Palladium-catalyzed external-oxidant-free coupling reactions between isoquinoline/quinoline N-oxides with olefins

Article abstract of DOI:10.1016/j.tetlet.2016.07.058

A convenient and efficient approach for the synthesis of 1-alkenylisoquinolines and 2-alkenylquinolines was developed via palladium-catalyzed coupling reactions between isoquinoline/quinoline N-oxides with olefins under external-oxidant-free conditions. B

Full text of DOI:10.1016/j.tetlet.2016.07.058

Accepted Manuscript
Palladium-catalyzed external-oxidant-free coupling reactions between isoqui-
noline/ quinoline N-oxides with olefins
Tao Guo, Yu Liu, Yun-Hui Zhao, Pan-Ke Zhang, Shu-Lei Han, Hong-Min Liu
PII:
S0040-4039(16)30904-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.058
TETL 47920
Reference:
Tetrahedron Letters
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Revised Date:
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22 June 2016
14 July 2016
15 July 2016
Please cite this article as: Guo, T., Liu, Y., Zhao, Y-H., Zhang, P-K., Han, S-L., Liu, H-M., Palladium-catalyzed
external-oxidant-free coupling reactions between isoquinoline/ quinoline N-oxides with olefins, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.058
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Tao Guo, Yu Liu, Yun-Hui Zhao, Pan-Ke Zhang, Shu-Lei Han, Hong-Min Liu

1
Tetrahedron Letters
Palladium-catalyzed external-oxidant-free coupling reactions between isoquinoline/
quinoline N-oxides with olefins
Tao Guo a,b, Yu Liu b, Yun-Hui Zhao d, Pan-Ke Zhang a, Shu-Lei Hanc,, Hong-Min Liu a ,
a School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, P. R.China
b School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, Henan 450001, P. R. China
c China National Tobacco Quality Supervision & Test Center, No. 2 Fengyang Street, Zhengzhou, Henan 450001, P. R. China
d School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan, Hunan, 411201, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient and efficient approach for the synthesis of 1-alkenylisoquinolines and 2-
alkenylquinolines was developed via palladium-catalyzed coupling reactions between
isoquinoline/quinoline N-oxides with olefins under external-oxidant-free conditions. Biological
evaluation revealed that some of the obtained 1-alkenylisoquinolines exhibited in vitro
antiproliferative activities on human-derived prostate, breast, esophageal, and stomach cancer
cell lines.
Available online
Keywords:
1-alkenylisoquinolines
Coupling reaction
Antiproliferative activity
MTT assay
2009 Elsevier Ltd. All rights reserved.
———
 Corresponding author. Tel.: +86-371-6775-6718; e-mail: hsl1983@163.com,liuhm@zzu.edu.cn

