Metal-Free Catalyzed Cyclization of N-Methoxybenzamides to Construct Quaternary Carbon-Containing Isoindolinones

Article abstract of DOI:10.1002/cjoc.202000534

Through the intramolecular cyclization of N-methoxybenzamides, a simple and efficient method for constructing valuable isoindolinones under metal-free conditions was developed. The reaction was featured by employing low-cost catalyst, simple operation, 100% atomic economy and excellent regioselectivity. Moreover, a detailed computational study on the reaction system has been performed to clarify the mechanism. This protocol tolerated a variety of functional groups and provided a metal-free protocol for the synthesis of chromane- or tetrahydroquinoline-fused isoindolinones in good yields.

Full text of DOI:10.1002/cjoc.202000534

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Metal-free Catalyzed Cyclization of N-methoxybenzamides to Construct
Quaternary Carbon-Containing Isoindolinones
Authors: Lin-Bao Zhang, Zi-Chen Wang, Sheng-Zheng Sun, Shao-Fei Ni,* Li-Rong
Wen,* and Ming Li*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000534.
The final Version of Record (VoR) of it with formal page numbers will soon be
published online in Early View: http://dx.doi.org/10.1002/cjoc.202000534.
ISSN 1001-604X • CN 31-1547/O6
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Zhang Lin-Bao (Orcid ID: 0000-0002-8334-4188)
Metal-free Catalyzed Cyclization of N-methoxybenzamides to Construct
Quaternary Carbon-Containing Isoindolinones
Lin-Bao Zhang,a Zi-Chen Wang,a Sheng-Zheng Sun,a Shao-Fei Ni, *,b Li-Rong Wen, *,a and Ming Li *,a
a State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology,
Qingdao 266042, P. R. China.
b Department of Chemistry and Key Laboratory for Preparation and Application of Ordered Structural Materials of Guangdong Province, Shantou University,
Shantou,Guangdong 515063, P. R. China.
Cite this paper:
Summary of main observation and conclusion Through the intramolecular cyclization of N-methoxybenzamides, a simple and efficient method for
constructing valuable isoindolinones under metal-free conditions was developed. The reaction was featured by employing low-cost catalyst, simple
operation, 100% atomic economy and excellent regioselectivity. Moreover, a detailed computational study on the reaction system has been performed to
clarify the mechanism. This protocol tolerated a variety of functional groups and provided a metal-free protocol for the synthesis of chromane- or
tetrahydroquinoline-fused isoindolinones in good yields.
allene formation/cyclization pathway.4 We disclosed a Co/Ag-
Background and Originality Content
catalyzed C-H alkynylation/annulation with alkynes for the
construction of 3-methyleneisoindolinones.5 Despite the fact that
significant development has been achieved on transition metals
promoting research of the cyclization of alkynes based on C-H
functionalizations or cascade reactions, an alternative route relying
on metal-free strategy to construct target products is still appealing
due to green and economy features.6
Among the large family of indoles, isoindolinone derivatives are
remarkable owing to their prevalence in natural products, drugs
and functional materials. For example, indoprofen is used in anti-
inflammatory drugs, falipamil demonstrates anti-ischemic
properties, chlortalidone has a diuretic effect and pestalachloride
A is identified as an antifungal drug.1 Therefore, the synthesis of this
class of compounds caused a great interest of chemists, and various
synthetic methods have been developed.2
Triflimide (HNTf2) as a special catalyst has been achieved
uniquely outstanding performance in
a range of organic
transformations, including C−C and C-heteroatom formation
processes because of its strong acidity and good compatibility with
organic solvents.7 In these cases, it has been extensively used as a
super Brønsted acid to catalyze Friedel−Crafts reactions,8 aldol
reactions,9 and cycloaddition reactions.10 Especially, Ye and co-
workers have developed a variety of HNTf2-initiated cascade
cyclizations of ynamides for the synthesis of functionalize
heterocycle compounds based on keteniminium ions.11 Inspired by
these successful results and as part of our interest in green
chemistry,12 we envisioned that HNTf2 might also active the simple
alkynes, thus allowing the facile and practical access to a variety of
highly functionalized isoindolinones. Herein, we describe the
realization of intramolecular HNTf2-initiated cascade cyclization of
alkynes, leading to chromane-fused isoindolinones in good yields,
providing a green and economical alternative among the previously
applicable metal-catalyzed protocols (Scheme 1b).
