Copper-catalyzed N-arylation and aerobic oxidation: One-pot synthesis of tetrahydroisoquinolino[2,1-a]quinazolinone derivatives

Article abstract of DOI:10.1039/c3ra44975k

An efficient and practical copper-catalyzed one-pot method for synthesis of tetrahydroisoquinolino[2,1-a]quinazolinone derivatives has been developed, and the corresponding target products were prepared in moderate to good yields. The one-pot approach underwent sequential copper-catalyzed N-arylation, intramolecular aerobic oxidative cyclization, and the newly synthesized products provided diverse structures for screening of biological molecules.

Full text of DOI:10.1039/c3ra44975k

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Copper-catalyzed N-arylation and aerobic oxidation:
one-pot synthesis of tetrahydroisoquinolino[2,1-a]-
quinazolinone derivatives†
Cite this: RSC Adv., 2014, 4, 2694
c
a
ab
Hua Tian,ab Hongwei Qiao, Changjin Zhu and Hua Fu
*
An efficient and practical copper-catalyzed one-pot method for synthesis of tetrahydroisoquinolino[2,1-a]-
quinazolinone derivatives has been developed, and the corresponding target products were prepared in
moderate to good yields. The one-pot approach underwent sequential copper-catalyzed N-arylation,
intramolecular aerobic oxidative cyclization, and the newly synthesized products provided diverse
structures for screening of biological molecules.
Received 10th September 2013
Accepted 7th November 2013
DOI: 10.1039/c3ra44975k
www.rsc.org/advances
on the selective transition metal-catalyzed aerobic oxidative
formation of bonds,7,8 and some N-heterocycles, have been
synthesized via aerobic oxidation.9 Since 1998, there has been
Introduction
It is a long-termed theme to develop novel, efficient and prac-
tical methods for the synthesis of N-heterocycles because they
are widely found in natural products, biologically and phar-
maceutically active molecules.1 Quinazolinone derivatives
broadly occurring in natural products show various biological
and pharmacological activities.2 For example, they exhibit many
central nervous system effects, cardiovascular and antiin-
ammatory activity, and act as psychotropic, hypnotic, cardio-
tonic and antihistamine agents.3 Some compounds are potent
antibacterial, antifungal, antiviral, antimycobacterial and anti-
malarial substances,4 and they are also used as inhibitors of
some enzymes including monoamine oxidase, aldose reduc-
tase, tumor necrosis factor a, thymidylate synthase.3,4 1,2,3,4-
Tetrahydroisoquinolines have been used as inhibitors of
phenylethanolamine N-methyltransferase5 and shown thera-
peutic value in the treatment of anxiety and ischemic heart
conditions.6 To the best of our knowledge, the N-fused structure
of quinazolinone and tetrahydroisoquinoline motifs, tetrahy-
droisoquinolino[2,1-a]quinazolinone (Fig. 1), has not been
developed including their synthesis and biological activity thus
far. Therefore, it is important to explore an efficient approach to
this kind of compound. Molecular oxygen is the ideal oxidant
for its abundance, low cost and lack of toxic by-products,7 but
the aerobic oxidation methods oen meet great challenges in
selectivity and scope. Recently, great advances have been made
great advance in copper-catalyzed cross coupling with inex-
pensive and low toxic copper-catalysts, and the methods have
displayed wide application with good functional tolerance.10,11
Further, some efficient copper-catalyzed aerobic oxidative
synthesis of heterocycles has been developed by us12 and other
groups.13 Herein, we report a novel and efficient copper-cata-
lyzed one-pot synthesis of tetrahydroisoquinolino[2,1-a]quina-
zolinone derivatives.
Results and discussion
At rst, copper-catalyzed reaction of N-ethyl-2-iodobenzamide
(1b) with 1,2,3,4-tetrahydroisoquinoline (2a) leading to 5-ethyl-
4b,5,12,13-tetrahydroisoquinolino[2,1-a]quinazolin-6-one (3b)
was used as the model to investigate experimental conditions
including catalysts, ligands, bases, solvents and temperature,
and the N-arylation was rst performed at 80 ꢀC for 12 h under
nitrogen atmosphere, and then the aerobic oxidation was
carried out at 120 ꢀC for 48 h under oxygen atmosphere. As
shown in Table 1, seven ligands of copper-catalysts (40 mol%)
were screened using 20 mol% CuI as the catalyst, two equiv. of
aDepartment of Applied Chemistry, Beijing Institute of Technology, Beijing 100081,
P. R. China. E-mail: fuhua@mail.tsinghua.edu.cn
bKey Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua University, Beijing 100084, P. R.
China
cDepartment of Chemistry, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen 361005, P. R. China
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of compounds 3a–f0 and 4a. See DOI: 10.1039/c3ra44975k
Fig. 1 Structure of tetrahydroisoquinolino[2,1-a]quinazolinone con-
taining tetrahydroisoquinoline and quinazolinone motifs.
2694 | RSC Adv., 2014, 4, 2694–2704
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Table 1 Investigation of conditions for copper-catalyzed synthesis of
5-ethyl-4b,5,12,13-tetrahydroisoquinolino[2,1-a]quinazolin-6-one (3b)
using N-ethyl-2-iodobenzamide (1b) and 1,2,3,4-tetrahydroisoquino-
line (2a) as the substratesa
13–18). No target product was observed in the absence of
copper-catalyst (entry 19). DMF, 1,4-dioxane and toluene were
applied as the solvents (entries 20–22), and DMF also provided
higher yield (entry 20). When reaction temperature was changed
(entries 23–26), the corresponding yields decreased. The reac-
tion gave lower yield when amount of 1b (entry 27) or CuI (entry
28) was reduced.
As shown in Table 2, the substrate scope for the copper-
catalyzed one-pot synthesis of tetrahydroisoquinolino[2,1-a]-
quinazolinone derivatives (3) was investigated under our
screened conditions (using 20 mol% CuI as the catalyst (relative
to amount of 1), two or four equiv. of K3PO4 as the base, DMSO
as the solvent under nitrogen atmosphere for the rst step;
under oxygen atmosphere for the second step), the tested
substrates provided moderate to good yields. For N-alkyl-2-hal-
oaryl amides (1), the electronic effect of substituents on the
aromatic ring including neutral, electron-donating and elec-
tron-withdrawing groups did not show the evident difference in
reactivity. The reactivity order is as follow: aryl iodides > aryl
bromides > aryl chlorides. Interestingly, N-alkyl-2-chloroaryl
amides (1s–u) also provide higher yields (entries 26–30). Actu-
ally, aryl chlorides are oen weak substrates in the Ullmann-
type couplings,10 so the results exhibited ortho-substituent effect
of amides in N-alkyl-2-chloroaryl amides (1s–u). For substrates 2,
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline exhibited higher
reactivity than 1,2,3,4-tetrahydroisoquinoline. The reactions
showed good tolerance of functional groups including amides
(entries 1–30), ether (entries 4, 7, 10, 14, 20, 22, 25, 31 and 34),
C–Cl bond (entries 5, 21 and 22), nitro (entries 30 and 31), and
pyridinyl (entries 32–34) in the substrates.
In order to explore the reaction mechanism for synthesis of
tetrahydroisoquinolino[2,1-a]quinazolinone derivatives, some
control experiments were performed. First, copper-catalyzed
coupling of 2-iodo-N-pentylbenzamide (1e) with 1,2,3,4-tetra-
hydroisoquinoline (2a) under nitrogen atmosphere provided
2-(3,4-dihydroisoquinolin-2(1H)-yl)-N-pentylbenzamide (4a) in
88% yield with small amount of 3i (8%) appearing (Scheme 1A).
Then, intramolecular aerobic oxidative cyclyzation of 4a under
various conditions were investigated (Scheme 1B). Product 3i
was obtained in 43% yield in the absence of base (K3PO4). A 81%
yield was found in the presence of one equiv. of K3PO4. When
the reaction was carried out under copper-catalysis, the reaction
Entry
Cat.
