Expeditious Approach to Indoloquinazolinones via Double Annulations of o-Aminoacetophenones and Isocyanates

Article abstract of DOI:10.1021/acs.joc.0c02155

A novel procedure for a one-pot cascade reaction of o-aminoacetophenones and aryl/aliphatic isocyanates catalyzed/oxidized by the [Pd]/[Ag] system was developed. The reaction involves two C-N bond and one C-C bond formations during the double annulation process and the desired indoloquinazolinones and derivatives were afforded up to 81% yields from readily available substrates with a tolerance of a broad variety.

Full text of DOI:10.1021/acs.joc.0c02155

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Article
Expeditious Approach to Indoloquinazolinones via Double
Annulations of o‑Aminoacetophenones and Isocyanates
#
#
Yuxin Ding, Huihui Yan, Rener Chen, Xuqiong Xiao, Zhiming Wang, Lei Wang, and Yongmin Ma*
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sı Supporting Information
ABSTRACT: A novel procedure for a one-pot cascade reaction of o-
aminoacetophenones and aryl/aliphatic isocyanates catalyzed/oxidized
by the [Pd]/[Ag] system was developed. The reaction involves two C−
N bond and one C−C bond formations during the double annulation
process and the desired indoloquinazolinones and derivatives were
afforded up to 81% yields from readily available substrates with a
tolerance of a broad variety.
1
5
INTRODUCTION
approach of indoloquinazolinones. However, all the above
cited protocols are presented on the synthesis of indolo[1,2-
a]quinazolinones (Figure 1A) or indolo[1,2-b]quinazolinones
■
1
2
Quinazolinone and indole are two important structural
motifs which can be found in many natural products and
synthetic pharmaceutical compounds, exhibiting a broad
spectrum of biological activities. Indole-fused quinazolinones
such as indoloquinazolinone derivatives are shown to possess a
variety of promising biological activities, including antibacte-
(
Figure 1B). There are a very few methods available for the
synthesis of indolo[1,2-c]quinazolinones (Figure 1C).
16
3
4
5
rial, anticancer, and antifungal activities. One typical
example is tryptanthrin (6-oxo indolo[1,2-b]quinazolinone),
3a,6
which has been found in many kinds of plants and exhibits
intriguing biological properties such as anticancer, antibacte-
rial, antifungal antiprotozoal, antiparasitic, and antitubercular
6
b,7
activities.
As such, the indole-fused quinazolinones have
attracted considerable attention as a pharmacophore.
Figure 1. Types of indoloquinazolinones.
To date, several synthetic methods have been developed to
prepare the indoloquinazolinones. The general procedure for
preparation of indoloquinazolinones is performed by a
coupling of isatin and isatoic anhydride under basic
Nakamura et al. described a platinum-catalyzed cyclization
of ortho-alkynylphenylureas to afford the corresponding
tetracyclic indoloquinazolinones (Scheme 1a).
developed a one-pot synthesis of indoloquinazolinones
through a nucleophilic addition/Cu-catalyzed N-arylation/
Pd-catalyzed C−H activation (Scheme 1b). The Soderberg
group reported a palladium-catalyzed carbon monoxide
mediated reductive cyclizations of chloro-substituted 1,2-
bis(2-nitrophenyl)alkenes (Scheme 1c).
reported reactions suffer from one or more drawbacks, such as
the use of complex raw materials or multistep preparation of
starting materials, expensive catalysts, and harsh reaction
conditions. Thus, a great demand exists for a straightforward,
8
conditions. Vaidya and Argade reported an aryne insertion
16c
Bao et al.
reaction to a variety of quinazolinones to achieve a concise
9
total synthesis of phaitanthrins. Wang and co-workers
developed a concise method for the preparation of
tryptanthrins from indoles and indoline-2,3-diones via
16d
1
0
copper-catalyzed aerobic oxidation.
Takemoto et al.
described a palladium(0)-catalyzed cyclization of chloroquina-
16e
However, all the
zolinones via C−H functionalization for the synthesis of
1
1
indoloquinazolinones. Lv and co-workers utilized gem-
dibromovinyl systems to build the indoloquinazolinones
framework by a copper-catalyzed domino intramolecular
1
2
cyclization. Alternatively, indoloquinazolinones can also be
synthesized based on a rearrangement of 11-oxo-10,11-
dihydrodibenzo[b,f]azepine-5-carbonnitrile under basic con-
Received: September 6, 2020
Published: December 29, 2020
1
3
ditions or from 2-iodobenzamide and indole derivatives via
palladium-catalyzed intramolecular C−H amidation in the
14
presence of a stoichiometric amount of silver salt as oxidant.
Recently, Badigenchala and Sekar reported NIS-mediated
2
cross-coupling of C(sp )-H and N−H bonds toward an
©
2020 American Chemical Society
https://dx.doi.org/10.1021/acs.joc.0c02155
1
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a
Scheme 1. Previous Reported Synthesis of Indolo[1,2-
Table 1. Optimization of Reaction Conditions
c]quinazolinones and Our Work
entry
solvent
catalyst
additive (equiv) T (°C) yield (%)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCl
Pd(OAc)2
-
-
-
-
110
110
110
110
110
110
110
110
110
110
110
110
110
110
75
21
0
trace
0
30
Ag CO3
2
Cu(OAc)2
Co(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc) (1)
Cu(OTf) (1)
Ag CO (1)
AgOAc (2)
Ag O (1)
Ag CO (1.5)
Ag CO (1.5)
Ag CO (1.5)
2
20
2
b
48, 46
52
2
3
c
0
2
1
1
1
1
1
1
1
1
1
52
23
13
trace
80
0
0
trace
78
2
3
2
3
DMF
2
3
DMSO
AcOH
CF CO H
Ag CO (1.5)
2
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ag CO (1.5)
2 3
convenient protocol for the synthesis of indolo[1,2-c]-
quinazolinones. We have previously reported a cyclization of
Ag CO (1.5)
Ag CO (1.5)
Ag CO (1.5)
Ag CO (1.5)
3
2
2
3
AcOH
AcOH
AcOH
80
100
120
2
-aminoacetophenones with isocyanate to form 4-methylene-
2
3
1
7
quinazolinones (4) promoted by sodium hydroxide.
2
3
Encouraged by several reports of palladium-catalyzed C−H
2
3
18
a
activation and C−C bond formation, we envisioned that the
in situ resultant compound 4 could perform a palladium-
catalyzed intramolecular C−C bond formation to afford
indolo[1,2-c]quinazolinone in a one-pot fashion. Herein, we
wish to report an efficient and atom-economical method for
direct cascade reaction of o-aminoacetophenones and aryl
isocyanates for a one-pot formation of indolo[1,2-c]-
quinazolinones via intermediate 4 (Scheme 1d).
