Divergent Synthesis of Quinolones and Dihydroepindolidiones via Cu(I)-Catalyzed Cyclization of Anilines with Alkynes

Article abstract of DOI:10.1021/acs.orglett.8b00436

A unique and efficient method for one-pot synthesis of diverse 4-quinolones from simple and readily available primary anilines and alkynes via Cu(I)-catalyzed direct cyclization has been developed. The (thio)phenols were also found to visible substrates for this reaction. Moreover, an unprecedented synthesis of dihydroepindolidiones has been demonstrated by using secondary anilines as the versatile substrates.

Full text of DOI:10.1021/acs.orglett.8b00436

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Divergent Synthesis of Quinolones and Dihydroepindolidiones via
Cu(I)-Catalyzed Cyclization of Anilines with Alkynes
Xuefeng Xu,† Ruzhong Sun,† Sheng Zhang,† Xu Zhang,*,† and Wei Yi*,‡
†Engineering Technology Research Center of Henan Province for Solar Catalysis, College of Chemistry and Pharmaceutical
Engineering, Nanyang Normal University, Nanyang 473061, China
‡Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou,
Guangdong 511436, China
S
* Supporting Information
ABSTRACT: A unique and efficient method for one-pot synthesis of diverse 4-quinolones from simple and readily available
primary anilines and alkynes via Cu(I)-catalyzed direct cyclization has been developed. The (thio)phenols were also found to
visible substrates for this reaction. Moreover, an unprecedented synthesis of dihydroepindolidiones has been demonstrated by
using secondary anilines as the versatile substrates.
4-Quinolones represent a ubiquitous structural motif that is
found in a broad range of biologically active compounds and
pharmaceuticals.1 Given the importance of 4-quinolones, the
development of efficient methods for direct and highly efficient
construction of 4-quinolone derivatives has attracted consid-
erable attention. In the past several decades, a number of classical
cyclocondensation reactions have been reported, such as
Niementowski reaction,2 Conrad−Limpach reaction,3 Camps
cyclizations,4 etc.5 However, most of them often suffer from
harsh conditions, corrosive reagents, and a limited substrate
scope. Therefore, the development of the mild, efficient and
general protocols for direct assembly of this key structural motif
is highly desired.
However, recently hot transition-metal (TM)-catalyzed direct
functionalization has emerged as one of the most popular and
powerful tools for the step- and atom-economical construction of
diverse N-heterocycles. As a result, many TM-catalyzed
protocols for the synthesis of quinolones has been extensively
explored thus far, which has provided a streamlined method for
building the desired quinolone products with an improved
substrate/functional group scope.6−8 For example, by using
ortho-haloaryl acetylenic ketones/amines or ortho-alkynylbenza-
mides/aldehydes as the substrates, the TM-catalyzed reactions
for building 4-quinolones have been well-established by several
groups (Scheme 1a,b).7 However, special starting materials and/
or preactivated substrates are generally required for finishing the
above transformations. To overcome the limitation, recently Lei
and co-workers have disclosed an elegant Pd-catalyzed oxidative
carbonylation of ketones, amines, and carbon monoxide for
straightforward synthesis of 4-quinolones (Scheme 1c, right).8e
Despite this compelling progress, it would be ideal to take
advantage of alternative and readily available starting materials as
versatile substrates for building 4-quinolone scaffolds in the
absence of relatively toxic CO gas. In this regard, it is appealing to
develop a more cost-effective and mild catalytic system for the
direct synthesis of 4-quinolones.
Very recently, we have revealed a Cu(II)-catalyzed cyclization
for one-pot construction of the 4-quinolone core by using N-
alkyl and N-aryl substituted secondary anilines and alkynes as the
substrates (Scheme 1d),9 whereas the primary aniline was
incompatible with the developed catalytic system. To expand this
approach and improve the substrate scope further, we herein
would like to report a novel and more general Cu(I)-catalyzed
direct cyclization of primary/secondary anilines or (thio)phenols
with alkynoates. Of note, the type and nature of anilines played a
crucial role in controlling the chemoselectivity, thus leading to
efficient and divergent synthesis of 4-quinolones and dihydroe-
pindolidiones (Scheme 1e). Considering the importance of both
of the resulting products in natural product chemistry and
medicinal chemistry, the two-step-/atom-economical trans-
formations should have broad synthetic utility.
