Synthesis of 4-Aryl Isoquinolinedione Derivatives by a Palladium-Catalyzed Coupling Reaction of Aryl Halides with Isoquinoline-1,3(2 H,4 H)-diones

Article abstract of DOI:10.1021/acs.joc.7b02961

The palladium-catalyzed cross-coupling reaction of aryl halides with isoquinoline-1,3(2H,4H)-diones for the synthesis of 4-aryl isoquinoline-1,3(2H,4H)-diones was developed. The reaction conditions exhibit remarkable compatibility with various aryl halide

Full text of DOI:10.1021/acs.joc.7b02961

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Note
Synthesis of 4-aryl isoquinolinedione derivatives by palladium-catalyzed
coupling reaction of aryl halides with isoquinoline-1,3(2H,4H)-diones
YUANYONG YANG, YINGXIAN LI, CHENG CHENG, GUO YANG, Jiquan
Zhang, YI ZHANG, YONGLONG ZHAO, LIN ZHANG, Chun Li, and Lei Tang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02961 • Publication Date (Web): 05 Feb 2018
Downloaded from http://pubs.acs.org on February 6, 2018
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Synthesis of 4-aryl isoquinolinedione derivatives by
palladium-catalyzed coupling reaction of aryl halides with
isoquinoline-1,3(2H,4H)-diones
Yuanyong Yang, †,‡ Yingxian Li,† Cheng Cheng,† Guo Yang,† Jiquan Zhang, †,‡ Yi
Zhang, †,‡ Yonglong Zhao, †,‡ Lin Zhang, †,‡ Chun Li*,†,‡ and Lei Tang*,‡,§
†School of Pharmacy, Guizhou Medical University, Guiyang 550004, China
‡State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou
Medcial University, Guiyang 550014, China.
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§State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203, China
*Corresponding authors: E-mail addresses: 2317972657@qq.com;
scuchunli@163.com
Abstract: Palladium catalyzed cross-coupling reaction of aryl halides
with isoquinoline-1,3(2H,4H)-diones for the synthesis of 4-aryl
isoquinoline-1,3(2H,4H)-diones was developed. The reaction conditions
exhibit remarkable compatibility with various aryl halides and
isoquinoline-1,3(2H,4H)-diones and the product could be conveniently
transformed to 4-aryl tetrahydroisoquinolines. ( ) Dichlorofensine was
synthesized using this protocol in two steps with an overall yield of 71%.
Isoquinoline-1,3-dione bears the core structure of tetrahydroisoquinoline,
which is an important structural motif present in pharmaceutical
compounds and natural products with a broad spectrum of biological
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properties.1 For instance, dihydrexidine 12 is the first high-affinity full
dopamine D1-selective agonist; dichlorofensine 23 can inhibit the uptake
of important central neurotransmitters such as norepinephrine or
dopamine at postsynaptic receptors and 34 is an important antidepressant
compound (Figure 1). The construction of these tetrahydroisoquinoline
architectures attracts wide explorations. However, most of the studies
focus on the construction of 1-substituted tetrahydroisoquinolines,5 while
4-substituted tetrahydroisoquinolines were much less explored. This is
because C-1 position of tetrahydroisoquinolines could be easily activated
by oxygen,6 electrode,7 visible light8 and other mild oxidants,9 while C-4
position is much harder to be activated. Herein, we would like to report a
general method for the synthesis of 4-aryl isoquinoline-
1,3(2H,4H)-diones, which could be conveniently converted to
corresponding 4-aryl tetrahydroisoquinolines through simple reductive
process.
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Figure 1. Examples of useful 4-aryl tetrahydroisoquinoline bioactive
molecules.
A literature survey revealed that the 4-substituted isoquinoline
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architectures
can
be
accessed
through
radical-promoted,
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visible-light-induced or other reagent induced intramolecular cyclization
reactions10 or palladium-mediated coupling reactions.11 Difunctionlization
of double bond is the common route for developing isoquinoline-type
architectures, which requires preinstall of conjugate double bond for the
cyclization. In 1987, Lowe group reported a convenient cross-coupling
pathway between isoquinoline-1,3(2H,4H)-dione and 2-bromobenzoic
acid under copper powder catalysis (scheme 1),12 copper(І) bromide
formed insitu was proposed as the active catalyst. Moderate yield could
be achieved but the substrate scope is limited to electron withdrawing
acid group. Moreover, reaction to isoquinoline-1,3-dione derivatives with
groups larger than methyl on nitrogen, such as ethyl, benzyl or
m-trifluoromethylphenyl, were unsuccessful. Recently, a range of
palladium-catalyzed coupling reactions were developed to prove their
versatility and utility in the synthesis of structurally interesting organic
compounds.13 So we envision that palladium-catalyzed coupling reaction
of aryl halides and isoquinoline-1,3(2H,4H)-diones would be a promising
procedure to construct this type of carbon framework.
