Copper-Mediated Oxidative Functionalization of C(sp3)-H Bonds with Isoquinolines: Two-Step Synthesis of 5-Oxaprotoberberinones

Article abstract of DOI:10.1021/acs.joc.6b02145

A copper-mediated oxidative functionalization of C(sp³)-H bonds with isoquinolines via a radical process without ligands was achieved. The present system exhibits a novel pathway for the preparation of N-alkyl (benzyl) isoquinolin-1(2H)-ones in moderate to high yields. In addition, this procedure provides a simple method to afford 5-oxaprotoberberinones and their derivatives in two steps.

Full text of DOI:10.1021/acs.joc.6b02145

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Article
Copper-mediated Oxidative Functionalization of C(sp3)-H Bonds
with Isoquinolines: Two-step Synthesis of 5-Oxaprotoberberinones
Dingyi Wang, Rongxing Zhang, Ruihong Deng, Sen Lin, Shengmei Guo, and Zhaohua Yan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02145 • Publication Date (Web): 13 Oct 2016
Downloaded from http://pubs.acs.org on October 14, 2016
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Copper-mediated Oxidative Functionalization of C(sp3)-H Bonds
with Isoquinolines: Two-step Synthesis of 5-Oxaprotoberberinones
Dingyi Wang, Rongxing Zhang, Ruihong, Deng, Sen Lin*, Shengmei Guo and Zhaohua Yan*
College of Chemistry, Nanchang University, Nanchang, Jiangxi 330031, China.
E-mail: senlin@ncu.edu.cn yanzh@ncu.edu.cn
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Abstract:
A copperꢀmediated oxidative functionalization of C(sp3)ꢀH bonds with isoquinolines via a
radical process without ligands was achieved. The present system exhibits a novel pathway for the
preparation of Nꢀalkyl (benzyl) isoquinolinꢀ1(2H)ꢀones in moderate to high yields. In addition,
this procedure provides a simple method to afford 5ꢀoxaprotoberberinones and their derivatives by
two steps.
Introduction
Isoquinolinꢀ1(2H)ꢀones are important structural motifs found in natural products.1 Therefore,
isoquinolinꢀ1(2H)ꢀones have been employed in the synthesis of pharmaceutical compounds, such
as dehydrogusanlung D, 6H,8Hꢀisoquino[2,3ꢀc][1,3]benzoxazinꢀ8ꢀone (1ab), and isoindolo
[2,1ꢀb]isoquinolinꢀ5(7H)ꢀone (Figure 1).2 From the foregoing, the studying on the synthetic
method of isoquinolinꢀ1(2H)ꢀones becomes significant. However, after a brief survey of the
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literature, we have found a lack of general methods for the preparation of these kinds of
compounds. Meanwhile, most of the synthesis of these compounds involved various expensive
metals as catalysts3.
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Figure 1. Examples of isoquinolinꢀ1(2H)ꢀoneꢀfused natural products and pharmaceutics.
Over the past few decades, there were some ways to synthesize Nꢀalkylisoquinolinꢀ1(2H)ꢀones.4
For example, Carlos4a disclosed that CpRuCl(PPh3)2 could catalyze cycloisomerizations of
aromatic homoꢀ and bisꢀhomopropargy licamines/amides to afford several nitrogen heterocyclic
rings in high yields. Anderson4f disclosed that the conversion of Oꢀalkylated 2ꢀhydroxy pyridines,
quinolines, and pyrimidines promoted by LiI gave the corresponding Nꢀalkylated heterocycles via
Oꢀ to Nꢀalkyl migration. However, these methods are often limited for involving expensive noble
metal catalysts, complicated ligands and infrequent substrates. For the preparation of
Nꢀbenzylisoquinolinꢀ1(2H)ꢀones, only a few methods were reported using isoquinolines as a
substrate. Examples include work by Arakawa5 and coꢀworkers who reported that
Nꢀbenzylisoquinolinꢀ1(2H)ꢀones were generated in low yields by treating isoquinolines with
benzyl bromides in the presence of a large amount of K3Fe(CN)6 and KOH. Recently, Yang6
disclosed a novel method to produce Nꢀbenzylisoquinolinꢀ1(2H)ꢀones in moderate to high yields
utilizing isoquinolines and toluene (2a) as reactants in the presence of catalytic amount of iodine
as the initiator. This method is simple and highly effective. However a limitation of this procedure
is that only toluenes and their derivatives acted as the effective substrates because the reaction
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occurred in the presence of benzyl iodides intermediate. C–N bond formation via C(sp3)−H
activation of alkyl/benzyl has gained much interest in recent years7. Wide variety of Cu salts has
been employed in these reactions.8 Therefore, we tried to find reaction system which has the wider
scope of substrates to achieve the construction of Nꢀalkyl(benzyl)isoquinolinꢀ1(2H)ꢀones via
C(sp3)−H activation. Herein, we would like to report an effective method of oxidative
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functionalization of various C (sp3)ꢀH bonds with isoquinolines via a radical process (Scheme 1).
