Asymmetric [4+2] cycloaddition of azlactones with dipolar copper–allenylidene intermediates for chiral 3,4-dhydroquinolin-2-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.06.041

In this paper, a pybox-copper catalyzed enantioselective decarboxylative [4+2] cycloaddition reaction of ethynyl benzoxazinanones with azlactones has been developed, which provides optically active 3,4-dihydroquinolin-2-ones in high yields with good enantioselectivities and diastereoselectivities. In this transformation, the chiral dipolar copper–allenylidene intermediates are kinetically generated via decarboxylative ethynyl benzoxazinanones, followed by the attack of the enolate azlactones to form enantiomerically enriched 3,4-dihydroquinolin-2-one structures.

Full text of DOI:10.1016/j.tetlet.2019.06.041

Accepted Manuscript
Asymmetric [4 + 2] Cycloaddition of Azlactones with Dipolar Copper-Alleny-
lidene intermediates for Chiral 3,4-Dhydroquinolin-2-one Derivatives
Bing-Bing Sun, Qing-Xian Hu, Jia-Ming Hu, Jie-Qiang Yu, Jun Jia, Xing-Wang
Wang
PII:
S0040-4039(19)30602-1
https://doi.org/10.1016/j.tetlet.2019.06.041
TETL 50882
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 May 2019
19 June 2019
21 June 2019
Please cite this article as: Sun, B-B., Hu, Q-X., Hu, J-M., Yu, J-Q., Jia, J., Wang, X-W., Asymmetric [4 + 2]
Cycloaddition of Azlactones with Dipolar Copper-Allenylidene intermediates for Chiral 3,4-Dhydroquinolin-2-one
Derivatives, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.041
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Asymmetric [4 + 2] Cycloaddition of
Azlactones with Dipolar Copper-Allenylidene
intermediates for Chiral 3,4-Dhydroquinolin-
2-one Derivatives
Leave this area blank for abstract info.
Bing-Bing Sun, Qing-Xian Hu, Jia-Ming Hu, Jie-Qiang Yu, Jun Jia and Xing-Wang Wang
O
R3
NH
O
O
O
/L10
CuI (10 mol %)
(11mol %)
R1
Bn
R1
Bn
O
DIPEA (2 equiv), rt, 12h
mesitylene (0.0125 M)
R3
N
N
R2
O
N
R2
up to 94% yield
up to >99:1 dr
up to 94:6 er
O
O
N
N
N
Ph
L10
Ph

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Asymmetric [4 + 2] Cycloaddition of Azlactones with Dipolar Copper-Allenylidene
intermediates for Chiral 3,4-Dhydroquinolin-2-one Derivatives
Bing-Bing Suna, Qing-Xian Hua, Jia-Ming Hua, Jie-Qiang Yua, Jun Jiab and Xing-Wang Wanga
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou
215123, P. R. China; bAnalysis and Testing Center, Soochow University, Suzhou 215123, P. R. China.
E-mail: jiajun@suda.edu.cn; wangxw@suda.edu.cn
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this paper, a pybox-copper catalyzed enantioselective decarboxylative [4 + 2] cycloaddition
reaction of ethynyl benzoxazinanones with azlactones has been developed, which provides
optically active 3,4-dihydroquinolin-2-ones in high yields with good enantioselectivities and
diastereoselectivities. In this transformation, the chiral dipolar copper−allenylidene
intermediates are kinetically generated via decarboxylative ethynyl benzoxazinanones, followed
by the acttack of the enolate azlactones to form enantiomerically enriched 3,4-dihydroquinolin-
2-one structures.
Available online
Keywords:
asymmetric cycloaddition
dipolar copper−allenylidene
3,4-dihydroquinolin-2-ones
enolate azlactones
Introduction
N
O
OH
OH
F
Over the past decades, nitrogen-containing heterocyclic
compounds have attracted extensive attention due to their
H
O
O
N
O
N
HN
important
biological
activities.1
Specifically,
3,4-
N
N
O
O
H
O
O
A
B
dihydroquinolin-2-one structures have proven to be quite
important core backbones of many natural products and synthetic
medicines, which commonly displays wide range of biological
activities.2 For example, compound A is used as a nonnucleoside
reverse transcriptase inhibitors and plays a vital role in
combination therapy for the treatment of AIDS2a, 2c. Compound B
was isolated by the extraction of dried roots of Boronia pinnata
Sma and found to have an inhibitory activity for tumor-
promotion2b. Among a series of 1-aryl-3,4-dihydro-1H-quinolin-
2-ones, compound C has been discovered as a potent and
selective norepinephrine reuptake inhibitors2d. Additionally,
C
D
Figure 1 Selected natural products containing 3,4-dihydroquinolin-
2-one skeletons
evidenced by chemical trapping of them. If dipolar metal
intermediates are kinetically formed, successful trapping of
dipolar intermediates is generally possible. For example, the
group of Xiao reported an unprecedented decarboxylation-
cycloaddition sequence of cyclic allylic esters with sulphur ylides
through the enantioselective trapping of Pd-stabilized
zwitterionic intermediates by the ylides in 2014.4b Chemists have
noticed that this type of intermediates can serve as 1,4-carbon–
nitrogen dipoles to perform formal [4 + n] cycloaddition.