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Scheme 1. Copper Catalyzed Coupling of Aryl Bromides and
2-Methyl-isoquinoline-1,3(2H,4H)-dione.
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O
Me
O
X
N
3 examples
NaOEt, Cu
N
7.6%-57% yield
O
Y
Me
Y
EtOH
O
Br
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X
In our initial studies, the reaction between bromobenzene and
2-benzylisoquinoline-1,3(2H,4H)-dione was applied as a model reaction
and the results were summarized in Table 1. In the presence of 2% mol
Pd(dba)2, 3% mol PPh3 and stoichiometric amount of K2CO3, the
cross-coupling failed to give any product after 12 hours (Table 1, entry 1).
Then, bidentate and electron-rich phosphine ligands were tested, which
provided a low conversion of starting material and yield of product (Table
1, entries 2-3). The electron-rich biphenyl-based phosphine ligands 7 and
8 were successfully applied in the α-arylation of oxindoles and
C3-selective mono-arylation of 4-hydroxycoumarins.14 Therefore, a
reaction employing ligand 7 was tested and the expected arylating
product was obtained in 43% yield (Table 1, entry 4); moreover, a
significant improvement was achieved when more sterically demanding
ligand 8 was employed, the expected arylating product was isolated in 75%
yield along with the recovered starting material 4a (Table 1, entry 5).
Given the low acidity of cyclic imide, we postulate that stronger base
would facilitate this reaction. Indeed, with the increase of basicity, the
yield of cross-coupling product increased steadily from 75% to
satisfactory 94% when tBuOK was applied as base (Table 1, entries 6-8).
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PdCl2 and Pd(OAc)2 can also effectively catalyze this coupling reaction
(Table 1, entry 9-10). Moreover, THF is an alternative solvent for this
coupling reaction with albeit slight lower yield (Table 1, entry 11).
Table 1. Reaction Condition for the Coupling of Bromobenzene and
2-Benzyl-isoquinoline-1,3(2H,4H)-dione.
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entrya
base(1.2 eq)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
ligand
time
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12
12
12
12
12
12
12
12
12
12
yield(%)b
0
1
2
PPh3
PCy3
<10
<10
43
3
BINAP
4
7
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8
5
75
6
72
7
Cs2CO3
tBuOK
tBuOK
tBuOK
tBuOK
91
8
94
9c
10d
11e
82
91
92
a Conditions: isoquinoline-1,3-dione 4 (0.5 mmol), bromobenzene (0.55 mmol), base (0.55 mmol),
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b
c
Pd(dba)2 (0.01 mmol), ligand (0.015 mmol), toluene 1ml, 100 ℃. Isolated yields. PdCl2 was
used as catalyst. d Pd(OAc)2 was used as catalyst. e THF was used as solvent, 70 ℃.
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With this established reaction protocol, we next explored variations in
both the substitution group on nitrogen and aryl halides coupling partners
(Table 2). Bromobenzene was employed first to react with
isoquinoline-1,3(2H,4H)-dione bearing different substitution groups to
study the steric effect and electronic effect on the cross-coupling reaction.
The results suggest that both steric effect and electronic effect have
limited effect on the isolated yield (Table 2, 6ba-6fa). Then the electronic
and steric effects on the aryl halides were screened. Other aryl halides
like chlorobenzene and iodobenzene proceed smoothly under current
reaction condition (Table 2, 6aa). The reactions also tolerate significant
functionalization of the aryl halides; both electron-withdrawing and
electron-donating groups can be accommodated, and substituents ortho,
meta or para to the halide group can all be included (Table 2, 6ab-6ak).
When both bromo- and chloro-substituents were present in the arene,
selective reaction at the bromosubstituent was always observed (Table 2,
6ad, 6af-6ag). Besides, heteroarenes are prevalent in bioactive
compounds,15 which could also be accommodated (Table 2, 6am-6an).
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However, when β-bromostyrene was applied instead of arylbromide for
this cross-coupling reaction, the TLC became messy and no major spot
was observed. Oxygen analogue of isoquinoline-dione was also tested.
