Copper-Catalyzed Aerobic Oxidative Ring Expansion of Isatins: A Facile Entry to Isoquinolino-Fused Quinazolinones

Article abstract of DOI:10.1002/cjoc.202000368

A copper-catalyzed aerobic oxidative ring expansion reaction of isatins with 1,2,3,4-tetrahydroisoquinoline for the synthesis of tetracyclic quinazolinones has been developed. This reaction is performed smoothly under simple conditions to give the corresponding products in moderate to good yields with good functional group tolerance. The capacity of the resultant 5H-isoquinolino[1,2-b]quinazolin-8(6H)-one for a range of palladium-catalyzed directing C—H activation has been further demonstrated, thus giving a broader access to diverse tetracyclic quinazolinones.

Full text of DOI:10.1002/cjoc.202000368

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Copper-Catalyzed Aerobic Oxidative Ring Expansion of Isatins: A Facile Entry
to Isoquinolino-Fused Quinazolinones
Authors: Dahan Wang, Fuhong Xiao,* Feng Zhang, Huawen Huang and Guo-Jun
Deng*
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.202000368.
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Chinese Journal
of Chemistry
Copper catalysis, Aerobic oxidation, Quinazolinones, C-H Activation,
Isatins
Report
CJC
中
国 化 学 - An International Journal
Copper-Catalyzed Aerobic Oxidative Ring Expansion of Isatins: A Facile Entry
to Isoquinolino-Fused Quinazolinones
Dahan Wang,a Fuhong Xiao, a,* Feng Zhang, a,b Huawen Huanga and Guo-Jun Deng a,*
a Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, Hunan Province Key Laboratory of Green Organic
Synthesis and Application, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
b School of Chemistry and Materials Science, Hunan Agricultural University, Changsha, 410128, China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion A copper-catalyzed aerobic oxidative ring expansion reaction of isatins with 1,2,3,4-tetrahydroisoquinoline
for the synthesis of tetracyclic quinazolinones has been developed. This reaction is performed smoothly under simple conditions to give the
corresponding products in moderate to good yields with good functional group tolerance. The capacity of the resultant
5H-isoquinolino[1,2-b]quinazolin-8(6H)-one for a range of palladium-catalyzed directing C-H activation has been further demonstrated, thus giving a
broader access to diverse tetracyclic quinazolinones.
Background and Originality Content
O
N
O
N
X
',
,
=
N
Quinazolinone and its derivatives are privileged structural
frameworks among valuable molecules possessing diverse
biological and medicinal activities,[1-2] such as Luotonin
X
NR
O S
R
c
b
A-anticancer,[2a]
Mackinazolinone-antidepressant,[2b]
and
Rutaecarpine-antithrombotic activity.[2c] Generally, classic
methods for the synthesis of this compound motif depend on
cyclic condensation of o-aminophenylformamide with aldehydes
or their substitutes.[3] Nevertheless, most reactions suffer from
certain limitations, such as the need for inaccessible starting
materials, harsh reaction conditions, and excessive oxidant.[4] In
this regard, the development of concise methods for the
construction of diverse quinazolinones from easily accessible
starting materials under simple conditions is highly desirable.
O
O
O
N
R2
COO
a
N
d
O
N
N
H
R1
H
v
ecar on
c c a o
y li ti
a
e
D
b
yl ti
O
z
n
e
f
O
O
N
N
N
N
S
Scheme 1. Decarbonylative cyclization of isatin.
w
r
k
s
o
Thi
Isatin (1H-indole-2,3-diones) is a subclass of the indole family
that has been employed in the discovery of biological scaffolds or
anticancer medicines.[5] Hence, isatin and their derivatives have
been attracting considerable interest in molecular synthesis. In
recent years, the synthesis of nitrogen-containing heterocycles
has been actively explored through isatin ring-expansion.