Carlos' work
CpRuCl(PPh3)2
N
NH
alkyl
Ar
alkyl
O
N
O
Yang's work
toluenes
benzyl iodide
intermediate
I2
N
O
TBHP
alkenes
No Reaction
This work
or ethers
[Cu]
DTBP
N
+
H-Csp3
N
Csp3
radical pathway
toluenes, alkenes
or ethers
O
Scheme 1. Various pathways for the construction of Nꢀsubstituted isoquinolinꢀ1(2H)ꢀones.
Results and Discussion
The initial explorations were completed by using isoquinoline (2a) and toluene (3a) as
substrates under different reaction conditions, including optimization of catalysts, oxidants and
temperature to yield desired Nꢀbenzylisoquinolinone 4aa. The results are summarized in Table 1.
The reaction was initially carried out by using CuOAc and diꢀtertꢀbutyl peroxide (DTBP) as a
catalyst and an oxidant, respectively (Table 1, entry 1). A small amount of the corresponding
product 4aa was obtained after heating at 120 °C for 8 h under nitrogen atmosphere in the sealed
tube. Inspired by this discovery, different kinds of Cu catalysts such as CuCl, CuSCN, Cu2O, CuBr,
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CuOAc and Cu powder were employed in the reaction (Table 1, entries 1ꢀ8). We found that CuBr
showed the best results for this reaction. Meanwhile, several oxidants [such as tert-butyl
hydroperoxide (TBHP), tert-butyl perbenzoate (TBPB), K2S2O8, etc.] were tested for this
transformation. It turned out that only DTBP exhibited reaction activity for the transformation, but
TBHP, TBPB, K2S2O8 and dicumyl peroxide (DCP) did not induce the reaction (Table 1, entries
9ꢀ12). Then, the reaction was carried out by using different amounts of CuBr and DTBP. We found
that the best result was obtained with 1.0 equiv of CuBr and 4.0 equiv of DTBP (Table 1, entries
13ꢀ17). When the reaction was completed at 100℃, the yields of the target product 4aa were
Table 1 Optimization of reaction conditionsa
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Entry
1
[Cu] (equiv)
CuOAc (0.2)
CuSCN (0.2)
CuI (0.2)
Oxidant (equiv) Temp (
℃)
Yieldb (%)
12
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
TBHP (2.0)
TBPB (2.0)
K2S2O8 (2.0)
DCP (2.0)
120
120
120
120
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100
2
trace
trace
trace
trace
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3
4
Cu2O (0.2)
CuCl (0.2)
CuBr (0.2)
CuBr2 (0.2)
Cu (0.2)
5
6
7
trace
17
8
9
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.5)
CuBr (1.0)
CuBr (1.0)
CuBr (1.0)
CuBr (1.0)
CuBr (1.0)
trace
trace
trace
trace
42
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18
DTBP (2.0)
DTBP (2.0)
DTBP (3.0)
DTBP (4.0)
DTBP (5.0)
DTBP (4.0)
57
67
77
75
78
aReaction conditions: 2a (0.30 mmol), 3a (1.5 mL), 8 h, under N2 atmosphere. b Yield of isolated
product.
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slightly raised (Table 1, entry 18). On the basis of the results shown in Table 1, the reaction was
carried out with 0.3 mmol of isoquinoline (2a), 1.5 mL of toluene substrates, 0.3 mmol of CuBr
and 1.2 mmol of DTBP at 100 °C for 8 h.