4H-isochromene-1,3-dione was used to replace isoquinoline-1,3(2H,4H)-
dione for the coupling reaction, the reaction system becomes messy and
no coupling product could be separated.
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Table 2. Substrate Scope for the Coupling of Aryl Halides and
Isoquinoline-1,3(2H,4H)-diones. a
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Ac
Cl
Cl
F
Cl
Cl
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O
O
O
O
N
N
N
N
Bn
Bn
Bn
Bn
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O
O
O
6ad
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6ae
6af
6ag
83% yield
89% yield
88% yield
74% yield
a
Conditions: isoquinoline-1,3-dione 4 (0.5 mmol), aryl halides (0.55 mmol), base (0.55 mmol),
Pd(dba)2 (0.01 mmol), ligand (0.015 mmol), toluene (1ml), 100 ℃.
To further illustrate the versatility of this protocol, the synthesis of ( )
dichlorofensine was demonstrated in scheme 2, which could be achieved
in two steps from 7-methoxy-2-methylisoquinoline-1,3(2H,4H)-dione and
4-bromo-1,2-dichlorobenzene with an overall yield of 71%.
Scheme 2. Synthesis of ( ) Dichlorofensine with Established Protocol.
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Based on the established mechanism of palladium catalyzed coupling
reactions between ketones, esters and amides with aryl halides,16 the
mechanism for this reaction was tentatively proposed in scheme 3. The
first step is oxidative addition of palladium complex into C-X bond to
form intermediate 7, then intermediate 7 undergoes transmetalation with
enolate 5 to get arylpalladium enolate complexes 8 and 9, after the
oxidative addition, equilibrium between the Pd-O and Pd-C species was
the rate-determining step,16 final reductive elimination of the desired
product 6 restores the original palladium catalyst and completes the
catalytic cycle.
Scheme 3. Proposed Mechanism for the Coupling Reaction.
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In summary, we have demonstrated a palladium catalyzed cross-coupling
reaction of aryl halides with isoquinoline-1,3(2H,4H)-dione to give 4-aryl
isoquinoline-1,3(2H,4H)-diones in high yields. The reaction conditions
exhibit remarkable compatibility with various aryl halides and
isoquinoline-1,3(2H,4H)-diones. More importantly, the product could be
conveniently reduced to 4-aryl tetrahydroisoquinoline, which is an
important complementary protocol for the construction of this core
structure.
Experiment Section
General information.
1. All solvents and inorganic reagents were from commercial sources and
used
without
purification
unless
otherwise
noted.
Isoquinoline-1,3(2H,4H)-dione 4a, 4b, 4c and 4e were known
compound,17 4d and 4f were prepared following the reference. 17a
1
13
2. Instruments: All products were characterized by their H NMR, C
NMR on a INOVA 400 MHz spectrometer (400 MHz and 100 MHz)
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spectrometer. Data for H NMR are reported as follows chemical shift,
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integration, multiplicity (s = singlet, d = doublet, dd = doublet doublet, t
= triplet, q = quarte, m = multiplet) and coupling constants are reported as
values in hertz (Hz). Chemical shifts (δ) are quoted in parts per million
(ppm) downfield of tetramethylsilane, using deuterated solvent as internal
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1
standard (CDCl3: 0.00 ppm for H and 77.00 ppm for 13C). High
resolution ESI mass experiments were operated on a Waters G2-XSQTof
mass spectrometer for HRMS measurements.
General
Procedure.
To
a
schlenk
tube
was
added
2-Benzyl-isoquinoline-1,3(2H,4H)-dione (0.5 mmol), bromobenzene (0.6
mmol), 2% mol Pd(dba)2 (0.01 mmol), 3% mol 8 (0.015 mmol) and
tBuOK (0.6 mmol). The mixture was subject to vacuum and back filled
with nitrogen five times to remove air, then fresh distilled degassed
toluene（0.5 ml）was added. The tube was sealed and heat to 100 ℃ for
12 h and then 1 ml NH4Cl (sat.) was added to quench the reaction. Extract
the mixture with EA (5 ml x 3), and the solvent was removed under rotary
vap. The residue was purified by silica gel chromatography (hexane/ethyl
acetate = 30:1 to 15:1) to yield the desired product 6a (153 mg, 94%) as
white solid.
Reduction of 6df to ( ) Dichlorofensine. To a rbf with 100 mg of 6df
dissolved in 2 ml THF, was added 2 ml of 1M BH3-THF complex at 0℃.