Common methods for the ring-expansion reaction of isatins and
their derivatives are as follows: 1) ring-expansion through the
cleavage of the C2-N1 bond with enamines to synthesize
multisubstituted quinoline-4-carboxamides derivatives;[6] 2)
ring-formation through the insertion of atoms into the C2-C3
bond or C3-C4.[7] For example, Zou and co-workers reported an
efficient and practical method for the construction of
benzimidazo[l,2-c]quinazolin-6- ones through the cleavage of the
C2–C3 bond to and insertion of heteroatoms using molecular
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First author et al.
Report
oxygen as the oxidant.[7a] And Interestingly, Bathini described an
efficient regioselective ring expansion reaction of isatins with
aldehydes for the synthesis of α-aryl/heteroaryldiazomethane
through the insertion of aldehydic carbonyl into the C3-C4
bond.[7c]
O
N
N
O
a a
s
t ly t
C
+
O
NH
30
oC
,
so ven
l
t 1
N
H
sea e u e
l d t b
O2
(
)
a
3
a
1
a
2
Over the past decade, the development of the synthesis of
nitrogen-containing heterocycles through the decarbonylative
Entry
1
Catalyst
none
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yieldb (%)
18
[8-11]
cyclization of isatins has been extensively studied.
For
instance, in 2013, Wang's group developed a concise method for
the synthesis of tryptanthrins from commercially available indoles
and isatins (Scheme 1, a).[8] In 2016, Huang's group found an
appealing strategy for the synthesis of pyrido-fused quinazolinone
derivatives by Cu-catalyzed decarbonylative cyclization of
substituted isatins and 2-bromopyridine derivatives (Scheme 1,
b).[9] Sanjib and co-workers described the copper(II)-catalyzed
decarboxylative coupling reactions of isatins arylglyoxylic acids
with arylglyoxylic acids involving C-N and C-O bond formation,
isatins affording 4H-benzo[d][1,3]oxazin-4-ones involving C-N and
C-O bond formation.[10a] In 2020, Wu and Chen disclosed an
FeCl3-mediated cascade coupling/decarbonylative annulation
reaction of isatin with fluorinated imidoyl chlorides (Scheme 1,
2
FeCl3
26
3
Mn(OAc)2
PdCl2
24
4
18
5
Ag2O
19
6
NiCl2
trace
62
7
CuSO4
8
CuCl
55
9
CuCl2
39
10
11
12
13
14
15
16
17c
18d
Cu(OAc)2
CuI
41
c).[10b] Likewise, Wu's group also reported
Baeyer-Villiger-type pathway for the
a
series of
56
synthesis of
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
83
nitrogen-containing heterocycles (Scheme 1, c-e).[11] Very recently,
Jia and co-workers developed a TFA/TBHP-promoted oxidative
cyclisation of isatins with 1,2,3,4-tetrahydroisoquinolines.[11e]
Within our own on-going program on sustainable oxidation
reactions to construct heterocycles,[12] herein, we present a
copper-catalyzed isatin decarbonylative cyclization with
1,2,3,4-tetrahydroisoquinoline (THIQ) to synthesize tetracycline
tetracyclic quinazolinones with 1,2,3,4-tetrahydroisoquinoline
(THIQ) enabling two C–N bond formation (scheme 1, f).
47
PhCl
trace
trace
trace
74
PhCH3
1,4-dioxane
DMSO
DMSO
0
a Conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (15 mol%), solvent
(0.6 mL), 130 oC, 24 h, under O2. b GC yields. c 120 oC. d under Ar.