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With optimized conditions in hand, we further carried out the reaction by using various
isoquinolines and methylbenzene derivatives to investigate the scope and generality of this
protocol (Table 2). A range of methylbenzene derivatives bearing electronꢀdonating and
electronꢀwithdrawing groups reacted with isoquinoline (2a) to give the target
Nꢀbenzylisoquinolinones 4. The reaction occurred in high yields by using methylbenzene
derivatives bearing electronꢀdonating substituents as substrates, such as pꢀdimethylbenzene (3b),
oꢀdimethylbenzene (3c) and 1,3,5ꢀtrimethylbenzene (3g). It is worth noting that we obtained two
different products 4ad1 and 4ad2 when 4ꢀmethylanisole (3d) was used as a substrate. Meanwhile,
different substituted isoquinolines were examined under the standard reaction conditions. The
lower yields of the corresponding products 4ba and 4ea were observed in the presence of
substituents at the 4 or 8 position of isoquinolines. To our delight, apart from isoquinolines,
phthalazine (2f) and quinoline (2g) could also be used as substrates with methylbenzene (3a) to
afford the desired compounds 4fa and 4ga respectively in moderate yields under the reaction
conditions.
Table 2 Scope of the reaction a,b affording products 4.
R1
R1
X
N
X
N
CuBr
H
+
DTBP
R2
R2
4
3a-h
2a-f or 2g quinoline
O
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aReaction conditions:
2 (0.30 mmol), 3 (1.5 mL), CuBr (1.0 equiv) and DTBP (4.0 equiv),
4ꢀ10 h, under N2 atmosphere. b Yield of isolated product. c120°C for 12 h.
Encouraged by the exciting results, we tried to apply a few other types of compounds
containing C(sp3)ꢀH bonds such as 1,4ꢀdioxane (6d), cyclohexene (5e), 1,2ꢀdimethoxyethane (6g),
methoxybenzene (6a) and their derivatives into this transformation under the typical reaction
conditions. It is nice to see that these compounds could act as the effective substrates in the
coupling reactions with isoquinoline (2a) in moderate yields and the results were summarized in
Table 3. The ratio of the regioisomeric products 7ag1 and 7ag2 in reaction of isoquinoline (2a)
with 1,2ꢀdimethoxyethane (6g) is 46% : 28%. Meanwhile, we could not found the target
compounds when isoquinoline (2a) reacts with ethers or alkenes by using Yang’s method6
(Scheme 1). Besides, we found an interesting phenomenon in the course of the experiments. A
mixture of two products (7ac and 8aa or 7ah and 8aa) in varying proportions were observed when
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the reaction was completed at 120 °C by using 2ꢀbromoanisole or 4ꢀbromoanisole (6c or 6h) as a
substrate (Scheme 2). The result showed that this competing exchange reaction existed at higher
temperatures utilizing anisoles with bromine group as a substrate.
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Table 3 Scope of the reaction a,b affording products 7.
aReaction conditions: 2a (0.30 mmol), 5 or 6 (1.5 mL), CuBr (1.0 equiv) and DTBP (4.0 equiv),
100 °C, 6ꢀ10 h, under N2 atmosphere. b Yield of isolated product. c6.0 equiv of DTBP.
d2ꢀPhenylpropene as a substrate.
Scheme 2. Intermolecular exchange reaction.
Furthermore, the versatile synthetic utilization of Nꢀbenzylisoquinolinones 4 was studied, and
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the results are summarized in Scheme 3. For the synthesis of 5ꢀoxaprotoberberinones, as far as we
know, only one method has been reported. Protoberberines are important natural isoquinoline
alkaloids. In 2014, Cho9 first employed o-toluamide 9 and MOM (methoxymethyl) protected
o-cyanophenol 10 as substrates to yield the target crossꢀcoupling product 1ab. The reaction was
carried out in dry tetrahydrofuran (THF) utilizing nꢀbutyllithium as an additive at ꢀ78℃. Then,
MOM group was removed to afford phenol 12 in the presence of 10% HCl or trifluoroacetic acid.
Finally, unsubstituted 5ꢀoxaprotoberberinone 1ab was obtained in moderate yield by SN2 reaction,
in which compound 12 reacts with diiodomethane by using K2CO3 as base. Cho’s method has
some drawbacks, such as intricate preꢀprocess, harsh conditions and long steps. Therefore, a more
convenient method for the generation of this class of compounds is still required. Herein we
present a new way for the preparation of 5ꢀoxaprotoberberinones by two steps using the method
reported above in this article. The corresponding compound 1ab was provided in 76% yield
utilizing readily available starting materials. Besides, its derivative 1aa could also be easily
assembled in moderate yield by this novel twoꢀstep procedure based on Argade’s method10.
Furthermore, isoindolo[2,1ꢀb]isoquinolinꢀ5(7H)ꢀone (topoisomerase I inhibitor) could also be
produced by using the above reported method and Daich’ s method11 in combination (Figure 1).
