Synthesis of Isoquinoline-Fused Quinazolinones through Ag(I)-Catalyzed Cascade Annulation of 2-Aminobenzamides and 2-Alkynylbenzaldehydes

Article abstract of DOI:10.1055/s-0037-1610910

A new route for the expedient synthesis of a specific regioisomer of isoquinoline-fused quinazolinones is reported. Silver(I)-catalyzed cascade cyclization of 2-aminobenzamides and 2-alkynylbenzaldehydes followed by in situ oxidation gives 12-butyl-or 12-aryl-6 H-isoquinolino[2,1- A [quinazolin-6-ones in 69-91% yields. The structure of the isoquinoline-fused quinazolinone was confirmed by X-ray crystallography analysis.

Full text of DOI:10.1055/s-0037-1610910

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–H
paper
A
en
Synthesis
A. D. Sonawane et al.
Paper
Synthesis of Isoquinoline-Fused Quinazolinones through
Ag(I)-Catalyzed Cascade Annulation of 2-Aminobenzamides
and 2-Alkynylbenzaldehydes
R1
Amol D. Sonawanea
Yunnus B. Shaikha
Dinesh R. Garud1,b
Mamoru Koketsu*a
R1
R2
NH2
AgNO3
R3
N
open flask
R3
R2
+
NH2
DMSO, 120 °C
N
CHO
O
O
a
14 examples; up to 91% yield
Good functional group tolerance
In situ oxidation
Department of Chemistry and Biomolecular Science,
Faculty of Engineering, Gifu University, Gifu 501-1193, Japan
Department of Chemistry, Sir Parashurambhau College, Tilak road,
Pune 411030, India
koketsu@gifu-u.ac.jp
R1 = Bu, aryl
b
Regioselectivity
Received: 31.07.2018
Accepted after revision: 23.08.2018
Published online: 21.09.2018
ring-fused quinazolinone derivatives.10 In particular, syn-
thetic strategies for ring-fused quinazolinones, as the core
structural skeletons in a variety of natural products and
pharmaceutical molecules, have been intensely explored in
recent years. Isoquinolines are ubiquitous structural motif
present in a numerous biologically active natural products
and pharmaceutically important compounds.11 Molecular
skeletons that integrate isoquinoline and quinazolinone
moieties might possess the properties of both and enhance
DOI: 10.1055/s-0037-1610910; Art ID: ss-2018-f0514-op
Abstract A new route for the expedient synthesis of a specific regio-
isomer of isoquinoline-fused quinazolinones is reported. Silver(I)-cata-
lyzed cascade cyclization of 2-aminobenzamides and 2-alkynylbenzal-
dehydes followed by in situ oxidation gives 12-butyl- or 12-aryl-6H-
isoquinolino[2,1-a]quinazolin-6-ones in 69–91% yields. The structure of
the isoquinoline-fused quinazolinone was confirmed by X-ray crystal-
lography analysis.
12
their activity.
Several reports are available for the synthesis of iso-
quinoline-fused quinazolinones.13 Pal and co-workers re-
ported the synthesis of 4b,5-dihydro-6H-isoquinolino[2,1-
a]quinazolin-6-ones via one-pot Yb(III)-mediated cascade
reaction [Scheme 1 (A)].14 Patil and co-workers reported
Au(I)-catalyzed synthesis of optically pure 4b,5-dihydro-
Key words isoquinoline, quinazolinone, regioisomer, silver catalyst,
cascade annulation
Over the past few decades, transition-metal-catalyzed
C–H bond functionalizations for C–C bond formation have
proved to be a powerful method for the construction of
15
6H-isoquinolino[2,1-a]quinazolin-6-ones [Scheme 1 (B)]
2
complex chemical compounds in an atom- and step-eco-
and Yan and co-workers used the Ir-catalyzed intramolecu-
lar acceptorless dehydrogenative cross-coupling of tertiary
amines and amides for the synthesis of 12,13-dihydro-6H-
3
nomic manner. To date these transformations are widely
used in the area of synthesis of both natural products and
therapeutic agents. Among the transition-metal-catalyzed
organic transformations, Ag-catalyzed C–H/C–C bond func-
tionalization is one of the frontier areas in organic chemis-
13f
isoquinolino[2,1-a]quinazolin-6-ones [Scheme
1 (C)].
