Palladium-catalyzed picolinamide-directed coupling of C(sp2)-H and C(sp2)-H: A straightforward approach to quinolinone and pyridone scaffolds

Article abstract of DOI:10.1039/c5cc00298b

An unprecedented palladium-catalyzed picolinamide-directed coupling of C(sp²)-H and C(sp²)-H has been developed with exclusive formation of the six-membered ring heterocyclics-quinolinone and pyridone. The method employs cyclic hypervalent iodine as oxidant and features good functional-group tolerance. Another advantage of this reaction is that sequential C-H/C-H and C-H/N-H coupling could be achieved. This journal is

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Palladium-Catalyzed Picolinamide-Directed Coupling
of C(sp2)-H and C(sp2)-H: a Straightforward Approach
to Quinolinone and Pyridone Scaffolds
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Dengyou Zhang†, Feng Gao†, Yong Nian, Yu Zhou, Hualiang Jiang, and Hong Liu*
DOI: 10.1039/x0xx00000x
www.rsc.org/
ꢀternatively intriguing difunctionalization of Nꢀaryl acrylamide is by
virtue of the radical approach catalyzed by various transition metal
catalysts or induced by light (Scheme 1b).4 Compared to the
construction of the fiveꢀmembered oxindole ring, the synthetic route
to sixꢀmembered quinolinone ring from Nꢀarylacrylamides is much
less reported. Zhao et.al demonstrated that phenyliodine
bis(trifluoroacetate) (PIFA) could mediate formation of arylquinolinꢀ
2ꢀone compounds (Scheme 1c) from Nꢀaryl acrylamides.5 Hu and
coꢀworkers also showed one example of synthesis of the 1ꢀ
methylquilolinꢀ2(1H)ꢀone from Nꢀarylacrylamide derivative.6
Although in term of limited substrate scopes, the two methods
provide an endoꢀcyclization pathway to sixꢀmembered quinolinone.
Given the importance of quinolinone with broad biological
activities,7 there still needs to develop efficient synthetic methods.
Recently, bidentate directing groups have been widely used in a
number of transformations of CꢀH bonds.8 Among these,
picolinamideꢀdirected functionalizations of C(sp2)ꢀH and C(sp3)ꢀH
bonds have received much attention.9 Herein, we present an
unprecedented palladiumꢀcatalyzed picolinamideꢀdirected or C(sp2)ꢀ
H/C(sp2)ꢀH coupling (Scheme 1d), with the exclusive formation of
the sixꢀmembered ring via an endoꢀcyclization pathway, providing a
convenient approach to the privileged quinolinone and pyridone
scaffolds. Furthermore, we demonstrated that the second CꢀH/NꢀH
coupling could be achieved by the judicious choice of reaction
conditions, which allowed for construction of fused heterocycle by
terminal difunctionalization of the alkene.
An unprecedented palladium-catalyzed picolinamide-directed
coupling of C(sp2)-H and C(sp2)-H was developed with
exclusive formation of the six-membered ring heterocyclics-
quinolinone and pyridone. The method employs cyclic
hypervalent iodine as oxidant and features good functional-
group tolerance. A further advantage of this reaction is that
sequential of C-H/C-H and C-H/N-H coupling could be
achieved.
Nꢀarylacrylamide derivatives have been widely employed as a useful
substrate for the construction of heterocyclic scaffolds. Zhu,1 Liu2
and Li3 presented their impressive studies on palladiumꢀcatalyzed
oxidative difunctionalization of the Nꢀarylacrylamides which involve
the initial aryl CꢀH activation to form a palladium (II or IV)
intermediate B via a 5ꢀendo cyclyzation process (Scheme 1a). An alꢀ
A preliminary study was performed with Nꢀaryl acrylamide 1a as
a benchmark substrate (Table 1). Exposure of 1a to various oxidants
(2 equiv) including hypervalent iodines (III), persulfate salts and
o
oxigen (see supporting information) in toluene at 80 C for 24 h in
the presence of Pd(OAc)2 (10 mol%) found that the cyclic
hypervalent iodine OA (III) gave the best result. The sixꢀmembered
ring product was obtained in 34% yield (entry 1). Interestingly,
lowering the Pd(OAc)2 loading from 10 to 2.5 mol% increased the
yield to 49% (entry 2). Investigation of solvents showed that xylene
was the optimal solvent (entry 4). Finally, a study of Pd sources
revealed that various counter anions of palladium (II) could be
tolerated and PdBr2 proved to be the most efficient catalyst (entry 8).
