Visible-light-promoted acyl radical cascade reaction for accessing acylated isoquinoline-1,3(2: H,4 H)-dione derivatives

Article abstract of DOI:10.1039/d0ob00086h

A visible-light-promoted decarboxylative acyl radical acylation/cyclization cascade reaction of N-methacryloylbenzamides for accessing acylated isoquinoline-1,3(2H,4H)-dione derivatives was described. In this report, α-keto acids were used for generating acyl radicals and inducing radical acylations. This protocol features mild reaction conditions, operational practicality and a broad substrate scope.

Full text of DOI:10.1039/d0ob00086h

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DOI: 10.1039/D0OB00086H
ARTICLE
Visible-Light-Promoted Acyl Radical Cascade Reaction for
Accessing Acylated Isoquinoline-1,3(2H,4H)-dione Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Yingpeng Su,* Rong Zhang, Wenxuan Xue, Xuan Liu, Yanan Zhao, Ke-Hu Wang, Danfeng Huang,
Congde Huo,* Yulai Hu*
DOI: 10.1039/x0xx00000x
A visible-light-promoted decarboxylative acyl radical acylation/cyclization cascade reaction of N-methacryloylbenzamides
for accessing acylated isoquinoline-1,3(2H,4H)-dione derivatives was described. In this report, α-keto acids were resorted
to generating acyl radicals and inducing the radical acylations. This protocol features mild reaction conditions, operational
practicality and a broad substrate scope.
NHCOR2
O
S
O
N
NH
NH
O
N
Br
Introduction
O
HO
N
N
O
R1
H
R
O
The isoquinoline-1,3(2H,4H)-dione skeleton is frequently found
in natural products and also serves as significant structural unit
for many potentially physiologically active compounds, which
shows obvious biological activities.1 In Figure 1, several
representative bioactive molecules possessing isoquinoline-
1,3(2H,4H)-dione moiety are listed.2 All of them exhibit
distinctive biological activities. Consequently, many efforts
from medicinal and synthetic chemists have been devoted to
develop convenient and versatile methods for the synthesis of
such molecules.3 In this scenario, various free-radical
additions/tandem cyclizations of N-methacryloylbenzamides
have emerged as effective approachs to access functionalized
isoquinoline-1,3(2H,4H)-dione derivatives.4 Specifically, several
HCV Inhibitor
Selective inhibitors of Antitumor activity against a human pancreatic
Hepatitis C Virus NS5B Polymerase Inhibitor cyclin-dependent kinase 4
carcinoma cell line
O
NH
O
O
O
R2
I
N
NH
R1
OH
N
O
O
O
H
O
O
S
N
NH
O
H
O
Selective inhibition of tyrosyl
DNA phosphodiesterase II
Aldose reductase (ALR2)
inhibitors
InhibiTOR of phosphorylation
of pRb
Figure 1. Biologically active isoquinoline-1,3(2H,4H)-dione derivatives.
and efficient methods to obtain acyl-containing isoquinoline-
1,3(2H,4H)-dione derivatives are still desirable and valuable.
In the past two decades, visible-light photo-redox catalysis
has been regard as an ecofriendly and effective strategy for
the advantages of convenience, availability and safety.5 In this
context, photo-redox catalysis has also been used to access
radical species, such as carbon-,4a-h acyl-,4i fluoro-alkyl-,4j-o
nitrogen-,4p,
sulfur- and phosphorus-containing radicals4r-x
4q
have been used to initiate this intriguing reaction. Among
these cascade radical addition/cyclization strategies for
rendering potentially bioactive functionalized isoquinoline-
1,3(2H,4H)-dione derivatives, few reports on the synthesis of
acylated isoquinoline relying on the acyl radical have been
disclosed. In 2014, Zhou and co-workers have reported the
method to obtain acylated isoquinoline-1,3(2H,4H)-dione
derivatives from N-alkyl-N-acylbenzamide resorting aromatic
aldehyde to forming acyl radical in high temperature4i (Scheme
1). Given the potential importance of acylated isoquinoline-
1,3(2H,4H)-dione derivatives in drug discovery, the more mild
various
functionalized
isoquinoline-1,3(2H,4H)-dione
derivatives via the light-induced radical strategies.4k-n, 4r, 4u, 4x
On the other hand, α-keto acids were regarded as highly
reactivity acylation reagents6 not only in transition-metal
catalyzed decarboxylative coupling reaction, but also in the
light-induced acyl radical-mediated transformations.7 For
instances, in 2014 Lei’s research group first revealed the
decarboxylative coupling of α-keto acids with amine by visible
light irradiation.7a Afterwards, various visible light-induced
acylated processes dealing with the functionalized compounds
via a decarboxylative radical acylation with α-keto acids were
reported.7b-t Inspired by these mild, efficient and good
functional tolerant decarboxylative acylation reactions with α-
keto acids, we herein report
a visible-light-promoted
decarboxylative acylation/cyclization cascade of N-aryl-N-acryl
benzamides 1 with α-keto acids to obtain acyl-containing
isoquinoline-1,3(2H,4H)-dione derivatives.
College of Chemistry and Chemical Engineering, Northwest Normal University, 967
Anning East Road, Lanzhou 730070, P. R. China. E-mail: suyp51@nwnu.edu.cn;
huocongde1978@hotmail.com; huyl@nwnu.edu.cn
Electronic Supplementary Information (ESI) available: General experimental details
and copies of 1H and 13C NMR spectra. For ESI see DOI: 10.1039/x0xx00000x
Results and discussion
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
Table 1. Optimization of Reaction Conditionsa
To investigate the feasibility of our design, the N-methacryloyl-
N-methylbenzamide (1a) and 2-oxo-2-phenylaceticd acid (2a)
were chosen as the model substrates (Table 1). Initially, the
reaction was performed by using eosin B as a photoredox
catalyst and (NH4)2S2O8 as an oxidant in DMSO upon
irradiation of 2 × 3 W blue LED lights under an air atmosphere.
To our delight, the desired product 2,4-dimethyl-4-(2-oxo-2-
phenylethyl)isoquinoline-1,3(2H,4H)-dione 4aa was obtained
in 56% yield, composing a reaction mixture of 1a (0.2 mmol),
2a (0.4 mmol), 2 mol% eosin B and (NH4)2S2O8 (0.4 mmol) in
DMSO (3 mL) at room temperature by irradiation for 12 h
(Table 1, entry 1). The structure of 4aa was determined
unambiguously by X-ray (Table 2, CCDC: 1937084).8 As
anticipated, the formation of the desired product 4aa was
completely impeded without the light irradiation (Table 1,
entry 2). Furthermore, running the reaction in the absence of
photocatalyst, or oxidant, the reactions gave significant
decrease in yield (29% and 36%; Table 1, entries 3 and 4).
These results indicated that the photocatalyst and oxidant
simultaneously promoted the decarboxylative acylation (Table
1, entries 2 and 3). In order to improve the yield, different
mole ratios of 2a and oxidant were screened (Table 1, entries
5–8). Gratifyingly, treatment of 1a with 3.0 equivalents of 2a
and 2.5 equivalents (NH4)2S2O8 led to acylated product 4aa in
good yield of 90% (Table 1, entry 7). Among the various
photoredox catalysts (Table 1, entries 9 and 10), eosin B was
found to be the best choice for this cascade reaction.
Subsequently, other common oxidants, such as K2S2O8, TBHP,
and O2, were also investigated but found to be less effective
than (NH4)2S2O8 for this transformation (Table 1, entries 7,
11−13). When other solvents, such as DMF, CH3CN and THF,
were used to instead of DMSO, the yield of the desired
product dramatically dropped (Table 1, entries 7, 14−16).
Finally, different irradiation sources were also tested in the
reaction, affording the desired product 4aa in lower yields
(Table 1, entries 17 and 18). Therefore, we identified eosin B (2
mol%)/(NH4)2S2O8 (2.5 equiv)/DMSO/2 × 3 W blue LEDs/2a
(3.0 equiv)/room temperature as optimal reaction conditions
for the cascade radical acylation/cyclization of N-
methacryloylbenzamides 1a; the desired product 4aa was
synthesized in 12 h and in 90% yield (Table 1, entry 7).
View Article Online
DOI: 10.1039/D0OB00086H
O
O
O
O
Me
N
photocatalyst
OH
Me
N
3
oxidant
+
O
O
Me
Me
rt, 12 h
air, solvent
visible light
O
2a
4aa
1a
Mole ratio
of 1a/2a/3
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.0/2.0
1.0/2.5/2.0
1.0/3.0/2.0
1.0/3.0/2.5
1.0/3.0/3.0
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
1.0/3.0/2.5
Yieldb
Entry
Photocatalyst
Oxidant
Solvent
(%)
56
0
1
2c
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17d
18e
eosin B
eosin B
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
—
DMSO
DMSO
DMSO
DMSO
DMSO
29
36
71
84
90
89
87
85
26
58
70
18
0
——
eosin B
eosin B
eosin B
eosin B
eosin B
eosin Y
(NH4)2S2O8
(NH4)2S2O8 DMSO.
