Silver-Catalyzed Decarboxylative Radical Addition/Cyclization of Oxamic Acids with Alkenes towards Quinolin-2-ones

Article abstract of DOI:10.1055/s-0040-1707891

An efficient silver-catalyzed tandem decarboxylative radical addition/cyclization of oxamic acids with alkenes has been developed. This method provides a novel and straightforward protocol toward a variety of 4-aryl-3,4-dihydroquinolin-2(1 H)-ones, 4-(α-c

Full text of DOI:10.1055/s-0040-1707891

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–F
letter
A
en
C. Jin et al.
Letter
Synlett
Silver-Catalyzed Decarboxylative Radical Addition/Cyclization of
Oxamic Acids with Alkenes towards Quinolin-2-ones
Chengan Jin
R3
Jing-Yao He
R3
Qi-Fan Bai
R1
Gaofeng Feng*
10 examples, 0–84% yield
O
N
R2
R4
College of Chemistry and Chemical Engineering, Shaoxing University,
Shaoxing, 312000, P. R. of China
chfeng@usx.edu.cn
O
R1
O
R4
OH
AgNO3/Na2S2O8
O
N
O
10 examples, 28–77% yield
6 examples, 23–80% yield
R2
R1
N
O
R2
SO2Ph
R1
N
O
R2
Received: 16.04.2020
Accepted after revision: 21.05.2020
Published online: 21.07.2020
context, it is highly desirable to develop easily operable and
highly effective methods for the construction of quinolin-2-
ones. In recent decades, a great deal of research has been
DOI: 10.1055/s-0040-1707891; Art ID: st-2020-u0216-l
Abstract An efficient silver-catalyzed tandem decarboxylative radical
addition/cyclization of oxamic acids with alkenes has been developed.
This method provides a novel and straightforward protocol toward a va-
riety of 4-aryl-3,4-dihydroquinolin-2(1H)-ones, 4-(-carbonyl)-3,4-di-
hydroquinolin-2(1H)-ones, and quinolin-2(1H)-ones in aqueous solu-
tion.
Table 1 Screening of the Reaction Conditionsa
AgNO3 (10 mol%)
O
oxidant
+
OH
Key words silver catalysis, addition, cyclization, tandem reaction,
solvent, N2, 80 °C, 36 h
N
N
O
oxamic acids, quinolinones
O
Me
Me
1a
2a
3a
Quinolin-2-one is a common and important N-hetero-
cyclic skeleton that is widely found in natural products,
commercial drugs, and bioactive molecules (Figure 1).1
Moreover, quinolin-2-ones are versatile precursors for syn-
thesizing 2-aminoquinolines, 2-alkoxyquinolines, 2-halo-
quinolines, and other useful quinoline derivatives.2 In this
Entry
Oxidant (equiv)
Solvent
Yieldb (%)
1
2
K2S2O8 (2.0)
Na2S2O8 (2.0)
(NH4)2S2O8 (2.0)
TBHP (2.0)
1:1 MeCN–H2O
1:1 MeCN–H2O
1:1 MeCN–H2O
1:1 MeCN–H2O
1:1 MeCN–H2O
1:1 MeCN–H2O
1:1 DMSO–H2O
1:1 THF–H2O
1:1 toluene–H2O
1:1 acetone–H2O
1:1 CH2Cl2–H2O
MeCN
45
65
60
0
3
4
5
Na2S2O8 (1.0)
Na2S2O8 (3.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
Na2S2O8 (2.0)
–
41
16
36
30
18
31
17
0
6
H
N
N
O
7
H
HO
NO2
O
8
9
Cl
N
N
O
N
H
O
H
H
10
11
12
13
14c
15d
NMDA antagonist
Carteolol
Meloscine
NH
OMe
OH
Ph
H2O
<5
0
Cl
1:1 MeCN–H2O
1:1 MeCN–H2O
N
O
0
N
H
O
H
N
O
OMe
H
a Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), AgNO3 (0.03 mmol,
10 mol%), solvent (3.0 mL), oxidant, under N2, 80 °C, 36 h.
b Isolated yield.
