Tunable Synthesis of 3-Hydroxylisoquinolin-1,4-dione and Isoquinolin-1-one Enabled by Copper-Catalyzed Radical 6- endo Aza-cyclization of 2-Alkynylbenzamide

Article abstract of DOI:10.1021/acs.joc.9b01643

In this work, switchable synthesis of isoquinolin-1-one and 3-hydroxylisoquinolin-1,4-dione from 2-alkynylbenzamide is reported. The transformation works well with good yields and a broad reaction scope. The synthetic switch for providing isoquinolin-1-one and 3-hydroxylisoquinolin-1,4-dione is enabled by the use of a N₂ or O₂ atmosphere. Mechanism studies show that the reaction proceeds in a regioselective manner via a N-center radical 6-endo-dig aza-cyclization pathway.

Full text of DOI:10.1021/acs.joc.9b01643

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Article
Tunable Synthesis of 3-Hydroxylisoquinolin-1, 4-dione
and Isoquinolin-1-one Enabled by Copper-Catalyzed
Radical 6-Endo Aza-Cyclization of 2-Alkynylbenzamide
Renzhi Liu, Meng Li, Wenlin Xie, Hongwei Zhou, Yajing Zhang, and Guanyinsheng Qiu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01643 • Publication Date (Web): 22 Aug 2019
Downloaded from pubs.acs.org on August 22, 2019
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Tunable Synthesis of 3-Hydroxylisoquinolin-1, 4-dione and Isoquinolin-1-one
Enabled by Copper-Catalyzed Radical 6-Endo Aza-Cyclization of 2-
Alkynylbenzamide
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*
Renzhi Liu,† Meng Li,‡ Wenlin Xie,†* Hongwei Zhou,‡ Yajing Zhang,‡ and Guanyinsheng Qiu†,
*
‡,
† School of Chemistry and Chemical Engineering, Hunan University of Science and Technology, Xiangtan 411201, China.
Email: xwl2000zsu@163.com (X. W.)
‡ College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing 314001, Zhejiang, China. Email:
qiuguanyinsheng@mail.zjxu.edu.cn (G. Q.); zhouhw@zju.edu.cn (H. Z.)
O
OR2
[Cu]
N
14 examples
up to 71% yields
R1
R3
O2 balloon
O
OH
NHOR2
R3
O
O
R1
OR2
R3
N
25 examples
up to 90% yields
[Cu]
N2
R1
H
O
O
N
OR2
R3
NOR2
R3
R1
R1
ABSTRACT: In this work, switchable synthesis of isoquinolin-1-one and 3-hydroxylisoquinolin-1,4-dione from 2-alkynylbenzamide is reported. The
transformation works well with good yields and a broad reaction scope. The synthetic switch for providing isoquinolin-1-one and 3-hydroxylisoquinolin-
1,4-dione is enabled by the use of N2 or O2 atmosphere. Mechanism studies show that the reaction proceeds in a regioselective manner via a N-center
radical 6-endo-dig aza-cyclization pathway.
Introduction
Considering its ubiquity of N-containing compounds, various N-containing synthons were developed for accordingly.1 Among them,
N-center radical species was a history-long yet many-issues-unsettled topic in the field of organic chemistry.2 As such, tremendous
efforts were made in past decades, thus enabling significant progress of amidyl-nitrogen radical and imine-nitrogen radical
chemistry.3 To the best of our knowledge, amidyl nitrogen-radical could be achieved through a metal-free process, metal catalysis
and photocatalysis etc.
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On the other hand, 2-alkynylbenzamide was a versatile dual-functional synthon towards many privileged skeletons, such as
isoquinolin-1-ones,4 isoindolin-1-ones,5 isocoumarin-1-imines6 and isobenzofuran-1-imines.7 For 2-alkynylbenzamide-based
chemistry, regiochemistry in N/O nucleophilicity and 5-exo cyclization/6-endo cyclization was still challenging. Generally, base-
promoted cyclization of 2-alkynylbenzamide preferred to undergoing N- nucleophilicity 5-exo-dig cyclization, whereas, O-
nucleophilic 6-endo-dig cyclization could be realized under Lewis acid catalysis. According to our recent findings, the metal-free
radical annulation of 2-alkynylbenzamide dominated in an O-nucleophilic cyclization manner, which served as an important
supplement of electrophilic cyclization.8 Given high importance of isoquinolin-1-one structural core,9 many research groups
devoted themself to its synthetic methodology development.4,12 As we know, a few elegant cases starting from 2-alkynylbenzamide
indicated that using indium salt4a,4b and platinum salt4c as Lewis acid catalysts could convert 2-alkynylbenzamide into isoquinolin-
1-one through N- nucleophilicity 6-endo cyclization. With catalytic Cu(OAc)2 and stoichiometric inorganic base, a two-step
procedure from 2-iodobenzamide and terminal alkyne also provided isoquinolin-1-one core.4d Inspired by what mentioned above
together with our continuous interest in radical chemistry,10 we would like to disclose a radical process for N-center radical-attacked
6-endo-dig cyclization of 2-alkynylbenzamide 1. Copper salt, recognized as cost-low metal salt, was always used in radical
transformations.11 Therefore, in this paper copper salt was employed as catalyst to trigger this projected transformation (Scheme 1).
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Scheme 1. Radical 6-endo-dig aza-cyclization of 2-alkynylbenzamide
O
O
NHR2
NR2
R3
R1
various
isoquinolin-1-ones
R1
R3
B
1
O
NR2
a
R1
b
R3
A
Theoretically, after being treated with copper salt, the substrate 2-alkynylbenzamide 1 led to a key amidyl N-center radical A
through a SET process. It is hypothesized that the amidyl N-center radical A occurred to undergo radical 6-endo-dig aza-cyclization
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to result in the intermediated B. It was envisioned that the intermediate B could be converted into isoquinolin-1-one derivatives.
Very recently, Han and co-workers developed a Cu-catalyzed N-center radical-based tandem 5-exo-dig cyclization of alkyne-
tethered N-alkoxylamide.12 This elegant example probably supported the reliability of our above assumption. It is imaginable that
this paper herein exploited a distinctive radical model for N-attacked 6-endo-dig cyclization of 2-alkynylbenzamide. Moreover, this
paper also provided an insight into the reactivity of the isoquinolin-1-one radical B, a kind of heterocyclic aryl radical. As such, we
started to optimize reaction conditions of model reaction.
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Table 1. Optimization of the Reaction Conditionsa
O
O
H
O
OMe
Ph
OMe
Ph
OMe
Ph
N
N
[M]
N
H
+
solvent, temp.
air
OH
2a
O
3a
1a
Yield of 2a
Yield of 3a
Entry
[M]
Solvent
T (oC)
(%)a,b
19
21
28
42
36
29
21
24
40
39
17
-
(%)a,b
43
32
41
37
49
40
38
61
36
53
48
57
49
32
29
50
35
1
2
Cu(OAc)2
CuF2
DCE
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
80
3
Cu(OTf)2
CuCl2
CuBr2
CuCl
DCE
4
DCE
5
DCE
6
DCE
7
CuI
DCE
8
Cu2O
DCE
9
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
THF
10
11
12
13
14
15
16
17c
MeCN
Toluene
1,4-dixane
DMF
CHCl3
DCM
DCE
-
41
32
41
47
DCE
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18 cd
19 cd
20cd
21de
22cd
23f
CuCl2
CuCl2
CuCl2
CuCl2
-
DCE
DCE ( 4 mL)
DCE ( 1 mL)
DCE
80
80
80
80
80
80
80
51
51
45
50
-
30
25
32
23
-
1
2
3
4
5
6
7
8
DCE
CuCl2
CuCl2
DCE
-
75
82
9
24fg
DCE
-
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b
aIsolated yield based on 2-alkynylbenzamide 1a. Standard conditions: 2-alknylbenzamide 1a (0.2 mmol), copper salt (10 mol%),
c
d
e
solvent (2 mL), air overnight. O2 atmoshpere instead of air was conducted. 2 mol% CuCl2 was added. bubbling O2 into the
reaction. fthe reaction was conducted under N2 atmosphere. g20 mol% CuCl2 was added.
Result and Discussion
Initially, various copper sources were explored. Interestingly, the reactions under air provided two products. Identified with NMR,
HRMS, IR, and X-Ray diffraction, the two products were defined as 3-hydroxylisoquinolin-1,4-dione 2a, which probably resulted
from the reaction of the intermediate B with O2, and isoquinolin-1-dione 3a, which was ascribed to H-abstraction of the
intermediate B, respectively. Considering high importance of 3-hydroxylisoquinolin-1,4-dione,9,13 its synthetic methodology
development thus attracted our attention. From the screening results, it seemed that copper chloride (CuCl2) was the best choice
(entry 4, Table 1), leading to the product 3-hydroxylisoquinolin-1,4-dione 2a in a 42% yield. Other copper salts did not provide
better outcomes (entries 1-8, Table 1). No better yields were produced when various solvents and reaction temperatures were used
(entries 9-16, Table 1). It was noteworthy that protonated product isoquinolin-1-one 3a was not excluded in the process.
