Direct Synthesis of 4-Quinolones via Copper-Catalyzed Anilines and Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b02495

A unique and direct approach for constructing 4-quinolones from simple and readily available anilines and alkynes is described. Under the optimal conditions, both N-alkyl- and N-aryl-substituted anilines can be successfully transformed into the corresponding 4-quinolones. This reaction is characterized by mild reaction conditions, high functional-group tolerance, and amenability to gram-scale synthesis.

Full text of DOI:10.1021/acs.orglett.7b02495

Letter
pubs.acs.org/OrgLett
Direct Synthesis of 4‑Quinolones via Copper-Catalyzed Anilines and
Alkynes
Xuefeng Xu and Xu Zhang*
College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
S
* Supporting Information
ABSTRACT: A unique and direct approach for constructing 4-
quinolones from simple and readily available anilines and
alkynes is described. Under the optimal conditions, both N-
alkyl- and N-aryl-substituted anilines can be successfully
transformed into the corresponding 4-quinolones. This reaction
is characterized by mild reaction conditions, high functional-
group tolerance, and amenability to gram-scale synthesis.
available anilines by C−H activation remains a challenging
task (Scheme 1b).
4-Quinolones represent a major class of nitrogen-containing
heterocycles that has been widely found in natural products,
pharmaceuticals, and biologically active molecules.1 Therefore,
the efficient synthesis of 4-quinolones has attracted the
interest of chemists and pharmacologists. Classical methods
such as Niementowski,2 Conrad−Limpet,3 and Camps
cyclizations4 are based on cyclocondensation and suffer from
harsh reaction conditions (high temperature and/or strong
bases or acids), the limitation of substrate scope, unsat-
isfactory yields, and poor regioselectivities. Recently, several
improved procedures for construction of a 4-quinolone
framework to make use of transition-metal catalysis5 or o-
haloaryl acetylenic ketones/amines or o-alkynylbenzamides/
aldehydes have been established (Scheme 1a).6 Despite
significant advances, special starting materials such as ortho-
halogen/amino substitution substrates are required for the
approach. The direct approach from simple and readily
Furthermore, the cross-coupling reaction of anilines with
dimethyl butynedioate for the synthesis of indoles catalyzed
by palladium has emerged,7 and it has been noted that
secondary enamines are generally inactive in palladium-
catalyzed C−H activation reactions.8 Inspired by this
chemistry and as part of our ongoing project on the
formation of heterocycles,9 we envisioned that the reaction
of secondary amines and alkynoates would provide a general
approach to quinolones by improving the electrophilicity of
catalysts under acidic conditions (Scheme 1d).
To test our hypothesis, we selected diphenylamine 1 and
methyl phenylpropiolate 2 as the model substrates for
reaction condition screening. The reaction was performed
with Cu(OTf)2 catalyst and HOAc as additive, 120 °C for 12
h in DCE (Table 1, entry 1). Disappointingly, a trace amount
of quinolone product 3l was detected. Thus, the additive
species was screened first (entries 2−5). Gratifyingly, when
HOTf was used, the desired quinolone product 3l was
obtained in 89% yield (entry 2), while TsOH and Tf2O show
no reactivity (Table 1, entries 3 and 4). Indeed, the yield of 3l
was improved to 32% when TFA was used as an additive
(Table 1, entry 5). No reaction was detected in the absence
of catalyst Cu(OTf)2 or additive HOTf, which shows that
Cu(OTf)2 and HOTf are essential in the course of the
reaction (Table 1, entries 6 and 7). Other reaction media
tested, including toluene, DMF, DMSO, CH3CN, MeOH,
EtOH, Diox, and THF (entries 8−15), could not effect the
desired transformation with a yield comparable to that in
DCE. Finally, lowering the temperature to more benign 100
°C still enables the product formation with a reasonable yield
(entry 16).
Scheme 1. Scope of Amines
With the optimized conditions established (Table 1, entry
2), we then studied the scope of the cyclization of methyl
Received: August 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02495
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Organic Letters
Letter
Table 1. Condition Screening for the Synthesis of 1,2-
Diphenyl-4-quinolone
Scheme 2. Copper-Catalyzed Intermolecular Cyclization of
2 with Different Anilines
a
a b
,
b
entry
catalyst
additive
solvent
temp (°C) yield (%)
1
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
HOAc
TfOH
TsOH
Tf2O
DCE
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
trace
89
0
2
DCE
3
DCE
4
DCE
0
5
TFA
DCE
32
0
6
DCE
7
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
DCE
0
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
PhMe
DMF
DMSO
CH3CN
MeOH
EtOH
Diox
12
0
9
10
11
12
13
14
15
16
0
21
0
0
34
26
42
THF
DCE
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Cu(OTf)2 (0.025
b
mmol), HOTf (0.025 mmol), in solvent (2 mL), 12 h. Yields of
isolated products are given.
phenylpropiolate with a series of amines, as shown in Scheme
2. First, we examined the effect of the R1 substituent on the