Ligand
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
Cu2O
CuO
Cu(OAc)2
Cu powder
—
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L-1
L-2
L-3
L-4
L-5
L-6
L-7
—
—
—
—
—
—
—
—
—
—
—
—
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
NaOAc
DBU
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
32
39
14
28
Trace
36
Trace
56
50
65
27
58
64
52
42
Trace
21
62
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
62
Trace
0
—
—
—
—
—
—
—
—
1,4-dioxane
PhMe
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
40c
56d
51e
27f
41g
52h
CuI
a
Reaction conditions: N-ethyl-2-iodobenzamide (1b) (0.5 mmol), 1,2,3,4-
tetrahydroisoquinoline (2a) (1 mmol), catalyst (0.1 mmol), ligand (0.2
mmol), base (1 mmol), solvent (1.0 mL), under nitrogen atmosphere provided a 80% yield. Therefore, a possible mechanism on the
for the rst step, under oxygen atmosphere for the second step.
copper-catalyzed one-pot synthesis of tetrahydroisoquinolino
[2,1-a]quinazolinone derivatives is proposed in Scheme 2. First,
b
c
d
Isolated yield. 120 ꢀC for the two steps. 50 ꢀC for the rst step
e
and 120 ꢀC for the second step. 25 ꢀC for the rst step and 120 ꢀC
f
for the second step. 80 ꢀC for the rst step and 150 ꢀC for the copper-catalyzed N-arylation of substituted 1,2,3,4-tetrahy-
g
h
second step. Using 0.5 mmol of 2a as the substrate. Using
droisoquinoline (2) with 1 provides I, and intramolecular
aerobic oxidation of I leads to II in the presence of base (K3PO4),
and intramolecular nucleophilic attack of nitrogen in amide to
carbon in imine in II gives the target product (3).
0.05 mmol of CuI as the catalyst.
K2CO3 as the base (relative to amount of 1b) in DMSO (entries
1–7), and they afforded low efficiency. A 56% yield was observed
in the absence of ligand (entry 8), and the result showed ortho-
Conclusions
substituent effect of amide in 1b. Effect of bases was investi- We have developed a novel, efficient and practical copper-
gated (compare entries 8–12), and K3PO4 afforded the highest catalyzed one-pot method for the synthesis of tetrahy-
yield (entry 10). Other six copper catalysts were screened (entries droisoquinolino[2,1-a]quinazolinone derivatives. The protocol
13–18), and CuI gave the highest efficiency (compare entries 10, uses inexpensive CuI as the catalyst, economical and
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Table 2 Copper-catalyzed one-pot synthesis of tetrahydroisoquinolino[2,1-a]quinazolinone derivatives (3)a
Entry
1
1
Time-1, Temp., Time-2
20 h, 120 ꢀC, 48 h
3 (Yieldb)
2
3
4
5
6
7
8
12 h, 120 ꢀC, 48 h
18 h, 120 ꢀC, 48 h
20 h, 125 ꢀC, 48 h
18 h, 120 ꢀC, 48 h
20 h, 120 ꢀC, 48 h
20 h, 125 ꢀC, 48 h
20 h, 120 ꢀC, 48 h
1b
1b
1b
1c
9
24 h, 120 ꢀC, 60 h
24 h, 125 ꢀC, 72 h
10
1e
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Table 2 (Contd.)
Entry
11
1
Time-1, Temp., Time-2
20 h, 120 ꢀC, 48 h
3 (Yieldb)
12
13
14
20 h, 120 ꢀC, 48 h
20 h, 125 ꢀC,48 h
24 h, 125 ꢀC, 72 h
1h
15
16
17
20 h, 120 ꢀC, 48 h
12 h, 120 ꢀC, 48 h
20 h, 120 ꢀC, 48 h
3b (60%)
18
19
20
20 h, 120 ꢀC, 48 h
20 h, 120 ꢀC, 48 h
20 h, 125 ꢀC, 48 h
1m
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Table 2 (Contd.)
Entry
21
1
Time-1, Temp., Time-2
24 h, 120 ꢀC, 48 h
3 (Yieldb)
22
23
24
25
1n
24 h, 125 ꢀC, 72 h
24 h, 120 ꢀC, 60 h
24 h, 120 ꢀC, 60 h
24 h, 125 ꢀC, 72 h
1p
26
27
24 h, 120 ꢀC, 60 h
18 h, 120 ꢀC, 48 h
1q
28
24 h, 120 ꢀC, 48 h
29
30
20 h, 120 ꢀC, 48 h
24 h, 120 ꢀC, 48 h
3b (52%)
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Table 2 (Contd.)
Entry
31
1
Time-1, Temp., Time-2
24 h, 125 ꢀC, 72 h
3 (Yieldb)
1t
32
33
24 h, 120 ꢀC, 60 h
18 h, 120 ꢀC, 48 h
1u
1u
34
24 h, 125 ꢀC, 72 h
a
Reaction conditions: N-alkyl-2-haloaryl amide (1) (0.5 mmol), substituted 1,2,3,4-tetrahydroisoquinoline (2) (1 mmol), CuI (0.1 mmol), K3PO4
(1 mmol using 2a, 2b and 2d as the substrates; 2 mmol using 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride as the substrate),
b
DMSO (1.0 mL), under nitrogen atmosphere for the rst step, under oxygen atmosphere for the second step. Isolated yield.
Scheme
2 Possible mechanism for copper-catalyzed one-pot
synthesis of tetrahydroisoquinolino[2,1-a]quinazolinone derivatives.
Scheme 1 (A) Copper-catalyzed coupling of 2-iodo-N-pentylbenza-
mide (1e) with 1,2,3,4-tetrahydroisoquinoline (2a) under nitrogen
atmosphere leading to 2-(3,4-dihydroisoquinolin-2(1H)-yl)-N-pen-
tylbenzamide (4a). (B) Intramolecular aerobic oxidative cyclyzation of
4a under various conditions.
Experimental section
General methods
All reactions were carried out under nitrogen atmosphere
environmentally friendly oxygen as the oxidant, and the corre- for the rst step; under oxygen atmosphere for the second
sponding N-fused heterocycles were prepared in moderate to step. Proton and carbon magnetic resonance spectra
good yields. The reactions underwent copper-catalyzed N- (1H NMR and 13C NMR) were recorded using tetramethylsi-
aryaltion, intramolecular aerobic oxidative cyclization. The lane (TMS) in the solvent of CDCl3 as the internal standard
newly synthesized products provided diverse structures for (1H NMR: TMS at 0.00 ppm, CDCl3 at 7.26 ppm; 13C NMR:
screening of biological molecules.
CDCl3 at 77.2 ppm).
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General procedure for one-pot synthesis of 3a–f 0
1H), 6.68 (s, 1H), 6.52 (s, 1H), 5.66 (s, 1H), 4.34– 4.44 (m, 1H), 4.11
(dd, J ¼ 14.1 Hz, 6.9 Hz, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 3.56–3.67
(m, 1H), 3.11–3.30 (m, 2H), 2.67 (dd, J ¼ 16.5 Hz, 4.8 Hz, 1H), 1.31
(t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 162.9, 149.0,
147.4, 147.3, 133.2, 129.1, 127.8, 126.7, 119.5, 119.0, 113.7, 112.0,
108.9, 72.2, 56.1, 55.9, 44.8, 42.3, 24.0, 14.1. ESI-MS: [M + H]+ m/z
339.1.
3-Chloro-5-ethyl-12,13-dihydro-4bH-isoquinolino[2,1-a]qui-
nazolin-6(5H)-one (3e). Eluent: petroleum ether/ethyl acetate
(3 : 1). Yield 93 mg (61%). Yellow oil. 1H NMR (CDCl3, 400 MHz)
d 7.88 (dd, J ¼ 7.6 Hz, 1.2 Hz, 1H), 7.31 (td, J ¼ 7.6 Hz, 1.2 Hz,
1H), 7.17 (s, 1H), 7.11 (dd, J ¼ 8.4 Hz, 2.0 Hz, 1H), 6.94 (d, J ¼ 8.4
Hz, 1H), 6.86 (d, J ¼ 8.4 Hz, 1H), 6.81 (t, J ¼ 7.6 Hz, 1H), 5.63 (s,
1H), 4.51–4.59 (m, 1H), 4.17 (dd, J ¼ 14.4 Hz, 6.4 Hz, 1H), 3.63–
3.71 (m, 1H), 3.11–3.24 (m, 2H), 2.71 (dd, J ¼ 17.2 Hz, 5.6 Hz,
1H), 1.33 (t, J ¼ 6.8 Hz, 3H). 13C NMR (CDCl3, 100 MHz) d 162.5,
146.6, 138.2, 133.4, 132.8, 132.0, 130.7, 129.3, 128.4, 125.6,
119.5, 118.6, 113.1, 72.0, 44.5, 42.7, 23.3, 13.9. ESI-MS: [M + H]+
m/z 313.0.
