Direct Synthesis of 2,3-Diaroyl Quinolines and Pyridazino[4,5- b]quinolines via an I2-Promoted One-Pot Multicomponent Reaction

Article abstract of DOI:10.1021/acs.orglett.9b00685

The first synthesis of 2,3-diaroyl quinolines via a formal [3 + 2 + 1] cycloaddition of enaminones, aryl methyl ketones, and aryl amines is disclosed. This reaction efficiently affords a 1,4-dicarbonyl scaffold, which is a useful building block for constructing complex fused heterocycles. Furthermore, the 1,4-dicarbonyl scaffold has been used directly to prepare pyridazino[4,5-b]quinoline skeletons in one-pot.

Full text of DOI:10.1021/acs.orglett.9b00685

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Synthesis of 2,3-Diaroyl Quinolines and
Pyridazino[4,5‑b]quinolines via an I2‑Promoted One-Pot
Multicomponent Reaction
Peng Zhao, Xia Wu, You Zhou, Xiao Geng, Can Wang, Yan-dong Wu, and An-Xin Wu*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
S
* Supporting Information
ABSTRACT: The first synthesis of 2,3-diaroyl quinolines via a formal [3 + 2 + 1] cycloaddition of enaminones, aryl methyl
ketones, and aryl amines is disclosed. This reaction efficiently affords a 1,4-dicarbonyl scaffold, which is a useful building block
for constructing complex fused heterocycles. Furthermore, the 1,4-dicarbonyl scaffold has been used directly to prepare
pyridazino[4,5-b]quinoline skeletons in one-pot.
dicarbonyl compounds, such as quinoline skeletons containing
1,4-dicarbonyl units, has rarely been reported.8
he 1,4-Dicarbonyl compounds are readily available and
Tversatile building blocks that can be used to prepare
carbocyclic and heterocyclic compounds,1 and many con-
venient and efficient methods for their synthesis have been
developed. Currently, typical methods for preparing 1,4-
dicarbonyl compounds can be mainly summarized into six
categories: (i) conjugate additions of in situ-generated acyl
radicals or acyl anions to Michael acceptors;2 (ii) chain
extensions of 1,3-dicarbonyls;3 (iii) oxidative couplings of
enolates;4 (iv) additions of homoenolate equivalents to
electrophilic acyl derivatives;5 (v) nucleophilic substitutions
of α-haloketones with highly reactive enolates;6 and (vi)
enolate heterocouplings7 (Scheme 1). Despite recent signifi-
cant advances in the construction of chain 1,4-dicarbonyl
scaffolds, the direct synthesis of cyclic or heterocyclic 1,4-
Quinolines are privileged aromatic aza-heterocycles widely
found in modern pharmaceuticals and natural products.
Methods for their synthesis, which include named reactions,
have been widely studied.9,10 Among these elegant methods,
the Povarov reaction is among the most effective, enabling the
rapid assembly of quinolines via the formal [4 + 2]
cycloaddition of electron-poor 2-azadienes to electron-rich
dienophiles. Recently, several quinoline syntheses using the
Povarov reaction as a key transformation have been reported.10
However, the latest developments in the Povarov reaction are
mainly reflected in the synthesis of quinolines containing only
one carbonyl group. To our knowledge, the direct use of two
different carbonyl precursors, such as electron-deficient α,β-
unsaturated ketones, as starting materials to synthesize
quinolines containing 1,4-dicarbonyl units via a Povarov
reaction has yet to be reported and remains challenging.
Povarov-type reactions have mainly been focused on electron-
rich alkene substrates.
Scheme 1. Synthesis of 1,4-Dicarbonyl Compounds
Therefore, we envisioned using enaminones as α,β-
unsaturated ketone surrogates, through HNMe2 elimination,
and as carbonyl precursors simultaneously to prepare quinoline
skeletons bearing dicarbonyl units via a Povarov-type reaction.
These structures could then be further functionalized to obtain
pyridazino[4,5-b]quinolines skeletons in one pot (Scheme 1).
