TBHP-Mediated Oxidative Decarboxylative Cyclization in Water: Direct and Sustainable Access to Anti-malarial Polycyclic Fused Quinazolinones and Rutaecarpine

Article abstract of DOI:10.1002/cjoc.202000154

Polycyclic fused quinazolinones with anti-malarial activity were synthesized through tert-butyl hydroperoxide (TBHP)-mediated oxidative decarboxylative cyclization between commercially available isatins and cyclic amines in one step. The reaction proceeds smoothly in water without additional transition-metal catalyst, acid and base. The newly synthesized products were evaluated to exhibit moderate to good anti-malarial activity against chloroquine drug-sensitive Plasmodium falciparum 3D7 strain. Additionally, this method also provides direct approach to Rutaecarpine in good yield.

Full text of DOI:10.1002/cjoc.202000154

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: TBHP-Mediated Oxidative Decarboxylative Cyclization in Water: Direct and
Sustainable Access to Anti-malarial Polycyclic Fused Quinazolinones and
Rutaecarpine
Authors: Xingyu Chen, Fei Xia, Yifan Zhao, Ji Ma, Yue Ma, Dong Zhang, Lan Yang,
and Peng Sun*
This manuscript has been accepted and appears as an Accepted Article online.
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Chinese Journal
of Chemistry
中 国 化 学 - An International Journal
Report
Quinazolinones, Rutaecarpine, Anti-malarial, Metal-free, Water
CJC
TBHP-Mediated Oxidative Decarboxylative Cyclization in Water: Direct
and Sustainable Access to Anti-malarial Polycyclic Fused Quinazolinones
and Rutaecarpine
a
a
a
a
a
a
a
a
Xingyu Chen, Fei Xia, Yifan Zhao, Ji Ma, Yue Ma, Dong Zhang, Lan Yang, and Peng Sun *
a
Artemisinin Research Center and Institute of Chinese Materia Medica, Academy of Chinese Medical Sciences, Beijing, 100700, P. R. China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion Polycyclic fused quinazolinones with anti-malarial activity were synthesized through
TBHP-mediated oxidative decarboxylative cyclization between commercially available isatins and cyclic amines in one step. The reaction proceeds
smoothly in water without additional transition-metal catalyst, acid and base. The newly synthesized products were evaluated to exhibit moderate to
good anti-malarial activity against chloroquine drug-sensitive Plasmodium falciparum 3D7 strain. Additionally, this method also provides direct approach
to Rutaecarpine in good yield.
Background and Originality Content
O
O
Malaria is one of the major global health issues which account
for two hundred million human infections and over half a million
deaths each year according to the World Malaria Report in 2018.
N
N
N
N
[1]
HN
O
Nitrogen heterocyclic compounds have played pivotal roles in
malaria chemotherapy progressing from quinine to chloroquine,
Rutaecarpine
Tryptanthrin
amma or ac
v
-
COX II I hibit
n
or
A
n
ti i fl
n
t
y
ti ity
[2]
mefloquine and amodiaquine in the last century. Recently, the
emerging of drug-resistant parasites resulted in failures of
response to the first-line drugs in the Greater Mekong Subregion
O
N
O
N
[3]
O
including Thailand, Myanmar, Laos and China. As a result, there
is always an urgent need to develop novel anti-malarial nitrogen
containing heterocyclic agents to overcome the resistance to
N
N
N
N
Luotonin A
Ci
d
a
rcum n
H
ti
ox ase
d i NADH id
clinical medications. Quinazolinones represent
a
class of
T
o
p
o somerase-
1 i hibit
or
n
i
Mit
oc on r a
h
interesting nitrogen heterocyclic compounds which are widely
[
4]
Figure 1 Bioactive polycyclic fused quinazolinones.
present in natural products and pharmaceutical materials. (Fig.
) A series of quinazolinone type alkaloids and its analogues have
been prepared and evaluated to show good antimalarial activity
1
for drug synthesis and modification which could minimize the use
or emission of hazardous materials is one of the most pressing
[
5]
against plasmodium malaria parasite. Nevertheless, the potent
of this privileged skeleton on malaria treatment remain
underestimated.
[
6]
tasks in medicinal chemistry. The classical method to obtain
quinazolinones are based on the condensations between
2
-aminobenzamides and other one carbon source such as
The exploration of green and sustainable chemical reactions
[7]
alcohols, aldehydes, toluene and etc. While, the construction of
polycyclic quinazolinones still relatively underdeveloped. Recently,
C-H activation strategy were explored to prepared polycyclic
quinazolinones
from
pre-synthesized
quinazolinones.
[8]
[9]
Representatively, Ma, Szostak and Jana developed Rh and Ru
catalyzed cyclization reaction respectively. Alternatively,
intramolecular oxidative cyclization were also achieved by
[10]
[11]
Zheng
and Pan
4 2 2 8
through (NH ) S O , light-diriven and
electrochemistry oxidation method. Isatins is a kind of common
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10.1002/cjoc.202000154
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First author et al.
used bulk chemical which are plentifully supplied in low price.[12]
In the last few years, a series of pioneering work have been
established by Prof. Wu and coworkers to construct privilege
heterocycles through TBHP-mediated decarboxylative cyclization
between isatins and corresponding materias.[ Based on these
brilliant works, and as our continued interests in the development
of anti-malarial agents from traditional Chinese herb and
synthetic molecules since the discovery of artemisinin by
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMF
Et
3
N
100
100
100
100
100
100
100
100
100
100
125
75
60%
63%
79%
62%
45%
51%
40%
80%
81%
83%
80%
52%
0%
pyridine
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
13]
THF
[14]
EtOH
HFIP
professor Youyou Tu and co-workers,
herein, we have
established an eco-friendly methodology to prepare a series of
anti-malarial polycyclic fused quinazolinones from readily
available isatins and cyclic amines in one step. (Fig. 2)
1
0
1
2
3
1
1
1
CH
3
CN
DCE
O
O

N
H
H
H
H
H
H
H
H
H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
TBHP
,
HN
R1
R1
+
A
r
R
2
O
H
O
100 o
C
N
N
2

Ar
14
15
H
R2
Green
R
eac on
ti M di
e
a
Simple
T
C
di
ti
on ons





e
conom
ransition- e a ree
S
t p E
y
M t l F
1
6
50
Figure 2 TBHP-mediated direct synthesis of polycyclic fused
1
7 c
8 d
100
100
100
100
100
82%
85%
85%
68%
0%
quinazolinones.