To a 25 mL Schlenk tube charged with a magnetic stirrer were
added N-ethyl-2-haloaryl amide (1) (0.5 mmol), substituted
1,2,3,4-tetrahydroisoquinoline (2) (1 mmol), CuI (0.1 mmol,
19 mg), K3PO4 (1 mmol, 212 mg using 2a, 2b and 2d as the
substrates; 2 mmol, 424 mg using 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline hydrochloride as the substrate), anhydrous
ꢀ
DMSO (1.0 mL). The mixture was stirred at 80 C for 12–24 h
under nitrogen atmosphere (Completion of reaction with TLC
determination). The nitrogen atmosphere was replaced with an
oxygen atmosphere, and the mixture was stirred at 120–125 C
ꢀ
for 48–72 h (Completion of reaction with TLC determination). The
resulting solution was cooled to room temperature, and the
solvent was removed by a rotary evaporator. The residue was
puried by column chromatography on silica gel (petroleum
ether/EtOAc) to give the target product (3a–f0).
5-Methyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-
6(5H)-one (3a). Eluent: petroleum ether/ethyl acetate (2 : 1).
Yield 81 mg (61%). Light yellow solid, mp 190–191 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.90 (dd, J ¼ 7.8 Hz, 1.8 Hz, 1H), 7.28–7.33
(m, 1H), 7.13–7.21 (m, 3H), 7.05 (dd, J ¼ 7.5 Hz, 1.8 Hz, 1H), 6.88
(d, J ¼ 8.1 Hz, 1H), 6.81 (td, J ¼ 7.5 Hz, 0.9 Hz, 1H), 5.66 (s, 1H),
4.06 (ddd, J ¼ 14.1 Hz, 6.6 Hz, 2.7 Hz, 1H), 3.54–3.64 (m, 1H),
3.31 (s, 3H), 3.15–3.26 (m, 1H), 2.79 (ddd, J ¼ 16.5 Hz, 5.1 Hz, 2.1
Hz, 1H). 13C NMR (CDCl3, 75 MHz) d 163.6, 147.4, 135.5, 134.6,
133.3, 129.3, 129.1, 128.3, 126.3, 126.1, 119.5, 118.9, 113.8, 74.1,
44.6, 35.2, 24.9. ESI-MS: [M + H]+ m/z 265.1.
5-Ethyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-
6(5H)-one (3b). Eluent: petroleum ether/ethyl acetate (3 : 1).
Yield 90 mg (65%) using 1b as the substrate; 83 mg (60%) using
1j as the substrate; 72 mg (52%) using 1s as the substrate.
Yellow solid, mp 131–132 ꢀC. 1H NMR (CDCl3, 300 MHz) d 7.88
(dd, J ¼ 7.8 Hz, 1.8 Hz, 1H), 7.25–7.32 (m, 1H), 7.08–7.21 (m,
3H), 7.02 (d, J ¼ 7.5 Hz, 1H), 6.87 (d, J ¼ 8.1 Hz, 1H), 6.79 (t, J ¼
7.8 Hz, 1H), 5.68 (s, 1H), 4.42–4.51 (m, 1H), 4.14 (ddd, J ¼ 14.4
Hz, 6.9 Hz, 2.1 Hz, 1H), 3.61–3.72 (m, 1H), 3.11–3.28 (m, 2H),
2.75 (dd, J ¼ 17.1 Hz, 4.8 Hz, 1H), 1.30 (t, J ¼ 6.9 Hz, 3H). 13C
NMR (CDCl3, 75 MHz) d 162.8, 147.2, 136.0, 134.5, 133.2, 129.3,
129.1, 128.2, 126.3, 125.8, 119.4, 118.9, 113.5, 72.3, 44.7, 42.3,
24.3, 14.0. ESI-MS: [M + H]+ m/z 279.1.
5-Isopropyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazo-
lin-6(5H)-one (3f). Eluent: petroleum ether/ethyl acetate (3 : 1).
Yield 93 mg (64%). White solid, mp 203–204 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.83 (dd, J ¼ 7.8 Hz, 1.8 Hz, 1H), 7.23–7.33
(m, 2H), 7.06–7.14 (m, 2H), 6.97–7.00 (m, 1H), 6.85 (d, J ¼ 8.1
Hz, 1H), 6.76 (t, J ¼ 7.5 Hz, 1H), 5.62 (s, 1H), 4.94–5.02 (m, 1H),
4.22 (dd, J ¼ 14.7 Hz, 6.9 Hz, 1H), 3.73–3.84 (m, 1H), 3.20–3.32
(m, 1H), 2.80 (dd, J ¼ 17.1 Hz, 6.0 Hz, 1H), 1.33–1.44 (m, 6H). 13
C
NMR (CDCl3, 75 MHz) d 163.5, 147.1, 137.4, 134.4, 133.1, 129.4,
129.2, 127.9, 126.5, 126.0, 119.7, 119.2, 113.2, 68.5, 46.8, 44.9,
23.9, 22.3, 20.3. ESI-MS: [M + H]+ m/z 293.1.
5-Isopropyl-2,3-dimethoxy-12,13-dihydro-4bH-isoquinolino-
[2,1-a]quinazolin-6(5H)-one (3g). Eluent: petroleum ether/ethyl
acetate (2 : 1). Yield 125 mg (70%). Yellow solid, mp 162–163 ꢀC.
1H NMR (CDCl3, 300 MHz) d 7.85 (dd, J ¼ 7.8 Hz, 1.2 Hz, 1H),
7.30 (td, J ¼ 7.8 Hz, 1.2 Hz, 1H), 6.88 (d, J ¼ 8.1 Hz, 1H), 6.76–
6.81 (m, 2H), 6.47 (s, 1H), 5.59 (s, 1H), 4.94–5.04 (m, 1H), 4.20
(dd, J ¼ 13.9 Hz, 6.6 Hz, 1H), 3.68–3.87 (m, 7H), 3.14–3.25 (m,
1H), 2.67 (dd, J ¼ 16.8 Hz, 6.0 Hz, 1H), 1.37–1.47 (m, 6H). 13C
NMR (CDCl3, 75 MHz) d 163.5, 148.6, 147.1, 133.1, 129.4, 126.4,
119.7, 119.3, 113.3, 111.9, 109.7, 68.6, 56.1, 55.9, 47.1, 45.0, 23.3,
22.2, 20.8. ESI-MS: [M + H]+ m/z 353.1.
5-Cyclopropyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quina-
zolin-6(5H)-one (3h). Eluent: petroleum ether/ethyl acetate
(2 : 1). Yield 65 mg (45%). Yellow solid, mp 157–158 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.89 (d, J ¼ 7.8 Hz, 1H), 7.26–7.36 (m, 2H),
7.10–7.17 (m, 2H), 6.99–7.02 (m, 1H), 6.87 (d, J ¼ 8.1 Hz, 1H),
6.77 (t, J ¼ 7.5 Hz, 1H), 5.70 (s, 1H), 4.14 (dd, J ¼ 14.4 Hz, 6.6 Hz,
1H), 3.60–3.71 (m, 1H), 3.11–3.26 (m, 2H), 2.74 (dd, J ¼ 17.1 Hz,
5.1 Hz, 1H), 1.02–1.08 (m, 1H), 0.80–0.94 (m, 3H). 13C NMR
(CDCl3, 75 MHz) d 164.9, 146.9, 136.9, 134.4, 133.5, 129.2, 128.1,
126.3, 125.9, 119.2, 118.5, 113.4, 74.1, 44.9, 30.6, 24.3, 10.2, 7.0.
ESI-MS: [M + H]+ m/z 291.1.
5-Ethyl-3-methyl-12,13-dihydro-4bH-isoquinolino[2,1-a]qui-
nazolin-6(5H)-one (3c). Eluent: petroleum ether/ethyl acetate
(3 : 1). Yield 102 mg (70%). Light yellow solid, mp 178–179 C.
ꢀ
1H NMR (CDCl3, 400 MHz) d 7.88 (dd, J ¼ 7.6 Hz, 1.2 Hz, 1H),
7.28 (td, J ¼ 7.6 Hz, 1.2 Hz, 1H), 6.84–6.98 (m, 4H), 6.78 (t, J ¼ 7.6
Hz, 1H), 5.65 (s, 1H), 4.46–4.53 (m, 1H), 4.11 (dd, J ¼ 14.0 Hz, 6.8
Hz, 1H), 3.60–3.67 (m, 1H), 3.11–3.23 (m, 2H), 2.69 (dd, J ¼ 16.8
Hz, 5.2 Hz, 1H) 2.24 (s, 3H), 1.31 (t, J ¼ 6.8 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) d 162.8, 147.2, 135.9, 133.2, 131.3, 129.2,
129.1, 129.0, 126.1, 119.2, 118.7, 113.3, 72.3, 44.8, 42.5, 23.8,
21.3, 14.0. ESI-MS: [M + H]+ m/z 293.1.