However, some of these procedures have significant draw-
backs, such as low yield, long reaction times, harsh reaction
conditions, and the use of expensive reagents. In an effort
to synthesize N-fused heterocycles by a transition-metal-
catalyzed C–C functionalization, herein we report, the syn-
thesis of isoquinoline-fused quinazolinones via a AgNO3-
catalyzed one-pot cascade cyclization of 2-aminobenz-
amides and 2-alkynylbenzaldehydes through an oxidation
process.
In the synthesis of isoquinoline-fused quinazolinones,
the fusion of quinazolinone ring may occur in two different
ways (linear and angular) for two different types of nitro-
gen atoms that would lead to the formation of two regioiso-
mers. Both of the isomers should have certain unique phar-
macological features. Therefore, a synthetic method that
4
try. Compared with other transition metals such as gold or
platinum, Ag(I) salts represent an inexpensive alternative
for the electrophilic activation of alkynes under mild condi-
4e,5
tions.
Thus, the development of new systems catalyzed
by Ag(I) for C–H/C–C functionalization represents a central
challenge for the construction of various types of fused N-
heterocycles. Nitrogen-containing heterocycles are import-
ant molecular motifs in natural products, materials, and
6
bioactive molecules. In this regard, quinazolinone deriva-
tives represent a class of privileged N-heterocyclic motifs
7
present in a broad range of alkaloid natural products. Fur-
thermore, they also show a wide range of biological activi-
8,9
ties. Much effort has focused on synthetic methods for
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

B
Synthesis
A. D. Sonawane et al.
Paper
Previous work:
R
H
N
R
O
R-NH2
Yb(OTF)3 (5 mol%)
N
O
+
(A)
O
RN
Ph
CHO
O
R
Ph
+
NH2
NH2
O
Au(I) (5 mol%)
N
O
O
P
ligand L1 (5 mol%)
H
OH
CHO
HN
O
(B)
O
R
L1; R = 9-anthryl
N
[Cp*IrCl2]2 (2.5 mol%)
N
H2N
ligand L2 (5 mol%)
N
(C)
N
OH
O
O
L2
This work:
Ph
Ph
NH2
NH2
AgNO3
open flask
+
N
(D)
DMSO, 120 °C
CHO
N
O
O
Scheme 1 Approaches for the synthesis of quinazolinones
can exclusively provide a single regioisomer instead of a
mixture is highly desirable. With this in mind, we initially
began with reaction optimization conditions with 2-ami-
nobenzamide (1a) and 2-(phenylethynyl)benzaldehyde (2a)
as model substrates (Table 1). We initially subjected com-
pounds 1a and 2a in an equimolar ratio to oxidative condi-
tions using 30 mol% of AgOTf in DMSO solvent at 100 °C for
was carried out in DMSO solvent at 120 °C which provided
required product 4a in 89% yield (entry 10). Also, we car-
ried out reaction of 2-aminobenzamide (1a) and 2-(phenyl-
ethynyl)benzaldehyde (2a) under a nitrogen atmosphere
5
hours (Table 1, entry 1). To our delight, the reaction was
very much regioselective and only a single regioisomer 4a
was formed (from TLC) as confirmed by NMR in low yield
(29%).
Next, the yield of compound 4a was increased to 54% by
increasing the temperature to 120 °C (entry 2). However,
the use of 10 mol% AgOTf in the reaction at this tempera-
ture resulted in a decrease in the product yield to 43% (en-
try 3). A significant improvement in the yield was observed
when 20 mol% of AgOTf was used in the reaction and the
desired product was isolated in 73% yield (entry 4). On the
other hand, the use of Ag O and AgPF catalysts in the reaction
2
6
afforded desired product 4a in 9% and 5% yields, respective-
ly (entries 5 and 7); AgClO yielded only 33% of product 4a
4
(entry 6). To improve the yield of the reaction, different sol-
vents were screened with 20 mol% of AgNO (entries 10,
3
Figure 1 X-ray crystal structure of 4a (ORTEP diagram); thermal ellip-
soids are drawn at 50% probability level
12–14) and the best result was obtained when the reaction
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

C
Synthesis
A. D. Sonawane et al.
Paper
Table 1 Optimization of the Synthesis of 12-Phenyl-6H-isoquinoli-
no[2,1-a]quinazolin-6-one (4a)
ence of an electron-withdrawing halide group in the 2-ami-
nobenzamide ring also did not make a significant difference
to the yield. The synthesized compounds 4a–n were charac-
a
H
1
13
terized by IR, HRMS, H and C NMR spectral analysis.