Reaction conditions: 1a (1 mmol), 2a (1 mmol), catalyst (10 mol
), solvent (3 mL), and an additive at the indicated amount in a
%
b
c
sealed tube at 110 °C for 24 h. Reaction under N atmosphere; The
2
starting materials were consumed, and unidentified mixtures were
detected.
(
entry 14). The effect of temperature on the reaction was also
examined. The desired product 3aa was obtained at 80% yield
at 110 °C (entry 14). Surprisingly, decreasing the temperature
slightly leads to a dramatic drop of the yield (entries 16 and 17
vs 14). On the other hand, no marked improvement of the
yield was achieved when the temperature was increased from
110 to 120 °C (entry 18 vs 14). Therefore, the optimal
reaction conditions were established as depicted in entry 14.
Under the optimal reaction conditions, the generality of the
synthetic protocol for various aryl isocyanates 2 was
investigated (Table 2). A series of ortho-, meta-, and para-
substituted aryl isocyanates containing an electron-donating
group (−Me, −OMe) or an electron-withdrawing group (−F,
−Cl) were investigated and the corresponding indolo[1,2-
c]quinazolinones were achieved in moderate to good yields
(3aa−3aj). In order to confirm the structures, 3ai
(CCDC2023639) was analyzed by X-ray crystallography (see
the Supporting Information). Both electron-donating group
(EDG) and electron-withdrawing group (EWG) on the aryl
ring were tolerated in the reaction conditions. However, the
yields of the products bearing with an EDG were markedly
higher than those bearing an EWG (3ad vs 3ab−3ac, 3af vs
3ae, 3ah vs 3ag). On the other hand, the stereochemistry
significantly influenced the yield. For instance, para- and meta-
methyl substituted isocyanates gave the desired products at
79% and 81% yield, respectively, whereas ortho-methyl
isocyanate only provided the corresponding indoloquinazoli-
none at 50% yield (3ad, 3af, and 3ah). Same results were
achieved for chloro- and fluoro-substituted analogues (3ae vs
3ac and 3ag vs 3ab). It is worthy to mention that when ortho-
chloro isocyanate (2c) was investigated for the annulation
RESULTS AND DISCUSSION
■
Initially, we began our study with o-aminoacetophenone (1a)
and phenylisocyanate (2a) as a model to investigate the
optimal reaction conditions (Table 1). When 1a and 2a at 1
equiv in the presence of Pd(OAc) (10 mol %) was refluxed in
2
toluene under air atmosphere for 24 h, to our delight, the
desired double-annulated product 9-methylindolo[1,2-c]-
quinazolin-6(5H)-one (3aa) was obtained in 21% yield
(
entry 1). Other catalysts such as Ag CO , Cu(OAc) , and
2 3 2
Co(OAc) were also examined but none was found to be
2
effective for the annulation (entries 2−4). It is well-known that
copper and silver salts have been widely used as oxidants in
palladium-catalyzed arylation reactions.
18c,e,19
Therefore, we
chose Cu(OAc) , Cu(OTf) , Ag CO , and Ag O as the
2
2
2
3
2
additive for the reaction. Among the additives selected (entries
5
−8), only Ag CO (1 equiv) gave significant improvement of
2
3
the product yield from 21% to 48%. The reaction was also
successively carried out under N atmosphere, indicating that
2
oxygen from air was not involved in the oxidation process
entry 7). The yield of the product was slightly increased by
(
replacing Ag CO3 with AgOAc (entry 8). Although the
2
conversion rate of the starting materials is high in the presence
of Ag O, a mixture of unidentified compounds was detected
2
(
(
entry 9). A slight improvement was achieved when Ag CO
1.5 equiv) was used (entry 10). We then screened the effect
of solvent on the reaction. When toluene was replaced by other
solvents (entries 11−15), the yield varies and acetic acid was
found to be the most effective solvent for the catalytic reaction
2 3
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a
Table 2. Substrate Scope Based on Aryl Isocyanates
their meta- and para-substituted analogues (3bb vs 3bg, 3bc vs
bj, 3cb vs 3cg) and the isocyanates attached with an EDG
offered higher yields than those with an EWG (3bh vs 3bg and
bj, 3ch vs 3cg). Again, when meta-chloro isocyanate (2e) was
3
3
employed, two regioisomeric indoloquinazolinones were
formed and the less crowded analogue predominated (Table
3
). In addition, when 2-aminoacetophenones containing a
Table 3. Substrate Scope with Respect to Both 2′-
a
Aminoacetophenones and Aryl Isocyanates
a
Reaction conditions: 1a (1 mmol), 2 (1 mmol), Pd(OAc) (10 mol
2
a
%
), Ag CO (1.5 mmol), and AcOH (3 mL) in a sealed tube at 110
Reaction conditions: 1 (1 mmol), 2 (1 mmol), Pd(OAc) (10 mol
2
3
2
°C for 24 h.
%), Ag CO (1.5 mmol), and AcOH (3 mL) in a sealed tube at 110
2
3
°
C for 24 h.
reaction, the C−Cl bond were found to be inactive in the
Pd(II)/Ag(I) catalytic system as the corresponding indoloqui-
nazolinones resulted from the cross-coupling between the C−
H bond from 1 and the C−Cl bond from isocyanates 2 were
not detected. On the other hand, two regioisomeric
indoloquinazolinones were afforded when meta-chloro iso-
cyanate (2e) was employed. Most likely because of the steric
factor, less crowded indoloquinazolinones predominated,
which the annulation mainly occurred at the para-position of
the isocyano group. In addition, disubstituted isocyanates were
also investigated and the corresponding indoloquinazolinones
were furnished in moderate yields (3ak and 3al). Furthermore,
when 2,6-dichloro isocyanate (2m) was attempted for the
reaction where both ortho-positions of the isocyano group were
blocked with a chloro group, the desired indoloquinazolinone
failed to be afforded. Instead, quinazolinone (4am) was
obtained in a high yield. This result also demonstrated that the
C−Cl bond is inactive in this Pd(II)/Ag(I) catalytic system. In
addition, several aryl isothiocyanates were examined to react
with 1a under the standard conditions but all failed.
To further explore the universality of the double annulation
reaction, another two substituted 2-aminoacetophenones (1b
and 1c) were also investigated. One contains a methyl group
and the other is a chloro-substituted analogue. In a similar
fashion to the aforesaid reaction, both electronic nature and
steric nature of the substituted isocyanates had considerable
influence on the reaction efficiency. For example, ortho-
substituted isocyanates gave lower yields by comparison to
strong electron-withdrawing group such as 5-NO or a strong
2
electron-donating group such as 3,4-dimethoxy on the
aromatic ring were investigated under the standard conditions,
the expected product was not afforded.
