A One-Pot Sonogashira Coupling and Annulation Reaction: An Efficient Route toward 4 H -Quinolizin-4-ones

Article abstract of DOI:10.1055/s-0037-1611748

An efficient one-pot Sonogashira coupling and annulation reaction affording 4 H -quinolizin-4-ones in moderate to excellent yields is described. A variety of substituted iodoarenes and 2-alkylazaarenes were well tolerated, and especially the unsaturated double and triple bonds were compatible under the standard conditions.

Full text of DOI:10.1055/s-0037-1611748

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
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Z. Chen et al.
Letter
Synlett
A One-Pot Sonogashira Coupling and Annulation Reaction:
An Efficient Route toward 4H-Quinolizin-4-ones
Zhengwang Chen*
Tanggao Liu
Xiaoyue Ma
Pei Liang
0
0
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0-0
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2-6
7
9
5-9
6
2
5
R2
(1) Pd(PPh3)2Cl2, CuI
R1
I
K2CO3, DMF, 80 °C, 10 min
R1
R3
CO2Me
N
(2)
80 °C, 8 h
R2
R3
O
Lipeng Long
Min Ye*
N
52–89%
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi
Province, Gannan Normal University, Ganzhou, Jiangxi, 341000,
P. R. of China
chenzwang@gnnu.cn
yemin811@gnnu.cn
Received: 20.01.2019
Accepted after revision: 08.02.2019
Published online: 19.03.2019
Alkynoates, as versatile building blocks, have been ex-
tensively utilized in many transformations.8 However, the
commercially available aryl-substituted alkynoates only in-
clude methyl phenylpropiolate and ethyl phenylpropiolate,
mainly due to the ease of polymerization and decomposi-
tion of this type of compounds. On the other hand, 2-al-
kylazaarenes and alkynes have been applied widely to syn-
thesize heterocyclic compounds.9 Herein, we described an
efficient route to obtain 4H-quinolizin-4-ones via one-pot
Sonogashira coupling and annulation reaction (Scheme 1).
Both the iodoarenes and methyl propiolate are easily avail-
able raw materials, and the unsaturated double and triple
bonds are compatible in the reaction conditions.
In our initial study, we examined the classical Pd/Cu co-
catalyzed Sonogashira coupling in basic conditions, we
found that the methyl phenylpropiolate intermediate was
formed from iodobenzene (1a) and methyl propiolate (2a)
in a short time. In order to obtain optimal reaction condi-
tions for the formation of 4a, different bases were evaluat-
ed, which were essential for the one-pot, two-step reac-
tions. As shown in Table 1, a variety of common inorganic
and organic bases were tried, three bases including NaOtBu,
K2CO3, and Cs2CO3can afford the product in good yields, and
K2CO3was more efficient than other bases (Table 1, entries
1–9). Then, the temperatures were examined, higher or
lower temperatures were disadvantageous to the transfor-
mation (Table 1, entries 10 and 11). Finally, the reaction can
afford the product in 86% yield when the reaction time was
extended to 8 h (Table 1, entries 12 and 13).
DOI: 10.1055/s-0037-1611748; Art ID: st-2019-v0035-l
Abstract An efficient one-pot Sonogashira coupling and annulation
reaction affording 4H-quinolizin-4-ones in moderate to excellent yields
is described. A variety of substituted iodoarenes and 2-alkylazaarenes
were well tolerated, and especially the unsaturated double and triple
bonds were compatible under the standard conditions.
Key words one-pot, Sonogashira coupling, quinolizinone, 2-alkyl-
azaarene, annulation reaction
Quinolizinones represent a unique class of N-heterocy-
cles, which have found favorable physicochemical proper-
ties and wide applications in pharmaceuticals for the treat-
ment of spinal muscular atrophy, Alzheimer’s disease, type
2 diabetes, HIV, and usage as Mg2+ fluorescent probes for in-
tracellular 3D imaging.1 To our surprise, in spite of the
strong pharmacological interest in these valuable bicyclic
compounds, facile and general approaches to 4H-quinoliz-
in-4-ones are relatively rare. The main synthetic routes in-
clude intramolecular cyclocarbonylation,2 double C–H acti-
vation,3 multicomponent approach for CO2fixation,4 ring-
closing metathesis,5 tandem Horner–Wadsworth–Emmons
olefination and cyclization,6 and so on.7 Despite the signifi-
cant advancement, the development of general and com-
plementary approaches toward quinolizinones from readily
available precursors are still desirable.