2
Tetrahedron
Isoquinoline is a common structural motif found in a wide
concentration, time and temperature (entries 13–17). A screening
of additives such as Py, PPh3, 1,10-phenanthroline and TFA was
also conducted, but provided no improvements (entries 18–21).
Therefore, we decided to use condition in entry 12 as the
standard reaction conditions.
range of natural products with remarkable pharmacological
properties.1 In particular, 1-alkenylisoquinolines as a privileged
scaffold, have attracted attention because of their wide activities
as antibacterial, anticancer as well as enzyme inhibitor.2 On the
other hand, they have emerged as significant and versatile
building blocks for the synthesis of biologically-active
molecules.3 Therefore, synthetic protocols that enable convenient
access to 1-alkenylisoquinolines are of great importance and
numerous attempts have been made by organic chemists in the
past decades.4
Table 1
Screening and optimization of the reaction conditions
Early in 1981, Papadopoulos described
a successful
palladium-mediated coupling of 1-isoquinolyl triflate with
organostannanes (Scheme 1a).5 Very recently, the synthesis of 1-
alkenylisoquinolines was applicable by using substituted 1-
methylisoquinoline. For example, Wang and Tian reported the
reactions of 1-methylisoquinoline with N-sulfonyl aldimines or
secondary amines (Scheme 1b).6 Teo and Uozumi reported cobalt
or iron-catalyzed alkenylation of 1-methylisoquinoline with
aldehydes via C-H functionalization (Scheme 1c).7 Wang
realized an easy access to biologically active 1-
styrylisoquinolines through direct deamination and benzylic
C(sp3)–H bond activation under metal-free conditions (Scheme
1d).8 However, the limited availability of substituted 1-
methylisoquinolines and 1-isoquinolyl triflate narrows their range
additive
Time
Yieldb
(%)
entrya
1
Cat.(10 mol%)
PdCl2
Solvent(mL)
（h）
(equiv.)
1,4-dioxane
(1)
—
28
32
10
2
3
DMF (1)
NMP (1)
PdCl2
PdCl2
PdCl2
PdCl2
10
10
10
10
10
20
20
20
20
20
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
30
26
4
DME (1)
DMSO (1)
Xylene (1)
5
50
6
PdCl2
trace
71
of
use.
Moveover,
compared
to
substituted
1-
7
Pd(TFA)2
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
DMSO (1)
methylisoquinolines, substituted isoquinoline N-oxides are more
obtainable through oxidation of isoquinoline.9 On the basis of
these findings, practical methods for the direct alkenylation of
isoquinolines at 1-positions would be highly desirable and enrich
the structural diversity of 1-alkenylisoquinolines (Scheme 1e).
8
PdBr2
Pd(PPh3)2(OAc)2
Pd(OAc)2
PdSO4
30
9
59
10
11
12
13
14
15
16
17c
18
19
42
trace
77
PdCl2
20
30
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
DMSO (1)
73
DMSO (0.5)
20
20
20
20
20
20
55
DMSO (1.5)
Neat
58
31
DMSO (1)
DMSO (1)
DMSO (1)
63
—
Py (0.2)
41
PPh3 (0.2)
52
1,10-
phenanthroline
(0.2)
20
21
PdCl2
PdCl2
DMSO (1)
DMSO (1)
20
20
24
35
TFA (1)
Scheme 1. Construction of 1-alkenylisoquinolines with different strategies.
a
1a (0.5 mmol), 2a (2.5 mmol), catalyst (10 mol%),
Optimization of the reaction conditions was carried out using
isoquinoline N-oxides with styrene as the model substrates. Some
screening results are shown in Table 1. As summarized, it was
found that using DMSO as solvent gave the best result, whereas
other solvents, such as 1,4-dioxane, DMF, NMP, DME, Xylene
were less effective or ineffective (entries 1–6). With an attempt to
improve the yield of the reaction, further efforts related the
influence of various palladium sources were examined. While
with PdBr2, Pd(OAc)2 and Pd(PPh3)2(OAc)2 the yields were
unsatisfactorily low (entries 8–10), Pd(TFA)2 provided 3a in 71%
yield (entry 7). With PdSO4 as the catalyst, only trace of the
product 3a was detected (entry 11). PdCl2 was the most suitable
catalyst and resulted in the desired product 3a being obtained in
77% yield (entry 12). In addition, obviously decreased yields
were obtained while further attempt to adjusting the reaction
solvent (0.5-1.5 mL).
b Isolated yield.
c The reaction was performed at 120oC.
After successfully identifying the optimal reaction conditions
for the synthesis of 1-alkenylisoquinolines, we turned our
attention to the substrate scope and generality. As depicted in
Table 2, the reaction can tolerate a variety of functional groups at
the o, m, p position of styrene. The coupling of isoquinoline N-
oxides with olefins with electron-donating (CH3, OCH3) and
electron-withdrawing groups (F, Br, Cl) on the aromatic ring
were smoothly alkenylated at the 1-position to afford the
corresponding products 3a-3h in moderate to good yields.
Notably, the tolerance of the chloro and bromo group under these