(NH4)2S2O8
(NH4)2S2O8
DMSO
DMSO
(NH4)2S2O8 DMSO.
Ru(bpy)3Cl2•6H2O (NH4)2S2O8
DMSO
DMSO
DMSO
DMSO
DMF
eosin B
eosin B
eosin B
eosin B
eosin B
eosin B
eosin B
eosin B
K2S2O8
TBHP
O2
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
CH3CN
THF
0
DMSO
DMSO
63
45
a
General reaction conditions: amide 1a (0.3 mmol), photocatalyst (2 mol %),
solvent(3 mL) in a sealed tube, air atmosphere, ambient temperature, irradiation
with 2 × 3 W blue LED lights, 12 h. bIsolated yield. Dark condition. Irradiation
c
d
with 2 × 3 W green LEDs. e Irradiation with 2 × 3 W white LEDs.
With the optimized reaction conditions established (Table 1,
entry 7), the scope of the decarboxylative acylation/cyclization
cascade reaction was explored by first varying the N-
arylacrylbenzamides 1 with the 2-oxo-2-phenylacetic acid 2a
(Table 2). The effect of various groups on the aromatic ring of
amides was examined firstly. A variety of substituents such as
methyl, methoxyl, ethoxyl, fluorine, chlorine, bromine and
acetyl on different positions of the aromatic ring of amide 1
were all compatible, leading the respective desired products
(4ba-4ka) in reasonable to good yields (52%-82%). The
presence of electron-donating substituents at the aryl rings
had positive effect on chemical yields. Exposing the amides
(1b-1f) to the standard conditions, the corresponding products
(4ba-4fa) were obtained in moderate to good yields
(67%-81%). As anticipated, meta-methyl-substituted substrate
1d furnished two region-isomers 4da and 4da’ in 77% total
yield with 4:1 isomeric ratio (determined by 1H NMR).
Comparing the ratio of two isomers, and the yields of 4ba with
4ca, it indicated that a steric effect is negative influence for
formation of the bulky products. Hence, the steric effect may
lead to the moderate yield of the para-phenyl-substituted 4ga
(64%). On the other hand, amides (1ha-1ka) with electron-
withdrawing groups (fluorine, chlorine, bromine and acetyl) on
the para- or meta-position of the aromatic rings just provided
the relative isoquinoline diones in reasonable yields (4ha-4ka,
in 52%-60% yields), on which a slight erosion occurred in
Previous work:4i
O
R1
O
N
O
O
TBHP, NaHCO3
N2, 90 oC, 24 h
Me
H
O
N
R1
+
Me
R2
O
R2
This work:
O
O
R2
O
O
O
N
eosin B
Me
R1
OH
N
R3
R1
+
(NH4)2S2O8, r.t.
O
R2
Me
O
R3
Scheme 1. Synthesis of acyl-containing isoquinoline-1,3(2H,4H)-dione derivatives
2 | J. Name., 2012, 00, 1-3
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ARTICLE
Table 2. Scope of methacryloyl benzamide derivatives.a, b
Table 3. Scope of α-keto acids.a, b
View Article Online
DOI: 10.1039/D0OB00086H
O
O
R2
O
O
O
O
Me
N
O
O
O
N
eosin B
(NH4)2S2O8
eosin B
(NH4)2S2O8
R1
Me
+
OH
Me
OH
3
3
N
R1
N
+
R3
O
R2
Me
O
DMSO, r.t.
2 × 3 W blue LEDs
DMSO, r.t.
2 × 3 W blue LEDs
Me
O
Me
O
R3
O
2a
1
4
1a
2
4
O
Me
O
O
O
O
O
O
O
Me
O
Me
N
Me
O
N
Me
O
Me
O
Me
N
N
N
N
O
Me
Me
Me
Me
O
Me
Me
Me
Me
O
O
Me
O
O
4aa: 90% yield, 12 h
CCDC: 1937084
O
4ba: 67% yield, 12 h
4ca: 82% yield, 12 h
Me
1.240 g, 81% yield
4ab:
4ad:
61% yield, 12 h
O
4ac:
70% yield, 12 h
O
68% yield, 12 h
O
O
O
O
Me
Me
N
Me
N
Me
N
Me
N
Me
N
Me
N
Me
N
O
O
Me
Me
Me
MeO
O
EtO
O
O
O
O
Me
Me
Me
Me
Me
O
O
O
O
O
O
O
Br
OMe
Cl
4da +4da': 77% yield (4:1), 12 h
4ea: 81% yield, 12 h
4fa: 78% yield, 24 h
4ae:
4af:
4ag:
74% yield, 12 h
O
69% yield, 24 h
O
63% yield, 24 h
O
O
O
O
O
Me
N
Me
O
Me
O
Me
N
Me
N
Me
N
Me
N
N
N
Ph
O
F
Cl
O
Br
O
O
O
Me
Me
Me
Me
Me
Me
Me
Br
Br
O
O
O
O
O
O
O
I
4ha: 53% yield, 12 h
4ia: 60% yield, 12 h
4ja: 53% yield, 12 h
4ga: 64% yield, 24 h
4ah:
65% yield, 24 h
O
4ai:
59% yield, 24 h
4aj:
60% yield, 24 h
O
O
O
O
O
O
O
O
O
O
n-Bu
Me
O
Et
N
Me
N
Me
Me
O
Me
N
N
N
MeO
N
N
N
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
Me
O
O
O
O
S
O
O
Me
4ka: 52 % yield, 24 h
4la: 77% yield, 12 h
4ma: 76% yield, 24 h
4na: 76% yield, 24 h
4ak:
4al:
4am:
4an:
34% yield, 72 h
67% yield, 48 h
73% yield, 48 h
38% yield, 48 h
0.659 g, 42% yield
O
O
O
O
Ph
N
Bn
N
OEt
N
N
a
Reaction conditions: Amide 1a (0.3 mmol), 2 (0.9 mmol, 3.0 equiv.), (NH4)2S2O8
O
O
O
O
O
Me
Me
Me
Me
(0.75 mmol, 2.5 equiv.), eosin B (2 mol%), DMSO (3 mL) in a sealed tube, air
atmosphere, ambient temperature, irradiation with 2 × 3 W blue LEDs. b Isolated
yield.
O
O
O
O
4oa: 60% yield, 24 h
4pa: 52% yield, 12 h
4qa: 49% yield, 24 h
4ra: 70% yield, 12 h
a
Variation of the substituents and positions at the phenyl rings
of α-keto acids had a minor influence on the yield of
corresponding isoquinoline-1,3-diones 4ab-4aj. However, α-
keto acids 2f-2j bearing electron-withdrawing substituents had
lower reactivity than α-keto acids 2b-2e containing electron-
donating groups at phenyl rings. To obtain the comparable
yields to 4ab-4ae, reactions with α-keto acids 2f-2j had to be
extended to 24 h. Moreover, the steric hindrance effect of α-
keto acids has negative influence on this coupling reaction,
comparing 4ab to 4ac and 4ad, 4ag to 4ai and 4aj. α-Keto acids
containing naphthyl and thienyl groups (2k and 2l) underwent
the reactions smoothly to provide the corresponding products
4ak in yield of 67% and 4al in yield of 73% for 48 h.
Noteworthily, aliphatic α-keto acids 2m and 2n were also
compatible with this coupling, although acylated isoquinoline-
1,3(2H,4H)-dione derivatives 4am and 4an were delivered in
merely around 35% yields. Finally, a gram-scale reaction of 1a
(5 mmol) with 2m was conducted under the standard
conditions and yielded the acylated product 4am in 42% yield
(0.659 g).
Reaction conditions: Amide 1 (0.3 mmol), 2a (0.9 mmol, 3.0 equiv.), (NH4)2S2O8
(0.75 mmol, 2.5 equiv.), eosin B (2 mol%), DMSO (3 mL) in a sealed tube, air
atmosphere, ambient temperature, irradiation with 2 × 3 W blue LEDs. Isolated
yield.
b
comparison to the electron-donating substituents. Notably,
para-NO2 substituted amide (not shown) generated the
corresponding product in very lower yield, which is prone to
decomposition. Subsequently, the N-substituents of
methacryloyl benzamides were also investigated. The ethyl, n-
butyl, isobutyl, ester, phenyl, allyl and benzyl substituted on
the N atom were compatible with this transformation (4la–
4ra). To explore the synthetic potential, a gram-scale reaction
was conducted for amide 1a (5 mmol) with 2a and furnished
4aa in 81% yield (1.240 g).