Interestingly, we observed the reaction efficiency was improved when the reaction was conducted under O2 atmosphere, and the
desired product 2a and the by-product 3a were detected in 47% and 35% yields, respectively (entry 17, Table 1). To further supress
H-abstraction, we attempted to reduce the loading of copper catalyst. Pleasingly, further decrease of copper loading to 2 mol%
improved the reaction efficiency, leading to the 3-hydroxylisoquinolin-1,4-dione 2a in a 51% yield and isoquinolin-1-one 3a in
30% yield as well (entry 18, Table 1). Additionally, changing concentration of 1a in DCE did not improve the reaction efficiency
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(entries 19-20, Table 1). Bubbling O2 into the reaction also did not increase the yield of 2a (entry 21, Table 1). Moreover, we also
optimized the reaction conditions for the synthesis of isoquinolin-1-one 3a. To our delight, the increase of the loading of CuCl2 to
0.2 equiv under N2 atmosphere improved the reaction efficiency, providing isoquinolin-1-one 3a in an 82% yield, and 3-
hydroxylisoquinolin-1,4-dione 2a was not observed (entry 24, Table 1).
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After optimizing the conditions, we then explored the reaction generality. The results are illustrated in Table 2. A series of 3-
hydroxylisoquinolin-1,4-diones 2 was achieved in moderate to good yields. However, the substituent R3 was solely equal to aryl
and heteroaryl groups. The reaction of n-butyl-connected substrate did not provide the final 3-hydroxylisoquinolin-1,4-dione 2n,
but gave rise to a protonated isoquinolin-1-one 3t in 21% yield.
Table 2 Reaction Scope for 2a,b
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O
O
O
1
2
3
4
OR2
NHOR2
CuCl2 (2 mol%)
R1
N
R1
OH
R3
O2 balloon
DCE, 80 oC
R3
1
2
5
6
7
8
9
O
O
OMe
OMe
2b
, Ar = 2-ClC6H4, 53%;
, Ar = 4-FC6H4, 47%;
N
N
2c
2d
OH
Ph
OH
Ar
, Ar = 4-NO2C6H4, 65%
, Ar = 3-FC6H4, 49%
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2e
O
2a
O
O
, 51%
O
O
OMe
MeO
OMe
OH
Ph
Br
OMe
OH
Ph
N
N
N
OH
S
O
2f
O
O
, 43%
, 40%
2h
2g
, 48%
O
O
O
F
OMe
Cl
OMe
OH
Ph
OMe
N
N
N
OH
Ph
OH
4-ClC6H4
O
O
O
2i
, 47%
2j
, 49%
2k
, 53%
O
O
O
Ph
O
Cl
OMe
OH
OMe
OH
Bun
N
N
N
OH
Ph
4-ClC6H4
O
O
O
2l
, 61%
2m
, 50%
2n
, N.D.
aReaction conditions: 1 (0.2 mmol), CuCl2 (2 mol%), O2 balloon in 2 mL of DCE were stirred at 80 oC. bIsolated yield based on 1.
Surprisingly, the reaction of substrate with 4-methoxylaryl 1q did give rise to an inseperable mixture of 6-endo-dig aza-cyclization
product 2o and 5-exo-dig aza-cyclization product 2o’, which was consitent with the hypervalent iodine-mediated results from Zhao
and Du.13 The total yield was 71%, and the ratio of 2o/2o’ was 1:2 (Table 3). Other more efficient synthetic methodologies towards
3-hydroxylisoquinolin-1,4-diones 2 are ongoing to be explored in our lab. The results will be reported in due course.
a
Table 3 Reaction Scope: the Reaction of 4-Methoxylphenylethynylbenzmiade Under O2
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O
1
OMe
OH
N
2
3
4
5
O
2o
OMe
Ar
N
CuCl2 (2 mol%)
O
H
+
Ar
DCE, 80°C
O2 balloon
O
6
7
8
9
10
11
N OMe
OH
1q
2o'
total yield: 71%;
2o/2o'
Ar
= 1:2
O
a) Isolated yield based on 1q.
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Subsequentially, we also explored the reaction scope for the synthesis of isoquinolin-1-one 3 (Table 4). As expected, a
series of substituted isoquinolin-1-one 3 was achieved in moderate to good yields. The substituent effects of R1 were
initially investigated. The results revealed that both electron-donating groups and electron-withdrawing groups were
compatible, leading to the desired isoquinolin-1-ones 3a-3f in 67-82% yields. For example, the reaction with the substrate
containing a 5-methoxyl group on R1 afforded the desired isoquinolin-1-one 3c in an 82% yield, while the substrate with
5-fluoro substitution provided the corresponding product 3b in a 67% yield. The reaction of naphthalene-linked substrate
1h offered the desired isoquinolin-1-one 3h in a 56% yield. However, cyclohexyl-connected and pyridinyl-connected
substrate 1g was not a good reaction partner.
Various N-protecting groups were also examined. Beyond N-methoxyl group, N-protecting group could be replaced by
benzyloxyl and allyloxyl, and the corresponding products 3i and 3j were achieved in 80% and 60% yields, respectively.
To our surprise, under standard conditions N-H, N-aryl and N-alkyl-linked substrates did not offer the desired isoquinolin-
1-ones, but provided O-nucleophilic 6-endo-dig cyclization products isocoumarin-1-imines (data not shown in Table 4).
Table 4 Reaction Scope for 3a,b
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O
1
2
3
4
5
6
O
OR2
OR2
R3
N
CuCl2 (20 mol%)
DCE, N2, 80oC
R1
N
R1
H
R3
3
1
7
8
9
O
O
R
OMe
R
OMe
Ar
N
N
3a
, R = H, 82%
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11
12
13
14
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3b
3c
, R = F, 67%
, R = OMe, 82%
Ph
O
3d
3e
3f
, R = Me, Ar = 4-ClC6H4, 75%;
, R = Br, Ar = 4-OMeC6H4, 74%
, R = Cl, Ar = 4-OMeC6H4, 82%
OMe
Ph
N
O
O
OR
Ph
3g
, trace
OMe
Ph
N
N
O
3i
3j
, R = allyl, 80%;
, R = benzyl, 60%
3h
, 56%
OMe
N
O
R
OMe
3k
, R = 4-OMeC6H4, 79%;
N
3l
3m,
, R = 2-OMeC6H4, 90%;
OTs
R = 4-MeC6H4, 73%;
, R = 4-FC6H4, 67%;
3n
3o
3p
3q
3u
, 53%
, R = 2-ClC6H4, 87%
O
, R = 2-thiophenyl, 49%
, R = 2-naphthalenyl, 83%;
, R = 1-cyclohexenyl, 81%
OMe
N
OR
3r
3s
, R = cyclopropyl, 58%
3v
3w
3x
, R = Me, 50%;
, R = Allyl, 42%;
, R = H, 63%
n
3t
, R = Bu, 60%
O
OMe
O
N
O
3y
, 51%
CH3
O
OMe
N
CH3
CH3
O
H
H
3z
, 53%
aReaction conditions: 1 (0.2 mmol), CuCl2 (20 mol%), N2 in 2 mL of DCE were stirred at 80 oC. bIsolated yield based on 1.
Finally, the substituent effect of R3 in starting materials was also explored accordingly. Based on the established results, it
seemed that R3 could be equal to aryl, heteroaryl and alkyl. The corresponding isoquinolin-1-ones 3k-3x were obtained in
moderate to good yields. For instance, thiopheneethynyl-connected substrate was an effective reaction partner, yielding
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the desired isoquinolin-1-one 3p in moderate yield. Other sensitive functional groups such as cyclohexenyl (entry 3r,
Table 4), cyclopropyl (entry 3s, Table 4), sulfonate (entry 3u, Table 4), allyl (entry 3w, Table 4), and free hydroxyl (entry
3x, Table 4) were compatible for the reactions.
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Interestingly, the reactions of estratrienone-linked 2-alkynylbenzamide 1y worked well under standard conditions, providing the
desired isoquinolin-1-one 3y in 51% yield (Table 4). With a similar outcome, the isoquinolin-1-one 3z was also afforded when
Cholesterol-connected substrate 1z was used. Compared to the simple substrates, the reactions with complex substrates were less
efficient as we detected several unknown products. The structure identification of these unknown products is ongoing in our lab.
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Table 5 Synthetic Elaboration of Isoquinolin-1-one a
O
O
O
NaH (3.0 equiv)
NH
Ph
N
DMF, 120 o
90% yield
C
Ph
3a
4
a) Isolated yield based on 3a.
The structural elaboration of isoquinolin-1-one 3 was also tested. As presented in Table 5, 3.0 equiv of NaH enabled removal of methoxyl
group in isoquinolin-1-one 3a, providing isoquinoline 4 in 90% yield (Table 5).
Scheme 2. Mechanistic Studies
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O
O
1
2
3
OMe
Ph
OMe
CuCl2 (20 mmol%)
N
N
N
H
(a)
(b)
DCE-d4, 80 oC, N2
4
5
H
O
80% yield
3a
1a
Ph
O
OMe
Ph
6
7
8
9
OMe
CuCl2 (20 mmol%)
DCE, 80 oC, N2
N
D
(40%)
-3a
D
d
1a
Ph
10
11
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O
O
OMe
OMe
N
N
CuCl2 (20 mmol%)
DCE, 80 oC, N2
H
(c)
(d)
(e)
Ph
1a
Ph
TEMPO (2.0 eq)
0% yield
H
3a
O
O
OMe
Ph
OMe
N
CuCl2 (2 mmol%)
N
O18
Ph
H
H
DCE, 80°C
18O2 balloon
O18
LC-MS: [M+H]+ = 288
O
O
OMe
Ph
OMe
N
N
without CuCl2
H
OH
DCE, 80°C
O2 balloon
0% yield
Ph
O
2a
To gain insights into mechanism, several control experiments were carried out. As illustrated in Scheme 2, the deuterium-labled
experiments indicated that hydrogen atom in C4-H of isoquinolin-1-one 3a was not derived from solvent, but probably came from
amide N-H of substrate. Secondly, the reaction was totally retarded when 2.0 equiv of TEMPO was added as a radical scavenger,
probably suggesting the reaction undergoing a radical pathway. Thirdly, the control reaction under 18O2 atmosphere was also
conduct, which showed one equivalent of O2 was installed into the final 3-hydroxylisoquinolin-1,4-dione 2a. Moreover, the blank
reaction without CuCl2 did not give the desired product 2a. This result implied that the use of copper salt was highly important for
this oxidative radical 6-endo-dig aza-cyclization of 2-alkynylbenzamide.