Scheme 1 The synthetic methods for isoindolinones.
a)
work:
Previous
Transition-metal-catalyzed
protocols
O
O
R
R
N
R1
R2
H
N
R
N2
Rh
Cu
Co
Pd
Au
R1 R1
al
et
work:
This
Metal-free catalytic
isoindolinones
O
b)
of
synthesis
O
OMe
N
Metal
OMe
N
R1
H
R2
R1
to 96%
up
R2
X
X
X
=
NTs
O,
metal-free catalysis
economy
construction
of
quarternary
scope
broad substrate
Results and Discussion
100% atomic
gram-scale
DFT calculations
synthesis
Table 1 Optimization of reaction conditions for 3a.a
O
O
Remarkable progress has been made in the Rh(III)-, Pd(II)-,
Cu(II)-, Co(II)- and Au(I)-catalyzed C−H bond functionalizations,
OMe
OMe
N
N
H
conditions
which provides
a
step- and atom-economical route to
isoindolinones from less functionalized substrates (Scheme 1a).3
For instance, the group of Ma reported the Rh(III)-catalyzed
synthetic route of isoindolinones via a sequential C−H activation/
O
O
1a
3a
aE-mail:wenlirong@qust.edu.cn;liming928@qust.edu.cn
bE-mail:shaofeinee@163.com
Chin. J. Chem. 2018, 36, 587－593© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim
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First author et al.
Report
reactive to provide 54−66% yields (3h-3k). For meta-substituted
and ortho-substituted benzamides, the reaction is affected by the
steric hindrance of the aromatic ring, both the electron-donating
Entry
Catalyst 2
AgOTf
Solvent
DCE
Temp (℃)
Yield (%)b
29
100
1
2
3
4
5
DCE
DCE
DCE
DCE
DCE
100
100
100
100
100
33
36
40
51
39
Cu(OTf)2
Zn(OTf)2
Sc(OTf)3
In(OTf)3
Yb(OTf)3
Scheme 2 Synthesis of isoindolinones 3.a,b
O
O
OMe
HNTf2
OMe
equiv)
(0.2
N
N
H
R1
DCE
6
7
100 o 12 h
R1
O
O
C,
DCE
DCE
100
100
100
100
100
100
100
100
80
49
63
CF3COOH
HOTf
3
1
8
,
,
=
=
p
-F,
3a R1 H,
3h R1
55%
p-Cl, 63%
-Br,
66%
80%
O
,
,
=
=
=
=
=
3b R1
3i R1
DCE
73
p-OMe, 96%
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
HNTf2
-
9
OMe
-
,
3c R1
t
3j R1
N
=
=
p Bu,
83%
74%
71%
68%
54%
p
,
DCM
toluene
MeOH
EtOH
HFIP
DCE
64
,
,
,
3d R1
3k R1
10
11
12
13
14
15
16
17 c
18d
19e
20
R
p
-Ph,
p-CF3 54%
m
,
,
=
=
3e R1
3l R1
3m R1
p
-Me,
-Cl, 62%
43
O
,
3f R1
m
-Me,
o
=
-Cl, 53%
,
3g R1
o
-Me,
O
=
,
trace
trace
46
O
O
OMe
OMe
S
OMe
N
N
N
O
3n
O
O
60
,
,
,
73%
N
3o
80%
3p
49%
DCE
120
100
100
100
100
71
O
O
O
DCE
80
OMe
N
OMe
H9
H
DCE
81
H
H
C4
O
O
3q,
DCE
82
DCE
n.r.f
63%
3r
, 80%
a Reaction conditions: 1a (0.1 mmol), catalyst 2 (0.01 mmol), solvent (2 mL),
aReaction conditions: 1 (0.20 mmol), HNTf2 (0.04 mmol), DCE (4 mL), 100 oC,
in air, 12 h. b Isolated yields. c 20 mol% of catalyst 2 was used. d25% mol of
12 h. bIsolated yields.
e
f
catalyst 2 was used. 100% mol of catalyst 2 was used. n.r. = no reaction,
groups and the electron-withdrawing groups have inferior results
with moderate yields (3f, 3g, 3l and 3m). The reaction of the
disubstituted benzamide 1n proceeded smoothly, and the
corresponding product 3n was obtained in 73% yield. To our delight,
heterocyclic substrate 1o underwent smoothly to produce product
3o in 80% yield. Additionally, the reaction with the alkyl-substituted
substrates gave the products (3p and 3q) in 49% and 63% yields,
respectively. It is worth noting that natural product derivative 1r
could also be employed to provide corresponding product 3r in a
yield of 80%.
DCE = 1,2-dichloroethane, HFIP = hexafluoroisopropanol.
At
the
outset,
N-methoxy-3-((3-phenylprop-2-yn-1-
yl)oxy)benzamide 1a was employed as the model substrate to
optimize the reaction conditions, and the results were summarized
in Table 1. To our delight, the desired product 3a was furnished in
29% yield when AgOTf was used as the catalyst in DCE under an air
o
atmosphere at 100 C (Table 1, entry 1). We then screened other
cheap metal catalysts including copper-, zinc-, scandium-, indium-
and ytterbium-salts (Table 1, entries 2−6) and found that In(OTf)3
could efficiently catalyze the cascade cyclization, delivering the
desired product 3a in 51% yield (Table 1, entry 5). Further
investigation of Brønsted acids revealed that HNTf2 could
effectively promote the reaction with a yield of 73% (Table 1,
entries 7-9). The solvents have a significant influence on the
transformation (Table 1, entries 10-14) and the protic solvents such
as MeOH, EtOH and HFIP gave inferior yields. The reaction
temperature was studied and the results showed that increasing or
decreasing the temperature was not conducive to the reaction
(Table 1, entries 15 and 16). Gratifyingly, by simple applying 20 mol%
of HNTf2 as a catalyst, the yields of 3a could be further increased to
80%. The further increasement of the catalyst did not significantly
promote the transformation with a better yield (Table 1, entries 18-
19). A control experiment showed that HNTf2 was essential to the
transformation, and the reaction did not take place without it
(Table 1, entry 20).