Furthermore, benzyl isocyanate (2n) and phenethyl
isocyanate (2o) were also examined for this double annulation
reaction. However, when the reaction was performed directly
from 1 and 2, low yields (<20%) of the desired products were
given. We then prepared the intermediates 4 using aqueous
1
7
NaOH as the catalyst as reported previously, and 4 was
carried out under standard conditions. Moderate yields of the
desired 6- and 7-membered rings were afforded (Scheme 2, eqs
1 and 2). Interestingly, when allyl isocyanate (2p) was
attempted to react with 1a under one-pot reaction conditions,
the double-annulated product was successively afforded and it
was easily converted to the more stable isomer (3ap) (Scheme
2, eq 3). Again, the corresponding product was not afforded
when 2p was replaced by allyl isothiocyanate (2q).
18
Based on the above results and those of previous studies,
a
plausible mechanism is proposed (Scheme 3). The coupling of
o-aminoacetophenone 1 and isocyanate 2 forms intermediate
A. The N-3 of urea A carried out a nucleophilic attack on the
carbonyl group and was followed by removal of one water to
afford intermediate 4. The reaction of the intermediate 4 with
Pd(OAc) performs an insertion of Pd between the methylene
2
group (affected by the lone pair of N atom next to the olefin)
and the ortho-position of the aryl ring originally from the
1
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General Procedure for the Synthesis of 3 (3aa as an Example).
-Aminoacetophenone (1a, 135 mg, 1 mmol), phenyl isocyanate (2a,
19 mg, 1 mmol), palladium acetate (22.4 mg, 0.1 mmol), silver
Scheme 2. Synthesis of Indoloquinazolinones (3) Based on
Aliphatic Isocyanates
2
1
carbonate (414 mg, 1.5 mmol), and acetic acid (3 mL) in a sealed
tube was heated at 110 °C in an oil bath for 24 h. The reaction was
monitored by TLC. Once the reaction was completed, the reaction
mixture was treated with H O (15.0 mL) and EtOAc (8.0 mL). The
2
organic and aqueous layers were then separated, and the aqueous
layer was extracted with EtOAc (3 × 8 mL). The combined organic
extracts were dried (Na SO ), then the solvent was removed under
2
4
reduced pressure, and the remaining residue was purified by column
chromatography (petroleum ether/EtOAc = 2:1). Compound 3aa
(
187 mg, 80% yield) was obtained as a white solid.
General Procedure for the Synthesis of 4 (4an as an Example).
2
-Aminoacetophenone (1a, 135 mg, 1 mmol) and benzyl isocyanate
(
2a, 133 mg, 1 mmol) in acetonitrile (3 mL) in a reaction vessel was
heated at 40 °C in an oil bath. NaOH solution (1 N, 10%) was added,
and the reaction was monitored by TLC. Once the reaction was
completed (1 h), the reaction mixture was cooled to room
Scheme 3. Possible Reaction Mechanism
temperature and treated with H O (5 mL). The precipitate was
2
filtered and washed with a mixture of acetonitrile/water. The crude
product was recrystallized from acetone/EtOH to afford a white solid
(
185 mg, 74%).
2
0
Indolo[1,2-c]quinazolin-6(5H)-one (3aa). Petroleum ether/
1
ethyl acetate = 2:1; pale brown powder (yield: 187 mg, 80%); H
NMR (400 MHz, DMSO-d ) δ 11.35 (s, 1H), 8.58−8.54 (m, 1H),
6
8
7
.11 (d, J = 8.4 Hz, 1H), 7.78−7.74 (m, 1H), 7.44 (t, J = 8.4 Hz, 1H),
13
.38−7.34 (m, 3H), 7.29−7.23 (m, 2H). C{H} NMR (101 MHz,
DMSO-d ) δ 147.6, 134.7, 134.6, 133.8, 130.1, 129.9, 124.2, 123.9,
1
6
+
23.4, 120.7, 116.0, 115.8, 114.1, 98.7. ESI-MS: m/z [M + H] 235.
8
-Fluoroindolo[1,2-c]quinazolin-6(5H)-one (3ab). Petroleum
ether/ethyl acetate = 2:1; magenta powder (yield: 129 mg, 51%);
1
H NMR (400 MHz, DMSO-d ) δ 11.35 (s, 1H), 8.11 (dd, J = 7.9,
6
2
.9 Hz, 1H), 7.58 (dd, J = 7.8, 2.3 Hz, 1H), 7.54−7.42 (m, 2H),
isocyanates, resulting in the palladacycle species C, respec-
tively. The C−C bond forming reductive elimination of the
intermediate C produces the final annulation compound 3 and
7.42−7.33 (m, 1H), 7.27 (dd, J = 9.5, 5.0 Hz, 2H), 7.18 (dd, J = 12.7,
1
3
1
7.8 Hz, 1H). C{H} NMR (101 MHz, DMSO-d ) δ 149.8 (d, J
6 C−F
3
=
254 Hz), 145.8, 136.6, 135.2, 134.4 (d, J
= 4.2 Hz), 130.3,
C−F
3
2
(
0)
125.1 (d, J
= 7.0 Hz), 124.4, 123.3, 120.3 (d, J
= 3.9 Hz), 115.6, 113.7, 111.1 (d, J
= 11.3 Hz),
= 22.2 Hz),
C−F
C−F
C−F
Pd , which can regenerate Pd(OAc) by the oxidation with
2
4
2
1
1
2
16.9 (d, J
C−F
Ag CO .
+
2
3
00.1. HRMS (ESI) m/z: calcd for C H FN O [M + H] :
1
5
10
2
53.0772, found 253.0764.
8-Chloroindolo[1,2-c]quinazolin-6(5H)-one (3ac). Petroleum
CONCLUSION
■
1
In summary, we have successfully developed an efficient Pd-
catalyzed one-pot cascade synthesis of indoloquinazolineones
from o-aminoacetophenones and aryl/aliphatic isocyanates.