Scheme 1. CꢀH functionalization of Nꢀaryl acrylamide derivatives.
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Table 1. Optimization of palladium catalyzed C(sp2)ꢀH/C(sp2)ꢀH coupling
of Nꢀarylacrylamide.a
ꢀns such as F, Cl and Br, ester and cyano groups were tolerated well
(2gꢀk) with reaction conditions. Variation of the Nꢀsubstituents
found substrates with ethyl group (2l) and tetrahydroquinolinyl core
(2m) could smoothly furnish the products. Reduction of the carbon
chain by one carbon atom resulted in a slightly lower yield (2n).
Next, we turned attention to Nꢀalkenyl acrylamide substrates
(Table 3), aiming to provide a new entry to the pyridone scaffold.
Gratifyingly, slight modification of standard conditions could
achieve the cyclization of 3a, giving the pyridone 4a in 45% yield.
Various substituents on the benzene were then investigated. Me (4b),
Cl (4c), Br (4d) and CF3 (4e) groups were tolerated well. Substrates
bearing naphthalene (4f) could also be transformed to the
corresponding product.
Oxidant
[equiv]
t
T
Yield
(%)b
Entry
Pd [mol%]
Solvent
[h]
[oC]
Pd(OAc)2
(10)
Pd(OAc)2
(2.5)
Pd(OAc)2
(2.5)
1
2
3
OA (2)
OA (2.5)
OA (2.5)
Toluene
Toluene
PhCF3
24
36
48
80
34
49
48
110
110
Table 3. Palladium catalyzed C(sp2)ꢀH/C(sp2)ꢀH coupling of Nꢀ
alkenylacrylamides.a
Pd(OAc)2
(2.5)
4
5
6
OA (2.5)
OA (2.5)
OA (2.5)
Xylene
Xylene
Xylene
48
48
48
110
110
110
61
PA
NH
PA
NH
O
PdCl2 (2.5)
PdCl2(MeC
N)2 (2.5)
Pd(acac)2
(2.5)
49%
43%
PA =
OA =
PdBr2
OA
N
OAc
Xylene
80 oC, 24 h
N
R2
O
I
N
R2
O
R1
R1
O
7
8
OA (2.5)
OA (2.5)
Xylene
Xylene
48
48
110
110
63%
3a-e
O
4a-e
65%(60
PdBr2 (2.5)
c
)
a
General reaction conditions: 1a (0.2 mmol), Pd (mol%), oxidant (equiv),
b
1
solvent (2.0 mL). Determined by H NMR analysis using CH2Br2 as an
internal standard. c Yields of isolated products are given in parentheses.
With the optimal reaction conditions in hand, we set up to explore
the scope of substrates (Table 2). Substrates bearing methyl and
benzenyl groups on the benzene ring gave moderate to good yields
(2bꢀc). Interestingly, a spiro product was obtained in 68% yield for
substrate with incorporation of OMe (2d). Substrate incorporating a
3, 5ꢀdimethyl group (2e) also worked well, indicating that the
reaction system was insensitive to steric hindrance. Of note, halogeꢀ
a General reaction conditions: 3a-e (0.2 mmol), PdBr2 (5 mol%), oxidant (2.0
equiv), xylene (2.0 mL) at 80 oC, 24 h.
Subsequently, to further broaden application of the reaction
system, we were eager to achieve the second CꢀH/NꢀH coupling
directed by the picolinamide, which would allowed for construction
of fused heterocycle by terminal difunctionalization of the alkene.
The pyridone 4a was chosen to test our hypothesis. However, the
established conditions by Chen,9b Daugulis9c and Shi,10 can not be
applied to 4a at all. After extensive attempts, we found that
treatment of 4a with Pd(OAc)2 and OA in ArmylOH/HAc (v/v, 4/1)
at 110 oC for 4 h yielded the desired product 5 in 53% yield (Scheme
2). Control of the reaction time is the key to achieve this
transformation owing to reversibility of the CꢀH/NꢀH coupling. It
was also demonstrated that the picolinamide directing group could
be readily removed by hydrolysis to give the bicyclic compound 6.
Table 2. Palladium catalyzed C(sp2)ꢀH/C(sp2)ꢀH coupling of Nꢀ
arylacrylamides.a
Scheme 2. CꢀH/NꢀH coupling and auxiliary removal.