1
Results and Discussion
Results (Optimization of reaction conditions)
9 e
1
0 f
2
Result 1 (Optimization of reaction conditions). In this study,
to provide effective and economically affordable potential
therapeutic agents for patients in many underdeveloped
malaria-endemic areas, we chose isatin (1a) and
tetrahydroisoquinoline (2a) as the model substrates to prepare
fused quinazolinones. Initially, the examination of 1a and 2a in
the presence of TBHP and potassium carbonate in DMSO at 100
1 g
2
a
Reaction conditions: 1a (0.75 mmol, 1.5 equiv.), 2a (0.5 mmol, 1.0 equiv.),
TBHP (70% in water, 4.0 equiv.), base (1.0 mmol, 2.0 equiv.), solvent (2
mL), 12 hours under air atmosphere; Isolated yields; 3.0 equiv. of TBHP
was used; 2.5 equiv. of TBHP was used; 2.0 equiv. of TBHP was used;
.5 equiv. of TBHP was used; g No TBHP was added.
b
c
d
e
f
1
o
C gave the desired polycyclic quinazolinone products 3a in the
1
, Entries 11-12). To our delight, water was proved to be
yield of 67% (Table 1, Entry 1). In order to improve the efficiency
of the reaction, tripotassium phosphate and potassium hydroxide
were tested to produce 3a in the yields of 65%, and 53%
respectively (Table 1, Entries 2-3). Organic bases such as
triethylamine and pyridine were also investigated, while the
yields were maintained at about 60%. The yield was promoted to
appropriate for this reaction in the later examination to provide a
high yield of 83% (Table 1, Entry 13). Due to its safe and green
specificity, water was chosen as the admirable medium of the
reaction. Increased the temperature to 125 C, 80% of 3a was
prepared (Table 1, Entry 14). The yield decreased rapidly with the
reduction of temperature to 75 C (Table 1, Entry 15). No product
was observed when the reaction was carried out at 50 C (Table 1,
o
o
7
1
9% when we removed the base from the reaction system (Table
, Entry 6). Next, a variety of solvents were screened (Table 1,
o
Entry 16). 82% yield was obtained when the amount of TBHP was
reduced to 3.0 equivalents (Table 1, Entry 17). The yield was
promoted to 85% with 2.5 equiv. of TBHP (Table 1, Entry 18). The
high yield of 85% was maintained when the amount of TBHP was
reduced to 2.0 equiv. (Table 1, Entry 19). A lower yield was
obtained with a further reduction of the oxidant to 1.5
equivalents (Table 1, Entry 20). When the reaction was conducted
in the absence of TBHP, no product was detected (Table 1, Entry
21).
Entries 7-13). The solvent DMF, THF, EtOH and HFIP gave inferior
product yields from 40% and 62% (Table 1, Entries 7-10). When
CH CN and DCE were used, over 80% yields were obtained (Table
3
Table 1 Optimization of reaction conditions.
O
N
O
,
ase
HN
+
TBHP
B
N
O
o ven , em era ure
S
l
t
T
p
t
N
H
1
a
2a
3a
Entry a
o
Yield b
67%
Result 2 (Scope exploration of the substrates). After the
condition optimization, we turned to examine the scope of the
substrates as shown in Table 2. We are pleased to find that various
isatins and cyclic amines performed smoothly under the standard
conditions to give corresponding fused quinazolinones in
moderate to good yields. Firstly, a series of isatins derivatives
were investigated. Electron neutral and donating groups (5-Me
Solvent
DMSO
Base
Temperature ( C)
100
1
2
3
K
K
2
CO
3
DMSO
DMSO
3
PO
4
100
100
65%
KOH
53%
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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.
and 5-OMe) proved to be favorable for this transformation,
could also be applied to the synthesis of Rutaecarpine (3w) from
affording 3b and 3c in excellent yields (83% and 86%, respectively). commercially available starting materials in 77% yield. This should
Trifluoromethoxy substituted products 3d was also obtained in
be the first aqueous synthetic route to Rutaecarpine (3w) as far as
[15]
we know. Isoindoline with five-membered ring was also proved
to be compatible with this procedure to give corresponding
product 3x in the yield of 72%.
Table 2 Scope exploration of the substrates. a, b
O
O
TBHP
,
R1
N
Result 3 (Synthetic applications for this reaction). To illustrate the
synthetic practicality of this reaction, scale- up experiment was
performed at 10 mmol scales to obtain 68% yield (Scheme 1a).
Morpholine and phenyl are common structural motif in
pharmaceutical molecules. Transition-metal catalysed late-stage
functionalization is efficient strategy in drug synthesis and
modification. Finally, to generate structural diverse products for
bio-evaluation, the generated product 3h was further transformed
through palladium-catalysed cross coupling reaction with
morpholine and phenylboronic acid leading to 4 and 5 in good
yields respectively (Scheme 1b).