The dual C−N bond and one C−C bond formations with the
generality and high selectivity utilizing readily available
substrates are the notable advantageous features of the present
method and make this protocol very attractive.
ether/ethyl acetate = 2:1; white powder (yield: 115 mg, 43%); H
NMR (400 MHz, DMSO-d ) δ 11.22 (s, 1H), 8.06 (d, J = 7.9 Hz,
6
1
1
1
1
H), 7.71 (d, J = 7.6 Hz, 1H), 7.49−7.39 (m, 3H), 7.35 (t, J = 7.7 Hz,
1
3
H), 7.29−7.19 (m, 2H). C{H} NMR (101 MHz, DMSO-d ) δ
6
46.4, 137.1, 135.2, 134.4, 130.8, 130.4, 126.5, 125.5, 124.5, 123.3,
20.7, 119.8, 115.5, 114.1, 100.4. HRMS (ESI) m/z: calcd for
+
C H ClN O [M + H] : 269.0476, found 269.0487.
1
5
10
2
8
-Methylindolo[1,2-c]quinazolin-6(5H)-one (3ad). Petroleum
1
ether/ethyl acetate = 2:1; white powder (yield: 124 mg, 50%); H
NMR (400 MHz, DMSO-d ) δ 11.15 (s, 1H), 8.08 (d, J = 7.8 Hz,
EXPERIMENTAL SECTION
■
6
General Methods. All reagents and solvents were used from
commercial sources unless otherwise stated. All raw materials are
obtained from commercial sources. All experiments were conducted
in the air. All the reactions were monitored by thin-layer
chromatography (TLC) and visualized with ultraviolet light. TLC
was performed on precoated silica gel plates (Qingdao Haiyang
Chemical Co., Ltd., China). Column chromatography was performed
on silica gel (240−400 mesh) with petroleum ether and ethyl acetate
as eluent. 1H and C NMR (400 and 101 MHz) spectra were
recorded on a Bruker Avance 400 MHz with tetramethylsilane as the
internal standard. Melting points were determined using an X-4 digital
micro melting point apparatus and are uncorrected. High-resolution
mass spectra (HRMS) were performed on a Waters SYNAPT G2-Si
mass spectrometer with quadrupole time-of-flight tandem mass
spectrometry analysis. The single crystal X-ray diffraction studies
were carried out on a Bruker Smart APEX-II CCD diffractometer
equipped with graphite monochromated Mo Kα radiation (λ =
1H), 7.58 (d, J = 7.7 Hz, 1H), 7.49−7.38 (m, 2H), 7.32−7.21 (m,
13
3H), 7.18 (d, J = 7.3 Hz, 1H), 2.86 (s, 3H). C{H} NMR (101 MHz,
DMSO-d ) δ 147.5, 135.7, 134.9, 133.6, 131.9, 129.9, 127.5, 126.4,
6
124.5, 124.1, 123.2, 118.6, 115.3, 114.5, 100.4, 24.6. HRMS (ESI) m/
+
z: calcd for C H N O [M + H] : 249.1022, found 249.1019.
1
6
13
2
Mixture of 9- and 11-Chloroindolo[1,2-c]quinazolin-6(5H)-one
(3ae and 3ae′) (2.5:1). Petroleum ether/ethyl acetate = 5:1; magenta
1
powder (yield: 188 mg, 70%); H NMR (400 MHz, DMSO-d
) δ
6
13
11.54 and 11.50 (s, 1H), 8.62 (s, 0.72H), 8.53 (d, J = 8.4 Hz, 0.28H),
8.23 (d, J = 7.6 Hz, 0.28H), 8.10 (d, J = 7.7 Hz, 0.72H), 7.77 (d, J =
1
3
8.5 Hz, 0.72H), 7.51−7.24 (m, 5.28H). C{H} NMR (101 MHz,
DMSO-d ) δ 147.4, 147.3, 135.7, 135.5, 134.9, 134.7, 134.5, 134.0,
6
132.0, 130.5, 130.2, 128.9, 127.7, 127.7, 124.6, 124.5, 124.3, 124.2,
124.2, 123.6, 123.5, 122.0, 115.9, 115.9, 115.5, 114.9, 113.9, 113.7,
+
98.5, 96.4. HRMS (ESI) m/z: calcd for C H ClN O [M + H] :
1
5
10
2
269.0472, found 269.0489.
9-Methylindolo[1,2-c]quinazolin-6(5H)-one (3af). Petroleum
1
0.71073 Å) using the ω-2θ scan mode.
ether/ethyl acetate = 4:1; white powder (yield: 201 mg, 81%); H
1
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Article
NMR (400 MHz, DMSO-d ) δ 11.36 (s, 1H), 8.41 (s, 1H), 8.08 (d, J
5,8-Dihydro-6H-isoquinolino[2,3-c]quinazolin-6-one (3an). Pe-
6
=
8.0 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.41 (td, J = 8.0, 1.6 Hz, 1H),
troleum ether/ethyl acetate = 5:1; white powder (yield: 169 mg,
1
3
1
7.32 (s, 1H), 7.28−7.19 (m, 3H), 2.61 (s, 3H). C{H} NMR (101
68%); H NMR (400 MHz, DMSO-d
6
) δ 10.63 (s, 1H), 8.18 (d, J =
MHz, DMSO-d ) δ 147.7, 134.6, 134.2, 134.0, 132.9, 129.6, 127.9,
8.0 Hz, 1H), 7.66−7.60 (m, 1H), 7.60−7.55 (m, 2H), 7.39−7.31 (m,
6
1
3
1
25.5, 124.0, 123.4, 120.3, 115.9, 115.8, 114.3, 98.6, 22.1. HRMS
3H), 7.29−7.24 (m, 2H), 7.16−7.11 (m, 1H), 5.33 (s, 2H). C{H}
NMR (101 MHz, DMSO-d ) δ 162.4, 150.7, 139.9, 137.8, 135.6,
128.9, 128.8, 128.1, 127.9, 127.5, 127.2, 126.5, 123.1, 115.7, 114.2,
+
(ESI) m/z: calcd for C H N O [M + H] : 249.1022, found
6
1
6
13
2
2
49.1028.
