Silver Triflate Catalyzed Synthesis of Isoquinolino[2,1- a ]quinazo-lino[3,2- c ]quinazoline Derivatives via Alkyne Hydroamination

Article abstract of DOI:10.1055/s-0037-1611808

Using 2-(2-aminophenyl)quinazolin-4(3 H)-one and 2-(2-phenylethynyl)benzaldehyde as the reactants, silver triflate (AgOTf) was proved to be an efficient catalyst to promote not only quinazoline cyclization, but also the intramolecular hydroamination of alkyne for the synthesis of 6-aryl-17 H,18a H -isoquinolino[2,1- a ]quinazolino[3,2- c ]quinazolin-17-one derivatives in high yields.

Full text of DOI:10.1055/s-0037-1611808

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
paper
A
en
Synthesis
W.-C. Pan et al.
Paper
Silver Triflate Catalyzed Synthesis of Isoquinolino[2,1-a]quinazo-
lino[3,2-c]quinazoline Derivatives via Alkyne Hydroamination
Wan-Chen Pan
Mei-Mei Zhang
O
O
Jian-Quan Liu*
CHO
NH
NH2
AgOTf
N
N
Ar
Xiang-Shan Wang*
0
0
0
0-0
0
0
2-
0
0
7
7-7
8
1
9
+
N
N
School of Chemistry and Materials Science, Jiangsu Key Laboratory
of Green Synthesis for Functional Materials, Jiangsu Normal Univer-
sity, Xuzhou Jiangsu 221116, P. R. China
Ar
hexacyclic heterocycle
one isoquinoline, two quinazolines
2 examples
9–89% yield
xswang@jsnu.edu.cn
2
7
Received: 26.11.2018
Accepted after revision: 01.04.2019
Published online: 24.04.2019
quinazoline moiety. However, a costly Pd was used as the
catalyst. In our previous paper, cyclization of 2-(o-amino-
phenyl)-4(3H)-quinazolinone with aromatic aldehydes was
DOI: 10.1055/s-0037-1611808; Art ID: ss-2018-h0793-op
developed as a very rapid method to build quinazolino-
Abstract Using 2-(2-aminophenyl)quinazolin-4(3H)-one and 2-(2-
phenylethynyl)benzaldehyde as the reactants, silver triflate (AgOTf) was
proved to be an efficient catalyst to promote not only quinazoline cy-
clization, but also the intramolecular hydroamination of alkyne for the
quinazoline derivatives (Scheme 1b).9
Bahadorikhalili's work
O
O
N
synthesis
of
6-aryl-17H,18aH-isoquinolino[2,1-a]quinazolino[3,2-
N
N
c]quinazolin-17-one derivatives in high yields.
Pd
(a)
N
H
Key words isoquinoline, quinazoline, hydroamination, AgOTf, synthe-
sis
Br
isoquinolino[1,2-b]quinazolin-8-one
Previous work
O
Isoquinoline and quinazoline are both bicyclic nitroge-
nous heterocycles and medicinal molecular skeleton. They
O
N
Ar
1
H
N
NH2
ArCHO
Cat.
N
NH
(b)
both possess a benzene ring and a six-membered heterocy-
cle but bearing different numbers of nitrogen atoms. Along
with the difference in their structures, it was reported that
they also indicated various kinds of bioactivities. As we all
know, the isoquinoline moieties are well known for their
N
quinazolino[4,3-b]quinazolin-8-one
This work
2
anti-inflammatory activities, while quinazolines are fa-
O
O
3
mous for their antitumor activities. Some of them have
CHO
(c)
Ar
NH
NH2
AgOTf
N
N
+
been developed as the clinical drugs, for example, atracuri-
4
5
N
um besylate and vandetanib.
N
Ar
According to the development of medicinal chemistry,
more and more attention has been devoted to the combina-
tion of two different types of heterocycles. The aim is to ob-
tain structurally diversified heterocycles to further enhance
the medicinal effect, or gain novel anti-inflammatory or an-
titumor activity via bioscreening. In view of the importance
of isoquinoline and quinazoline, lots of novel procedures
have been established for the construction of isoquinolino-
hexacyclic heterocycle
one isoquinoline, two quinazolines
Scheme 1 Approach to heterocycles containing isoquinoline and
quinazoline
To the best of our knowledge, there is no study concern-
ing about the synthesis of isoquinolino[2,1-a]quinazoli-
no[3,2-c]quinazolines, and it is a novel fused hexacyclic
moiety bearing both isoquinoline and two quinazolines. In
our investigation, hydroamination of alkyne is an efficient
method to build nitrogenous six-membered ring especially
for isoquinoline analogue.10 Therefore, we reasoned that the
6
7
quinazolines and quinazolinoquinazolines in recent years.
8
In 2018, Bahadorikhalili group reported a palladium-cata-
lyzed intramolecular Heck reaction of 3-allyl-2-(2-bro-
mophenyl)-2,3-dihydroquinazolin-4(1H)-ones
(Scheme
1a). It was an efficient isoquinoline construction based on
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

B
Synthesis
W.-C. Pan et al.
Paper
first condensation cyclization, and then hydroamination cy-
clization would take place (Scheme 1c) when 2-(o-amino-
phenyl)quinazolin-4(3H)-one (1a) was submitted to react
with 2-(2-phenylethynyl)benzaldehyde (2a). Taking this
good idea, we performed the designed reaction in our lab
catalyzed by silver triflate (AgOTf), which is a powerful re-
agent to activate the C≡C bond. To our delight, the desired
twice cascade cyclizations occurred to give 6-phenyl-
Table 1 Optimization of the Reaction Conditionsa
O
O
N
CHO
NH
NH2
Cat.
N
N
Ph
11
+
solvent
N
Ph
1a
2a
3a
1
1
7H,18aH-isoquinolino[2,1-a]quinazolino[3,2-c]quinazolin-
7-one (3a) in high yield (Table 1). As our ongoing study to-
Entry
Catalyst (mol%)
Solvent
Yield (%)b
12
ward polycyclic heterocycles, herein, we would like to re-
port the synthesis of fused hexacyclic isoquinolino[2,1-
a]quinazolino[3,2-c]quinazolines catalyzed by AgOTf.
As depicted in Table 1, we began our study to optimize
the reaction conditions using the reaction of 1a and 2a as a
model. The first screening was to change various kinds of
catalysts. The Lewis acids, such as CuI, CuBr, Cu(OTf)2,
Yb(OTf) , Sc(OTf) , Zn(OTf) , Bi(OTf) , AgOAc, and AgOTf
1
2
3
4
5
6
7
8
9
10
CuI (5)
DMF
trace
trace
trace
72
CuBr (5)
DMF
Cu(OTf)
2
(5)
(5)
DMF
Yb(OTf)
3
DMF
Sc(OTf) (5)
3
DMF
69
Zn(OTf) (5)
2
DMF
trace
32
3
3
2
3
Bi(OTf)
3
(5)
DMF
were all tested in this reaction. Ag(I) indicated the best cat-
alytic effect, and the next was Yb(III) in the metal cations.