Following these encouraging results for different N-
methacryloylbenzamides, the scope of the reaction with
respect to the α-keto acid unit was investigated (Table 3, 4ab–
4an). A variety of aromatic α-keto acids bearing different
electron property substituents at the phenyl rings were
employed to this reaction and smoothly afforded the
respective products in moderate to good yields (59-74%).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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ARTICLE
Journal Name
a)
eosin B with blue LED generated the excited-state species
eosin B*, which underwent a single-electron transfer (SET)
View Article Online
DOI: 10.1039/D0OB00086H
O
O
Me
O
Me
Me
Me
Me
O
O
O
O
N
N
O
OH
Me
standard conditions
TEMPO (2.0 equiv)
N
+
with the persulfate anion to produce the eosin B radical cation,
sulfate dianion, and sulfate radical anion.10 The hydrogen atom
transfer (HAT) and the SET between the 2-oxo-2-phenylacetic
acid 2a and the sulfate radical anion led decarboxylation to
yield a benzoyl radical 6 via the path I. Then, benzoyl radical 6
added to the carbon-carbon double bond of N-methacryloyl-N-
methylbenzamide 1a to generate the radical intermediate 7,
which underwent an intramolecular cyclization to give the
radical intermediate 8. The carbocation intermediate 9 was
then produced through the single-electron oxidation of the
+
Me
O
Me
1a
2a
4aa
5
0% yield
detected by HRMS
b)
O
Me
O
O
O
N
OH
Me
standard conditions
BHT (2.0 equiv)
N
+
O
Me
O
Me
O
1a
2a
4aa
0% yield
radical
8 by the eosin B radical cation. Finally, the
deprotonation of the carbocation 9 regenerated the aromatic
system and formed the desired isoquinoline-1,3-diones 4aa.
Additionally, formation of the benzoyl radical 6 via the path II,
promoted by (NH4)2S2O8 through the decarboxylation of α-
keto acid 2a with visible light irradiation, could not be
excluded (Table 1, entries 2 vs 3).7f
Scheme 2. Control Experiments for Mechanism
In order to probe the reaction mechanism, common control
experiments were performed in the presence of the radical
scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or
2,6-di-tert-butyl-4-methylphenol (BHT) under the standard
reaction conditions. As shown in scheme 2, when 2 equiv. of
radical inhibitors TEMPO or BHT were loaded, the reactions
were completely restricted. Furthermore, the addition of
TEMPO as the radical scavengers led to formation of the
TEMPO-benzoyl adduct 5, detecting by HRMS, and the
recovery of the starting material 1a (Scheme 2, equation a).
These results indicated that this visible-light-promoted
decarboxylative acylation/cyclization cascade likely occurred
via a radical pathway.
Conclusions
In summary, we developed a mild visible-light-promoted
decarboxylative acylation/radical addition/cyclization cascade
reaction to access acyl-containing isoquinoline-1,3(2H,4H)-
dione derivatives under transition-metal-free conditions. The
(NH4)2S2O8/eosin B system is valid for the decarboxylation of
α-keto acids through a radical pathway with blue light
irradiation. This method features mild reaction conditions,
operational practicality and a broad substrate scope. The
introduction of acyl groups and the construction of fused
heterocycles take place in one efficient step.
On the basis of the above experimental results and previous
literature reports,6, 9 a possible reaction mechanism was
proposed in Scheme 3. Initially, the photo excitation of the
-
HSO4 + SO4
2-
S2O8
Experimental section
General Methods
CO2
O
O
All solvents were treated according to standard procedures.
Reagents were obtained from commercial suppliers and used
without further purification unless otherwise noted. Silica gel
column chromatography was carried out using 250–400 mesh
silica gel. The progress of reactions was monitored by TLC. TLC
plates were analyzed by an exposure to ultraviolet (UV) light.
NMR experiments were carried out in deuteron chloroform
O
Me
O
OH
Path I
SO4
1a
N
Ph
Ph
O
-
HSO4
6
2a
Me
2-
+ SO4
2-
O
Ph
S2O8
7
SET
O
H
1
(CDCl3). H NMR, 13C NMR spectra were recorded at 400 MHz
Me
N
eosin B
or 600 MHz and 100 MHz or 150 MHz spectrometers,
respectively. Chemical shifts are reported as δ values relative
to internal TMS (δ = 0.00 ppm for 1H NMR), chloroform (δ =
7.26 ppm for 1H NMR, 77.0 ppm for 13C NMR) in parts
permillion (ppm). The following abbreviations are used for the
multiplicities: s: singlet, d: doublet, dd: doublet of doublet, t:
triplet, q: quartet, m: multiplet. Coupling constants (J) are
reported in Hertz (Hz). Melting points were uncorrected. High
resolution mass spectra (HRMS) were recorded on Micro TOF-
QII mass instrument (ESI).
eosin B*
O
Me
eosin B
O
Ph
8
O
O
H
Me
O
Me
O
- H+
N
N
Me
Me
O
Ph
O
Ph
9
4aa
General procedures for synthesis of the isoquinoline-1,3(2H,4H)-
dione 4
Scheme 3. Proposed Mechanism
4 | J. Name., 2012, 00, 1-3
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N-arylacrylbenzamides 1 (0.30 mmol), α-keto acids 2 (0.90 -1,3(2H,4H)-dione (4ea). 82 mg, 81% yield, white solid, mp 164
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o
1
DOI: 10.1039/D0OB00086H
mmol), eosin B (0.006 mmol, 2.0 mol%) and (NH4)2S2O8 (0.75 –165 C; H NMR (600 MHz, CDCl3) δ 8.26 (d, J = 9.0 Hz, 1H), 7.8
mmol) were dissolved in DMSO (3.0 mL). Then, the solution 6 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2
was stirred at room temperature under 2 × 3 W blue LEDs H), 6.89 (dd, J = 9.0, 1.8 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.20 (d
irradiation for 24 hrs- 72 hrs. After the reaction was completed , J = 18.0 Hz, 1H), 3.91 (d, J = 18.0 Hz, 1H), 3.78 (s, 3H), 3.42 (s,
by TLC monitoring, the reaction mixture was diluted by adding 3H), 1.59 (s, 3H)；13C NMR (100 MHz, CDCl3) δ 196.1, 176.8, 1
NaHCO3 and brine. The aqueous layer was extracted with 64.2, 163.8, 145.8, 135.8, 133.5, 131.7, 128.6, 127.9, 118.0, 11
EtOAc. The combined organic layer was dried over Na2SO4, 2.0, 109.7, 55.4, 49.0, 44.7, 30.9, 27.1; HRMS (ESI): calcd for C2
filtered and concentrated. The residue was purified by flash 0H20NO4 [M + H]+ 338.13868; found 338.13865.
column chromatography (petroleum ether/ethyl acetate 5:1 as 6-Ethoxy-2,4-dimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,
the eluant) on silica gel to give the desired isoquinoline- 3(2H,4H)-dione (4fa). 82 mg, 78% yield, white solid, mp 103–1
1,3(2H,4H)-diones 4.
2,4-Dimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-
05 oC; 1H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 1H), 7.87
(d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H)
1,3(2H,4H)-dione (4aa). 58 mg, 90% yield, white solid, mp , 6.87 (dd, J = 9.0, 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 4.20 (d, J
o
1
143–145 C; H NMR (600 MHz, CDCl3) δ 8.31 (d, J = 7.8 Hz, = 18.0 Hz, 1H), 4.02 (q, J = 7.2 Hz, 2H), 3.90 (d, J = 18.0 Hz, 1H),
1H), 7.86 (d, 2H), 7.56–7.49 (m, 2H), 7.44–7.37 (m, 3H), 7.27 3.42 (s, 3H), 1.59 (s, 3H), 1.37 (t, J = 6.6. Hz, 3H); 13C NMR (150
(d, J = 7.2 Hz, 1H), 4.22 (d, J = 18.6 Hz, 1H), 3.97 (d, J = 18.0 Hz, MHz, CDCl3) δ 196.1, 176.8, 164.3, 163.3, 145.9, 135.9, 133.4,
1H), 3.45 (s, 3H), 1.62 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 131.7, 128.6, 128.0, 117.9, 112.4, 110.1, 63.8, 49.1, 44.7, 31.0,
196.2, 176.7, 164.6, 143.7, 135.9, 133.7, 133.5, 129.3, 128.6, 27.1, 14.6; HRMS (ESI): calcd for C21H22NO4 [M + H]+ 352.15433
128.0, 127.1, 125.0, 123.5, 49.1, 44.5, 30.9, 27.3; HRMS (ESI): ; found 352.15430.
calcd for C19H17NO3Na [M + Na]+ 330.11006; found 330.11004.
