Palladium-Catalyzed Selective C-H Activation: A Simple Method to Synthesize C-3 Site Arylated Quinoline Derivatives

Article abstract of DOI:10.1002/adsc.201500763

A novel protocol for the synthesis of 3-arylated quinoline derivatives has been developed using silver carbonate (Ag₂CO₃) and dioxygen (O₂) as the oxidants. In this method, quinolines acting as the parent reagent react wit

Full text of DOI:10.1002/adsc.201500763

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DOI: 10.1002/adsc.201500763
À
Palladium-Catalyzed Selective C H Activation: A Simple
Method to Synthesize C-3 Site Arylated Quinoline Derivatives
Yongqin He,a Zhaoyang Wu,a Chaowei Ma,a Xiaoqiang Zhou,a Xingxing Liu,a
Xiajun Wang,a and Guosheng Huanga,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
Fax: (+86)-93-1891-2596; phone: (+86)-93-1891-2586; e-mail: hgs@lzu.edu.cn
Received: August 14, 2015; Revised: October 25, 2015; Published online: January 12, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500763.
Abstract: A novel protocol for the synthesis of 3-
arylated quinoline derivatives has been developed
using silver carbonate (Ag2CO3) and dioxygen (O2)
as the oxidants. In this method, quinolines acting as
the parent reagent react with arenes under palladi-
um acetate [Pd(OAc)2] catalysis along with 1-ada-
mantanecarboxylic acid (Adm). The combination of
the 1-adamantanecarboxylic acid ligand and the
palladium catalyst is found to be an essential factor
for achieving high activity and selectivity, and
allows a wide range of 3-arylquinoline derivatives
to be obtained in high yields. Moreover, a relevant
mechanism is proposed, revealing that un der the
palladium(II) catalysis a migratory insertion to C-
Figure 1. Biologically active quinoline derivatives.
À
À
3 H of quinolines and insertion to the C H of
arenes are key steps in this reaction. Mild reaction
conditions and high selectivity of the reactive site
provide potential for promising applications in drug
discovery and functional materials.
À
Keywords: C H activation; one-pot reaction; palla-
dium catalysts; quinolones; selective functionaliza-
tion
Quinoline, as an important skeleton motif involved in
many biologically active compounds[1] and functional
materials,[2] was often employed for the formation of
useful heterocycles, such as quinine, primaquine and
zinquin (Figure 1).[3] As a consequence, the selective
functionalization of quinolines at different active sites
has received considerable attention over the past de-
cades.[4] In the cases reported, transition metal-cata-
Scheme 1. Selective arylation of quinolones.
À
À
lyzed C H activation leading to C C bond forma-
tion,[5,6] as one of promising approaches, makes the in- and quinolines at the C-2 position [Scheme 1, Eq.
active sites of quinolines more simple and easy to be (1)].[7] Changꢀs group developed a Rh(NHC)-cata-
tailored. In 2008, Ellmanꢀs group developed a Rh(I)- lyzed arylation of quinolines. Under these Rh(NHC)
catalyzed strategy for the direct arylation of pyridines catalytic condition, a wide range of 8-arylquinoline
Adv. Synth. Catal. 2016, 358, 375 – 379
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Table 1. Optimization of the reaction conditions.[a]
derivatives was obtained in high yields for the first
time [Scheme 1, Eq. (2)].[8] Yuꢀs group achieved the
C-3 selective arylation of quinolines by using the com-
bination of 1,10-phenanthroline (Phen) and a palladi-
um complex as catalyst. The Phen ligand was found
to be necessary to access 3-arylquinolines in high se-
lectivity and yield. This was the first report on non-di-
rected C-3 selective arylation of unprotected quino-
lines and pyridines [Scheme 1, Eq. (3)].[9] However, it
is still a tremendous challenge to regioselectively con-
trol the active site of quinolines in the construction of
En- Oxidant
try (equiv.)
Additive
(equiv.)
Time Solvent Yield[b]
[h]
[%]
À
C C bonds.
