Copper-Catalyzed Selective 1,2-Difunctionalization of N-Heteroaromatics through Cascade C-N/CC/CO Bond Formation

Article abstract of DOI:10.1021/acs.orglett.0c02910

This study presents an efficient strategy for constructing 1,2-difunctionalized quinoline derivatives via the multicomponent cascade coupling of N-heteroaromatics with alkyl halides and different terminal alkynes. This reaction was achieved through sequential functionalization at the one- and two-positions of quinolines, which displayed a broad substrate scope, environmental friendliness, excellent functional group tolerance, high atom efficiency, and chemoselectivity. The multicomponent coupling involved the abnormal construction of new C-N, CC, and CO bonds in one pot. The applicability of this method was further demonstrated by the late-stage functionalization of complex drug molecules under the established conditions.

Full text of DOI:10.1021/acs.orglett.0c02910

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Selective 1,2-Difunctionalization of
N‑Heteroaromatics through Cascade C−N/CC/CO Bond
Formation
Qianlin He,† Feng Xie,† Chuanjiang Xia, Wanyi Liang, Ziyin Guo, Zhongzhi Zhu,* Yibiao Li,
and Xiuwen Chen*
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ABSTRACT: This study presents an efficient strategy for
constructing 1,2-difunctionalized quinoline derivatives via the
multicomponent cascade coupling of N-heteroaromatics with
alkyl halides and different terminal alkynes. This reaction was
achieved through sequential functionalization at the one- and two-
positions of quinolines, which displayed a broad substrate scope,
environmental friendliness, excellent functional group tolerance, high atom efficiency, and chemoselectivity. The multicomponent
coupling involved the abnormal construction of new C−N, CC, and CO bonds in one pot. The applicability of this method was
further demonstrated by the late-stage functionalization of complex drug molecules under the established conditions.
Scheme 1. Reaction of Quinolines with Alkynes
uinoline and its derivatives are widely used in the fields
Q of pharmaceutical and organic syntheses owing to their
unique properties.1 Therefore, the development of new and
efficient synthetic strategies for functionalized quinoline
frameworks is important in both synthetic organic chemistry
and medicinal chemistry.2 In recent years, reactions of alkynes
with quinolines or quinoline N-oxides to construct quinoline
derivatives have been well developed.3 One of the most well
studied reaction routes is the CO and C−C bond formation
between quinoline N-oxide and internal alkynes. For instance,
Li and Sundararaju have developed a redox-neutral coupling of
quinoline N-oxide with alkynes to synthesize quinolines with a
carbonyl group.4 Maulide and coworkers reported the
oxyarylation of alkynes with pyridine and quinonline N-
oxides.5 Furthermore, Zhang reported metal-free reactions of
alkynes with isoquinoline and quinoline N-oxides (Scheme
1a).6
heteroaromatics through cascade C−N/CC/CO bond
formation.
On the contrary, the functionalization of quinolinium salts
has been shown to be a useful method for the synthesis of the
substituted quinoline skeleton.2b,7 In general, the addition of
electrophiles to (iso)quinoline generates (iso)quinolinium salts
that can be captured by nucleophiles (e.g., terminal alkyne),
which provides a facile pathway to access quinoline with
different functionalities (Scheme 1b).8 On the basis of the
previously described advancements and our recent work on the
construction of functionalized N-heterocycles,9 we envisaged a
direct transformation of alkynes into functionalized quinolones
via in situ quinolinium salt formation. This multicomponent
coupling of alkyl halides with different N-heteroaromatics and
terminal alkynes involved the creation of multiple bonds in one
pot, providing various substituted quinolines (Scheme 1c).
This reaction realized the 1,2-difunctionalization of N-
This investigation was initiated by screening reaction
conditions for the copper-catalyzed three-component coupling
of quinoline, benzyl bromide, and phenyl acetylene (Table 1).
First, many additives were tested by performing the reaction in
CH3CN−H2O (1:1 v/v) under open-air conditions for 8 h at
60 °C. Subsequently, different additives including CH3CO2K,
CH3CO2Na, CH3CO2NH4, and t-BuONa were tested, and the
Received: August 30, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02910
© XXXX American Chemical Society
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A

