Pd/Cu-Catalyzed Cascade C(sp3)-H Arylation and Intramolecular C-N Coupling: A One-Pot Synthesis of 3,4-2 H-Quinolinone Skeletons

Article abstract of DOI:10.1021/acs.orglett.9b00214

In this letter, we successfully explored a cascade Pd/Cu-catalyzed intermolecular C(sp³)-H arylation of amides and intramolecular C-N coupling reaction. This method provides a one-pot strategy to synthesize 3,4-2H-quinolinone with good regioselectivity of C-H arylation and C-N coupling from C-I and C-X bonds from readily available starting materials.

Full text of DOI:10.1021/acs.orglett.9b00214

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd/Cu-Catalyzed Cascade C(sp3)−H Arylation and Intramolecular
C−N Coupling: A One-Pot Synthesis of 3,4‑2H‑Quinolinone
Skeletons
Han-Zhi Xiao,† Wen-Shu Wang,†,¶ Yu-Song Sun,† Hao Luo,† Bo-Wen Li,† Xiao-Dong Wang,†
Wei-Li Lin,† and Fei-Xian Luo*,†,§,¶
†College of Life and Environment Science, §MUC Center on Translational Neuroscience, and ¶Experimental Center of Chemistry,
Minzu University of China, Beijing 100081, China
S
* Supporting Information
ABSTRACT: In this letter, we successfully explored a cascade Pd/Cu-catalyzed intermolecular C(sp3)−H arylation of amides
and intramolecular C−N coupling reaction. This method provides a one-pot strategy to synthesize 3,4-2H-quinolinone with
good regioselectivity of C−H arylation and C−N coupling from C−I and C−X bonds from readily available starting materials.
3,4-2H-Quinolinone is a bioactive molecular skeleton present-
ing in numerous natural alkaloids, synthetic bioactive com-
pounds, and commercial drugs (Scheme 1a).1 Recently, this
the substrate scope and step-economy should be further
explored.
Transition metal-catalyzed C(sp3)−H functionalization has
gained great progress in the past two decades and are still being
widely applied to the construction of C−C or C−heteroatom
bonds.6−8 Among these reactions, arylation of C(sp3)−H bonds
has been investigated extensively and become one of the most
reliable tools for synthetic chemists.7 However, C−H
functionalization should be given further attention on exploring
the potential application in functional molecular construction,
such as pharmaceuticals and materials. The reactive site N−H
bond of a bidentate directing group, which was frequently
applied in unactivated C(sp3)−H activation, is the potential
nitrogen source to construct heterocycles. We proposed that an
additional halogen introduced to the ortho position of aryl
iodides may lead to a cascade intramolecular Ullman-type C−N
coupling after C−H arylation (Scheme 1b), thus blocking the
active N−H bond to form a heterocycle. In the meantime, the
arising issue of the selective reactivity of C−I and C−X bonds in
C−H arylation to reach good regioselectivity of construction of
3,4-2H quinolinone should be overcome.7g,h Here, we report a
one-pot strategy to provide alternative access to 3,4-2H-
quinolinone by Pd/Cu-catalyzed cascade C−H arylation and
C−N coupling. In this reaction, four chemical bonds were
cleaved and two new chemical bonds were forged simulta-
neously.
Scheme 1. Our Strategy for Facile Synthesis of 3,4-2H-
Quinolinone
motif exhibited good activity as an bromodomain inhibitor
candidate.1b Various synthetic strategies for 3,4-2H-quinolinone
have been developed, including Friedel−Crafts cyclization,2
transition metal-catalyzed cascade reaction,3 and radical
reactions.4 However, these methods suffered from harsh
reaction conditions, limited substrate scopes, multiple reaction
steps, and/or the use of prefunctionalized substrates. In recent
years, several strategies through C−H activation to construct
3,4-2H-quinolinones have been developed.5 For example, Shi
and co-workers reported an intramolecular C(sp3)−H arylation
to synthesize 3,4-2H-quinolinones by an oxidative addition-
initiated strategy that features seven-membered palladacycles as
key intermediates.5b Zhao and co-workers reported a sequential
C(sp3)−H arylation and intramolecular oxidative amination to
synthesize such skeletons.5a These two elegant examples show
the power of C−H activation in constructing such biomotifs, but
With this envision in mind, we initially designed and
synthesized amides 1 with various bidentate directing groups
(Scheme S1). Reactions of amides 1 and 2-bromo iodobenzene
Received: January 17, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00214
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
were conducted with catalytic amount of Pd(OAc)2 and K2CO3
in DCE at 100 °C for 24 h. It was found that reaction of 1a
bearing a pyridin-2-ylmethyl directing group gave the desired
product 3,4-2H-quinolinone 3a in 15% NMR yield, but
reactions with amides (1a-1−1a-4) containing directing groups
(such as 8-amino quinolinyl and picolinyl groups) that are
commonly employed in the functionalization of C(sp3)−H
bonds did not form the corresponding products. It should be
pointed out that the pyridin-2-ylmethyl directing group, first
used by Daugulis group8h and well-developed by Chatani group
in C−H activation with ruthenium or nickel catalyst,9 was
successfully explored in C−H arylation with palladium catalyst.