To understand the preliminary mechanism, some control
experiments were carried out as shown in Scheme 3. Replacement of
picolinamide with benzamide (7), block the NH of picolinamide with
methyl group (8) or removal of picolinamide (9) completely shut
down the reaction, which indicates that the picolinamide directing
group is essential for the transformation. Aromatic CꢀH cleavage is
not a rateꢀdetermining step by kinetic effect (KH/KD) study in either
a General reaction conditions: 1b-n (0.2 mmol), PdBr2 (5 mol%), oxidant (2.5
b
equiv), xylene (2.0 mL) at 110 oC, 48 h. The ratio of 2f and 2f′ was
intramolecular or intermolecular experiments.11
A
radical
determined by 1HꢀNMR.
mechanism can be ruled out because addition of the radical
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5CC00298B
scavenger (TEMPO) has no significant impact on the yield. (2012AA020302), National Basic Research Program of China
Treatment of 1a with 1.0 equiv. PdBr2 in CH3CN gave a palladium (2012CB518005).
complex12, which was smoothly converted to the desired product in
61% yield upon treatment of the cyclic hypervalent iodine (III).
Notes and references
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai
201203, P. R. China
Eꢀmail: hliu@mail.shcnc.ac.cn
† These authors contributed equally.
Electronic Supplementary Information (ESI) available: Experimental
details and additional spectra. See DOI: 10.1039/c000000x/
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Scheme 3. Control experiments.
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J
Based on these observations above, a possible mechanism is
depicted in Scheme 4. First, reaction of 1a with PdBr2 affords a
palladium (II) complex 11. Upon treatment of 11 with the cyclic
hypervalent iodine (III), the palladium (II) is oxidized to the
palladium (IV) 12 which dramatically enhanced the Lewis acidity of
palladium, thus leading to activation of the acrylamide, with
subsequent nucleophilic attack of the arene and elimination of a
ligand and proton. Then the enolate intermediate 14 is further
trapped by the cyclic hypervalent iodine (III) to give the intermediate
15. Elimination of 2ꢀiodobenzoic acid affords the intermediate 16,
which undergoes ligand exchange with substrate 1a to give the
product 2a.
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OAc
I
O
O
O
H
I
O
I
N
O
N
O
N
AcO
O
O
O
N
O
N
O
O
Br
11
O
N
O
N
N
N
L
Br
13
12
and C. Zhu, Chem, -Eur. J., 2013, 19, 14039.
2a
1a
5
6
7
L. Liu, H. Lu, H. Wang, C. Yang, X. Zhang, D. ZhangꢀNegrerie, Y.
Du and K. Zhao, Org. Lett., 2013, 15, 2906.
H
O
O
I
OAc
I
O
I
O
B. Ma, F. L. Chen, X. Y. Xu, Y. N. Zhang and L. H. Hu, Adv. Synth.
Catal., 2014, 356, 416.
N
O
O
O
OAc
+
O
N
Pd
L
N
I
I
N
O
O
H
Pd
L
N
O
O
N
O
O
N
Selected papers of quinolinone based biological active
compounds: (a) R. M. McKinnell, S. R. Armstrong, D. T. Beattie,
S. K. Choi, P. R. Fatheree, R. A. L. Gendron, A. Goldblum, P. P.
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O
N
O
O
N
O
14
16
15
Scheme 4. Proposed mechanism of cyclyzation.
Conclusions
In conclusion, we have developed a novel picolinamideꢀdirected
aryl or alkenyl C(sp2)ꢀH/alkenyl C(sp2)ꢀH coupling of Nꢀaryl or
alkenyl acrylamide derivatives. This new reaction system provides a
straightforward approach to the sixꢀmembered quinolinone and
pyridone scaffolds. Furthermore, the second CꢀH/NꢀH coupling
could be achieved, allowing for construction of fused heterocycle by
terminal difunctionalization of the alkene. Future directions of the
work will involve elucidating the detailed reaction mechanism and
expanding the application.
We gratefully acknowledge financial support from the National
Natural Science Foundation of China Grants (91229204
and 81220108025), Major Project of Chinese National Programs for
Fundamental Research and Development (2015CB910304), National
High Technology Research and Development Program of China
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4
11 For detailed analysis, please see supporting information.
12 The characteristic data for palladium complex please see supporting
information.
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