R2
(1) Pd(PPh3)2Cl2, CuI
K2CO3, DMF, 80 °C, 10 min
R1
I
R1
R3
CO2Me
N
(2)
80 °C, 8 h
R2
R3
O
N
Scheme 1 The synthesis of 4H-quinolizin-4-ones via one-pot Sonogashira coupling and annulation reaction
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
Z. Chen et al.
Letter
Synlett
Table 1 Optimization of Reaction Conditions for the Synthesis of 4H-
Quinolizin-4-onesa
COOEt
COOEt
N
Pd(PPh3)2Cl2, CuI
DMF, 10 min
Ph
I
3a
CO2Me
N
base, temperature
DMF, temperature
O
1a
2a
4a
Entry
Base
NaOtBu
Temp (°C)
Time (h)
Yield (%)b
1
2
80
80
80
80
80
80
80
80
80
60
100
80
80
6
6
74
KOH
n.p.c
80
3
K2CO3
CH3ONa
Cs2CO3
K3PO4
Et3N
6
Figure 1 X-ray structure of 4a
4
6
n.p.
68
5
6
COOEt
R1
(1) Pd(PPh3)2Cl2, CuI
K2CO3, DMF,
80 °C, 10 min
6
6
52
I
7
6
25
R1
CO2Me
N
(2) 3a, 80 °C, 8 h
8
DABCO
DMAP
K2CO3
K2CO3
K2CO3
K2CO3
6
32
O
9
6
n.p.
56
2a
1
4
10
11
12
13
6
Ph
CO2Et
CO2Et
CO2Et
6
63
Ph
8
86
N
N
N
10
85
O
O
O
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.2 mmol),
Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), base (2 equiv), and DMF 1.0 mL.
b Isolated yield.
4a: 86%
4b: 88%
4c: 76%
c n.p. = no product.
F
F
F
Cl
CO2Et
CO2Et
CO2Et
With the optimized reaction conditions available, the
scope of one-pot quinolizinone synthesis was screened. A
range of iodoarenes, methyl propiolate, and 2-pyridyl ethyl
ester were converted into the corresponding quinolizinones
in moderate to good yields (Scheme 2). Both the electron-
donating or the electron-withdrawing groups on the ben-
zene ring were tolerated and rendered the desired products
in good yields (4b–k). The reaction was compatible with a
set of substituents, such as alkyl, aryl, fluoro, chloro, cyano,
trifluoromethyl, acetyl, ester, and nitro groups (4b–k). It is
noteworthy that the products containing cyano, acetyl, es-
ter, or nitro groups could be further functionalized and
have potential applications in organic synthesis and phar-
maceutical chemistry (4g,i–k). Fortunately, the heteroaryl-
substituted quinolizinone could be successfully formed in
high yields (4l). The regiochemistry and structure of 4a
were further confirmed by X-ray crystal-diffraction mea-
surements (Figure 1).10
N
N
N
O
O
O
4d: 67%
4e: 84%
4f: 55%
O
CN
CO2Et
CO2Et
CO2Et
CF3
N
N
N
O
O
O
4g: 72%
4h: 70%
4i: 65%
O
NO2
CO2Et
CO2Et
S
CO2Et
O
N
N
O
N
O
4l: 89%
O
4j: 52%
4k: 56%
Scheme 2 Substrate scope of iodoarenes. Reaction conditions: 1 (0.2
mmol), 2a (0.3 mmol), 3a (0.2 mmol), Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%),
K2CO3 (2 equiv), and DMF (1.0 mL) at 80 °C for 8 h.; yields of isolated
products are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Letter
Synlett
Next, we investigated the scope of 2-alkylazaarenes un-
der the standard conditions. Initially, a variety of ester moi-
eties were explored, and the results are shown in Scheme 3.
The ester-containing bulky tert-butyl skeleton furnished
the products in good yields (5b and 5c). To our delight, the
challenging substrates bearing unsaturated double or triple
bonds reacted smoothly to produce the desired products in
satisfactory yields (5d–h). When the ester groups were re-
placed with cyano group, the corresponding product 5i was
obtained in 61% yield (5i). The substituents on the pyridine
ring with opposite nature were also tested, and the results
implied that this one-pot approach can be effective for the
4H-quinolizin-4-one library (5m,n).