Although the pyridin-2-ylmethyl directing group has been
reported in the C−H functionalization, no cascade C−H
activation/C−X coupling reaction with this directing group is
known.
the Ullman type C−N coupling (entries 9 and 11). Finally, the
reaction atmosphere is not essential and the reaction also
proceeded well under N2.
Having identified conditions for the cascade C−H arylation/
C−N coupling of 1a, different ortho-halogen substituted
iodobenzenes were tested in this reaction. The 1,2-diiodoben-
zene exhibited better than 2-bromo iodobenzene in this
reaction, while 2-chloro iodobenzene give low reactivity,
which possibly arises from the low reactivity of C−Cl bond.
Subsequently, various other amides 1 with different substituents
were tested (Scheme 2). Reactions with substrates (1a−1d)
a
Scheme 2. Scope of Amides
To identify conditions for the cascade C−H arylation/C−N
coupling reaction, various parameters were examined (Table 1).
a
Table 1. Optimization of Reaction Conditions
b
entry
variations from standard condition
yield (%)
c
1
2
3
4
None
86 (82)
50
30
K2CO3 instead of K3PO4
Na2CO3 instead of K3PO4
tAmylOH only
45
5
6
7
8
o-DCB only
1,4-dioxane as solvent
DCE as solvent
120 °C instead of 140 °C
in the absence of Pd(OAc)2
Ni(OAc)2 instead of Pd(OAc)2
in the absence of CuI
under N2 atmosphere
78
n.r.
28
65
n.r.
n.r.
35(40)
85
d
d
9
d
10
11
12
e
a
Reagents and conditions: 1a (0.1 mmol), 2a (1.5 equiv), Pd(OAc)2
(10 mol %), CuI (5 mol %), K3PO4 (0.2 equiv), o-DCB/tAmylOH
b
(1.0 mL, 9/1, v/v), 140 °C. 1H NMR yield with dibromo methane as
c
d
internal standard. Isolated yield. No reaction occurred, and starting
e
material was fully recovered. Arylation product 1p.
a
Reagents and conditions: 1 (0.1 mmol), 2a (1.5 equiv), Pd(OAc)2
(10 mol %), CuI (5 mol %), K3PO4 (0.2 equiv), o-DCB/tAmylOH
(1.0 mL, 9/1, v/v), 140 °C, if not otherwise noted, X = Br.
After extensive investigation of the reaction, it was found that
product 3a could be obtained in 82% isolated yield when dual
catalysts Pd(OAc)2 and CuI were employed with K3PO4 as the
base in the mixed solvents 1,2-dichlorobenzene (o-DCB)/t-
AmylOH. Replacement of K3PO4 with other bases, such as
K2CO3 and Na2CO3, did not result in higher yields (entries 2−
3). The combination of o-DCB with tAmylOH significantly
improved the reaction efficiency compared to the other solvents
(entries 4−7). Lower yield was observed when the reaction was
conducted at 120 °C instead of 140 °C (entry 8). Notably, the
palladium catalyst was crucial for this transformation. In the
absence of the Pd(OAc)2, no desired product was observed, and
the amide 1a was fully recovered, indicating that the reaction was
initiated by palladium-catalyzed C−H arylation (entry 9).
Nickel catalyst Ni(OAc)2 (entry 10) was not workable in this
reaction, which has been successfully explored as catalyst in
C(sp3)−H activation.10 In addition, copper catalyst is of
particular importance to improve the efficiency by promoting
containing both acyclic and cyclic alkyl groups underwent
smooth reaction to give corresponding products 3a−3d in good
yields. When both secondary benzylic C−H bonds and primary
alkyl C−H bonds exist in a single molecule (1e−1g), the C−H
arylation occurred preferably at primary alkyl C−H bonds to
give 3e−3g in good yields. Lower yields were obtained (3h and
3i), when two of the three methyl groups on the substrates were
substituted by ethyl and benzyl group. The trifluoromethyl and
bromo substituents were well tolerated in this reaction.
Compound 1j with the phenyl ethyl and ethyl substituent
gave 3j as a better result (52% yield) than substrates 1h and 1i
with benzyl substituent. Encouragingly, 3k or 3l was obtained in
a moderate yield, indicating the quaternary carbon center of the
α position to carbonyl group is not necessary. The linear
substrate 1m with PIP directing group can also work well in this
B
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Letter
reaction to give 3m (57%) and 3m-OMe (53%, with 2i),
respectively. To our delight, the other bidentate directing groups
1-(pyridin-2-yl)ethyl (3n) and pyrimidin-2-ylmethyl (3o) can
also work well in this reaction.