HN
R1
+
r
R2
O
A
100 o
C
H
2
O
N
H
N
Ar R2
R1
R1
=
H
3
a
,
,
85%
R1
O
O
N
=
e
M
3b 83%
R1
,
N
R1 OM
=
=
e
c
3
86%
N
R1 OCF
=
3d 79%
3e 77%
,
3
N
1
,
R
F
=
R1 Cl
=
,
3f 71%
1
1
= Cl 3i 73%
,
R1
R1
B
r
3g 75%
,
R
R
= Br 4j, 69
=
,
%
I
3h 70%
O
N
N
O
O
N
N
Br
MeO
N
F
N
Scheme 1 Synthetic applications for this reaction.
,
,
,
a
3
k
88%
3l 60%
3m 67%
)
O
N
O
N
O
N
O
F
O
N
O +
HN
TBHP
,
100 oC
H
2
O
Me
N
N
N
N
( )
1
0
mmol scale
H
a
1
2a
3a
N
F
.
6
8% (1 69 g)
Me
Cl
Me
3o,
n
,
68%
75%
,
3
p
62%
3
O
N
O
b
Ph
)
O
O
3
( )
Pd PPh
4
N
CO3,
,
o
O
K
2
THF 80
C
N
N
N
I
PhB(OH)2
N
,
F
N
4
90%
Cl
N
N
R2
R2
R2
=
=
=
M
e
3s
86%
N
O
O
R2
,
,
,
N
3
q
59%
3r 72%
F
B
3t 71%
(db )3/X tph
an os
a
Pd
2
t
N
3u 75
,
%
3h
r
NaO B
u
,
t
o uene
,
110 o
l
C
O
N
N
O
N
N
morpholine
O
,
N
5
87%
N
N
OMe
HN
Result 4 (Anti-malarial evaluation). With the newly
OMe
synthesized fused quinazolones in hand, we set out to evaluate
the anti-malarial activities of selected examples against
chloroquine drug-sensitive Plasmodium falciparum 3D7 strain.
The inhibition of parasite growth was measured at the
concentrations ranging from 0.5 nM to 400.0 μM by the SYBR
Green assay (For comprehensive details of the assay, see
Electronic Supplementary Information Table S1). The results
indicated the selected examples exhibited moderate to good
anti-malarial activity.
3
v
,
68%
3w Rutaecarpine 77%
,
3x 72%
,
(
)
a
Reaction conditions: 1 (0.75 mmol, 1.5 equiv.), 2 (0.5 mmol, 1.0 equiv.),
TBHP (70% in water, 2.0 equiv.), solvent (2 mL), 12 hours under air
atmosphere; Isolated yields.
b
the yield of 79%. In addition, an array of halogen-substituted
isatins, including fluoro-, chloro-, bromo- and iodo- at the C-5
position, were also compatible with the reaction conditions, and
the corresponding products (3e-3h) were generated in the yield
from 70% to 77%, which provide the possibility for further
synthetic elaboration. Apart from 6-substituted quinazolones,
products with substituent group at 5-, 7- and 8- position were also
synthesized in over 60% yield (3i-3n). Furthermore,
multi-substituted products were provided through our method in
the yield from 59% to 75% (3o-3q). Next, the scope of substituted
cyclic amines was also explored. Methyl and halogen substituted
tetrahydroisoquinolines at 5- and 7- position were tried to
prepared desired products in the yields from 71% to 86% (3r-3u).
To our satisfaction, di-substituted quinazolones 3v was also
obtained in 68% yield. It was exiting that the developed approach
Result 5 (Mechanism study). Next, a series of experiments
were conducted in order to figure out the mechanism of this
procedure, as shown in Scheme 2. Firstly, 1a was treated with 1.0
o
equivalent of TBHP at 100 C for 2 hours individually, and 6 was
generated in the yield of 90% (Scheme 2a1). Substrate 2a could
be transformed to 7 in the function of 1.0 equivalent of TBHP or
air (Scheme 2a2). Compound 6 could react with 2a under
standard conditions to yield 3a in 79% yield (Scheme 2a3). When
7 was treated with 1a with 2 equiv. of TBHP, 3a was obtained in
the yield of 80% (Scheme 2a4). When we treated 6 and 7 in the
standard conditions, 90% 3a was generated. These results
revealed that 6, 7 could be identified as the intermediates of the
Chin. J. Chem. 2019, 37, XXX－XXX
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First author et al.
reaction. Based on these observations and literature precedent, a
plausible reaction pathway is depicted for the formation of
compound 3 (Scheme 2b). At first, intermediate 8 generated via
the nucleophilic attack of TBHP to 1. Next, intramolecular
rearrangement occurred to offer isatin anhydride 6 with the
release of tertiary butanol. The following decarboxylative
cyclization between 6 and 7 which generated from 2 in the
function of TBHP or air afforded intermediate 9. Ultimately, 3 was
produced via the oxidation of 8 by air or TBHP.
Experimental
Experiment detail for the oxidative decarboxylative cyclization:
A round bottom flask was charged with isatins 1 (0.75 mmol, 1.5
equiv.), tetrahydroisoquinolines 2 (0.5 mmol, 1.0 equiv.), H O
2 2
70% in water, 1 mmol, 2.0 equiv.) and 2 mL H
mixture was vigorously stirred at 100 C (oil temperature) for 12
hours. After cooling to room temperature, the reaction mixture
was extracted with ethyl acetate (10 mL). The organic phase was
washed with water and brine respectively. The solvent was
concentrated in vacuo and purified by flash chromatography on
silica gel to afford the desired product.