AgOAc (5)
AgOTf (5)
AgOTf (10)
AgOTf (1)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
DMF
59
–
DMF
83
The best anion was TfO for this conversion, and 5 mol%
AgOTf gave an obviously higher yield (83%). Zn(OTf) , Cu(I),
DMF
83
2
and Cu(II) almost had no catalytic activity for this cascade
reaction. Furthermore, 5 mol% AgOTf was enough to pro-
mote the twice cyclizations, and the reaction gave the same
yield when 10 mol% AgOTf was used. However, the yield de-
creased obviously using 1 mol% amount of AgOTf. In the fol-
lowing solvent screening, it was found that it had a slight
effect on the yields. To our delight, the reaction yield could
be improved to 86% when DMSO was used as a solvent. Fur-
thermore, the aprotic polar solvents, such as DMF, DMA,
and DMSO were in favor of the reaction, while toluene and
11
12
13
14
15
DMF
52
DME
69
DMSO
DMA
1,4-dioxane
toluene
85
83
78
16
72
a
Reaction conditions: 1a (118 mg, 0.5 mmol), 2a (113 mg, 0.55 mmol),
solvent (5.0 mL), 100 °C, 10 h.
b
Isolated yield.
1
,4-dioxane led to slightly lower yields.
Through above screening, we obtained the optimal re-
arylethynyl)benzaldehydes 2 to react with 1a one by one
under the optimal reaction conditions. Compound 2 bear-
ing two benzene rings whether carrying electron-donating
substituent (methyl, methoxy, ethyl, pentyl, and ethoxy) or
electron-drawing group (fluoro and chloro), all underwent
the condensation and hydroamination to give 3a–m in good
to high yields (Scheme 2).
action condition that was catalyzed by 5 mol% AgOTf in
DMSO at 100 °C. The next step was to test the adaptability
of the two substances. In our lab, the 2-(o-aminophenyl)-
4(3H)-quinazolinone (1a) was used as an unchanged reac-
tant first, and varied the different substituents on the 2-(2-
R
O
O
CHO
NH
NH2
AgOTf
N
N
Ar
+
R
DMSO
N
N
Ar
1a
2
3
R
3
a, R = H, 85%
3b, R = 3-Cl, 89%
c, R = 3-F, 82%
Ph 3d, R = 3-Me, 78%
e, R = 2-Cl, 84%
3f, R = 2-F, 85%
g, R = 2,3-OCH2O, 86%
3h, Ar = 3-ClC6H4, 89%
3i, Ar = 4-MeC6H4, 83%
O
O
3
3
3
3
j, Ar = 4-EtC6H4, 83%
N
N
N
N
Ar
k, Ar = 4-PentylC6H4, 84%
l, Ar = 4-MeOC6H4, 88%
3
N
N
3
3m, Ar = 4-EtOC6H4, 82%
Scheme 2 The cascade reaction with various ethynylbenzaldehydes. Reagents and conditions: 1a (118 mg, 0.5 mmol), 2 (0.55 mmol), AgOTf (6 mg,
.025 mmol), DMSO (5.0 mL), 100 °C. Isolated yields are shown.
0
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W.-C. Pan et al.
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However, when 1-[2-(phenylethynyl)phenyl]ethan-1-
one or 1-[2-(prop-1-yn-1-yl)phenyl]ethan-1-one was used
as a reactant to react with 1a under the optimal reaction
conditions (Scheme 3), no reaction was observed by TLC.
Perhaps, the activity of ketone is lower than that of alde-
hyde.
The structure of 3l was unambiguously confirmed by X-
ray diffraction analysis, and its crystal structure is shown in
Figure 1. X-ray diffraction analysis of 3l indicates that the
newly formed quinazoline moiety is slightly distorted, and
the pyrimidine adopts a skew boat confirmation. The atoms
N3 and C22 deviate the defined plane (N1, C8–C14) by
sation cyclization of 2-aminobenzamides with 2-nitrobenz-
aldehyde followed by a reductive reaction of nitro group us-
ing 85% hydrazine hydrate as a reductant in the presence of
FeCl . Subsequently, 1 was submitted to react with 2 at 100
3
°C in DMSO using 5 mol% AgOTf as a catalyst, and afforded
3n–v in 79–87% yields as expected. The substituents on two
benzene rings also had no obvious influence on the reac-
tion yields (Scheme 4).
In conclusion, an efficient method for the synthesis of 6-
aryl-17H,18aH-isoquinolino[2,1-a]quinazolino[3,2-c]quin-
azolin-17-ones has been established via a reaction of 2-(2-
aminophenyl)quinazolin-4(3H)-ones
and
2-(2-aryl-
0
.271(2) and 0.679(2) Å, respectively. The isoquinoline is
ethynyl)benzaldehydes. AgOTf proved to be an efficient cat-
alyst to activate the C=N and C≡C bonds, which undergo
two cyclization leading to hexacyclic heterocycles contain-
ing both isoquinoline and two quinazoline moieties.
also a twisted moiety while the pyridine ring adopts a skew
confirmation. The atoms C1–C6 and C22–C23 are coplanar
with mean deviation being 0.029(2) Å while C7 and C8 de-
viate from the basal plane by 0.423(2) and 0.817(2) Å, re-
spectively. Another quinazoline ring is a plane moiety. X-
ray diffraction analysis also reveals that the newly formed
quinazoline ring is nearly parallel to another quinazoline
forming a dihedral angle of 10.6 (1)°, and it is nearly per-
pendicular to isoquinoline ring forming a dihedral angle of
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded on a Tensor 27 spectrophotometer in
1
KBr pellets. H NMR spectra were obtained from a solution in CDCl3
with Me Si as internal standard using a Bruker 400 spectrometer.
4
HRMS analyses were carried out using a Bruker micro-TOF-Q-MS an-
alyzer. All the chemicals were obtained from Beijing InnoChem Sci-
ence & Technology Co., Ltd except for DMF and EtOH, which were pur-
chased from Sinopharm Chemical Reagent Co., Ltd.
8
9.8 (1)°. In addition, the isoquinoline ring makes a dihe-
dral angle of 22.9 (1)° to its connected benzene ring (C24–
C29).
6
-Phenylisoquinolino[2,1-a]quinazolino[3,2-c]quinazolin-
17(18aH)-one (3a); Typical Procedure
-(2-Aminophenyl)quinazolin-4(3H)-one (1a; 118 mg, 0.5 mmol), 2-
O
O
O
N
2
NH
NH2
AgOTf
DMSO
N
N
R
+
(phenylethynyl)benzaldehyde (2a; 113 mg, 0.55 mmol), and AgOTf (6
N
mg, 0.025 mmol) were added to a dry reaction flask with high vacu-
R
um valve. After three times in vacuum and replacement of N , DMSO
2
(5.0 mL) was injected into the mixture. Before reaching completion,
1a
R = Me, Ph
the reaction mixture was stirred and heated at 100 °C under N atmo-
2
Scheme 3 Attempts at reactions involving ketones
sphere. The mixture was poured into H O (50 mL), and the yellow
2
precipitate formed was collected by filtration. The crude product was
purified by chromatography over silica gel using EtOAc and petro-
leum ether (1:5) as an eluent to give 3a; yield: 181 mg (85%); pale yel-
low solid; mp 267–268 °C.
The products 3 were obtained with residual solvents, such as EtOAc or
petroleum ether as observed by NMR spectroscopy, and were hard to
be removed (see Supporting Information).
IR (KBr): 3063, 1652, 1610, 1574, 1509, 1488, 1473, 1454, 1391, 1345,
1
7
1
332, 1293, 1243, 1196, 1175, 1158, 1129, 1051, 949, 903, 891, 771,
–1
47, 693 cm
.
