) Xia, Y.; Yang, Z.-Y.; Xia, P.; Bastow, K. F.; Tachibana, Y.;
Kuo, S.-C.; Hamel, E.; Hackl, T.; Lee, K.-H. J. Med. Chem. 1998, 41, 1155.
(b) Zhang, S.-X.; Feng, J.; Kuo, S.-C.; Brossi, A.; Hamel, E.; Tropsha, A.;
Lee, K.-H. J. Med. Chem. 2000, 43, 167.
(4) Lei, B.-L.; Ding, C.-H.; Yang, X.-F.; Wan, X.-L.; Hou, X.-L. J. Am.
Chem. Soc. 2009, 131, 18250.
(3) Shintani, R.; Yamagami, T.; Kimura, T.; Hayashi, T. Org. Lett. 2005,
7, 5317.
(5) Liu, X.; Lu, Y. Org. Biomol. Chem. 2010, 8, 4063.
10.1021/ol102519z  2010 American Chemical Society
Published on Web 11/03/2010

Figure 2
in the study.
. Bifunctional tertiary amine-thiourea catalysts employed
Figure 1. Preparation of of 2-aryl-2,3-dihydro-4-quinolones via an
intramolecular cyclization reaction.
Scheme 1. Synthesis of 2-Phenyl-2,3-dihydro-4-quinolone 6a
via Conjugate Addition-Decarboxylation Sequence
thiourea catalysts,6 the acidic proton of the sulfonamide can
be readily removed, initiating the subsequent intramolecular
cyclization reaction. To better activate the electrophiles, an
ester group could be installed at the R-position of the
carbonyl function.7 Such an ester group is expected to
facilitate hydrogen bonding interactions between the sub-
strates and the thiourea catalysts, leading to a better stere-
ochemical control. With the established protocols for its
decarboxylative cleavage,7 the ester group can be readily
removed at the end of the synthesis, without affecting the
integrity of the newly created stereogenic center at the
2-position of chiral quinolones.
To prove the validity of our proposed synthetic strategy,
alkylidene ꢀ-ketoester 4a with a properly installed neighbor-
ing sulfonamide group was treated with catalyst 1 (Figure
2). To our delight, the intramolecular cyclization occurred
smoothly to yield product 5a in quantitative yield and with
87% ee. The next step is the cleavage of the ester group.
Upon further treatment with TsOH at the elevated temper-
ature, the decarboxylation8 took place readily, and 2-phenyl-
2,3-dihydro-4-quinolone 6a was obtained in excellent yield
and with 87% ee (Scheme 1).9
The enantiomeric purity of the final quinolone products
is determined by the stereochemical outcome of the first
intramolecular cyclization step, as the second decarboxylation
step will not compromise the stereogenic integrity of the
quinolone intermediates created. We therefore investigated
the catalytic effects of various bifunctional catalysts (Figure
2) and explored different reaction conditions for the intramo-
lecular conjugate addition step, aiming to improve the
enantioselectivity of the process. L-Threonine-derived 2, and
L-tryptophan-based bifunctional catalysts 3a10 and 3b all
could promote the reactions; however, the desired products
were obtained with disappointing enantioselectivity (Table
1, entries 2-4). A solvent screening revealed that toluene
was the best reaction medium. By lowering the reaction
temperature to 0 °C, the desired quinolone 6a could be
obtained in high yield and with 94% ee (entry 12). The
sulfonyl group on the nitrogen was crucial, employment of
alkylidene ꢀ-ketoester with the free amino group resulted in
formation of the product with only 78% ee, comparing to a
94% ee under otherwise same reaction conditions.
The reaction scope was next studied, various alkylidene
ꢀ-ketoesters with different substituents were examined, and
the results are summarized in Table 2. It was found that para-
or meta- substituted aromatic rings, regardless their electronic
nature, were well-tolerated for the reaction. In all the
examples examined, good yields and excellent enantiose-
lectivities were obtained (entries 1-6). For the alkene bearing
an ortho-methyl-phenyl substituent, the desired product could
still be obtained in good yield and with excellent enantiose-
lectivity, although much longer reaction was required (entry
(6) For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520. (b) Connon, S. J. Chem. Commun. 2008, 2499. (c)
Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. (d) Schreiner, P. R. Chem.
Soc. ReV. 2003, 32, 289. (e) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth.
Catal. 2006, 348, 999. (f) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007,
107, 5713. For selective examples, see: (g) Zhu, Q.; Lu, Y. Angew. Chem.,
Int. Ed. 2010, 49, 7753. (h) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2003, 125, 12672. (i) Huang, H.; Jacobsen, E. N. J. Am. Chem.
Soc. 2006, 128, 7170. (j) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2006, 45, 6366. (k) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang,
W. Org. Lett. 2005, 7, 4293. (l) Li, B.-J.; Jiang, L.; Liu, M.; Chen, Y.-C.;
Ding, L.-S.; Wu, Y. Synlett 2005, 603. (m) Vakulya, B.; Varga, S.; Csampai,
A.; Soos, T. Org. Lett. 2005, 7, 1967. (n) McCooey, S. H.; Connon, S. J.
Angew. Chem., Int. Ed. 2005, 44, 6367. (o) Ye, J.; Dixon, D. J.; Hynes,
P. S. Chem. Commun. 2005, 4481.
(7) For a catalytic enantioselective synthesis of flavanones and chro-
manones, see: Biddle, M. M.; Lin, M.; Scheidt, K. A. J. Am. Chem. Soc.
2007, 129, 3830.
(8) For reviews and selective examples for asymmetric decarboxylation
reactions, see: (a) Blanchet, J.; Baudoux, J.; Amere, M.; Lasne, M.-C.;
Rouden, J. Eur. J. Org. Chem. 2008, 73, 5493. (b) Brunner, H.; Baur, M. A.
Eur. J. Org. Chem. 2003, 68, 2854. (c) Kukula, P.; Matousek, V.; Mallat,
T.; Baiker, A. Tetrahedron: Asymmetry 2007, 18, 2859. (d) Detalle, J. F.;
Riahi, A.; Steinmetz, V.; Henin, F.; Muzart, J. J. Org. Chem. 2004, 69,
6528. (e) Roy, O.; Diekmann, M.; Riahi, A.; Henin, F.; Muzart, J. Chem.
Commun. 2001, 533.
(9) Alternatively, this two-step reaction sequence could be carried out
without isolating the intermediates. However, we opted to perform the two
steps separately since compounds 4 and 6 tend to have very similar pola-
rity.
(10) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew.
Chem., Int. Ed. 2009, 48, 7604.
Org. Lett., Vol. 12, No. 23, 2010
5593