Characterization of the products:
5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3a)
Yield 85%; White solid, m.p. 193-195 C; H NMR (600 MHz, CDCl )
3
δ 8.49 (dd, J = 7.7, 1.4 Hz, 1H), 8.36 – 8.28 (m, 1H), 7.81 – 7.72 (m,
(
2
O. The reaction
o
Scheme 2 Mechanism study and proposed reaction pathway.
a
Mechanism study
)
O
O
.
1
equiv TBHP
1
( )
O
O
,
100 o
,
o
1
H
2
O
C
2h
N
H
N
H
O
1
a
6, 90%
,
2H), 7.52 – 7.40 (m, 3H), 7.29 (d, J = 7.4 Hz, 1H), 4.42 (t, J = 6.5 Hz,
no TBHP 26%
equiv TBHP 78%
H O 100 o
.
,
1
13
(
2)
2
1
1
H), 3.11 (t, J = 6.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl
61.7, 149.4, 147.8, 137.1, 134.2, 131.7, 129.6, 128.0, 127.6,
27.5, 126.9, 126.5, 120.8, 100.0, 39.6, 27.5 ppm; HRMS (ESI)
3
) δ
,
,
2h
HN
C
N
2
2
a
7
calcd for [C16
12 2
H N O+H]+ 249.0950, found 249.1062.
standard conditions
12 hours
3a, 79%
(
3
)
6
+
10-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3b)
HN
O
o
1
Yield 83%; White solid, m.p. 182-183 C; H NMR (600 MHz, CDCl
δ 8.46 (dd, J = 7.7, 1.5 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.67 (d, J =
.3 Hz, 1H), 7.56 (dd, J = 8.3, 2.0 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.27
(d, J = 7.2 Hz, 1H), 4.41 (t, J = 6.5 Hz, 2H), 3.09 (t, J = 6.5 Hz, 2H),
3
)
2
a
8
standard conditions
2 hours
(
4)
5)
+
3a, 80%
3a 90%
O
7
1
N
H
13
2.50 (s, 3H) ppm; C NMR (150 MHz, CDCl3) δ 161.7, 148.6, 145.8,
36.9, 136.7, 135.7, 131.5, 129.7, 127.9, 127.6, 127.5, 127.4,
126.3, 120.5, 39.6, 27.5, 21.4 ppm; HRMS (ESI) calcd for
O+H]+ 263.1179, found 263.1176.
0-methoxy-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3c)
1
a
1
standard conditions
+
7
,
(
6
1
2 hours
17 14 2
[C H N
1
b) Plausible reaction pathway
O
o
1
Yield 86%; Light yellow solid, m.p. 169-170 C; H NMR (600 MHz,
CDCl ) δ 8.45 (dd, J = 7.6, 1.5 Hz, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.68
O
O
O
O
tB
u-
O
O
3
t
O B
u
TBHP
O
(d, J = 3.0 Hz, 1H), 7.49 – 7.40 (m, 2H), 7.36 (dd, J = 8.9, 3.0 Hz,
1H), 7.28 (d, J = 7.3 Hz, 1H), 4.43 (t, J = 6.5 Hz, 2H), 3.94 (s, 3H),
N
H
N
H
N
H
6
O
1
8
13
3
1
.10 (t, J = 6.5 Hz, 2H) ppm; C NMR (75 MHz, CDCl
58.3, 147.4, 142.5, 136.7, 131.3, 129.7, 129.3, 127.7, 127.6,
3
) δ 161.5,
TBHP or Air(O
2
)
-
HN
N
CO
2
127.5, 124.6, 121.5, 106.2, 55.8, 39.8, 27.5 ppm; HRMS (ESI) calcd
for [C1 H N O +H]+ 279.1128, found 279.1125.
7
2
7
14 2 2
1
0-(trifluoromethoxy)-5H-isoquinolino[1,2-b]quinazolin-8(6H)
O
O
o
1
-
one (3d) Yield 79%; white solid, m.p. 194-196 C; H NMR (600
MHz, CDCl ) δ 8.47 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 2.9 Hz, 1H), 7.80
(d, J = 8.8 Hz, 1H), 7.58 (dd, J = 8.9, 2.8 Hz, 1H), 7.47 (dt, J = 31.4,
.5 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 3.11 (t,
N
TBHP or Air O2
N
(
)
3
N
3
N
H
9
7
13
J = 6.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl
3
) δ 160.9, 149.8,
47.1, 147.0, 146.3, 137.0, 132.0, 129.7, 129.2, 128.1, 127.7,
27.6, 127.6, 121.6, 121.3, 119.6, 118.2, 39.8, 27.4 ppm; HRMS
+H]+ 333.0845, found 333.0840.
10-fluoro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3e)
1
1
Conclusions
In conclusion, a green and sustainable procedure has been
developed to construct polycyclic fused quinazolinones and
Rutaecarpine in water. Highly effective antimalarial agent was
synthesized directly from cheap bulk chemical raw materials
without the emissions of toxic contaminants, which may provide
affordable alternatives for people from impoverished malaria
epidemic areas. Comprehensive bio-evaluations of the products
are underway in our laboratory.
11 3 2 2
(ESI) calcd for [C17H F N O
o
1
3
Yield 77%; white solid, m.p. 206-208 C; H NMR (600 MHz, CDCl )
δ 8.39 (dd, J = 7.8, 1.4 Hz, 1H), 7.87 (dd, J = 8.5, 3.0 Hz, 1H), 7.70
(dd, J = 8.9, 4.9 Hz, 1H), 7.43 – 7.38 (m, 2H), 7.37 (td, J = 7.6, 1.3
Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 4.34 (t, J = 6.5 Hz, 2H), 3.04 (t, J =
13
6.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl
147.8, 143.5, 135.9, 130.8, 129.0, 129.0, 128.4, 126.9, 126.7,
26.5, 122.0, 121.8, 120.9, 110.7, 110.6, 38.8, 26.4 ppm; HRMS
ESI) calcd for [C16 O+H]+ 267.0928, found 267.0924.