OH
Procaterol
Edulitine
HBV inhibitor
c Without the catalyst.
Figure 1 Several representative compounds containing quinolin-2-one
scaffolds
d Without the oxidant.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
C. Jin et al.
Letter
Synlett
conducted on the synthesis of quinolin-2-ones, and various
effective preparation methods, such as intramolecular
Friedel–Crafts reactions, transition-metal-catalyzed tandem
cyclizations, or radical addition/ring formation reactions,
have been developed.3–5 In particular, in the last ten years
the radical addition/6-endo-trig-cyclization of cinnama-
mides has infused new vigor into the synthesis of quinolin-
2-ones.5 Although this strategy has shown good perfor-
mance in the construction of 3,4-disubstituted dihydro-
quinolinones, it suffers from a limited substrate scope and
cannot directly synthesize 3,4-unsubstituted or monosub-
stituted quinolin-2-ones. Therefore, direct and efficient
methods for constructing such compounds remain highly
desirable.
Carbamoyl radicals are key synthetic intermediates that
play an important role in the synthesis of isocyanates, am-
ides, and nitrogenous heterocyclic compounds.6–8 In recent
years, the synthesis of substituted quinolin-2-ones through
N-arylcarbamoyl radical addition/cyclization has attracted
particular attention. Petersen and co-workers reported a
photoredox-catalyzed single-electron-reductive decarbox-
ylation of N-hydroxyphthalimidooxamides to produce N-
arylcarbamoyl radicals that undergo an addition/cycliza-
tion reaction with electron-deficient alkenes to form 3,4-
dihydroquinolin-2-one architectures.9 As carbamoyl radical
precursors, compared with N-hydroxyphthalimidooxam-
ides, oxamic acids have advantages in terms of atom econo-
my, greenness, and ease of preparation. Our group previ-
ously generated N-arylcarbamoyl radicals from N-aryl-
oxamic acids through visible-light-mediated oxidative
decarboxylation and then reacted them with electron-defi-
cient alkenes to give quinolin-2-ones (Scheme 1a).10 Re-
cently, Wang’s group reported a decarboxylative lactamiza-
tion of 2-vinylphenyloxamic acids mediated by hypervalent
iodine(III), involving a ring-strain-permitted radical decar-
boxylation process.11 Liu and co-workers recently reported
an approach to the construction of CF2-containing 3,4-dihy-
droquinolin-2-ones through the decarboxylative radical ad-
dition/cyclization of oxamic acids with gem-difluoroolefins
(Scheme 1b).12 Despite the advances made in this area, the
scope of the alkene substrates is very limited and consider-
able challenges remain in the reactions of electron-rich ole-
fins with N-arylcarbamoyl radicals and in the synthesis of
3,4-unsubstituted quinolinones by a radical pathway. We
recently filed two patents on the preparation of 3,4-dihy-
droquinolin-2(1H)-ones from oxamic acids by Ag cataly-
sis.13 Here, we provide full details of the reaction develop-
ment; we also further explore the scope of the reaction,
particularly in terms of various substituted N-arylcarbam-
oyl radical precursors and alkenes, and we introduce an ex-
tension of the original approach for synthesis of the quino-
lin-2(1H)-ones under our optimized reaction conditions
(Scheme 1c).
We began our investigations by reacting N-methyl-N-
phenyloxamic acid (1a) with styrene (2a) as model sub-
strates to identify the optimal reaction conditions (Table 1).
