Enantioselective synthesis of 2-aryl-2,3-dihydro-4-quinolones by chiral Bronsted acid catalyzed intramolecular aza-Michael addition reaction

Article abstract of DOI:10.3987/COM-09-S(S)66

Asymmetric intramolecular aza-Michael addition of activated α,β-unsaturated ketones catalyzed by chiral N-triflyl phosphoramide was realized. Enantioenriched 2-aryl-2,3-dihydroquinolin-4-ones can be obtained in excellent yields (7798%) with up to 82% ee.

Full text of DOI:10.3987/COM-09-S(S)66

HETEROCYCLES, Vol. 80, No. 2, 2010
765
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 765 - 771. © The Japan Institute of Heterocyclic Chemistry
Received, 22nd July, 2009, Accepted, 4th September, 2009, Published online, 7th September, 2009
DOI: 10.3987/COM-09-S(S)66
ENANTIOSELECTIVE SYNTHESIS OF
2-ARYL-2,3-DIHYDRO-4-QUINOLONES BY CHIRAL BRØNSTED ACID
CATALYZED INTRAMOLECULAR AZA-MICHAEL ADDITION
REACTION
Zhen Feng, Qing-Long Xu, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai
2
00032, China; E-mail: slyou@mail.sioc.ac.cn
Abstract – Asymmetric intramolecular aza-Michael addition of activated
α,β-unsaturated ketones catalyzed by chiral N-triflyl phosphoramide was realized.
Enantioenriched 2-aryl-2,3-dihydroquinolin-4-ones can be obtained in excellent
yields (77-98%) with up to 82% ee.
2-Aryl-2,3-dihydroquinolin-4-ones are a class of heterocyclic compounds with significantly biological
1-3
4-9
importance. Consequently, enormous synthetic efforts have been devoted to their efficient synthesis.
Despite the recent progress towards the synthesis of 2-aryl-2,3-dihydroquinolin-4-ones, the catalytic
enantioselective synthesis is rather limited. Notably, Hayashi and co-workers developed
rhodium-catalyzed enantioselective 1,4-addition of arylzinc reagents to 4-quinolones, leading to
10
optically pure 2-aryl-2,3-dihydro-4-quinolones. More interestingly, during the studies on testing
1
-2
2
-aryl-2,3-dihydro-4-quinolones as a new class of antitumor agents, their two enantiomers were found
to display distinct activities. This difference in reactivity of two enantiomers together with only limited
enantioselective synthesis has made that the development of efficient asymmetric catalytic synthesis of
2
-aryl-2,3-dihydro-4-quinolones is urgent and highly desirable. As a straightforward synthesis, the route
to 2-aryl-2,3-dihydro-4-quinolones by intramolecular aza-Michael addition of enone is very attractive.
However, the catalytic asymmetric synthesis by this means is still unknown despite of the fact that the
1
1-15
intermolecular aza-Michael addition of enone have been demonstrated efficiently by several groups.
1
6-18
As part of our ongoing program in exploring chiral Brønsted acid catalysis,
we recently realized the
chiral Brønsted acid-catalyzed asymmetric intramolecular oxa-Michael addition of activated
1
9
α,β-unsaturated ketones. The flavanone products can be synthesized with excellent yields (50-95%)

766
HETEROCYCLES, Vol. 80, No. 2, 2010
2
0-22
and up to 74% ee by chiral N-triflyl phosphoramide.
We then envisaged that chiral N-triflyl
phosphoramide might be suitable for the aza-Michael addition of activated α,β-unsaturated ketones to
afford the enantioenriched 2-aryl-2,3-dihydro-4-quinolones. In this paper, we report the preliminary
study on this subject.
O
O
CBA
no reaction
NH2 Ph
N
H
Ph
1
3a
Ac
O
NH
O
Ph
t
CO Bu
2
NH2 Ph
1
2a
The initial testing of substrate 1 with chiral N-triflyl phosphoramide did not lead to the cyclization
product. To increase the reactivity of enone, tert-butyl ester activated α,β-unsaturated ketone 2a is
2
3-24
employed as substrate, and the tert-butyl ester moiety can be removed after the cyclization.
To our
delight, substrate 2a underwent the cyclization in the presence of chiral N-triflyl phosphoramide smoothly.
Several chiral N-triflyl phosphoramide catalysts have been tested, and the results are summarized in Table
1
. All the tested chiral N-triflyl phosphoramides were able to catalyze this reaction smoothly with
excellent yields. The best enantioselectivity (72% ee) was obtained when (S)-4g, catalyst bearing
-naphthyl substituent, was used (entry 7, Table 1).
1
Table 1. Screening of catalysts for the intramolecular aza-Michael addition
O
Ac
NH
O
Ph
1
) catalyst (10 mol%)
toluene
*
t
o
N
Ph
CO Bu
2) p-TsOH, 80 C
2
Ac
2a
3a
R
4
4
4
4
4
4
4
4
a: R = 3,5-(CF ) -C H
b: R = 9-anthryl
3
2
6
3
O
O
c: R = 9-phenanthryl
P
i
d: R = 2,4,6-( Pr) -C H
6 2
NHTf
3
O
e: R = SiPh3
f: R = 3,5-(Me) -C H
2
6
3
R
g: R = 1-naphthyl
(S)
h: R = 3,5-(CF ) -C H
12 7
3
2