Initially, we use aryl methyl ketones (1a), p-toluidine (2a),
and enaminone (3a) as model substrates in the presence of
CuCl2 and I2 in DMSO at 100 °C afforded (6-methylquino-
line-2,3-diyl)bis(phenylmethanone) 4a in 46% yield (Table 1,
Received: February 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00685
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Aryl Methyl Ketone Substrates
b
entry
temp (°C)
I2 (equiv)
additive
yield (%)
1
2
3
4
5
6
7
8
100
90
1.6
1.6
1.6
1.6
1.6
1.0
2.0
2.5
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
ZnCl2
FeCl3
TFA
46
40
52
50
45
47
50
49
55
53
68
65
72
62
42
70
69
67
110
120
130
110
110
110
110
110
110
110
110
110
110
110
110
110
9
10
11
12
13
14
15
16
17
18
TfOH
HCl
HI
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol),
c
HCl
HCl
HCl
hydrochloric acid (0.2 mmol), I2 (1.6 mmol) in DMSO (3.0 mL) at
d
b
110 °C for 24 h. Isolated yields.
e
a
a b
,
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol),
additive (0.2 mmol), I2 (1.6 mmol) and DMSO (3.0 mL) within 24 h
Scheme 3. Scope of Anilines and Enaminones
b
c
unless noted. Isolated yields. Hydrochloric acid 1.0 mmol.
d
e
Hydrochloric acid 1.5 mmol. Hydrochloric acid 2.0 mmol.
entry 1). Encouraged by the results, we began to screen the
reaction conditions to further improve the yield. First, the
reaction was screened at a temperature ranging from 90 to 130
°C, and the results showed that the optimum reaction
temperature was 110 °C (Table 1, entries 2−5).
Then, different amounts of iodine were screened, finding
that 1.6 equiv of iodine has the best effect (Table 1, entries 6−
8). Moreover, various Bronsted acids and Lewis acids are
screened to increase the yield of the reaction, with hydro-
chloric acid determined to be the optimal additive (Table 1,
entries 9−15). We also tested the amount of hydrochloric acid
on the yield of the reaction. The best results were seen with 20
mmol % hydrochloric acid (Table 1, entries 16−18).
After the best reaction conditions were established, we next
investigated the scope of this Povarov reaction using a variety
of different aryl ketones. To our satisfaction, various
acetophenone derivatives were compatible with this reaction
under the optimized reaction conditions, providing the desired
products in moderate to good yields (Scheme 2). Aryl methyl
ketones substituted with electron-donating group and electron-
withdrawing group (including methyl, methoxyl, ethoxyl, 3,4-
methylenedioxyl, chloro, bromo, and nitro groups) could
participate smoothly in this reaction, giving the corresponding
products in good yields (4a−4j, 50%−75%). Notably, sterically
hindered substrate 1-naphthyl methyl ketone reacted smoothly
in this transformation, furnishing desired product 4k in 65%
yield. Furthermore, 3-acetylthiophene was investigated under
the optimized reaction conditions, affording corresponding
product 4l in 72% yield.
a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol),
hydrochloric acid (0.2 mmol), I2 (1.6 mmol) in DMSO (3.0 mL) at
110 °C for 24 h. Isolated yields.
b
(4-CO2Et) were tolerated in this reaction, and the correspond-
ing 2,3-diaroyl quinolines were obtained in moderate yield
(4m−4r, 48%−75%). Notably, 2-naphthylamine was con-
ducted in this reaction, affording desired product 4s in 49%
yield. Furthermore, we investigated the substrate scope of
different enaminones in the reaction. Enaminone derivatives
bearing different phenyl ring substituents (including 4-Me, 4-
OMe, 4-Cl, and 4-Br) performed smoothly in this reaction, and
desired products 4t−4w were obtained in 53%−70% yields. A
heteroaryl functionalized enaminone was also tolerated in the
reaction, affording desired product 4x in 56% yield.
Furthermore, we also tested alkyl reactants, including alkyl
ketones, alkyl amines, and alkyl enaminones under the
optimized reaction conditions. To our disappointment, alkyl
reactants were not compatible with this transformation.
Next, we tested a variety of substituted anilines and
enaminones to further extend the reaction scope (Scheme
3). Anilines substituted with electron-rich (4-C(CH3)3, 3,5-
dimethyl, 4-OMe), halogen (4-Cl, 4-Br), and electron-deficient
B
DOI: 10.1021/acs.orglett.9b00685
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Polycyclic structures containing quinoline skeleton are
frequently found in natural products and pharmaceuticals.11
Therefore, the development of efficient and concise methods
for constructing polycyclic heterocycles containing quinoline
skeleton in one pot is highly desirable. Note that quinoline
skeletons contain 1,4-dicarbonyl units bearing two electrophilic
sites, which can serve as useful intermediate for the preparation
pyridazine. To our delight, we succeeded in the highly efficient
and concise synthesis of various pyridazino[4,5-b]quinoline
skeletons using this method (Scheme 4). Aryl methyl ketones,
acetophenone (1a) and iodine in dimethyl sulfoxide
(DMSO) at 110 °C (Scheme 5a). Next, the reaction of α-
iodoacetophenone 1aa, p-toluidine (2a), and enaminone (3a)
under the standard conditions gave 4a in 75% yield (Scheme
5b). Hydrated species 1ac also reacted smoothly in this
multicomponent reaction, and the 4a was obtained in 78%
yield (Scheme 5c). These results revealed that α-iodoaceto-
phenone 1aa and phenylglyoxal 1ac were important inter-
mediates for this reaction. Moreover, product 4o was obtained
in 55% yield by the reaction of C-acylimine 6o and enaminone
(3a) under optimized reaction conditions. However, this
multicomponent reaction did not proceed without the addition
of iodine. These results implied that C-acylimine was a key
intermediate in this Povarov reaction and indicated that iodine
played an important role in the Povarov/oxidation process.