H NMR (CDCl , 400 MHz):  = 6.35 (d, J = 8.8 Hz, 1 H, CH), 6.73 (d, J =
3
7.6 Hz, 1 H, ArH), 6.87 (t, J = 7.6 Hz, 1 H, ArH), 7.01–7.05 (m, 1 H, ArH),
7.14 (t, J = 7.6 Hz, 1 H, ArH), 7.23–7.31 (m, 4 H, ArH), 7.37–7.45 (m, 3
H, ArH), 7.49–7.53 (m, 1 H, ArH), 7.83–7.87 (m, 4 H, ArH), 8.35 (dd, J =
8.0 Hz, J′ = 1.2 Hz, 1 H, ArH), 8.39 (d, J = 7.6 Hz, 1 H, ArH).
13
C NMR (CDCl , 100 MHz):  = 66.7, 117.2, 117.8, 118.3, 120.3, 121.1,
3
Figure 1 The crystal structure of 3l shown in 30% probability
1
1
1
20.3, 125.9, 126.1, 126.6, 127.3, 127.4, 127.8, 128.4, 128.6, 129.2,
29.4, 130.4, 132.8, 133.0, 134.89, 134.93, 142.9, 143.1, 146.9, 148.4,
60.8.
After careful examination of the reactant 2, we next
turned to prepare several 2-(2-aminophenyl)quinazolin-
+
HRMS (APCI): m/z calcd for C29H30N O [M + H] : 426.1601; found:
3
426.1606.
4(3H)-ones 1 via a two-step reaction. The first is a conden-
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Synthesis
W.-C. Pan et al.
Paper
O
R
CHO
O
NH
NH2
R
R2
AgOTf
DMSO
+
N
N
Ar
R1
R2
N
R1
Ar
N
1
2
3
Cl
Cl
O
Cl
O
N
O
N
N
Ph
N
N
Ph
N
N
Ph
Cl
N
N
Cl
3p, 79%
3n, 87% Cl
3o, 80%
Cl
O
N
O
O
N
N
N
N
N
Ph
N
N
OMe
OMe
N
Me
Me
Cl
3q, 86%
3r, 82%
3s, 81%
Cl
O
N
O
N
N
O
Me
N
N
Ph
Me
N
Ph
N
N
Ph
N
Me
3t, 85%
3u, 83%
3v, 87%
Scheme 4 Structurally diversified products 3. Reagents and conditions: 1 (0.5 mmol), 2 (0.55 mmol), AgOTf (6 mg, 0.025 mmol), DMSO (5.0 mL), 100
C. Isolated yields are shown.
°
3
-Chloro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
3-Fluoro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3c)
c]quinazolin-17(18aH)-one (3b)
Yield: 205 mg (89%); pale yellow solid; mp 269–270 °C.
Yield: 182 mg (82%); pale yellow solid; mp 229–230 °C.
IR (KBr): 3056, 1683, 1611, 1587, 1561, 1487, 1474, 1465, 1448, 1392,
IR (KBr): 3061, 1652, 1610, 1559, 1589, 1571, 1474, 1463, 1448, 1392,
1
7
1
342, 1329, 1315, 1277, 1247, 1155, 1133, 1085, 1024, 932, 895, 877,
1330, 1316, 1234, 1156, 1145, 1127, 1099, 1024, 958, 892, 761 cm–1
.
–1
64 cm
.
1
H NMR (CDCl , 400 MHz):  = 6.34 (d, J = 8.4 Hz, 1 H, CH), 6.67–6.70
3
H NMR (CDCl , 400 MHz):  = 6.33 (d, J = 8.0 Hz, 1 H, CH), 6.66 (d, J =
(m, 1 H, ArH), 6.79–6.84 (m, 1 H, ArH), 6.90 (t, J = 7.6 Hz, 1 H, ArH),
7.00–7.07 (m, 2 H, ArH), 7.19 (s, 1 H, ArH), 7.20 (s, 1 H, ArH), 7.38–
7.46 (m, 3 H, ArH), 7.50–7.54 (m, 1 H, ArH), 7.82–7.87 (m, 4 H, ArH),
8.35 (dd, J = 8.0 Hz, J′ = 1.2 Hz, 1 H, ArH), 8.80 (d, J = 7.6 Hz, 1 H, ArH).
3
8
.0 Hz, 1 H, ArH), 6.89–6.93 (m, 1 H, ArH), 7.04–7.12 (m, 2 H, ArH),
.17 (s, 1 H, ArH), 7.20 (s, 1 H, ArH), 7.30 (d, J = 2.0 Hz, 1 H, ArH), 7.41–
.47 (m, 3 H, ArH), 7.51–7.55 (m, 1 H, ArH), 7.82–7.87 (m, 4 H, ArH),
.34 (dd, J = 7.6 Hz, J′ = 1.2 Hz, 1 H, ArH), 8.38 (d, J = 7.6 Hz, 1 H, ArH).
7
7
8
13
C NMR (CDCl , 100 MHz):  = 66.4, 113.0 (d, J = 22.9 Hz), 114.8 (d,
3
C,F
13
C NMR (CDCl , 100 MHz):  = 66.4, 116.6, 117.2, 118.3, 120.2, 121.4,
JC,F = 22.1 Hz), 116.9 (d, JC,F = 2.3 Hz), 117.2, 118.4, 120.2, 121.3, 124.8
(d, JC,F = 8.8 Hz), 126.1, 126.7, 127.3, 127.5, 127.8, 129.3, 129.8, 133.0,
134.5, 134.7 (d, JC,F = 8.8 Hz), 135.0, 142.7, 144.3, 146.7, 148.3, 160.7,
162.9 (d, JC,F = 244.6 Hz).
3
1
1
1
24.5, 125.9, 126.1, 126.8, 127.3, 127.5, 127.8, 128.1, 128.7, 129.3,
29.8, 133.1, 134.4, 134.45, 134.48, 135.1, 142.6, 144.4, 146.6, 148.3,
60.7.
+
19
HRMS (APCI): m/z calcd for C29H19ClN O [M + H] : 460.1211; found:
F NMR (CDCl , 376 MHz):  = 113.507.
3
3
460.1208.
+
HRMS (APCI): m/z calcd for C29H19FN O [M + H] : 444.1507; found:
3
444.1506.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

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W.-C. Pan et al.
Paper
3-Methyl-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
11-Phenyl-[1,3]dioxolo[4′,5′:6,7]isoquinolino[2,1-a]quinazoli-
c]quinazolin-17(18aH)-one (3d)
no[3,2-c]quinazolin-19(17bH)-one (3g)
Yield: 171 mg (78%); pale yellow solid; mp 271–272 °C.
Yield: 202 mg (86%); pale yellow solid; mp 280–281 °C.
IR (KBr): 3080, 3065, 3034, 1679, 1610, 1587, 1471, 1392, 1341, 1292,
IR (KBr): 3062, 2924, 2852, 1679, 1609, 1588, 1576, 1494, 1472, 1464,
–1
–1
1241, 1181, 1154, 1134, 1049, 1023, 911, 869, 766 cm
.
1447, 1431, 1394, 1319, 1290, 1262, 1112, 1032, 965, 829 cm
.