HETEROCYCLES, Vol. 80, No. 2, 2010
767
[
a]
o
[b]
[c]
entry
catalyst
4a
T ( C)
60
time (h) yield (%)
ee (%)
11
1
2
3
4
5
6
7
48
36
12
48
48
48
48
48
90
90
91
88
86
86
95
97
4b
60
66
4c
60
50
4d
60
4
4e
80
30
4f
60
43
4g
60
72
[
d]
8
4h
60
60
[
[
[
[
a] Reaction conditions: 10 mol% of (S)-4, 0.10 mol/L of 2a in toluene.
b] Isolated yields.
c] Determined by chiral HPLC analysis (Chiralpak AD-H).
d] Without adding p-TsOH.
With 10 mol% of (S)-4g, N-Ac substrate 2a was chosen to further optimize the reaction conditions. As
summarized in Table 2, several commonly used solvents have been tested. Nonpolar solvents such as
4
toluene, p-xylene and CCl were all well tolerated, giving almost identical yields and ees. The optimized
reaction condition was chosen as the following: 10 mol% (S)-4g, 60 ˚C, and toluene as the solvent.
Table 2. Influence of solvents on the intramolecular aza-Michael addition
Ac
O
NH
O
Ph
1) (S)-4g (10 mol%)
t
o
*
CO Bu
2) p-TsOH, 80 C
N
Ph
2
Ac
a
2
a
3
[
a]
o
[b]
[c]
entry
solvent
toluene
benzene
p-xylene
T ( C)
60
time (h) yield (%)
ee (%)
1
2
3
4
5
6
7
48
48
36
48
48
48
36
95
trace
94
72
-
60
60
72
-
Et
CH
2
O
reflux
reflux
60
-
2
Cl
2
-
-
DCE
CCl4
trace
95
-
60
72
[
[
[
a] Reaction conditions: 10 mol% of (S)-4g, 0.10 mol/L of 2a in solvent.
b] Isolated yields.
c] Determined by chiral HPLC analysis (Chiralpak AD-H)

768
HETEROCYCLES, Vol. 80, No. 2, 2010
Table 3. Substrate scope of the intramolecular aza-Michael addition
Ac
O
NH
O
R
1
) (S)-4g (10 mol%)
toluene, 60 C
o
t
o
*
CO Bu
2) p-TsOH, 80 C
N
R
2
Ac
2
3
[
a]
[b]
[c]
entry
2, R
3, yield (%)
3a, 95
3b, 90
3c, 90
ee (%)
(-) 72
1
2
3
4
5
6
7
8
9
2a, Ph
[
d]
2b, 4-Br-C
6
H
4
(-) 58 (S)
(-) 67
(-) 20
(-) 82
(-) 60
(+) 4
2c, 4-Cl-C H
6
4
2d, 4-NO
2e, 4-Me-C
2f, 4-MeO-C
2g, 2-MeO-C
2
-C
6
H
4
3d, 77
3e, 98
H
6 4
6
H
4
3f, 94
6
H
4
3g, 95
3h, 81
3i, 98
2h, 1-naphthyl
2i, 2-naphthyl
(+) 76
(-) 76
[
[
[
[
a] Reaction conditions: 10 mol% of (S)-4g, 0.10 mol/L of 2 in toluene.
b] Isolated yields.
c] Determined by chiral HPLC analysis, and with the sign of the optical rotation.
d] Absolute configuration was determined by X-ray analysis of enantiopure 3b.
Under these optimized reaction condition, different substrates were explored to examine the generality of
2
5
the reaction. The results are summarized in Table 3. A variety of aryl groups could be accommodated in
the reaction, and the corresponding products were obtained in high yields with moderate
enantioselectivities (77-98% yields, 4-82% ees). However, substrate 2d bearing NO led to the cyclization
2
product in only 77% yield with a low ee (entry 4, Table 3). When the substrate 2g with electron-donating
group (MeO) at ortho-position was used, excellent yield could be obtained, but with only 4% ee (entry 7,
Table 3). The para-tolyl substituted substrate 2e gave the highest enantioselectivity (82% ee, entry 5,
Table 3). The 1-naphthyl and 2-naphthyl substituted substrates gave the good enantioselectivity (76% ee,
entries 8,9, Table 3).
In order to determine the absolute configuration of the products obtained here, the enantiopure 3b was
obtained preparative chiral HPLC separation. The crystal structure of enantiopure 3b was obtained, and a
single-crystal X-ray analysis determined its configuration as S (Figure 1).