Results and Discussion
With the optimized reaction conditions in hand, we next
investigated the substrate scope for the synthesis of tetracyclic
quinazolinones. The results are summarized in Table 2. The model
reaction of THIQ (1a) and isatin (2a) gave the desired product 3a
in 85% isolated yield. Then, THIQs bearing various substituents
Initially, THIQ (1a) and isatin (2a) were selected as model
substrates to evaluate the feasibility and selectivity of this
transformation. To our pleasure, the mixture of 1a and 2a simply
stirred at 130 °C under oxygen atmosphere (sealed tube) led to
the formation of the isoquinolino-fused quinazolinone product 3a
(18% yield). Then, transition metal catalyst screening revealed
that the corresponding product 3a was obtained in 62% yield
when the reaction was carried out with CuSO4 in DMSO at 130 °C
for 24 h, while other metal salts such as FeCl3, Mn(OAc)2, PdCl2,
Ag2O, and NiCl2 did not significantly promote the reaction
(entries 2−7). Encouraged by these results, we further screened
other copper catalysts such as CuCl, CuCl2, Cu(OAc)2, CuI, and
Cu(OTf)2 (entries 8-12). To our delight, the formation of 3a was
observed in 83% yield when the catalyst was replaced by Cu(OTf)2
(entry 12). The investigation of solvent effect revealed that PhCl
demonstrated the best performance, while DMF, PhCl, PhCH3, and
1,4-dioxane were proved to be unsuitable reaction media (entries
13-16). Decreasing the temperature of this reaction afforded an
inferior result (entry 17). Finally, no desired product was detected
when the reaction was performed under argon atmosphere (entry
18).
could
smoothly
couple
with
isatin
(2a).
(1b)
When
and
5-bromo-1,2,3,4-tetrahydroisoquinoline
7-bromo-1,2,3,4-tetrahydroisoquinoline (1d) were employed,
the corresponding product 3b and 3d were obtained in 63% and
68% yields, respectively. Slightly lower yield was obtained when
the methoxy group was located at the C-6 position in the
isoquinoline ring (3c). It is worth noting that the
4,5,6,7-tetrahydrothieno- [3,2-c]pyridine was also suitable in this
reaction and afforded the corresponding products 3e in 31% yield.
The substituent position significantly affected the reaction yield
and the reaction yield decreased dramatically when functional
group chloro (2f) was located at the C-4 position in isatin. Better
yields were obtained when the functional groups such as methyl
(2g and 2n), methoxy (2h), fluoro (2i and 2o), chloro (2j, 2m and
2p), bromo (2k and 2q) and iodine (2l) were located at C-5, C-6
and C-7 position. It appeared that various electron-donating and
electron-withdrawing substituents were well tolerated in the
reaction and there was no straightforward correlation between
Table 1 Optimization of the reaction conditiona
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Running title
Chin. J. Chem.
the electronic properties of the substituents and reaction
efficiency. It should be noted that the cleavage of C–halogen
bonds (even C-I bond) was not observed in our copper catalysis,
as determined by GC-MS analysis.
cleavage using diphenyl disulfide, which gave the corresponding
product 4e in 51% yield. Moreover, Rh-catalyzed directing
amidation of 3a using sulfonyl azides as the amine source
afforded the desired product 4f in moderate yield. Finally, the
Pd-catalyzed reaction of 3a with diethyl azodicarboxylate DEAD
and K2S2O8 furnished the product esters 4g in 58% yield.
Table 2 Substrate scope.a
O
u
O
C
OTf
)
(
2
u
Scheme 2. Further direct C–H bond functionalization of 3a.
sea e
e
)
N
O2
l
d
t
b
(
R2
R1
R2
+
O
NH
O
N
O
°
,
N
N
DMSO 130
C
R1
H
N
H
N
R