1
1
H NMR (CDCl , 400 MHz):  = 2.27 (s, 3 H, CH ), 6.35 (d, J = 8.4 Hz, 1
H NMR (CDCl , 400 MHz):  = 5.86 (s, 2 H, OCH O), 6.22 (s, 1 H, ArH),
3 2
3
3
H, CH), 6.61 (d, J = 7.6 Hz, 1 H, ArH), 6.86 (t, J = 7.6 Hz, 1 H, ArH), 6.93
d, J = 7.6 Hz, 1 H, ArH), 7.00–7.05 (m, 1 H, ArH), 7.10 (s, 1 H, ArH),
6.36 (d, J = 8.4 Hz, 1 H, CH), 6.78 (s, 1 H, ArH), 6.89–6.93 (m, 1 H, ArH),
7.05–7.09 (m, 1 H, ArH), 7.15 (d, J = 0.8 Hz, 1 H, ArH), 7.16 (s, 1 H,
(
7.20 (s, 1 H, ArH), 7.23 (s, 1 H, ArH), 7.35–7.44 (m, 3 H, ArH), 7.48–
ArH), 7.35–7.44 (m, 3 H, ArH), 7.50–7.54 (m, 1 H, ArH), 7.79–7.85 (m,
7.52 (m, 1 H, ArH), 7.80–7.86 (m, 4 H, ArH), 8.34 (dd, J = 7.6 Hz, J′ = 0.8
4 H, ArH), 8.35 (dd, J = 8.0 Hz, J′ = 1.6 Hz, 1 H, ArH), 8.37–8.39 (m, 1 H,
Hz, 1 H, ArH), 8.38 (d, J = 8.0 Hz, 1 H, ArH).
ArH).
13
13
C NMR (CDCl , 100 MHz):  = 21.2, 66.7, 117.2, 118.0, 118.3, 120.3,
C NMR (CDCl , 100 MHz):  = 66.4, 101.4, 104.6, 106.7, 117.1, 117.6,
3
3
1
1
1
21.0, 123.0, 125.8, 126.6, 126.9, 127.3, 127.4, 127.7, 127.8, 129.1,
29.2, 129.3, 132.7, 133.0, 134.9, 135.0, 138.3, 142.9, 143.3, 147.0,
48.4, 160.8.
118.4, 120.2, 121.1, 124.8, 125.7, 126.6, 127.1, 127.3, 127.4, 127.8,
129.09, 129.13, 133.0, 134.8, 135.0, 141.4, 143.2, 146.8, 147.8, 148.1,
148.3, 160.7.
+
+
HRMS (APCI): m/z calcd for C30H22N O [M + H] : 440.1757; found:
HRMS (APCI): m/z calcd for C30H20N O [M + H] : 470.1499; found:
3
3
3
440.1756.
470.1475.
2
-Chloro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
6-(3-Chlorophenyl)isoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3h)
c]quinazolin-17(18aH)-one (3e)
Yield: 193 mg (84%); pale yellow solid; mp 248–249 °C.
Yield: 205 mg (89%); pale yellow solid; mp 273–274 °C.
IR (KBr): 3065, 2916, 1675, 1620, 1605, 1560, 1492, 1482, 1473, 1463,
1
IR (KBr): 3068, 3058, 2923, 1675, 1608, 1588, 1575, 1558, 1473, 1459,
1416, 1386, 1341, 1277, 1235, 1200, 1128, 1077, 1052, 907, 881, 790,
760 cm .
388, 1324, 1251, 1210, 1133, 1050, 904, 871, 833, 763, 747 cm–1
.
–1
1
H NMR (CDCl , 400 MHz):  = 6.34 (dd, J = 8.0 Hz, J′ = 0.4 Hz, 1 H, CH),
3
1
6.69 (s, 1 H, ArH), 6.90–6.94 (m, 1 H, ArH), 7.04–7.08 (m, 1 H, ArH),
H NMR (CDCl , 400 MHz):  = 6.32 (d, J = 8.4 Hz, 1 H, CH), 6.73 (d, J =
3
7
.18 (d, J = 0.8 Hz, 1 H, ArH), 7.23–7.24 (m, 3 H, ArH), 7.40–7.45 (m, 3
7.6 Hz, 1 H, ArH), 6.90 (t, J = 7.6 Hz, 1 H, ArH), 7.07 (t, J = 7.6 Hz, 1 H,
ArH), 7.16 (t, J = 7.6 Hz, 1 H, ArH), 7.21 (s, 1 H, ArH), 7.24–7.31 (m, 3 H,
ArH), 7.35 (s, 1 H, ArH), 7.36 (s, 1 H, ArH), 7.50–7.54 (m, 1 H, ArH),
7.71–7.73 (m, 1 H, ArH), 7.83–7.87 (m, 3 H, ArH), 8.36 (d, J = 8.0 Hz, 1
H, ArH), 8.39 (d, J = 8.0 Hz, 1 H, ArH).
H, ArH), 7.52–7.56 (m, 1 H, ArH), 7.81–7.87 (m, 4 H, ArH), 8.36 (dd, J =
7
.6 Hz, J′ = 1.2 Hz, 1 H, ArH), 8.38–8.40 (m, 1 H, ArH).
13
C NMR (CDCl , 100 MHz):  = 66.3, 116.8, 117.2, 118.4, 120.2, 121.4,
3
1
1
1
23.5, 125.9, 126.8, 127.2, 127.4, 127.5, 127.9, 128.9, 129.2, 129.6,
31.4, 132.1, 133.0, 134.3, 134.5, 135.1, 142.7, 143.3, 146.6, 148.3,
60.7.
13
C NMR (CDCl , 100 MHz):  = 66.6, 117.0, 118.4, 119.1, 120.3, 121.3,
3
123.1, 124.0, 125.8, 126.3, 126.7, 127.3, 127.5, 127.8, 128.7, 128.9,
129.3, 130.46, 130.49, 132.4, 133.0, 135.0, 135.3, 136.9, 141.6, 142.8,
+
HRMS (APCI): m/z calcd for C29H19ClN O [M + H] : 460.1211; found:
3
146.8, 148.3, 160.8.
460.1203.
+
HRMS (APCI): m/z calcd for C29H19ClN O [M + H] : 460.1211; found:
3
460.1211.
2-Fluoro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3f)
6
1
-(p-Tolyl)isoquinolino[2,1-a]quinazolino[3,2-c]quinazolin-
7(18aH)-one (3i)
Yield: 188 mg (85%); pale yellow solid; mp 272–273 °C.
IR (KBr): 3064, 3038, 2950, 1679, 1610, 1586, 1559, 1507, 1492, 1483,
Yield: 182 mg (83%); pale yellow solid; mp 260–261 °C.
1
8
1
396, 1330, 1316, 1267, 1245, 1186, 1150, 1049, 1024, 947, 899, 846,
–1
29, 775, 744 cm
.
IR (KBr): 3059, 3024, 2920, 1672, 1611, 1588, 1559, 1509, 1473, 1394,
1335, 1317, 1295, 1203, 1183, 1155, 1131, 1050, 1018, 1007, 965,
H NMR (CDCl , 400 MHz):  = 6.36 (d, J = 8.0 Hz, 1 H, CH), 6.46 (dd, J =
3
–1
859, 797, 742 cm .