After stirred at 0℃ for 4 h and the mixture was heat to reflux for 10 h,
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followed by addition of 2 ml 1M NaOH and heat to reflux for 1 h to
quench the reaction. Extract the mixture with EA (5 ml x 3), and the
solvent was removed under rotary vap. The residue was purified by silica
gel chromatography (DCM/MeOH = 100:1 to 20:1) to yield the desired
product Dichlorofensine (75 mg, 81%) as colorless oil.
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7-methoxy-2-methylisoquinoline-1,3(2H,4H)-dione (4d)
1
white solid, Mp 159-160 ℃. H NMR (400 MHz, CDCl3) δ 7.68 (d, J =
2.4 Hz, 1H), 7.20 – 7.11 (m, 2H), 3.98 (s, 2H), 3.88 (s, 3H), 3.37 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 170.5, 165.1, 159.0, 128.3, 126.2, 126.1,
122.0, 111.2, 55.6, 35.6, 26.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C11H12NO3 206.0817, found 206.0822.
2-benzyl-7-methoxyisoquinoline-1,3(2H,4H)-dione (4f)
1
white solid, Mp 126-127 ℃. H NMR (400 MHz, CDCl3) δ 7.67 (d, J =
1.6 Hz, 1H), 7.45 (d, J = 7.1 Hz, 2H), 7.27 (ddd, J = 8.9, 7.7, 1.8 Hz, 3H),
13
7.14 (d, J = 2.3 Hz, 2H), 5.18 (s, 2H), 3.99 (s, 2H), 3.86 (s, 3H). C
NMR (101 MHz, CDCl3) δ 170.1, 164.8, 159.0, 137.0, 128.9, 128.4,
128.3, 127.5, 126.2, 126.2, 122.1, 111.2, 55.6, 43.3, 35.8. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H16NO3 282.1130, found
282.1123.
2-benzyl-4-phenylisoquinoline-1,3(2H,4H)-dione (6aa)
153 mg, 94% yield, white solid, Mp 83-84 ℃.1H NMR (500 MHz,
CDCl3) δ 8.28 (d, J = 7.1 Hz, 1H), 7.53 (td, J = 7.6, 1.3 Hz, 1H), 7.46 (t,
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J = 7.3 Hz, 1H), 7.34 (d, J = 6.5 Hz, 2H), 7.31 – 7.17 (m, 6H), 7.15 –
5
6
7
13
7.05 (m, 3H), 5.23 (d, J = 13.9 Hz, 1H), 5.14 – 4.98 (m, 2H). C NMR
8
9
(126 MHz, CDCl3) δ 171.8, 164.6, 138.9, 138.2, 136.9, 134.0, 129.0,
128.9, 128.7, 128.5, 128.3, 128.3, 128.0, 127.9, 127.4, 125.4, 52.7, 43.7.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H18NO2 328.1338, found
328.1335.
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2-isopropyl-4-phenylisoquinoline-1,3(2H,4H)-dione (6ba)
113 mg, 81% yield, white solid, Mp 61-62 ℃.1H NMR (500 MHz,
CDCl3) δ 8.26 (dd, J = 7.9, 1.4 Hz, 1H), 7.52 (td, J = 7.5, 1.4 Hz, 1H),
7.46 (td, J = 7.7, 0.8 Hz, 1H), 7.32 – 7.25 (m, 3H), 7.16 – 7.08 (m, 3H),
5.14 – 5.07 (m, 1H), 5.02 (s, 1H), 1.45 (d, J = 6.9 Hz, 3H), 1.35 (d, J =
13
6.9 Hz, 3H). C NMR (126 MHz, CDCl3) δ 172.2, 165.0, 138.9, 138.0,
133.6, 129.0, 128.8, 128.1, 127.9, 127.9, 127.9, 126.0, 53.4, 45.5, 20.1,
18.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H18NO2 280.1338,
found 280.1334.
2-methyl-4-phenylisoquinoline-1,3(2H,4H)-dione (6ca)
116 mg, 92% yield, white solid, Mp 121-122 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.29 (d, J = 7.7 Hz, 1H), 7.54 (td, J = 7.5, 1.2 Hz, 1H), 7.47 (t,
J = 7.4 Hz, 1H), 7.33 – 7.25 (m, 3H), 7.13 (dd, J = 5.9, 1.8 Hz, 3H), 5.09
(s, 1H), 3.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 172.0, 164.9, 139.0,
138.2, 133.9, 129.0, 128.7, 128.5, 128.3, 127.9, 127.9, 125.3, 52.4, 27.2.