5-Ethyl-2,3-dimethoxy-12,13-dihydro-4bH-isoquinolino[2,1-a]-
quinazolin-6(5H)-one (3d). Eluent: petroleum ether/ethyl acetate
(3 : 2). Yield 121 mg (71%). Yellow solid, mp 174–175 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.89 (dd, J ¼ 7.5 Hz, 1.5 Hz, 1H), 7.31 (td, J ¼
7.5 Hz, 1.5 Hz, 1H), 6.90 (d, J ¼ 8.1 Hz, 1H), 6.83 (t, J ¼ 7.5 Hz,
5-Pentyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-
6(5H)-one (3i). Eluent: petroleum ether/ethyl acetate (2 : 1).
Yield 117 mg (73%). Light yellow oil. 1H NMR (CDCl3, 300 MHz)
d 7.87 (dd, J ¼ 7.5 Hz, 1.2 Hz, 1H), 7.25–7.30 (m, 1H), 7.18–
7.21 (m, 1H), 7.07–7.16 (m, 2H), 7.00 (d, J ¼ 7.5 Hz, 1H), 6.86 (d,
2700 | RSC Adv., 2014, 4, 2694–2704
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J ¼ 8.1 Hz, 1H), 6.77 (t, J ¼ 7.5 Hz, 1H), 5.66 (s, 1H), 4.42–4.52
(m, 1H), 4.08–4.17 (m, 1H), 3.60–3.70 (m, 1H), 3.16–3.32 (m,
1H), 3.00–3.10 (m, 1H), 2.73 (dd, J ¼ 16.8 Hz, 5.1 Hz, 1H), 1.69–
1.72 (m, 2H), 1.33–1.38 (m, 4H), 0.89 (t, J ¼ 7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 163.0, 147.1, 136.2, 134.5, 133.2, 129.3, 129.2,
128.2, 126.3, 125.7, 119.2, 118.7, 113.3, 72.8, 47.7, 44.8, 29.1,
28.5, 24.2, 22.5, 14.1. ESI-MS: [M + H]+ m/z 321.1.
5-Dodecyl-2,3-dimethoxy-12,13-dihydro-4bH-isoquinolino-
[2,1-a]quinazolin-6(5H)-one (3n). Eluent: petroleum ether/ethyl
acetate (3 : 1). Yield 166 mg (69%). Colourless oil. 1H NMR
(CDCl3, 300 MHz) d 7.89 (dd, J ¼ 7.8 Hz, 1.2 Hz, 1H), 7.32 (td, J ¼
7.5 Hz, 1.2 Hz, 1H), 6.90 (d, J ¼ 8.1 Hz, 1H), 6.83 (t, J ¼ 7.5 Hz,
1H), 6.68 (s, 1H), 6.51 (s, 1H), 5.64 (s, 1H), 4.37–4.45 (m, 1H),
4.15 (dd, J ¼ 14.1 Hz, 5.1 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.57–
3.68 (m, 1H), 3.05–3.24 (m, 2H), 2.66 (dd, J ¼ 16.8 Hz, 4.8 Hz,
1H), 1.67–1.75 (m, 2H), 1.19–1.38 (m, 18H), 0.88 (t, J ¼ 6.3 Hz,
3H). 13C NMR (CDCl3, 75 MHz) d 163.0, 149.0, 147.4, 147.2,
133.2, 129.2, 128.0, 126.6, 119.4, 118.9, 113.5, 112.0, 108.8, 72.7,
56.1, 55.9, 47.7, 44.9, 32.0, 29.71, 29.68, 29.61, 29.5, 29.4, 28.9,
27.0, 23.8, 22.8, 14.2. ESI-MS: [M + H]+ m/z 479.4.
2,3-Dimethoxy-5-pentyl-12,13-dihydro-4bH-isoquinolino[2,1-a]
quinazolin-6(5H)-one (3j). Eluent: petroleum ether/ethyl acetate
1
ꢀ
(2 : 1). Yield 146 mg (75%). Yellow solid, mp 78–79 C. H NMR
(CDCl3, 300 MHz) d 7.90 (d, J ¼ 7.5 Hz, 1H), 7.33 (td, J ¼ 7.2 Hz, 1.2
Hz, 1H), 6.81–6.92 (m, 2H), 6.69 (s, 1H), 6.51 (s, 1H), 5.64 (s, 1H),
4.38–4.48 (m, 1H), 4.16 (dd, J ¼ 13.2 Hz, 6.3 Hz, 1H), 3.79–3.83 (m,
6H), 3.60–3.68 (m, 1H), 3.06–3.24 (m, 2H), 2.67 (dd, J ¼ 16.8 Hz,
5.1 Hz, 1H), 1.66–1.79 (m, 2H), 1.30–1.43 (m, 4H), 0.90 (t, J ¼ 6.9
Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 163.0, 149.0, 147.4, 147.2,
133.2, 129.2, 128.0, 126.6, 119.4, 118.9, 113.5, 112.0, 108.8,
72.7, 56.1, 55.9, 47.6, 44.9, 29.1, 28.6, 23.9, 22.5, 14.1. ESI-MS:
[M + H]+ m/z 381.1.
5-Phenyl-12,13-dihydro-4bH-isoquinolino[2,1-A]quinazolin-
6(5H)-one (3o). Eluent: petroleum ether/ethyl acetate (5 : 1).
Yield 76 mg (47%). White solid, mp 71–72 ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.00 (dd, J ¼ 7.8 Hz, 1.8 Hz, 1H), 7.47–7.50 (m, 2H),
7.31–7.41 (m, 4H), 6.97–7.23 (m, 5H), 6.87 (d, J ¼ 7.2 Hz, 1H),
6.16 (s, 1H), 4.25 (ddd, J ¼ 14.4 Hz, 6.9 Hz, 2.1 Hz, 1H), 3.67–3.77
(m, 1H), 3.23–3.35 (m, 1H), 2.84 (dd, J ¼ 16.8 Hz, 5.1 Hz, 1H). 13
C
5-Cyclohexyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazo-
lin-6(5H)-one (3k). Eluent: petroleum ether/ethyl acetate (5 : 1).
Yield 93 mg (56%). White solid, mp 204–205 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.84 (dd, J ¼ 7.5 Hz, 1.2 Hz, 1H), 7.33–7.36
(m, 1H), 7.22–7.28 (m, 1H), 7.05–7.13 (m, 2H), 6.96–6.98 (m,
1H), 6.84 (d, J ¼ 8.1 Hz, 1H), 6.75 (t, J ¼ 7.5 Hz, 1H), 5.65 (s, 1H),
4.60–4.68 (m, 1H), 4.22 (dd, J ¼ 14.7 Hz, 7.2 Hz, 1H), 3.73–3.84
(m, 1H), 3.20–3.32 (m, 1H), 2.79 (dd, J ¼ 17.4 Hz, 6.6 Hz, 1H),
2.15–2.18 (m, 1H), 2.02–2.06 (m, 1H), 1.80–1.89 (m, 2H), 1.66–
1.72 (m, 1H), 1.40–1.60 (m, 4H), 1.09–1.19 (m, 1H). 13C NMR
(CDCl3, 75 MHz) d 163.4, 147.0, 137.7, 134.4, 133.1, 129.5, 129.1,
127.8, 126.5, 125.9, 119.6, 119.1, 113.2, 68.9, 54.6, 44.9, 33.0,
32.5, 30.9, 26.0, 25.6, 23.8. ESI-MS: [M + H]+ m/z 333.1.
5-Benzyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-
6(5H)-one (3l). Eluent: petroleum ether/ethyl acetate (3 : 1).