To investigate the mechanism, several control experiments were completed (Scheme 4). Firstly,
when the reaction was carried out under the standard condition by using benzyl bromide intead of
toluene, we could not find the target compound 4a (Scheme 4a). This shows that the
corresponding product could not be obtained by benzyl bromide intermediate. When 4 equiv of
2,6ꢀdiꢀtertꢀbutylꢀ4 ꢀmethylphenol (BHT) was introduced to this transformation under the
optimized conditions, no desired product was detected (Scheme 4b). It turned out that the free
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radical inhibitor completely suppressed the reaction. Finally, we tried to take advantage of
ESIꢀMS analysis on the model reaction of 2a and 3a to further probe the reaction pathway. When
the reaction was completed under the standard condition, we took a few samples from the reaction
mixture and directly analyzed by ESIꢀMS in positive ion mode. Several peaks with m/z signals
characterized for cationic intermediates were trapped. On the analysis of the present m/z signals,
structures of the cationic intermediates were proposed, the results were summarized in Scheme 4c.
The results indicated that benzylic radical firstly attack the nitrogen of C=N in the pathway to get
the carbon radical intermediate.
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On the basis of these preliminary results above, together with previous studies7,8, we proposed a
plausible mechanism in Scheme 5. Initially, the reaction between [Cu]I and DTBP would give
copper(II) alkoxide A and tertꢀbutoxy radical B. Meanwhile, homolysis of other DTBP gives B
under heating, Benzyl radical C would be generated by abstracting hydrogen from toluene by B.
Subsequently, isoquinoline 2a reacts with A to afford
Scheme 3. Transformations of 2ꢀ[(2ꢀbromophenoxy)methyl]isoquinolinꢀ1(2H)ꢀone (6ah).
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Scheme 4. Control experiment.
intermediate D, which combined with the benzyl radical C to produce the intermediate E. Then E
works with B to afford the corresponding compound F. The reaction of compound F with
tertꢀbutoxy radical B would generate free radical intermediate G which would reduce the [Cu]II to
[Cu]I and simultaneously generate carbonium ion intermediate H. Finally, the desired product 4aa
was formed with the release of tertiary butyl cation which would generate isobutene involving
tertꢀbutoxy ion. Our hypothesis accounts for 1.0 equiv of CuBr employed in this transformation.
Quantitative intermediate D was yielded to afford compound F. Uncoordinated isoquinolines
would lose their stability to result in side reaction in the presence of DTBP when the amount of
Cu salts was reduced.
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Scheme 5. Plausible mechanism for the synthesis of 4aa.
Conclusion
In conclusion, we have developed an efficient and practical copperꢀmediated oxidative
functionalization of azaarenes with various C(sp3)−H bonds via a radical process in moderate to
high yields without any ligands. This novel transformation provided a useful strategy for the
synthesis of Nꢀbenzyl/alkyl isoquinolinone utilizing readily available starting substrates.
Importantly, 5ꢀoxaprotoberberinones and their derivatives could be concisely prepared by using
this method. Further investigation of this procedure to focus on the detailed reaction mechanism
and synthetic applications is underway in our laboratory.
Experimental Section
General Procedure for the Synthesis of the Target Compounds 4
DTBP (1.2 mmol) was added to a solution of 2 (0.3 mmol), 3 (1.5 mL) and CuBr (0.3 mmol),
and the reaction mixture was stirred under nitrogen atmosphere at 100℃ for 4ꢀ10 h. Afterwards
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the resulting mixture was cooled to room temperature, transferred to silica gel column directly and
purified by column chromatography with petroleum ether/ethyl acetate (20:1) as eluent to give 4.
General Procedure for the Synthesis of the Target Compounds 7
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DTBP (1.2 mmol) was added to a solution of 2a (0.3 mmol), 5 or 6 (1.5 mL) and CuBr (0.3
mmol), and the reaction mixture was stirred under nitrogen atmosphere at 100℃ for 4ꢀ10 h.
Afterwards the resulting mixture was cooled to room temperature, transferred to silica gel column
directly and purified by column chromatography with petroleum ether/ethyl acetate (20:1) as
eluent to give 7.
1
2-Benzylisoquinolin-1(2H)-one (4aa),6 yellow solid. Yield: 54.9 mg (78%); mp 65−66 °C. H
NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz,
2H), 7.33ꢀ7.28 (m ,5H), 7.08 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H). 13C NMR
(100 MHz, CDCl3) δ 162.2, 137.0, 136.9, 132.2, 131.2, 128.8, 128.1, 127.9, 127.8, 126.8, 126.4,
125.9, 106.3, 51.7.