Next, the synthesis of tetrahydroquinoline-fused isoindolinones
was also explored under the optimized reaction conditions by
employing the aniline-typed N-methoxybenzamides 4 (Scheme 3).
For R3 groups, N-methoxybenzamides 4 with electron-donating
substituents achieved good yields of 76−91% (5b-5e). Although the
electronic effect on the aryl rings reduced the yields to some extent,
the desired products 5h−5j were still generated with yields ranging
from 60% to 66%. Compared to para-substituted benzamides, the
yields of ortho- and meta-substituents were slightly reduced (5f, 5g
and 5k). The cyclization strategy was also compatible with
disubstituted benzamide 4l, and the product 5l was got in 69% yield.
Thiophene-substituted benzamide was also successfully converted
to the corresponding heterocyclic product 5m in 82% yield. For R2
groups, when the methyl substituent was installed at ortho or para
position of benzene ring, the desired isoindolinones were obtained
in good yields (5n and 5o)
Under the existing conditions (Table 1, entry 17), the cyclization
reaction of various alkyne-tethered N-methoxybenzamides 1 were
explored. As shown in Scheme 2, the transformations proceeded
smoothly and gave the corresponding products isoindolinones 3a-
3r with good to excellent yields. N-methoxybenzamides 1 with
electron-donating substituents achieved excellent yields of 71−96%
Scheme 3 Synthesis of isoindolinones 5.a,b
(3b-3e). However, N-methoxybenzamides
1 with electron-
withdrawing groups such as F, Cl, Br and CF3 showed slightly less
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Chin. J. Chem. 2019, 37, XXX－XXX

Running title
Chin. J. Chem.
O
O
electron-donating groups (see Supporting information for
details).15
OMe
HNTf2
OMe
equiv)
(0.2
N
N
R2
H
R3
R2
DCE 0.05 M
100 o 12 h
OMe
R3
N
N
C,
Ts
O
NH
Ts
5
4
2 . 1 0 5
OMe
NH
O
O
Ph
3
2
,
,
=
O
o
=
=
=
=
5a
5b
5g
R
R
R
R
R
H,
78%
R
R
R
R
R
70%
-OMe,
,
,
Ph
=
=
=
=
∆
Gsol
3
p-OMe, 91%
1
5h
p-F,
p-Cl,
p-Br,
60%
66%
63%
55%
OMe
-
H
H
,
,
,
N
,
,
kcal/mol
5c
5d
p tBu, 80%
2.229
5i
5j
TS1-2'
O
I1
16.5
R
p-Ph, 82%
p-Me, 76%
-OMe, 73%
2
19.2
TS1-2'
5e
5f
m
=
5k
,
-Cl,
m
=
N
R
,
17.8
Ts
TS4-5
OMe
NH
-
TS1-2
NTf2
O
O
O
O
O
15.8
OMe
HNTf2
OMe
NH
NH
H
OMe
OMe
S
OMe
N
O
OMe
Ph
3
N
N
N
OMe
NH
O
1.0
Ph
H
O
O
O
2
1
Ph
1
0.0
H
H
3
O
N
N
N
N
H
Ts
Ts
Ts
Ts
O
2
0.3
OMe
NH Ph
I2'
O
,
,
,
,
5o
84%
5l
5m
5n
69%
82%
78%
O
TS4-5
Ph
3
I1'
OMe
NH
OMe
NH
OMe
NH
3
H
aReaction conditions: 4 (0.20 mmol), HNTf2 (0.04 mmol), DCE (4 mL), 100 oC,
O
1
O
Ph
4
-6.9
Ph
Ph
4
H
12 h. bIsolated yields.
3
H
3
1
H
H
H
H
O
1
2
4
1a
O
O
O
I4
-18.8
Scheme 4 Gram-scale experiment and synthetic application of 3a.