We commenced our investigation with the reaction of aniline
(1a) and dimethyl butynedioate (2a) in the presence of CuI (5
mol %) and HOTf (1.0 equiv) in DCE at 120 °C (Table 1). To
our delight, the desired product 3a was observed in a 24%
Received: February 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00436
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Letter
desired product was found in the absence of both HOTf and
Tf2O (entry 4), suggesting that the introduction of them is
essential for the reaction outcome and also hinting that the
proper and strong acidic conditions are more favorable for
improving the electrophilicity of the catalyst.9 Inspired by these
findings, a variety of additives was examined, and the coadditives
of HOTf (1.0 equiv) and Tf2O (1.0 equiv) were found to be the
best choice (entries 5−7). The control experiment revealed that
the CuI catalyst was indispensable for this reaction (Table 1,
entry 8). The switching of solvent from DCE to various other
reaction media obviously inhibited the process (entries 9−15),
revealing that DCE was the optimal choice. Finally, changing CuI
to other well-known copper species and TM catalysts, such as
CuCl, CuBr, CuOTf, Cu(OTf)2, Pd(OAc)2, and Cp*Co(CO)I2
gave inferior results (entries 16−21).
Scheme 1. Transition Metal-Catalyzed Reactions for
Quinolone Synthesis
Having the optimal reaction conditions in hand (Table 1, entry
3), the scope of the reaction with respect to various free-NH
anilines and dimethyl butynedioate was then evaluated. As shown
in Scheme 2, the results revealed that the electronic and steric
a,b
Scheme 2. Variation of Aryl Amines
a b
,
Table 1. Optimization of Reaction Conditions
yield
b
entry
catalyst
additive A additive B
solvent
(%)
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
HOTf
Tf2O
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
PhMe
DMF
DMSO
MeOH
Diox
24
42
65
0
2
3
HOTf
Tf2O
4
5
TFA
Tf2O
Tf2O
Ac2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
Tf2O
6
6
HOAc
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
HOTf
0
7
0
8
0
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
0
10
11
12
13
14
15
16
17
18
19
20
21
0
a
Reaction conditions: aniline 1 (0.5 mmol), dimethyl butynedioate 2a
27
24
14
11
0
(0.6 mmol), CuI (0.025 mmol), HOTf (0.5 mmol), and Tf2O (0.5
b
mmol), in solvent (2 mL), 24 h. Yields of isolated products are given.
THF
CH3CN
DCE
DCE
DCE
DCE
DCE
DCE
effects of the substituents on the aniline substrate had little
influence on the efficiency of the reaction. First, free-NH anilines
bearing the electron-donating (Me, OMe, SMe, Et, t-Bu, Ph,
OPh) substituents at the ortho-position showed good compat-
ibility, and the corresponding products 3b−h were obtained in
66−85% yields. Similarly, para-substituted anilines were also
successful in affording the corresponding quinoline products 3i−
3l in good yields. It was worth emphasizing that, for 3,5-
dimethylaniline, 3,4-dimethylaniline, and 2,5-dimethylaniline,
the sole regioisomer was detected, in which the cyclization
exclusively occurred at the less-hindered ortho-position. Notably,
sterically hindered aniline, including those bearing a o-tolyl (3p),
o-(p-fluorophenyl) (3q), or p-tolyl (3r) group, also demon-
strated excellent reactivity under the optimized conditions.
The scope of alkynes was next examined (Scheme 3). A methyl
butynoate and dimethyl butynedioate substrate could be
CuCl
37
25
42
5
CuBr
CuOTf
Cu(OTf)2
Pd(OAc)2
Cp*Co(CO)I2
0
0
a
Reaction conditions: aniline 1a (0.5 mmol), dimethyl butynedioate
2a (0.6 mmol), CuI (0.025 mmol), HOTf (0.5 mmol), and Tf2O (0.5
mmol), in solvent (2 mL), 24 h. Yields of isolated products are given.
b
isolated yield (entry 1). Moreover, 42% of 3a was achieved when
Tf2O (1.0 equiv) was employed as the additive (entry 2).
Gratefully, with the use of both HOTf (1.0 equiv) and Tf2O (1.0
equiv) as coadditives, the target product 3a led to an improved
yield of 65% (entry 3). Further investigation showed that no
B
DOI: 10.1021/acs.orglett.8b00436
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a,b
transformation proceeded smoothly to give the desired 5f in
good yields.
