Direct C-C Bond Cleavage of 1,3-Dicarbonyl Compounds as a Single-Carbon Synthon: Synthesis of 2-Aryl-4-quinolinecarboxylates

Article abstract of DOI:10.1021/acs.orglett.1c02267

A novel [2 + 1 + 3] cyclization reaction for the synthesis of 2-aryl-4-quinolinecarboxylates from aryl methyl ketones, arylamines, and 1,3-dicarbonyl compounds has been established. This metal-free process achieved the C-C bond cleavage of 1,3-dicarbonyl compounds directly as a single-carbon synthon. The reaction is highly efficient and has good substrate compatibility while operating under mild conditions. This method has good practicability and successfully realized the synthesis of bioactive molecules.

Full text of DOI:10.1021/acs.orglett.1c02267

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Letter
Direct C−C Bond Cleavage of 1,3-Dicarbonyl Compounds as a
Single-Carbon Synthon: Synthesis of 2‑Aryl-4-quinolinecarboxylates
You Zhou, Peng Zhao, Li-Sheng Wang, Xiao-Xiao Yu, Chun Huang, Yan-Dong Wu, and An-Xin Wu*
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ABSTRACT: A novel [2 + 1 + 3] cyclization reaction for the synthesis of 2-aryl-4-quinolinecarboxylates from aryl methyl ketones,
arylamines, and 1,3-dicarbonyl compounds has been established. This metal-free process achieved the C−C bond cleavage of 1,3-
dicarbonyl compounds directly as a single-carbon synthon. The reaction is highly efficient and has good substrate compatibility while
operating under mild conditions. This method has good practicability and successfully realized the synthesis of bioactive molecules.
he 2-arylquinoline-4-carboxylic acid derivatives have a
wide range of physiological activities, some of which can
limited to the cyclization of isatins and arylmethyl ketones1−5
and the [4 + 2] cycloaddition of aromatic imines and
acrylates.8 Therefore, it is essential to study new synthetic
methods for these compounds.
T
be used as potential anticancer and antiviral drugs. (Figure 1).1
Recently, functionalization reactions of the α-position of 1,3-
dicarbonyl compounds have been widely reported.9 In
addition, many studies have focused on the cyclization of
1,3-dicarbonyl compounds as a multicarbon synthon.10
Nevertheless, to realize the C−C bond activation cleavage of
1,3-dicarbonyl compounds is challenging, and the relevant
reports are relatively rare. In the past 10 years, the Lei and
Peng groups have reported the transition-metal-catalyzed
cleavage activation reaction of 1,3-dicarbonyl compounds,
achieving the formal arylation and phosphonation of the C−C
bond at the carbonyl α-position (Scheme 1a).11 Although
some progress has been made in the C−C bond cleavage of
1,3-dicarbonyl compounds, cleavage processes in the cycliza-
tion reaction as a single-carbon synthon have rarely been
reported. In 2017, the You group reported α-diazoesters that
were prepared by 1,3-dicarbonyl compounds as substrates for
the construction of indazole, realizing the rhodium-catalyzed
C−C bond cleavage of 1,3-dicarbonyl compounds as a single-
carbon synthon participating in the cyclization reaction
(Scheme 1b).12 However, to our knowledge, the direct
involvement of 1,3-dicarbonyl compounds without preprepara-
Figure 1. Bioactive molecules of 2-arylquinoline-4-carboxylic acid
derivatives.
Some metal complexes of Compound I have a DNA-binding
effect, which can be used for DNA structural probes and as
potential anticancer drugs.2 Brequinar (II) is an effective
inhibitor of dihydroorotate dehydrogenase (DHODH).3
Compound III has strong inhibitory activity against enter-
ovirus EV-D68 and CVB3.4 Compound IV has good activity
against nonsmall cell lung cancer and chronic myeloid
leukemia.5 Compound V induces apoptosis in pancreatic and
breast cancer cell lines.6 Compound VI strongly inhibits
STAT3 transcription in HeLa cells.7 At present, the methods
of 2-arylquinoline-4-carbon compound synthesis are mainly
Received: July 7, 2021
https://doi.org/10.1021/acs.orglett.1c02267
© XXXX American Chemical Society
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a b
,
Scheme 1. Reaction of the C−C Bond Cleavage in 1,3-
Dicarbonyl Compounds
Scheme 2. Scope of the Aryl Methyl Ketones
tion in the cyclization reaction via cleavage of the C−C bond
as a single-carbon synthon has not been reported. Herein we
realized 1,3-dicarbonyl compounds directly as a single-carbon
synthon through the cleavage of the C−C bond for the
synthesis of 2-aryl-4-quinolinecarboxylates without any metal
catalyst (Scheme 1c). Simultaneously, we used our method to
complete the multistep synthesis of several bioactive
molecules, which further proves the practical value of our work.
To evaluate this proposal, we investigated the reaction
conditions using acetophenone (1a), ethyl carbamoylacetate
(2a), and p-toluidine (3a) as examples. (See the Supporting
Information for details.) Through optimization of the acid,
equivalent of I2, and temperature, we found the following
optimal conditions: I2 (1.6 equiv) and TfOH (2.0 equiv) at
100 °C for 4 h under air.
a
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol),
I2 (1.6 mmol), TfOH (2.0 mmol), DMSO (4 mL), air, 100 °C, and 4
b
h. Isolated yields.
Scheme 3. Scope of the Arylamines and Carbamoyl
Acetates
a b
,
After confirming the optimal conditions, we used aryl methyl
ketones to investigate the applicability of a three-component
reaction for the synthesis of the 2-aryl-4-quinolinecarboxylates
(Scheme 2). Various alkyl-substituted acetophenones showed
good compatibility under the optimal reaction conditions (4a−
4d, 67−76%). Alkoxy- and methylthio-substituted products