Gratifyingly, in the presence of simple AgNO3 (10 mol%) as a
catalyst and K2S2O8 (2.0 equiv) as an oxidant in 1:1 MeCN–
H2O at 80 °C, the reaction gave the desired product 3a in
45% yield after 36 hours (Table 1, entry 1). The choice of ox-
(a) Our previous work
O
R4
R3
Ir[dF(CF3)ppy]2(dtbbpy)PF6
(2 mol%)
R4
R1
R1
OH
+
N
R3
N
O
CH2Cl2-H2O (2:1)
36 W blue LEDs
30 °C, 40 h
O
R2
electron-deficient alkenes
R2
(b) Liu and co-workers' work
R3
F
F
AgNO3 (10 mol%)
K2S2O8 (2.0 equiv)
O
R1
F
+
R1
OH
R3
N
acetone/H2O (1:1)
50 °C, 9 h
F
N
O
O
R2
R2
(c) This work
R3
O
R1
OH
N
+
R1
R3
styrenes or
O
AgNO3 (10 mol%)
R2
N
O
O
Na2S2O8 (2.0 equiv)
electron-deficient alkenes
R2
MeCN/H2O, N2, 80 °C, 36 h
O
R1
OH
N
R1
+
SO2Ph
N
O
R2
R2
Scheme 1 Decarboxylative tandem cyclizations of oxamic acids with alkenes for synthesizing quinolin-2-ones
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

C
C. Jin et al.
Letter
Synlett
R3
AgNO3 (10 mol%)
O
N
Na2S2O8 (2.0 equiv)
R1
+
R1
R3
OH
MeCN/H2O, N2, 80 °C, 36 h
N
O
O
R2
1
R2
3
2
Cl
F
MeO
Me
N
O
N
O
N
Me
O
N
O
N
O
Me
Me
Me
Me
3a, 65%
3e, 30%
3c, 84%
3d, 51%
3b, 77%
Cl
Me
F3C
N
Me
O
N
O
N
O
N
O
N
O
Bn
Me
Ph
H
3f, 71%
3g, 64%
3h, 35%
3i, 22%
3j, 0%
Scheme 2 Decarboxylative tandem cyclization of oxamic acids with styrenes
idant was found to have a dramatic effect on the yield (en-
tries 2–4). Among the oxidants tested, Na2S2O8 was found to
be the most efficient in this transformation, and the yield of
the desired product was increased to 65% (entry 2). Reduc-
ing or increasing the amount of the Na2S2O8 did not im-
prove the yield of 3a (entries 5 and 6). Additionally, chang-
ing the solvent to DMSO–H2O, THF–H2O, toluene–H2O, ace-
tone–H2O, CH2Cl2–H2O, MeCN, or H2O led to lower yields of
O
R3
AgNO3 (10 mol%)
O
+
R1
R3
Na2S2O8 (2.0 equiv)
R1
OH
N
MeCN/H2O, N2, 80 °C, 36 h
N
O
O
O
R2
R2
1
4
5
O
O
O
O
O
O
O
O
Me
MeO
N
O
N
O
N
O
N
O
N
O
Me
Me
Me
Me
Me
5b, 77%
5c, 32%
5e, 59%
5a, 76%
5d, 43%
O
O
O
O
O
O
O
O
O
Cl
F
Me
Cl
F3C
N
O
N
O
N
O
N
O
N
O
Me
Bn
Me
Me
Me
5j, 42%
5f, 44%
5h, 56%
5i, 28%
5g, 50%
Scheme 3 Decarboxylative tandem cyclization of oxamic acids with electron-deficient alkenes
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

D
C. Jin et al.
Letter
Synlett
3a (entries 7–13). Controlled experiments confirmed that
the reaction did not occur in the absence of AgNO3 or
Na2S2O8 (entries 14 and 15).
Unfortunately, the oxamic acid lacking an N-protecting
group did not undergo this conversion (3j).
To further test the applicability of this protocol, the
scope of the electron-deficient alkene was explored
(Scheme 3). Various substituted electron-deficient alkenes,
such as ethyl acrylate, ethyl vinyl ketone, and -methylene-
-butyrolactone displayed good reactivities in this transfor-
mation, giving the desired products 5a–c in yields of 32–
77%. Oxamic acids with either electron-donating or elec-
tron-withdrawing groups were also well tolerated in the
same fashion, and afforded the corresponding products 5d–
i in moderate yields. Moreover, an N-benzyl-substituted
oxamic acid also reacted efficiently with ethyl acrylate to
give the 3,4-dihydroquinolin-2(1H)-one 5j in 42% yield.