Scheme 3. Variation of Alkynes
To extend the applicability of our reaction, we next turned our
attention to thiophenol or phenol derivatives as substrates.
Under the standard reaction conditions, the reactions of various
thiophenol or phenol derivatives 1 also proceeded well with
alkyne 2 to afford the desired chromenes (6a−6e) or
thiochromene 6f in decent isolated yield (Scheme 5).
a,b
Scheme 5. Variation of Thiophenols or Phenols
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuI (0.025
mmol), HOTf (0.5 mmol), and Tf2O (0.5 mmol), in solvent (2 mL),
b
24 h. Yields of isolated products are given.
accommodated in the catalytic system, giving their correspond-
ing products 4a−4b in moderate yields. A wide variety of
functionalized aryl alkynoates bearing the substituents at the
ortho-, meta-, or para-position on the aryl ring all gave the
corresponding products in moderate to good yields (58−78%)
(4c−4h). Both electron-donating (Me, OMe, t-Bu) and
-withdrawing (F, Cl) groups that attached at the aryl ring part
of alkynes were also well tolerated. Interestingly, the alkynes can
also be extended to the naphthalene (1i) substrate in the catalytic
system, giving the desired product 4i in moderate yield.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), CuI (0.025
mmol), HOTf (0.5 mmol), and Tf2O (0.5 mmol), in solvent (2 mL),
24 h. Yields of isolated products are given.
b
Considering the remarkably broad substrate scope and the
switchable reactivity displayed by the Cu(I) catalysis, we
performed a series of control experiments to gain more insight
into the reaction mechanism (Scheme 6). First, when the
It is worth noting that differently N-substituted anilines 1
furnished the unexpected dihydroepindolidione products 5a−5h
(Scheme 4) in moderate to good yields when the dimethyl
butynedioate 2a was explored as the coupling partner. Various
substituents, such as Me (5a−5d), Et (5g), and Ar (5e, 5h)
groups were fully tolerated. It should be emphasized that 1,2,3,4-
tetrahydroquinoline was also a visible substrate since this
Scheme 6. Mechanistic Studies
a,b
Scheme 4. Variation of N-Substituted Anilines
enamine substrate 7 was subjected to the optimized conditions,
the quinolone product was obtained in 67% yield, which
suggested that the enamine might be used as a key intermediate
for the Cu(I)-catalyzed synthesis of 4-quinolones.10 Further-
more, to probe the divergent access to dihydroepindolidiones, if
taking advantage of the quinoline form as the corresponding
intermediate, quinoline-3-carboxylic acid methyl ester 8 was
prepared and then coupled with 1,2,3,4-tetrahydroquinoline
under the standard reaction conditions. The results show that no
desired dione product 5f was detected (Scheme 6b). In addition,
the treatment of the diphenylamine with methyl acrylate under
the standard reaction conditions gave the expected 9 in 32% yield
(Scheme 6c). Taken together, the results revealed that the
reaction might undergo an aza-Michael addition before the
reaction of electrophilic addition/cyclization of carbonyl group
to afford the dihydroepindolidione product.11
a
Reaction conditions: 1 (1.0 mmol), 2a (0.6 mmol), CuI (0.025
mmol), HOTf (0.5 mmol), and Tf2O (0.5 mmol), in solvent (2 mL),
24 h. Yields of isolated products are given.
b
C
DOI: 10.1021/acs.orglett.8b00436
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On the basis of these results and the literature precedents, a
plausible catalytic cycle is depicted in Scheme 7. Alkyne 2a is
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21502100) and Guangdong Natural Science Funds for
Distinguished Young Scholar (2017A030306031) for financial
support of this study.
Scheme 7. Mechanistic Studies
REFERENCES
■
(1) (a) Mugnaini, C.; Pasquini, S.; Corelli, F. Curr. Med. Chem. 2009,
16, 1746. (b) Chang, Y. H.; Hsu, M. H.; Wang, S. H.; Huang, L. J.; Qian,
K.; Morris-Natschke, S. L.; Hamel, E.; Kuo, S. C.; Lee, K. H. J. Med.
Chem. 2009, 52, 4883. (c) Chou, L. C.; Tsai, M. T.; Hsu, M. H.; Wang, S.