Yield 87 mg (51%). Light yellow solid, mp 193–194 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.96 (dd, J ¼ 7.5 Hz, 1.2 Hz, 1H), 7.25–7.36
(m, 7H), 7.13–7.21 (m, 2H), 7.01 (d, J ¼ 8.1 Hz, 1H), 6.83–6.89
(m, 2H), 5.66–5.72 (m, 2H), 4.37 (d, J ¼ 15.3 Hz, 1H), 4.00 (dd,
J ¼ 13.8 Hz, 4.2 Hz, 1H), 3.45–3.55 (m, 1H), 3.04–3.15 (m, 1H),
2.71 (dd, J ¼ 17.1 Hz, 3.9 Hz, 1H). 13C NMR (CDCl3, 75 MHz) d
163.6, 147.6, 137.3, 135.3, 134.9, 133.5, 129.6, 129.3, 128.7,
128.3, 127.7, 127.5, 126.3, 126.0, 119.5, 118.7, 113.7, 71.8, 49.7,
44.7, 24.7. ESI-MS: [M + H]+ m/z 341.1.
5-Dodecyl-12,13-dihydro-4bH-isoquinolino[2,1-a]quinazolin-
6(5H)-one (3m). Eluent: petroleum ether/ethyl acetate (5 : 1).
Yield 140 mg (67%). Yellow oil. 1H NMR (CDCl3, 300 MHz) d 7.88
(dd, J ¼ 7.5 Hz, 1.2 Hz, 1H), 7.27–7.33 (m, 1H), 7.19–7.23 (m,
1H), 7.12–7.17 (m, 2H), 7.03 (d, J ¼ 7.5 Hz, 1H), 6.88 (d, J ¼ 7.8
Hz, 1H), 6.80 (t, J ¼ 7.8 Hz, 1H), 5.67 (s, 1H), 4.42–4.52 (m, 1H),
4.11–4.20 (m, 1H), 3.62–3.73 (m, 1H), 3.19–3.36 (m, 1H), 3.00–
3.10 (m, 1H), 2.77 (dd, J ¼ 17.1 Hz, 4.8 Hz, 1H), 1.67–1.75 (m,
2H), 1.21–1.39 (m, 18H), 0.88 (t, J ¼ 6.6 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 163.0, 147.1, 136.1, 134.4, 133.2, 129.3, 129.2,
128.2, 126.3, 125.8, 119.3, 118.8, 113.3, 72.8, 47.7, 44.8, 32.0,
29.73, 29.69, 29.6, 29.5, 28.8, 26.9, 24.2, 22.8, 14.2. ESI-MS:
[M + H]+ m/z 419.4.
NMR (CDCl3, 75 MHz) d 162.9, 147.5, 141.7, 135.7, 134.5, 133.9,
130.0, 129.2, 128.9, 128.3, 127.3, 126.2, 126.0, 125.2, 119.8,
119.3, 114.2, 75.4, 45.2, 24.7. ESI-MS: [M + H]+ m/z 327.1.
5-Ethyl-9-methyl-12,13-dihydro-4bH-isoquinolino[2,1-a]qui-
nazolin-6(5H)-one (3p). Eluent: petroleum ether/ethyl acetate
(2 : 1). Yield 82 mg (56%). Yellow solid, mp 147–148 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.77 (d, J ¼ 7.8 Hz, 1H), 7.10–7.22 (m, 3H),
7.04 (d, J ¼ 7.5 Hz, 1H), 6.68 (s, 1H), 6.63 (d, J ¼ 7.8 Hz, 1H), 5.66
(s, 1H), 4.42–4.49 (m, 1H), 4.15 (ddd, J ¼ 14.4 Hz, 6.6 Hz, 2.1 Hz,
1H), 3.62–3.72 (m, 1H), 3.13–3.31 (m, 2H), 2.78 (dd, J ¼ 17.1 Hz,
4.2 Hz, 1H), 2.30 (s, 3H), 1.30 (t, J ¼ 6.9 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 163.0, 147.1, 143.9, 136.1, 134.6, 129.3, 129.2,
128.2, 126.3, 125.8, 120.6, 116.4, 113.9, 72.3, 44.7, 42.2, 24.3,
22.2, 14.0. ESI-MS: [M + H]+ m/z 293.1.
10-Methyl-5-propyl-12,13-dihydro-4bH-isoquinolino[2,1-a]-
quinazolin-6(5H)-one (3q). Eluent: petroleum ether/ethyl
acetate (3 : 1). Yield 73 mg (48%). Yellow solid, mp 97–98 ꢀC. 1H
NMR (CDCl3, 300 MHz) d 7.95 (d, J ¼ 7.5 Hz, 1H), 7.25–7.39 (m,
5H), 7.16 (t, J ¼ 7.5 Hz, 1H), 5.67 (s, 1H), 3.36–3.46 (m, 1H), 3.20–
3.31 (m, 2H), 3.05–3.15 (m, 2H), 2.87–2.96 (m, 1H), 2.33 (s, 3H),
1.17–1.35 (m, 2H), 0.65 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3,
75 MHz) d 164.6, 148.2, 135.5, 134.5, 131.9, 130.5, 130.1, 129.3,
129.2, 126.4, 125.7, 125.5, 124.7, 71.5, 44.3, 42.4, 28.8, 22.2, 16.7,
11.4. ESI-MS: [M + H]+ m/z 307.1.
5-Butyl-8-methyl-12,13-dihydro-4bH-isoquinolino[2,1-a]qui-
nazolin-6(5H)-one (3r). Eluent: petroleum ether/ethyl acetate
(4 : 1). Yield 99 mg (62%). Light yellow oil. 1H NMR (CDCl3,
300 MHz) d 7.68 (d, J ¼ 2.1 Hz, 1H), 7.18–7.21 (m, 1H), 7.07–7.16
(m, 3H), 7.00 (dd, J ¼ 7.2 Hz, 1.8 Hz, 1H), 6.78 (d, J ¼ 8.1 Hz, 1H),
5.63 (s, 1H), 4.44–4.49 (m, 1H), 4.07–4.14 (m, 1H), 3.57–3.67 (m,
1H), 3.15–3.27 (m, 1H), 3.02–3.11 (m, 1H), 2.72 (dd, J ¼ 16.8 Hz,
4.5 Hz, 1H), 2.18 (s, 3H), 1.64–1.74 (m, 2H), 1.37–1.47 (m, 2H),
0.94 (t, J ¼ 7.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 163.2, 144.9,
136.2, 134.5, 134.0, 129.33, 129.31, 128.7, 128.1, 126.2, 125.8,
118.8, 113.6, 72.9, 47.4, 44.8, 31.0, 24.1, 20.4, 20.2, 14.0. ESI-MS:
[M + H]+ m/z 321.1.
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111.7, 72.8, 55.7, 47.0, 45.0, 31.0, 24.4, 20.2, 13.9. ESI-MS:
[M + H]+ m/z 337.1.
5-Butyl-2,3-dimethoxy-8-methyl-12,13-dihydro-4bH-isoquinol-
ino[2,1-a]quinazolin-6(5H)-one (3s). Eluent: petroleum ether/
ethyl acetate (3 : 2). Yield 136 mg (72%). Light yellow solid, mp
69–70 ꢀC. 1H NMR (CDCl3, 300 MHz) d 7.70 (s, 1H), 7.13 (dd, J ¼
8.1 Hz, 1.8 Hz, 1H), 6.82 (d, J ¼ 8.1 Hz, 1H), 6.68 (s, 1H), 6.50 (s,
1H), 5.61 (s, 1H), 4.37–4.47 (m, 1H), 4.11 (dd, J ¼ 13.2 Hz, 5.1 Hz,
1H), 3.82 (s, 3H), 3.78 (s, 3H), 3.54–3.64 (m, 1H), 3.07–3.22 (m,
2H), 2.64 (dd, J ¼ 16.8 Hz, 4.5 Hz, 1H), 2.22 (s, 3H), 1.65–1.75 (m,
2H), 1.35–1.47 (m, 2H), 0.94 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3,
75 MHz) d 163.2, 148.9, 147.4, 145.0, 134.0, 129.3, 128.9, 128.0,
126.6, 118.9, 113.8, 111.9, 108.9, 72.7, 56.1, 55.9, 47.4, 44.9, 31.1,
23.8, 20.4, 20.2, 14.0. ESI-MS: [M + H]+ m/z 381.2.
5-Butyl-2,3,8-trimethoxy-12,13-dihydro-4bH-isoquinolino-
[2,1-a]quinazolin-6(5H)-one (3x). Eluent: petroleum ether/ethyl
ꢀ
acetate (3 : 2). Yield 177 mg (89%). Yellow solid, mp 64–65 C.