2,4-Dimethyl-4-(2-oxo-2-phenylethyl)-6-phenylisoquinoline-1,
2,4,8-Trimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3(2H,4 3(2H,4H)-dione (4ga). 74 mg, 64% yield, white solid, mp 178–1
H)-dione (4ba). 64 mg, 67% yield, white solid, mp 156–157 oC; 80 oC; 1H NMR (600 MHz, CDCl3) δ 8.37 (d, J = 7.8 Hz, 1H), 7.87
1H NMR (600 MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 2H), 7.54 (t, J = (d, J = 7.8 Hz, 2H), 7.60 (dd, J = 8.4, 1.8 Hz, 1H), 7.54 (t, J = 7.8
7.8 Hz, 1H), 7.42 (t, J = 8.4 Hz, 2H), 7.34 (t, J = 6.6 Hz, 1H), 7.17 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H), 7.42 (t, J = 7.2 Hz, 5H), 7.37 (t, J
(d, J = 7.2 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 4.22 (d, J = 18.0 Hz, 1 = 7.2 Hz, 1H), 4.27 (d, J = 18.0 Hz, 1H), 4.03 (d, J = 18.0 Hz, 1H),
H), 3.98 (d, J = 18.0 Hz, 1H), 3.41 (s, 3H), 2.82 (s, 3H), 1.60 (s, 3 3.47 (s, 3H), 1.68 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 196.2, 17
H); 13C NMR (150 MHz, CDCl3) δ 196.4, 176.4, 165.2, 145.0, 142 6.7, 164.5,146.6, 144.2, 139.8, 135.9, 133.5, 129.9, 128.9, 128.
.9, 136.0, 133.4, 132.5, 131.2, 128.6, 127.9, 123.2, 121.6, 49.1, 6, 128.4, 128.0, 127.3, 126.2, 123.9, 122.2, 49.3, 44.7, 31.0, 27.
44.6, 31.4, 27.3, 24.1; HRMS (ESI): calcd for C20H20NO3 [M + H]+ 3; HRMS (ESI): calcd for C25H22NO3 [M + H]+ 384.15942; found 3
322.14377; found 322.14379.
84.15910.
2,4,6-Trimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3(2H,4 6-Fluoro-2,4-dimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,
H)-dione (4ca). 79 mg, 82% yield, white solid, mp 121–122 oC; 1 3(2H,4H)-dione (4ha). 52 mg, 53% yield, white solid, mp 127–1
H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 8 28 oC; 1H NMR (600 MHz, CDCl3) δ 8.33 (dd, J = 8.4, 6.0 Hz, 1H),
.4 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.18 ( 7.87–7.85 (m, 2H), 7.56 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H
d, J = 7.8 Hz, 1H), 7.04 (s, 1H), 4.21 (d, J = 18.0 Hz, 1H), 3.95 (d, ), 7.08 (t, J = 8.4 Hz, 1H), 6.93 (dd, J = 9.0, 2.4 Hz, 1H), 4.25 (d, J
J = 18.0 Hz, 1H), 3.43 (s, 3H), 2.34 (s, 3H), 1.60 (s, 3H); 13C NMR = 18.0 Hz, 1H), 3.87 (d, J = 18.0 Hz, 1H), 3.43 (s, 3H), 1.61 (s, 3H
(150 MHz, CDCl3) δ 196.2, 176.9, 164.6, 144.4, 143.7, 135.9, 13 ); 13C NMR (150 MHz, CDCl3) δ 196.0, 176.2, 166.1 (d, J = 253.5
3.4, 129.3, 128.6, 128.2, 128.0, 124.0, 122.5, 49.1, 44.4, 30.9, 2 Hz), 163.7, 146.7 (d, J = 9.0 Hz), 135.7, 133.7, 132.4 (d, J = 9.0 H
7.2, 21.9; HRMS (ESI): calcd for C20H20NO3 [M + H]+ 322.14377; z), 128.7, 128.0, 121.5 (d, J = 3.0 Hz), 114.9 (d, J = 22.5 Hz), 110
found 322.14373.
.6 (d, J = 22.5 Hz), 49.2, 44.8, 30.7, 27.3; HRMS (ESI): calcd for C
2,4,7-Trimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3(2H,4 19H17FNO3 [M + H]+ 326.11870; found 326.11872.
H)-dione (4da) and 2,4,5-Trimethyl-4-(2-oxo-2-phenylethyl)iso 6-Chloro-2,4-dimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,
quinoline-1,3(2H,4H)-dione (4da')(asterisk denotes minor iso 3(2H,4H)-dione (4ia). 62 mg, 60% yield, white solid, mp 73–74
mer 4da' peaks). 74 mg, 77% yield, yellow liquid; 1H NMR (600 oC; 1H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 8.4 Hz, 1H), 7.87 (d,
MHz, CDCl3) δ 8.10 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.53 (t, J = 7. J = 7.8 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 2H), 7.
2 Hz, 1H), 7.41 (t, J = 7.8 Hz, 2H), 7.31 (m, 1H), 7.15 (d, J = 7.8 H 36 (dd, J = 8.4, 1.8 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 4.25 (d, J = 1
z, 1H), 4.45* (d, J = 18.6 Hz, 1H), 4.27* (d, J = 18.6 Hz, 1H), 4.18 8.0 Hz, 1H), 3.88 (d, J = 18.0 Hz, 1H), 3.43 (s, 3H), 1.61 (s, 3H); 13
(d, J = 18.0 Hz, 1H), 3.95 (d, J = 18.0 Hz, 1H), 3.43 (s, 3H), 2.50* C NMR (150 MHz, CDCl3) δ 196.0, 176.1, 163.8, 145.5, 140.2, 1
(s, 3H), 2.37 (s, 3H), 1.71* (s, 3H), 1.59 (s, 3H); 13C NMR (150 M 35.7, 133.7, 131.0, 128.7, 128.0, 127.8, 123.9, 123.6, 49.2, 44.6
Hz, CDCl3) δ 196.5*, 196.2, 177.5*, 176.9, 164.9*, 164.8, 140.8, , 30.7, 27.4; HRMS (ESI): calcd for C19H17ClNO3 [M + H]+ 342.08
140.6*, 138.3*, 137.0, 135.9*, 134.7, 133.4, 129.4, 128.6*, 128 915; found 342.08911.
.6, 128.3*, 127.9, 127.9*, 127.1*, 126.3*, 124.7, 123.5, 49.1, 4 6-Bromo-2,4-dimethyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,
7.3*, 46.0*, 44.2, 30.9, 27.6*, 27.3, 27.0*, 22.9*, 20.9; HRMS ( 3(2H,4H)-dione (4ja). 61 mg, 53% yield, white solid, mp 155–1
ESI): calcd for C20H20NO3 [M + H]+ 322.14377; found 322.14375 56 oC; 1H NMR (600 MHz, CDCl3) δ 8.17 (d, J = 9.0 Hz, 1H), 7.86
.
(d, J = 7.8 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.52 (dd, J = 8.4, 1.2
6-Methoxy-2,4-dimethyl-4-(2-oxo-2-phenylethyl)isoquinoline Hz, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.40 (d, J = 1.2 Hz, 1H), 4.25 (d,
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J = 18.0 Hz, 1H), 3.88 (d, J = 18.0 Hz, 1H), 3.42 (s, 3H), 1.61 (s, 3 , 41.4, 30.9, 14.1; HRMS (ESI): calcd for C22H22NO5 [M + H]+ 380.
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H); 13C NMR (150 MHz, CDCl3) δ 196.0, 176.0, 163.9, 145.5, 135 14925; found 380.14923.
DOI: 10.1039/D0OB00086H
.6, 133.7, 131.0, 130.7, 128.9, 128.7, 128.0, 126.9, 124.0, 49.2, 4-Methyl-4-(2-oxo-2-phenylethyl)-2-phenylisoquinoline-1,3(2
44.5, 30.7, 27.4; HRMS (ESI): calcd for C19H17BrNO3 [M + H]+ 38 H,4H)-dione (4pa). 58 mg, 52% yield, white liquid; 1H NMR (60
6.03863; found 386.03865.
0 MHz, CDCl3) δ 8.34 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 7.2 Hz, 2H),
Methyl 2,4-dimethyl-1,3-dioxo-4-(2-oxo-2-phenylethyl)-1,2,3, 7.59–7.53 (m, 2H), 7.51 (t, J = 7.8 Hz, 2H), 7.45–7.40 (m, 4H), 7.
4-tetrahydroisoquinoline-7-carboxylate (4ka). 57 mg, 52% yiel 36–7.32 (m, 3H), 4.21 (d, J = 18.0 Hz, 1H), 4.05 (d, J = 18.0 Hz, 1
d, white solid, mp 154–155 oC; 1H NMR (600 MHz, CDCl3) δ 8.3 H), 1.75 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 196.2, 176.6, 164.
9 (d, J = 8.4 Hz, 1H), 8.02 (dd, J = 8.4, 1.8 Hz, 1H), 7.96 (d, J = 1. 6, 143.8, 135.9, 135.9, 134.0, 133.5, 129.6, 129.2, 128.6, 128.5,
2 Hz, 1H), 7.86 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.43 (t 128.4, 128.0, 127.3, 125.2, 123.8, 49.7, 45.0, 30.7; HRMS (ESI):
, J = 7.8 Hz, 2H), 4.27 (d, J = 18.0 Hz, 1H), 4.02 (d, J = 18.0 Hz, 1 calcd for C24H20NO3 [M + H]+ 370.14377; found 370.14376.