CO2Et
R
K2CO3 (2 equiv)
DMF, 80 °C, 8 h
R
CO2Me
CO2Et
N
N
O
6a, R = Me, 65%
6b, R = Et, 61%
2
3a
6
Scheme 4 Preparation of 2-alkyl substituted 4H-quinolizin-4-ones
A control experiment was conducted between methyl
3-phenylpropiolate (7a) and 2-pyridyl ethyl ester (3a), and
4a was formed in excellent yield, which suggested the
Sonogashira coupling was the first step with high efficiency
(Scheme 5). Consequently, a proposed mechanism has been
depicted on the basis of earlier related literature4,9 and our
experimental results (Scheme 6). In the first step, interme-
diate 7a was easily prepared in a typical Sonogashira cou-
pling procedure. Then 3a underwent successively deproton-
ation, Michael addition with 7a, and protonation to furnish
Furthermore, commercially available methyl but-2-
ynoate and methyl pent-2-ynoate were used to react with
2-pyridyl ethyl ester in base conditions, the desired prod-
ucts were delivered with 65% and 61% yields, respectively
(Scheme 4).
R2
(1) Pd(PPh3)2Cl2, CuI
R1
I
K2CO3, DMF, 80 °C, 10 min
R1
R3
CO2Me
X
N
(2)
80 °C, 8 h
R2
R3
O
N
2a
3
5
1
CO2Me
Ph
O
N
O
O
O
O
O
O
N
O
Ph
Ph
Ph
N
Ph
N
N
O
O
O
O
O
5a: 88%
5b: 76%
5c: 72%
5d: 84%
5e: 69%
O
O
CN
O
O
Ph
O
O
O
O
O
N
O
Ph
N
O
Ph
N
Ph
N
N
N
O
O
O
5k: 60%
O
O
5f: 75%
5g: 63%
5h: 78%
5i: 61%
5j: 71%
O
O
COOMe
Ph
O
O
Ph
N
N
O
N
Br
N
O
O
5l: 72%
5m: 77%
5n: 74%
Scheme 3 Substrate scope of iodoarenes and 2-alkylazaarenes. Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), 3 (0.2 mmol), Pd(PPh3)2Cl2 (2
mol%), CuI (4 mol%), K2CO3 (2 equiv), and DMF (1.0 mL) at 80 °C for 8 h; yields of isolated products are given.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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Letter
Synlett
intermediate A. The intermediate A might be transformed
to a trans-configuration B in the reaction conditions. Final-
ly, the intramolecular cyclization produced the quinoliz-
inone product through a nucleophilic addition–elimination
mechanism.
References and Notes
(1) (a) Kuduk, S. D.; Chang, R. K.; Di Marco, C. N.; Ray, W. J.; Ma, L.;
Wittmann, M.; Seager, M. A.; Koeplinger, K. A.; Thompson, C. D.;
Hartman, G. D.; Bilodeau, M. T. ACS Med. Chem. Lett. 2010, 1,
263. (b) Xu, Y.-S.; Zeng, C.-C.; Jiao, Z.-G.; Hu, L.-M.; Zhong, R.-G.
Molecules 2009, 14, 868. (c) Fujii, T.; Shindo, Y.; Hotta, K.;
Citterio, D.; Nishiyama, S.; Suzuki, K.; Oka, K. J. Am. Chem. Soc.
2014, 136, 2374. (d) Komatsu, H.; Iwasawa, N.; Citterio, D.;
Suzuki, Y.; Kubota, T.; Tokuno, K.; Kitamura, Y.; Oka, K.; Suzuki,
K. J. Am. Chem. Soc. 2004, 126, 16353. (e) Felts, A. S.; Rodriguez,
A. L.; Smith, K. A.; Engers, J. L.; Morrison, R. D.; Byers, F. W.;
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Niswender, C. M.; Daniels, J. S.; Conn, P. J.; Lindsley, C. W.;
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Chang, R. K.; Marco, C. N. D.; Pitts, D. R.; Greshock, T. J.; Ma, L.;
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Hartman, G. D.; Bilodeau, M. T.; Ray, W. J. J. Med. Chem. 2011, 54,
4773.
CO2Et
Ph
Ph
CO2Me
CO2Et
N
N
DMF, 80 °C, 8 h
O
7a
3a
4a, 90%
Scheme 5 A control experiment
Pd(PPh3)2Cl2
CuI, K2CO3
CO2Me
2a
I
Ph
CO2Me
DMF, 80 °C, 10 min
1a
7a
(2) Yu, H.; Zhang, G.; Huang, H. Angew. Chem. Int. Ed. 2015, 54,
10912.
(3) Li, J.; Yang, Y.; Wang, Z.; Feng, B.; You, J. Org. Lett. 2017, 19, 3083.
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(6) Muir, C. W.; Kennedy, A. R.; Redmond, J. M.; Watson, A. J. B. Org.
Biomol. Chem. 2013, 11, 3337.