compound D, which bears
a p-methoxyphenylquinolinone
skeleton fused with an isoprenyl pyran ring, is used as an
antibiotic insecticide2e (Figure 1). In view of the interesting 3,4-
dihydroquinolin-2-one structures and excellent biological
properties, the development of new methods for the synthesis of
3,4-dihydroquinolin-2-one derivatives is highly desirable and
interesting.
Subsequently,
a series of Pd-catalyzed formal [4 + n]
cycloadditions of vinyl benzoxazinanones were reported.5 In
particularly, when the intermediates are performed for a formal
[4 + 2] cycloaddition, it is a shortcut to construct 3,4-
dihydroquinolin-2-one backbones.5b Recently, the group of Shi
has reported the iridium/B-H co-catalyzed reactions of vinyl
benzoxazinanones with azlactones, giving the 3,4-
dihydroquinolin-2-one derivatives in excellent yields with high to
Asymmetric transition-metal catalysis involving a chiral
organic ligand has been a powerful strategy for the construction
of chiral core structures of many important medicinal compounds
and agricultural candidates.3 In fact, many organic reactions
proceed via metal-associated dipolar intermediates, which
contain two independent reaction centers.4-5 The formation of
dipolar metal intermediates in an organic reaction can be
excellent
diastereoselectivities,
albeit
with
moderate
enantioselectivity for the asymmetric version.5f

2
Tetrahedron Letters
In 2016, Xiao and co-workers reported the first asymmetric
formal [4 1] cycloaddition of sulfur ylides with
desire product (Table 2, entry 3). The azlactones 2ac–2ae
+
provided the corresponding products in good yields with good
diastereoselectivity, but with decreased enantioselectivity
copper−allenylidenes.6 Later, various asymmetric reactions with
copper−allenylidenes were developed to construct five,7 six8 and
seven9-membered cyclic compounds. Over the past few years,
azlactones were employed as the substrates in many
enantioselective reactions.10-11 Azlactones reacted with
electrophiles at the C2 or C4 site to accomplish a series of [3 + 2]
or [n + 2] cycloaddition reactions.11 In this case, we envisioned
that azlactones could serve as enolate nucleophiles to react with
the decarboxylated copper−allenylidenes resulted from
benzoxazinanones, which then underwent an intramolecular
aminolysis to fullfill the formal [4 + 2] cycloaddition. Finally, the
synthetic concept was successfully carried out, and a series of
3,4-dihydroquinolin-2-one derivatives were obtained in high
yields with moderate enantioselectivities and excellent
diastereoselectivities (Scheme 1). During the preparation of our
manuscript, the enantioselective decarboxylative [4 + 2]-
annulation of ethynyl benzoxazinanones with azlactones via
cooperative copper and bifunctional tertiary aminourea catalysis
has been reported by Mukherjee and co-workers.[12]
Table 1 Optimization of the reaction conditions a
O
Ph
NH
O
O
O
L
CuI (10 mol %)/ (11 mol %)
Bn
O
Bn
solvent, DIPEA (2 equiv), rt
N
N
O
N
Ph
Ts
1a
Ts
2a
3a
R
R
O
O
O
O
O
Ph
Ph
O
O
Ph
Ph
N
N
N
N
N
N
Fe PPh2