2-(4-methylbenzyl)isoquinolin-1(2H)-one (4ab),6 yellow solid. Yield: 67.9 mg (91%); mp
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103−105 °C. H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H),
7.23 (d, J = 4.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 7.08ꢀ7.06 (m ,3H), 7.47 (d, J = 8.0 Hz, 1H), 5.18
(s, 2H), 2.32 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 137.5, 137.0, 133.9, 132.1, 131.2,
129.4, 128.0, 128.0, 126.8, 126.4, 125.8, 106.2, 51.4, 21.0.
2-(2-methylbenzyl)isoquinolin-1(2H)-one (4ac),6 Yellow solid. Yield: 62.0 mg (83%); mp
109−110 °C. 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50
(d, J = 4.0 Hz, 2H), 7.21ꢀ7.15 (m ,3H), 7.05 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.46 (d, J
= 8.0 Hz, 1H), 5.22 (s, 2H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 136.9, 136.5,
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134.4, 132.2, 130.8, 130.7, 128.4, 128.1, 128.0, 126.8, 126.3, 126.2, 125.9, 106.3, 49.3, 19.1.
2-(4-methoxybenzyl)isoquinolin-1(2H)-one (4ad1),6 Yellow solid. Yield: 41.3 mg (52%); mp
107−108 °C. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.0 Hz, 1H), 7.62(d, J = 8.0 Hz, 1H), 7.48
(d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 8.0 Hz, 2H),
6.46 (d, J = 8.0 Hz, 1H), 5.15 (s, 2H), 3.77 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2, 159.3,
137.0, 132.1, 131.1, 129.5, 129.1, 128.0, 126.8, 126.4, 125.8, 114.2, 106.2, 55.2, 51.2.
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2-(4-methoxybenzyl)isoquinolin-1(2H)-one (4ad2), white soild. Yield: 25.4 mg (32%); mp
117−118 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48
(d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 2H),
6.49 (d, J = 8.0 Hz, 1H), 5.94 (s, 2H), 2.25 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.0, 154.1,
137.0, 132.6, 131.8, 130.1, 129.4, 128.2, 127.0, 126.1, 126.0, 115.9, 106.8, 74.2, 20.4. HRMS
(ESI) m/z: calcd for C17H19N2O2: 283.1441 [M+NH4]+; found: 283.1426.
2-(4-fluorobenzyl)isoquinolin-1(2H)-one (4ae),6 white solid. Yield: 54.6 mg (72%); mp
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107−108 °C. H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H),
7.33 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 7.08ꢀ6.98 (m ,3H), 6.49 (d, J = 8.0 Hz, 1H), 5.17
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(s, 2H). 13C NMR (100 MHz, CDCl3) δ 162.4 (d, JCꢀF = 250.0 Hz), 162.2, 137.0, 132.7, 132.7,
132.3, 131.1, 129.8, 129.7, 128.0, 127.0, 126.3, 125.9, 115.8, 115.6, 106.6, , 51.2.
2-(4-bromobenzyl)isoquinolin-1(2H)-one (4af),6 yellow solid. Yield: 70.4 mg (75%); mp
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157−158 °C. H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H),
7.52ꢀ7.44 (m ,4H), 7.21 (d, J = 4.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 5.16
(s ,2H). 13C NMR (100 MHz, CDCl3) δ 162.1, 136.9, 135.9, 132.3, 131.9, 131.0, 129.6, 128.0,
127.0, 126.3, 125.9, 121.8, 106.6, 51.2.
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2-(3,5-dimethylbenzyl)isoquinolin-1(2H)-one (4ag),6 white solid. Yield: 66.3 mg (84%); mp
100−103 °C. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.62 (m ,1H), 7.49(d, J = 8.0
Hz, 2H), 7.07 (d, J = 4.0 Hz, 1H), 6.92ꢀ6.90 (m ,3H), 6.46 (d, J = 8.0 Hz, 1H), 5.14 (s, 2H), 2.27 (s,
6H). 13C NMR (100 MHz, CDCl3) δ 162.4, 138.4, 137.0, 136.8, 132.1, 131.3, 129.5, 128.1, 126.8,
125.8, 125.8, 125.7, 106.2, 51.5, 21.2.