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HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H14NO2 252.1025, found
252.1027.
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7-methoxy-2-methyl-4-phenylisoquinoline-1,3(2H,4H)-dione(6da)
130 mg, 92% yield, white solid, Mp 145-146 ℃. 1H NMR (400 MHz,
CDCl3) δ 7.74 (d, J = 2.7 Hz, 1H), 7.28 (t, J = 7.3 Hz, 3H), 7.17 – 7.07
(m, 3H), 7.02 (d, J = 8.6 Hz, 1H), 5.03 (s, 1H), 3.89 (s, 3H), 3.34 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 172.2, 164.9, 159.1, 139.2, 130.4, 129.6,
129.0, 128.4, 127.8, 126.2, 122.2, 110.7, 55.6, 51.8, 27.3. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H16NO3 282.1130, found
282.1125.
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2,4-diphenylisoquinoline-1,3(2H,4H)-dione (6ea)
130 mg, 83% yield, white solid, Mp 182-183 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.32 (dd, J = 7.9, 1.2 Hz, 1H), 7.61 (td, J = 7.5, 1.4 Hz, 1H),
7.51 (td, J = 7.7, 0.7 Hz, 1H), 7.47 – 7.38 (m, 3H), 7.36 – 7.29 (m, 3H),
13
7.23 (td, J = 7.5, 2.2 Hz, 3H), 7.10 (d, J = 7.2 Hz, 2H), 5.24 (s, 1H). C
NMR (101 MHz, CDCl3) δ 171.8, 164.9, 138.7, 138.1, 135.0, 134.2,
129.2, 129.1, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 125.6, 53.2.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H16NO2 314.1181, found
314.1189.
2-benzyl-7-methoxy-4-phenylisoquinoline-1,3(2H,4H)-dione (6fa)
165 mg, 92% yield, white solid, Mp 98-99 ℃. 1H NMR (400 MHz,
CDCl3) δ 7.73 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 7.7, 1.5 Hz, 2H), 7.29 –
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7.21 (m, 6H), 7.14 – 7.06 (m, 3H), 7.01 (d, J = 8.6 Hz, 1H), 5.22 (d, J =
13.9 Hz, 1H), 5.05 (t, J = 6.9 Hz, 2H), 3.87 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 172.0, 164.6, 159.2, 139.1, 136.9, 130.4, 129.6, 129.0, 128.7,
128.4, 128.3, 127.9, 127.4, 126.3, 122.4, 110.8, 55.6, 52.0, 43.7. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C23H20NO3 358.1443, found
358.1445.
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2-benzyl-4-(p-tolyl)isoquinoline-1,3(2H,4H)-dione (6ab)
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145 mg, 85% yield, white solid, Mp 101-102 ℃. H NMR (400 MHz,
CDCl3) δ 8.26 (d, J = 7.9 Hz, 1H), 7.57 – 7.40 (m, 2H), 7.35 (d, J = 6.5
Hz, 2H), 7.28 – 7.16 (m, 3H), 7.10 (dd, J = 12.9, 7.8 Hz, 3H), 6.98 (d, J =
8.0 Hz, 2H), 5.22 (d, J = 13.9 Hz, 1H), 5.04 (d, J = 13.6 Hz, 2H), 2.30 (s,
13
3H). C NMR (101 MHz, CDCl3) δ 171.9, 164.6, 138.4, 137.7, 136.9,
136.0, 133.9, 129.7, 128.8, 128.7, 128.3, 128.3, 128.3, 127.9, 127.4,
125.3, 52.3, 43.6, 21.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C23H20NO2 342.1487, found 342.1486.
2-benzyl-4-(4-methoxyphenyl)isoquinoline-1,3(2H,4H)-dione (6ac)
156 mg, 87% yield, white solid, Mp 145-146 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.31 – 8.21 (m, 1H), 7.57 – 7.49 (m, 1H), 7.45 (d, J = 7.5 Hz,
1H), 7.34 (dd, J = 7.7, 1.3 Hz, 2H), 7.26 – 7.19 (m, 3H), 7.13 (d, J = 7.7
Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.22 (d, J =
13.9 Hz, 1H), 5.04 (t, J = 6.9 Hz, 2H), 3.76 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 172.1, 164.6, 159.2, 138.5, 136.9, 133.9, 131.0, 129.5, 128.8,
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128.7, 128.3, 128.3, 127.9, 127.4, 125.3, 114.4, 55.3, 51.8, 43.6. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C23H20NO3 358.1443, found
358.1448.