C-H bond activation
1
2
3
N
O
O
N
O
N
O
N
3a
4
N
N
N
N
r
B
N
O
O
N
O
N
O
N
e
OM
N
N
N
N
,
,
,
c
,
3d
r
B
a
3
3b
3
45
8
5
%
63%
%
68%
O
N
,
O
Cl
O
O
e
e
M
M
O
Cl
94% a
Br
MeO
4c
AcO
61% d
4d
,
N
N
N
N
76% b
4b
,
65% c
4a
,
N
,
N
N
N
S
O
O
N
N
S
O
N
,
3h
,
,
e
3g
7
8%
68%
3f
4
6%
3
1
%
N
3
N
O
O
O
O
N
r
B
Cl
I
F
HN
S
EtO
N
N
N
N
O
O
Ph
N
,
O
N
N
,
N
p-Tol
51% e
45% f
58% g
,
4e
4f
4g
,
,
,
,
3
j
71
3i 74
%
3k
7
0%
%
3l
6
4
%
O
O
O
O
Reaction conditions: (a) 3a (0.2 mmol), Pd(OAc)2 (5 mol%), NCS (1.2
equiv.), CH3CN (1 mL), 100 oC, 72 h. (b) 3a (0.2 mmol), Pd(OAc)2 (5 mol%),
NBS (1.2 equiv.), CH3CN (1 mL), 100 oC, 36 h. (c) 3a (0.2 mmol), Pd(OAc)2 (5
mol%), PhI(OAc)2 (2.0 equiv.), CH3OH (1 mL), 100 oC, 24 h. (d) 3a (0.2
mmol), Pd(OAc)2 (5 mol%), PhI(OAc)2 (2.0 equiv.), CH3CN (1 mL), 100 oC, 72
h. (e) 3a (0.2 mmol), diphenyl disulfide (0.3 mmol), Pd(OAc)2 (10 mol%),
CuBr (2.0 equiv.), DMF (1 mL), 140 oC, N2, 72 h. (f) 3a (0.2 mmol),
p-toluenesulfonyl azide (0.22 mmol), [RhCp*Cl2]2 (4 mol%), AgSbF6 (16
mol%.), 1,2-DCE (0.5 mL), 80 oC, N2, 12 h. (g) 3a (0.2 mmol), Pd(OAc)2 (5
mol%), DEAD (2.0 equiv.), K2S2O8 (0.6 equiv.), DCE (0.5 mL), 100 oC, 6 h.
N
N
N
N
N
C
l
N
N
,
N
,
e
M
F
C
l
,
,
m
o
n
3
63%
3
7
6%
3p
3
74
69%
O
%
O
O
O
N
Ph
Ph
N
Ph
N
N
N
N
,
Ph
race
N
,
r
B
N
,
,
r
3
s
3
s
3
3q 41
%
ND
t
ND
a
Conditions: 1 (0.2 mmol), 2 (0.3 mmol), Cu(OTf)2 (15 mol%), DMSO
To gain insight into reaction mechanism, several control
experiments were conducted. First, The addition of radical
scavengers TEMPO (2,2,6,6-tetramethylpiperidinooxy) and BHT
(2,6-di-tert-butyl-4-hydroxytoluene) to the reaction system did
not obviously influence this reaction, which indicates that a
radical pathway might not be involved in this reaction (Scheme 3,
a). The product 3a was obtained in 40% yield when isatoic
anhydride 2a', which may be generated by Baeyer-Villiger-type
oxidation of isatins, was used as the substrate with 1a under O2
atmosphere, and trace yield was obtained under Ar atmosphere
(Scheme 3, b). This result indicates that isatin is probably oxidized
by O2 in the initial step to form the intermediate 2a'. The
treatment of the hypothesized intermediate 1a' with intermediate
2a' in the absence of copper catalyst could be harvested to the
target product 3a in 93% yield under oxygen atmosphere, while
68% yield under argon atmosphere (Scheme 3, c).
(0.6 mL), 130 oC, 24 h, under O2. Isolated yield based on 1.
Directing C-H bond functionalization has emerged as a
powerful tool in organic synthesis.[13] Functional group-assisted
C-H bond cleavage shows great promise to the control of site
selectivity.[14] We attempted to conduct further transformation to
other structurally novel molecules through C-H activation of
tetracyclic quinazolinones.[15] A series of C-H activation reactions
have proved feasible when using 3a. This is the first reported
using quinazolinones as directing group for C-H bond
functionalization. The halogenation products 4a and 4b could be
obtained in 94% and 76% yields, respectively, when using
N-chlorosuccinimide or N-bromosuccinimide as halogen source
and oxidant. The reaction of 3a with Pd(II)/PhI(OAc)2 system in
methanol solvent produced methoxylation product 4c in 65%
yield. Pd-catalyzed acetoxylation of 3a furnished the expected
product 4d in 61% yield. The sulfenylation of 3a was
demonstrated by Pd-catalyzed C−S bond formation via C−H
Scheme 3 Control experiments under various conditions.
Chin. J. Chem. 2019, 37, XXX－XXX
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This article is protected by copyright. All rights reserved.

First author et al.