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2-(1-phenylethyl)isoquinolin-1(2H)-one (4ah),6 yellow oil. Yield: 45.6 mg (61%).1H NMR (400
MHz, CDCl3) δ 8.49 (d, J = 8.0 Hz, 1H), 7.64ꢀ7.60 (m ,1H), 7.51ꢀ7.46 (m ,2H), 7.35ꢀ7.26 (m ,5H),
6.91 (d, J = 8.0 Hz, 1H), 6.59ꢀ6.54 (m ,1H), 6.44 (d, J = 8.0 Hz, 1H), 1.76 (d, J = 4.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3) δ 162.2, 140.6, 136.6, 132.1, 128.7, 128.2, 127.9, 127.7, 127.3, 126.7,
126.1, 125.7, 106.4, 52.1, 18.7.
2-benzyl-4-bromoisoquinolin-1(2H)-one (4ba),6 yellow solid. Yield: 53.5 mg (57%); mp
112−113 °C. 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 8.0 Hz, 1H), 7.82ꢀ7.73 (m ,2H), 7.58ꢀ7.55
(m ,1H), 7.35ꢀ7.26 (m, 6H), 5.20 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 161.9, 136.2, 135.5,
133.0, 132.9, 131.7, 131.6, 128.9, 128.5, 128.1, 128.0, 127.9, 125.8, 51.7.
2-benzyl-5-bromoisoquinolin-1(2H)-one (4ca),6 yellow solid. Yield: 70.4 mg (75%); mp
110−113 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 1H), 7.87ꢀ7.85 (m ,1H), 7.32ꢀ7.16
(m ,7H), 6.82 (d, J = 8.0 Hz, 1H), 5.21 (s ,2H). 13C NMR (100 MHz, CDCl3) δ 161.9, 136.5, 136.3,
136.0, 132. 5, 128.9, 128.0, 127.9, 127.8, 127.7, 127.4, 120.6, 105.0, 51.9.
2-benzyl-6-bromoisoquinolin-1(2H)-one (4da),6 Yellow solid. Yield: 71.6 mg (76%); mp
112−113 °C. 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 1H), 7.66ꢀ7.56 (m ,2H), 7.32ꢀ7.26
(m ,5H), 7.10 (d, J = 8.0 Hz, 1H), 6.38 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H). 13C NMR (100 MHz,
CDCl3) δ 161.9, 138.4, 136.5, 132.6, 130.1, 129.9, 128.9, 128.3, 128.0, 127.9, 127.4, 125.0, 105.2,
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2-benzyl-8-chloroisoquinolin-1(2H)-one (4ea), yellow oil. Yield: 41.9 mg (52%). 1H NMR (400
MHz, CDCl3) δ 7.45 (d, J = 8.0 Hz, 2H), 7.36ꢀ7.25 (m, 6H), 7.09 (d, J = 8.0 Hz, 1H), 6.39 (d, J =
8.0 Hz, 1H), 5.17 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 162.8, 140.1, 136.7, 135.7, 132.1, 131.9,
130.1, 128.9, 128.8, 128.1, 127.8, 125.1, 105.8, 51.8. HRMS (ESI) m/z: calcd for C17H13ClNO3:
314.0589 [M+COOH]ꢀ; found: 314.0586.
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2-benzylphthalazin-1(2H)-one (4fa),6 white solid. Yield: 35.4 mg (50%); mp 84−87 °C. 1H NMR
(400 MHz, CDCl3) δ 8.41 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 7.70ꢀ7.24 (m ,8H), 5.40 (s, 2H). 13C
NMR (100 MHz, CDCl3) δ 159.4, 138.0, 137.0, 133.1, 131.6, 130.0, 129.7, 128.6, 128.5, 127.7,
126.8, 126.0, 54.6.
1-benzylquinolin-2(1H)-one (4ga),6 brown solid. Yield: 26.1 mg (37%); mp 64−67 °C. 1H NMR
(400 MHz, CDCl3) δ 7.74 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.44ꢀ7.40 (m ,1H),
7.31ꢀ7.16 (m, 7H), 6.82 (d, J = 8.0 Hz, 1H), 5.56 (s, 2H).
2-(phenoxymethyl)isoquinolin-1(2H)-one (7aa), White solid. Yield: 54.2 mg (72%); mp
99−100 °C. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.66ꢀ7.63 (m ,1H), 7.51ꢀ7.48
(m, 2H), 7.28ꢀ7.24 (m ,3H), 7.08 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz,
1H), 5.99 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 162.0, 156.2, 137.0, 132.7, 129.7, 129.3, 128.2,
127.1, 126.10, 126.0, 122.4, 115.9, 106.9, 73.9. HRMS (ESI) m/z: calcd for C16H13NO2Na:
274.0838 [M+Na]+; found: 274.0844.