0-chloro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3f)
3
) δ 160.6, 160.0, 158.9,
1
(
H11FN
2
1
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
o
1
Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl
) δ
3
167.3, 165.7, 161.0, 150.6, 150.0, 149.9, 137.2, 132.1, 129.6,
129.5, 129.3, 128.2, 127.7, 127.6, 117.5, 117.5, 115.4, 115.2,
112.8, 112.6, 39.6, 27.4 ppm; HRMS (ESI) calcd for
Yield 71%; white solid, m.p. 179-180 C; H NMR (600 MHz, CDCl
δ 8.45 (dd, J = 7.8, 1.5 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 7.73 – 7.64
m, 2H), 7.51 – 7.41 (m, 2H), 7.29 (d, J = 7.5 Hz, 1H), 4.40 (t, J = 6.5
3
)
(
1
3
Hz, 2H), 3.10 (t, J = 6.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl
3
) δ
60.7, 149.6, 146.3, 137.0, 134.7, 132.2, 132.0, 129.3, 129.3,
28.0, 127.7, 127.6, 126.2, 121.7, 39.8, 27.4 ppm; HRMS (ESI)
O+H]+ 283.0633, found 283.0631.
0-bromo-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3g)
1
1
[C16
H
11FN
2
O+H]+ 267.0928, found 267.0923.
11-bromo-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3m)
o
1
calcd for [C16
H
11ClN
2
3
Yield 67%; white solid, m.p. 176-178 C; H NMR (600 MHz, CDCl )
1
δ 8.43 (dd, J = 7.8, 1.3 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.92 (d, J =
1.8 Hz, 1H), 7.53 (dd, J = 8.5, 1.9 Hz, 1H), 7.48 (td, J = 7.4, 1.4 Hz,
1H), 7.45 – 7.39 (m, 1H), 7.27 (d, J = 7.5 Hz, 1H), 4.37 (t, J = 6.5 Hz,
o
1
Yield 75%; light yellow solid, m.p. 190-192 C; H NMR (600 MHz,
CDCl ) δ 8.45 (dd, J = 7.8, 1.4 Hz, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.81
dd, J = 8.7, 2.3 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.49 (td, J = 7.4,
3
13
13
(
2H), 3.09 (t, J = 6.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl
NMR (150 MHz, CDCl ) δ 161.2, 150.4, 148.8, 137.1, 132.0, 130.2,
129.8, 129.2, 128.8, 128.3, 128.2, 127.7, 127.5, 119.5, 39.6, 27.3
3
)
C
1
6
.5 Hz, 1H), 7.46 – 7.39 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 4.40 (t, J =
3
.5 Hz, 2H), 3.10 (t, J = 6.5 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl
3
)
δ 160.6, 149.8, 146.6, 137.4, 137.0, 132.0, 129.4, 129.4, 129.3,
28.1, 127.7, 127.6, 122.1, 119.9, 39.8, 27.4 ppm; HRMS (ESI)
calcd for [C16 O+H]+ 327.0126, found 327.0126.
0-iodo-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3h)
ppm; HRMS (ESI) calcd for [C16
327.0127.
12-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3n)
3
Yield 68%; white solid, m.p. 165-167 C; H NMR (600 MHz, CDCl )
2
H11BrN O+H]+ 327.0128, found
1
H
11ClN
2
o
1
1
o
1
Yield 70%; white solid, m.p. 194-196 C; H NMR (600 MHz, CDCl
δ 8.62 (d, J = 2.1 Hz, 1H), 8.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.98 (dd, J =
.6, 2.1 Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.46 – 7.39 (m, 1H), 7.28
d, J = 7.5 Hz, 1H), 4.39 (t, J = 6.5 Hz, 2H), 3.09 (t, J = 6.5 Hz, 2H)
3
)
δ 8.53 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 7.2 Hz,
1H), 7.50 – 7.40 (m, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.3 Hz,
1H), 4.41 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.5 Hz, 2H), 2.71 (s, 3H)
8
1
3
(
ppm; C NMR (150 MHz, CDCl
3
) δ 162.1, 148.0, 146.3, 136.9,
1
3
ppm; C NMR (150 MHz, CDCl
1
3
3
) δ 160.3, 149.9, 147.1, 142.9,
37.0, 135.7, 132.0, 129.4, 129.3, 128.1, 127.7, 127.6, 122.3, 90.8,
9.8, 27.4 ppm; HRMS (ESI) calcd for [C12 O+H]+ 374.9989,
136.1, 134.7, 131.5, 130.0, 128.0, 127.6, 127.5, 126.1, 124.5,
120.7, 39.5, 27.5, 17.3 ppm; HRMS (ESI) calcd for [C17
263.1179, found 263.1175.
14 2
H N O+H]+
H
11IN
2
found 374.9986.