H), 3.90 (s, 3H), 3.45 (s, 3H), 1.65 (s, 3H); 13C NMR (150 MHz, C 2-Allyl-4-methyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3(2H,
DCl3) δ 196.2, 176.3, 166.0, 163.9, 143.9, 135.7, 134.6, 133.7, 1 4H)-dione (4qa). 49 mg, 49% yield, white solid, mp 100–101 oC
29.6, 128.6, 128.5, 128.1, 127.9, 125.1, 52.6, 49.4, 44.6, 30.6, 2 ; 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 8.4, 1.2 Hz, 1H), 7.86
7.5; HRMS (ESI): calcd for C21H20NO5 [M + H]+ 366.13360; found (d, J = 7.8 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.2 Hz, 1H)
366.13374.
, 7.42 (t, J = 7.8 Hz, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 3.6 H
2-Ethyl-4-methyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3(2H, z, 1H), 5.97–5.90 (m, 1H), 5.34 (dd, J = 16.8, 1.2 Hz, 1H), 5.18 (d
4H)-dione (4la). 74 mg, 77% yield, yellow liquid; 1H NMR (600 d, J = 10.2, 1.2 Hz, 1H), 4.72–4.64 (m, 2H), 4.22 (d, J = 18.6 Hz,
MHz, CDCl3) δ 8.31 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7. 1H), 3.98 (d, J = 18.0 Hz, 1H), 1.62 (s, 3H); 13C NMR (150 MHz, C
54 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, DCl3) δ 196.0, 176.1, 164.0, 143.8, 136.0, 133.8, 133.5, 132.1, 1
2H), 7.38 (t, J = 7.2 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 4.21 (d, J = 29.5, 128.6, 128.0, 127.2, 125.0, 123.4, 116.8, 48.9, 44.6, 42.5,
18.6 Hz, 1H), 4.17–4.06 (m, 2H), 3.97 (d, J = 18.0 Hz, 1H), 1.61 ( 31.0; HRMS (ESI): calcd for C21H20NO3 [M + H]+ 334.14377; foun
s, 3H), 1.27 (t, J = 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 196. d 334.14378.
1, 176.1, 164.1, 143.7, 136.0, 133.6, 133.4, 129.3, 128.6, 127.9, 2-Benzyl-4-methyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3(2
127.1, 125.2, 123.5, 49.1, 44.4, 35.6, 30.8, 12.9; HRMS (ESI): ca H,4H)-dione (4ra). 80 mg, 70% yield, white solid, mp 165–166 o
lcd for C20H20NO3 [M + H]+ 322.14377; found 322.14374.
2-Butyl-4-methyl-4-(2-oxo-2-phenylethyl)isoquinoline-
C; 1H NMR (600 MHz, CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.8
6 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1
1
1,3(2H,4H)-dione (4ma). 80 mg, 76% yield, yellow liquid; H H), 7.44–7.40 (m, 4H), 7.37 (t, J = 8.4 Hz, 1H), 7.29 (t, J = 7.2 Hz,
NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 7.6 2H), 7.25 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 5.31 (d, J =
Hz, 2H), 7.56–7.47 (m, 2H), 7.43–7.34 (m, 3H), 7.25 (d, J = 8.0 14.4 Hz, 1H), 5.23 (d, J = 14.4 Hz, 1H), 4.23 (d, J = 18.0 Hz, 1H),
Hz, 1H), 4.21 (d, J = 18.0 Hz, 1H), 4.13–4.01 (m, 2H), 3.97 (d, J = 3.99 (d, J = 18.6 Hz, 1H), 1.58 (s, 3H); 13C NMR (150 MHz, CDCl3)
18.0 Hz, 1H), 1.73–1.62 (m, 2H), 1.60 (s, 3H), 1.46–1.36 (m, δ 196.0, 176.4, 164.3, 143.8, 137.3, 136.0, 133.8, 133.5, 129.6,
2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 196.0, 128.6, 128.3, 128.1, 128.0, 127.2, 127.1, 125.0, 123.4, 48.8, 44.
176.3, 164.3, 143.7, 136.0, 133.6, 133.4, 129.3, 128.5, 127.9, 8, 43.7, 30.9; HRMS (ESI): calcd for C25H22NO3 [M + H]+ 384.159
127.0, 125.1, 123.4, 48.9, 44.5, 40.3, 30.9, 29.8, 20.2, 13.8; 42; found 384.15939.
HRMS (ESI): calcd for C22H24NO3 [M + H]+ 350.17507; found 2,4-Dimethyl-4-(2-oxo-2-(o-tolyl)ethyl)isoquinoline-1,3(2H,4H
o
350.17503.
)-dione (4ab). 59 mg, 61% yield, white solid, mp 140–141 C; 1
2-Isobutyl-4-methyl-4-(2-oxo-2-phenylethyl)isoquinoline-1,3( H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 7
2H,4H)-dione (4na). 79 mg, 76% yield, white liquid; 1H NMR (6 .2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.34 (t
00 MHz, CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 1H), 7.86 (d, J = 7.2 H , J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H),
z, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.15 (d, J = 7.8 Hz, 1H), 4.19 (d, J = 18.0 Hz, 1H), 3.83 (d, J = 18.
7.8 Hz, 2H), 7.38 (t, J = 8.4 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 4.23 0 Hz, 1H), 3.44 (s, 3H), 2.13 (s, 3H), 1.59 (s, 3H); 13C NMR (150
(d, J = 18.0 Hz, 1H), 3.98–3.93 (m, 2H), 3.92–3.87 (m, 1H), 2.22 MHz, CDCl3) δ 200.1, 176.7, 164.6, 143.7, 138.3, 136.8, 133.6,
–2.14 (m, 1H), 1.61 (s, 3H), 0.96 (q, J = 6.6 Hz, 6H); 13C NMR (15 131.9, 131.6, 129.3, 128.3, 127.1, 125.6, 125.1, 123.5, 51.9, 44.
0 MHz, CDCl3) δ 196.0, 176.7, 164.6, 143.8, 136.0, 133.6, 133.4 9, 30.8, 27.3, 20.9; HRMS (ESI): calcd for C20H20NO3 [M + H]+ 32
, 129.5, 128.6, 127.9, 127.1, 125.1, 123.3, 48.8, 47.3, 44.6, 31.2 2.14377; found 322.14378.
, 27.3, 20.2; HRMS (ESI): calcd for C22H24NO3 [M + H]+ 350.1750 2,4-Dimethyl-4-(2-oxo-2-(m-tolyl)ethyl)isoquinoline-1,3(2H,4
7; found 350.17502.
H)-dione (4ac). 65 mg, 68% yield, white solid, mp 155–156 oC; 1
Ethyl 2-(4-methyl-1,3-dioxo-4-(2-oxo-2-phenylethyl)-3,4-dihy H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8
droisoquinolin-2(1H)-yl)acetate (4oa). 68 mg, 60% yield, white .4 Hz, 2H), 7.50 (t, J = 7.2 Hz, 1H), 7.39–7.34 (m, 2H), 7.30 (t, J =
liquid; 1H NMR (600 MHz, CDCl3) δ 8.30 (d, J = 8.4 Hz, 1H), 7.87 7.2 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.20 (d, J = 18.6 Hz, 1H), 3.9
(d, J = 7.8 Hz, 2H), 7.56–7.51 (m, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7. 7 (d, J = 18.0 Hz, 1H), 3.45 (s, 3H), 2.36 (s, 3H), 1.61 (s, 3H); 13
C
39 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.89 (d, J = 16.8 Hz NMR (150 MHz, CDCl3) δ 196.4, 176.7, 164.6, 143.7, 138.4, 135
, 1H), 4.78 (d, J = 16.8 Hz, 1H), 4.26–4.17 (m, 3H), 4.03 (d, J = 1 .9, 134.2, 133.7, 129.3, 128.5, 128.4, 127.1, 125.2, 125.0, 123.5
8.0 Hz, 1H), 1.67 (s, 3H), 1.27 (t, J = 7.8 Hz, 3H); 13C NMR (150 , 49.2, 44.5, 30.8, 27.3, 21.2; HRMS (ESI): calcd for C20H20NO3 [
MHz, CDCl3) δ 196.0, 176.1, 168.1, 163.8, 143.9, 135.8, 134.1, M + H]+ 322.14377; found 322.14375.
133.5, 129.6, 128.6, 128.0, 127.2, 124.5, 123.4, 61.4, 48.5, 44.8 2,4-Dimethyl-4-(2-oxo-2-(p-tolyl)ethyl)isoquinoline-
6 | J. Name., 2012, 00, 1-3
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1,3(2H,4H)-dione (4ad). 67 mg, 70% yield, white solid, mp for C19H17BrNO3 [M + H]+ 386.03863; found 386.03864.