Scheme 4. Synthesis of Various Pyridazino[4,5-b]quinoline
a b
,
Skeletons
On the basis of the above results and previous studies,10,12
a
plausible mechanism is proposed (Scheme 6). Acetophenone
Scheme 6. Proposed Mechanism
a
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol),
hydrochloric acid (0.2 mmol), I2 (1.6 mmol) in DMSO (3.0 mL) at
110 °C for 24 h, and then 10 equiv of hydrazine hydrate was added to
b
the reaction for 10 min. Isolated yields.
anilines, and enaminones attached with different substituents
were tolerated in this transformation, and the desired products
5a−5l were obtained in 40%−65% yields.
To further investigate the mechanism of the reaction, some
control experiments were conducted (Scheme 5). The
phenylglyoxal 1ab and corresponding hydrated species 1ac
was afforded in quantitative yield by the reaction of
(1a) is converted to phenylglyoxal 1ab with the release of HI
and dimethyl sulfide (DMS) via sequential iodination/
Kornblum oxidation. Then, intermediate 1ab′ activated by
acid is attacked by p-toluidine (2a), affording iminium ion A,
which reacts with enaminone (3a) to generate intermediate B.
Finally, 4a is obtained via elimination of HNMe2 and oxidative
aromatization. This quinoline formed in situ contains two
activated carbonyl groups that can be further functionalized to
afford pyridazino[4,5-b]quinoline 5a via a one-pot, two-step
protocol.
Scheme 5. Control Experiments
In conclusion, we have disclosed a concise protocol for the
direct synthesis of 2,3-diaroyl quinolines using a simple
carbonyl precursor and aryl amine. This multicomponent
reaction enriched the scope of 1,4-dicarbonyl compounds
synthesized by the Povarov reaction. Furthermore, the 2,3-
diaroyl quinoline generated in situ is endowed with two
activated electrophilic sites that can be functionalized to afford
pyridazino[4,5-b]quinolines in one pot. The application of this
method is being further studied in our laboratory.
C
DOI: 10.1021/acs.orglett.9b00685
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00685.
■
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Crystal data and structure refinement, atomic coordi-
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(PDF)
Experimental procedures, product characterizations,
crystallographic data, and copies of the H and 13C
1
NMR spectra (PDF)
Accession Codes
CCDC 1866721 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chwuax@mail.ccnu.edu.cn.
ORCID
̈
2812. (c) Friedlander, P.; Henriques, S. Ber. Ber. Dtsch. Chem. Ges.
1882, 15, 2572. (d) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(e) Yan, R.; Liu, X.; Pan, C.; Zhou, X.; Li, X.; Kang, X.; Huang, G.
Org. Lett. 2013, 15, 4876. (f) Gao, Q.; Liu, Z.; Wang, Y.; Wu, X.;
Zhang, J.; Wu, A. Adv. Synth. Catal. 2018, 360, 1364.
An-Xin Wu: 0000-0001-7673-210X
Notes
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P.; Zhang, J. J.; Wu, Y. D.; Wu, A. X. Org. Lett. 2017, 19, 4179.
(b) Wu, X.; Geng, X.; Zhao, P.; Zhang, J. J.; Gong, X.; Wu, Y. D.; Wu,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21472056, 21602070, and 21772051) and
the Fundamental Research Funds for the Central Universities
(CCNU15ZX002 and CCNU18QN011) for financial support.
This work was also supported by the 111 Project B17019.
Biomol. Chem. 2017, 15, 9585. (i) Richter, H.; García Mancheno, O.
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Org. Lett. 2011, 13, 6066. (j) Dai, W.; Jiang, X. L.; Tao, J. Y.; Shi, F. J.
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DOI: 10.1021/acs.orglett.9b00685
Org. Lett. XXXX, XXX, XXX−XXX