8
.0 Hz, J′ = 1.6 Hz, 1 H, ArH), 6.89–6.97 (m, 2 H, ArH), 7.04–7.08 (m, 1
H, ArH), 7.19 (s, 1 H, ArH), 7.24–7.29 (m, 2 H, ArH), 7.36–7.44 (m, 3 H,
ArH), 7.51–7.55 (m, 1 H, ArH), 7.81–7.88 (m, 4 H, ArH), 8.35–8.40 (m,
1
H NMR (CDCl , 400 MHz):  = 2.39 (s, 3 H, CH ), 6.36 (d, J = 8.4 Hz, 1
3
3
H, CH), 6.72 (d, J = 7.6 Hz, 1 H, ArH), 6.87 (t, J = 7.6 Hz, 1 H, ArH), 7.01–
7.05 (m, 1 H, ArH), 7.12 (t, J = 7.6 Hz, 1 H, ArH), 7.21–7.29 (m, 6 H,
ArH), 7.49–7.53 (m, 1 H, ArH), 7.72 (s, 1 H, ArH), 7.74 (s, 1 H, ArH),
2
H, ArH).
13
C NMR (CDCl , 100 MHz):  = 66.3, 111.1 (d, J = 23.4 Hz), 115.6 (d,
3
C,F
7.81–7.87 (m, 2 H, ArH), 8.34 (dd, J = 8.0 Hz, J′ = 1.2 Hz, 1 H, ArH), 8.38
JC,F = 21.9 Hz), 116.8, 117.1, 118.3, 120.2, 121.3, 125.8, 126.8, 127.3,
(d, J = 7.6 Hz, 1 H, ArH).
1
1
27.5, 127.7 (d, JC,F = 8.1 Hz), 127.9, 129.0 (d, JC,F = 3.3 Hz), 129.2,
29.4, 132.9 (d, JC,F = 6.5 Hz), 133.0, 134.7, 135.1, 142.4 (d, JC,F = 2.4
13
C NMR (CDCl , 100 MHz):  = 21.4, 66.7, 116.9, 117.2, 118.3, 120.3,
3
Hz), 142.9, 146.6, 148.3, 160.7, 163.0 (d, JC,F = 248.6 Hz).
121.0, 123.0, 125.8, 125.9, 126.6, 127.3, 127.4, 127.8, 128.2, 128.5,
129.9, 130.3, 132.1, 132.9, 133.0, 134.9, 139.6, 143.0, 143.2, 147.0,
19
F NMR (CDCl , 376 MHz):  = 111.546.
3
148.4, 160.8.
+
HRMS (APCI): m/z calcd for C29H19FN O [M + H] : 444.1507; found:
3
+
HRMS (APCI): m/z calcd for C30H22N O [M + H] : 440.1757; found:
444.1500.
3
440.1751.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

F
Synthesis
W.-C. Pan et al.
Paper
6
-(4-Ethylphenyl)isoquinolino[2,1-a]quinazolino[3,2-
IR (KBr): 3066, 3048, 2951, 1683, 1603, 1560, 1448, 1385, 1271, 1238,
1184, 1157, 1086, 1027, 957, 912, 896, 864, 802, 746 cm .
–1
c]quinazolin-17(18aH)-one (3j)
1
Yield: 188 mg (83%); pale yellow solid; mp 289–290 °C.
H NMR (CDCl , 400 MHz):  = 1.43 (t, J = 7.2 Hz, 3 H, CH ), 4.03–4.09
3 3
(
m, 2 H, OCH ), 6.37 (d, J = 8.0 Hz, 1 H, CH), 6.71 (d, J = 7.6 Hz, 1 H,
IR (KBr): 2970, 2958, 2926, 1672, 1589, 1571, 1473, 1460, 1390, 1342,
2
330, 1238, 1144, 1061, 1007, 972, 904, 891, 838, 762 cm–
1
ArH), 6.87 (t, J = 7.6 Hz, 1 H, ArH), 6.93 (d, J = 8.8 Hz, 2 H, ArH), 7.02–
7
7
ArH), 7.81–7.87 (m, 2 H, ArH), 8.34 (dd, J = 8.0 Hz, J′ = 1.6 Hz, 1 H,
ArH), 8.38 (d, J = 7.6 Hz, 1 H, ArH).
1
.
.06 (m, 1 H, ArH), 7.09–7.14 (m, 2 H, ArH), 7.19 (s, 1 H, ArH), 7.21–
.25 (m, 2 H, ArH), 7.49–7.53 (m, 1 H, ArH), 7.75 (d, J = 8.4 Hz, 2 H,
1
H NMR (CDCl , 400 MHz):  = 1.27 (t, J = 7.6 Hz, 3 H, CH ), 2.70 (q, J =
3
3
7
.6 Hz, 2 H, CH ), 6.37 (d, J = 8.0 Hz, 1 H, CH), 6.72 (d, J = 7.2 Hz, 1 H,
2
ArH), 6.88 (t, J = 7.6 Hz, 1 H, ArH), 7.05 (t, J = 8.0 Hz, 1 H, ArH), 7.13 (t,
J = 7.2 Hz, 1 H, ArH), 7.20 (s, 1 H, ArH), 7.23 (s, 1 H, ArH), 7.26–7.30
1
3
C NMR (CDCl , 100 MHz):  = 14.8, 63.6, 66.7, 115.0, 115.7, 117.3,
(
7
m, 4 H, ArH), 7.50–7.54 (m, 1 H, ArH), 7.75 (d, J = 8.0 Hz, 2 H, ArH),
.82–7.87 (m, 2 H, ArH), 8.34 (d, J = 8.0 Hz, 1 H, ArH), 8.39 (d, J = 8.0
Hz, 1 H, ArH).
3
1
1
1
18.3, 120.3, 120.9, 123.0, 125.8, 126.6, 127.2, 127.3, 127.8, 127.9,
28.5, 130.1, 133.0, 133.1, 134.9, 142.8, 143.3, 147.0, 148.4, 160.1,
60.8.
13
C NMR (CDCl , 100 MHz):  = 15.3, 28.7, 66.7, 117.0, 117.3, 118.3,
3
+
HRMS (APCI): m/z calcd for C31H24N O [M + H] : 470.1863; found:
4
1
1
1
20.3, 120.9, 123.0, 125.9, 126.0, 126.5, 127.3, 127.8, 128.2, 128.5,
28.7, 130.3, 132.3, 132.9, 133.0, 134.9, 143.0, 143.2, 145.8, 147.0,
48.4, 160.8.
3
2
70.1871.
+
2,10-Dichloro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3n)
HRMS (APCI): m/z calcd for C31H24N O [M + H] : 454.1914; found:
3
454.1915.
Yield: 214 mg (87%); pale yellow solid; mp 257–258 °C.
6
-(4-Pentylphenyl)isoquinolino[2,1-a]quinazolino[3,2-
IR (KBr): 3071, 2950, 2925, 2854, 1682, 1609, 1587, 1558, 1474, 1326,
1276, 1247, 1197, 1179, 1153, 1050, 948, 882, 773, 698 cm .
–1
c]quinazolin-17(18aH)-one (3k)
1
Yield: 208 mg (84%); pale yellow solid; mp 214–215 °C.
H NMR (CDCl , 400 MHz):  = 6.28 (d, J = 8.8 Hz, 1 H, CH), 6.67 (d, J =
3
0
.8 Hz, 1 H, ArH), 7.00 (dd, J = 8.8 Hz, J′ = 2.4 Hz, 1 H, ArH), 7.16 (s, 1 H,
IR (KBr): 3067, 2922, 2851, 1684, 1606, 1589, 1560, 1509, 1474, 1465,
–1
ArH), 7.24–7.26 (m, 3 H, ArH), 7.41–7.46 (m, 3 H, ArH), 7.55–7.59 (m,
1
2
1395, 1329, 1293, 1249, 1175, 1156, 1026, 832, 762, 695 cm .