To our surprise, the reaction between phenyl vinyl sul-
fone and oxamic acids in the presence of the AgNO3/Na2S2O8
catalytic system gave completely different results to those
obtained by using our previous photocatalytic system.10
4-(Phenylsulfonyl)-3,4-dihydroquinolin-2(1H)-ones were
not obtained; instead quinolin-2(1H)-ones 7a–f were ob-
tained in isolated yields of 23–80% (Scheme 4). We specu-
late that the original target products, the 4-(phenylsulfo-
With the optimized reaction conditions in hand, we
started to investigate the substrate scope of the radical cy-
clization reaction with various substituted oxamic acids
and styrenes (Scheme 2). To our satisfaction, the optimized
conditions were found to be generally applicable for p-fluo-
rostyrene and p-chlorostyrene, providing products 3b and
3c in yields of 77 and 84%, respectively. The reaction was
compatible with methyl, methoxy, chloro, and trifluoro-
methyl functional groups on the aromatic ring of the oxam-
ic acid; both electron-rich and electron-deficient oxamic
acids reacted effectively with styrene to give the desired
products 3e–g in yields of 30–71%. In addition, an N-ben-
zyl-protected oxamic acid was also accommodated by this
reaction system, and the corresponding product 3h was ob-
tained in 35% yield. When an N-phenyl-protected oxamic
acid reacted with styrene, two products were formed: 1,4-
diphenyl-3,4-dihydroquinolin-2(1H)-one (3i) in 22% yield
and the radical rearrangement product N,3,3-triphenylpro-
panamide (3i′) in 23% yield (see Supporting Information).
AgNO3 (10 mol%)
O
R1
R1
Na2S2O8 (2.0 equiv)
OH
SO2Ph
+
N
N
O
MeCN/H2O, N2, 80 °C, 36 h
O
R2
R2
7
6
1
Me
Me
MeO
F3C
Cl
N
O
N
Bn
O
N
O
N
O
N
O
N
O
Me
7b, 60%
Me
Me
Me
Me
7d, 37%
7a, 80%
7c, 62%
7e, 23%a
7f, 75%
Scheme 4 Reaction of oxamic acids with phenyl vinyl sulfone to give quinolin-2(1H)-ones. a At 90 °C for 48 h.
O
R1
2–
R1
S2O8
OH
N
N
O
O
R2
E
1
2–
R2
SO4
+
SO4
Ag(II)
Ag(I)
CO2, H+
– PhSO2H
When R3 = PhSO2
R3
H
C
R1
N
O
R2
R3
N
R3
R3
O
R1
R1
R1
N
O
N
O
A
R2
B
R2
D
R2
Figure 2 Proposed reaction mechanism
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F

E
C. Jin et al.
Letter
Synlett
nyl)-3,4-dihydroquinolin-2(1H)-ones, undergo an addition-
al classical Julia–Lythgoe elimination at high temperature to
form the corresponding quinolin-2(1H)-ones.
Kasibhatla, S. Cancer Lett. 2009, 274, 243. (h) Cheng, P.; Zhang,
Q.; Ma, Y.-B.; Jiang, Z.-Y.; Zhang, X.-M.; Zhang, F.-X.; Chen, J.-J.
Bioorg. Med. Chem. Lett. 2008, 18, 3787.
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2004, 898.
Based on the present results and related reports in the
literature,6,10–12 a plausible reaction mechanism is proposed
as shown in Figure 2. First, Ag(I) is oxidized by persulfate
anion to form Ag(II), which then triggers a single-electron-
transfer process of the N-aryloxamic acid 1 to regenerate
the Ag(I) and form the N-arylcarbamoyl radical A with re-
lease of CO2. Subsequently, the N-arylcarbamoyl radical A
adds to the alkene to form radical intermediate B, which
undergoes an intramolecular cyclization to produce radical
C. Radical C then undergoes an oxidative single-electron-
transfer/deprotonation/aromatization sequence to give cor-
responding product D. In addition, it is noteworthy that
when phenyl vinyl sulfone is used, the quinolin-2(1H)-one
E is obtained as the final product through a Julia–Lythgoe
elimination reaction of D.