N
N
Ph
Ph
Ph
Ph
Bn
Bn
L4
L3
L1
L2
R
R
O
O
O
O
N
N
N
PPh2
PPh2
N
N
Ph
Ph
O
O
Ph
L7
L8
L9
: R = -(CH2)2-
: R = -(CH2)4-
: R = -CH3
Ph
L10
N
N
L5
Ph
L6
Ph
Cl
Br
Ph
Ph
O
O
Ph
Ph
O
O
N
N
Ph
Ph
O
O
N
O
O
Ph
Ph
N
N
N
N
N
N
N
N
N
Bn
Bn
Ph
Ph
L14
Ph
Ph
Ph
Ph
L11
L12
L13
Cu/L
O
L
solvent
yield
(%) b
84
O
Ph
NH
entry
dr c
er (%) d
75:25
54:45
--
O
Bn
L1
L2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
mesitylene
DCE
87:13
50/50
--
N
Cu/L
CO2
1
2
3
4
5
6
7
8
9
O
R
Bn
O
93
trace
93
92
92
78
68
66
88
90
75
88
80
92
92
85
78
78
Base
N
N
O
Ts
Ts
N
L3
Ts
L4
90/10
90/10
94/6
12:88
87:13
40:70
59:41
60:40
64:36
90:10
91:9
Scheme 1 Construction of the chiral 3,4-dihydroquinolin-2-ones via
an amphiphilic Cu-allenylidene intermediate
L5
L6
Results and discussion
L7
43/57
40/60
38/62
92/8
L8
Initially, a model reaction between ethynyl benzoxazinanone
1a and azlactone 2a were chosen to examine the feasibility of
Cu-catalyzed [4 + 2] cycloaddition reactions. The screening
results are given in Table 1 (see the ESI† for more details). It was
found that this reaction was carried out well in the presence of 10
L9
L10
L11
L12
L13
L14
L10
L10
L10
L10
L10
10
11
88/12
84/16
82/18
83/17
94/6
12
13
14
15
78:22
83:17
16:84
91:9
i
mol % of CuI and ligand L1 and with two equiv of Pr2NEt in
toluene at room temperature, the desired product 3a was obtained
in 84% yield with 87 : 13 dr and 75 : 25 er (Table 1, entry 1).
Then, a series of chiral ligands L2–L10 were examined (Table 1,
entries 2–10). According to the catalytic results, chiral ligands
had a profound influence on the catalytic outcomes, and the ph-
pybox L10 was proven to be the optimal ligand. The
corresponding reaction proceeded smoothly to give the desired
product 3a in 88% yield with 90 : 10 er and 92 : 8 dr (Table 1,
entry 10). In addition, other types of chiral pyboxs were also
investigated (Table 1, entries 11–14), but no improvements was
observed. To further optimize the reaction conditions, several
solvents, such as mesitylene, dichloroethane, tetrahydrofuran and
acetonitrile, were investigated (Table 1, entries 15−19). Finally,
the use of mesitylene as the reaction medium resulted in a
considerable improvement on reactivity (Table 1, entry 15).
65/35
83/17
88/12
75/25
82:18
81:19
91:9
16
17
18
19
THF
dioxane
CH3CN
53:47
a Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol), CuI (10 mol %),
b
L (11 mol %), DIPEA (0.1 mmol), solvents (0.5 mL), 2 hours. Isolated
yield. c Determined by HPLC analysis and the er values refer to the major
diastereoisomer. d Determined by HPLC analysis.
(Table 2, entries 4−6). In contrast, the phenylalanine-derived
azlactone 2a was finally proven to be the optimal substrate
(Table 2, entry 1). Next, the substrate concentration was further
examined for the reaction (Table 2, entries 7−9). When the
substrate concentration was adjusted from 0.1 M to 0.0125 M,
the reaction furnished the desired product 3a in 90% yield with
96 : 4 dr and 93 : 7 er, albeit with prolonged reaction time of 12
hours (Table 2, entry 7, see ESI for details).