I2
2.248
-17.8
I5
-
-
NTf2
NTf2
O
O
-
NTf2
OMe
HNTf2
OMe
HNTf2
N
N
g
HNTf2
H
TS1-2
reaction conditions
a)
b)
-28.8
OMe
NH
para-cyclization
ortho-cyclization
O
O
O
Ph
mmol
1a
3a
(6.0
)
61 %)
(1.03
3
H
4
1
3a -33.7
O
O
O
O
I3
OMe
OMe
N
N
NH
SmI
NaH
equiv)
equiv)
2 (3.0
(3.0
DMF, 120 o 1 h
THF, rt, 3 h
C,
OH
O
O
Figure 1 Calculated Gibbs free energy profiles for the possible reaction
7
6
86%
,
88%
,
3a
mechanism in kcal mol-1
The Cleavage of N-O Bond
The Cleavage of C-O Bond
Moreover, density functional theory (DFT) calculations were
performed to clarify the regioselectivity of the reaction (Figure 1;
for the details see the Supporting Information). The initiation of the
reaction involves the protonation of the alkynyl of 1a to form a
cationic intermediate I1, where the electrophilic ortho-cyclization
process between the carbon cation C3 and C1 takes place via
transition state TS1-2 to afford I2.16 The barrier needed for this step
is 17.8 kcal mol-1, which is affordable under the current
experimental conditions. The electrophilic para-cyclization
transition state TS1-2’ was also located and the barrier is 1.4 kcal
mol-1 higher than TS1-2, which agrees well with experimental
results. The origin of the regioselectivity could be explained by the
NBO charges in Figure 1. The NBO charges suggest that the
electrostatic interaction between C1 and C3 in TS1-2 is stronger
than that between C2 and C3 in TS1-2’. This means that the C3
carbon would prefer to attack the C1 atom rather than C2 atom of
the phenyl ring, generating the corresponding ortho-cyclization
intermediate I2. From I2, the proton transfer from C1 to C4
(stepwise deprotonation and protonation via I3, moreover, a trace
amount of I3 was detected through HRMS) takes place with the help
To demonstrate the practical application of the present protocol,
a gram-scale experiment was carried out for the reaction of 1a (6
mmol) under the optimized reaction conditions, and 3a was
obtained in 61% yield (Scheme 4a). The product 3a could be
efficiently deprotected by treating with SmI2 in THF, providing 6 in
88% yield, while the cleavage of C-O bond of 3a by treatment with
NaH in DMF produced the 4-hydroxyisoindolin-1-one 7 in 86% yield,
which might have anti-HIV13 and anti-inflammatory activities
(Scheme 4b).14
Scheme 5 Control experiments.
Radical inhibition
O
experiment
O
OMe
OMe
N
N
standard conditions
H
eq.1
2.0
2.0
TEMPO
BHT
equiv
equiv
(69%)
(61%)
O
O
1a
3a
Hammett-plot correlation study
O
O
OMe
-
OMe
N
R
reaction
40 min,
conditions
N
of NTf2 /HNTf2 species, leading the reaction to intermediate I4,
H
eq.2
=
ρ
-1.07
where the last ring closing process via C-N bond formation occurs.
This is the rate-determining step with a reaction barrier of 21.9 kcal
mol-1. The desired product 3a will be generated by the last
deprotonation process. The whole reaction is exothermic about
33.7 kcal mol-1 with a rate-determining barrier of 21.9 kcal mol-1,
agreeing well with the experimental observations.
R
O
O
1
3
The control experiments were performed to gain some
understanding of the mechanism (Scheme 5). The addition of
radical inhibitor into the reaction system provided 3a smoothly,
indicating that the radical pathway may not be involved in the
process (Scheme 5, eq.1). Moreover, the reaction of different para-
substituted N-methoxybenzamides 1 was studied (Scheme 5, eq.2).
In the Hammett curve, lg(kX/kH) is linear with σ, and the negative
value of ρ (-1.07) indicates that the reaction is facilitated by
Conclusions
In conclusion, we have developed an efficient metal-free
intramolecular cyclization of N-methoxybenzamides, enabling
facile access to chromane- or tetrahydroquinoline-fused
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de

First author et al.
Report
isoindolinones in good yields from easily available starting
materials. This reaction was characterized by employing cheap
catalyst, simple operation, broad substrate scope, 100% atomic
economy and excellent regioselectivity. The gram-scale experiment
rendered this method highly practical in organic synthesis.
Moreover, a detailed computational study on the reaction system
have been performed to clarify the mechanism. Further synthetic
applications are currently undergoing in our laboratory.
2887; (e) Zhang, Y.; Wang, D.-H.; Cui, S.-L. Facile Synthesis of
Isoindolinones via Rh(III)-Catalyzed One-Pot Reaction of Benzamides,
Ketones, and Hydrazines. Org. Lett. 2015, 17, 2494–2497; f) Lu, Y.;
Wang, H.-W.; Spangler, J. E.; Chen, K.; Cui, P.-P.; Zhao, Y.; Sun, W.-Y.;
Yu, J.-Q. Rh(III)-Catalyzed C–H Olefination of N-pentafluoroaryl
Benzamides using Air as the sole Oxidant. Chem. Sci. 2015, 6, 1923–
1927; (g) Zhou, Z.; Liu, G.-X.; Lu, X.-Y. Regiocontrolled Coupling of
Aromatic and Vinylic Amides with α-Allenols To Form γ-Lactams via
Rhodium(III)-Catalyzed C–H Activation. Org. Lett. 2016, 18, 5668−5671;
(h) Wu, X.-W.; Wang, B.; Zhou, Y.; Liu, H. Propargyl Alcohols as One-
Carbon Synthons: Redox-Neutral Rhodium(III)-Catalyzed C–H Bond
Activation for the Synthesis of Isoindolinones Bearing a Quaternary
Carbon. Org. Lett. 2017, 19, 1294−1297; (i) Ji, W.-W.; Lin, E.; Li Q.-J.;
Wang, H.-G. Heteroannulation Enabled by a Bimetallic Rh(III)/Ag(I)
Relay Catalysis: Application in the Total Synthesis of Aristolactam BII.