aromatic amine (Scheme 2, products 3a−h). In general, both
electron-donating groups (EDGs) and electron-withdrawing
groups (EWGs) on the phenyl ring were well tolerated to give
the corresponding quinolones in good to excellent yields
(67%−89%). All ortho-, meta-, and para-substituted anilines
were smoothly transformed into the desired products, which
indicated that steric bulk did not significantly affect the
reactivity.
To explore the substrate scope further, we examined the
substituent effect of R2 moieties on this system. When R2
was an aliphatic group, such as −Me, −Et, −iPr, or −nBu, all
of the substrates tested were smoothly convented to the
corresponding quionlines (3a−j). Moreover, when 1,2,3,4-
tetrahydroquinoline was used as the substrate in this
transformation, the 1,7-five-membered annulated quinolone
3l was obtained in 76% yield. Replacement of the aliphatic
groups at the R2 position with aryl groups led to quinolones
(3m−p) in somewhat higer yields. As expected, this reaction
was not limited to simple aromatic amines, and the
naphthalene substrates also afforded 3t and 3u in good yields
with complete regioselectivity, respectively. In addition, this
protocol is also applicable with active amino group remained
intact under the reaction conditions (3v and 3w).
Then our attention turned to explore the effect of
substituents alkynes under the optimal conditions (Scheme
3). A variety of amines with an electron-withdrawing alkynyl
ester (dimethyl butynedioate) gave the desired quinolones in
excellent yields (4a−i). Gratifyingly, alkynyl ester substrates
R3 (aliphatic and aryl groups) afforded moderate yields (4k−
t). Alkynyl esters bearing 4-substituted electron-withdrawing
groups (halogen and trifluoromethyl) were relatively sluggish
and afforded moderate yields (4n, 4p, 4r, and 4s). Alkyl 4-
substituted alkynyl esters gave the desired quinolones in
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OTf)2 (0.025
b
mmol), HOTf (0.025 mmol), DCE (2 mL), 120 °C, 12 h. Isolated
yield after chromatography.
excellent yields (4o and 4q). Naphthyl, anthracenyl, and
phenanthyl substrates participated efficiently as well to give
the corresponding product (4v−x), which was obtained in a
slightly lower yield, suggesting that the reaction was
influenced by the steric effect. It is also worth noting that
this protocol was readily scaled up to produce grams of
quinolone 2a without loss of yield, demonstrating the
practicability of this procedure (Scheme 4).
To gain insight into the reaction mechanism, we carried out
several control experiments (Scheme 5a). First, when the
secondary enamine substrate 4 was subjected to the optimized
conditions, the quinolone product was obtained in 92% yield,
which showed that the enamines might be used as a key
intermediate for the copper-catalyzed cascade reaction. At the
same time, no quinolone 3l was discovered when the reaction
was carried out in the absence of acid or Cu catalyst, which
indicates that the acidic condition may be favorable for
improving the electrophilic properties of the catalyst (Scheme
5b). On the other hand, if the quinolone product could
obtain by reductive elimination, the oxidant must play an
essential role in the catalytic cycle, and dioxygen is the only
possible oxidant and an ideal oxidant.10 However, the reaction
proceed smoothly under nitrogen atmosphene with an
acceptable yield (Scheme 5c), which shows that deprotona-
tion is much faster that reductive elimination.
B
DOI: 10.1021/acs.orglett.7b02495
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Organic Letters
Letter
Scheme 3. Copper-Catalyzed Intermolecular Cyclization of
1 with Different Alkynes
Scheme 6. Proposed Mechanism for the Transformation
ab
,
coordinated by the carbamoyl group of the enamine 5 and
delivers the intermediate A;13 thus, a more electrophilic
carbomyl moiety would lead to nucleophilic attack and, thus,
directly protodemetalation to deliver the quinolone 3 and
regenerate the catalyst.
In conclusion, we have developed a unique and direct
approach for constructing 4-quinolones from simple and
readily available anilines and alkynes. Through this method,
both N-alkyl- and N-aryl-substituted anilines can be
successfully transformed into the corresponding 4-quinolones.
The reaction conditions are mild, require manipulation, and
do not require the addition of oxidizing agent, which provides
an attractive methodology. Further scope investigation is
ongoing and will be reported.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OTf)2 (0.025
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02495.
b
mmol), HOTf (0.025 mmol), DCE (2 mL), 120 °C, 12 h. Yield of
the isolated product shown.
Experimental procedures, characterization of products,
Scheme 4. Gram-Scale Production of 1,2-Diphenyl-4-
quinolone
1
and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zhangxuedu@126.com.
ORCID
Xu Zhang: 0000-0002-3588-3240
Notes
Scheme 5. Control Experiments
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science Foundation of Nanyang Normal
University (QN2016018) and the National Natural Science
Foundation of China (21502100).
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