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a
a
Table 1. Screening Conditions
Scheme 2. Substrate Scope of Terminal Alkynes
b
entry
[Cu]
additives
solvent
yield (%)
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuCl2
CuBr
CuI
CH3CO2K
CH3CO2Na
CH3CO2NH4
t-BuONa
CH3CO2Na
CH3CO2Na
CH3CO2Na
CH3CO2Na
toluene−H2O
toluene−H2O
toluene−H2O
toluene−H2O
toluene−H2O
toluene−H2O
toluene−H2O
toluene−H2O
toluene−H2O
MeCN−H2O
DMF−H2O
40
44
21
12
26
22
49
trace
trace
85
82
62
9
CuI
CuI
CuI
CuI
CuI
10
11
12
13
CH3CO2Na
CH3CO2Na
CH3CO2Na
CH3CO2Na
DMSO−H2O
MeCN−H2O
c
80, 82
a
Conditions: Quinoline 1a (0.3 mmol), [Cu] (10 mol %), benzyl
bromide (1.0 equiv), phenylacetylene (1.2 equiv), additive (1.0
equiv), temperature (60 °C), 1.0 mL of mixed solvent (v/v 6/1), 8 h,
b
c
unless otherwise noted. Isolated yield. 1a/2a/3a (1:1.2:1 or
a
Conditions: Quinoline 1a (0.3 mmol), CuI (10 mol %), benzyl
1:1:1.5).
bromide 2a (1.0 equiv), terminal alkynes 3 (1.2 equiv), NaOAc (1.0
equiv), and mixed solvent (1.0 mL; MeCN/H2O 6:1 v/v) at 60 °C
for 8 h under an air atmosphere.
results showed that CH3CO2Na was the most effective
additive, affording product 4a in 44% yield (Table 1, entries
1−4). Among the various [Cu] catalysts tested, CuI gave the
best results (entries 5−7). Control experiments established the
importance of CuI and CH3CO2Na in achieving the efficient
1,2-difunctionalization of quinoline (entries 8 and 9). The
solvent system used also significantly affected the related
reaction efficiency. An investigation of solvent systems (entries
10−12) indicated that MeCN−H2O (6:1 v/v entry 10) gave
the best result.
After the reaction conditions were established, the cascade
multicomponent coupling reaction was successfully extended
to different terminal alkynes. As shown in Scheme 2, various
terminal alkyne classes (including aryl-, alkyl-, and heteroaryl-
substituted) were examined. Aromatic alkynes with electron-
deficient (p-F, p-Cl, p-Br, p-CO2Me, p-Ph, and p-NO2) and
electron-rich (p-Me, p-OMe, p-tBu, and 3,5-dimethoxy) groups
all reacted well, giving 1,2-difunctionalized products in good
yields (4a−4l). 2-Ethynylnaphthalene and methyl propiolate
also showed good compatibility with this reaction, affording
4m and 4o in 82 and 70% yields, respectively. Using aliphatic
alkyne ethynylcyclopropane (3n), the desired product was
obtained in moderate yield. Regarding heteroarylacetylenes, 2-
thienyl and 3-pyridine acetylenes afforded 4p and 4q in
moderate yields of 78 and 66%, respectively. However, no
reaction occurred when nonterminal alkyne 1,2-diphenyle-
thyne was used as a substrate under the same reaction
conditions.
matics, including 1,5-naphthyridine, 1,8-naphthyridine, and
pyrido[2,3-b]pyrazine, isolated in moderate to high yields (5l−
5p). The structures of 5a and 5l were unambiguously assigned
by X-ray crystallography. (See the Supporting Information.)
Remarkably, this method was also useful for the addition of
hydroxy-substituted quinolines, such as 5-hydroxyquinoline, 6-
hydroxyquinoline, and 7-hydroxyquinoline, giving the multi-
functionalized products 5q−5u in moderate yield (65−75%).
When pyridine and isoquinoline were subjected to the
established conditions, no reactions were observed. As shown
in Schemes 2 and 3, the method developed had a broad
substrate scope, excellent functional group tolerance, and high
atom efficiency.
To demonstrate its potential application, this synthetic
method was applied to the late-stage functionalization of drug
molecules. Specifically, ethisterone and norethindrone were
selectively installed at the C2 position of quinoline (6a, 6b).
Furthermore, site-selective 1,2-difunctionalization proceeded
well when substrates derived from quinoline-based drugs, such
as N-benzylcinchonidinium chloride, were employed (6c).
Owing to its generality, this method will likely be useful for
fragment couplings, leading to a broad range of complex
structures and drug molecules. We were also interested in the
subsequent conversion of the target product using a simple
method for the selective reduction of the olefinic bonds in the
α,β-unsaturated carbonyl moiety.10 Reactions were performed
using a 1:4:2 ratio of product 4a (0.2 mmol)/NaBH4/HOAc
with 2.5 mol % Pd/C in toluene (2 mL) in open air at room
temperature for 2 h, achieving effective reduction of the
alkenone and producing the synthetically useful hydrogenated
product 4a′ in 78% yield (Scheme 4).
Subsequently, the substrate scopes of N-heteroaromatics and
alkyl halides were examined (Scheme 3). Various electron-
donating, electron-withdrawing, and halogen groups at differ-
ent positions on the quinoline ring were well tolerated in the
coupling with phenylacetylene, with 1,2-difunctionalized
products isolated in 58−87% yields. In general, both benzyl
bromide and alkyl iodide were suitable for this protocol.
Interestingly, the N-heteroaromatics were not limited to
quinoline systems, with other pyridine-based N-heteroaro-
To investigate the reaction mechanism, a series of control
experiments were conducted (Scheme 5). First, presynthesized
quinolinium salt 4A-1 was reacted with phenylacetylene 3a
B