H.; Way, T. D.; Huang, C. H.; Lin, H. Y.; Qian, K. D.; Dong, Y. Z.; Lee,
K. H.; Huang, L. J.; Kuo, S. C. J. Med. Chem. 2010, 53, 8047. (d) Huse,
H.; Whiteley, M. Chem. Rev. 2011, 111, 152. (e) Chen, C. T.; Hsu, M.
H.; Cheng, Y. Y.; Liu, C. Y.; Chou, L. C.; Huang, L. J.; Wu, T. S.; Yang, X.
M.; Lee, K. H.; Kuo, S. C. Eur. J. Med. Chem. 2011, 46, 6046. (f) Greeff,
J.; Joubert, J.; Malan, S. F.; van Dyk, S. Bioorg. Med. Chem. 2012, 20, 809.
(g) Dhiman, R.; Sharma, S.; Singh, G.; Nepali, K.; Singh Bedi, P. Arch.
Pharm. 2013, 346, 7. (h) Zhi, Y.; Gao, L. X.; Jin, Y.; Tang, C. L.; Li, J. Y.;
Li, J.; Long, Y. Q. Bioorg. Med. Chem. 2014, 22, 3670. (i) Krishnamurthy,
M.; Gooch, B. D.; Beal, P. A. Org. Lett. 2004, 6, 63. (j) Krishnamurthy,
M.; Simon, K.; Orendt, A. M.; Beal, P. A. Angew. Chem., Int. Ed. 2007, 46,
7044.
(2) (a) Niementowski, S. Ber. Dtsch. Chem. Ges. 1894, 27, 1394.
(b) Alexandre, F. R.; Berecibar, A.; Besson, T. Tetrahedron Lett. 2002,
43, 3911.
(3) (a) Reitsema, R. H. Chem. Rev. 1948, 43, 43. (b) Brouet, J. C.; Gu,
S.; Peet, N. P.; Williams, J. D. Synth. Commun. 2009, 39, 1563.
(c) Romek, A.; Opatz, T. Eur. J. Org. Chem. 2010, 2010, 5841.
(4) (a) Camps, R. Ber. Dtsch. Chem. Ges. 1899, 32, 3228. (b) Jones, C.
P.; Anderson, K. W.; Buchwald, S. L. J. J. Org. Chem. 2007, 72, 7968.
(c) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.; Larsen, R. D.; Faul,
M. M. Org. Lett. 2008, 10, 2609.
(5) (a) Zhao, T. K.; Xu, B. Org. Lett. 2010, 12, 212. (b) Okamoto, N.;
Takeda, K.; Ishikura, M.; Yanada, R. J. Org. Chem. 2011, 76, 9139.
(c) Hu, W.; Lin, J.-P.; Song, L.-R.; Long, Y.-Q. Org. Lett. 2015, 17, 1268.
(d) Åkerbladh, L.; Nordeman, P.; Wejdemar, M.; Odell, L. R.; Larhed,
M. J. Org. Chem. 2015, 80, 1464. (e) Hu, W.; Lin, J.-P.; Song, L.-R.; Long,
Y.-Q. Org. Lett. 2015, 17, 1268.
(6) (a) Samanta, R.; Matcha, K.; Antonchick, A. P. Eur. J. Org. Chem.
2013, 2013, 5769. (b) Li, C. J. Acc. Chem. Res. 2009, 42, 335. (c) Yeung,
C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Girard, S. A.;
Knauber, T.; Li, C. J. Angew. Chem., Int. Ed. 2014, 53, 74.
(7) (a) Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem.
2007, 72, 7968. (b) Deng, Y.; Gong, W.; He, J.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2014, 53, 6692. (c) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani,
M.; Larsen, R. D.; Faul, M. M. Org. Lett. 2008, 10, 2609. (d) Torii, S.;
Okumoto, H.; Xu, L. H. Tetrahedron Lett. 1991, 32, 237. (e) Seppanen,
O.; Muuronen, M.; Helaja, J. Eur. J. Org. Chem. 2014, 2014, 4044.
(f) Zhao, T. K.; Xu, B. Org. Lett. 2010, 12, 212. (g) Åkerbladh, L.;
Nordeman, P.; Wejdemar, M.; Odell, L. R.; Larhed, M. J. Org. Chem.
2015, 80, 1464. (h) Fei, X. D.; Zhou, Z.; Li, W.; Zhu, Y. M.; Shen, J. K.