Chem. Commun. 2017, 53, 5665−5668; (j) Cheng, X.-F.; Wang, T.; Li, Y.;
Wu, Y.; Sheng, J.; Wang, R.; Li, C.; Bian, K.-J.; Wang, X.-S. Palladium(II)-
Catalyzed C(sp2)–H Carbonylation of Sterically Hindered Amines with
Carbon Monoxide. Org. Lett. 2018, 20, 6530−6533; (k) Fu, L.-Y.; Ying,
J.; Qi, X.-X.; Peng, J.-B.; Wu, X.-F. Palladium-Catalyzed Carbonylative
Synthesis of Isoindolinones from Benzylamines with TFBen as the CO
Source. J. Org. Chem. 2019, 84, 1421−1429; (l) Lukasevics, L.; Cizikovs,
A.; Grigorjeva, L. Synthesis of 3-Hydroxymethyl Isoindolinones via
Cobalt-Catalyzed C(sp2)–H Carbonylation of Phenylglycinol Derivatives.
Org. Lett. 2020, 22, 2720–2723; (m) Tian, C.; Dhawa, U.; Scheremetjew,
A.; Ackermann, L. Cupraelectro-Catalyzed Alkyne Annulation: Evidence
for Distinct C–H Alkynylation and Decarboxylative C–H/C–C Manifolds.
ACS Catal. 2019, 9, 7690−7696; (n) Ding, D.; Mou, T.; Feng, M.; Jiang,
X.-F. Utility of Ligand Effect in Homogenous Gold Catalysis: Enabling
Regiodivergent π-Bond-Activated Cyclization. J. Am. Chem. Soc. 2016,
138, 5218-5221.
Experimental
General experimental procedure for products 3a-3r and 5a-5o
(using 3a as an example): To a stirred solution of N-methoxy-3-((3-
phenylprop-2-yn-1-yl)oxy)benzamide 1a (56.2 mg, 0.2 mmol) in
DCE (4 mL) was added HNTf2 ( 11.2 mg, 0.04 mmol) at room
temperature in a sealing tube (10 mL). Next, the reaction mixture
was sealed and heated at 100 °C for 12 h. Then, the solvent was
evaporated in vacuum and purified by silica gel column
chromatography to afford pure desired product 3a (45 mg, 80%) as
a yellow solid.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We thank Natural Science Foundation of China (21801152 and
21572110) and the Natural Science Foundation of Shandong
Province (ZR2019BB005 and ZR2019MB010) for financial support.
Shao-Fei Ni acknowledge funding from the STU Scientific Research
Foundation for Talents (NTF20022).
Wu, S.-Z.; Wu, X.-Y.; Fu, C.-L.; Ma, S.-M. Rhodium(III)-Catalyzed C–H
Functionalization in Water for Isoindolin-1-one Synthesis. Org. Lett.
2018, 20, 2831-2834.
Zhang, L.-B.; Hao, X.-Q.; Liu, Z.-J.; Zheng, X.-X.; Zhang, S.-K.; Niu, J.-L.;
Song, M.-P. Cobalt(II)-Catalyzed Csp2-H Alkynylation/Annulation with
Terminal Alkynes: Selective Access to 3-Methyleneisoindolin-1-one.
Angew. Chem. Int. Ed. 2015, 54, 10012–10015.
References
(a) Ravikumar, K. Non-steroidal Anti-Inflammatory Drugs. III. Structure
of Indoprofen: 2-[4-(1-oxo-2-isoindolinyl) phenyl] Propionic Acid. Sect.
C: Cryst. Struct. Commun. 1994, 50, 589-592; (b). Reiffen, M.;
Eberlein, W.; Muller, P.; Psiorz, M.; Noll, K.; Heider, J.; Lillie, C.;
Kobinger, W.; Luger, P. Specific Bradycardic Agents. 1. Chemistry,
Pharmacology, and Structure-Activity Relationships of Substituted
Benzazepinones, a new Class of Compounds Exerting Antiischemic
Properties. J. Med. Chem. 1990, 33, 1496-1504; (c) Volpe, R.; Mautner,
L. S. Chlorthalidone, a new Oral Diuretic: Preliminary Report. Appl.
Ther. 1961, 3, 521-528; (d) Li, E.-W.; Jiang, L.-H.; Guo, L.; Zhang, H.; Che,
Y.-S. Pestalachlorides A–C, Antifungal Metabolites from the Plant
Endophytic Fungus Pestalotiopsis Adusta. Bioorg. Med. Chem. 2008,
16, 7894-7899.