CO2Et
Ph
CO2Me
(7a)
base
Ph
CO2Et
CO2Et
N
N
N
CO2Me
3a
H+
CO2Et
CO2Et
Ph
H
CO2Et
Ph
Ph
base
N
(7) (a) Rosas-Sánchez, A.; Toscano, R. A.; Ĺopez-Corté s, J. G.;
Ortega-Alfaro, M. C. Dalton Trans. 2015, 44, 578. (b) He, H.; Qi,
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Huang, L.; Wu, W.; Li, J.; Jiang, H. Org. Lett. 2016, 18, 3514.
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C.; Zhou, Z.-W.; Zhang, Q.; Wen, X.-H.; Jia, F.-C.; Wu, A.-X. Org.
Lett. 2018, 20, 4231. (g) Chen, Z.; Wen, Y.; Luo, G.; Ye, M.; Wang,
Q. RSC Adv. 2016, 6, 86464. (h) Chen, Z.; Wen, Y.; Ding, H.; Luo,
G.; Ye, M.; Liu, L.; Xue, J. Tetrahedron Lett. 2017, 58, 13.
(9) (a) Wu, T.; Chen, M.; Yang, Y. J. Org. Chem. 2017, 82, 11304.
(b) Tang, S.; Liu, K.; Long, Y.; Qi, X.; Lan, Y.; Lei, A. Chem.
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Wang, H.; Pan, Y. Tetrahedron 2014, 70, 6717.
N
N
– MeOH
CO2Me
O
4a
O
MeO
A
B
Scheme 6 Proposed mechanism for the synthesis of 4H-quinolizin-4-ones
In conclusion, we have developed an efficient one-pot
Sonogashira coupling and annulation procedure to access
4H-quinolizin-4-ones.11 The approach results in good yields
with various substituted iodoarenes and 2-alkylazaarenes.
The reaction features simple one-pot operation, easily
available raw materials, broad functional group compatibil-
ities, and high regioselectivity. Further utilization of this
procedure in synthetic and pharmaceutical chemistry and
understanding the mechanism are current in our laboratory.
Funding Information
The authors thank the NSF of Jiangxi Province (20171ACB21048), the
NSF of Jiangxi Provincial Education Department (GJJ160924), the In-
novation Fund of Jiangxi Province (YC2018-S385), and University Stu-
dents’ Innovative Undertaking of Gannan Normal University
(201710418007) for financial support.()
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611748.
(10) CCDC 1874167 contains the supplementary crystallographic
data for this paper (compound 4a). The data can be obtained
free of charge from Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

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(11) Ethyl 4-oxo-2-phenyl-4H-quinolizine-1-carboxylate (4a) –
Typical Procedure
finished, water (5 mL) was added, and the solution was
extracted with ethyl acetate (3 × 5 mL), the combined extract
was dried with anhydrous MgSO4. Solvent was removed, and
the residue was separated by column chromatography (petro-
leum ether/ethyl acetate, 2:1) to give 4a (50 mg, 86%) as a
yellow solid. 1H NMR (400 MHz, CDCl3):  = 9.20 (d, J = 7.3 Hz, 1
H), 8.20–8.14 (m, 1 H), 7.50 (ddd, J = 9.2, 6.6, 1.4 Hz, 1 H), 7.35
(dtt, J = 9.7, 7.0, 2.5 Hz, 5 H), 7.10–7.05 (m, 1 H), 6.55 (s, 1 H),
3.91 (q, J = 7.2 Hz, 2 H), 0.74 (t, J = 7.2 Hz, 3 H). 13C NMR (100
MHz, CDCl3):  = 167.3, 157.4, 152.0, 142.1, 140.1, 132.2, 128.3,
128.3, 127.9, 127.4, 123.2, 115.5, 109.0, 106.9, 61.2, 13.2. MS
(EI): m/z = 293, 265, 248, 237, 220, 193, 165, 95, 78, 51.
An oven-dried screw cap test tube was charged with a magnetic
stir bar, Pd(PPh3)2Cl2 (2 mol%), CuI (4 mol%), and K2CO3 (0.4
mmol). The tube was then evacuated and backfilled with argon.
The evacuated/backfill sequence was repeated two additional
times. Under a counter-flow of argon, DMF (1 mL), iodoarene
(1a, 0.2 mmol), and methyl propiolate (2a, 0.3 mmol) were
added. The tube was placed in a preheated oil bath at 80 °C, and
the mixture was stirred vigorously for 10 min. Then the screw
cap was opened and 2-pyridyl ethyl ester (3a, 0.2 mmol) was
added in air at 80 °C. The mixture was allowed to react for
another 8 h at 80 °C in air atmosphere. After the reaction was
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E