Report
O
Further studies on functionalization of indole family are ongoing
in our laboratory.
O
standard
conditions
N
O
+
NH
(a)
N
N
3a
H
Experimental
1a
2a
with TEMPO
54%
(2.0 equiv):
General procedure: (3a)
with BHT
51%
(2.0 equiv):
A 10 mL reaction vessel was charged with 1 (0.2 mmol), 2 (0.3
mmol), Cu(OTf)2 (0.015 mmol ), DMSO (0.6 mL) under O2. The
reaction vessel was stirred at 130 oC for 24 h. After cooling to
room temperature, the reaction was diluted with ethyl acetate (5
mL) and washed with saturated sodium chloride solution. The
organic layer was separated, and the aqueous layer was extracted
with ethyl acetate for three times. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate = 5:1) to yield the desired product 3a as yellow solid (42.2
mg, 85%).
O
O
standard
conditions
N
O
+
(b)
NH
N
N
H
O
1a
2a'
3a
:
under O2 40%
under
:
trace
Argon
O
O
°
N
O
DMSO,
130 C
+
(c)
N
N
N
O
H
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
3a
1a'
2a'
:
Under O2 93%
:
Under
68%
Argon
According to the above control experiments and related
references, a proposed mechanism for 3a formation is illustrated
in Scheme 4.[16] Accordingly, 1,2,3,4-tetrahydroisoquinoline 1a is
oxidized to 3,4-dihydroisoquinoline 1a' in the presence of Cu/O2.
Isatoic anhydride 2a' is formed through the oxidation of 2a under
a oxygen atmosphere. Then the condensation reaction between
1a' and 2a' generate the intermediate A. Subsequently, an
intramolecular attack of the nitrogen atom to imine carbocation
followed by releasing a molecule of carbon dioxide provides the
tetracyclic intermediate B. Finally, the desired products 3a is
obtained through dehydrogenative oxidation of B.
Acknowledgement
This work was supported by the National Natural Science
Foundation of China (21871226, 21502160 and 21572194),
Scientific Research Fund of Hunan Provincial Education
Department (19B564), Hunan Provincial Natural Science
Foundation of China (2020JJ3032), Efficient Resource Utilization,
the China Postdoctoral Science Foundation (2018M632976 and
2019T120709), Scientific Research Fund of Xiangtan University
(XDCX2020B110).
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Scheme 4 Proposed mechanism.
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O
, O2
Cu(OTf)2
N
+
O
NH
N
N
H
3a
1a
2a
CuII
CuI
O2
O2
O
[O]
H2O
O
O
N
-CO2
N
+
O
N
H
NH
N
N
H
O
O
O
1a'
2a'
A
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Conclusions
In conclusion, we have demonstrated
a Cu-catalyzed
decarbonylative ring-opening reaction of isatin with
1,2,3,4-tetrahydroisoquinoline for the synthesis of tetracycline
quinazolinones in moderate to good yields. Environmentally
friendly molecular oxygen is used as the oxidant. This method
exhibits good functional group tolerance and easy operation.
Meanwhile, more diversity tetracycline quinazolinone derivatives
can be obtained by group-assisted C-H bond functionalization.
(a) Cheng, R.; Guo, T.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. One-Pot
Synthesis of Quinazolinones from Anthranilamides and Aldehydes via
p-Toluenesulfonic
Acid
Catalyzed
Cyclocondensation
and
Phenyliodine Diacetate Mediated Oxidative Dehydrogenation.
www.cjc.wiley-vch.de
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Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
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(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
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Copper-Catalyzed Aerobic Oxidative Ring
Expansion of Isatins:
A Facile Entry to
Isoquinolino-Fused Quinazolinones
O
N
R1
O
N
NH
N
+
C-H activation
R1
[Cu]/O2
N
H
R2
O
R2
R1
O
R2
X
N
H
=
X
Cl, Br, OMe, OAc, SPh, NHTs, COOEt
Text for Table of Contents.
Dahan Wang, Fuhong Xiao,* Feng Zhang,
Huawen Huang and Guo-Jun Deng*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.