+
1
0-Fluoroindolo[1,2-c]quinazolin-6(5H)-one (3ag). Petroleum
43.6. HRMS (ESI) m/z: calcd for C16H N O [M + H] : 249.1022,
13 2
found 249.1036.
ether/ethyl acetate = 4:1; magenta powder (yield: 189 mg, 75%);
1
2
-Methylpyrrolo[1,2-c]quinazolin-5(6H)-one (3ap). Petroleum
H NMR (400 MHz, DMSO-d ) δ 11.60 (d, J = 2.6 Hz, 1H), 7.96 (d,
6
1
ether/ethyl acetate = 5:1; white powder (yield: 149 mg, 75%); H
J = 7.9 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.46−7.38 (m, 2H), 7.38−
1
3
NMR (400 MHz, DMSO-d ) δ 11.39 (s, 1H), 7.85 (d, J = 7.9 Hz,
7
.30 (m, 2H), 7.29−7.21 (m, 2H). C{H} NMR (101 MHz, DMSO-
6
1
1H), 7.37 (s, 1H), 7.31−7.28 (m, 1H), 7.25−7.15 (m, 2H), 6.85 (s,
d ) δ 162.8, 162.1 (d, J
= 243 Hz), 150.7, 140.3, 138.9, 135.7,
= 3.2 Hz), 131.7 (d, J
= 22.6 Hz), 115.7, 114.8, 112.7 (d, J
Hz). HRMS (ESI) m/z: calcd for C H FN O [M + H] : 253.0772,
6
C−F
13
4
3
1H), 2.20 (s, 3H). C{H} NMR (101 MHz, DMSO-d ) δ 145.68,
6
1
1
32.4 (d, J
= 8.8 Hz), 128.1, 125.2,
C−F
C−F
2
2
133.02, 129.57, 127.86, 124.46, 123.40, 122.48, 115.88, 114.50,
23.0, 116.1 (d, J
= 21.1
C−F
C−F
+
113.62, 106.59, 12.53. HRMS (ESI) m/z: calcd for C12
H] : 199.0866, found 199.0873.
H
N
11
O [M +
2
1
5
10
2
+
found 253.0767.
0-Methylindolo[1,2-c]quinazolin-6(5H)-one (3ah). Petroleum
8
-Fluoro-3-methylindolo[1,2-c]quinazolin-6(5H)-one (3bb). Pe-
1
1
troleum ether/ethyl acetate = 4:1; magenta powder (yield: 120 mg,
ether/ethyl acetate = 4:1; white powder (yield: 196 mg, 79%); H
1
4
8
1
5%); H NMR (400 MHz, DMSO-d ) δ 11.29 (s, 1H), 7.97 (d, J =
6
NMR (400 MHz, DMSO-d ) δ 11.39 (s, 1H), 8.44 (d, J = 8.4 Hz,
6
.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.36−7.31 (m,
1
H), 8.10 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.44 (t, J = 7.6 Hz, 1H),
.32−7.23 (m, 3H), 7.20 (d, J = 8.5, 1.7 Hz, 1H), 2.48 (s, 3H).
H), 7.13 (dd, J = 8.0, 12.4 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 7.05 (s,
7
13
1
H), 2.37 (s, 3H). C{H} NMR (101 MHz, DMSO-d ) δ 149.8 (d,
13
6
C{H} NMR (101 MHz, DMSO-d ) δ 147.5, 134.8, 134.6, 132.9,
1
3
6
JC−F = 254 Hz), 145.9, 140.3, 136.7, 135.2, 134.5 (d, J
= 4.2 Hz),
= 10.9 Hz),
C−F
1
9
2
32.1, 130.4, 129.8, 124.9, 124.1, 123.4, 120.3, 115.8, 115.6, 114.1,
3
2
1
1
9
2
25.1 (d, J
= 7.5 Hz), 124.5, 124.3, 120.2 (d, J
= 3.0 Hz), 115.5, 111.2, 110.9 (d, J
9.3, 21.7. HRMS (ESI) m/z: calcd for C H FN O [M + H] :
+
C−F
C−F
C−F
8.4, 21.7. HRMS (ESI) m/z: calcd for C H N O [M + H] :
4
2
1
6
13
2
16.7 (d, J
= 22.5 Hz),
C−F
49.1022, found 249.1030.
0-Methoxyindolo[1,2-c]quinazolin-6(5H)-one (3ai). Petroleum
+
1
6
12
2
1
67.0928, found 267.0927.
-Chloro-3-methylindolo[1,2-c]quinazolin-6(5H)-one (3bc). Pe-
troleum ether/ethyl acetate = 4:1; white powder (yield: 124 mg,
1
ether/ethyl acetate = 4:1; white solid (yield: 203 mg, 77%); H NMR
8
(
(
4
400 MHz, DMSO-d ) δ 11.34 (s, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.07
6
d, J = 7.6 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.22−7.29 (m,
1
4
8
4%); H NMR (400 MHz, DMSO-d ) δ 11.16 (s, 1H), 7.94 (d, J =
6
1
3
H), 6.97 (dd, J = 8.8, 2.8 Hz, 1H), 3.83 (s, 3H). C{H} NMR (101
.0 Hz, 1H), 7.68 (dd, J = 7.6, 1.3 Hz, 1H), 7.42−7.29 (m, 4H),
MHz, DMSO-d ) δ 156.5, 147.4, 135.0, 134.6, 131.1, 129.8, 128.5,
13
6
7.08−7.04 (m, 1H), 7.02 (s, 1H), 2.37 (s, 3H). C{H} NMR (101
1
24.0, 123.4, 116.6, 115.8, 113.9, 112.8, 102.6, 98.5, 55.8. HRMS
MHz, DMSO-d ) δ 146.6, 140.5, 137.3, 135.3, 134.5, 130.7, 126.3,
6
+
(ESI) m/z: calcd for C H N O [M + H] : 265.0972, found
16 13 2 2
125.4, 124.5, 124.4, 120.7, 119.6, 115.4, 111.6, 99.7, 21.7. HRMS
2
65.0958.
+
(
2
ESI) m/z: calcd for C H ClN O [M + H] : 283.0633, found
1
6
12
2
1
0-Chloroindolo[1,2-c]quinazolin-6(5H)-one (3aj). Petroleum
83.0617.
1
ether/ethyl acetate = 4:1; white solid (yield: 188 mg, 70%); H
3
,9-Dimethylindolo[1,2-c]quinazolin-6(5H)-one (3bf). Petroleum
1
NMR (400 MHz, DMSO-d ) δ 11.49 (s, 1H), 8.53 (d, J = 8.8 Hz,
6
ether/ethyl acetate = 4:1; white powder (yield: 191 mg, 73%); H
1H), 8.10 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.46 (t, J = 8.0
NMR (400 MHz, DMSO-d ) δ 11.28 (s, 1H), 8.38 (s, 1H), 7.94 (d, J
6
Hz, 1H), 7.36 (dd, J = 8.8, 2.0 Hz, 1H), 7.34 (s, 1H), 7.27 (t, J = 8.8
= 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.18 (d, J = 8.0
Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.04 (s, 1H), 2.49 (s, 3H), 2.36 (s,
Hz, 2H). 13C{H} NMR (101 MHz, DMSO-d ) δ 147.3, 136.0, 134.8,
6
1
3
1
1
2
32.2, 131.5, 130.4, 128.4, 124.3, 123.6, 123.3, 119.9, 117.3, 115.9,
3H). C{H} NMR (101 MHz, DMSO-d ) δ 147.8, 139.5, 134.6,
6
+
13.7, 98.0. HRMS (ESI) m/z: calc. for C H ClN O [M + H] :
134.1, 134.1, 132.6, 128.0, 125.4, 124.5, 123.9, 120.2, 115.9, 115.7,
1
5
10
2
69.0476, found 269.0486.