H, ArH), 7.78–7.81 (m, 2 H, ArH), 7.88–7.90 (m, 2 H, ArH), 8.34 (d, J =
.4 Hz, 1 H, ArH), 8.39 (d, J = 8.0 Hz, 1 H, ArH).
1
H NMR (CDCl , 400 MHz):  = 0.90 (t, J = 6.8 Hz, 3 H, CH ), 1.32–1.37
3
3
(
m, 4 H, 2 × CH ), 1.63–1.68 (m, 2 H, CH ), 2.63 (t, J = 7.6 Hz, 2 H, CH ),
2
2
2
13
C NMR (CDCl , 100 MHz):  = 66.2, 116.9, 118.6, 119.7, 120.3, 123.5,
6.37 (d, J = 8.0 Hz, 1 H, CH), 6.72 (d, J = 7.6 Hz, 1 H, ArH), 6.87 (t, J = 7.6
3
1
1
1
25.9, 126.9, 127.0, 127.2, 127.3, 127.4, 128.0, 129.0, 129.3, 129.8,
31.2, 131.9, 132.8, 134.1, 134.5, 135.2, 141.2, 143.0, 145.4, 148.0,
60.4.
Hz, 1 H, ArH), 7.02–7.06 (m, 1 H, ArH), 7.10–7.14 (m, 1 H, ArH), 7.20–
.29 (m, 6 H, ArH), 7.49–7.53 (m, 1 H, ArH), 7.74 (d, J = 8.4 Hz, 2 H,
7
ArH), 7.81–7.87 (m, 2 H, ArH), 8.34 (dd, J = 8.0 Hz, J′ = 1.2 Hz, 1 H,
ArH), 8.39 (d, J = 8.0 Hz, 1 H, ArH).
+
HRMS (APCI): m/z calcd for C29H18Cl N O [M + H] : 494.0821; found:
2
3
13
494.0812.
C NMR (CDCl , 100 MHz):  = 14.0, 22.5, 31.0, 31.6, 35.8, 66.7, 116.9,
3
1
1
1
17.3, 118.3, 120.3, 120.9, 123.0, 125.8, 125.9, 126.5, 127.3, 127.7,
28.1, 128.5, 129.2, 130.3, 132.3, 132.9, 134.9, 143.1, 143.2, 144.6,
47.0, 148.4, 160.8.
3,9-Dichloro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3o)
+
HRMS (APCI): m/z calcd for C34H30N O [M + H] : 496.2383; found:
Yield: 197 mg (80%); pale yellow solid; mp 249–250 °C.
3
496.2380.
IR (KBr): 3055, 2951, 1679, 1601, 1584, 1485, 1448, 1429, 1340, 1291,
–1
1272, 1240, 1194, 1155, 1043, 1030, 937, 821, 768, 695 cm .
6
-(4-Methoxyphenyl)isoquinolino[2,1-a]quinazolino[3,2-
1
H NMR (CDCl , 400 MHz):  = 6.31 (d, J = 2.0 Hz, 1 H, CH), 6.64 (d, J =
.0 Hz, 1 H, ArH), 6.88 (dd, J = 8.4 Hz, J′ = 1.6 Hz, 1 H, ArH), 7.12 (dd, J =
3
c]quinazolin-17(18aH)-one (3l)
8
Yield: 200 mg (88%); pale yellow solid; mp 241–242 °C.
8.0 Hz, J′ = 2.0 Hz, 1 H, ArH), 7.17 (s, 1 H, ArH), 7.21 (s, 1 H, ArH), 7.32
(
d, J = 1.6 Hz, 1 H, ArH), 7.43–7.48 (m, 3 H, ArH), 7.51–7.55 (m, 1 H,
ArH), 7.81–7.87 (m, 4 H, ArH), 8.28 (d, J = 8.4 Hz, 1 H, ArH), 8.37 (d, J =
.0 Hz, 1 H, ArH).
IR (KBr): 3067, 2954, 2925, 1683, 1606, 1589, 1560, 1509, 1474, 1465,
–1
1420, 1394, 1329, 1314, 1247, 1175, 1045, 923, 835, 797, 694 cm .
8
1
1
H NMR (CDCl , 400 MHz):  = 3.83 (s, 3 H, OCH ), 6.36 (d, J = 8.4 Hz, 1
3
3
3
C NMR (CDCl , 100 MHz):  = 66.4, 116.9, 117.1, 117.2, 120.2, 121.9,
H, CH), 6.71 (d, J = 7.6 Hz, 1 H, ArH), 6.87 (t, J = 7.6 Hz, 1 H, ArH), 6.94
d, J = 8.8 Hz, 2 H, ArH), 7.04 (t, J = 8.0 Hz, 1 H, ArH), 7.11 (t, J = 7.2 Hz,
H, ArH), 7.14 (s, 1 H, ArH), 7.19–7.28 (m, 3 H, ArH), 7.49–7.53 (m, 1
H, ArH), 7.77 (d, J = 8.4 Hz, 2 H, ArH), 7.85 (t, J = 8.0 Hz, 2 H, ArH), 8.34
3
1
1
1
24.4, 126.0, 126.2, 126.9, 127.4, 127.8, 128.3, 128.65, 128.74, 129.4,
30.1, 133.9, 134.2, 134.7, 135.1, 139.3, 143.7, 143.9, 145.9, 148.1,
60.5.
(
1
+
(d, J = 7.6 Hz, 1 H, ArH), 8.39 (d, J = 7.6 Hz, 1 H, ArH).
HRMS (APCI): m/z calcd for C29H18Cl N O [M + H] : 494.0821; found:
2
3
13
494.0814.
C NMR (CDCl , 100 MHz):  = 55.4, 66.7, 114.6, 115.9, 117.3, 118.3,
3
120.3, 121.0, 123.0, 125.8, 126.6, 127.3, 127.4, 127.8, 128.0, 128.5,
1
30.1, 133.0, 133.1, 134.9, 142.7, 143.2, 147.0, 148.4, 160.6, 160.8.
2,9-Dichloro-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3p)
+
HRMS (APCI): m/z calcd for C30H22N O [M + H] : 456.1707; found:
3
2
456.1704.
Yield: 195 mg (79%); pale yellow solid; mp 282–283 °C.
IR (KBr): 3049, 2996, 2935, 1678, 1585, 1559, 1510, 1473, 1431, 1342,
1329, 1307, 1294, 1251, 1213, 1161, 1135, 1110, 1028, 936, 845, 786,
754, 697 cm .
6
-(4-Ethoxyphenyl)isoquinolino[2,1-a]quinazolino[3,2-
–1
c]quinazolin-17(18aH)-one (3m)
Yield: 192 mg (82%); pale yellow solid; mp 233–234 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

G
Synthesis
W.-C. Pan et al.
Paper
1
H NMR (CDCl , 400 MHz):  = 6.31 (s, 1 H, CH), 6.68 (s, 1 H, ArH), 6.88
7.09–7.14 (m, 2 H, ArH), 7.18 (s, 1 H, ArH), 7.21–7.28 (m, 2 H, ArH),
3
(d, J = 8.8 Hz, 1 H, ArH), 7.17 (s, 1 H, ArH), 7.24–7.26 (m, 3 H, ArH),
7.39 (t, J = 7.6 Hz, 1 H, ArH), 7.68 (d, J = 7.2 Hz, 1 H, ArH), 7.76 (d, J =
7.41–7.46 (m, 3 H, ArH), 7.52–7.56 (m, 1 H, ArH), 7.80–7.81 (m, 2 H,
8.8 Hz, 2 H, ArH), 8.23 (d, J = 8.0 Hz, 1 H, ArH), 8.39 (d, J = 7.6 Hz, 1 H,
ArH), 7.85–7.86 (m, 2 H, ArH), 8.29 (d, J = 8.4 Hz, 1 H, ArH), 8.38 (d, J =
ArH).