To identify the valent state of copper salt in the reaction, XRD test on copper species after reaction ran accordingly (Scheme 3).
From the result, XRD spectrum of the sample was extremely overlapped with that of CuCl, whose standard XRD spectrum was
numbered as PDF#06-0344. This result indicated that in the process CuCl2 was reduced into CuCl, probably providing a solid
evidence for the projected radical annulation.
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Scheme 3. Mechanistic Studies
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O
O
H
OMe
OMe
Ph
N
N
CuCl2 (20 mmol%)
DCE, 80 oC, N2
H
1a
Ph
3a
XRD of copper species after reaction:
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In light of aforementioned results, a plausible mechanism was proposed in Scheme 4. It is believed that 2-alkynylbenzamide-
containing N-center radical A, generated from treatment of 2-alkynylbenzamide 1 with CuCl2, was a key intermediate.14 The
resulting intermediate A occurred to go through 6-endo-dig aza-cyclization to deliver isoquinolin-1-one radical species B. Under N2
atmosphere, hydrogen abstraction of the intermediate B from the starting material 1 afforded the targeted products 3. Otherwise,
under O2 atmosphere the intermediate B was trapped by O2, leading to the intermediate C.11h A sequential intramolecular radical
cyclization of the intermediate C affordeed an intermediate D.15 It was noteworthy that the cyclization from the intermediate C to
intermediate D seemed disfavored. However, Han and co-workers found that anti-Baldwin’s rule cyclization was reliable when
peroxy radical was involved.15c Electron rearrangement of the intermediate D together with H-abstraction gave rise to the final
products 2. In some cases, the intermediate A occurred to undergo 5-exo-trig aza-cyclization to form another radical species F,
which was trapped by molecular O2 to provide peroxyl radical species G. Followed anti-Baldwin’s rule 4-endo cyclization and ring
opening, a 5-exo cyclization oxygenated product H was formed. In the process, we reasoned that selectivity of forming intermediate
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B and intermediate F was subjected to stability of their radical intermediates B and F. Electronic effect of the R3 group made
1
2
3
4
significant impact on the stability of the intermediates.
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Scheme 4. Proposed Mechanism
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O
5-exo cyclization
NOR2
R1
[Cu2+
O
]
6-endo
cyclization
[Cu+]
R3
A
O
O
NHOR2
R1
R1
NOR2
R3
OR2
N
1
R1
1
R3
F
R3
O2
B
3
O
O
1
A
O2
NOR2
O
R3
R1
O
2
O
NOR2
R3
R1
R1
OR2
O
A
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E
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G
O
O
R3
NOR2
R3
O
R1
C
O
O
D
O
R1
OR2
O
N
HO
R3
H
In conclusion
We have developed a copper-catalyzed radical cyclization of 2-alkynylbenzamide for the synthesis of isoquinolin-1-one under N2
atmosphere. Interestingly, the above strategy could be used to the formation of 3-hydroxylisoquinolin-1,4-diones as well when the
reaction was conducted in the presence of O2 balloon. Mechanism studies showed that the reaction proceeds in a regioselective
manner via an N-center radical-based 6-endo-dig aza-cyclization pathway.
Experimental Section
General procedure for the synthesis of compound 1a:
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To a solution of 2-iodobenzoyl chloride (4 g, 15.0 mmol) in AcOEt/H2O (v/v = 2:1, 180 mL) were added potassium carbonate (4.14 g,
30 mmol) and methoxyamine hydrochloride (1.5 g, 18.0 mmol). The mixture was stirred at room temperature overnight, and then extracted
with AcOEt (3 × 40 mL), washed with water (50 mL) and brine (50 mL) and dried over MgSO4. Evaporation gave a crude solid that was
recrystallized from AcOEt and collected by filtration. Then 2-iodo-N-methoxybenzamide was provided (white solid, 4.46 g, 84% yield).
Sodium hydride (640 mg, 16 mmol) added into a solution of 2-iodo-N-methoxybenzamide (4.05 g, 14.6 mmol) in dry THF (100 mL) at
0°C. After that, Boc2O (3.83 g, 17.5 mmol) was then added slowly at 0°C. The mixture was stirred at room temperature overnight and then
quenched with saturated aqueous NH4Cl solution (30 mL). The mixture was extracted with AcOEt (3 × 30 mL), washed with saturated
aqueous bicarbonate solution (30 mL), brine (30 mL), and dried over MgSO4. Using flash column chromatography, a white solid tert-butyl
methoxy(2-(phenylethynyl)benzoyl)carbamate was provided (4.80 g, 87% yield).
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To a solution of the above solid tert-butyl methoxy(2-(phenylethynyl)benzoyl)carbamate (1.56 g, 4.4 mmol) in toluene (20 mL) were
successively added PdCl2(PPh3)2 (308.8 mg, 0.44 mmol), CuI (41.9 mg, 0.22 mmol), phenylacetylene (1.4 mL, 13.2 mmol) and tert-
butylamine (0.93 mL , 8.8mmol). The mixture was stirred at 50 °C in oil bath for 3h. After completion of the reaction, the crude was
flitrated by chromatography on silica gel (Pentane/Et2O 9:1 to 8:2) to afford the crude product. Then, the solvent was removed, and
trifluoroacetic acid (3 mL) in CH2Cl2 (5 mL) was added at 0°C The crude mixture was purified by flash chromatography on silica gel to
afford the pure product 1a in (0.905g, 82%) as a white solid. Other substrates 1 were prepared according to the above procedure.
General procedure for the synthesis of compound 2: N-methoxy-2-(phenylethynyl)benzamide 1 (0.2 mmol), CuCl2 (0.02 equiv)
were added to a test tube. Under an oxygen atmosphere the solvent DCE (2.0 mL) was added. The mixture was stirred at 80
oC in heating mantle overnight. After the disappearance of substrate as indicated by TLC, the mixture was filtrated.
Evaporation of the solvent and purification by flash column chromatograph provided the desired products 2.
General procedure for the synthesis of compound 3: N-methoxy-2-(phenylethynyl)benzamide 1 (0.2 mmol), CuCl2 (0.2 equiv)
were added to a test tube. Under a nitrogen atmosphere the solvent DCE (2.0 mL) was added. The mixture was stirred at 80
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oC in heating mantle overnight. After the disappearance of substrate as indicated by TLC, the mixture was filtrated.
Evaporation of the solvent and purification by flash column chromatograph provided the desired products 3.
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General procedure for the synthesis of compound 4: NaH (3 equiv) was added into a stirred solution of 2-methoxy-3-
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phenylisoquinolin-1(2H)-one 2a (0.2 mmol) in DMF (1mL), and the resulting mixture was heated at 120 C in heating mantle
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for 1 h. After the reaction was completed, the reaction mixture was allowed to cool to room temperature, and H2O (8 mL) was
added, followed by extraction with DCM (4 mL × 3). The combined organic layer was dried over anhydrous Na2SO4, filtered
and evaporated under reduced pressure. The residue was purified by flash chromatography to give the products 4 as a white
solid.
N-methoxy-2-(phenylethynyl)benzamide (1a)4c Following the general procedure, 1a was purified by silica gel chromatography (EA/PE =
1/5). Yield: 82%, 906 mg, white solid, mp 107-109 °C;
1H NMR (400 MHz, CDCl3) δ: 9.88 (s, 1H), 7.83 (d, J = 5.8 Hz, 1H), 7.56 – 7.47 (m, 3H), 7.42 – 7.29 (m, 5H), 3.86 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ: 165.1, 133.6, 133.0, 131.5, 130.8, 129.5, 129.1, 128.8, 128.5, 122.0, 119.9, 95.1, 87.1, 64.6
2-((2-chlorophenyl)ethynyl)-N-methoxybenzamide (1b)13 Following the general procedure, 1b was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 76%, 953 mg, white solid, mp 107-109 °C;
1H NMR (400 MHz, CDCl3) δ: 10.19 (s, 1H), 8.11 – 8.05 (m, 1H), 7.61 (m, 2H), 7.50 – 7.42 (m, 3H), 7.35 – 7.27 (m, 2H), 3.90 (s, 3H).
2-((4-fluorophenyl)ethynyl)-N-methoxybenzamide (1c)13 Following the general procedure, 1c was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 75%, 888 mg, white solid, mp 148-150 °C;
1H NMR (400 MHz, CDCl3) δ: 9.62 (s, 1H), 7.89 (d, J = 6.3 Hz, 1H), 7.57 – 7.49 (m, 3H), 7.48 – 7.40 (m, 2H), 7.07 (t, J = 8.5 Hz, 2H),
3.89 (s, 3H).