Finally, the regioselectivity achieved through Ag(I)-cata-
lyzed cascade annulation of 2-aminobenzamides and 2-
alkynylbenzaldehydes in the synthesis of isoquinoline-
fused quinazolinones 4 was confirmed by X-ray crystallog-
raphy analysis. The crystal structure of the representative
compound 12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-
one (4a) was confirmed by the X-ray crystallography analy-
sis (Figure 1).16
A plausible mechanism for the formation of isoquino-
line-fused quinazolinones 4 is presented in Scheme 3. The
reaction of 2-aminobenzamide 1 and 2-alkynylbenzalde-
hyde 2 gives an imine in which the C≡C bond coordinates to
the Ag catalyst to give intermediate I. Intermediate I on 6-
endo-dig cyclization via protodemetalation delivers inter-
mediate II. Finally, in situ oxidation of intermediate II deliv-
ers the desired isoquinoline-fused quinazolinone derivative
Ph
Ph
NH2
Ag catalyst (3)
N
O
+
NH2
O
6-endo-dig
cyclization
N
1
a
O
2a
4
a
b
Entry
Ag catalyst 3
Solvent
Time (h) Temp (°C) Yield (%)
(
mol%)
1
2
3
4
5
6
7
8
9
AgOTf (30)
AgOTf (30)
AgOTf (10)
AgOTf (20)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
5
4
100
120
120
120
120
120
120
120
120
120
120
120
120
110
29
54
43
73
9
8
4
Ag
AgClO
AgPF
2
O (20)
(20)
(20)
6
4
6
33
5
6
6
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
AgNO
3
(2)
10
9
77
82
89
13c
42
58
34
4
and regenerates the silver catalyst for a new catalytic
3
3
3
3
3
3
(5)
cycle.
10
11
12
13
4
(20)
(20)
(20)
(20)
(20)
6
In summary, we developed a novel AgNO -catalyzed
3
6
cascade cyclization of 2-aminobenzamides and 2-alkynyl-
benzaldehydes which underwent in situ oxidation to deliv-
er isoquinoline-fused quinazolinone derivatives in good to
excellent yields. This novel synthetic approach is amenable
6
DMAd
toluene
6
1
6
to the generation of
a library of isoquinoline-fused
a
Reaction conditions: 2-aminobenzamide (1a; 0.242 mmol), 2-(phenyl-
quinazolinone analogues. Further expansion of the current
strategies and evaluation of biological activities are in prog-
ress.
ethynyl)benzaldehyde (2a; 0.242 mmol); solvent (4 mL), open flask.
b
Isolated yield.
c
2
Reaction was carried out under N atmosphere. 4a was obtained together
with 12-phenyl-4b,5-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-one
72%).
(
d
DMA = dimethylacetamide.
All solvents and reagents were purchased from the suppliers and used
without further purification. IR spectra were recorded on a JASCO
FT/IR-460 Plus spectrophotometer. Reactions were monitored by TLC
(
entry 11), interestingly we obtained unaromatized 12-
on silica plates using UV-light or I chamber for visualization. Evapo-
2
phenyl-4b,5-dihydro-6H-isoquinolino[2,1-a]quinazolin-6-
one in 72% yield and only 13% of the required product 4a.
ration and condensation were carried out in vacuo. NMR spectra were
recorded with JEOL JNM-ECS 400 spectrometers with TMS as an in-
ternal standard. The data of all known compounds data are consistent
with the literature reports. Scale up reactions also performed as per
the given general procedure without any deviation. Melting points
were measured by a Yanaco micro melting point apparatus.
15
Next, to assess the substrate scope and generality of the
newly developed AgNO -catalyzed cascade reaction, a vari-
3
ety of 2-alkynylbenzaldehydes 2 bearing different variously
substituted alkynyl groups and/or substitution on the benz-
aldehyde ring and a range of 2-aminobenzamides 1 were
employed under the optimized reaction conditions
2
-(Phenylethynyl)benzaldehyde (2a); Typical Procedure17
To a solution of 2-bromobenzaldehyde (500 mg, 2.7 mmol, 1 equiv) in
THF (10 mL) were added PdCl (PPh ) (95 mg, 5 mol%) and Et N (820
(Scheme 2). As shown in Scheme 2, 2-alkynylbenzalde-
2
3
2
3
hydes 2 with alkynyl groups bearing a variety of substitu-
ents, such as butyl, phenyl, 4-methoxyphenyl, and 4-fluoro-
3
mg, 8.1 mmol, 3 equiv); the resulting mixture was stirred and purged
with N gas for 10 min. Then phenylacetylene (414 mg, 4.054 mmol,
2
-methylphenyl, and/or the benzaldehyde ring containing
1.5 equiv) and CuI (26 mg, 5 mol%) were added. The mixture was fur-
electron-withdrawing halide groups or electron-donating
methoxy groups were well tolerated under the present re-
action conditions and afforded the desired isoquinoline-
fused quinazolinones 4a–n in good to excellent yields
ther stirred under N gas at r.t. for 24 h. After completion, the reaction
2
was quenched with sat. NH Cl and extracted with EtOAc. Organic lay-
4
er was washed with brine, dried (Na
SO ), and evaporated. The crude
2
4
residue was purified by chromatography (silica gel, EtOAc/n-hexane
3
:97) to afford 2a (347 mg, 62%) as a brown oil. Spectroscopic data are
(Scheme 2, 69–91%). Electron-donating groups on the benz-
17
consistent with those previously reported.