1H NMR (CDCl3, 300 MHz) d 7.41 (d, J ¼ 2.7 Hz, 1H), 6.91 (dd,
J ¼ 8.7 Hz, 3.0 Hz, 1H), 6.85 (d, J ¼ 9.0 Hz, 1H), 6.65 (s, 1H), 6.50
(s, 1H), 5.57 (s, 1H), 4.24–4.29 (m, 1H), 3.88–4.98 (m, 1H), 3.80
(s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.46–3.56 (m, 1H), 3.01–3.17
(m, 2H), 2.67 (d, J ¼ 15.1 Hz, 1H), 1.61–1.67 (m, 2H), 1.32–1.39
(m, 2H), 0.89 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d
163.1, 153.5, 149.0, 147.4, 141.6, 126.8, 121.3, 120.3, 116.4,
115.8, 111.9, 111.6, 109.3, 72.6, 56.1, 55.9, 55.7, 47.1, 45.0, 31.1,
23.9, 20.2, 13.9. ESI-MS: [M + H]+ m/z 397.3.
8-Chloro-5-propyl-12,13-dihydro-4bH-isoquinolino[2,1-a]-
quinazolin-6(5H)-one (3t). Eluent: petroleum ether/ethyl acetate
(3 : 1). Yield 82 mg (50%). Yellow solid, mp 123–124 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 7.82 (d, J ¼ 2.4 Hz, 1H), 7.10–7.25 (m, 4H),
7.03 (d, J ¼ 7.2 Hz, 1H), 6.81 (d, J ¼ 8.7 Hz, 1H), 5.66 (s, 1H),
4.41–4.51 (m, 1H), 4.12 (dd, J ¼ 14.7 Hz, 5.1 Hz, 1H), 3.63–3.73
(m, 1H), 3.16–3.28 (m, 1H), 2.98–3.08 (m, 1H), 2.76 (dd, J ¼ 17.1
8-Methoxy-5-pentyl-12,13-dihydro-4bH-isoquinolino[2,1-a]-
quinazolin-6(5H)-one (3y). Eluent: petroleum ether/ethyl acetate
(3 : 1). Yield 144 mg (82%). Yellow oil. 1H NMR (CDCl3, 300
MHz) d 7.43 (d, J ¼ 2.7 Hz, 1H), 7.10–7.22 (m, 3H), 7.04 (d, J ¼ 7.5
Hz, 1H), 6.93 (dd, J ¼ 9.0 Hz, 2.7 Hz, 1H), 6.86 (d, J ¼ 8.7 Hz, 1H),
5.64 (s, 1H), 4.26–4.37 (m, 1H), 4.02 (d, J ¼ 11.4 Hz, 1H), 3.73 (s,
3H), 3.55–3.68 (m, 1H), 3.07–3.24 (m, 2H), 2.78 (d, J ¼ 17.1 Hz,
1H), 1.62–1.72 (m, 2H), 1.31–1.38 (m, 4H), 0.88 (t, J ¼ 7.2 Hz,
3H). 13C NMR (CDCl3, 75 MHz) d 163.1, 153.4, 141.5, 135.4,
134.6, 129.3, 128.3, 127.3, 126.2, 121.3, 120.1, 115.9, 111.7, 72.8,
55.7, 47.2, 44.8, 29.1, 28.5, 24.5, 22.3, 14.1. ESI-MS: [M + H]+ m/z
351.1.
8-Methoxy-3-methyl-5-pentyl-12,13-dihydro-4bH-isoquinol-
ino[2,1-a]quinazolin-6(5H)-one (3z). Eluent: petroleum ether/
ethyl acetate (5 : 1). Yield 87 mg (48%). Yellow oil. 1H NMR
(CDCl3, 400 MHz) d 7.44 (d, J ¼ 3.2 Hz, 1H), 6.98–7.00 (m, 2H),
6.91–6.94 (m, 2H), 6.86 (d, J ¼ 9.2 Hz, 1H), 5.61 (s, 1H), 4.36–4.42
(m, 1H), 4.06 (d, J ¼ 12.0 Hz, 1H), 3.75 (s, 3H), 3.55–3.68 (m, 1H),
3.04–3.20 (m, 2H), 2.73 (d, J ¼ 14.0 Hz, 1H), 2.27 (s, 3H), 1.65–
1.74 (m, 2H), 1.31–1.38 (m, 4H), 0.88 (t, J ¼ 6.8 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) d 163.0, 153.3, 141.5, 135.8, 135.0, 131.3,
129.2, 129.0, 126.6, 124.2, 123.6, 121.3, 111.6, 72.9, 55.8, 47.5,
45.0, 29.1, 28.5, 23.9, 22.5, 21.3, 14.1. ESI-MS: [M + H]+ m/z
365.1.
6-Oxo-N,5-dipentyl-5,6,12,13-tetrahydro-4bH-isoquinolino-
[2,1-a]quinazoline-8-carboxamide (3a0). Eluent: petroleum
ether/ethyl acetate (2 : 1). Yield 124 mg (65%). Yellow solid, mp
75–76 ꢀC. 1H NMR (CDCl3, 300 MHz) d 8.12 (d, J ¼ 2.1 Hz, 1H),
7.94 (dd, J ¼ 9.0 Hz, 2.4 Hz, 1H), 7.10–7.20 (m, 3H), 7.03 (d, J ¼
6.9 Hz, 1H), 6.92 (d, J ¼ 9.0 Hz, 1H), 6.27 (t, J ¼ 5.1 Hz, 1H), 5.71
(s, 1H), 4.48–4.57 (m, 1H), 4.22 (dd, J ¼ 14.4 Hz, 6.0 Hz, 1H),
3.67–3.78 (m, 1H), 3.35 (q, J ¼ 6.3 Hz, 2H), 3.18–3.30 (m, 1H),
3.00–3.10 (m, 1H), 2.78 (dd, J ¼ 17.1 Hz, 5.1 Hz, 1H), 1.69–1.79
(m, 2H), 1.49–1.58 (m, 2H), 1.24–1.44 (m, 8H), 0.82–0.98 (m,
6H). 13C NMR (CDCl3, 75 MHz) d 166.5, 162.5, 149.4, 136.1,
134.2, 133.5, 129.4, 128.4, 126.6, 126.4, 125.3, 125.2, 117.2,
113.3, 72.8, 47.9, 45.0, 40.0, 29.4, 29.2, 29.0, 28.4, 24.3, 22.5,
22.4, 14.1. ESI-MS: [M + H]+ m/z 434.3.
Hz, 5.1 Hz, 1H), 1.67–1.78 (m, 2H), 0.98 (t, J ¼ 7.5 Hz, 3H). 13
C
NMR (CDCl3, 75 MHz) d 162.0, 145.7, 135.8, 134.2, 133.1, 129.4,
128.9, 128.4, 126.4, 125.6, 124.5, 119.9, 114.8, 72.9, 49.4, 44.9,
24.0, 22.0, 11.4. ESI-MS: [M + H]+ m/z 327.1.
8-Chloro-2,3-dimethoxy-5-propyl-12,13-dihydro-4bH-iso-
quinolino[2,1-a]quinazolin-6(5H)-one (3u). Eluent: petroleum
ether/ethyl acetate (2 : 1). Yield 111 mg (57%). Yellow solid, mp
125–126 ꢀC. 1H NMR (CDCl3, 300 MHz) d 7.84 (d, J ¼ 2.4 Hz, 1H),
7.24 (dd, J ¼ 8.7 Hz, 2.4 Hz, 1H), 6.84 (d, J ¼ 8.7 Hz, 1H), 6.66 (s,
1H), 6.51 (s, 1H), 5.63 (s, 1H), 4.34–4.44 (m, 1H), 4.10 (dd, J ¼
14.4 Hz, 6.3 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.57–3.68 (m, 1H),
3.03–3.20 (m, 2H), 2.66 (dd, J ¼ 16.8 Hz, 5.1 Hz, 1H), 1.69–1.81
(m, 2H), 0.99 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d
162.0, 149.1, 147.5, 145.8, 133.0, 128.8, 127.7, 126.3, 124.6,
120.0, 115.0, 112.0, 108.7, 72.8, 56.1, 55.9, 49.3, 45.0, 23.7, 22.1,
11.4. ESI-MS: [M + H]+ m/z 387.2.
5-Ethyl-8-methoxy-12,13-dihydro-4bH-isoquinolino[2,1-a]-
quinazolin-6(5H)-one (3v). Eluent: petroleum ether/ethyl acetate
(2 : 1 to 1 : 1). Yield 88 mg (57%). Yellow solid, mp 57–58 ꢀC. 1H
NMR (CDCl3, 400 MHz) d 7.44 (d, J ¼ 2.8 Hz, 1H), 7.19–7.21 (m,
2H), 7.12–7.17 (m, 1H), 7.06 (d, J ¼ 7.2 Hz, 1H), 6.94 (dd, J ¼ 9.2
Hz, 3.2 Hz, 1H), 6.88 (d, J ¼ 9.2 Hz, 1H), 5.66 (s, 1H), 4.29–4.32
(m, 1H), 3.98 (d, J ¼ 11.2 Hz, 1H), 3.74 (s, 3H), 3.55–3.62 (m, 1H),
3.13–3.28 (m, 2H), 2.82 (d, J ¼ 16.4 Hz, 1H), 1.25 (t, J ¼ 6.4 Hz,
3H). 13C NMR (CDCl3, 100 MHz) d 162.9, 153.6, 141.6, 135.0,
134.6, 129.3, 128.3, 126.5, 126.2, 121.3, 120.5, 116.4, 111.6, 72.3,
55.7, 44.9, 41.7, 24.8, 14.0. ESI-MS: [M + H]+ m/z 309.1.