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2-benzyl-4-(4-chlorophenyl)isoquinoline-1,3(2H,4H)-dione (6ad)
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161 mg, 89% yield, white solid, Mp 109-110 ℃. H NMR (400 MHz,
CDCl3) δ 8.33 – 8.24 (m, 1H), 7.59 – 7.43 (m, 2H), 7.38 – 7.18 (m, 7H),
7.06 (dd, J = 26.8, 8.0 Hz, 3H), 5.22 (d, J = 13.8 Hz, 1H), 5.05 (d, J =
15.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 171.3, 164.4, 137.6, 137.3,
136.7, 134.1, 134.0, 129.9, 129.2, 129.1, 128.7, 128.4, 128.2, 127.5,
125.3, 51.9, 43.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H17ClNO2 362.0940, found 362.0939.
4-(4-acetylphenyl)-2-benzylisoquinoline-1,3(2H,4H)-dione (6ae)
162 mg, 88% yield, white solid, Mp 147-148 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.33 – 8.27 (m, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.57 – 7.45 (m,
2H), 7.36 (dd, J = 7.6, 1.5 Hz, 2H), 7.27 – 7.17 (m, 5H), 7.08 (d, J = 7.6
Hz, 1H), 5.28 – 5.15 (m, 2H), 5.07 (d, J = 13.8 Hz, 1H), 2.56 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 197.4, 170.9, 164.3, 143.8, 137.3, 136.7,
136.5, 134.1, 129.1, 129.0, 128.8, 128.8, 128.4, 128.3, 128.2, 127.5,
125.3, 52.4, 43.7, 26.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C24H20NO3 370.1443, found 370.1445.
2-benzyl-4-(3,4-dichlorophenyl)isoquinoline-1,3(2H,4H)-dione (6af)
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146 mg, 74% yield, white solid, Mp 107-108 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.33 – 8.25 (m, 1H), 7.60 – 7.46 (m, 2H), 7.35 (dd, J = 4.7, 3.7
Hz, 3H), 7.23 (ddd, J = 15.9, 8.3, 1.9 Hz, 4H), 7.09 (d, J = 7.7 Hz, 1H),
6.92 (dd, J = 8.3, 2.1 Hz, 1H), 5.21 (d, J = 13.8 Hz, 1H), 5.07 (d, J = 14.3
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 170.8, 164.2, 138.7, 136.9, 136.6,
134.2, 133.1, 132.4, 130.9, 130.5, 129.2, 128.8, 128.5, 128.4, 128.2,
127.9, 127.6, 125.3, 51.5, 43.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C22H16Cl2NO2 396.0545, found 396.0551.
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2-benzyl-4-(3-chloro-4-fluorophenyl)isoquinoline-1,3(2H,4H)-dione
(6ag) 157 mg, 83% yield, white solid, Mp 102-103 ℃. 1H NMR (400
MHz, CDCl3) δ 8.29 (d, J = 7.8 Hz, 1H), 7.57 (td, J = 7.5, 1.4 Hz, 1H),
7.50 (dd, J = 11.3, 3.9 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.31 – 7.18 (m, 3H),
7.16 – 6.91 (m, 4H), 5.21 (d, J = 13.8 Hz, 1H), 5.07 (d, J = 13.9 Hz, 2H).
13C NMR (126 MHz, CDCl3) δ 171.0, 164.2, 158.7, 156.7, 137.1, 136.6,
135.7, 135.7, 134.2, 130.7, 129.2, 128.7, 128.4, 128.4, 128.4, 128.3,
128.2, 127.6, 125.3, 121.7, 121.5, 117.1, 116.9, 51.4, 43.7. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C22H16ClFNO2 380.0854, found
380.0838.
3-(2-benzyl-1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-4-yl)benzonitrile
(6ah) 155 mg, 88% yield, white solid, Mp 123-124 ℃. 1H NMR (400
MHz, CDCl3) δ 8.32 (dd, J = 7.8, 1.1 Hz, 1H), 7.62 – 7.49 (m, 3H), 7.44
– 7.32 (m, 5H), 7.27 – 7.20 (m, 3H), 7.07 (d, J = 7.6 Hz, 1H), 5.23 – 5.03
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(m, 3H). 13C NMR (101 MHz, CDCl3) δ 170.6, 164.0, 140.2, 136.5, 136.5,
134.3, 133.1, 132.1, 131.6, 129.8, 129.3, 128.7, 128.6, 128.4, 128.1,
127.6, 125.4, 118.1, 113.1, 51.8, 43.8. HRMS (ESI-TOF) m/z: [M + H] +
Calcd for C23H17N2O2 353.1295, found 353.1293.