Eur. J. Org. Chem. 2012, 2012, 3001.
initially activated by Cu(I), which acts as a Lewis acid,12 followed
by the hydroamination to give enamine 10 or 11.13 Then, the
Cu(I) is coordinated by the carbamoyl group of the enamine 11
and directly protodemetalation delivers the quinolone 3a and
regenerates the catalyst.9 Alternatively, a Cu-catalyzed aza-
Michael addition of 1a with enamine 10 may be involved in the
reaction when N-substituted secondary anilines as the substrates.
To this end, the Cu(I) is coordinated with the carbamoyl group
of A to deliver the intermediate B, which undergoes directly
protodemetalation to generate the dihydroepindolidione 5a and
regenerate the catalyst.
In conclusion, we have developed a unique, direct, and more
general Cu(I)-catalyzed cyclization for constructing 4-quinolines
or dihydroepindolidiones from simple and readily available
substrates in a one-pot and chemoselective manner by switching
the type and nature of anilines. The (thio)phenols could be used
as visible substrates for the Cu(I)-catalyzed system to replace the
primary aniline substrates. In consideration of these impressive
features, including tunable chemoselectivity, excellent substrate/
functional group tolerance, good yield, and highly valuable
chemical structures of the obtained products, we believe that the
present protocol should have the potential for broad synthetic
utility.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00436.
Experimental procedures, characterization of products,
and copies of 1H and 13C NMR spectra (PDF)
(8) (a) Torii, S.; Okumoto, H.; Long, H. X. Tetrahedron Lett. 1990, 31,
7175. (b) Torii, S.; Okumoto, H.; Xu, L. H. Tetrahedron Lett. 1991, 32,
237. (c) Kalinin, V. N.; Shostakovsky, M. V.; Ponomaryov, A. B.
Tetrahedron Lett. 1992, 33, 373. (d) Haddad, N.; Tan, J.; Farina, V. J.
Org. Chem. 2006, 71, 5031. (e) Wu, J.; Zhou, Y.; Wu, T.; Zhou, Y.;
Chiang, C.-W.; Lei, A. Org. Lett. 2017, 19, 6432.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: yiwei@gzhmu.edu.cn.
*E-mail: zhangxuedu@126.com.
ORCID
(9) Xu, X.; Zhang, X. Org. Lett. 2017, 19, 4984.
(10) (a) Ikemoto, H.; Yoshino, T.; Sakata, K.; Matsunaga, S.; Kanai, M.
J. Am. Chem. Soc. 2014, 136, 5424. (b) Lian, Y.; Bergman, R. G.; Lavis, L.
D.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 7122. (c) Lian, Y.; Huber,
T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed.
2013, 52, 629. (d) Hummel, J. R.; Ellman, J. A. J. Am. Chem. Soc. 2015,
137, 490. (e) Moselage, M.; Li, J.; Ackermann, L. ACS Catal. 2016, 6,
498.
Sheng Zhang: 0000-0002-9686-3921
Xu Zhang: 0000-0002-3588-3240
Wei Yi: 0000-0001-7936-9326
Notes
The authors declare no competing financial interest.
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(11) (a) Roy, S. R.; Chakraborti, A. K. Org. Lett. 2010, 12, 3866.
(b) Kobayashi, S.; Kakumoto, K.; Sugiura, M. Org. Lett. 2002, 4, 1319.
(c) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Org. Lett.
2004, 6, 197. (d) Takizawa, S.; Sako, M.; Abozeid, M. A.; Kishi, K.;
Wathsala, H. D. P.; Hirata, S.; Murai, K.; Fujioka, H.; Sasai, H. Org. Lett.
2017, 19, 5426. (e) Jouha, J.; Buttard, F.; Lorion, M.; Berthonneau, C.;
̀
Khouili, M.; Hiebel, M.-A.; Guillaumet, G.; Briere, J.-F. Org. Lett. 2017,
19, 4770. (f) Saito, K.; Moriya, Y.; Akiyama, T. Org. Lett. 2015, 17, 3202.
(12) (a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 764. (b) Xiao, Y.; Zhang, J. Angew. Chem., Int. Ed.
2008, 47, 1903. (c) Ouyang, K.; Hao, W.; Zhang, W. X.; Xi, Z. Chem. Rev.
2015, 115, 12045.
(13) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew.
Chem., Int. Ed. 2009, 48, 4572.
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