5-Butyl-8-methoxy-12,13-dihydro-4bH-isoquinolino[2,1-a]-
quinazolin-6(5H)-one (3w). Eluent: petroleum ether/ethyl
acetate (3 : 1). Yield 129 mg (77%). Yellow oil. 1H NMR (CDCl3,
300 MHz) d 7.43 (d, J ¼ 3.0 Hz, 1H), 7.11 - 7.22 (m, 3H), 7.04 (d,
J ¼ 7.2 Hz, 1H), 6.94 (dd, J ¼ 9.0 Hz, 3.0 Hz, 1H), 6.87 (d, J ¼ 9.0
Hz, 1H), 5.64 (s, 1H), 4.31–4.41 (m, 1H), 4.03 (d, J ¼ 13.5 Hz, 1H),
3.73 (s, 3H), 3.55–3.68 (m, 1H), 3.08–3.24 (m, 2H), 2.79 (d, J ¼
16.8 Hz, 1H), 1.61–1.71 (m, 2H), 1.33–1.45 (m, 2H), 0.92 (t, J ¼
7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 163.1, 153.4, 141.5,
135.4, 134.6, 129.3, 128.3, 127.3, 126.2, 121.3, 120.1, 115.9,
5-Butyl-9-nitro-12,13-dihydro-4bH-isoquinolino[2,1-a]quina-
zolin-6(5H)-one (3b0). Eluent: petroleum ether/ethyl acetate
(2 : 1). Yield 72 mg (41%). Yellow solid, mp 139–140 ꢀC. 1H NMR
(CDCl3, 300 MHz) d 8.01 (d, J ¼ 8.7 Hz, 1H), 7.69 (d, J ¼ 1.8 Hz,
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1H), 7.58 (dd, J ¼ 8.4 Hz, 2.1 Hz, 1H), 7.13–7.23 (m, 3H), 7.08 (d, (88%). White solid, mp 84–85 C. H NMR (CDCl3, 400 MHz) d
J ¼ 7.2 Hz, 1H), 5.74 (s, 1H), 4.49–4.58 (m, 1H), 4.17–4.26 (m, 9.71 (br.s., 1H), 8.22 (dd, J ¼ 8.0 Hz, 1.2 Hz, 1H), 7.45 (td, J ¼ 8.0
1H), 3.75–3.85 (m, 1H), 3.23–3.35 (m, 1H), 3.04–3.14 (m, 1H), Hz, 1.2 Hz, 1H), 7.15–7.27 (m, 5H), 7.04 (d, J ¼ 7.2 Hz, 1H), 4.11 (s,
2.86 (dd, J ¼ 17.1 Hz, 5.1 Hz, 1H), 1.69–1.81 (m, 2H), 1.37–1.50 2H), 3.36 (t, J ¼ 5.6 Hz, 2H), 3.29 (q, J ¼ 6.0 Hz, 2H), 3.07 (t, J ¼ 5.6
(m, 2H), 0.96 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d Hz, 2H), 1.18–1.25 (m, 2H), 1.03–1.12 (m, 4H), 0.74 (t, J ¼ 6.8 Hz,
161.2, 151.2, 147.7, 135.6, 133.9, 130.5, 129.5, 128.7, 126.6, 3H). 13C NMR (CDCl3, 100 MHz) d 166.3, 151.1, 134.2, 133.4,
125.4, 123.0, 113.5, 108.1, 72.9, 47.8, 45.1, 30.7, 24.0, 20.2, 13.9. 132.0, 131.7, 129.0, 128.3, 126.9, 126.5, 126.2, 125.1, 120.8, 56.9,
ESI-MS: [M + H]+ m/z 352.2.
50.5, 39.6, 29.6, 29.3, 28.9, 22.4, 14.0. ESI-MS: [M + H]+ m/z 322.3.
5-Butyl-2,3-dimethoxy-9-nitro-12,13-dihydro-4bH-isoquino-
lino[2,1-a]quinazolin-6(5H)-one (3c0). Eluent: petroleum ether/
ethyl acetate (3 : 1). Yield 99 mg (46%). Yellow solid, mp 62–
Acknowledgements
63 ꢀC. 1H NMR (CDCl3, 300 MHz) d 8.03 (d, J ¼ 8.7 Hz, 1H), 7.72 The authors wish to thank the National Natural Science Foun-
(d, J ¼ 1.8 Hz, 1H), 7.61 (dd, J ¼ 8.4 Hz, 2.1 Hz, 1H), 6.65 (s, 1H), dation of China (Grant nos. 21172128, 21372139 and 21221062),
6.54 (s, 1H), 5.70 (s, 1H), 4.44–4.54 (m, 1H), 4.23 (dd, J ¼ 14.7 Hz, and the Ministry of Science and Technology of China (Grant no.
6.3 Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.68–3.78 (m, 1H), 3.08– 2012CB722605) for nancial support.
3.28 (m, 2H), 2.75 (dd, J ¼ 17.1 Hz, 5.1 Hz, 1H), 1.67–1.79 (m,
2H), 1.37–1.50 (m, 2H), 0.97 (t, J ¼ 7.2 Hz, 3H). 13C NMR (CDCl3,
Notes and references.
75 MHz) d 161.3, 151.2, 149.3, 147.8, 147.7, 130.6, 127.5, 126.0,
123.2, 113.7, 112.1, 108.5, 108.2, 72.9, 56.2, 56.0, 47.8, 45.2, 30.8,
23.7, 20.2, 13.9. ESI-MS: [M + H]+ m/z 412.2.
1 Comprehensive Heterocyclic Chemistry ed. A. R. Katritzky and
C. W. Rees, Pergamon, New York, 1984.
11-Propyl-5,6,10b,11-tetrahydro-4,4b,11-triaza-chrysen-12-
one. (3d0). Eluent: petroleum ether/ethyl acetate (2 : 1). Yield 65
mg (44%). Yellow solid, mp 136–137 ꢀC. 1H NMR (CDCl3,
300 MHz) d 8.21 (dd, J ¼ 4.8 Hz, 2.1 Hz, 1H), 8.05 (dd, J ¼ 7.5 Hz,
2.1 Hz, 1H), 7.05–7.20 (m, 4H), 6.69 (dd, J ¼ 7.5 Hz, 4.8 Hz, 1H),
5.76 (s, 1H), 4.83 (ddd, J ¼ 13.8 Hz, 7.2 Hz, 2.1 Hz, 1H), 4.51–4.60
(m, 1H), 3.50–3.60 (m, 1H), 3.23–3.34 (m, 1H), 2.98–3.07 (m,
1H), 2.76 (dd, J ¼ 16.8 Hz, 4.8 Hz, 1H), 1.73–1.85 (m, 2H), 1.02 (t,
J ¼ 7.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz) d 162.6, 157.4, 152.0,
137.0, 136.4, 135.3, 129.5, 128.3, 126.2, 124.9, 115.0, 112.9, 71.8,
49.5, 43.1, 25.0, 21.9, 11.4. ESI-MS: [M + H]+ m/z 294.1.