(4) For selected examples, see: (a) Tsuritani, T.; Yamamoto, Y.;
Kawasaki, M.; Mase, T. Org. Lett. 2009, 11, 1043. (b) Felpin, X.-F.;
Coste, J.; Zakri, C.; Fouquet, E. Chem. Eur. J. 2009, 15, 7238.
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15, 2128. (d) Wu, J.; Xiang, S.; Zeng, J.; Leow, M.; Liu, X.-W. Org.
Lett. 2014, 17, 222. (e) Manikandan, R.; Jeganmohan, M. Org.
Lett. 2014, 16, 3568. (f) Li, B.; Park, Y.; Chang, S. J. Am. Chem. Soc.
2014, 136, 1125. (g) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H.
J. Am. Chem. Soc. 1996, 118, 4264.
(5) For selected examples, see: (a) Wu, T.; Mu, X.; Liu, G. Angew.
Chem. Int. Ed. 2011, 50, 12578. (b) Mai, W.-P.; Wang, J.-T.; Yang,
L.-R.; Yuan, J.-W.; Xiao, Y.-M.; Mao, P.; Qu, L.-B. Org. Lett. 2013,
16, 204. (c) Zhou, S.-L.; Guo, L.-N.; Wang, S.; Duan, X.-H. Chem.
Commun. 2014, 50, 3589. (d) Mai, W.-P.; Sun, G.-C.; Wang, J.-T.;
Song, G.; Mao, P.; Yang, L.-R.; Yuan, J.-W.; Xiao, Y.-M.; Qu, L.-B.
J. Org. Chem. 2014, 79, 8094. (e) Wang, F.-X.; Tian, S.-K. J. Org.
Chem. 2015, 80, 12697. (f) Gao, F.; Yang, C.; Gao, G.-L.; Zheng, L.;
Xia, W. Org. Lett. 2015, 17, 3478. (g) Wang, Q.; Han, G.; Liu, Y.;
Wang, Q. Adv. Synth. Catal. 2015, 357, 2464. (h) Zhang, H.; Gu, Z.;
Li, Z.; Pan, C.; Li, W.; Hu, H.; Zhu, C. J. Org. Chem. 2016, 81, 2122.
(i) Wang, K.; Chen, X.; Yuan, M.; Yao, M.; Zhu, H.; Xue, Y.; Luo, Z.;
Zhang, Y. J. Org. Chem. 2018, 83, 1525. (j) Wu, J.; Zhang, J.-Y.;
Gao, P.-G.; Xu, S.-L.; Guo, L.-N. J. Org. Chem. 2018, 83, 1046.
(k) Cui, Z.; Du, D.-M. J. Org. Chem. 2018, 83, 5149. (l) Ling, A.;
Zhang, L.; Tan, R. X.; Liu, Z.-Q. J. Org. Chem. 2018, 83, 14489.
(m) Ren, H.; Zhang, M.; Zhang, A. Synthesis 2018, 50, 575.
(n) Gao, R.-X.; Luan, X.-Q.; Xie, Z.-Y.; Yang, L.; Pei, Y. Org. Biomol.
Chem. 2019, 17, 5262.
In conclusion, we have developed a practical silver-cata-
lyzed tandem decarboxylative radical addition/cyclization
of oxamic acids with alkenes to give various 4-aryl-3,4-di-
hydroquinolin-2(1H)-ones,
4-(-carbonyl)-3,4-dihydro-
quinolin-2(1H)-ones, or quinolin-2(1H)-ones in aqueous
solution.14 This general protocol features mild reaction con-
ditions and a broad range of easily accessible substrates.
Funding Information
Financial support from the National Natural Science Foundation of
China (21302130 and 21676166), the Science and Technology De-
partment of Zhejiang Province (2014C31141 and LGG20B060002),
and the Department of Education of Zhejiang Province (Y201941045)
are acknowledged with thanks.
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Supporting Information
(6) (a) Minisci, F.; Coppa, F.; Fontana, F. J. Chem. Soc., Chem.