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4-(3-acetylphenyl)-2-benzylisoquinoline-1,3(2H,4H)-dione (6ai)
170 mg, 92% yield, white solid, Mp 98-99 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.74 (s,
1H), 7.58 – 7.45 (m, 2H), 7.42 – 7.34 (m, 3H), 7.28 – 7.20 (m, 4H), 7.08
(d, J = 7.6 Hz, 1H), 5.29 – 5.15 (m, 2H), 5.08 (d, J = 13.8 Hz, 1H), 2.52
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 197.4, 171.2, 164.3, 139.5, 137.7,
137.5, 136.7, 134.1, 133.0, 129.3, 129.1, 128.8, 128.5, 128.4, 128.3,
128.2, 127.9, 127.5, 125.3, 52.3, 43.7, 26.6. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C24H20NO3 370.1443, found 370.1447.
2-benzyl-4-(3-methoxyphenyl)isoquinoline-1,3(2H,4H)-dione (6aj)
168 mg, 94% yield, white solid, Mp 86-87 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.27 (d, J = 7.2 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.45 (t,
J = 7.3 Hz, 1H), 7.36 (d, J = 6.5 Hz, 2H), 7.22 (ddd, J = 11.3, 8.4, 3.1 Hz,
4H), 7.17 – 7.11 (m, 1H), 6.80 (dd, J = 8.2, 2.2 Hz, 1H), 6.64 (dd, J =
12.6, 4.8 Hz, 2H), 5.23 (d, J = 13.9 Hz, 1H), 5.06 (t, J = 6.9 Hz, 2H), 3.69
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 171.6, 164.6, 159.9, 140.2, 138.1,
136.9, 134.0, 130.0, 128. 9, 128.8, 128.3, 128.3, 128.0, 127.4, 125.2,
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120.7, 114.2, 113.3, 55.2, 52.6, 43.6. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C23H20NO3 358.1443, found 358.1441.
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2-benzyl-4-(2-fluorophenyl)isoquinoline-1,3(2H,4H)-dione (6ak)
140 mg, 81% yield, white solid, Mp 86-87 ℃. 1H NMR (500 MHz,
CDCl3) δ 8.27 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 – 7.40 (m, 4H), 7.35 – 7.21
(m, 4H), 7.13 – 7.02 (m, 4H), 5.33 – 5.25 (m, 2H), 5.16 (d, J = 13.9 Hz,
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1H). C NMR (100 MHz, CDCl3) δ 170.9, 164.4, 161.4, 159.4, 137.6,
136.9, 133.9, 130.9 (d, J = 3.5 Hz), 130.0 (d, J = 8.3 Hz), 129.0 (d, J =
14.0 Hz), 128.4, 127.9, 127.5 (d, J = 8.8 Hz), 126.4 (d, J = 14.6 Hz),
124.9, 124.6 (d, J = 3.6 Hz), 116.3, 116.1, 46.8 (d, J = 1.9 Hz), 43.7.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H17FNO2 346.1243, found
280. 346.1246.
2-benzyl-4-(naphthalen-2-yl)isoquinoline-1,3(2H,4H)-dione (6al)
161 mg, 85% yield, white solid, Mp 106-107 ℃. 1H NMR (400 MHz,
CDCl3) δ 8.31 (dd, J = 7.7, 1.3 Hz, 1H), 7.83 – 7.67 (m, 3H), 7.59 – 7.43
(m, 5H), 7.37 (dd, J = 7.3, 2.0 Hz, 2H), 7.28 – 7.10 (m, 5H), 5.25 (t, J =
13
6.9 Hz, 2H), 5.07 (d, J = 13.9 Hz, 1H). C NMR (101 MHz, CDCl3) δ
171.7, 164.6, 138.1, 136.9, 136.2, 134.0, 133.3, 132.7, 129.0, 129.0,
128.8, 128.4, 128.3, 128.0, 127.9, 127.9, 127.6, 127.4, 126.5, 126.4,
125.7, 125.3, 52.7, 43.7. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C26H20NO2 378.1494, found 378.1510.