111.8, 97.8, 22.1, 21.7. HRMS (ESI) m/z: calcd for C H N O [M +
17
15
2
+
9
,10-Difluoroindolo[1,2-c]quinazolin-6(5H)-one (3ak). Petroleum
H] : 263.1179, found 263.1193.
1
ether/ethyl acetate = 4:1; white powder (yield: 194 mg, 72%); H
10-Fluoro-3-methylindolo[1,2-c]quinazolin-6(5H)-one (3bg). Pe-
NMR (400 MHz, DMSO-d ) δ 11.43 (s, 1H), 8.10 (d, J = 8.0 Hz,
troleum ether/ethyl acetate = 4:1; magenta powder (yield: 176 mg,
6
1
1
1
1
H), 7.48 (t, J = 7.2 Hz, 1H), 7.46 (s, 1H), 7.41 (dd, J = 7.6, 2.4 Hz,
H), 7.27 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.17 (ddd, J =
66%): H NMR (400 MHz, DMSO-d
6
) δ 11.39 (s, 1H), 8.52 (dd, J =
9.0, 4.9 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.50 (dd, J = 9.5, 2.6 Hz,
1
3
2.1, 9.7, 2.4 Hz, 1H). C{H} NMR (101 MHz, DMSO-d ) δ 159.0
1H), 7.26 (s, 1H), 7.20−7.11 (m, 1H), 7.11−7.03 (m, 2H), 2.37 (s,
6
1
2
1
13
1
(
dd, J
= 239.7, J
= 10.3 Hz), 149.5 (dd, J
= 257.0 Hz,
= 12.2 Hz,
= 11.0 Hz),
3H). C{H} NMR (101 MHz, DMSO-d
6
) δ 159.5 (d, JC−F = 231
C−F
C−F
C−F
2
3
3
JC−F = 14.2 Hz), 145.5, 138.2, 135.2, 134.3 (dd, J
Hz), 147.4, 140.3, 136.4, 134.9, 131.3 (d, JC−F = 10.6 Hz), 130.3,
124.7, 124.3, 117.1 (d, J
25.1 Hz), 105.6 (d, J
HRMS (ESI) m/z: calcd for C H FN O [M + H] : 267.0928, found
C−F
3
2
4J
3
= 9.6 Hz), 115.8, 111.2, 110.9 (d, J
=
= 5.5 Hz), 130.7, 124.6, 123.4, 117.3 (d, J
C−F
C−F
C−F
C−F
2
4
2
3
= 23.5 Hz), 97.7 (d, J
= 4.3 Hz), 21.7.
C−F
C−F
1
15.6, 113.3, 102.0 (dd, J
= 23.5 Hz, J
= 4.2 Hz), 100.4, (d,
C−F
C−F
+
2
16 12 2
JC−F = 27.3 Hz), 100.0. HRMS (ESI) m/z: calcd for C H F N O
15
9
2
2
+
267.0934.
,10-Dimethylindolo[1,2-c]quinazolin-6(5H)-one (3bh). Petrole-
[
M + H] : 271.0677, found 271.0683.
,10-Difluoroindolo[1,2-c]quinazolin-6(5H)-one (3al). Petroleum
3
8
1
um ether/ethyl acetate = 4:1; white powder (yield: 199 mg, 76%); H
1
ether/ethyl acetate = 4:1; magenta powder (yield: 151 mg, 56%); H
NMR (400 MHz, DMSO-d ) δ 11.27 (s, 1H), 8.40 (d, J = 8.4 Hz,
6
NMR (400 MHz, DMSO-d ) δ 11.42 (s, 1H), 8.10 (d, J = 7.6 Hz,
6
1
8
H), 7.95 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 7.18 (s, 1H), 7.15 (d, J =
1
1
1
H), 7.47 (t, J = 7.2 Hz, 1H), 7.45 (s, 1H), 7.40 (dd, J = 8.0, 2.4 Hz,
.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 7.05 (s, 1H), 2.45 (s, 3H), 2.37
H), 7.26 (d, J = 8.0 Hz, 1H), 7.25 (t, J = 7.2 Hz, 1H), 7.17 (ddd, J =
13
(s, 3H). C{H} NMR (101 MHz, DMSO-d ) δ 147.6, 139.7, 134.7,
1
3
6
2, 9.6, 2.4 Hz, 1H). C{H} NMR (101 MHz, DMSO-d ) δ 159.0
6
1
1
32.8, 132.0, 130.5, 124.6, 124.5, 124.0, 120.2, 115.7, 115.5, 111.7,
06.6, 97.6, 21.7, 21.7. HRMS (ESI) m/z: calcd for C H N O [M +
1
3
1
(
dd, J
= 239 Hz, J
= 10.1 Hz), 149.5 (dd, J
= 256 Hz,
= 11.9 Hz,
= 10.9 Hz),
C−F
C−F
C−F
C−F
3
2
17 15
2
JC−F = 13.9 Hz), 145.5, 138.2, 135.2, 134.3 (dd, J
+
H] : 263.1179, found 263.1178.
4J
= 5.3 Hz), 130.7, 124.5, 123.4, 117.3 (d, J
3
C−F
C−F
10-Chloro-3-methylindolo[1,2-c]quinazolin-6(5H)-one (3bj). Pe-
2
4
1
15.6, 113.2, 102.0 (dd, J
= 22.9 Hz, J
= 4.5 Hz), 100.3 (dd,
troleum ether/ethyl acetate = 4:1; white powder (yield: 172 mg,
C−F
C−F
2
1
JC−F = 29.3, 26.7 Hz), 100.1. HRMS (ESI) m/z: calcd for
61%); H NMR (400 MHz, DMSO-d ) δ 11.45 (s, 1H), 8.52 (d, J =
6
+
C H F N O [M + H] : 271.0677, found 271.0692.