Commun. 1994, 679. (b) Minisci, F.; Fontana, F.; Coppa, F.; Yan,
Y. M. J. Org. Chem. 1995, 60, 5430.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707891.
S
u
p
p
orti
n
gInformati
o
n
S
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p
p
orit
n
gInformati
o
n
(7) (a) Pawar, G. G.; Robert, F.; Grau, E.; Cramail, H.; Landais, Y.
Chem. Commun. 2018, 54, 9337. (b) DiLabio, G. A.; Scanlan, E.
M.; Walton, J. C. Org. Lett. 2005, 7, 155. (c) Kim, I.; Kang, G.; Lee,
K.; Park, B.; Kang, D.; Jung, H.; He, Y.-T.; Baik, M.-H.; Hong, S.
J. Am. Chem. Soc. 2019, 141, 9239. (d) Jatoi, A.-H.; Pawar, G.-G.;
Robert, F.; Landais, Y. Chem. Commun. 2019, 55, 466.
(8) (a) Millán-Ortiz, A.; López-Valdez, G.; Cortez-Guzmán, F.;
Miranda, L.-D. Chem. Commun. 2015, 51, 8345. (b) Betou, M.;
Male, L.; Steed, J.-W.; Grainger, R.-S. Chem. Eur. J. 2014, 20, 6505.
(c) López-Valdez, G.; Olguín-Uribe, S.; Miranda, L.-D. Tetrahe-
dron Lett. 2007, 48, 8285.
(9) Petersen, W. F.; Taylor, R. J. K.; Donald, J. R. Org. Lett. 2017, 19,
874.
(10) Bai, Q.-F.; Jin, C.; He, J.-Y.; Feng, G. Org. Lett. 2018, 20, 2172.
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(12) Chen, G.; Li, C.; Peng, J.; Yuan, Z.; Liu, P.; Liu, X. Org. Biomol.
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References and Notes
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Kohri, H. Biochem. Pharmacol. 1976, 25, 1837. (b) Hayashi, H.;
Miwa, Y.; Miki, I.; Ichikawa, S.; Yoda, N.; Ishii, A.; Kono, M.;
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C. Jin et al.
Letter
Synlett
(14) Quinolin-2(1H)-ones 3, 5, and 7; General Procedure
A 10 mL reaction vial was charged sequentially with the appro-
priate oxamic acid 1 (0.3 mmol, 1.0 equiv), AgNO3 (0.03 mmol,
10 mol%), Na2S2O8 (0.6 mmol, 2.0 equiv), MeCN (1.5 mL), and
H2O (1.5 mL). The vial was closed and bubbled with N2 for 5
min. The appropriate alkene 2, 4, or 6 (0.9 mmol, 3.0 equiv) was
then injected into the vial, and the mixture was stirred at 80 °C
for 36 h. The resulting mixture was diluted with EtOAc (40 mL)
and H2O (10 mL), and the organic layer was recovered, washed
with brine, dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by column chroma-
tography (silica gel, EtOAc–PE).
6-Chloro-1-methyl-4-phenyl-3,4-dihydroquinolin-2(1H)-
one (3f)
Colorless oil; yield: 57.7 mg (71%; 0.3 mmol scale). IR (film):
2928, 1676, 1491, 1416, 1360, 1267, 1130 cm–1 1H NMR (400
.
MHz, CDCl3):  = 7.36–7.33 (m, 2 H), 7.30–7.23 (m, 2 H), 7.15–
7.13 (m, 2 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.87 (dd, J = 2.0, 0.4 Hz, 1
H), 4.19 (t, J = 7.2 Hz, 1 H), 3.36 (s, 3 H), 2.95 (d, J = 3.6 Hz, 1 H),
2.93 (d, J = 1.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3):  = 169.1,
140.2, 139.0, 131.0, 129.1, 128.4, 128.0, 127.8, 127.5, 116.2,
41.4, 38.5, 29.7. GC/MS: m/z (%) = 228 (68), 271 (100) [M+].
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–F