Subsequently, we evaluated the scope of arylation partner 2
(Scheme 3). The electron-withdrawing group methoxycarbonyl
N coupling reaction, late-stage C−H functionalization of
estrone derivative 2n was conducted. Under the newly
developed conditions, complex estrone derivative 4n was
obtained in 70% yield (eq 2).
To understand the reaction mechanism, some control
experiments were conducted. The possible intermediates, (1p
and 1q) for this reaction were synthesized. When proposed
intermediate 1p initiated from the C−H arylation was subjected
to the standard reaction, 96% isolated yield of 3a was obtained
(eq 3). While, in the absence of palladium catalyst, 3a could also
a
Scheme 3. Scope of Arylation Partner
a
Reagents and conditions: 1a (0.1 mmol), 2 (1.5 equiv), Pd(OAc)2
(10 mol %), CuI (5 mol %), K3PO4 (0.2 equiv), o-DCB/tAmylOH
(1.0 mL, 9/1, v/v), 140 °C.
(2a), nitro (2b), and cyano (2c) all tolerated this reaction well.
The trifluoromethyl (2d), trifluoromethoxyl (2e), and fluoro
(2f) groups, frequently presenting in commercial drugs and
agrochemicals, proceeded well to give 4d (76%), 4e (68%), and
4f (75%), respectively. Aryl iodides with electron-donating
methyl (2g), Boc-protected amino (2h), and methoxyl (2i)
groups worked well to deliver the desired product in good yield.
Importantly, the Boc-protected amino group, which is an
important intermediate for many drugs, was retained in this
reaction. Encouragingly, the chloro-(2j) or bromo-(2k)
substituent, which can be used for further diverse trans-
formations, survived well in this reaction. Notably, the para-
bromo substituent for 2k remained, indicating the arylation
unambiguously occurred at C−I bond, and good regioselectivity
for this cascade C−H arylation and C−N coupling was obtained.
Encouragingly, heterocycle pyridinyl and thiophenyl groups can
also be tolerated in this reaction, giving (4l) and (4m) in 56%
and 70% yield, respectively.
be obtained in 97% isolated yield under Ullman-coupling
condition (eq 4). Further study found that only 30% isolated
yield of product was obtained in the absence of CuI catalyst (eq
5), matching well with the result observed in entry 11 (Table 1).
This observation confirmed that the copper catalyst is crucial in
this transformation for its significant promotion of the C−N
bond formation. However, the proposed intermediate 1q
initiated from C−N coupling was subjected to standard reaction
condition (eq 6), in the absence of Pd (eq 7) or Cu catalyst (eq
8) from standard conditions, no C−H arylation product 3a was
obtained, and the substrate was fully recovered. Those results
were confirmed that the reaction was initiated from
intermolecular C−H arylation. In addition, 1,2-dibromoben-
zene cannot work in this reaction, and the starting material was
fully recovered (eq 9), indicating the C−H arylation originated
unambiguously from C−I bond and cascade C−N coupling
occurred at C−Br bond. This result can elucidate the good
regioselectivity in this reaction. Finally, TEMPO did not
interrupt the reaction (eqs 10 and 11). These results can rule
out a radical pathway in this reaction.
This reaction can be scaled up, and 78% yield of 3a (on gram
scale) was obtained. In addition, following the reported
method,9e the pyridin-2-ylmethyl group can be smoothly
removed to give 5 in good yield (eq 1), indicating the directing
In conclusion, we explored a Pd/Cu-catalyzed cascade C−H
arylation/C−N coupling reaction to form 3,4-2H-quinolinones
that are common substructures in natural products and
pharmaceuticals. The introduction of a halogen atom to the
ortho position of aryl iodide can realize cascade intermolecular
C(sp3)−H arylation and intramolecular C−N coupling with
four chemical bond cleavages in this one-pot reaction. Good
regioselectivity was obtained by the using ortho-bromo-
substituted aryl iodide. The bidentate directing group pyridin-
2-ylmethyl as nitrogen source can be removed and offer the
opportunity to diversify quinolinone. Further investigation of
the detailed mechanism of this reaction and the scope of amides
with different C−H bonds is ongoing in our laboratory.
group can serve as nitrogen source and offer the opportunity to
diversify quinolinone. To apply this cascade C−H arylation/C−
C
DOI: 10.1021/acs.orglett.9b00214
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Letter
Chen, K.; Rao, W.-H.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem.,
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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.orglett.9b00214.
■
S
Detailed experimental data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: luofeixian@muc.edu.cn.
ORCID
Xiao-Dong Wang: 0000-0002-1045-583X
Fei-Xian Luo: 0000-0002-6279-1165
Notes
́
́
3944. (f) Rodríguez, N.; Romero-Revilla, J. A.; Fernandez-Ibanez, A.;
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Angew. Chem., Int. Ed. 2012, 51, 5188. (h) Zaitsev, V. G.; Shabashov, D.;
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Support of this work by the Project of Ministry of Education of
China “Double Top-Class” (yldxxk2018). Promotion Program
for Young Teacher in Science and Technology Research of
Minzu University of China (317201961). National Science
Foundation of China (91744206).
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