(a) Li, Y.; Li, J.-H. Decarbonylative Formation of Homoallyl Radical
Capable of Annulation with N-Arylpropiolamides via Aldehyde Auto-
oxidation. Org. Lett. 2018, 20, 5323–5325; (b) Tan, F.-L.; Hu, M.; Song,
R.-J.; Li, J. H. Metal-Free Annulation Cascades of 1,7-Enynes Using Di-
tert-butyl Peroxide as the Methyl Source towards the Synthesis of
Polyheterocyclic Scaffolds. Adv. Synth. Catal. 2017, 359, 3602-3610; (c)
Niu, Z.-J.; Li, L.-H.; Liu, X.-Y.; Liang, Y.-M. Transition-Metal-Free
Alkylation/Arylation of Benzoxazole via Tf2O-Activated-Amide. Adv.
Synth. Catal. 2019, 361, 5217 –5222; (d) Li, L.-H.; Niu, Z.-J.; Li, Y.-X.;
Liang, Y.-M. Transition-Metal-Free Multinitrogenation of Amides by C–
C Bond Cleavage: a new Approach to Tetrazoles. Chem. Commun. 2018,
54, 11148-11151; (e) Kuang, Z.; Yang, K.; Zhou, Y.; Song, Q. Base-
Promoted Domino-Borylation-Protodeboronation Strategy. Chem.
Commun. 2020, 56, 6469-6479; (f) Zhang, J.-J.; Cheng, Y.-B.; Duan, X.-
H. Metal-Free Oxidative Decarboxylative Acylation/Ring Expansion of
Vinylcyclobutanols with α-Keto Acids by Visible Light Photoredox
Catalysis. Chin. J. Chem. 2017, 35, 311-315; (g) Tang, B.-Z.; Li, J.-Z.;
Zhang, A.-W.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Merging [2+2]
Cycloaddition with 1,6-/1,4-Aza-Binucleophilic Additions toward
Unprecedented Indazole-Containing Polycycles. Adv. Synth. Catal.
2019, 361, 3394 –3402; (h) Zhang, Z.; Zhu, C. -J.; Miao, M.; Han, J. -L.;
Ju, T.; Song, L.; Ye, J. -H.; Li, J.; Yu, D. -G. Lactonization of C(sp2)—H
Bonds in Enamides with CO2. Chin. J. Chem. 2018, 36, 430-436.
Zhao, W.-X.; Sun, J.-W. Triflimide (HNTf2) in Organic Synthesis. Chem.
Rev. 2018, 118, 10349-10392.
(a) Glavac, D.; Zheng, C.; Dokli, I.; You, S.-Li.; Gredicak, M. Chiral
Brønsted Acid Catalyzed Enantioselective aza-Friedel–Crafts Reaction
of Cyclic α-Diaryl N-Acyl Imines with Indoles. J. Org. Chem. 2017, 82,
8752−8760; (b) Ray, S. K.; Sadhu, M. M.; Biswas, R. G.; Unhale, R. A.;
Singh, V. K.
A General Catalytic Route to Enantioenriched
Isoindolinones and Phthalides: Application in the Synthesis of (S)-PD
172938. Org. Lett. 2019, 21, 417−422.
(a) Wang, F.; Song, G.-Y.; Li, X.-W. Rh(III)-Catalyzed Tandem Oxidative
Olefination−Michael Reactions between Aryl Carboxamides and
Alkenes. Org. Lett. 2010, 12, 5430–5433; (b) Hyster, T. K.; Ruhl, K. E.;
Rovis, T. A Coupling of Benzamides and Donor/Acceptor Diazo
Compounds To Form γ-Lactams via Rh(III)-Catalyzed C–H Activation. J.
Am. Chem. Soc. 2013, 135, 5364–5367; (c) Ye, B.-H.; Cramer, N.
Asymmetric Synthesis of Isoindolones by Chiral Cyclopentadienyl-
Rhodium(III)-Catalyzed C-H Functionalizations. Angew. Chem. Int. Ed.
2014, 53, 7896–7899; (d) Dong, J.-X.; Wang, F.; You, J.-S. Copper-
Mediated Tandem Oxidative C(sp2)–H/C(sp)–H Alkynylation and
Annulation of Arenes with Terminal Alkynes. Org. Lett. 2014, 16, 2884–
(a) Mendoza, O.; Rossey, G.; Ghosez, L. Brönsted Acid-Catalyzed
Synthesis of Diarylmethanes under Non-Genotoxic Conditions.
Tetrahedron Lett. 2011, 52, 2235−2239; (b) Nomiyama, S.; Tsuchimoto,
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX

Running title
Chin. J. Chem.
T. Metal-Free Regioselective β-Alkylation of Pyrroles with Carbonyl
Yoakim, C.; Malenfant, E.; Thavonekham, B.; Ogilvie, W.; Deziel, R. U.S.
Patent Appl. Publ. U.S. 2,004,106,791, 2004.