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Scheme 3. Substrate Scope of N-Heteroaromatics and Alkyl
Halides
Scheme 4. Potential Application of This Method
a
Scheme 5. Control Experiments
a
Conditions: N-Heteroaromatics 1 (0.3 mmol), CuI (10 mol %),
alkyl halides 2 (1.0 equiv), phenylacetylene 3a (1.2 equiv), NaOAc
(1.0 equiv), and mixed solvent (1.0 mL, MeCN/H2O 6:1 v/v) at 60
b
°C for 8 h under an air atmosphere. 2.0 equiv of alkyl halides 2 was
used.
formation, as shown in Scheme 6. Initially, quinoline and
benzyl bromide quickly form quinoline salt 4A-1. Copper
under the established reaction conditions, producing the
desired product 4a in 88% yield (eq 1). This result clearly
showed that 4A-1 was a reaction intermediate. The low
reaction yield under an argon atmosphere showed that an
oxygen atmosphere played an important role in this reaction
(eq 2). To prove that water provides a source of oxygen in the
reaction, H2O-labeling experiments were conducted.11 When
conducting the reaction in the presence of 18O-labeled water
instead of H216O, the ratio of 18O-labeled product 4a-O
increased accordingly, as determined by LC−MS analysis (eq
3). This suggested that oxygen atoms in the unsaturated
ketones mainly originated from H2O. Furthermore, a D2O-
labeling experiment resulted in product 4a-D with deuterium
incorporated into the conjugated diene unit, showing that D
atoms were transferred from D2O to the alkynyl group (eq 4).
Meanwhile, the deuterium ratio in the conjugated diene of 4a
implied that double-bond tautomerization was involved in the
reaction.
Scheme 6. Plausible Reaction Pathways
activates phenylacetylene to form copper(I) phenylacetylide
3a′.12 Next, the addition of the copper(I) phenylacetylide to
quinolinium salt 4A-1 forms intermediate 4A-2. In the
presence of oxygen, copper catalyzes the formation of imine-
type intermediate 4A-3 through oxidation adjacent to the
nitrogen atom.13 Intermediate 4A-3 undergoes further
From these results and LC−MS reaction monitoring, a
tentative mechanism was proposed for this cascade trans-
C
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conjugate addition with water to produce intermediate 4A-4,
which isomerizes into the more stable intermediate 4a.14
In summary, we have described an unprecedented N-
alkylation/alkenylation tandem process for the construction of
1,2-difunctionalized quinoline derivatives. This protocol
exhibits a high atom economy, a broad substrate scope,
functional group tolerance, and environmental friendliness.
The applicability of this method was further demonstrated by
the late-stage functionalization of complex drug molecules
under the established conditions.
ACKNOWLEDGMENTS
■
We thank the “Climbing Program” (pdjh2020a0596) Special
Funds, the Foundation for Young Talents (nos.
2018KQNCX272 and 2018KQNCX273), the Guangdong
Basic and Applied Basic Research Foundation
(2019A1515110866, 2019A1515110522), the Science Foun-
dation for Young Teachers of Wuyi University (2019td06),
and the Foundation of the Department of Education of
G u a n g d o n g P r o v i n c e ( n o . 2 0 1 8 K Z D X M 0 7 0 ,
2017KZDXM085 and 2019KZDXM052) for financial support.
ASSOCIATED CONTENT
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REFERENCES
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02910.
Detailed experimental procedures, characterization data,
crystallographic data for 5a and 5l, and copies of NMR
spectra for all isolated compounds (PDF)
Accession Codes
CCDC 2024307 and 2024309 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 Authors
Xiuwen Chen − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China; orcid.org/0000-
0003-3301-6730; Email: chenxiuwen2010@126.com
Zhongzhi Zhu − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China; orcid.org/0000-
0003-1690-9238; Email: zhongzhi_zhu@126.com
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Authors
Qianlin He − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China
Feng Xie − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China; orcid.org/0000-0003-
4260-0146
Chuanjiang Xia − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China
Wanyi Liang − School of Biotechnology and Health Sciences,
Wuyi University, Jiangmen 529020, China
Ziyin Guo − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China
Yibiao Li − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China; orcid.org/0000-
0001-8249-5630
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Chem., Int. Ed. 2017, 56, 14232−14236. (b) Chen, X.; Yang, Z.; Chen,
X.; Liang, W.; Zhu, Z.; Xie, F.; Li, Y. J. J. Org. Chem. 2020, 85, 508−
514. (c) Zhu, Z.; Lin, H.; Liang, B.; Huang, J.; Liang, W.; Chen, L.;
Huang, Y.; Chen, X.; Li, Y. Chem. Commun. 2020, 56, 5621−5624.
(d) Liang, W.; Xie, F.; Yang, Z.; Zeng, Z.; Xia, C.; Li, Y.; Zhu, Z.;
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02910
Author Contributions
†Q.H. and F.X. contributed equally to this work.
Notes
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2015, 17, 2768−2771. (b) Zhao, Y.; Huang, B.; Yang, C.; Chen, Q.;
The authors declare no competing financial interest.
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