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N-methoxy-2-((4-nitrophenyl)ethynyl)benzamide (1d) 13 Following the general procedure, 1d was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 69%, 899 mg, white solid, mp 144-146 °C;
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1H NMR (400 MHz, CDCl3) δ: 9.34 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 6.4 Hz, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 7.1
Hz, 1H), 7.52 – 7.42 (m, 2H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 147.4, 133.3, 132.3 (3C), 131.0, 129.7, 129.2, 129.0,
123.7 (3C), 119.4, 92.6, 91.6, 64.7.
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2-((3-fluorophenyl)ethynyl)-N-methoxybenzamide (1e) 13 Following the general procedure, 1e was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 73%, 864 mg, white solid, mp 120-122 °C;
1H NMR (400 MHz, CDCl3) δ: 9.65 (s, 1H), 7.82 (d, J = 6.7 Hz, 1H), 7.55 (d, J = 7.1 Hz, 1H), 7.46 – 7.39 (m, 2H), 7.35 – 7.29 (m, 2H),
7.20 (d, J = 9.5 Hz, 1H), 7.09 – 7.05 (m, 1H), 3.88 (s, 3H).
N,5-dimethoxy-2-(phenylethynyl)benzamide (1g)13 Following the general procedure, 1g was purified by silica gel chromatography (EA/PE
= 1/5). Yield: 80%, 990 mg, white solid, mp 155-158 °C;
1H NMR (400 MHz, CDCl3) δ: 9.98 (s, 1H), 7.52 – 7.45 (m, 4H), 7.40 – 7.33 (m, 3H), 6.99 – 6.96 (m, 1H), 3.89 (s, 3H), 3.84 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ: 164.7, 159.9, 134.9, 134.6, 131.3, 128.9, 128.6, 122.2, 118.1, 114.0, 111.7, 94.0, 87.3, 64.6, 55.6.
5-bromo-N-methoxy-2-(phenylethynyl)benzamide (1h)4c Following the general procedure, 1h was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 80%, 1158 mg, white solid, mp 112-114 °C;
1H NMR (400 MHz, CDCl3) δ: 9.87 (s, 1H), 8.05 (s, 1H), 7.58 – 7.49 (m, 3H), 7.42 – 7.37 (m, 4H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ: 163.6, 134.9, 134.3, 134.0, 132.7, 131.5, 129.4, 128.6, 123.2, 121.6, 118.7, 96.4, 86.3, 64.7.
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5-chloro-N-methoxy-2-(phenylethynyl)benzamide (1i)13 Following the general procedure, 1i was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 78%, 978 mg, white solid, mp 110-112 °C;
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1H NMR (400 MHz, CDCl3) δ: 9.89 (s, 1H), 7.90 (s, 1H), 7.54 – 7.47 (m, 3H), 7.43 – 7.35 (m, 4H), 3.89 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ: 163.7, 135.1, 134.8, 134.2, 131.5, 131.1, 129.9, 129.4, 128.6, 121.5, 118.3, 96.3, 86.2, 64.7.
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5-fluoro-N-methoxy-2-(phenylethynyl)benzamide (1j)13 Following the general procedure, 1j was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 81%, 923 mg, white solid, mp 133-135 °C;
1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.57 – 7.50 (m, 3H), 7.37 –7.34(m, 3H), 7.17 – 7.11 (m, 1H), 3.88 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 162.3 (d, J = 252.2 Hz), 135.7, 135.2 (d, J = 8.0 Hz), 131.4, 129.3, 128.6, 121.7, 118.5 (d, J =
22.3 Hz), 117.0 (d, J = 24.4 Hz), 116.0, 113.5, 95.1, 86.2, 64.6.
2-((4-chlorophenyl)ethynyl)-N-methoxy-5-methylbenzamide (1k)13 Following the general procedure, 1k was purified by silica gel
chromatography (EA/PE = 1/5). Yield:74 %, 974 mg, white solid, mp 105-108 °C;
1H NMR (400 MHz, CDCl3) δ: 9.67 (s, 1H), 7.68 (s, 1H), 7.43 (d, J = 8.1 Hz, 3H), 7.32 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 3.87
(s, 3H), 2.37 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 165.3, 139.6, 135.0, 133.4, 132.9, 132.6, 131.8, 130.2, 128.9, 120.6, 116.6, 93.3,
88.2, 64.6, 21.3.
5-chloro-2-((4-chlorophenyl)ethynyl)-N-methoxybenzamide (1l)13 Following the general procedure, 1l was purified by silica gel
chromatography (EA/PE = 1/5). Yield:70 %, 983 mg, white solid, mp 162-164 °C;
1H NMR (400 MHz, CDCl3) δ: 9.68 (s, 1H), 7.85 (s, 1H), 7.49 – 7.40 (m, 4H), 7.34 (d, J = 8.1 Hz, 2H), 3.88 (s, 3H).
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N-(benzyloxy)-2-(phenylethynyl)benzamide (1m)5d Following the general procedure, 1m was purified by silica gel chromatography
(EA/PE = 1/5). Yield:80 %, 1151 mg, white solid, mp 129-131 °C;
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1H NMR (400 MHz, CDCl3) δ: 9.86 (s, 1H), 7.97 (s, 1H), 7.58 – 7.52 (m, 1H), 7.46 – 7.32 (m, 9H), 7.28 – 7.25 (m, 3H), 5.06 (s, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ: 164.9, 135.3, 133.2, 131.6, 131.0, 129.8, 129.1, 128.8, 128.6, 128.5, 128.5, 121.7, 119.9, 95.5, 87.2,
78.4.
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2-(hex-1-yn-1-yl)-N-methoxybenzamide (1n)4c Following the general procedure, 1n was purified by silica gel chromatography (EA/PE =
1/5). Yield: 65%, 661 mg, white solid, mp 79-81 °C;
1H NMR (400 MHz, CDCl3) δ: 10.08 (s, 1H), 7.94 (d, J = 6.3 Hz, 1H), 7.44 – 7.34 (m, 3H), 3.87 (s, 3H), 2.47 (t, J = 7.1 Hz, 2H), 1.65 –
1.57 (m, 2H), 1.47 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 165.0, 133.3, 132.9, 130.9, 129.8, 128.2, 120.3,
97.4, 79.3, 64.5, 30.4, 22.0, 19.2, 13.5.
N-methoxy-2-(naphthalen-2-ylethynyl)benzamide (1o)13 Following the general procedure, 1o was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 60%, 795 mg, white solid, mp 156-158 °C;
1H NMR (400 MHz, CDCl3) δ: 9.88 (s, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.95 – 7.84 (m, 3H), 7.76 (d, J = 7.1 Hz, 1H), 7.68 (d, J = 7.5 Hz,
1H), 7.61 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.50 – 7.39 (m, 3H), 3.86 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 165.2, 133.5,
133.2, 133.1, 133.0, 131.0, 130.8, 129.7, 129.6, 128.9, 128.4, 127.2, 126.7, 125.9, 125.2, 120.2, 119.6, 93.5, 91.8, 64.6.
N-methoxy-3-(phenylethynyl)-2-naphthamide (1p)4c Following the general procedure, 1p was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 62%, 821 mg, white solid, mp 130-132 °C;
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1H NMR (400 MHz, CDCl3) δ: 9.84 (s, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.89 – 7.83 (m, 3H), 7.66 – 7.57 (m, 4H), 7.47 – 7.39 (m, 3H), 3.94
(s, 3H).13C{1H} NMR (100 MHz, CDCl3) δ: 165.9, 134.0, 132.7, 132.3, 131.6, 129.4, 129.2, 128.7, 128.3, 127.9, 127.7, 127.0, 125.3,
122.0, 118.1, 100.9, 85.1, 64.7.
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N-(allyloxy)-2-(phenylethynyl)benzamide (1q) Following the general procedure, 1q was purified by silica gel chromatography (EA/PE =
1/5). Yield: 40%, 487 mg, white solid, mp 94-96 °C;
1H NMR (400 MHz, CDCl3) δ: 9.82 (s, 1H), 7.94 (d, J = 7.0 Hz, 1H), 7.60 – 7.51 (m, 3H), 7.48 – 7.33 (m, 5H), 6.05 – 5.95 (m, 1H), 5.33
(d, J = 17.2 Hz, 1H), 5.25 – 5.22 (m, 1H), 4.52 (d, J = 6.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ: 164.9, 133.4, 133.1, 132.0, 131.6,
130.9, 129.8, 129.2, 128.8, 128.5, 121.9, 120.8, 119.8, 95.4, 87.2, 77.4; HRMS (ESI-TOF) calcd for C18H16NO2+: 278.1176 (M+H+),
found: 278.1176
N-methoxy-2-((2-methoxyphenyl)ethynyl)benzamide (1r)4c Following the general procedure, 1r was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 81%, 1001 mg, white solid, mp 95-97 °C;
1H NMR (400 MHz, CDCl3) δ: 11.23 (s, 1H), 8.26 – 8.24 (m, 1H), 7.60 – 7.54 (m, 1H), 7.50 – 7.41 (m, 3H), 7.38 – 7.34 (m, 1H), 6.99 –
6.93 (m, 2H), 3.98 (s, 3H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 163.8, 160.2, 133.0, 132.7, 132.0, 131.1, 130.8, 130.7, 128.7,
120.8, 119.5, 111.0, 110.4, 92.7, 92.4, 64.1, 55.8.