8.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.34
15
9
2
2
1
452
https://dx.doi.org/10.1021/acs.joc.0c02155
J. Org. Chem. 2021, 86, 1448−1455

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(
(
1
1
dd, J = 8.8, 2.2 Hz, 1H), 7.27 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.07
= 8.0 Hz, 1H). 13C{H} NMR (101 MHz, DMSO-d ) δ 148.4, 140.2,
6
1
3
s, 1H), 2.38 (s, 3H). C{H} NMR (101 MHz, DMSO-d ) δ 147.4,
136.0, 135.0, 133.8, 131.4, 131.2, 129.8, 124.8, 123.0, 115.9, 115.6,
6
+
40.4, 136.3, 135.0, 132.2, 131.7, 128.3, 124.8, 124.3, 123.0, 121.1,
84.7. HRMS (ESI) m/z: calcd for C H Cl N O [M + H] :
1
5
11
2
2
19.7, 117.2, 115.9, 97.3, 21.7. HRMS (ESI) m/z: calcd for
305.0243, found 305.0237.
3-Benzyl-4-methylene-3,4-dihydroquinazolin-2(1H)-one (4an).
White powder (yield: 185 mg, 74%); H NMR (400 MHz, DMSO-
+
17
C H ClN O [M + H] : 283.0633, found 283.0631.
16
12
2
1
3
-Methyl-8,9-dihydrobenzo[4,5]azepino[1,2-c]quinazolin-6(5H)-
one (3bo). Petroleum ether/ethyl acetate = 5:1; white powder (yield:
d ) δ 10.28 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.36−7.19 (m, 6H),
6
1
1
35 mg, 49%); H NMR (400 MHz, DMSO-d ) δ 11.39 (s, 1H), 7.82
7.00−6.92 (m, 2H), 5.01 (s, 2H), 4.82 (d, J = 2.4 Hz, 1H), 4.12 (d, J
6
1
3
(
(
2
d, J = 8.0 Hz, 1H), 7.34−7.27 (m, 2H), 7.27−7.18 (m, 3H), 7.03
= 2.5 Hz, 1H). C{H} NMR (101 MHz, DMSO-d ) δ 150.6, 140.2,
6
dd, J = 8.1, 1.6 Hz, 1H), 6.98−6.93 (m, 1H), 4.09 (t, J = 7.92 Hz,
137.5, 136.1, 130.7, 128.9, 127.2, 126.8, 124.4, 122.6, 116.5, 115.1,
1
3
+
H), 2.87 (t, J = 7.76 Hz, 2H), 2.37 (s, 3H). C{H} NMR (101
85.7, 46.3. ESI-MS: m/z [M + H] : 251.
MHz, DMSO-d ) δ 162.1, 150.6, 146.1, 139.9, 139.1, 132.7, 129.1,
7-Methyl-4-methylene-3-phenethyl-3,4-dihydroquinazolin-
6
1
1
28.9, 128.8, 127.8, 126.8, 124.3, 115.9, 115.3, 111.9, 41.6, 33.8, 21.9.
2(1H)-one (4bo). White powder (yield: 89 mg, 32%); H NMR (400
+
HRMS (ESI) m/z: calcd for C H N O [M + H] : 277.1335, found
MHz, DMSO-d ) δ 10.15 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.34−
6
1
8
17
2
2
77.1332.
-Chloro-8-fluoroindolo[1,2-c]quinazolin-6(5H)-one (3cb). Pe-
troleum ether/ethyl acetate = 4:1; magenta powder (yield: 152 mg,
7.26 (m, 4H), 7.25−7.19 (m, 1H), 6.80 (dd, J = 8.3, 1.7 Hz, 1H), 6.69
(t, J = 1.3 Hz, 1H), 4.88 (d, J = 2.4 Hz, 1H), 4.36 (d, J = 2.5 Hz, 1H),
2
3.93 (t, J = 8.12 Hz, 2H), 2.88 (t, J = 7.84 Hz, 2H), 2.25 (s, 3H).
1
13
5
3%); H NMR (400 MHz, DMSO-d ) δ 11.44 (s, 1H), 8.23 (d, J =
C{H} NMR (101 MHz, DMSO-d ) δ 150.0, 140.3, 140.2, 139.3,
6
6
2
.4 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.47
136.0, 129.1, 128.9, 126.7, 124.5, 123.6, 115.0, 114.0, 83.3, 44.2, 31.8,
+
(
1
dd, J = 8.7, 2.3 Hz, 1H), 7.40−7.33 (m, 1H), 7.24 (d, J = 8.7 Hz,
21.3. HRMS (ESI) m/z: calcd for C18H N O [M + H] : 279.1492,
18 2
1
3
H), 7.18 (dd, J = 12.0, 7.2 Hz, 1H). C{H} NMR (101 MHz,
found 279.1523.
1
DMSO-d ) δ 149.8 (d, J
= 254.2 Hz), 145.5, 135.3, 134.2 (d,
3-Benzyl-6-chloro-4-methylene-3,4-dihydroquinazolin-2(1H)-
6
C−F
17
1
3
3
one (4cn). White powder (yield: 261 mg, 92%); H NMR (400
JC−F = 4.2 Hz), 134.0, 130.0, 127.3, 125.3 (d, J
= 6.9 Hz), 123.7,
C−F
2
2
MHz, DMSO-d ) δ 10.44 (s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.33 (dd,
120.5 (d, J
= 11.2 Hz), 117.4, 117.2, 115.3, 111.5 (d, JC−F = 22.5
6
C−F
+
J = 8.8, 6.8 Hz, 3H), 7.27−7.21 (m, 3H), 6.95 (d, J = 8.6 Hz, 1H),
.99 (s, 2H), 4.93 (d, J = 2.8 Hz, 1H), 4.17 (d, J = 2.8 Hz, 1H).
Hz), 101.4. HRMS (ESI) m/z: calcd for C H ClFN O [M + H] :
1
5
9
2
4
2
87.0382, found 287.0379.
Mixture of 2,9- and 2,11-Dichloroindolo[1,2-c]quinazolin-6(5H)-
1
3
C{H} NMR (101 MHz, DMSO-d ) δ 150.3, 139.1, 137.3, 135.1,
6
one (3ce and 3ce′) (2.9:1). Petroleum ether/ethyl acetate = 5:1;
130.5, 129.0, 127.3, 126.8, 126.6, 123.9, 118.2, 117.0, 87.4, 46.3. ESI-
1
+
white powder (yield: 181 mg, 60%); H NMR (400 MHz, DMSO-d )
MS: m/z [M + H] : 285.
6
δ 11.58 and 11.54 (s, 1H), 8.50 and 8.47 (s, 1H), 8.33 and 8.17 (d, J
2.0 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.5−7.35 (m, 3H), 7.25 and
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02155.
1
3
■
6
*
+
1
5
9
2
2
1H NMR, 13C NMR, and X-ray crystallographic data
(PDF)
2
1
Accession Codes
6
CCDC 2023639 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
6
C−F
3
236 Hz), 147.0, 134.9, 133.7, 130.9 (d, J
= 10.6 Hz), 130.4,
C−F
3
= 9.5 Hz), 115.3, 111.7 (d,
C−F
2
4
= 23.8 Hz), 99.7 (d, J
= 4.4 Hz).