Subsequently, some azlactones A–E were synthesized from
some aromatic or aliphatic -amino acids, including
phenylglycine-derived azlactone (2aa), tert-leucine-derived
azlactone (2ab), alanine-derived azlactone (2ac), aminobutyric
acid-derived azlactone (2ad) as well as valine-derived azlactone
(2ae). The catalytic results are shown in Table 2. It was disclosed
that the alkyl and aryl substituents on azlactones had significantly
effect on the catalytic results. The phenylglycine-derived
azlactone (2aa) displayed very poor diastereo- and enantio-
selectivity, albeit with high reactivity (Table 2, entry 2). The tert-
leucine-derived azlactone (2ab) only gave trance amount of the
With the optimized conditions in hand, we proceeded to
investigate the utility of the process for the synthesis of optically
active 3,4-dihydroquinolin-2-one derivatives. As summarized in
Scheme 2, the variation of ethynyl benzoxazinanones 1 was first
studied. Substrates 1b−1f with -methyl, -methoxyl, -chloro, and -

3
Table 2 Azlactone effects for copper-catalyzed formal [4+2]
method for synthetic application, a hydrogenation reaction of
3k was smoothly performed with the Pd/C catalyst under 1 atm
cycloaddition a
O
R3
O
Ph
NH
O
5
O
NH
6
O
O
R1
CuI (10 mol %)/L10 (11mol %)
Bn
R1
Bn
O
O
O
L10
CuI (10 mol %)/
(11 mol %)
R3
N
DIPEA (2 equiv), rt, 12h
mesitylene
N
R2
O
N
R2
R
R
O
7
8
N
mesitylene, DIPEA (2 equiv), rt
N
O
N
Ph
1
2
3
Ts
1a
Ts
3
2
O
Ph
O
Ph
NH
O
Ph
O
Ph
NH
O
O
O
NH
O
NH
Bn
O
Cl
Ph
Bn
O
Bn
O
Bn
O
O
O
O
Ph
N
N
N
N
N
N
N
Ts
Ts
Ts
Ts
Ph
Ph
Ph
Ph
2a
2aa
2ab
3a
3b
3c
3d
, 90% yield, 96:4 dr,
93:7 er
, 67% yield, 92:8 dr,
88:12 er
, 58% yield, 93:7 dr,
91:9 er
, 85% yield, 99:1 dr,
88:12 er
O
O
O
O
Ph
O
Ph
O
Ph
O
Ph
O
O
O
NH
NH
NH
NH
Bn
O
Bn
O
Bn
O
Bn
O
N
N
N
Ph
Ph
F
N
Cl
N
N
N
2ac
2ad
2ae
Ts
Ts
Ts
Ns
3e
3f
3g
3h
, 73% yield, >99:1 dr,
88:12 er
, 83% yield, 96:4 dr,
93:7 er
, < 5% yield
, 85% yield, 92:8 dr,
90:10 er
entry
azlactone
yield(%) b
dr c
94/6
er (%) d
F
Cl
Br
O
1
2
2a
2aa
2ab
2ac
2ad
2ae
2a
92
93
91:9
54:46
--
O
O
O
NH
Bn
NH
Bn
NH
Bn
NH
Bn
O
50/50
--
N
O
N
O
N
O
N
3
trace
93
Ts
Ts
Ts
Ts
3i
3j
3k
3l
, 73% yield, 92:8 dr,
92:8 er
, 79% yield, 96:4 dr,
90:10 er
, 89% yield, 98:2 dr,
90:10 er
, 90% yield, 95:5 dr,
91:9 er
4
90/10
90/10
94/6
96/4
96/4
96/4
88:12
86:14
70:30
92:8
93:7
93:7
5
92
O
O
O
O
6
92
OMe
F
Br
NH
Bn
NH
Bn
O
NH
Bn
NH
Bn
7 e
8 f
9 g
90
N
O
N
N
O
N
O
2a
90
Ts
Ts
Ts
Ts
3m
3n
3o
3p
, 62% yield, 88:12 dr,
88:12 er
, 75% yield, 93:7 dr,
91:9 er
, 78% yield, 94:6 dr,
91:9 er
, 81% yield, 95:5 dr,
94:6 er
2a
83
a Unless otherwise noted, reactions were carried out with 1a (0.05 mmol), 2a
(0.06 mmol, 1.2 equiv), CuI (10 mol %) and L10 (11 mol %), 0.1 M based on
1a, 2 hours. b Isolated yield. c Determined by HPLC analysis and the er values
O
O
O
S
O
O
NH
Bn
NH
Bn
NH Cl
Bn
NH
Bn
O
N
Ts
N
O
N
O
N
O
d
e
refer to the major diastereoisomer. Determined by HPLC analysis. 0.025
M based on 1a, 4 hours. f 0.0125 M based on 1a, 12 hours. g 0.01 M based on
1a, 12 hours.
Ts
Ts
Ts
3q
3r
3s
3t
, 94% yield, 95:5 dr,
92:8 er
, 62% yield, 95:5 dr,
94:6 er
, 69% yield, 92:8 dr,
93:7 er
, 71% yield, 95:5 dr,
89:11 er
a
Unless otherwise noted, reactions were carried out with 1a (0.1 mmol), 2a
(0.12 mmol, 1.2 equiv), CuI (10 mol %) and L10 (11 mol %), 0.0125 M
based on 1a.
fluoro groups on the 6- or 7- positions of phenyl rings were tested
in the reactions, which provided the annulation products in
58−85% yields with 92 : 8 to >99 :1 drs and 88: 12 to 93 : 7 ers,
respectively. However, 8-methyl-substituted substrate 1g almost
did not react with the substrate 2a under the optimized
conditions, affording the desired product 3g in less than 5%
yield. Then, the substrate 1h with N-(4-nitrophenyl) sulfonyl
group were also well-tolerated, which gave the desired product
3h in 85% yield with 92 : 8 dr and 90 : 10 er. Then, the
azlactones 2 were further investigated for this transformation.