-chloro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3i)
10,12-dimethyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
o
1
9
(3o) Yield 75%; white solid, m.p. 201-203 C; H NMR (600 MHz,
CDCl ) δ 8.52 (dd, J = 7.6, 1.6 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.50
– 7.38 (m, 3H), 7.27 (d, J = 7.2 Hz, 1H), 4.41 (t, J = 6.5 Hz, 2H), 3.09
o
1
Yield 73%; light yellow solid, m.p. 200-202 C; H NMR (600 MHz,
CDCl ) δ 8.45 (dd, J = 7.9, 1.6 Hz, 1H), 7.66 (dd, J = 8.1, 1.4 Hz, 1H),
3
3
13
7
7
3
1
1
.59 (t, J = 8.0 Hz, 1H), 7.49 (td, J = 7.4, 1.5 Hz, 1H), 7.44 (dd, J =
(t, J = 6.5 Hz, 2H), 2.68 (s, 3H), 2.45 (s, 3H) ppm; C NMR (150
MHz, CDCl ) δ 162.0, 147.3, 144.3, 136.8, 136.3, 136.2, 135.8,
131.3, 130.1, 127.9, 127.5, 127.4, 124.0, 120.5, 39.6, 27.5, 21.4,
.8, 1.3 Hz, 2H), 7.29 (d, J = 7.5 Hz, 1H), 4.37 (t, J = 6.5 Hz, 2H),
3
.10 (t, J = 6.5 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl
) δ 159.8,
3
50.2, 150.0, 137.2, 134.1, 133.5, 132.0, 129.2, 129.0, 128.0,
27.6, 127.5, 127.0, 117.9, 39. 6, 27.4 ppm; HRMS (ESI) calcd for
16 2
17.2 ppm; HRMS (ESI) calcd for [C18H N O+H]+ 277.1335, found
277.1332.
[
C
16
H
11ClN
2
O+H]+ 283.0633, found 283.0631.
9,11-difluoro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3p)
Yield 62%; white solid, m.p. 223-224 C; H NMR (600 MHz, CDCl )
3
δ 8.45 (dd, J = 7.8, 1.4 Hz, 1H), 7.52 (td, J = 7.4, 1.4 Hz, 1H), 7.45
(td, J = 7.7, 1.3 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.23 (ddd, J = 9.4,
o
1
9
-bromo-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3j)
o
1
Yield 69%; white solid, m.p. 220-222 C; H NMR (600 MHz, CDCl
δ 8.47 (dd, J = 7.9, 1.5 Hz, 1H), 7.75 – 7.69 (m, 2H), 7.55 – 7.48 (m,
3
)
2
2
1
1
H), 7.48 – 7.43 (m, 1H), 7.30 (d, J = 7.5 Hz, 1H), 4.39 (t, J = 6.5 Hz,
H), 3.12 (t, J = 6.5 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl
) δ
59.9, 150.1, 149.7, 137.2, 133.8, 133.0, 132.0, 129.0, 128.0,
27.7, 127.6, 127.5, 121.5, 118.8, 39.7, 27.4 ppm; HRMS (ESI)
2.6, 1.4 Hz, 1H), 6.87 (ddd, J = 11.1, 9.0, 2.5 Hz, 1H), 4.37 (t, J = 6.5
13
3
Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl
3
) δ
166.6, 166.5, 164.9, 163.4, 161.6, 158.2, 158.2, 151.3, 151.2,
151.1, 137.4, 132.4, 128.8, 128.3, 127.7, 127.6, 109.2, 109.2,
109.1, 109.0, 107.5, 103.0, 102.8, 102.8, 102.7, 39.2, 27.3 ppm;
calcd for [C16
2
H11BrN O+H]+ 327.0128, found 327.0127.
1
1-methoxy-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3k)
HRMS (ESI) calcd for [C16
285.0829.
10 2
H F N2O +H]+ 285.0834, found
o
1
Yield 88%; light yellow solid, m.p. 177-179 C; H NMR (600 MHz,
CDCl ) δ 8.44 (dd, J = 7.8, 1.5 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.46
td, J = 7.4, 1.5 Hz, 1H), 7.44 – 7.38 (m, 1H), 7.27 (d, J = 7.3 Hz, 1H), Yield 59%; Light yellow solid, m.p. 230-232 C; H NMR (600 MHz,
.13 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 8.8, 2.5 Hz, 1H), 4.38 (t, J = 6.5 CDCl ) δ 8.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.51
3
9,11-dichloro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3q)
o
1
(
7
3
13
Hz, 2H), 3.93 (s, 3H), 3.08 (t, J = 6.5 Hz, 2H) ppm; C NMR (150
MHz, CDCl ) δ 164.5, 161.2, 150.0, 150.0, 137.1, 131.7, 129.6,
28.4, 127.9, 127.6, 127.5, 116.8, 114.4, 108.0, 55.6, 39.4, 27.5
ppm; HRMS (ESI) calcd for [C17 +H]+ 279.1128, found
79.1125.
1-fluoro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3l)
(td, J = 7.4, 1.4 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.42 (t, J = 2.4 Hz,
1H), 7.30 (d, J = 7.5 Hz, 1H), 4.35 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.5
3
13
1
3
Hz, 2H) ppm; C NMR (150 MHz, CDCl ) δ 163.4, 159.3, 151.0,
H
14
2
N O
2
150.7, 139.3, 137.3, 135.3, 132.4, 129.0, 128.7, 128.1, 127.7,
127.6, 126.4, 116.4, 39.6, 27.3 ppm; HRMS (ESI) calcd for
2
1
[C16
H
10Cl
2
N
2
O+H]+ 317.0243, found 317.0240.
o
1
Yield 60%; white solid, m.p. 169-170 C; H NMR (600 MHz, CDCl
δ 8.50 – 8.43 (m, 1H), 8.32 (dd, J = 8.9, 6.2 Hz, 1H), 7.50 (td, J = 7.4, Yield 72%; Light yellow solid, m.p. 198-200 C; H NMR (600 MHz,
3
)
4-fluoro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3r)
o
1
1
7
.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.40 (dd, J = 9.7, 2.5 Hz, 1H),
.30 (d, J = 7.5 Hz, 1H), 7.17 (td, J = 8.5, 2.5 Hz, 1H), 4.40 (t, J = 6.5
CDCl
3
) δ 8.32 (t, J = 8.2 Hz, 2H), 7.81 – 7.74 (m, 2H), 7.49 (ddd, J =
8.1, 5.1, 3.1 Hz, 1H), 7.41 (td, J = 8.0, 5.5 Hz, 1H), 7.23 (t, J = 8.5 Hz,
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.