N-methoxy-2-(p-tolylethynyl)benzamide (1s)13 Following the general procedure, 1s was purified by silica gel chromatography (EA/PE =
1/5). Yield: 72%, 840 mg, white solid, mp 109-112 °C;
1H NMR (400 MHz, CDCl3) δ: 9.87 (s, 1H), 7.92 (d, J = 6.2 Hz, 1H), 7.58 – 7.52 (m, 1H), 7.45 – 7.38 (m, 4H), 7.17 (d, J = 7.9 Hz, 2H),
3.88 (s, 3H), 2.37 (s, 3H).
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2-(cyclohex-1-en-1-ylethynyl)-N-methoxybenzamide (1t) Following the general procedure, 1t was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 62%, 696 mg, yellow oil.
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1H NMR (400 MHz, CDCl3) δ: 10.00 (s, 1H), 7.97 – 7.90 (m, 1H), 7.48 – 7.30 (m, 3H), 6.31 – 6.19 (m, 1H), 3.87 (s, 3H), 2.23 – 2.11 (m,
4H), 1.69 – 1.56 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3) δ: 164.9, 137.2, 132.9, 132.8, 130.9, 129.8, 128.3, 120.2, 119.9, 97.5, 84.9,
64.6, 28.7, 25.8, 22.1, 21.2; HRMS (ESI-TOF) calcd for C16H18NO2+: 256.1332 (M+H+), found: 256.1332
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2-(cyclopropylethynyl)-N-methoxybenzamide (1u)4c Following the general procedure, 1u was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 67%, 634 mg, white solid, mp 80-82 °C ;
1H NMR (400 MHz, CDCl3) δ: 9.94 (s, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.43 – 7.31 (m, 3H), 3.89 (s, 3H), 1.53 – 1.46 (m, 1H), 0.97 – 0.91
(m, 2H), 0.88 – 0.82 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ: 165.1, 133.2, 133.1, 130.9, 129.7, 128.1, 120.2, 100.4, 74.1, 64.5, 8.8,
0.2.
4-(2-(methoxycarbamoyl)phenyl)-2-methylbut-3-yn-2-yl 4-methylbenzenesulfonate (1v) Following the general procedure, 1v was purified
by silica gel chromatography (EA/PE = 1/5). Yield: 45%, 766 mg, white solid, mp 118-120 °C;
1H NMR (400 MHz, CDCl3) δ:9.92 (s, 1H), 7.88 (d, J = 6.1 Hz, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.43 – 7.37 (m, 2H), 7.37 – 7,33 (m, 1H),
7.30 (d, J = 8.1 Hz, 2H), 3.83 (s, 3H), 2.41 (s, 3H), 1.64 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ: 164.3, 145.5, 134.1, 133.2, 131.4,
130.8, 130.6, 130.0, 129.5 (2C), 118.3, 93.0, 84.5, 64.3, 59.7, 23.2, 21.7; HRMS (ESI-TOF) calcd for C20H22NO5S+: 388.1213 (M+H+),
found: 388.1215
2-(3-(allyloxy)prop-1-yn-1-yl)-N-methoxybenzamide (1w) Following the general procedure, 1w was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 54%, 582 mg, yellow oil.
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1H NMR (400 MHz, CDCl3) δ: 9.97 (s, 1H), 7.59 (d, J = 6.9 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.32 – 7.24 (m, 2H), 5.86 – 5.76 (m, 1H),
5.24 (d, J = 17.2 Hz, 1H), 5.19 – 5.06 (m, 1H), 4.29 (s, 2H), 4.02 (d, J = 5.7 Hz, 2H), 3.74 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ:
164.9, 134.1, 133.6, 133.1, 130.6, 128.9, 128.7, 119.6, 118.1, 90.8, 84.0, 70.8, 64.2, 57.7; HRMS (ESI-TOF) calcd for C14H16NO3+:
246.1125 (M+H+), found: 246.1125
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2-(3-hydroxyprop-1-yn-1-yl)-N-methoxybenzamide (1x) Following the general procedure, 1x was purified by silica gel chromatography
(EA/PE = 1/5). Yield: 44%, 397 mg, white solid, mp 110-112 °C;
1H NMR (400 MHz, CDCl3) δ: 10.13 (s, 1H), 7.68 (d, J = 6.0 Hz, 1H), 7.42 – 7.29 (m, 3H), 4.47 (s, 2H), 3.95 (s, 1H), 3.81 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ: 165.3, 133.7, 133.0, 130.8, 129.1, 128.7, 119.8, 93.7, 82.9, 64.4, 51.1; HRMS (ESI-TOF) calcd for
C11H12NO3+: 206.0812 (M+H+), found: 206.0818
N-methoxy-2-(3-(((13S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-3-yl)oxy)prop-1-yn-1-
yl)benzamide (1y) Following the general procedure, 1y was purified by silica gel chromatography (EA/PE = 1/5). Yield: 38%, 765 mg,
yellow oil.
1H NMR (400 MHz, CDCl3) δ: 9.59 (s, 1H), 7.84 (s, 1H), 7.48 – 7.46 (m, 1H), 7.41 – 7.39 (m, 2H), 7.22 (d, J = 8.6 Hz, 1H), 6.81 – 6.79
(m, 1H), 6.73 (s, 1H), 4.91 (s, 2H), 3.77 (s, 3H), 2.92 – 2.87 (m, 2H), 2.51 – 2.44 (m, 1H), 2.38 – 2.36 (m, 1H), 2.26 – 2.19 (m, 1H), 2.14 –
2.07 (m, 1H), 1.95 – 1.90 (m, 1H), 1.63 – 1.49 (m, 4H), 1.48 – 1.39 (m, 4H), 0.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 220.9,
155.4, 138.1, 133.3, 133.1, 130.8, 129.6, 129.2, 126.5, 118.9, 114.8, 112.2, 104.9, 90.3, 84.9, 64.4, 60.3, 56.3, 50.3, 47.9, 43.9, 38.2, 35.8,
31.5, 29.6, 26.4, 25.8, 21.5, 13.8; HRMS (ESI-TOF) calcd for C29H32NO4+: 458.2326 (M+H+), found: 458.2316
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2-(3-(((3S,8S,10R,13R,14S)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-
cyclopenta[a]phenanthren-3-yl)oxy)prop-1-yn-1-yl)-N-methoxybenzamide (1z) Following the general procedure, 1z was purified by silica
gel chromatography (EA/PE = 1/5). Yield: 39%, 984 mg, white solid, mp 126-128 °C;
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1H NMR (400 MHz, CDCl3) δ: 9.77 (s, 1H), 7.91 (s, 1H), 7.50 – 7.38 (m, 3H), 5.38 – 5.32 (m, 1H), 4.45 (d, J = 1.7 Hz, 2H), 3.89 (s, 3H),
3.45 – 3.36 (m, 1H), 2.44 – 2.37 (m, 1H), 2.29 – 2.20 (m, 1H), 2.03 – 1.75 (m, 6H), 1.60 – 1.41 (m, 7H), 1.40 – 1.21 (m, 5H), 1.21 – 1.01
(m, 8H), 0.99 (s, 3H), 0.90 (d, J = 6.3 Hz, 3H), 0.84 (d, J = 6.6 Hz, 6H), 0.66 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 164.7, 140.2,
133.5, 133.3, 130.9, 129.7, 129.0, 122.1, 119.2, 92.4, 83.7, 78.7, 64.5, 56.7, 56.0, 55.8, 50.0, 42.2, 39.7, 39.4, 38.7, 37.0, 36.8, 36.1, 35.7,
31.9, 31.8, 28.2, 28.1, 28.0, 24.2, 23.8, 22.8, 22.5, 21.0, 19.3, 18.7, 11.8; HRMS (ESI-TOF) calcd for C38H56NO3+: 574.4255 (M+H+),
found: 574.4255
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3-hydroxy-2-methoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (2a)13 Following the general procedure, 2a was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 51%, 29 mg, white solid, mp 138-140 °C;
1H NMR (400 MHz,CDCl3) δ: 8.35 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.82 – 7.78 (m, 1H), 7.67 – 7.63 (m, 1H), 7.41 – 7.39
(m, 2H), 7.31 – 7.27 (m, 3H), 4.93 (s, 1H), 4.04 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.7, 161.5, 136.5, 135.7, 133.4, 130.7,
129.4, 129.1, 128.9, 128.7, 127.5, 126.4, 93.9, 65.3. IR(neat) 3264, 3059, 2937, 1702, 1644, 1579, 1385, 1283, 1132, 993, 869, 757;
HRMS (ESI-TOF) calcd for C16H14NO4+: 284.0917 (M+H+), found: 284.0910
3-(2-chlorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquinoline-1,4-dione (2b) Following the general procedure, 2b was purified by
silica gel chromatography (EA/PE = 1/5). Yield: 53%, 36 mg, white solid, mp 153-155 °C;
1H NMR (400 MHz, CDCl3) δ: 8.14 – 8.09 (m, 3H), 7.78 – 7.70 (m, 2H), 7.47 – 7.43 (m, 1H), 7.40 – 7.32 (m, 2H), 5.60 (s, 1H),
3.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 188.5, 161.3, 135.1, 135.0, 133.3, 131.7, 130.6, 130.1, 130.0, 129.8, 128.6,
127.2, 127.0, 90.3, 63.6. IR(neat) 3348, 3227, 2943, 1700, 1655, 1598, 1367, 1284, 1133, 993, 858, 763, 715; HRMS (ESI-
TOF) calcd for C16H13ClNO4+: 318.0528 (M+H+), found: 318.0516