aldehyde aromatic ring were also well tolerated. The pres-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

D
Synthesis
A. D. Sonawane et al.
Paper
H
N
R3
R3
NH2
AgNO3 (20 mol%)
R1
N
O
R2
+
NH2
O
R2
R1
DMSO, 120 °C
2
1
O
4
OMe
F
Ph
N
O
N
N
N
N
O
N
N
N
4a, 89%
O
4b, 83%
O
4c, 74%
4d, 85%
OMe
MeO
MeO
Ph
N
MeO
MeO
Ph
N
N
N
O
N
N
N
N
Br
Br
4h, 85%
O
O
O
4e, 78%
4f, 81%
4g, 91%
OMe
F
Ph
N
Cl
N
O
Cl
N
N
Cl
N
Cl
N
N
N
O
O
O
4i, 88%
4j, 87%
4k, 69%
4l, 81%
MeO
Ph
MeO
MeO
N
O
Cl
N
O
Cl
MeO
N
N
4m, 86%
4n, 77%
Scheme 2 Synthesis of 12-substituted 6H-isoquinolino[2,1-a]quinazolin-6-one derivatives 4 via AgNO catalyst. Reagents and conditions: 2-aminobenz-
3
amide 1 (0.24 mmol), 2-alkynylbenzaldehyde 2 (0.24 mmol), AgNO (20 mol%), DMSO, 120 °C; isolated yields are given.
3
Ag
R3
12-Butyl- or 12-Aryl-6H-isoquinolino[2,1-a]quinazolin-6-ones 4;
General Procedure
R3
NH2
R1
Ag catalyst R2
+
To a solution of 2-aminobenzamide 1 (0.24 mmol, 1 equiv) and 2-
alkynylbenzaldehyde 2 (0.24 mmol, 1 equiv) in DMSO (4 mL) was
R2
N
O
NH3
O
R1
1
O
2
H N
2
added AgNO (8 mg, 20 mol%). The resulting mixture was then heated
3
at 120 °C for 4 h. After completion of the reaction, the mixture was
extracted with EtOAc. The combined extracts were washed with
brine, dried (Na SO ), and evaporated. The crude product was purified
I
2
4
6
-endo-dig
by chromatography (silica gel, acetone/hexane 20:80) to afford the
product.
H
H
N
R3
R3
12-Phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4a)
White solid; yield: 70 mg (89%); mp 211–213 °C.
[O]
N
N
R2
R1
R2
R1
HN
IR (neat): 2999, 1655, 1630, 1599, 1586, 1561, 1479, 1467, 1254,
–1
1
179, 1136, 1066, 858, 832, 752, 676, 580, 542 cm .
O
4
O
1
H NMR (400 MHz, DMSO-d ): δ = 8.69 (d, J = 8.1 Hz, 1 H), 8.08 (d, J =
6
II
Isoquinolino quinazolinone
6.7 Hz, 1 H), 7.87 (d, J = 4.0 Hz, 2 H), 7.71 (q, J = 3.9 Hz, 1 H), 7.50 (d, J =
3
.6 Hz, 2 H), 7.40–7.46 (m, 5 H), 7.31 (t, J = 7.2 Hz, 1 H), 6.97 (d, J = 9.0
Scheme 3 Plausible mechanism for the formation of isoquinoline-
fused quinazolinones
Hz, 1 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

E
Synthesis
A. D. Sonawane et al.
Paper
13
1
C NMR (100 MHz, DMSO-d ): δ = 166.44, 153.40, 138.49, 138.23,
H NMR (400 MHz, CDCl ): δ = 8.35 (d, J = 12.1 Hz, 2 H), 7.37 (d, J = 8.1
6
3
1
1
36.86, 133.54, 130.44, 129.10, 128.91, 128.70, 127.48, 127.02,
26.79, 126.70, 126.49, 125.30, 122.28, 122.19, 117.16.