8
.0 Hz, 1 H, ArH).
13
C NMR (CDCl , 100 MHz):  = 17.4, 55.4, 66.7, 114.6, 115.8, 117.2,
3
13
C NMR (CDCl , 100 MHz):  = 66.3, 117.0, 117.17, 117.24, 120.1,
118.7, 120.2, 120.9, 123.0, 125.0, 125.8, 126.2, 127.3, 127.4, 127.5,
127.9, 128.4, 130.2, 132.8, 133.1, 135.4, 136.3, 142.7, 143.1, 145.7,
146.8, 160.3, 161.1.
3
1
1
1
21.9, 123.5, 125.8, 127.0, 127.4, 127.5, 127.9, 128.8, 129.1, 129.4,
29.9, 131.17, 132.01, 133.9, 134.6, 135.2, 139.3, 142.8, 143.7, 145.8,
48.1, 160.5.
+
HRMS (APCI): m/z calcd for C31H24N O [M + H] : 470.1863; found:
470.1885.
3
2
+
HRMS (APCI): m/z calcd for C29H18Cl N O [M + H] : 494.0821; found:
2
3
494.0812.
3-Chloro-15-methyl-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
9-Chloro-6-(4-methoxyphenyl)isoquinolino[2,1-a]quinazoli-
c]quinazolin-17(18aH)-one (3t)
no[3,2-c]quinazolin-17(18aH)-one (3q)
Yield: 201 mg (85%); pale yellow solid; mp >300 °C.
Yield: 210 mg (86%); pale yellow solid; mp >300 °C.
IR (KBr): 2949, 2920, 2851, 1671, 1606, 1593, 1567, 1509, 1490, 1476,
1463, 1391, 1325, 1313, 1300, 1246, 1217, 1175, 1132, 1108, 1077,
951, 888, 773, 695 cm .
IR (KBr): 3068, 2921, 2852, 1675, 1607, 1591, 1567, 1490, 1465, 1448,
–1
1
9
1
389, 1335, 1325, 1304, 1280, 1251, 1220, 1183, 1133, 1082, 1017,
53, 907, 886, 692 cm–
1
.
1
H NMR (CDCl , 400 MHz):  = 2.55 (s, 3 H, CH ), 6.33 (d, J = 8.4 Hz, 1
3
3
H NMR (CDCl , 400 MHz):  = 3.85 (s, 3 H, OCH ), 6.34 (d, J = 2.0 Hz, 1
H, CH), 6.67 (s, 1 H, ArH), 6.91 (t, J = 7.2 Hz, 1 H, ArH), 7.04 (t, J = 7.6
Hz, 1 H, ArH), 7.18 (s, 1 H, ArH), 7.23 (s, 3 H, ArH), 7.37–7.44 (m, 3 H,
ArH), 7.68 (d, J = 8.4 Hz, 1 H, ArH), 7.78 (d, J = 8.4 Hz, 1 H, ArH), 7.83
(d, J = 7.2 Hz, 2 H, ArH), 8.18 (s, 1 H, ArH), 8.34 (d, J = 7.6 Hz, 1 H, ArH).
13
3
3
H, CH), 6.70 (d, J = 7.6 Hz, 1 H, ArH), 6.84 (dd, J = 8.4 Hz, J′ = 2.0 Hz, 1
H, ArH), 6.96 (d, J = 8.8 Hz, 2 H, ArH), 7.11–7.15 (m, 2 H, ArH), 7.18 (s,
1
8
H, ArH), 7.26–7.30 (m, 2 H, ArH), 7.50–7.54 (m, 1 H, ArH), 7.75 (d, J =
.8 Hz, 2 H, ArH), 7.83–7.84 (m, 2 H, ArH), 8.27 (d, J = 8.4 Hz, 1 H,
C NMR (CDCl , 100 MHz):  = 21.4, 66.3, 116.7, 117.2, 118.5, 119.9,
3
ArH), 8.38 (d, J = 8.0 Hz, 1 H, ArH).
121.3, 123.5, 125.9, 126.8, 127.2, 127.4, 127.7, 128.8, 129.2, 129.6,
13
C NMR (CDCl , 100 MHz):  = 55.4, 66.7, 114.7, 116.3, 116.9, 117.2,
131.4, 132.2, 132.8, 134.3, 134.6, 136.6, 137.1, 142.6, 143.4, 145.8,
3
1
1
1
20.3, 121.5, 122.9, 126.1, 126.7, 126.8, 127.3, 127.4, 127.7, 128.1,
28.6, 128.7, 130.1, 132.9, 135.0, 139.1, 142.2, 144.3, 146.3, 148.2,
60.6, 160.8.
146.3, 160.6.
+
HRMS (APCI): m/z calcd for C30H21ClN O [M + H] : 474.1368; found:
3
474.1385.
+
HRMS (APCI): m/z calcd for C30H21ClN O [M + H] : 490.1317; found:
3
2
490.1301.
13,14-Dimethyl-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-17(18aH)-one (3u) Yield: 188 mg (83%); pale yellow
2-Chloro-13-methyl-6-phenylisoquinolino[2,1-a]quinazolino[3,2-
solid; mp >300 °C.
c]quinazolin-17(18aH)-one (3r)
IR (KBr): 3051, 2932, 1674, 1610, 1591, 1574, 1560, 1511, 1489, 1474,
1432, 1396, 1336, 1271, 1244, 1179, 1158, 1132, 1025, 955, 856, 810,
Yield: 194 mg (82%); pale yellow solid; mp 253–254 °C.
–1
761, 694 cm .
IR (KBr): 3050, 2996, 2913, 1678, 1603, 1584, 1559, 1510, 1485, 1430,
1
1
6
1
341, 1293, 1250, 1212, 1175, 1160, 1135, 1110, 1027, 935, 845, 785,
H NMR (CDCl , 400 MHz):  = 2.51 (s, 3 H, CH ), 2.72 (s, 3 H, CH ),
3 3 3
–1
96 cm
.
6.34 (d, J = 8.0 Hz, 1 H, CH), 6.72 (d, J = 7.6 Hz, 1 H, ArH), 6.88 (t, J = 7.6
Hz, 1 H, ArH), 7.03 (t, J = 7.6 Hz, 1 H, ArH), 7.13 (t, J = 7.6 Hz, 1 H, ArH),
H NMR (CDCl , 400 MHz):  = 2.78 (s, 3 H, CH ), 6.33 (d, J = 8.0 Hz, 1
3
3
7.21–7.34 (m, 5 H, ArH), 7.38–7.44 (m, 3 H, ArH), 7.84 (d, J = 7.2 Hz, 2
H, CH), 6.69–6.70 (m, 1 H, ArH), 6.91 (t, J = 7.6 Hz, 1 H, ArH), 7.04 (t, J =
.6 Hz, 1 H, ArH), 7.18 (s, 1 H, ArH), 7.22 (s, 3 H, ArH), 7.38–7.43 (m, 4
H, ArH), 7.70 (d, J = 7.2 Hz, 1 H, ArH), 7.81 (d, J = 7.6 Hz, 2 H, ArH), 8.24
H, ArH), 8.15 (d, J = 8.4 Hz, 1 H, ArH), 8.40 (d, J = 8.0 Hz, 1 H, ArH).