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3-(4-fluorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquinoline-1,4-dione (2c)13 Following the general procedure, 2c was purified by
silica gel chromatography (EA/PE = 1/5). Yield: 47%, 36 mg, white solid, mp 160-162 °C;
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1H NMR (400 MHz, CDCl3) δ: 8.37 (d, J = 7.7 Hz, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.69 (t, J = 7.5 Hz,
1H), 7.42 – 7.35 (m, 2H), 7.00 – 6.96 (m, 2H), 4.78 (s, 1H), 4.05 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.6, 163.2 (d, J
= 249.4 Hz), 161.4, 135.9, 133.5, 132.3 (d, J = 2.9 Hz), 130.6, 128.9, 128.8, 128.5 (d, J = 8.7 Hz), 127.5, 116.0 (d, J = 22.0
Hz), 93.3, 65.4. IR(neat) 3271, 2934, 1701, 1648, 1508, 1284, 1230, 1135, 995, 873, 842, 694; HRMS (ESI-TOF) calcd for
C16H13FNO4+: 302.0823 (M+H+), found: 302.0829
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3-hydroxy-2-methoxy-3-(4-nitrophenyl)-2,3-dihydroisoquinoline-1,4-dione (2d) Following the general procedure, 2d was purified by
silica gel chromatography (EA/PE = 1/5). Yield: 65%, 43mg, white solid, mp 136-138 °C;
1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 7.7 Hz, 1H), 8.16 – 8.14 (m, 2H), 7.96 (d, J = 7.7 Hz, 1H), 7.90 – 7.86 (m, 1H), 7.74
– 7.70 (m, 1H), 7.61 – 7.59 (m, 2H), 5.00 (s, 1H), 4.04 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.1, 161.3, 148.4, 143.5,
136.4, 133.8, 130.6, 129.0, 128.7, 127.8, 127.7, 124.0, 93.1, 65.5. IR(neat) 3276, 3077, 2920, 1706, 1665, 1523, 1347, 996,
837, 712; HRMS (ESI-TOF) calcd for C16H13N2O6+: 329.0768 (M+H+), found: 329.0792
3-(3-fluorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquinoline-1,4-dione (2e) Following the general procedure, 2e was purified by
silica gel chromatography (EA/PE = 1/5). Yield: 49%, 30 mg, white solid, mp 128-130 °C;
1H NMR (400 MHz, CDCl3) δ: 8.34 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.84 – 7.80 (m, 1H), 7.70 – 7.66 (m, 1H), 7.26
– 7.10 (m, 3H), 6.99 – 6.99 (m, 1H), 5.14 (s, 1H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.4, 162.9 (d, J = 247.9
Hz), 161.2, 139.2 (d, J = 6.8 Hz), 135.9, 133.5, 130.6, 130.4 (d, J = 8.1 Hz), 129.0, 128.8, 127.5, 121.9 (d, J = 3.1 Hz), 116.5
(d, J = 21.2 Hz), 114.0 (d, J = 23.5 Hz), 93.2, 65.4. IR(neat) 3259, 2940, 1701, 1647, 1442, 1383, 1271, 1133, 1003, 827, 803,
717; HRMS (ESI-TOF) calcd for C16H13FNO4+: 302.0823 (M+H+), found: 302.0812
3-hydroxy-2-methoxy-3-(thiophen-2-yl)-2,3-dihydroisoquinoline-1,4-dione (2f) Following the general procedure, 2f was purified by silica
gel chromatography (EA/PE = 1/5). Yield: 40%, 35 mg, white solid, mp 145-147 °C;
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1H NMR (400 MHz, CDCl3) δ: 7.93 – 7,91 (m, 1H), 7.61 – 7.57 (m, 3H), 7.35 –7.32(m, 2H), 6.95 (t, J = 4.4 Hz, 1H), 5.96 (s,
1H), 4.01 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 186.5, 164.1, 141.2, 136.5, 135.8, 135.6, 133.7, 131.0, 129.6, 128.7,
124.2, 122.9, 89.8, 66.2. IR(neat) 3214, 2925, 1702, 1654, 1411, 1352, 1126, 1065, 1000, 821, 724; HRMS (ESI-TOF) calcd
for C14H12NO4S+: 290.0482 (M+H+), found: 290.0480
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3-hydroxy-2,7-dimethoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (2g)13 Following the general procedure, 2g was purified by silica
gel chromatography (EA/PE = 1/5). Yield: 48%, 30 mg, white solid, mp 148-151 °C;
1H NMR (400 MHz, CDCl3) δ: 7.89 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.40 – 7.39 (m, 2H), 7.28 (s, 3H), 7.13 (d, 1H), 4.81 (s,
1H), 4.04 (s, 3H), 3.96 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 189.5, 165.8, 161.1, 137.0, 133.5, 129.9, 129.2, 128.8,
126.2, 122.0, 120.6, 111.8, 93.5, 65.2, 56.1. IR(neat) 3261, 3053, 2943, 1686, 1639, 1594, 1448, 1282, 1132, 999, 874, 758;
HRMS (ESI-TOF) calcd for C17H16NO5+: 314.1023 (M+H+), found: 314.1027
7-bromo-3-hydroxy-2-methoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (2h) Following the general procedure, 2h was purified by
silica gel chromatography (EA/PE = 1/5). Yield: 43%, 31 mg, white solid, mp 175-177 °C;
1H NMR (400 MHz, CDCl3) δ: 8.50 (s, 1H), 7.79 (s, 2H), 7.39 – 7.37 (m, 2H), 7.33 – 7.29 (m, 3H), 4.75 (s, 1H), 4.04 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ: 189.8, 160.2, 136.7, 136.2, 132.0, 131.8, 131.6, 129.6, 129.1, 128.9, 127.7, 126.3, 93.9,
65.4. IR(neat) 3277, 2955, 2924, 2854, 1700, 1641, 1581, 1351, 1020, 997, 875, 716; HRMS (ESI-TOF) calcd for
C16H13BrNO4+: 362.0022 (M+H+), found: 362.0022
7-chloro-3-hydroxy-2-methoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (2i) Following the general procedure, 2i was purified by silica
gel chromatography (EA/PE = 1/5). Yield: 47%, 30 mg, white solid, mp 163-165 °C;
1H NMR (400 MHz, CDCl3) δ: 8.30 (s, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.62 – 7.59 (m, 1H), 7.41 – 7.36 (m, 2H), 7.31 – 7.30 (m,
3H), 4.98 (s, 1H), 4.03 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 189.6, 160.3, 142.8, 136.2, 133.6, 132.2, 129.6, 129.0,
128.9, 128.8, 127.4, 126.3, 93.9, 65.4. IR(neat) 3287, 2943, 1701, 1646, 1586, 1354, 1136, 977, 875, 747, 718, 690; HRMS
(ESI-TOF) calcd for C16H13ClNO4+: 318.0528 (M+H+), found: 318.0533
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7-fluoro-3-hydroxy-2-methoxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (2j)13 Following the general procedure, 2j was purified by
silica gel chromatography (EA/PE = 1/5). Yield: 49%, 24 mg, white solid, mp 133-135 °C;
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1H NMR (400 MHz,CDCl3) δ: 8.00 – 7.95 (m, 2H), 7.39 – 7.38 (m, 2H), 7.35 – 7.28 (m, 4H), 4.94 (s, 1H), 4.04 – 4.01 (m, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ: 189.2, 167.2 (d, J = 260.4 Hz), 160.2, 136.3, 134.0 (d, J = 9.6 Hz), 130.8 (d, J = 9.5 Hz),
129.6, 129.0, 126.3, 125.6, 121.0 (d, J = 22.7 Hz), 115.7 (d, J = 24.5 Hz), 93.9, 65.3. IR(neat) 3296, 3083, 2946, 1699, 1647,
1602, 1441, 1277, 1156, 1008, 763, 730; HRMS (ESI-TOF) calcd for C16H13FNO4+: 302.0823 (M+H+), found: 302.0822
3-(4-chlorophenyl)-3-hydroxy-2-methoxy-7-methyl-2,3-dihydroisoquinoline-1,4-dione (2k)13 Following the general procedure,2k was
purified by silica gel chromatography (EA/PE = 1/5). Yield: 53%, 35 mg, white solid, mp 158-160 °C;
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1H NMR (400 MHz, CDCl3) δ: 8.12 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.48 – 7.43 (m, 1H), 7.34 – 7.32 (m, 2H), 7.25 – 7.23 (m,
2H), 5.05 (s, 1H), 4.02 (s, 3H), 2.49 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.2, 161.5, 147.7, 135.5, 135.3, 134.3,
130.5, 129.1, 129.0, 127.9, 127.7, 126.5, 93.3, 65.3, 22.1. IR(neat) 3260, 2940, 1701, 1644, 1599, 1350, 1288, 1160, 1006,
877,826, 742; HRMS (ESI-TOF) calcd for C17H15ClNO4+: 332.0684 (M+H+), found: 332.0648
7-chloro-3-(4-chlorophenyl)-3-hydroxy-2-methoxy-2,3-dihydroisoquinoline-1,4-dione (2l) Following the general procedure, 2l was