Japtap, P.; Southan, G.; Salzman, A.; Szabo, C.; Ram, S. PCT Int. Appl.
WO2001077075, 2001.
Compounds and Hydrosilanes: Use of a Brønsted Acid as a Catalyst.
Adv. Synth. Catal. 2014, 356, 3881−3891; (c) Liu, M.-W.; Zhang, J.-L.;
Zhou, H.; Yang, H.-M.; Xia, C.-G.; Jiang, G.-X. Efficient Hydroarylation
and Hydroalkenylation of Vinylarenes by Brønsted Acid Catalysis. RSC
Adv. 2016, 6, 76780−76784; (d) Reddel, J. C. T.; Wang,W.; Koukounas,
K.; Thomson, R. J. Triflimide-Catalyzed Allylsilane Annulations of
Benzylic Alcohols for the Divergent Synthesis of Indanes and Tetralins.
Chem. Sci. 2017, 8, 2156−2160.
(a) Brady, P. B.; Yamamoto, H. Rapid and Stereochemically Flexible
Synthesis of Polypropionates: Super-Silyl-Governed Aldol Cascades.
Angew. Chem. Int. Ed. 2012, 51, 1942−1946; (b) Izumiseki, A.;
Yamamoto, H. Intermolecular/Intramolecular Sequential Aldol
Reaction. J. Am. Chem. Soc. 2014, 136, 1308−1311.
(a) Zhao, W.-X.; Wang, Z.-B.; Sun, J.-W. Synthesis of Eight-Membered
Lactones: Intermolecular [6+2] Cyclization of Amphoteric Molecules
with Siloxy Alkynes. Angew. Chem. Int. Ed. 2012, 51, 6209–6213; (b)
Zhao, W.-X.; Qian, H.; Li, Z.-G.; Sun, J.-W. Catalytic Ring Expansion of
Cyclic Hemiaminals for the Synthesis of Medium-Ring Lactams.
Angew. Chem. Int. Ed. 2015, 54, 10005–10008; (c) Wang, Y.; Song, L.-
J.; Zhang, X.-H.; Sun, J.-W. Metal-Free [2+2+2] Cycloaddition of
Ynamides and Nitriles: Mild and Regioselective Synthesis of Fully
Substituted Pyridines. Angew. Chem. Int. Ed. 2016, 55, 9704–9708; (d)
Zhang, Y.-S.; Hsung, R.-P.; Zhang, X.-J.; Huang, J.; Slafer, B. W.; Davis, A.
Brønsted Acid-Catalyzed Highly Stereoselective Arene-Ynamide
Cyclizations. A Novel Keteniminium Pictet−Spengler Cyclization in
Total Syntheses of (±)-Desbromoarborescidines A and C. Org. Lett.
2005, 7, 1047.
(a) Aihara, Y.; Chatani, N. Ruthenium-Catalyzed Direct Arylation of C–
H Bonds in Aromatic Amides Containing a Bidentate Directing Group:
Significant Electronic Effects on Arylation. Chem. Sci. 2013, 4, 664-670;
(b) Mo, J.; Müller, T.; Oliveira, J.-C.; Demeshko, S.; Meyer, F.;
Ackermann, L. Iron-Catalyzed C−H Activation with Propargyl Acetates:
Mechanistic Insights into Iron(II) by Experiment, Kinetics, Mössbauer
Spectroscopy, and Computation. Angew. Chem. Int. Ed. 2019, 58,
12874-12878.
[a] Huo, Z.; Gridnev, I. D.; Yamamoto, Y. A Method for the Synthesis of
Substituted Quinolines via Electrophilic Cyclization of 1-Azido-2-(2-
propynyl)benzene. J. Org. Chem. 2010, 75, 1266-1270; (b) Kanyiva, K.
S.; Hamada, D.; Makino, S.; Takano, H.; Shibata, T. α-Amino Acid
Sulfonamides as Versatile Sulfonylation Reagents:Silver-Catalyzed
Synthesis of Coumarins and Oxindoles by Radical Cyclization. Eur. J.
Org. Chem. 2018, 43, 5905–5909; (c) Zheng, D.; Yu, J.; Wu, J.
Generation
of
Sulfonyl
Radicals
from
Aryldiazonium
Tetrafluoroborates and Sulfur Dioxide: The Synthesis of 3-Sulfonated
Coumarins. Angew. Chem. Int. Ed. 2016, 55, 11925-11929.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
(a) Zhang, Y.-Q.; Zhu, X.-Q.; Chen, Y.-B.; Tan, T.-D.; Yang, M.-Y.; Ye, L. -
W. Synthesis of Isothiochroman-3-ones via Metal-Free Oxidative
Cyclization of Alkynyl Thioethers. Org. Lett. 2018, 20, 7721-7725; (b)
Zhang, Y.-Q.; Zhu, X.-Q.; Xu, Y.; Bu, H.-Z.; Wang, J.-L.; Zhai, T.-Y.; Zhou,
J.-M.; Ye, L.-W. Synthesis of Functionalized 3-Isochromanones via
Metal-Free Intramolecular Alkoxylation-Initiated Cascade Cyclization.