Hz, 6 H), 7.20 (t, J = 7.9 Hz, 1 H), 7.01 (q, J = 8.7 Hz, 3 H), 4.09 (s, 3 H),
4.05 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H15N O: 323.1184; found:
13
C NMR (100 MHz, CDCl ): δ = 168.13, 154.63, 153.62, 150.59,
2
3
323.1155.
138.61, 137.68, 137.25, 130.43, 129.52, 129.43, 128.96, 127.70,
127.21, 126.68, 122.50, 122.31, 120.11, 117.53, 108.19, 106.56, 56.80,
56.41.
12-(4-Methoxyphenyl)-6H-isoquinolino[2,1-a]quinazolin-6-one
+
(4b)
HRMS (ESI): m/z [M + Na] calcd for C24H18N O Na: 405.1215; found:
2
3
Yellow solid; yield: 62 mg (83%); mp 235–236 °C.
405.1226.
IR (neat): 3067, 2905, 1651, 1626, 1602, 1523, 1510, 1337, 1258,
–1
12-Butyl-2,3-dimethoxy-6H-isoquinolino[2,1-a]quinazolin-6-one
4f)
1023, 831, 822, 772, 762, 544 cm .
(
1
H NMR (400 MHz, DMSO-d ): δ = 8.65 (d, J = 8.1 Hz, 1 H), 8.05 (d, J =
6
Brown sticky liquid; yield: 60 mg (81%).
6.3 Hz, 1 H), 7.82 (d, J = 5.4 Hz, 2 H), 7.63–7.67 (m, 1 H), 7.39–7.45 (m,
3
H), 7.32 (t, J = 7.2 Hz, 1 H), 7.27 (s, 1 H), 6.97 (dd, J = 14.8, 8.5 Hz, 3
IR (neat): 2934, 2961, 1719, 1630, 1604, 1592, 1439, 1398, 1340,
H), 3.77 (s, 3 H).
1267, 1226, 1166, 1064, 1032, 998, 878, 862, 771, 755, 664, 644 cm–1
.
13
1
C NMR (100 MHz, DMSO-d ): δ = 166.43, 159.57, 153.43, 138.40,
H NMR (400 MHz, CDCl ): δ = 8.42 (d, J = 7.6 Hz, 1 H), 8.28 (s, 1 H),
6
3
1
38.36, 133.71, 133.44, 130.35, 129.16, 128.90, 128.31, 126.73,
7.66 (d, J = 3.6 Hz, 2 H), 7.55–7.60 (m, 1 H), 6.94 (d, J = 5.8 Hz, 2 H),
4.06 (s, 3 H), 4.04 (s, 3 H), 3.13 (t, J = 7.6 Hz, 2 H), 1.47–1.54 (m, 2 H),
1.17–1.25 (m, 2 H), 0.82 (t, J = 7.2 Hz, 3 H).
126.60, 126.43, 125.09, 122.20, 122.13, 116.15, 114.44, 55.28.
+
HRMS (ESI): m/z [M + Na] calcd for C23H16N O Na: 375.1109; found:
2
2
13
375.1133.
C NMR (100 MHz, CDCl ): δ = 168.03, 154.56, 153.76, 150.11,
3
1
1
1
38.66, 138.30, 131.03, 129.78, 128.10, 127.24, 123.04, 120.72,
19.50, 115.18, 107.99, 105.88, 56.77, 56.37, 34.71, 32.31, 22.23,
3.78.
1
2-Butyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4c)
Brown solid; yield: 60 mg (74%); mp 95–96 °C.
HRMS (ESI): m/z [M + H]+ calcd for C22H23N O : 363.1709; found:
363.1679.
2
3
IR (neat): 2931, 2872, 1647, 1634, 1603, 1592, 1516, 1456, 1343,
–1
1271, 1189, 1114, 1066, 787, 759, 710, 544 cm .
1
H NMR (400 MHz, DMSO-d ): δ = 8.58 (d, J = 8.1 Hz, 1 H), 8.14 (dd, J =
6
8
-Bromo-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4g)
7
.9, 1.6 Hz, 1 H), 7.96 (d, J = 8.5 Hz, 1 H), 7.74–7.83 (m, 3 H), 7.60–7.66
Yellow solid; yield: 21 mg (91%); mp 218–219 °C.