were obtained in excellent yields (4e-4h, 66−80%). Multi-
substituted acetophenones 4i and 4j were also compatible with
the reaction, achieving yields of 65 and 60%, respectively.
Additionally, substrates containing large steric hindrance
groups, including fused rings, achieved the target compounds
in satisfactory yields (4k−4n, 65−74%). Pleasingly, halogen
substituents and even acetophenones with electron-with-
drawing groups could be converted into the target compounds
in good yields (4o−4s, 45−67%).
Subsequently, we investigated the compatibility of the
substituents on both sides of the arylamines and carbamoyl
acetates (Scheme 3). First, alkyl- and phenyl-substituted
arylamines were converted into target compounds with great
yields (5a−5d, 65−76%). The alkoxy group and methylthio
group attached to the aryl group of arylamines were also
compatible with the reaction (5e−5g, 66−75%). When the
aryl group of the arylamine contained two substituents or even
multiple substituents, the 2-aryl-4-quinoline esters were
obtained in satisfactory yields (5h−5n, 64−81%). Finally, we
replaced the ethyl ester in the substrate ethyl carbamoylacetate
a
Reaction conditions: 1e (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), I2
(1.6 mmol), TfOH (2.0 mmol), DMSO (4 mL), air, 100 °C, and 4 h.
b
Isolated yields.
B
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with a methyl ester to participate in the reaction and obtained
the final products in relatively good yields (5o−5r, 55−75%).
To verify the practicability of our method, we completed the
synthesis of three bioactive molecules (Scheme 4). First,
(1ab) in high yield under the promotion of the I2-DMSO
system (Scheme 5a). Subsequently, we confirmed that
phenylglyoxal monohydrate (1ac), α-iodoacetophenone
(1ad), and 2-hydroxyacetophenone (1ae) were the inter-
mediates of the reaction (Scheme 5b−d). Finally, we used 13C-
labeled acetophenone as the substrate under standard
conditions and found that the 13C-labeled product could be
successfully obtained, which proved that ethyl carbamoylace-
tate participated in the [2 + 1 + 3] cyclization process as a one-
carbon synthon (Scheme 5e).
Scheme 4. Study on the Practicability of the Reaction
On the basis of the previously described results and the
related literature,15 we propose a plausible mechanism
involving [2 + 1 + 3] cyclization (Scheme 6). First,
Scheme 6. Proposed Mechanism
product 4a was efficiently converted into 4ab with hydrazine
hydrate and then condensed with salicylaldehyde to produce
the bioactive molecule I-Me (Scheme 4a).2 Product 4a was
easily converted into amide III-Me with antiviral activity under
the catalysis of FeCl3 (Scheme 4b).4,13 Finally, 4a was
hydrolyzed to carboxylic acid 4ac and then reacted with
preprepared amino-oxadiazole VI-c under the conditions of
HOAt and HATU to produce VI-Me, which possessed
anticancer activity (Scheme 4c).7,14
Control experiments were performed to obtain preliminary
evidence of the reaction mechanism for this method (Scheme
5). First, acetophenone (1a) was converted to phenylglyoxal
acetophenone (1a) undergoes iodination and Kornblum
oxidation under I2-DMSO conditions to form phenylglyoxal
(1ab). Subsequently, 1ab reacts with ethyl carbamoylacetate
(2a) to produce intermediate A under acid catalysis, and A is
detected by LC-MS. Next, imine B, which is also detected by
LC-MS, is afforded by intermediate A and p-toluidine (3a).
Intermediate B may then undergo intramolecular cyclization to
generate C. Finally, the C−C bond of amide intermediate C is
cleaved to obtain the aromatization product 4a.
Scheme 5. Control Experiments
In conclusion, we developed a method to directly cleave the
C−C bond of 1,3-dicarbonyl compounds as a single-carbon
synthon to construct 2-aryl-4-quinolinecarboxylates. This
metal-free catalyzed reaction has good substrate compatibility
and practicability and successfully achieved the synthesis of
three biologically active molecules. Research on the direct
cleavage of 1,3-dicarbonyl compounds promoted by iodine to
construct other novel heterocycles is under further develop-
ment in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02267.
Experimental procedures, product characterizations,
1
crystallographic data, and copies of the H, 13C, and
19F NMR spectra (PDF)
C
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Accession Codes
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CCDC 2083400 and 2098045 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
An-Xin Wu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. China;
orcid.org/0000-0001-7673-210X; Email: chwuax@
mail.ccnu.edu.cn
Authors
You Zhou − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China
Peng Zhao − Key Laboratory of Pesticide & Chemical Biology,
Ministry of Education, College of Chemistry, Central China
Normal University, Wuhan 430079, P. R. China
Li-Sheng Wang − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. China
Xiao-Xiao Yu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. China
Chun Huang − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. China
Yan-Dong Wu − Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education, College of Chemistry, Central
China Normal University, Wuhan 430079, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02267
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (grants 21971079, 21971080, and
21772051). This work was supported by “The Fundamental
Research Funds for the Central Universities”. This work was
also supported by the 111 Project B17019.
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