2-((3-methoxyphenoxy)methyl)isoquinolin-1(2H)-one (7ab), yellow oil. Yield: 65.8 mg (78%).
1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.0
Hz, 2H), 7.25ꢀ7.14 (m, 2H), 6.67 (s, 2H), 6.56ꢀ6.50 (m, 2H), 5.96 (s, 2H), 3.75 (s, 3H). 13C NMR
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(100 MHz, CDCl3) δ 162.0, 160.9, 157.3, 137.0, 132.7, 130.1, 129.4, 128.2, 127.1, 126.1, 126.0,
108.4, 107.8, 106.9, 102.0, 73.8, 55.3. HRMS (ESI) m/z: calcd for C18H16NO5: 326.1034
[M+COOH]ꢀ; found: 326.1043.
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2-((4-bromophenoxy)methyl)isoquinolin-1(2H)-one (7ac), white solid. Yield: 66.1 mg (67%);
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mp 151−152 °C. H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 1H), 7.67ꢀ7.63 (m ,1H),
7.51ꢀ7.47 (m, 2H), 7.37ꢀ7.35 (m ,2H), 7.21 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.52 (d, J
= 8.0 Hz, 1H), 5.95 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 162.1, 155.1, 137.0, 132.9, 132.6,
129.2, 128.2, 127.3, 126.7, 126.1, 117.7, 114.9, 107.3, 73.8. HRMS (ESI) m/z: calcd for
C16H12BrNO2Na: 351.9944 [M+Na]+; found: 351.9926.
2-(1,4-dioxan-2-yl)isoquinolin-1(2H)-one (7ad), White solid. Yield: 43.0 mg (62%); mp
118−120 °C. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 7.67ꢀ7.63 (m, 1H),
7.51ꢀ7.40 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.27ꢀ6.24 (m, 1H), 4.05ꢀ4.03
(m, 3H), 3.83 (d, J = 12.0 Hz, 1H), 3.74ꢀ3.70 (m, 1H), 3.48ꢀ3.43 (m, 1H). 13C NMR (100 MHz,
CDCl3) δ 161.3, 136.6, 132.6, 128.0, 126.9, 126.5, 125.9, 125.7, 106.3, 78.7, 68.8, 67.2, 65.8.
HRMS (ESI) m/z: calcd for C13H13NO3Na: 254.0788 [M+Na]+; found: 254.0793.
2-(cyclohex-2-en-1-yl)isoquinolin-1(2H)-one (7ae), colorless oil. Yield: 34.4 mg (51%). 1H
NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.0 Hz, 1H), 7.62ꢀ7.48 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H),
6.50 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 8.0 Hz, 1H), 5.71ꢀ5.60 (m, 2H), 2.15 (s, 3H), 1.78ꢀ1.63 (m,
3H). 13C NMR (100 MHz, CDCl3) δ 162.1, 136.8, 133.3, 132.0, 128.6, 128.0, 126.9, 126.6, 126.1,
125.7, 105.7, 51.1, 29.6, 24.7, 20.2. HRMS (ESI) m/z: calcd for C15H15NONa: 248.1046 [M+Na]+;
found: 248.1050.
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2-(2-phenylallyl)isoquinolin-1(2H)-one (7af), yellow oil. Yield: 40.7 mg (52%); H NMR (400
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MHz, CDCl3) δ 8.45 (d, J = 8.0 Hz, 1H), 7.63ꢀ7.59 (m, 4H), 7.34ꢀ7.25 (m, 3H), 7.07 (d, J = 8.0 Hz,
1H), 6.45 (d, J = 8.0 Hz, 1H), 5.56 (s, 1H), 5.10 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.2,
143.6, 138.1, 137.0, 132.1, 130.6, 128.5, 128.2, 128.1, 127.9, 126.8, 126.2, 125.8, 115.1, 106.2,
50.8. HRMS (ESI) m/z: calcd for C18H14NO: 260.1081 [MꢀH]ꢀ; found: 260.1110.
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2-(1,2-dimethoxyethyl)isoquinolin-1(2H)-one (7ag1), colorless oil. Yield: 32.2 mg (46%). H
NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 1H), 7.67ꢀ7.63 (m, 1H), 7.53ꢀ7.47 (m, 2H), 7.27 (d,
J = 8.0 Hz, 1H), 6.57 (d, J = 4.0 Hz, 1H), 6.28ꢀ6.25 (m, 1H), 3.65 (d, J = 4.0 Hz, 2H), 3.41 (s, 3H),
3.36 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.4, 136.8, 132.5, 128.0, 126.8, 126.1, 126.0, 125.9,
106.3, 83.9, 73.2, 59.4, 56.8. HRMS (ESI) m/z: calcd for C13H15NO3K: 272.0684 [M+K]+; found:
272.0654.