(m, 2 H), 7.27 (s, 1 H), 3.12 (t, J = 7.6 Hz, 2 H), 1.37–1.44 (m, 2 H),
1
.08–1.16 (m, 2 H), 0.72 (t, J = 7.4 Hz, 3 H).
IR (neat): 3027, 1772, 1630, 1508, 1482, 1491, 1317, 1250, 1183,
1168, 895, 814, 712, 638, 529 cm .
–1
13
C NMR (100 MHz, DMSO-d ): δ = 166.22, 153.40, 140.10, 137.75,
6
1
1
1
33.76, 133.34, 131.57, 127.89, 127.42, 126.60, 126.53, 126.03,
24.60, 122.32, 121.39, 114.50, 33.67, 30.98, 21.50, 13.48.
H NMR (400 MHz, DMSO-d ): δ = 8.69 (d, J = 8.1 Hz, 1 H), 8.14 (d, J =
6
2.2 Hz, 1 H), 7.88 (q, J = 1.8 Hz, 2 H), 7.69–7.74 (m, 1 H), 7.49–7.55 (m,
3 H), 7.42–7.45 (m, 4 H), 6.91 (d, J = 9.4 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H19N O: 303.1497; found:
3
2
13
03.1469.
C NMR (100 MHz, DMSO-d ): δ = 165.22, 153.56, 138.32, 137.40,
6
1
1
36.57, 133.75, 133.60, 133.02, 129.22, 129.07, 128.82, 128.55,
27.52, 127.07, 126.91, 125.16, 124.64, 123.84, 119.46, 117.40.
1
2-(4-Fluoro-3-methylphenyl)-6H-isoquinolino[2,1-a]quinazolin-
HRMS (ESI): m/z [M + H]+ calcd for C22H14N OBr: 401.0289; found:
6-one (4d)
2
Brown solid; yield: 63 mg (85%); mp 86–87 °C.
401.0300.
IR (neat): 3015, 1651, 1646, 1629, 1519, 1362, 1215, 1157, 1033, 824,
–1
8-Bromo-12-(4-methoxyphenyl)-6H-isoquinolino[2,1-a]quinazo-
lin-6-one (4h)
754, 666, 645, 537 cm .
1
H NMR (400 MHz, CDCl ): δ = 8.95 (d, J = 8.1 Hz, 1 H), 8.33 (d, J = 8.1
3
Yellow solid; yield: 23 mg (85%); mp 254–256 °C.
Hz, 1 H), 7.75 (t, J = 7.0 Hz, 1 H), 7.61 (dd, J = 13.0, 7.6 Hz, 2 H), 7.40 (t,
J = 7.6 Hz, 1 H), 7.22–7.29 (m, 2 H), 7.10 (s, 1 H), 6.97–7.03 (m, 3 H),
IR (neat): 1648, 1628, 1603, 1506, 1478, 1317, 1277, 1248, 1163,
–1
2.27 (s, 3 H).
1122, 1026, 890, 833, 813, 793, 618, 540 cm .
13
1
C NMR (100 MHz, CDCl ): δ = 168.03, 162.79, 160.26, 154.24,
H NMR (400 MHz, DMSO-d ): δ = 8.66 (d, J = 8.1 Hz, 1 H), 8.12 (d, J =
3
6
1
1
1
38.50, 137.89, 133.57, 132.80, 130.65, 130.32, 130.26, 128.75,
28.20, 127.72, 126.88, 126.54, 126.46, 126.40, 125.99, 122.45,
22.03, 117.53, 116.23, 116.00, 14.76, 14.72.
+
2.2 Hz, 1 H), 7.86 (dd, J = 14.6, 8.3 Hz, 2 H), 7.66–7.70 (m, 1 H), 7.53
(dd, J = 9.2, 2.5 Hz, 1 H), 7.46 (d, J = 9.0 Hz, 2 H), 7.33 (d, J = 7.2 Hz, 1
H), 6.94–7.00 (m, 3 H), 3.79 (s, 3 H).
13
HRMS (ESI): m/z [M + Na] calcd for C23H15N OFNa: 377.1066; found:
C NMR (100 MHz, DMSO-d ): δ = 165.25, 159.70, 153.62, 138.30,
2
6
377.1096.
137.56, 133.79, 133.69, 132.99, 129.03, 128.91, 128.50, 126.87,
124.98, 124.54, 123.89, 119.41, 116.43, 114.58, 55.31.