7
13
C NMR (CDCl , 100 MHz):  = 13.1, 21.1, 66.6, 117.2, 117.8, 118.2,
3
(
1
d, J = 8.0 Hz, 1 H, ArH), 8.40 (d, J = 7.6 Hz, 1 H, ArH).
118.8, 120.9, 123.1, 124.2, 125.9, 126.0, 127.3, 128.4, 128.5, 128.7,
129.2, 129.3, 130.6, 132.6, 132.8, 134.2, 135.0, 143.0, 143.9, 145.4,
3
C NMR (CDCl , 100 MHz):  = 17.5, 66.3, 116.7, 117.2, 118.8, 120.1,
3
146.4, 161.2.
1
1
1
21.3, 123.5, 125.0, 125.9, 126.4, 127.2, 127.5, 128.8, 129.2, 129.6,
31.4, 132.2, 132.9, 134.3, 134.6, 135.6, 136.5, 142.6, 143.3, 145.2,
46.7, 161.0.
+
HRMS (APCI): m/z calcd for C31H24N O [M + H] : 454.1914; found:
3
454.1908.
+
HRMS (APCI): m/z calcd for C30H21ClN O [M + H] : 474.1368; found:
3
474.1373.
4-Phenylbenzo[7,8]isoquinolino[2,1-a]quinazolino[3,2-
c]quinazolin-15(16aH)-one (3v)
6-(4-Methoxyphenyl)-13-methylisoquinolino[2,1-a]quinazoli-
Yield: 207 mg (87%); pale yellow solid; mp 288–289 °C.
no[3,2-c]quinazolin-17(18aH)-one (3s)
IR (KBr): 3058, 2893, 2776, 1682, 1608, 1589, 1573, 1560, 1499, 1473,
1400, 1360, 1323, 1313, 1247, 1209, 1187, 1154, 1092, 1036, 936,
Yield: 190 mg (81%); pale yellow solid; mp 277–278 °C.
–1
894, 773, 760, 696 cm .
IR (KBr): 3062, 2958, 1679, 1622, 1605, 1590, 1573, 1559, 1492, 1464,
1
1
1
1
447, 1391, 1339, 1326, 1307, 1276, 1241, 1210, 1166, 1147, 1132,
H NMR (CDCl , 400 MHz):  = 6.37 (d, J = 8.4 Hz, 1 H, CH), 6.83–6.88
3
–1
049, 915, 871, 823, 762, 750, 693 cm
.
(m, 2 H, ArH), 7.00 (t, J = 8.0 Hz, 1H, ArH), 7.39 (s, 1 H, ArH), 7.42–7.49
(m, 4 H, ArH), 7.53 (t, J = 7.6 Hz, 1 H, ArH), 7.59 (t, J = 7.6 Hz, 1 H, ArH),
H NMR (CDCl , 400 MHz):  = 2.77 (s, 3 H, CH ), 3.83 (s, 3 H, OCH ),
3
3
3
6.36 (d, J = 8.4 Hz, 1 H, CH), 6.72 (d, J = 7.2 Hz, 1 H, ArH), 6.87 (t, J = 7.6
Hz, 1 H, ArH), 6.94 (d, J = 8.8 Hz, 2 H, ArH), 7.03 (t, J = 8.0 Hz, 1 H, ArH),
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H

H
Synthesis
W.-C. Pan et al.
Paper
7
.65 (d, J = 8.4 Hz, 1 H, ArH), 7.77 (d, J = 8.0 Hz, 1 H, ArH), 7.83–7.89
(5) (a) Viola, D.; Valerio, L.; Molinaro, E.; Agate, L.; Bottici, V.;
Biagini, A.; Lorusso, L.; Cappaqli, V.; Pieruzzi, L.; Giani, C.;
Sabini, E.; Passannati, P.; Puleo, L.; Matrone, A.; Pontillo-Con-
tillo, B.; Battaqlia, V.; Mazzeo, S.; Vitti, P.; Elisei, R. Endocr. Relat.
Cancer 2016, 23, 185. (b) Martin, P.; Oliver, S.; Kennedy, S. J.;
Partridge, E.; Hutchison, M.; Clarke, D.; Giles, P. Clin. Ther. 2012,
(m, 2 H, ArH), 7.95–7.97 (m, 3 H, ArH), 8.29 (d, J = 8.4 Hz, 1 H, ArH),
8.34 (d, J = 8.0 Hz, 1 H, ArH), 8.41 (d, J = 7.6 Hz, 1 H, ArH).
13
C NMR (CDCl , 100 MHz):  = 67.2, 114.0, 117.2, 118.4, 120.4, 120.7,
3
1
1
1
21.2, 122.6, 126.1, 126.2, 126.7, 126.9, 127.36, 127.39, 127.8, 128.1,
28.76, 128.79, 128.8, 129.1, 129.3, 129.6, 133.0, 133.5, 135.0, 135.1,
42.9, 143.4, 147.0, 148.4, 161.0.
34, 221.
(
6) (a) Lou, M.-H.; Deng, Z.-H.; Mao, X.-C.; Fu, Y.; Yang, Q.; Peng, Y.-
Y. Org. Biomol. Chem. 2018, 16, 1851. (b) Neel, A. J.; Hehn, J. P.;
Tripet, P. F.; Toste, F. J. Am. Chem. Soc. 2013, 135, 14044.
+
HRMS (APCI): m/z calcd for C33H22N O [M + H] : 476.1757; found:
3
476.1775.
(c) Kumar, K. S.; Kumar, P. M.; Reddy, M. A.; Ferozuddin, M. D.;
Sreenivasulu, M.; Jafar, A. A.; Krishna, G. R.; Reddy, C. M.;
Rambabu, D.; Shiva-Kumar, K.; Pal, S.; Pal, M. Chem. Commun.
Funding Information
2
011, 47, 10263.
7) (a) Qiu, G.-Y.-S.; He, Y.-H.; Wu, J. Chem. Commun. 2012, 48, 3836.
b) Solomos, M. A.; Bertke, J. A.; Swift, J. A. New J. Chem. 2018,
2, 7125. (c) Tajfirooz, F.; Davoodnia, A.; Pordel, M.; Ebrahimi,
M.; Beyramabadi, S. A. Russ. J. Gen. Chem. 2017, 87, 2429.
d) Duan, F.-J.; Liu, M.-C.; Chen, J.-X.; Ding, J.-C.; Hu, Y.-F.; Wu,
This work was financially supported by NSFC of China (No.
(
21702078), the NSF of Jiangsu Province (No. BK20170231), and TAPP.
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Supporting Information
H.-Y. RSC Adv. 2013, 3, 24001. (e) Venkateswarlu, S.;
Satyanarayana, M.; Ravikiran, P.; Siddaiah, V. J. Heterocycl.
Chem. 2013, 50, 1089. (f) Shafii, B.; Saeedi, M.; Mahdavi, M.;
Foroumadi, A.; Shafiee, A. Synth. Commun. 2014, 44, 215.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611808.
S
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S
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g Inform ati
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(8) Bahadorikhalili, S.; Mahdavi, M.; Ma’mani, L.; Shafiee, A.;
Mahdavi, H.; Akbarzadeh, T. New J. Chem. 2018, 42, 5499.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–H