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o
161–163 C; 1H NMR (600 MHz, CDCl3) δ 8.30 (dd, J = 7.8, 1.2 4-(2-(3-Bromophenyl)-2-oxoethyl)-2,4-dimethylisoquinoline-1
Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.37 (t, J ,3(2H,4H)-dione (4aj). 70 mg, 60% yield, white solid, mp 123–1
= 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.8 Hz, 2H), 24 oC; 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 7.8, 1.2 Hz, 1H),
4.18 (d, J = 18.0 Hz, 1H), 3.96 (d, J = 18.0 Hz, 1H), 3.44 (s, 3H), 7.97 (t, J = 1.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 H
2.38 (s, 3H), 1.61 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 195.8, z, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.30 (t, J =
176.7, 164.6, 144.4, 143.8, 133.6, 133.5, 129.3, 129.2, 128.0, 7.8 Hz, 1H), 7.25 (s, 1H), 4.18 (d, J = 18.6 Hz, 1H), 3.91 (d, J = 18
127.1, 125.0, 123.5, 49.0, 44.5, 30.8, 27.3, 21.6; HRMS (ESI): .0 Hz, 1H), 3.44 (s, 3H), 1.62 (s, 3H); 13C NMR (150 MHz, CDCl3)
DOI: 10.1039/D0OB00086H
calcd for C20H20NO3 [M + H]+ 322.14377; found 322.14379.
δ 194.9, 176.5, 164.5, 143.4, 137.5, 136.3, 133.8, 131.1, 130.2,
4-(2-(4-Methoxyphenyl)-2-oxoethyl)-2,4-dimethylisoquinolin
129.4, 127.3, 126.5, 125.0, 123.4, 123.0, 49.1, 44.5, 30.8, 27.3;
e-1,3(2H,4H)-dione (4ae). 75 mg, 74% yield, white solid, mp 14 HRMS (ESI): calcd for C19H17BrNO3 [M + H]+ 386.03863; found 3
1–143 oC; 1H NMR (600 MHz, CDCl3) δ 8.30 (dd, J = 7.8, 1.2 Hz, 86.03866.
1H), 7.83 (d, J = 8.4 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 8 2,4-Dimethyl-4-(2-(naphthalen-2-yl)-2-oxoethyl)isoquinoline-
.4 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 9.0 Hz, 2H), 4.16 ( 1,3(2H,4H)-dione (4ak). 72 mg, 67% yield, white solid, mp 171
d, J = 18.0 Hz, 1H), 3.93 (d, J = 18.0 Hz, 1H), 3.84 (s, 3H), 3.44 (s –172 oC; 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 8.33 (dd, J = 7
, 3H), 1.60 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 194.6, 176.8, 16 .8, 1.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.87–7.82 (m, 3H), 7.60 (
4.6, 163.7, 143.8, 133.6, 130.2, 129.3, 129.0, 127.0, 125.0, 123. t, J = 7.8 Hz, 1H), 7.55 (t, J = 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H),
5, 113.7, 55.5, 48.8, 44.5, 30.8, 27.23; HRMS (ESI): calcd for C20 7.39 (t, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.36 (d, J = 18.0
H20NO4 [M + H]+ 338.13868; found 338.13866.
Hz, 1H), 4.13 (d, J = 18.0 Hz, 1H), 3.47 (s, 3H), 1.67 (s, 3H); 13C N
4-(2-(4-Chlorophenyl)-2-oxoethyl)-2,4-dimethylisoquinoline-1 MR (150 MHz, CDCl3) δ 196.1, 176.8, 164.7, 143.7, 135.7, 133.7
,3(2H,4H)-dione (4af). 70 mg, 69% yield, white solid, mp 171–1 , 133.3, 132.4, 129.8, 129.5, 129.4, 128.7, 128.5, 127.8, 127.2,
72 oC; 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 8.4, 1.8 Hz, 1H), 126.9, 125.1, 123.5, 123.5, 49.2, 44.6, 30.9, 27.4; HRMS (ESI): c
7.79 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 7.41–7.38 (m, 3 alcd for C23H20NO3 [M + H]+ 358.14377; found 358.14377.
H), 7.25 (d, J = 8.4 Hz, 1H), 4.18 (d, J = 18.0 Hz, 1H), 3.91 (d, J = 2,4-Dimethyl-4-(2-oxo-2-(thiophen-2-yl)ethyl)isoquinoline-1,3
18.0 Hz, 1H), 3.44 (s, 3H), 1.61 (s, 3H); 13C NMR (150 MHz, CDCl (2H,4H)-dione (4al). 69 mg, 73% yield, white solid, mp 107–10
3) δ 195.0, 176.6, 164.5, 143.5, 140.0, 134.2, 133.7, 129.4, 129. 8 oC; 1H NMR (600 MHz, CDCl3) δ 8.28 (dd, J = 7.8, 1.2 Hz, 1H), 7
4, 129.0, 127.2, 125.0, 123.4, 49.1, 44.5, 30.9, 27.3; HRMS (ESI) .72 (dd, J = 4.2, 1.2 Hz, 1H), 7.59 (dd, J = 4.8, 1.2 Hz, 1H), 7.52 (t
: calcd for C19H17ClNO3 [M + H]+ 342.08915; found 342.08910.
, J = 7.8 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H),
7.10 (t, J = 4.2, 1H), 4.16 (d, J = 18.0 Hz, 1H), 3.88 (d, J = 18.0 Hz
4-(2-(4-Bromophenyl)-2-oxoethyl)-2,4-dimethylisoquinoline-
1,3(2H,4H)-dione (4ag). 73 mg, 63% yield, white solid, mp , 1H), 3.43 (s, 3H), 1.60 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 189
o
176–177 C; 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 7.8, 1.2 .0, 176.5, 164.5, 143.3, 142.9, 134.0, 133.7, 132.1, 129.3, 128.1
Hz, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.52 (t, , 127.2, 124.9, 123.6, 49.5, 44.5, 30.8, 27.3; HRMS (ESI): calcd f
J = 7.8 Hz, 1H), 7.40 (t, J = 8.4 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), or C17H16NO3S [M + H]+ 314.08454; found 314.08454.
4.18 (d, J = 18.0 Hz, 1H), 3.90 (d, J = 18.0 Hz, 1H), 3.44 (s, 3H), 4-(2-Cyclohexyl-2-oxoethyl)-2,4-dimethylisoquinoline-1,3(2H,
1.61 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 195.0, 176.6, 164.5, 4H)-dione (4am). 36 mg, 38% yield, yellow liquid; 1H NMR (600
143.5, 140.0, 134.2, 133.7, 129.4, 129.4, 128.9, 127.2, 125.0, MHz, CDCl3) δ 8.26 (dd, J = 7.8, 1.2 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1
123.4, 49.0, 44.5, 30.9, 27.3; HRMS (ESI): calcd for C19H17BrNO3 H), 7.38 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 3.67 (d, J = 1
[M + H]+ 386.03863; found 386.03866.
8.0 Hz, 1H), 3.40 (d, J = 18.6 Hz, 1H), 3.40 (s, 3H), 2.24–2.18 (m,
4-(2-(4-Iodophenyl)-2-oxoethyl)-2,4-dimethylisoquinoline-
1H), 1.77–1.67 (m, 4H), 1.62–1.57 (m, 1H), 1.49 (s, 3H), 1.26–1.
1,3(2H,4H)-dione (4ah). 84 mg, 65% yield, white solid, mp 17 (m, 3H), 1.14–1.03 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 210
o
183–185 C; 1H NMR (600 MHz, CDCl3) δ 8.31 (dd, J = 7.8, 1.2 .1, 176.7, 164.5, 143.6, 133.5, 129.3, 127.1, 125.0, 123.4, 51.0,
Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.52 (d, 50.1, 44.2, 30.6, 28.1, 28.0, 27.3, 25.7, 25.5, 25.4; HRMS (ESI):
J = 7.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), calcd for C19H24NO3 [M + H]+ 314.17507; found 314.17507.
4.16 (d, J = 18.0 Hz, 1H), 3.89 (d, J = 18.0 Hz, 1H), 3.44 (s, 3H), 2,4-Dimethyl-4-(2-oxopropyl)isoquinoline-1,3(2H,4H)-dione
1.61 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 195.6, 176.6, 164.5, (4an). 25 mg, 34% yield, white liquid; 1H NMR (600 MHz, CDCl3)
143.5, 137.9, 135.1, 133.7, 129.4, 129.3, 127.2, 125.0, 123.4, δ 8.28 (dd, J = 7.8, 1.2 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.40 (t, J
101.6, 49.0, 44.5, 30.9, 27.3; HRMS (ESI): calcd for C19H17INO3 = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 3.70 (d, J = 18.6 Hz, 1H),
[M + H]+ 434.02476; found 434.02472.