Herein, inspired by our previous work on the devel-
opment of C-2 selective arylation of quinolines,[10] we
examined the feasibility of a direct arylation at the C-
3 site of quinolines catalyzed by Pd(II) and used qui-
nolines and chlorobenzenes as substrates. In the for-
mation of chlorphenylquinoline derivatives, Ag2CO3
and O2 were used as the oxidants, the Adm ligand
1
2
3
3
4
5
6
7
Ag2CO3 (3.0)
PivOH (2.0) 72
PivOH (3.0) 72
PivOH (4.0) 72
PivOH (5.0) 72
AcOH (4.0) 72
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMSO 15
toluene 42
DMA 50
DMF
DMF
DMF
DMF
DMF
40
47
60
53
20
trace
66
47
0
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
AgOAc (3.0)
Cu(OAc)2 (3.0) Adm (4.0)
MnO2 (3.0)
DDQ (3.0)
K2S2O8 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
Ag2CO3 (3.0)
TFA (4.0)
Adm (4.0)
Adm (4.0)
72
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
À
plays a key role in the selective C H activation. This
8
9
method would represent a significant advance in the
highly selective functionalization of quinolones and,
subsequently, it would open up new opportunities in
chemical synthesis.
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
Adm (4.0)
37
42
0
10
11
12
13
14
15
35
At the outset of our investigations, a combined cat-
alytic system of Pd(OAc)2 (10 mol%), Ag2CO3
(3.0 equiv.) as oxidant and PivOH (2.0 equiv.) as addi-
tive was employed. When the reaction was accom-
plished in DMF (1.5 mL) at 1408C for 72 h, only
a 40% isolated yield was obtained. When the amount
of PivOH was increased up to 4.0 equiv., the yield of
product 3ab increased to 60%. Subsequently, a variety
of additives was screened (Table 1, entries 4–6), the
result revealed that Adm offered the better yield and
decreased appreciably the reaction time. Exploration
of oxidants disclosed that only Ag2CO3 was more
active as compared to AgOAc, Cu(OAc)2, MnO2,
DDQ and K2S2O8, which was in agreement with our
previous reports. Screening of solvents showed that
DMF was the best choice. Although all of these reac-
tion pathways did not require external oxidants, the
addition of O2 (1 atm) could increase the yield from
60% to 70% (Table 1, entry 16). Additionally, the use
16[c] Ag2CO3 (3.0)
17[d] Ag2CO3 (3.0)
18[e] Ag2CO3 (3.0)
19[f] Ag2CO3 (3.0)
20[g] Ag2CO3 (3.0)
70
33
27
57
50
[a]
Reaction conditions: quinolines (0.2 mmol), Pd(OAc)2
(10 mol%), 1,3,5-trichlorobenzene (2.0 mmol), oxidant,
and additive in DMF (1.5 mL) at 1408C for 48 or 72 h.
Yields of isolated products.
O2 (1 atm) was used.
PPh3 was used as ligand.
1,10-Phen was used as ligand.
DPPB was used as ligand.
DPPE was used as ligand.
[b]
[c]
[d]
[e]
[f]
[g]
of PPh3, 1,10-phenanthroline (phen), DPPB, DPPE as tions.[11] Notably, when quinolines possessing a methyl
ligands provided the product in lower yields. group at the pyridyl ring C-2 and C-4 sites were ex-
With the optimized reaction conditions in hand, the amined (3jb, 3kb), only trace amounts of products
substrate scope was investigated as shown in Table 2. were detected on the silica gel TLC. It was deduced
The quinoline (1a) reacts with the 1,3,5-trichloroben- that this result was due to both electronic effects and
zene (2b) to afford 3ab in 70% isolated yield. Next, steric effects. Additionally, compared with quinolines,
a variety of substrates bearing a single substituent on 5,6,7,8-tetrahydroquinoline and 6,7-dihydro-5H-cyclo-
the aryl ring was surveyed, both electron-donating penta[b]pyridine as substrates also exhibited some re-
and electron-withdrawing groups, such as methoxy, activity to give the desired products 3-(2,4,6-trichloro-
nitro, halogen, methyl and ester, were compatible phenyl)-5,6,7,8-tetrahydroquinoline and 3-(2,4,6-tri-
with this transformation. The predicted products were chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine,
formed in moderate to good yields (3bb–3ib). It is respectively.
noteworthy that methoxy and chloride on the ring
Encouraged by the above results, further explora-
represent versatile handles for further transforma- tion of the reactivity of diverse arenes was undertak-
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Palladium-Catalyzed Selective C H Activation
Table 2. Synthesis of 3-(1,3,5-trichlorophenyl)quinolines from substituted quinolines and 1,3,5-trichlorobenzene.[a]
[a]
Reaction condition: quinolines (0.2 mmol), Pd(OAc)2 (10 mol%), 1,3,5-trichlorobenzene (2.0 mmol), Ag2CO3
(0.6 mmol), and Adm (0.8 mmol) in DMF (1.5 mL) at 1408C for 48 h, O2 (1 atm).