HRMS (ESI): m/z [M + H]+ calcd for C23H16N O Br: 431.0395; found:
2,3-Dimethoxy-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-
2
2
one (4e)
431.0394.
Yellow solid; yield: 56 mg (78%); mp 209–211 °C.
9
-Chloro-12-phenyl-6H-isoquinolino[2,1-a]quinazolin-6-one (4i)
IR (neat): 3061, 1644, 1621, 1602, 1495, 1416, 1368, 1195, 1131, 991,
–1
752, 698, 641, 529, 501 cm .
Yellow solid; yield: 76 mg (88%); mp 268–270 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

F
Synthesis
A. D. Sonawane et al.
Paper
IR (neat): 3170, 3040, 1707, 1646, 1629, 1586, 1509, 1474, 1302,
9-Chloro-2,3-dimethoxy-12-phenyl-6H-isoquinolino[2,1-a]quin-
azolin-6-one (4m)
1
067, 869, 843, 832, 756, 705, 681, 547 cm–1
.
1
H NMR (400 MHz, CDCl ): δ = 8.99 (d, J = 7.6 Hz, 1 H), 8.29 (d, J = 8.5
Yellow solid; yield: 67 mg (86%); mp 256–258 °C.
3
Hz, 1 H), 7.77–7.81 (m, 1 H), 7.66 (t, J = 7.2 Hz, 2 H), 7.46 (t, J = 3.4 Hz,
IR (neat): 3061, 3004, 1619, 1584, 1495, 1454, 1393, 1270, 1220,
3
H), 7.36–7.39 (m, 3 H), 7.12 (s, 1 H), 6.96 (d, J = 1.8 Hz, 1 H).
–1
1195, 1072, 998, 880, 771, 701, 646, 532 cm
.
13
C NMR (100 MHz, CDCl ): δ = 167.24, 154.53, 139.20, 138.44,
1
3
H NMR (400 MHz, CDCl ): δ = 8.35 (s, 1 H), 8.28 (d, J = 8.5 Hz, 1 H),
3
1
1
37.04, 136.31, 133.79, 133.53, 129.61, 129.51, 129.19, 128.96,
28.35, 127.37, 127.21, 126.47, 125.87, 122.12, 120.72, 117.88.
7.43–7.45 (m, 3 H), 7.34–7.37 (m, 3 H), 7.05 (d, J = 14.8 Hz, 2 H), 6.97
(d, J = 1.3 Hz, 1 H), 4.09 (s, 3 H), 4.05 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H14N OCl: 357.0795; found:
13
2
C NMR (100 MHz, CDCl ): δ = 167.38, 154.92, 153.91, 150.77,
3
357.0770.
1
1
39.32, 137.47, 136.91, 136.62, 129.69, 129.56, 129.38, 129.24,
27.30, 127.25, 122.37, 120.83, 119.95, 117.73, 108.29, 106.66, 56.84,
9-Chloro-12-(4-methoxyphenyl)-6H-isoquinolino[2,1-a]quinazo-
56.46.
lin-6-one (4j)
HRMS (ESI): m/z [M + H]+ calcd for C24H18N O Cl: 417.1006; found:
2
3
Yellow solid; yield: 71 mg (87%); mp 177–178 °C.
417.0987.
IR (neat): 3066, 3000, 1655, 1630, 1599, 1586, 1479, 1467, 1316,
–1
1254, 1136, 1098, 833, 788, 754, 663, 453 cm
.
12-Butyl-9-chloro-2,3-dimethoxy-6H-isoquinolino[2,1-a]quin-
1
azolin-6-one (4n)
H NMR (400 MHz, CDCl ): δ = 8.93 (d, J = 7.6 Hz, 1 H), 8.25 (d, J = 8.5
3
Hz, 1 H), 7.75 (t, J = 7.4 Hz, 1 H), 7.60 (t, J = 8.8 Hz, 2 H), 7.35 (d, J = 8.5
Hz, 1 H), 7.26 (d, J = 8.5 Hz, 2 H), 7.00 (d, J = 9.0 Hz, 2 H), 6.94 (d, J = 8.5
Hz, 2 H), 3.86 (s, 3 H).
Yellow solid; yield: 62 mg (77%); mp 96–97 °C.
IR (neat): 2959, 2931, 1634, 1603, 1592, 1516, 1481, 1343, 1271,
–1
1155, 962, 935, 760, 710, 622, 473 cm
.