Green Chem. 2019, 21, 3023-3028; (c) Li, L.; Zhu, X.-Q.; Zhang, Y.-Q.;
Bu, H.-Z.; Yuan, P.; Chen, J.; Su, J.-Y.; Deng, X.-M.; Ye, L.-W. Metal-Free
Alkene Carbooxygenation following Tandem Intramolecular
Alkoxylation/Claisen Rearrangement: Stereocontrolled Access to
Bridged [4.2.1] Lactones. Chem. Sci. 2019, 10, 3123–3129; (d) Zhou, B.;
Zhang, Y.-Q.; Zhang, K.-R.; Yang, Y.-M.; Chen, Y.-B.; Li, Y.; Peng, Q.; Zhu,
S.-F.; Zhou, Q.-L.; Ye, L.-W. Stereoselective Synthesis of Medium
Lactams Enabled by Metal-Free Hydroalkoxylation/Stereospecific
[1,3]-Rearrangement. Nat. Commun. 2019, 10, 3234; (e) Bu, H.-Z.; Li,
H.-H.; Luo, W.-F.; Luo, C.; Qian, P.-C.; Ye, L.-W. Synthesis of 2H-
Chromenes via Unexpected [4 + 2] Annulation of Alkynyl Thioethers
with o-Hydroxybenzyl Alcohols. Org. Lett. 2020, 22, 648−652.
(a) Li, M.; Wang, J.-H.; Li, W.; Wen, L.-R.; Metal-Free Direct
Construction of 2-(Oxazol-5-yl)phenols from N-Phenoxyamides and
Alkynylbenziodoxolones
via
Sequential
[3,3]-
Rearrangement/Cyclization. Org. Lett. 2018, 20, 7694-7698; (b) Guo,
W.-S.; Gong, H.; Zhang, Y.-A.; Wen, L.-R.; Li, M. Fast Construction of
1,3-Benzothiazepines by Direct Intramolecular Dehydrogenative C–S
Bond Formation of Thioamides under Metal-Free Conditions. Org. Lett.
2018, 20, 6394-6397; (c) Wen, L.-R.; Sun, Y.-X.; Zhang, J.-W.; Guo, W.-
S.; Li, M. Catalyst- and Solvent-Free Bisphosphinylation of
Isothiocyanates:
A
Practical Method for the Synthesis of
Bisphosphinoylaminomethanes. Green Chem. 2018, 20, 125-129; (d)
Zhang, L.-B.; Geng, R.-S.; Wang, Z.-C.; Ren, G.-Y.; Wen, L.-R.; Li, M.
Electrochemical Intramolecular C–H/N–H Functionalization for the
Synthesis of Isoxazolidine-Fused Isoquinolin-1(2H)-ones. Green Chem.
2020, 22, 16-21; (e) Wen, L.-R.; Ren, G.-Y.; Geng, R.-S.; Zhang, L.-B.; Li,
M. Fast Construction of Isoquinolin-1(2H)-ones by Direct
Intramolecular C–H/N–H Functionalization under Metal-Free
Conditions. Org. Biomol. Chem. 2020, 18, 225-229.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Entry for the Table of Contents
Page No.
O
O
Metal-free Catalyzed Cyclization of N-
methoxybenzamides to Construct Quaternary
Carbon-Containing Isoindolinones
OMe
Metal
OMe
N
N
R1
H
R2
R1
R2
X
X
=
X
NTs
O,
carbon
metal-free catalysis
economy
construction
of
quarternary
scope
broad substrate
atomic
100%
DFT calculations
gram-scale
synthesis
Through the intramolecular cyclization of N-methoxybenzamides, a simple and efficient method for
constructing valuable isoindolinones under metal-free conditions was developed. The reaction was
featured by employing low-cost catalyst, simple operation, 100% atomic economy and excellent
regioselectivity. Moreover, a detailed computational study on the reaction system has been
performed to clarify the mechanism. This protocol tolerated a variety of functional groups and
provided a metal-free protocol for the synthesis of chromane- or tetrahydroquinoline-fused
isoindolinones in good yields.
Lin-Bao Zhang, Zi-Chen Wang, Sheng-Zheng Sun,
Shao-Fei Ni, * Li-Rong Wen, * and Ming Li *
a
State Key Laboratory Base of Eco-Chemical Engineering, College of
Chemistry and Molecular Engineering, Qingdao University of Science and
Technology, Qingdao 266042, P. R. China.
E-mail: wenlirong@qust.edu.cn; liming928@qust.edu.cn
b
Department of Chemistry and Key Laboratory for Preparation and
Application of Ordered Structural Materials of Guangdong Province,
Shantou University, Shantou,Guangdong 515063, P. R. China
E-mail: shaofeinee@163.com
Chin. J. Chem. 2018, template© 2018 SIOC, CAS, Shanghai,
&
WILEY-VCH Verlag GmbH
&
Co. KGaA,
Weinheim