en. As shown in Table 3, 1,4-dichlorobenzene was
The C-3 arylation probably follows the pathway de-
suitable to react with a series of quinolines and pyri- lineated in Figure 2. The first step involves quinoline
dines, respectively, generating the desired products (1a) which can potentially coordinate with Pd(II)
(5ab–5fb) in moderate to good yields. Beyond that through the N atom to form A, assisted by the ligand
other dichlorobenzenes such as 1,2-dichlorobenzene Adm.[10] Under the steric effect of the Adm ligand, A
and 1,3-dichlorobenzene also furnished the corre- subsequently reorients itself to the p system through
À
sponding products in good yields (5ac, 5ad). Further- a trans effect process, which triggers C-3 H activa-
more, the reaction of multi-chloro-substituted arenes tion, and a molecule of Adm leaves to form B.[9] Then
À
with quinoline also proceeded smoothly to give the C H activation of 2b by electrophilic palladation, af-
product 3-(2,3,5,6-tetrachlorophenyl)quinoline (5ae), fords an intermediate C.[12] The last step is reductive
À
albeit in low yield. Furthermore, mono-substituted elimination from C to furnish the 3-aryl C C bond.
arenes, like chlorobenzene, generated m/p mixtures Pd(0) is reoxidized to Pd(II) by Ag(I)/Adm/O2 to
(5af). When the reaction was run with quinoline and close the catalytic cycle.
2,6-dichloro-1-methylbenzene, the only product with
In summary, a novel protocol for the effective Pd-
a specific structure (5ag) was isolated in 53% yield. catalyzed C-3 arylation of quinolines has been devel-
The electronic effect of substituents on the arenes oped using O2 and Ag2CO3 as the oxidants, with Adm
was clearly present, for example, 1,3,5-trifluoroben- as the ligand. The choice of Adm ligand in combina-
zene and quinoline were compatible with the reaction tion with the poalladium catalyst source was found to
conditions and gave the corresponding product 3- be essential in achieving high activity and selectivity,
(2,4,6-trifluorophenyl)quinoline (5ah) in 47% yield, allowing a wide range of 3-arylquinoline derivatives
while tribromobenzene and triiodobenzene furnished to be obtained in moderate to high yields. This strat-
a trace of product and failure, respectively. Under the egy provides a simple and efficient method for quino-
À
standard conditions, benzene methyl ether and nitro- line C-3 H bond activation. The resulting C-3 arylat-
benzene also failed to react. Interestingly, the parent ed quinolines can be used as building blocks for the
pyridine and 1,2,3,4-tetrachlorobenzene can undergo synthesis of bioactive alkaloid natural products and
À
a dehydrogenative C C coupling to form the product drug molecules. Ongoing work seeks to exploit this
3-(2,3,4,5-tetrahlorophenyl)pyridine in 19% yield.
mechanistic manifold for other synthetically useful
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Yongqin He et al.
Table 3. Synthesis of 3-arylquinolines from quinolines and substituted chlorobenzenes.[a]
[a]
Reaction conditions: quinolines (0.2 mmol), Pd(OAc)2 (10 mol%), substituted chlorobenzenes (2.0 mmol),
Ag2CO3 (0.6 mmol), and Adm (0.8 mmol) in DMF (1.5 mL) at 1408C for 48 h, O2 (1 atm) was used.
Figure 2. Plausible mechanistic pathway.
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Palladium-Catalyzed Selective C H Activation
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General Procedure
A
test tube was charged with quinoline (0.2 mmol),
Pd(OAc)2 (10 mol%), Ag2CO3 (0.6 mmol), 1,3,5-trichloro-
benzene (2.0 mmol), and Adm (0.8 mmol) in DMF
(1.5 mL). The reaction mixture was stirred at 1408C under
1 atm of dioxygen (balloon pressure) for 48 h. After cooling
to room temperature, the solution was diluted with 10 mL
ethyl acetate and washed with 5 mL brine and dried over
anhydrous Na2SO4. After the solvent was evaporated under
vacuum, the residues were purified by column chromatogra-
phy, eluting with petroleum ether/EtOAc to afford pure 3-
(2,4,6-trichlorophenyl)quinolines.
Acknowledgements
The authors are grateful for financial support by the Funda-
mental Research Funds for the Central Universities, P. R.
China.
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Ellman, J. Am. Chem. Soc. 2008, 130, 14926.
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