13
C NMR (100 MHz, CDCl ): δ = 167.25, 160.48, 154.63, 139.36,
1
3
H NMR (400 MHz, CDCl ): δ = 8.35 (d, J = 8.1 Hz, 1 H), 8.25 (s, 1 H),
3
1
1
38.34, 136.93, 133.72, 129.13, 128.61, 128.28, 127.29, 126.29,
25.69, 122.09, 120.76, 116.99, 114.96, 55.53.
7
2
.67 (d, J = 1.8 Hz, 1 H), 7.54 (dd, J = 8.5, 1.8 Hz, 1 H), 6.94 (d, J = 6.7 Hz,
H), 4.06 (s, 3 H), 4.04 (s, 3 H), 3.10 (t, J = 7.9 Hz, 2 H), 1.51–1.58 (m, 2
HRMS (ESI): m/z [M + Na]+ calcd for C23H15N O ClNa: 409.0720;
H), 1.26 (td, J = 14.7, 7.5 Hz, 2 H), 0.85 (t, J = 7.2 Hz, 3 H).
2
2
found: 409.0749.
13
C NMR (100 MHz, CDCl ): δ = 167.26, 154.80, 154.05, 150.26,
3
1
39.04, 138.22, 137.44, 129.77, 129.73, 127.72, 121.36, 120.57,
119.34, 115.66, 108.05, 105.99, 56.78, 56.41, 34.49, 32.29, 22.19,
3.77.
HRMS (ESI): m/z [M + Na]+ calcd for C22H21N O ClNa: 419.1138;
12-Butyl-9-chloro-6H-isoquinolino[2,1-a]quinazolin-6-one (4k)
1
Brownish sticky liquid; yield: 63 mg (69%).
IR (neat): 2960, 2873, 1719, 1561, 1479, 1466, 1450, 1423, 1340,
2
3
–1
found: 419.1145.
1316, 1266, 1155, 913, 876, 780, 564, 515 cm .
1
H NMR (400 MHz, CDCl ): δ = 8.86 (d, J = 8.1 Hz, 1 H), 8.34 (d, J = 8.5
3
Hz, 1 H), 7.74 (t, J = 7.6 Hz, 1 H), 7.67 (s, 1 H), 7.54–7.60 (m, 3 H), 7.00
Funding Information
(s, 1 H), 3.10 (t, J = 7.9 Hz, 2 H), 1.50–1.58 (m, 2 H), 1.27 (d, J = 7.2 Hz,
2
H), 0.83–0.90 (m, 3 H).
This study was supported by JSPS KAKENHI Grant Number 17550099
13
C NMR (100 MHz, CDCl ): δ = 167.10, 154.62, 139.18, 138.87,
3
to M.K.
a
Jp
a
n
S
o
ecity
o
f
r
hte
Pro
m
o
itn
of
Secince
1(
7
5
5
0
0
9
9)
1
1
37.60, 133.68, 133.57, 129.63, 128.28, 128.01, 127.78, 125.67,
25.36, 121.21, 120.34, 115.85, 34.34, 32.02, 22.07, 13.64.
HRMS (ESI): m/z [M + H]+ calcd for C20H18N OCl: 337.1108; found:
Supporting Information
2
337.1097.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610910.
S
u
p
p
o
nrtogI
i
f
rm oaitn
S
u
p
p
ortioIgnfmr oaitn
9-Chloro-12-(4-fluoro-3-methylphenyl)-6H-isoquinolino[2,1-
a]quinazolin-6-one (4l)
Brown solid; yield: 66 mg (81%); mp 252–254 °C.
References
IR (neat): 3139, 3033, 1637, 1597, 1583, 1511, 1501, 1481, 1444,
–1
(1) Affiliated to Savitribai Phule Pune University, Pune 411007
India (formerly University of Pune).
1
318, 1128, 1120, 833, 809, 772, 754, 611 cm .
1
H NMR (400 MHz, CDCl ): δ = 8.97 (d, J = 7.6 Hz, 1 H), 8.28 (d, J = 8.5
3
(
2) For reviews, see: (a) Gladysz, J. A. Chem. Rev. 2011, 111, 1167.
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(
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C NMR (100 MHz, CDCl ): δ = 167.23, 162.94, 160.40, 154.50,
3
139.14, 137.56, 137.05, 133.83, 133.46, 132.17, 132.13, 130.26,
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126.42, 125.80, 121.96, 120.71, 117.73, 116.41, 116.19, 14.73, 14.70.
HRMS (ESI): m/z [M + H]+ calcd for C23H15N OClF: 389.0857; found:
2
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H

H
Synthesis
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Paper
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–H