HETEROCYCLES, Vol. 80, No. 2, 2010
769
O
N
Ac
b
Br
3
Figure 1. X-Ray structure of enantiopure (S)-3b. Ellipsoids at 30% probability
In summary, we have developed the asymmetric intramolecular aza-Michael addition of activated
α,β-unsaturated ketones by utilizing chiral N-triflyl phosphoramide. The enantioenriched
2
-aryl-2,3-dihydroquinolin-4-ones can be synthesized in excellent yields (77-98%) with up to 82% ee.
Further tuning the catalyst to broaden the substrate scope is ongoing in the lab.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China (20732006, 20821002), National Basic
Research Program of China (973 Program 2010CB833300), and the Chinese Academy of Sciences for
generous financial support.
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2
D
0
o
5. Selected data for new compounds: 3g: white solid, 95% yield, 4% ee, [α]
+3.7 (c 0.30, acetone).
1
H NMR (300 MHz, CDCl
3
) δ 2.41 (s, 3H), 3.19-3.35 (m, 2H), 3.84 (s, 3H), 6.30 (brs, 1H), 6.69 (t, J
=
7.8 Hz, 1H), 6.84 (t, J = 8.1 Hz, 2H), 7.14-7.27 (m, 2H), 7.54 (t, J = 8.1 Hz, 1H), 7.68 (brs, 1H),
1
3
7
1
1
.96 (d, J = 7.8 Hz, 1H); C NMR (75 MHz, CDCl
3
) δ 23.6, 42.8, 52.9, 55.2, 110.6, 120.2, 124.8,
24.9, 125.8, 126.1, 127.0, 127.5, 129.0, 134.4, 142.7, 156.9, 170.0, 193.4; IR (film) 3002, 1683,
-1
664, 1653, 1600, 1479, 1461, 1365, 1317, 1292, 1255, 1228, 1211, 1109, 1033, 775, 758, 418 cm ;
+
MS (EI): 295 (M , 27), 253 (38), 252 (100), 146 (51), 119 (22), 91 (23), 77 (12), 43 (22); HRMS (EI):
+
Exact mass calcd for C18
H17NO
3
[M] : 295.1208. Found: 295.1211. mp 198 - 200 °C. Chiral HPLC

HETEROCYCLES, Vol. 80, No. 2, 2010
771
analysis：Daicel Chiralpak AD-H (25 cm), Hexanes / IPA = 80 / 20, 0.6 mL/min, λ = 230 nm, t
2
0
(
D
major) = 26.89 min, t (minor) = 24.82 min. 3h: white solid, 81% yield, 76% ee, [α] +8.9° (c 0.30,
1
acetone). H NMR (300 MHz, CDCl
3
) δ 2.29 (s, 3H), 3.37-3.41 (m, 2H), 6.85 (brs, 1H), 7.02 (d, J =
7
8
1
.8 Hz, 1H), 7.00-7.17 (m, 4H), 7.47-7.57 (m, 3H), 7.79 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 7.5 Hz, 1H),
1
3
.35 (d, J = 8.4 Hz, 1H); C NMR (75 MHz, CDCl
3
) δ 23.0, 43.3, 52.1, 123.7, 124.4, 125.4, 125.8,
26.0, 126.4, 126.9, 127.0, 127.4, 128.7, 129.0, 131.4, 133.6, 133.7, 134.2, 141.7, 169.5, 194.5; IR
-
1
(
(
(
film) 3049, 2966, 1687, 1663, 1598, 1481, 1363, 1293, 1276, 1228, 794, 774, 539 cm ; MS (EI): 315
+
M , 56), 273 (77), 272 (100), 154 (24), 153 (39), 152 (26), 146 (70), 141 (17), 128 (19), 90 (10), 43
+
28); HRMS (EI): Exact mass calcd for C21
H
17NO
2
[M] : 315.1259. Found: 315.1260. mp 196 –
1
98 °C. Chiral HPLC analysis: Daicel Chiralpak AD-H (25 cm), Hexanes / IPA = 80 / 20, 0.6 mL/min,
2
D
0
λ = 230 nm, t (major) = 15.12 min, t (minor) = 16.92 min. 3i: white solid, 98% yield, 76% ee, [α]
o
1
-
3
76.1 ( c 0.30, acetone). H NMR (300 MHz, CDCl ) δ 2.47 (s, 3H), 3.38-3.56 (m, 2H), 6.68 (brs, 1H),
1
3
7
4
1
8
3
.10-7.54 (m, 7H), 7.69-7.72 (m, 3H), 7.92 (d, J = 7.8 Hz, 1H); C NMR (75 MHz, CDCl ) δ 23.3,
2.3, 54.6, 124.9, 125.0, 125.6, 126.0, 126.2, 126.3, 127.2, 127.4, 127.9, 128.6, 132.4, 132.8, 134.4,
35.4, 141.6, 170.2, 193.2; IR (film) 1664, 1601, 1480, 1459, 1379, 1379, 1283, 1228, 1116, 1025,
-1
+
62, 780, 477 cm ; MS (EI): 315 (M , 20), 273 (40), 272 (100), 154 (17), 146 (32), 43 (19); HRMS
+
(
EI): Exact mass calcd for C21
H17NO
2
[M] : 315.1259. Found: 315.1262. mp: 154 – 156 °C. Chiral
HPLC analysis：Daicel Chiralpak AD-H (25 cm), Hexanes / IPA = 80 / 20, 0.6 mL/min, λ = 230 nm, t
major) = 22.00 min, t (minor) = 25.48 min.
(