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4-(benzo[b]thiophen-5-yl)-2-benzylisoquinoline-1,3(2H,4H)-dione
(6am) 174 mg, 91% yield, white solid, Mp 116-117 ℃. 1H NMR (400
MHz, CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H),
7.56 – 7.41 (m, 4H), 7.38 – 7.31 (m, 2H), 7.20 (dt, J = 4.6, 4.2 Hz, 4H),
7.14 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 8.4, 1.7 Hz, 1H), 5.32 – 5.18 (m,
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2H), 5.06 (d, J = 13.9 Hz, 1H). C NMR (101 MHz, CDCl3) δ 171.9,
164.6, 140.0, 139.3, 138.4, 136.8, 135.2, 134.0, 128.9, 128.8, 128.4,
128.3, 128.0, 127.5, 127.4, 125.3, 124.4, 123.7, 123.6, 123.1, 52.5, 43.7.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H18NO2S 384.1058, found
384.1066.
2-benzyl-4-(1H-indol-5-yl)isoquinoline-1,3(2H,4H)-dione (6an)
165 mg, 90% yield, white solid, Mp 119-120 ℃. 1H NMR (500 MHz,
CDCl3) δ 8.27 (dd, J = 7.9, 1.2 Hz, 2H), 7.49 (td, J = 7.5, 1.4 Hz, 1H),
7.42 (t, J = 7.3 Hz, 1H), 7.37 – 7.31 (m, 3H), 7.24 – 7.11 (m, 6H), 6.88
(dd, J = 8.4, 1.7 Hz, 1H), 6.50 – 6.39 (m, 1H), 5.25 (d, J = 14.0 Hz, 1H),
13
5.17 (s, 1H), 5.05 (d, J = 14.0 Hz, 1H). C NMR (126 MHz, CDCl3) δ
172.7, 164.9, 139.3, 137.0, 135.2, 133.9, 130.5, 128.7, 128.5, 128.3,
128.1, 127.7, 127.3, 125.2, 125.1, 122.1, 120.8, 111.7, 102.7, 52.8, 43.7.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H19N2O2 367.1438, found
367.1439.
4-(3,4-dichlorophenyl)-7-methoxy-2-methylisoquinoline-1,3(2H,4H)-d
ion (6df) 148 mg, 85% yield, white solid, Mp 129-130 ℃. 1H NMR
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(400 MHz, CDCl3) δ 7.75 (d, J = 2.8 Hz, 1H), 7.38 (d, J = 8.3 Hz, 1H),
7.21 (d, J = 2.1 Hz, 1H), 7.14 (dd, J = 8.5, 2.8 Hz, 1H), 7.03 – 6.92 (m,
2H), 4.99 (s, 1H), 3.91 (s, 3H), 3.35 (s, 3H). 13C NMR (126 MHz, CDCl3)
δ 171.2, 164.5, 159.5, 139.1, 133.0, 132.3, 130.8, 130.6, 129.5, 129.0,
128.0, 126.3, 122.4, 111.1, 55.7, 50.7, 27.4. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H14Cl2NO3 350.0351, found 350.0342.
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( ) Dichlorofensine
75 mg, 83% yield, colorless oil, 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J
= 8.2 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 8.3, 2.0 Hz, 1H),
6.76 (d, J = 8.5 Hz, 1H), 6.70 – 6.65 (m, 1H), 6.62 (d, J = 2.5 Hz, 1H),
4.19 – 4.11 (m, 1H), 3.78 (s, 3H), 3.64 (s, 2H), 2.95 (dd, J = 11.5, 5.4 Hz,
13
1H), 2.55 (dd, J = 11.5, 7.6 Hz, 1H), 2.41 (s, 3H). C NMR (126 MHz,
CDCl3) δ 158.0, 145.5, 136.3, 132.1, 130.8, 130.3, 130.2, 128.4, 127.9,
112.9, 110.8, 61.3, 58.3, 55.2, 45.8, 44.3. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C17H18Cl2NO 322.0761, found 322.0765.
ASSOCIATED CONTENT
Supporting Information
Supporting Information 1 H and 13C NMR spectra of compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
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Financial support from the National Natural Science Foundation of China
(81660348, 81703356, 21502030), GMU(J[2014]015, J[2014]017),
Office of Science & Technology of Guiyang ([20151001]06), Office of
Science & Technology of Guizhou ([2015]7343, QKHSY[2015]3030),
Guizhou Provincial Engineering Laboratory for Chemical Drug R&D,
Guizhou High-School Engineering Research Center for Medicinal
Chemistry (KY2014-219) were greatly appreciated.
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