Table 1. Catalyst Screening for the Synthesis of Quinolones via
Table 2. Preparation of Various
an Intramolecular Cyclization-Decarboxylation Sequencea
2-Substituted-2,3-dihydro-4-quinolonesa
entry cat. solvent tb (h) temp (°C) yieldc (%) eed (%)
1
2
3
4
5
6
7
8
1
2
Toluene
Toluene
5
72
24
12
9
51
72
3
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
99/95
79/89
99/95
99/95
99/95
99/95
<30
99/95
99/95
99/91
99/95
92/91
87
11
57
20
35
79
3a Toluene
3b Toluene
1
1
1
1
1
1
1
1
MeOH
CH2Cl2
Hexane
EtOAc
THF
CH3CN
Acetone
Toluene
e
-
42
36
73
42
94
9
51
5
5
10
11
12
28
a Reactions were performed with 4a (0.05 mmol) and catalyst (0.005
mmol) in anhydrous toluene (0.2 mL) at the temperature specified. b Time
for step a. c Isolated yields for both steps. d ee value was determined by
HPLC analysis on a chiral stationary phase. e Not determined.
7). 2-Naphthyl-substituted alkylidene could also be em-
ployed, and high ee was attainable (entry 8). When the alkyl
substituent was used, the final 2-iPr-2,3-dihydro-4-quinolone
was prepared with 78% ee (entry 9).
The reductive cleavage of the sulfonyl protection was
demonstrated in Scheme 2.11 When 6a (94% ee) was treated
with magnesium in methanol at the refluxing condition, the
desulfonated 2,3-dihydro-2-aryl-quinolin-4(1H)-one 7 with
93% ee was obtained.
Scheme 2. Cleavage of the N-Sulfonyl Group
To account for the stereochemical outcome, a transition
state model is proposed and shown in Figure 3. The thiourea
moiety in the catalyst is believed to bind to the substrate
through hydrogen bonding interactions. Removal of the
acidic sulfonamide proton by the tertiary amine group in 1,
followed by a conjugate addition to the alkylidene from its
Si face, gives rise to the major stereoisomer.
In conclusion, we have developed a new approach for the
asymmetric preparation of biologically important 2-aryl-2,3-
a Reactions were performed with 4 (0.05 mmol), 1 (0.005 mmol) and
4 Å molecular sieves in anhydrous toluene (0.2 mL) at 0 °C for the first
step; 0.05 mmol TsOH in toluene (0.2 mL) was used for the second step.
b Isolated yields for both steps. c ee value was determined by HPLC analysis
on a chiral stationary phase. d The first step was performed at -30 °C.
(11) (a) Zhu, Q.; Lu, Y. Org. Lett. 2008, 10, 4803. (b) Najera, C.; Yus,
M. Tetrahedron 1999, 55, 10547. (c) Kundig, E. P.; Cunningham, A. F.,
Jr. Tetrahedron 1988, 44, 6855.
5594
Org. Lett., Vol. 12, No. 23, 2010

decarboxylative process without affecting the newly gener-
ated 2-stereogenic center of the quinolones. The reported
procedure represents a practical asymmetric route to 2-sub-
stituted-2,3-dihydro-4-quinolones, and this method may find
wide applications in the synthesis of other bioactive nitrogen-
containing cyclic structures.
Acknowledgment. We thank the National University of
Singapore and the Ministry of Education (MOE) of
Singapore (R-143-000-362-112) for generous financial
support.
Figure 3. Proposed transition state model.
Supporting Information Available: Representative ex-
perimental procedures for the intramolecular cyclization, the
decarboxylative cleavage, and the desulfonylation reaction,
HPLC chromatogram, analytical data, and NMR spectra of
the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
dihydro-quinolin-4(1H)-ones. By installing a sulfonyl group
on the nitrogen of anilines and an ester function on the
unsaturated ketones, the intramolecular cyclization reactions
proceeded in a highly enantioselective manner in the presence
of tertiary amine-thiourea organic catalysts, and the subse-
quent removal of the ester group was realized via an acidic
OL102519Z
Org. Lett., Vol. 12, No. 23, 2010
5595