3
coupling conditions offer versatile synthetic functionalization for
further elaboration. Futhermore, a broad range of isoquinoline N-
oxides were screened. To our delight, The coupling between
styrene and isoquinoline N-oxides derivatives with substituent
group (CH3, OCH3, F, NO2) at the 5, 6-position were found to be
favored affording the desired products 3i-3l. Steric effects in the
isoquinoline N-oxides turned out to be stronger, and a sharp
decrease yield of 34% 3m was obtained when 8-
Chloroisoquinoline N-oxide was employed. Meanwhile, the
scope of the reaction was expanded with its compatibility with
polycyclic, heterocyclic olefins and acrylates. Either 2-
vinylnaphthalene or 2-vinylpyridine could be successfully
applied, furnishing the desired products 3o and 3p in good yields.
Methyl acrylate could also be applied, providing the
corresponding product 3q in 31% yield.
Scheme 2. Synthesis of 2-alkenylquinolines
A plausible mechanism for the reaction is depicted in Scheme
3. C1-palladated species I is formed via electrophilic addition of
N-oxide and subsequent rearomatization. Then coordination of
the palladium complex I with olefins followed by insertion of
C=C bond gives intermediate III. Palladium hydride and
intermediate IV are released from β-H elimination of III. Finally,
products and PdCl2 are obtained through oxidation of palladium
hydride by intermediate IV to complete the catalytic cycle.
Table 2
Synthesis of 1-alkenylisoquinolinesab
Scheme 3. Plausible mechanism for the transformation
In addition, compounds 3c-3f, and 3o-3p were evaluated for
their in vitro antiproliferative activity on a panel of four human-
derived tumor cell lines, using the conventional MTT assay.
Compound 5-fluorouracil, a drug which is widely used in the
treatment of cancer in clinic, was used as the positive control.
The data in Table 3 show that compounds 3e, 3p displayed
antiproliferative activities against MGC803 and MCF7 with IC50
values of 12.82±1.60 and 19.64±1.89 μM, respectively, better
than the positive control compound 5-fluorouracil. The result
well supports our approach to entry into new potentially
antiproliferative agents, based on the framework of 1-
alkenylisoquinolines.
Table 3
In vitro antiproliferative activity of 3c-3f, and 3o-3p on DU145 (prostate),
MCF7 (breast), EC109 (esophageal), MGC803 (stomach) cancer cell lines
IC50 (μmol)
Compound
DU145
115.37±5.67
>125
MCF7
85.49±4.23
>125
EC109
>125
MGC803
83.22±5.12
>125
3c
109.84±4.25
21.56±2.84
>125
3d
106.45±5.47
>125
64.83±3.25
>125
12.82±1.60
3e
>125
3f
a Reaction was performed with 1 (0.5 mmol), 2 (2.5 mmol) and PdCl2 (10
38.87±3.69
>125
47.05±3.40
19.64±1.89
22.52±0.21
121.04±4.51
48.31±4.80
10.43±0.09
3o
3p
mol%) in 1 mL DMSO at 100 oC for 20h.
38.30±4.09
24.36±0.33
81.08±5.49
b Isolated yield.
5-Fluorouracil
20.67 ± 1.79
With the established facile approach to the synthesis of 1-
alkenylisoquinolines in hand, we wondered that this method
might offer valuable 2-alkenylquinolines10 if quinoline N-oxides
was employed instead of isoquinoline N-oxides under similar
conditions. As predicted, the coupling reactions of quinoline N-
oxides with styrene worked well, giving the expected products
5a-5b in moderate yields.
In conclusion, a novel and straightforward way for the
construction of 1-alkenylisoquinolines and 2-alkenylquinolines
via
palladium-catalyzed
coupling
reaction
between
isoquinoline/quinoline N-oxides with olefins has been found.
External-oxidant-free conditions make this approach very
attractive. In addition, some compounds have been proven to
possess antitumor activity by MTT assay which demonstrated the
value of this method. Further library construction and antitumor
activity tests are underway in our group.
Acknowledgments
Financial support from National Natural Science Foundation
of China (No. 21307021, 21502175), Doctor Fund of Henan
University of Technology (No. 2013BS053), and Science
Foundation Of Henan University of Technology (No.
2015QNJH08) are greatly appreciated. The authors are also

4
Tetrahedron
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Supplementary data
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5
Palladium-catalyzed external-oxidant-free
coupling reactions.
A range of 1-alkenylisoquinolines and 2-
alkenylquinolines are provided.
Some of the derivatives exhibit good
antiproliferative activity.