Report
First author et al.
1
(
1
1
H), 4.43 (t, J = 6.5 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H) ppm; 13C NMR
150 MHz, CDCl
10-phenyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (4) A
3
) δ 161.6, 159.9, 158.3, 148.4, 147.5, 134.4, 131.6, sealed tube was charged with 3h (0.5 mmol, 1.0 equiv), Pd(PPh
28.4, 128.4, 127.7, 126.9, 126.9, 124.4, 124.2, 123.7, 123.6, (0.05 mmol, 10 mol%), CO (1.0 mmol, 2.0 equiv.),
20.8, 118.2, 118.0, 38.9, 20.1, 20.0 ppm; HRMS (ESI) calcd for
O+H]+ 267.0924, found 267.0924.
-methyl-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3s)
3 4
)
K
2
3
phenylboronic acid (1.0 mmol, 2.0 equiv.) and THF 2 mL. The
o
[
C
16
H
11FN
2
reaction mixture was then vigorously stirred at 80 C (oil
2
temperature) for 12 hours. After cooling to room temperature,
the reaction mixture was diluted with ethyl acetate (20 mL) and
filtered through a plug of celite. The mixture was concentrated in
vacuo and purified by flash chromatography on silica gel to afford
the desired product 4 in 90% yield. Yield 90%; Light yellow solid,
o
1
Yield 86%; white solid, m.p. 165-167 C; H NMR (600 MHz, CDCl
δ 8.31 (dd, J = 7.9, 1.5 Hz, 1H), 8.29 (s, 1H), 7.81 – 7.70 (m, 2H),
7
7
2
1
1
3
)
.45 (ddd, J = 8.1, 6.6, 1.6 Hz, 1H), 7.28 (dd, J = 7.7, 1.8 Hz, 1H),
.17 (d, J = 7.6 Hz, 1H), 4.39 (t, J = 6.5 Hz, 2H), 3.05 (t, J = 6.5 Hz,
H), 2.45 (s, 3H) ppm; 13C NMR (150 MHz, CDCl
o
1
3
) δ 161.7, 149.6,
3
m.p.188-189 C; H NMR (600 MHz, CDCl ) δ 8.55 (d, J = 2.2 Hz,
47.8, 137.4, 134.2, 132.6, 129.3, 128.2, 127.5, 127.4, 126.9,
26.4, 120.8, 39.8, 27.1, 21.2 ppm; HRMS (ESI) calcd for
1H), 8.52 – 8.46 (m, 1H), 8.01 (dd, J = 8.5, 2.2 Hz, 1H), 7.83 (d, J =
8.4 Hz, 1H), 7.75 – 7.70 (m, 2H), 7.48 (t, J = 7.5 Hz, 3H), 7.44 (t, J =
7.5 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 4.44 (t,
[
C
17
H
14
N
2
O+H]+ 263.1179, found 263.1175.
13
2
-fluoro-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3t)
J = 6.5 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H) ppm; C NMR (150 MHz,
CDCl ) δ 161.8, 149.3, 147.1, 139.8, 139.4, 137.0, 133.1, 131.7,
129.6, 129.0, 128.2, 128.0, 127.8, 127.6, 127.5, 127.2, 124.7,
o
1
Yield 71%; light yellow solid, m.p. 211-213 C; H NMR (600 MHz,
CDCl ) δ 8.31 (d, J = 8.0 Hz, 1H), 8.19 (dd, J = 9.5, 2.7 Hz, 1H), 7.77
d, J = 4.0 Hz, 2H), 7.48 (dt, J = 8.1, 4.1 Hz, 1H), 7.27 (q, J = 5.2 Hz,
3
3
(
121.0, 39.7, 27.5 ppm; HRMS (ESI) calcd for [C22
16 2
H N O+H]+
1
6
1
1
2
2
H), 7.18 (td, J = 8.3, 2.7 Hz, 1H), 4.41 (t, J = 6.5 Hz, 2H), 3.08 (t, J =
324.1332, found 324.1330.
10-morpholino-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (5)
A sealed tube was charged with 3h (0.2 mmol, 1.0 equiv),
13
3
.5 Hz, 2H) ppm; C NMR (150 MHz, CDCl ) δ 163.0, 161.6, 161.3,
48.4, 148.3, 147.6, 134.4, 132.7, 132.7, 131.4, 131.4, 129.2,
29.2, 127.7, 126.9, 126.9, 120.9, 119.0, 118.8, 114.6, 114.5, 39.7,
Pd
NaO
2
(dba)
3
(0.01 mmol, 5 mol%), XantPhos (0.02 mmol, 10 mol%),
6.8 ppm; HRMS (ESI) calcd for [C16
H
2
14FN O+H]+ 267.0928, found
t
Bu (0.4 mmol, 2.0 equiv), morpholine (0.4 mmol, 2.0 equiv)
67.0924.