4-(2-(2-Bromophenyl)-2-oxoethyl)-2,4-dimethylisoquinoline-
3.40 (s, 3H), 3.35 (d, J = 18.6 Hz, 1H), 2.01 (s, 3H), 1.50 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 204.7, 176.6, 164.5, 143.4, 133.7,
1,3(2H,4H)-dione (4ai) 69 mg, 59% yield, white liquid; 1H NMR 129.3, 127.2, 125.0, 123.5, 53.8, 44.3, 30.5, 29.5, 27.2; HRMS
(600 MHz, CDCl3) δ 8.31 (dd, J = 7.8, 1.2 Hz, 1H), 7.59–7.54 (m, (ESI): calcd for C14H16NO3 [M + H]+ 246.11247; found
2H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 246.11245.
7.2 Hz, 1H), 7.28–7.25 (m, 1H), 7.22 (dd, J = 7.2, 1.8 Hz, 1H),
4.19 (d, J = 18.6 Hz, 1H), 3.91 (d, J = 18.6 Hz, 1H), 3.45 (s, 3H),
1.58 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 200.1, 176.4, 164.5,
143.0, 140.3, 133.7, 133.6, 131.9, 129.3, 128.7, 127.4, 127.3,
125.1, 124.0, 118.6, 52.9, 44.9, 30.8, 27.4; HRMS (ESI): calcd
Conflicts of interest
There are no conflicts to declare.
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Z. Bian, C. Pittman and A. Zhou, Org. Biomol. Chem., 2014,
Acknowledgements
12, 7690; (j) Z. Zhang, L. Zhang, Y. Cao, F. Li, G.VBieawi,ArGtic.leLiOun,linYe.
DOI: 10.1039/D0OB00086H
Yang and F. Mo, Org. Lett., 2019, 21, 762; (k) S. Wang, P. Dai,
Z. Yan, Y. Wang, J. Shao, Y. Wu, C. Deng and W. Zhang,
ChemistrySelect, 2019, 4, 10329; (l) G. Zou and X. Wang, Org.
Biomol. Chem., 2017, 15, 8748; (m) L. Zheng, C. Yang, Z. Xu,
F. Gao and W. Xia, J. Org. Chem., 2015, 80, 5730; (n) S. Tang,
Y.-L. Deng, J. Li, W.-X. Wang, G.-L. Ding, M.-W. Wang, Z.-P.
Xiao, Y.-C. Wang and R.-L. Sheng, J. Org. Chem., 2015, 80,
12599; (o) L. Li, M. Deng, S.-C. Zheng, Y.-P. Xiong, B. Tan and
X.-Y. Liu, Org. Lett., 2014, 16, 504; (p) X. Li, S. Zhuang, X.
Fang, P. Liu and P. Sun, Org. Biomol. Chem., 2017, 15, 1821;
(q) X.-F. Xia, S.-L. Zhu, J.-B. Liu, D. Wang and Y.-M. Liang, J.
Org. Chem., 2016, 81, 12482; (r) K.-L. Zuo, Y.-H. He and Z.
Guan, Eur. J. Org. Chem., 2019, 2019, 939; (s) Q. Tang, P. Xie,
J. Wang, J. Lin, C. Feng, C. U. Pittman and A. Zhou,
Tetrahedron, 2017, 73, 5436; (t) Y.-q. Yuan, P. S. Kumar, C.-n.
Zhang, M.-h. Yang and S.-r. Guo, Org. Biomol. Chem., 2017,
15, 7330; (u) X.-F. Xia, S.-L. Zhu, D. Wang and Y.-M. Liang,
Adv. Synth. Catal., 2017, 359, 859; (v) J. Wu, Y. Gao, X. Zhao,
L. Zhang, W. Chen, G. Tang and Y. Zhao, RSC Advances, 2016,
6, 303; (w) M. Zhang, P. Xie, W. Zhao, B. Niu, W. Wu, Z. Bian,
C. U. Pittman and A. Zhou, J. Org. Chem., 2015, 80, 4176; (x)
X. Liu, T. Cong, P. Liu and P. Sun, Org. Biomol. Chem., 2016,
14, 9416.
(a) X.-Q. Hu, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int.
Ed., 2017, 56, 1960; (b) S. Roslin and L. R. Odell, Eur. J. Org.
Chem., 2017, 2017, 1993; (c) N. A. Romero and D. A.
Nicewicz, Chem. Rev., 2016, 116, 10075; (d) K. L. Skubi, T. R.
Blum and T. P. Yoon, Chem. Rev., 2016, 116, 10035; (e) J.-R.
Chen, X.-Q. Hu, L.-Q. Lu and W.-J. Xiao, Chem. Soc. Rev.,
2016, 45, 2044; (f) I. Ghosh, L. Marzo, A. Das, R. Shaikh and
B. König, Acc. Chem. Res., 2016, 49, 1566; (g) J.-R. Chen, X.-
Q. Hu, L.-Q. Lu and W.-J. Xiao, Acc. Chem. Res., 2016, 49,
1911; (h) J.-P. Goddard, C. Ollivier and L. Fensterbank, Acc.
Chem. Res., 2016, 49, 1924; (i) J. C. Tellis, C. B. Kelly, D. N.
Primer, M. Jouffroy, N. R. Patel and G. A. Molander, Acc.
Chem. Res., 2016, 49, 1429; (j) T. Hering, A. U. Meyer and B.
König, J. Org. Chem., 2016, 81, 6927; (k) T. Courant and G.
Masson, J. Org. Chem., 2016, 81, 6945; (l) D. Staveness, I.
Bosque and C. R. J. Stephenson, Acc. Chem. Res., 2016, 49,
2295; (m) M. D. Levin, S. Kim and F. D. Toste, ACS Central
Science, 2016, 2, 293; (n) J. J. Douglas, M. J. Sevrin and C. R. J.
Stephenson, Org. Process. Res. Dev., 2016, 20, 1134; (o) C. K.
Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev., 2013,
113, 5322; (p) D. Ravelli, M. Fagnoni and A. Albini, Chem. Soc.
Rev., 2013, 42, 97; (q) T. P. Yoon, ACS Catal., 2013, 3, 895; (r)
Y. Xi, H. Yi and A. Lei, Org. Biomol. Chem., 2013, 11, 2387; (s)
L. Shi and W. Xia, Chem. Soc. Rev., 2012, 41, 7687; (t) J. Xuan
and W.-J. Xiao, Angew. Chem., Int. Ed., 2012, 51, 6828; (u) J.
W. Tucker and C. R. J. Stephenson, J. Org. Chem., 2012, 77,
1617; (v) J. M. R. Narayanam and C. R. J. Stephenson, Chem.
Soc. Rev., 2011, 40, 102; (w) T. P. Yoon, M. A. Ischay and J.
Du, Nature Chemistry, 2010, 2, 527; (x) D. A. Nicewicz and D.
W. C. MacMillan, Science, 2008, 322, 77; (y) H. E. Ho, A.
Pagano, J. A. Rossi-Ashton, J. R. Donald, R. G. Epton, J. C.
Churchill, M. J. James, P. O'Brien, R. J. K. Taylor and W. P.
Unsworth, Chem. Sci., 2020, DOI: 10.1039/c9sc05311e; (z)
Q.-B. Zhang, P.-F. Yuan, L.-L. Kai, K. Liu, Y.-L. Ban, X.-Y. Wang,
L.-Z. Wu and Q. Liu, Org. Lett., 2019, 21, 885; (aa) H. Sahoo,
A. Mandal, S. Dana and M. Baidya, Adv. Synth. Catal., 2018,
360, 1099.
We are thankful for financial support from the National
Natural Science Foundation of China (Grant No. 21502154,
21961034, 21362033) and the Gansu Provincial Science and
Technology Program (No. 17JR5RA073). We thank Prof. Dr.
Yao. X. (NWNU) for X-ray crystallographicanalysis and Prof. Dr.
Yang C. (NWNU) for NMR assignment.
Notes and references
1
(a) S. K. V. Vernekar, Z. Liu, E. Nagy, L. Miller, K. A. Kirby, D. J.
Wilson, J. Kankanala, S. G. Sarafianos, M. A. Parniak and Z.
Wang, J. Med. Chem., 2015, 58, 651; (b) Y.-L. Chen, J. Tang,
M. J. Kesler, Y. Y. Sham, R. Vince, R. J. Geraghty and Z. Wang,
Bioorg. Med. Chem., 2012, 20, 467.
2
(a) J. Kankanala, C. Marchand, M. Abdelmalak, H. Aihara, Y.
Pommier and Z. Wang, J. Med. Chem., 2016, 59, 2734; (b) B.-
R. Kang, J. Wang, H. Li, Y. Li, Q.-B. Mei and S.-Q. Zhang, Med.
Chem. Res., 2014, 23, 1340; (c) H.-R. Tsou, X. Liu, G. Birnberg,
J. Kaplan, M. Otteng, T. Tran, K. Kutterer, Z. Tang, R. Suayan,
A. Zask, M. Ravi, A. Bretz, M. Grillo, J. P. McGinnis, S. K.
Rabindran, S. Ayral-Kaloustian and T. S. Mansour, J. Med.