Those azlactones 2b–2i bearing -methyl, -methoxyl, -fluoro, -
chloro, and -bromo groups on the 3- or 4- positions of phenyl
rings were all suitable partners for the reactions, which provided
the desire products 3i–3p with 62–90% yields, 88 : 12 to 98 : 2
dr, and 88 : 12 to 94 : 6 er, respectively. When the azlactone 2j
with a -chloro group on the 2- position of phenyl ring was
employed in the reaction, and the desired product 3q was
obtained in 94% yield with 95 : 5 dr and 92 : 8 er. In addition,
the substrates 2k and 2l containing heteroaromatic rings of 2-
furyl or 2-thienyl were also suitable substrates, and the
corresponding reactions resulted in the corresponding products
3r and 3s in 62% and 69% yields with 95 : 5 and 92 : 8 dr and 94
: 6 and 93 : 7 er, respectively. The substrate 2m bearing a fused
aromatic ring of 2-naphthyl was also well-tolerated for this
reaction, which gave the desired products 3t in 71% yield with 95
: 5 dr and 89 : 11 er.
Scheme 2 The substrate scope of the copper-catalyzed formal [4+2]
Cl
Cl
O
O
NH
Bn
O
NH
Bn
O
Pd/C (10 mol %)
H2 (1 atm)
EtOAc, rt, 12 h
N
N
Ts
Ts
3k
4
99% yield, >99:1 dr, 90 : 10 er
cycloaddition a
Scheme 3 Hydrogenation reaction of 3k
hydrogen pressure, which provided the desire product 4 in 99%
yield with over 99 : 1 dr and 90 : 10 er (Scheme 3).
Conclusion
In summary, we have developed a formal [4 + 2] cycloaddition
reaction between ethynyl benzoxazinanones and azlactones,
which is catalyzed by a chiral copper−pybox mediated complex.
A series of enantiomerically enriched 3,4-dihydroquinolin-2-one
derivatives were obtained in high yields with good
enantioselectivities and diastereoselectivities. Notably, 3,4-
dihydroquinolin-2-one backbones are constructed by the reaction
of the dipolar copper−allenylidene intermediates with the ready
enolate azlactones. Generally, this transformation provides a
The alkynyl group of the resulted products is a versatile and
valuable functional group. To demonstrate the potential of this

4
Tetrahedron Letters
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Acknowledgments
We are grateful for financial support from the National
Natural Science Foundation of China (21572150), the Program
for New Century Excellent Talents in University (NCET-12-
0743) and a Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
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Supplementary Material
Highlights
1. Developing a high efficient enantioselective
decarboxylative [4 + 2] cycloaddition
4.
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2. Providing a series of enantio-enriched 3,4-
dihydroquinolin-2-one derivatives in high
yields
3. Dipolar copper−allenylidenes as the key
intermediates to react enolate azlactones
6.
7.
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J. Am. Chem. Soc. 2016, 138, 8360−8363.
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Graphical Abstract
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8.
For selected reviews, see: (a) Li, T.-R.; Lu, L.-Q.; Wang, Y.-N.;
Wang, B.-C.; Xiao, W.-J., Org. Lett. 2017, 19, 4098−4101; (b)
Shao, W.; You, S.-L., Chem. - Eur. J. 2017, 23, 12489−12493; (c)

5
Asymmetric [4 + 2] Cycloaddition of Azlactones
with Dipolar Copper-Allenylidene intermediates for
Chiral 3,4-Dhydroquinolin-2-one Derivatives
Leave this area blank for abstract info.
Bing-Bing Sun, Qing-Xian Hu, Jia-Ming Hu, Jie-Qiang Yu, Jun Jia and Xing-Wang Wang
O
R3
NH
O
O
O
/L10
CuI (10 mol %)
(11mol %)
R1
Bn
R1
Bn
O
DIPEA (2 equiv), rt, 12h
mesitylene (0.0125 M)
R3
N
N
R2
O
N
R2
up to 94% yield
up to >99:1 dr
up to 94:6 er
O
O
N
N
N
Ph
L10
Ph