C−F
C−F
+
1
5
9
2
found 287.0398.
-Chloro-10-methylindolo[1,2-c]quinazolin-6(5H)-one (3ch). Pe-
troleum ether/ethyl acetate = 4:1; white powder (yield: 200 mg,
AUTHOR INFORMATION
2
■
Corresponding Author
1
7
8
1
2
1
1
1%); H NMR (400 MHz, DMSO-d ) δ 11.45 (s, 1H), 8.41 (d, J =
6
Yongmin Ma − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China; School of
Pharmaceutical Science, Zhejiang Chinese Medical University,
Hangzhou 310053, P R China; orcid.org/0000-0002-
9521-767X; Email: yongmin.ma@tzc.edu.cn
.4 Hz, 1H), 8.23 (s, 1H), 7.54 (s, 1H), 7.45 (dd, J = 8.8, 2.4 Hz,
H),7.43 (s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H),
.46 (s, 3H). 13C{H} NMR (101 MHz, DMSO-d ) δ 147.2, 133.5,
6
33.1, 132.2, 130.2, 129.5, 127.4, 125.4, 123.4, 120.6, 117.6, 115.8,
15.6, 108.0, 99.8, 21.6. HRMS (ESI) m/z: calcd for C H ClN O
1
6
12
2
+
[
M + H] : 283.0633, found 283.0627.
-Chloro-5,8-dihydro-6H-isoquinolino[2,3-c]quinazolin-6-one
3cn). Petroleum ether/ethyl acetate = 5:1; white powder (yield: 161
2
Authors
(
1
mg, 57%); H NMR (400 MHz, DMSO-d ) δ 11.70 (s, 1H), 7.88 (d,
Yuxin Ding − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China; School of
Pharmaceutical Science, Zhejiang Chinese Medical University,
Hangzhou 310053, P R China
Huihui Yan − School of Pharmaceutical Science, Zhejiang
Chinese Medical University, Hangzhou 310053, P R China
Rener Chen − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China
6
J = 2.5 Hz, 1H), 7.73 (dd, J = 8.7, 2.5 Hz, 1H), 7.33−7.30 (m, 4H),
1
3
7
6
.25−7.21 (m, 2H), 5.08 (s, 2H). C{H} NMR (101 MHz, DMSO-
d ) δ 161.5, 150.4, 138.8, 137.6, 135.5, 130.5, 128.9, 128.8, 128.0,
1
27.6, 127.3, 127.0, 126.8, 118.0, 115.6, 43.8. HRMS (ESI) m/z:
+
calcd for C H ClN O [M + H] : 283.0633, found 283.0636.
16
12
2
3
-(2,6-Dichlorophenyl)-4-methylene-3,4-dihydroquinazolin-
1
2
(1H)-one (4am). White powder (yield: 271 mg, 89%); H NMR
(
2
400 MHz, DMSO-d ) δ 7.73 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz,
H), 7.53 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.04 (t, J = 8.0
6
Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 4.83 (d, J = 2.4 Hz, 1H), 3.38 (d, J
1
453
https://dx.doi.org/10.1021/acs.joc.0c02155
J. Org. Chem. 2021, 86, 1448−1455

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Xuqiong Xiao − Key Laboratory of Organosilicon Chemistry
and Material Technology of Ministry of Education,
Hangzhou Normal University, Hangzhou 311121, P R
China; orcid.org/0000-0001-8424-9898
Zhiming Wang − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China; orcid.org/0000-
thiazolo 2,3-b quinazolinones: Synthesis, characterization and
evaluation of anticancer and antimicrobial activities. Bioorg. Med.
Chem. Lett. 2014, 24, 4239−4242. (b) Long, S.; Resende, D. I. S. P.;
Kijjoa, A.; Silva, A. M. S.; Pina, A.; Fernandez-Marcelo, T.;
Vasconcelos, M. H.; Sousa, E.; Pinto, M. M. M. Antitumor Activity
of Quinazolinone Alkaloids Inspired by Marine Natural Products.
Mar. Drugs 2018, 16, 261. (c) Sonawane, V.; Mohd Siddique, M. U.;
Jadav, S. S.; Sinha, B. N.; Jayaprakash, V.; Chaudhuri, B. Cink4T, a
quinazolinone-based dual inhibitor of Cdk4 and tubulin polymer-
ization, identified via ligand-based virtual screening, for efficient
anticancer therapy. Eur. J. Med. Chem. 2019, 165, 115−132.
0
002-6583-3826
Lei Wang − Institute of Advanced Studies and School of
Pharmaceutical and Chemical Engineering, Taizhou
University, Taizhou 318000, P R China
(5) (a) Ashok, P.; Chander, S.; Chow, L. M. C.; Wong, I. L. K.;
Singh, R. P.; Jha, P. N.; Sankaranarayanan, M. Synthesis and in-vitro
anti-leishmanial activity of (4-arylpiperazin-1-yl) (1-(thiophen-2-yl)-
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02155
9H-pyrido 3,4-b indol-3-yl) methanone derivatives. Bioorg. Chem.
2
017, 70, 100−106. (b) Chripkova, M.; Zigo, F.; Mojzis, J.
Author Contributions
Y.D. and H.Y. contributed equally.
Antiproliferative Effect of Indole Phytoalexins. Molecules 2016, 21,
#
1626. (c) Kornsakulkarn, J.; Saepua, S.; Srijomthong, K.; Rachtawee,
Notes
P.; Thongpanchang, C. Quinazolinone alkaloids from actinomycete
Streptomyces sp BCC 21795. Phytochem. Lett. 2015, 12, 6−8.
The authors declare no competing financial interest.
(6) (a) Garcellano, R. C.; Moinuddin, S. G. A.; Young, R. P.; et al.
Isolation of Tryptanthrin and Reassessment of Evidence for Its
Isobaric Isostere Wrightiadione in Plants of the Wrightia Genus. J.
Nat. Prod. 2019, 82, 440−448. (b) Kaur, R.; Manjal, S. K.; Rawal, R.
K.; Kumar, K. Recent synthetic and medicinal perspectives of
tryptanthrin. Bioorg. Med. Chem. 2017, 25, 4533−4552.
ACKNOWLEDGMENTS
Financial support from the Leading Innovative and Entrepre-
neur Team Introduction Program of Zhejiang (Grant No.
■
2
019R01005) is gratefully acknowledged.
(7) (a) Shankar, G. M.; Antony, J.; Anto, R. J. Quercetin and
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