Chem., 2009, 52, 2289; (d) J. M. Ontoria, E. H. Rydberg, S. Di
Marco, L. Tomei, B. Attenni, S. Malancona, J. I. Martin
Hernando, N. Gennari, U. Koch, F. Narjes, M. Rowley, V.
Summa, S. S. Carroll, D. B. Olsen, R. De Francesco, S.
Altamura, G. Migliaccio and A. Carfì, J. Med. Chem., 2009, 52,
5217; (e) S. C. Mayer, A. L. Banker, F. Boschelli, L. Di, M.
Johnson, C. H. Kenny, G. Krishnamurthy, K. Kutterer, F. Moy,
S. Petusky, M. Ravi, D. Tkach, H.-R. Tsou and W. Xu, Bioorg.
Med. Chem. Lett., 2008, 18, 3641; (f) M. S. Malanias, T. C.
Hohman and J. Millen, J. Med. Chem., 1994, 37, 2043.
(a) R. S. Phatake, P. Patel and C. V. Ramana, Org. Lett., 2016,
18, 2828; (b) X.-F. Xia, S.-L. Zhu, Y. Li and H. Wang, RSC
Advances, 2016, 6, 51703; (c) J. Shi, J. Zhou, Y. Yan, J. Jia, X.
Liu, H. Song, H. E. Xu and W. Yi, Chem. Commun., 2015, 51,
668; (d) W. Kong, E. Merino and C. Nevado, Angew. Chem.,
Int. Ed., 2014, 53, 5078; (e) L. Li, Y.-L. Zhao, H. Wang, Y.-J. Li,
X. Xu and Q. Liu, Chem. Commun., 2014, 50, 6458; (f) W.
Kong, M. Casimiro, N. Fuentes, E. Merino and C. Nevado,
Angew. Chem., Int. Ed., 2013, 52, 13086; (g) M.-B. Zhou, R.-J.
Song, X.-H. Ouyang, Y. Liu, W.-T. Wei, G.-B. Deng and J.-H. Li,
Chem. Sci., 2013, 4, 2690; (h) J. Vicente, P. González-Herrero,
R. Frutos-Pedreño, M.-T. Chicote, P. G. Jones and D. Bautista,
Organometallics., 2011, 30, 1079; (i) S. Ozcan, C. Dengiz, M.
K. Deliömeroglu, E. Sahin and M. Balci, Tetrahedron Lett.,
2011, 52, 1495; (j) Y. Pan, C. P. Holmes and D. Tumelty, J.
Org. Chem., 2005, 70, 4897; (k) M. K. Dongare, V. V.
Bhagwat, C. V. Ramana and M. K. Gurjar, Tetrahedron Lett.,
2004, 45, 4759; (l) B. Quiclet-Sire and S. Z. Zard, Chem.
Commun., 2002, 2306; (m) S. D. Young, J. M. Wiggins and J.
R. Huff, J. Org. Chem., 1988, 53, 1114.
5
3
4
(a) S. Huang, P. Niu, Y. Su, D. Hu and C. Huo, Org. Biomol.
Chem., 2018, 16, 7748; (b) Y.-N. Niu, X.-F. Xia and Y. Yuan,
Synlett, 2018, 14, 617; (c) Z.-Z. Li, J. Yu, L.-N. Wang, S.-L.
Chen, R.-L. Sheng and S. Tang, Tetrahedron, 2018, 74, 6558;
(d) C. Pan, C. Chen and J.-T. Yu, Org. Biomol. Chem., 2017, 15,
1096; (e) S. Tang, Y.-L. Deng, J. Li, W.-X. Wang, Y.-C. Wang, Z.-
Z. Li, L. Yuan, S.-L. Chen and R.-L. Sheng, Chem. Commun.,
2016, 52, 4470; (f) P. Qian, B. Du, W. Jiao, H. Mei, J. Han and
Y. Pan, Beilstein J. Org. Chem., 2016, 12, 301; (g) X.-F. Xia, S.-
L. Zhu, C. Chen, H. Wang and Y.-M. Liang, J. Org. Chem.,
2016, 81, 1277; (h) Y.-L. Deng, S. Tang, G.-L. Ding, M.-W.
Wang, J. Li, Z.-Z. Li, L. Yuan and R.-L. Sheng, Org. Biomol.
Chem., 2016, 14, 9348; (i) W. Zhao, P. Xie, M. Zhang, B. Niu,
6
(a) F. Penteado, E. F. Lopes, D. Alves, G. Perin, R. G. Jacob
and E. J. Lenardão, Chem. Rev., 2019, 119, 7113; (b) L.-N.
Guo, H. Wang and X.-H. Duan, Org. Biomol. Chem., 2016, 14,
7380; (c) A. Banerjee, Z. Lei and M.-Y. Ngai, Synthesis, 2019,
51, 303.
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(a) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan and A. Lei,
View Article Online
DOI: 10.1039/D0OB00086H
Angew. Chem., Int. Ed., 2014, 53, 502; (b) P. Bao, F. Liu, Y. Lv,
H. Yue, J.-S. Li and W. Wei, Org. Chem. Front., DOI:
10.1039/C9QO01334B, 2020; (c) J.-J. Zhao, H.-H. Zhang, X.
Shen and S. Yu, Org. Lett., 2019, 21, 913; (d) H.-H. Zhang and
S. Yu, Org. Lett., 2019, 21, 3711; (e) S. Manna and K. R.
Prabhu, J. Org. Chem., 2019, 84, 5067; (f) L. Guillemard, F.
Colobert and J. Wencel-Delord, Adv. Synth. Catal., 2018, 360,
4184; (g) J.-Q. Chen, R. Chang, Y.-L. Wei, J.-N. Mo, Z.-Y. Wang
and P.-F. Xu, J. Org. Chem., 2018, 83, 253; (h) M. Zhang, J. Xi,
R. Ruzi, N. Li, Z. Wu, W. Li and C. Zhu, J. Org. Chem., 2017, 82,
9305; (i) J.-J. Zhang, Y.-B. Cheng and X.-H. Duan, Chinese. J.
Chem., 2017, 35, 311; (j) L. Gu, C. Jin, J. Liu, H. Zhang, M.
Yuan and G. Li, Green Chem., 2016, 18, 1201; (k) Q. Shi, P. Li,
X. Zhu and L. Wang, Green Chem., 2016, 18, 4916; (l) W. Ji, H.
Tan, M. Wang, P. Li and L. Wang, Chem. Commun., 2016, 52,
1462; (m) N. Xu, P. Li, Z. Xie and L. Wang, Chem.-Eur. J., 2016,
22, 2236; (n) T. Xiao, L. Li and L. Zhou, J. Org. Chem., 2016,
81, 7908; (o) C. Zhou, P. Li, X. Zhu and L. Wang, Org. Lett.,
2015, 17, 6198; (p) G.-Z. Wang, R. Shang, W.-M. Cheng and Y.
Fu, Org. Lett., 2015, 17, 4830; (q) H. Tan, H. Li, W. Ji and L.
Wang, Angew. Chem., Int. Ed., 2015, 54, 8374; (r) H. Huang,
G. Zhang and Y. Chen, Angew. Chem., Int. Ed., 2015, 54,
7872; (s) L. Chu, J. M. Lipshultz and D. W. C. MacMillan,
Angew. Chem., Int. Ed., 2015, 54, 7929; (t) W.-M. Cheng, R.
Shang, H.-Z. Yu and Y. Fu, Chem.-Eur. J., 2015, 21, 13191; (u)
C. Wang, J. Qiao, X. Liu, H. Song, Z. Sun and W. Chu, J. Org.
Chem., 2018, 83, 1422; (v) M. Kim, J. Park, S. Sharma, A. Kim,
E. Park, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun.,
2013, 49, 925; (w) Z.-Y. Li, D.-D. Li and G.-W. Wang, J. Org.
Chem., 2013, 78, 10414; (x) H. Li, P. Li, Q. Zhao and L. Wang,
Chem. Commun., 2013, 49, 9170; (y) H. Li, P. Li, H. Tan and L.
Wang, Chem.-Eur. J., 2013, 19, 14432; (z) P. Fang, M. Li and
H. Ge, J. Am. Chem. Soc., 2010, 132, 11898.
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CCDC-1937084 (4aa) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
(a) Y. Yu, W. Yuan, H. Huang, Z. Cai, P. Liu and P. Sun, J. Org.
Chem., 2018, 83, 1654; (b) X.-Z. Wang and C.-C. Zeng,
Tetrahedron, 2019, 75, 1425.
10 R. A. Garza-Sanchez, A. Tlahuext-Aca, G. Tavakoli and F.
Glorius, ACS Catal., 2017, 7, 4057.
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