purified by silica gel chromatography (EA/PE = 1/5). Yield: 61%, 43 mg, white solid, mp 147-149 °C;
1H NMR (400 MHz, CDCl3) δ: 8.33 – 8.24 (m, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.66 – 7.61 (m, 1H), 7.34 – 7.26 (m, 4H), 4.92 (s,
1H), 4.02 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 189.4, 160.2, 143.1, 135.9, 134.8, 133.8, 132.0, 129.2, 129.1, 128.9,
127.8, 127.2, 93.4, 65.4. IR(neat) 3314, 2940, 1706, 1644, 1587, 1347, 1139, 1000, 877, 824, 742; HRMS (ESI-TOF) calcd for
C16H12Cl2NO4+: 352.0138 (M+H+), found: 352.0118
2-(benzyloxy)-3-hydroxy-3-phenyl-2,3-dihydroisoquinoline-1,4-dione (2m) Following the general procedure, 2m was purified by silica gel
chromatography (EA/PE = 1/5). Yield: 50%, 36 mg, white solid, mp 115-117 °C;
1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J = 7.8 Hz, 1H), 7.96 (d, J = 7.7 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 7.6 Hz,
1H), 7.48 – 7.41 (m, 4H), 7.33 – 7.27 (m, 6H), 5.22 (s, 2H), 4.63 (s, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ: 190.8, 161.7,
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136.7, 135.7, 134.9, 133.4, 130.8, 129.6, 129.3, 129.2, 128.9, 128.7 (2C), 128.3, 127.5, 126.4, 93.8, 79.6. IR(neat) 3309,
3053, 2955, 2925, 1698, 1646, 1447, 1362, 1284, 976, 757, 693; HRMS (ESI-TOF) calcd for C22H18NO4+: 360.1230 (M+H+),
found: 360.1246
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3-hydroxy-2-methoxy-3-(naphthalen-1-yl)-2,3-dihydroisoquinoline-1,4-dione (2o) and 3-(1-naphthoyl)-3-hydroxy-2-methoxyisoindolin-1-
one (2o') Following the general procedure, 2o and 2o' was purified by silica gel chromatography (EA/PE = 1/5). Total yield 71% (2o:2o’ =
1:2), 47 mg, white solid.13
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1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 7.7 Hz, 0.7H), 8.00 (d, J = 7.8 Hz, 1.2H), 7.89 – 7.78 (m, 5.2 H), 7.75 – 7.64 (m, 3 H), 7.57 –
7.34 (m, 8.2 H), 7.25 – 7.16 (m, 2H), 6.04 (s, 1.2H), 4.86 (s, 0.6H), 4.12 (s, 3H), 3.53 (s, 1.6H). 13C{1H} NMR (100 MHz, CDCl3) δ: 199.1,
189.0, 164.4, 162.6, 139.6, 135.4, 134.2, 133.6, 133.5, 133.3, 132.5, 131.6, 130.8, 130.7, 130.1, 129.9, 129.8, 129.1, 128.7, 128.4, 127.6,
127.6, 126.6, 126.4, 126.3, 125.7, 125.1, 125.0, 124.8, 124.4, 124.1, 123.9, 122.4, 91.8, 66.5, 64.5. IR(neat) 3304, 2940, 1705, 1652, 1593,
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1358, 1283, 1081, 1008, 870, 796, 723; HRMS (ESI-TOF) calcd for C20H16NO4 : 334.1074 (M+H+), found: 334.1076
2-methoxy-3-phenylisoquinolin-1(2H)-one (3a)4 Following the general procedure, 3a was purified by silica gel chromatography (EA/PE =
1/10). Yield: 82%, 41 mg, white solid, mp 108-110 °C;
1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 8.0 Hz, 1H), 7.65 – 7.59 (m, 3H), 7.53 – 7.42 (m, 5H), 6.45 (s, 1H), 3.67 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ: 158.6, 142.0, 135.7, 132.5, 132.4, 129.2 (2C), 128.2, 127.7, 126.6, 126.2, 126.2, 106.7,
63.4. IR(neat) 3056, 2985, 2937, 1656, 1624, 1603, 1480, 1173, 985, 835, 782, 710, 686
7-fluoro-2-methoxy-3-phenylisoquinolin-1(2H)-one (3b) Following the general procedure, 3b was purified by silica gel chromatography
(EA/PE = 1/10). Yield: 67%, 36 mg, white solid, mp 128-130 °C;
1H NMR (400 MHz, CDCl3) δ: 8.11 – 8.05 (m, 1H), 7.61 – 7.58 (m, 2H), 7.54 – 7.50 (m, 1H), 7.46 – 7.44 (m, 3H), 7.39 – 7.34
(m, 1.3 Hz, 1H), 6.45 (s, 1H), 3.67 (d, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 161.2 (d, J = 248.3 Hz), 157.8 (d, J = 3.5 Hz), 141.3
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(d, J = 2.9 Hz), 132.2, 129.3, 129.2, 128.6 (d, J = 8.0 Hz), 128.2, 127.8 (d, J = 8.2 Hz), 125.9, 121.4 (d, J = 23.8 Hz), 112.8 (d, J = 23.1
Hz), 106.1, 63.4. IR(neat) 3065, 2982, 2931, 1655, 1626, 1596, 1492, 1245, 884, 790, 693; HRMS (ESI-TOF) calcd for
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C16H13FNO2 : 270.0925 (M+H+), found: 270.0929
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2,7-dimethoxy-3-phenylisoquinolin-1(2H)-one (3c) Following the general procedure, 3c was purified by silica gel chromatography (EA/PE
= 1/10). Yield: 82%, 46 mg, white solid, mp 146-148 °C;
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1H NMR (400 MHz, CDCl3) δ: 7.83 (d, J = 2.1 Hz, 1H), 7.62 – 7.57 (m, 2H), 7.45 – 7.43 (m, 4H), 7.26 – 7.23 (m, 1H), 6.43 (s,
1H), 3.92 (s, 3H), 3.67 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.6, 158.3, 139.6, 132.6, 129.8, 129.3, 128.9, 128.1,
127.9, 127.5, 123.3, 107.3, 106.6, 63.3, 55.7. IR(neat) 2391, 2845, 1650, 1633, 1573, 1495, 1363, 1256, 1008, 852,788;
HRMS (ESI-TOF) calcd for C17H16NO3+: 282.1125 (M+H+), found: 282.1117
3-(4-chlorophenyl)-2-methoxy-7-methylisoquinolin-1(2H)-one (3d) Following the general procedure, 3d was purified by silica gel
chromatography (EA/PE = 1/10). Yield: 75%, 45 mg, white solid, mp 137-139 °C;
1H NMR (400 MHz, CDCl3) δ: 8.22 (s, 1H), 7.53 (d, J = 7.8 Hz, 2H), 7.46 – 7.38 (m, 4H), 6.40 (s, 1H), 3.65 (s, 3H), 2.46 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.5, 139.8, 137.1, 135.2, 134.1, 133.2, 131.0, 130.5, 128.4, 127.3, 126.2, 126.2,
106.8, 63.3, 21.4. IR(neat) 3086, 2982, 2931, 1651, 1608, 1496, 1340, 1090, 989, 861, 834, 691; HRMS (ESI-TOF) calcd for
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C17H15ClNO2 : 300.0786 (M+H+), found: 300.0740
7-bromo-2-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (3e) Following the general procedure, 3e was purified by silica gel
chromatography (EA/PE = 1/10). Yield: 74%, 53 mg, white solid, mp 148-150 °C;
1H NMR (400 MHz, CDCl3) δ: 8.55 (s, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 6.96 (d,
J = 8.5 Hz, 2H), 6.38 (s, 1H), 3.85 (s, 3H), 3.66 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 160.4, 157.6, 142.4, 135.5, 134.5,
130.6, 130.2, 127.7, 127.3, 124.4, 120.1, 113.7, 105.5, 63.3, 55.3. IR(neat) 2968, 2923, 1666, 1617, 1606, 1505, 1238, 1177,
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1026, 859, 847; HRMS (ESI-TOF) calcd for C17H15BrNO3 : 360.0230 (M+H+), found: 360.0252
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7-chloro-2-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (3f) Following the general procedure, 3f was purified by silica gel
chromatography (EA/PE = 1/10). Yield: 82%, 52 mg, white solid, mp 133-135 °C;
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1H NMR (400 MHz, CDCl3) δ: 8.37 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 3H), 7.42 (d, J = 8.5 Hz, 1H), 6.95 (d, J = 8.8 Hz,
2H), 6.38 (s, 1H), 3.85 (s, 3H), 3.65 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 160.4, 157.7, 142.2, 134.2, 132.8, 132.3,
130.6, 127.7, 127.1, 127.0, 124.4, 113.6, 105.5, 63.3, 55.3. IR(neat) 2970,2925, 1667, 1616, 1606, 1505, 1476, 1238, 1177,
1026, 848; HRMS (ESI-TOF) calcd for C17H15ClNO3+: 316.0735 (M+H+), found: 316.0739
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2-methoxy-3-phenylbenzo[g]isoquinolin-1(2H)-one (3h) Following the general procedure, 3h was purified by silica gel chromatography