and toluene 2 mL. The reaction mixture was then vigorously
o
2
-bromo-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (3u)
stirred at 110 C (oil temperature) for 12 hours. After cooling to
o
1
Yield 75%; light yellow solid, m.p. 223-225 C; H NMR (600 MHz,
CDCl ) δ 8.53 – 8.48 (m, 1H), 8.35 – 8.29 (m, 1H), 7.81 – 7.72 (m,
H), 7.52 – 7.42 (m, 3H), 7.30 (d, J = 7.4 Hz, 1H), 4.43 (t, J = 6.5 Hz,
H), 3.11 (t, J = 6.5 Hz, 2H) ppm; 13C NMR (150 MHz, CDCl
) δ
room temperature, the reaction mixture was diluted with ethyl
acetate (20 mL) and filtered through a plug of celite. The mixture
was concentrated in vacuo and purified by flash chromatography
on silica gel to afford the desired product 5 in 87% yield. Yield
87%; Light yellow solid, m.p. 193-195 C; H NMR (600 MHz, CDCl )
3
δ 8.43 (d, J = 7.4 Hz, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.65 (d, J = 2.9 Hz,
1H), 7.42 (ddt, J = 12.4, 8.1, 5.0 Hz, 3H), 7.27 (s, 1H), 4.41 (t, J =
3
2
2
1
1
3
o
1
61.8, 149.4, 147.9, 137.1, 134.2, 131.7, 129.6, 128.1, 127.6,
27.5, 126.9, 126.5, 120.8, 39.6, 27.5 ppm; HRMS (ESI) calcd for
[
C
16
H
11BrN
2
O+H]+ 327.0128, found 327.0120.
2
,3-dimethoxy-5H-isoquinolino[1,2-b]quinazolin-8(6H)-one
6.4 Hz, 2H), 3.90 (t, J = 4.7 Hz, 4H), 3.30 (t, J = 4.7 Hz, 4H), 3.09 (t, J
o
1
13
(
3v) Yield 68%; Light yellow solid, m.p. 207-209 C; δ H NMR (600
) δ 8.29 (d, J = 7.9 Hz, 1H), 7.98 (s, 1H), 7.79 – 7.70 (m,
H), 7.43 (t, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.40 (t, J = 6.5 Hz, 2H),
.04 (s, 3H), 3.96 (s, 3H), 3.03 (t, J = 6.5 Hz, 2H) ppm; 13C NMR
) δ 161.8, 152.2, 149.3, 148.6, 147.9, 134.1, 130.9,
27.3, 126.9, 126.1, 121.8, 120.5, 110.1, 109.7, 56.2, 56.1, 39.7,
3
= 6.4 Hz, 2H) ppm; C NMR (150 MHz, CDCl ) δ 161.6, 149.8,
MHz, CDCl
3
147.0, 141.5, 136.6, 131.1, 129.8, 128.7, 127.6, 127.6, 127.4,
123.6, 121.4, 109.7, 66.8, 49.0, 39.7, 27.6 ppm; HRMS (ESI) calcd
for [C20H N O +H]+ 334.1547, found 334.1546.
19 3 2
2
4
(
1
2
3
150 MHz, CDCl
3
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
7.0 ppm; HRMS (ESI) calcd for [C18
09.1228.
16 2 3
H N O +H]+ 309.1234, found
8
,8a,13,13a-tetrahydroindolo[2',3':3,4]pyrido[2,1-b]quinazoli
o
n-5(7H)-one (3w) Yield 77%; Light yellow solid, m.p. 260-261 C;
H NMR (600 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.15 (dd, J = 7.9, 1.6
Hz, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.60 (d, J =
.9 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.25 (t,
J = 7.6 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 4.43 (t, J = 6.8 Hz, 2H), 3.13
t, J = 6.8 Hz, 2H) ppm; C NMR (150 MHz, DMSO-d6) δ 161.0,
47.8, 145.7, 139.1, 134.7, 127.5, 127.0, 126.8, 126.3, 125.4,
25.1, 121.2, 120.3, 120.1, 118.2, 113.0, 41.2, 19.4 ppm.
isoindolo[1,2-b]quinazolin-10(12H)-one (3x) Yield 72%; White
1
Acknowledgement
Generous financial support from the National Natural Science
Foundation of China (21702235, 81841001), the Fundamental
Research Funds for the Central Public Welfare Research Institutes
7
13
(
1
1
(
ZZ13-YQ-098, ZZ10-024, ZXKT17053), Major National Science and
Technology Program of China for Innovative Drug
(
2017ZX09101002-001-001)
1
yellow solid; H NMR (600 MHz, CDCl
3
) δ 8.30 (d, J = 8.1 Hz, 1H),
8
1
1
1
1
.09 (d, J = 7.7 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.4 Hz,
H), 7.55 (d, J = 5.4 Hz, 2H), 7.52 – 7.47 (m, 1H), 7.42 (t, J = 7.3 Hz,
H), 5.06 (s, 2H) ppm; 13C NMR (150 MHz, CDCl
) δ 160.6, 154.9,
49.5, 139.7, 134.2, 132.7, 132.3, 128.9, 127.4, 126.5, 126.4,
23.5, 120.6, 49.8 ppm.
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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
－
3201.
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© 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.

Report
First author et al.
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
O
N
O

TBHP-Mediated Oxidative Decarboxylative
Cyclization in Water: Direct and Sustainable
Access to Anti-malarial Polycyclic Fused
Quinazolinones and Rutaecarpine
TBHP
N
R
1
O
+
HN
Ar
R
2
R
1
,
100 o
C
N
H
2
O
H

A
r
G
St p E
ti
reen eac on
e
a
Si pl
Trans
m
e
on ons
R
2


R
M
di


C
diti
ition-Me a ree
l F
e
conom
y
t
O
O
N
N
F
3
CO
N
N
HN
-
Anti malarial activity
P
.
Rutaecarpine
falciparum 3D7
A green and sustainable decaboxylative cyclization between isatins and cyclic amines has been
established to synthesize anti-malarial polycyclic fused quinazolinones and Rutaecarpine in water.
Xingyu Chen, Fei Xia, Yifan Zhao, Ji Ma, Yue Ma,
Dong Zhang, Lan Yang, and Peng Sun*
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.