2-((2-methoxyethoxy)methyl)isoquinolin-1(2H)-one (7ag2), colorless oil. Yield: 19.6 mg (32%).
1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 7.66ꢀ7.63 (m, 1H), 7.51ꢀ7.47 (m, 2H),
7.21 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 5.50 (s, 2H), 3.75ꢀ3.74 (m, 2H), 3.53ꢀ3.52 (m,
2H), 3.36 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 162.8, 137.1, 132.6, 130.2, 128.1, 126.9, 126.1,
125.9, 106.5, 76.9, 71.5, 68.5, 58.9. HRMS (ESI) m/z: calcd for C13H15NO3K: 272.0684 [M+K]+;
found: 272.0657.
2-((2-bromophenoxy)methyl)isoquinolin-1(2H)-one (7ah), White solid. Yield: 35.5 mg (36%);
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mp 148−149 °C. H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.0 Hz, 1H), 7.66ꢀ7.62 (m, 1H),
7.53ꢀ7.47 (m, 3H), 7.30ꢀ7.24 (m, 3H), 6.90ꢀ6.86 (m, 1H), 6.53 (d, J = 8.0 Hz, 1H), 6.05 (s, 2H).
13C NMR (100 MHz, CDCl3) δ 162.1, 152.6, 137.0, 133.5, 132.8, 129.4, 128.7, 128.2, 127.1,
126.1, 126.0, 124.0, 116.6, 113.3, 107.1, 74.6. HRMS (ESI) m/z: calcd for C16H13BrNO2:
330.0124 [M+H]+; found: 330.0145.
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13,13a-Dihydro-6H,8H-isoquino[2,3-c][1,3]benzoxazin-8-one (1aa),10 white solid. Yield: 18.2
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mg (67%). H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 4.0 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H),
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7.41ꢀ7.37 (m, 1H), 7.27ꢀ7.21 (m, 3H), 7.08ꢀ7.00 (m, 2H), 6.47 (d, J = 16.0 Hz, 1H), 5.08ꢀ5.03 (m,
1H), 4.60 (d, J = 8.0 Hz, 1H), 3.28ꢀ3.24 (m, 1H), 3.04ꢀ2.96 (m, 1H). 13C NMR (100 MHz, CDCl3)
δ 163.3, 153.8, 137.0, 132.5, 128.7, 128.4, 128.1, 127.5, 127.2, 126.0, 123.6, 122.3, 118.0, 70.9,
52.9, 37.0. HRMS (ESI) m/z: calcd for C16H14NO2: 252.1019 [M+H]+; found: 252.1017.
6H,8H-Isoquino[2,3-c][1,3]benzoxazin-8-one (1ab),9 white solid. Yield: 20.4 mg (76%); mp
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174−175 °C. H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H),
7.66ꢀ7.63 (m, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48ꢀ7.44 (m, 1H), 7.38ꢀ7.34 (m, 1H), 7.18ꢀ7.14 (m,
1H), 7.09 (d, J = 8.0 Hz, 1H), 6.89 (s, 1H), 5.91 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 160.5,
154.1, 136.7, 133.2, 132.7, 131.0, 128.0, 126.7, 126.4, 125.2, 124.1, 123.5, 119.1, 117.7, 100.9,
71.6.
Acknowledgements
We are grateful for the financial support from the National Natural Science Foundation of China
(21362022 and 21302084).
Associated content
Supporting Information: 1H and 13C NMR spectral data of all compounds found in the SI.
References：
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68, 250.
(2) (a) Wang, J. C. Nat. Rev. Mol. Cell. Biol. 2002, 3, 430. (b) Zhang, J.ꢀS.; Le MenꢀOlivier. L.;
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Massiot, G. Phytochemistry. 1995, 39, 439. (c) Poindexter, G. S. J. Org. Chem. 1982, 47, 3787.
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