(EA/PE = 1/15). Yield: 56%, 34 mg, white solid, mp 155-157 °C;
1H NMR (400 MHz, CDCl3) δ: 8.38 (t, J = 8.7 Hz, 2H), 7.89 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.69 – 7.57 (m, 4H),
7.49 – 7.48 (m, 3H), 7.21 (s, 1H), 3.73 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.5, 142.8, 134.8, 134.2, 132.6, 129.3
(2C), 128.8, 128.4, 128.3, 128.2, 127.2, 126.8, 123.9, 123.7, 123.5, 102.4, 63.5. IR(neat) 3059, 2988, 2940, 1650, 1619,
1607, 1435, 1366, 1072, 989, 819, 765, 710; HRMS (ESI-TOF) calcd for C20H16NO2+: 302.1176 (M+H+), found: 302.1170
2-(allyloxy)-3-phenylisoquinolin-1(2H)-one (3i) Following the general procedure, 3i was purified by silica gel chromatography (EA/PE =
1/10). Yield: 80%, 44 mg, white solid, mp 100-102 °C;
1H NMR (400 MHz, CDCl3) δ: 8.45 (d, J = 8.0 Hz, 1H), 7.66 – 7.58 (m, 3H), 7.53 – 7.43 (m, 5H), 6.46 (s, 1H), 5.66 – 5.54 (m,
1H), 5.07 (t, J = 13.7 Hz, 2H), 4.39 (d, J = 6.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 158.9, 142.6, 135.7, 132.8, 132.4,
130.6, 129.5, 129.1, 128.1, 127.7, 126.6, 126.2, 121.6, 106.4, 76.8. IR(neat) 3062, 2920, 2863, 1652, 1618, 1482, 1176, 980,
910, 756, 699, 687; HRMS (ESI-TOF) calcd for C18H16NO2+: 278.1176 (M+H+), found: 278.1178
2-(benzyloxy)-3-phenylisoquinolin-1(2H)-one (3j) Following the general procedure, 3j was purified by silica gel chromatography (EA/PE
= 1/10). Yield: 60%, 39 mg, white solid, mp 114-116 °C;
1H NMR (400 MHz, CDCl3) δ: 8.51 (d, J = 8.0 Hz, 1H), 7.68 – 7.64 (m, 1H), 7.55 – 7.40 (m, 7H), 7.28 – 7.24 (m, 1H), 7.21 –
7.17 (m, 2H), 6.97 – 6.95 (m, 2H), 6.46 (s, 1H), 4.88 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.8, 142.7, 135.8, 133.3,
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132.8, 132.4, 130.0, 129.6, 129.1, 128.8, 128.3, 128.0, 127.7, 126.6, 126.3, 126.2, 106.4, 77.6. IR(neat) 3059, 3024, 2922,
1650, 1625, 1480, 1173, 966, 769, 751, 718, 688; HRMS (ESI-TOF) calcd for C22H18NO2+: 328.1332 (M+H+), found: 328.1330
2-methoxy-3-(4-methoxyphenyl)isoquinolin-1(2H)-one (3k)1 Following the general procedure, 3k was purified by silica gel
chromatography (EA/PE = 1/10). Yield: 79%, 44 mg, white solid, mp 130-132 °C;
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1H NMR (400 MHz, CDCl3) δ: 8.43 (d, J = 7.4 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.7 Hz,
1H), 7.43 (t, J = 6.8 Hz, 1H), 6.95 (d, J = 7.9 Hz, 2H), 6.40 (s, 1H), 3.85 (s, 3H), 3.67 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ: 160.3, 141.8, 135.9, 132.4, 130.6, 127.7, 126.4, 126.1, 124.8, 113.6, 106.3, 63.2, 55.3. IR(neat) 3068, 2976, 1655, 1620,
1512, 1292, 1258, 1176, 990, 829, 753; HRMS (ESI-TOF) calcd for C17H16NO3+: 282.1125 (M+H+), found: 282.1123
2-methoxy-3-(2-methoxyphenyl)isoquinolin-1(2H)-one (3l) Following the general procedure, 3l was purified by silica gel chromatography
(EA/PE = 1/10). Yield: 90%, 51 mg, white solid, mp 150-152 °C;
1H NMR (400 MHz, CDCl3) δ: 8.45 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.2 Hz, 1H), 7.50 – 7.41 (m, 3H), 7.33 (d, J = 7.1 Hz, 1H),
7.04 – 6.95 (m, 2H), 6.39 (s, 1H), 3.78 (s, 3H), 3.72 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.6, 157.6, 139.9, 135.9,
132.2, 130.9, 130.7, 127.6, 126.5, 126.4, 126.1, 122.1, 120.2, 110.8, 106.7, 63.6, 55.6. IR(neat) 3059, 2925, 1647, 1621,
1593, 1494, 1255, 1018, 993, 765, 752; HRMS (ESI-TOF) calcd for C17H16NO3+: 282.1125 (M+H+), found: 282.1113
2-methoxy-3-(p-tolyl)isoquinolin-1(2H)-one (3m) Following the general procedure, 3m was purified by silica gel chromatography (EA/PE
= 1/10). Yield: 73%, 39 mg, white solid, mp 132-134 °C;
1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 8.1 Hz, 1H), 7.65 – 7.60 (m, 1H), 7.51 (d, J = 8.0 Hz, 3H), 7.48 – 7.44 (m, 1H), 7.28
– 7.23 (m, 2H), 6.44 (s, 1H), 3.68 (s, 3H), 2.42 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.7, 142.1, 139.3, 135.8,132.4,
129.6, 129.1, 128.9, 127.7, 126.4, 126.1, 125.7, 106.5, 63.3, 21.3. IR(neat) 3053, 3027, 2934, 1657, 1619, 1510, 1435, 1172,
986, 828, 810, 689; HRMS (ESI-TOF) calcd for C17H16NO2+: 266.1176 (M+H+), found: 266.1178
3-(4-fluorophenyl)-2-methoxyisoquinolin-1(2H)-one (3n) Following the general procedure, 3n was purified by silica gel chromatography
(EA/PE = 1/10). Yield: 67%, 36 mg, white solid, mp 131-133 °C;
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1H NMR (400 MHz, CDCl3) δ: 8.44 (d, J = 8.1 Hz, 1H), 7.67 – 7.59 (m, 3H), 7.53 – 7.46 (m, 2H), 7.17 – 7.12 (m, 2H), 6.44 (s,
1H), 3.68 (d, J = 1.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 163.2 (d, J = 249.7 Hz), 158.6, 141.0, 135.6, 132.5, 131.2 (d,
J = 8.4 Hz), 128.5 (d, J = 3.5 Hz), 127.8, 126.7, 126.3, 126.2, 115.3 (d, J = 21.8 Hz), 106.7, 63.4. IR(neat) 3053, 2997, 2934,
1656, 1504, 1337, 1218, 1165, 757, 687, 614; HRMS (ESI-TOF) calcd for C16H13FNO2+: 270.0925 (M+H+), found: 270.0921
3-(2-chlorophenyl)-2-methoxyisoquinolin-1(2H)-one (3o) Following the general procedure, 3o was purified by silica gel chromatography
(EA/PE = 1/10). Yield: 87%, 50 mg, white solid, mp 153-155 °C;
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1H NMR (400 MHz, CDCl3) δ: 8.48 (d, J = 8.0 Hz, 1H), 7.67 – 7.64 (m, 1H), 7.55 – 7.48 (m, 3H), 7.47 – 7.39 (m, 2H), 7.37 –
7.33 (m, 1H), 6.41 (s, 1H), 3.75 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.4, 139.4, 135.4, 134.3, 132.5, 131.9, 131.3,
130.6, 129.6, 127.7, 126.9, 126.8, 126.4, 126.3, 107.1, 63.7. IR(neat) 3062, 2985, 2937, 1657, 1626, 1430, 1381, 1251, 1175,
990, 826, 769; HRMS (ESI-TOF) calcd for C16H13ClNO2+: 286.0629 (M+H+), found: 286.0625
2-methoxy-3-(thiophen-2-yl)isoquinolin-1(2H)-one (3p) Following the general procedure, 3p was purified by silica gel chromatography
(EA/PE = 1/10). Yield: 49%, 25 mg, yellow solid, mp 100-102 °C;
1H NMR (400 MHz, CDCl3) δ: 8.42 (d, J = 8.0 Hz, 1H), 7.65 – 7.62 (m, 1H), 7.57 (d, J = 3.3 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H),
7.48 – 7.45 (m, 2H), 7.14 – 7.10 (m, 1H), 6.74 (s, 1H), 3.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ: 158.7, 135.6, 135.5,
132.7, 132.5, 128.9, 128.5, 127.7, 127.2, 126.7, 126.2, 125.8, 105.5, 63.6. IR(neat) 3071, 2931, 1664, 1611, 1554, 1334,
1265, 1170, 985, 706, 685; HRMS (ESI) calcd for C14H12NO2S+: 258.0583 (M+H+), found: 258.0587
2-methoxy-3-(naphthalen-2-yl)isoquinolin-1(2H)-one (3q) Following the general procedure, 3q was purified by silica gel chromatography
(EA/PE = 1/10). Yield: 83%, 50 mg, white solid, mp 150-152 °C;
1H NMR (400 MHz, CDCl3) δ: 8.54 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.3 Hz,
1H), 7.70 –7.66 (m, 1H), 7.61 – 7.59 (m, 1H), 7.57 – 7.52 (m, 4H), 7.50 – 7.44 (m, 1H), 6.52 (s, 1H), 3.64 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ: 158.6, 141.0, 135.8, 133.1, 132.5, 132.1, 130.5, 129.9, 128.2, 127.8, 127.7, 126.8, 126.8, 126.7,
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