9-Methyl-11-propyl-5,6,10b,11-tetrahydro-4,4b,11-triaza-
chrysen-12-one. (3e0). Eluent: petroleum ether/ethyl acetate
(4 : 1). Yield 76 mg (52%). Yellow solid, mp 146–147 ꢀC. 1H NMR
(CDCl3, 400 MHz) d 8.20 (dd, J ¼ 5.2 Hz, 2.0 Hz, 1H), 8.05 (dd,
J ¼ 7.2 Hz, 2.0 Hz, 1H), 6.93–7.00 (m, 3H), 6.68 (dd, J ¼ 7.2 Hz,
5.2 Hz, 1H), 5.74 (s, 1H), 4.81 (ddd, J ¼ 13.6 Hz, 7.2 Hz, 2.0 Hz,
1H), 4.54–4.61 (m, 1H), 3.49–3.56 (m, 1H), 3.19–3.28 (m, 1H),
2.99–3.01 (m, 1H), 2.71 (dd, J ¼ 16.8 Hz, 5.6 Hz, 1H), 2.27 (s, 3H),
1.76–1.82 (m, 2H), 1.02 (t, J ¼ 7.6 Hz, 3H). 13C NMR (CDCl3, 100
MHz) d 162.6, 157.4, 152.0, 137.0, 136.2, 135.8, 132.0, 129.4,
129.1, 125.3, 114.9, 112.9, 71.8, 49.6, 43.2, 24.6, 21.8, 21.3, 11.4.
ESI-MS: [M + H]+ m/z 308.1.
2 (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62,
9787; (b) D. A. Horton, G. T. Bourne and M. L. Smythe,
Chem. Rev., 2003, 103, 893.
3 N. J. Liverton, D. J. Armstrong, D. A. Claremon, D. C. Remy,
J. J. Baldwin, R. J. Lynch, G. Zhang and R. J. Gould, Bioorg.
Med. Chem. Lett., 1998, 8, 483.
4 W. Zhang, J. P. Mayer, S. E. Hall and J. A. Weigel, J. Comb.
Chem., 2001, 3, 255.
5 W. L. Mendelson, C. B. Spainhour Jr, S. S. Jones, B. L. Lam
and K. L. Wert, Tetrahedron Lett., 1980, 21, 1393.
6 R. M. DeMarinis, W. M. Bryan, L. M. Hillegass,
D. McDermott and R. G. Pendleton, J. Med. Chem., 1981,
24, 756.
7 A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem.,
Int. Ed., 2011, 50, 11062.
8 For some reviews, see: (a) S. S. Stahl, Angew. Chem., Int. Ed.,
2004, 43, 3400; (b) T. Punniyamurthy, S. Velusamy and
J. Iqbal, Chem. Rev., 2005, 105, 2329; (c) C. Liu, H. Zhang,
W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; (d) Z. Shi,
C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 41,
3381; (e) A. N. Campbell and S. S. Stahl, Acc. Chem. Res.,
2012, 45, 851.
9 (a) W. C. P. Tsang, N. Zheng and S. L. Buchwald, J. Am. Chem.
Soc., 2005, 127, 14560; (b) W. C. P. Tsang, R. H. Munday,
G. Brasche, N. Zheng and S. L. Buchwald, J. Org. Chem.,
2008, 73, 7603; (c) J. A. Jordan-Hore, C. C. C. Johansson,
M. Gulias, E. M. Beck and M. J. Gaunt, J. Am. Chem. Soc.,
2008, 130, 16184; (d) M. Wasa and J.-Q. Yu, J. Am. Chem.
Soc., 2008, 130, 14058; (e) K. Inamoto, T. Saito, M. Katsuno,
T. Sakamoto and K. Hiroya, Org. Lett., 2007, 9, 2931; (f)
T.-S. Mei, X. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2009,
8,9-Dimethoxy-11-propyl-5,6,10b,11-tetrahydro-4,4b,11-tri-
aza-chrysen-12-one (3f0). Eluent: petroleum ether/ethyl acetate
1
ꢀ
(2 : 1). Yield 98 mg (53%). Yellow solid, mp 61–62 C. H NMR
(CDCl3, 300 MHz) d 8.23 (dd, J ¼ 5.1 Hz, 1.8 Hz, 1H), 8.06 (dd,
J ¼ 7.5 Hz, 2.1 Hz, 1H), 6.72 (dd, J ¼ 7.5 Hz, 4.8 Hz, 1H), 6.66 (s,
1H), 6.53 (s, 1H), 5.73 (s, 1H), 4.82 (dd, J ¼ 13.5 Hz, 6.0 Hz, 1H),
4.48–4.57 (m, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 3.45–3.55 (m, 1H),
3.16–3.28 (m, 1H), 3.02–3.11 (m, 1H), 2.64 (dd, J ¼ 16.8 Hz, 5.1
Hz, 1H), 1.76–1.83 (m, 2H), 1.02 (t, J ¼ 7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz) d 162.7, 157.5, 152.0, 149.1, 147.3, 137.0, 128.3,
127.4, 115.0, 113.0, 112.2, 108.1, 71.8, 56.2, 55.9, 49.6, 43.4, 24.5,
21.9, 11.4. ESI-MS: [M + H]+ m/z 354.2.
¨
131, 10806; (g) J. J. Neumann, S. Rakshit, T. Droge and
F. Glorius, Angew. Chem., Int. Ed., 2009, 48, 6892; (h)
Q. Xiao, W.-H. Wang, G. Liu, F.-K. Meng, J.-H. Chen,
Z. Yang and Z.-J. Shi, Chem.–Eur. J., 2009, 15, 7292.
2-(3,4-Dihydroisoquinolin-2(1H)-yl)-N-pentylbenzamide. (4a). 10 For recent reviews on copper-catalyzed cross couplings, see: (a)
Eluent: dichloromethane/tetrahydrofuran (250 : 1). Yield 141 mg
S. V. Ley and A. W. Thomas, Angew. Chem., Int. Ed, 2003, 42,
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5400; (b) K. Kunz, U. Scholz and D. Ganzer, Synlett, 2003, 2428;
(c) I. P. Beletskaya and A. V. Cheprakov, Coord. Chem. Rev.,
2004, 248, 2337; (d) G. Evano, N. Blanchard and M. Toumi,
Chem. Rev., 2008, 108, 3054; (e) D. Ma and Q. Cai, Acc. Chem.
2007, 72, 672; (m) C. Wan, J. Zhang, S. Wang, J. Fan and
Z. Wang, Org. Lett., 2010, 12, 2338; (n) Z. Wu, Q. Huang,
X. Zhou, L. Yu, Z. Li and D. Wu, Eur. J. Org. Chem., 2011,
5242.
Res., 2008, 41, 1450; (f) F. Monnier and M. Taillefer, Angew. 12 (a) H. Xu and H. Fu, Chem.–Eur. J., 2012, 18, 1180; (b)
Chem., Int. Ed, 2009, 48, 6954; (g) D. S. Surry and
S. L. Buchwald, Chem. Sci., 2010, 1, 13; (h) H. Rao and H. Fu,
Synlett, 2011, 745, and references cited therein.
X. Wang, Y. Jin, Y. Zhao, L. Zhu and H. Fu, Org. Lett., 2012,
14, 452; (c) W. Xu and H. Fu, J. Org. Chem., 2011, 76, 3846;
(d) J. Lu, Y. Jin, H. Liu, Y. Jiang and H. Fu, Org. Lett., 2011,
13, 3694; (e) W. Xu, Y. Jin, H. Liu, Y. Jiang and H. Fu, Org.
Lett., 2011, 13, 1274; (f) C. Wang, S. Li, H. Liu, Y. Jiang and
H. Fu, J. Org. Chem., 2010, 75, 7936.
11 For selected papers, see: (a) D. Ma, Y. Zhang, J. Yao, S. Wu
and F. Tao, J. Am. Chem. Soc., 1998, 120, 12459; (b)
R. K. Gujadhur, C. G. Bates and D. Venkataraman, Org.
Lett., 2001, 3, 4315; (c) A. Klapars, J. C. Antilla, X. Huang 13 For selected papers, see: (a) S. Ueda and H. Nagasawa,
and S. L. Buchwald, J. Am. Chem. Soc., 2001, 123, 7727; (d)
J. C. Antilla, A. Klapars and S. L. Buchwald, J. Am. Chem.
Soc., 2002, 124, 11684; (e) A. Klapars, X. H. Huang and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 7421; (f)
K. Okano, H. Tokuyama and T. Fukuyama, Org. Lett., 2003,
5, 4987; (g) D. Ma, Q. Cai and H. Zhang, Org. Lett., 2003, 5,
2453; (h) A. S. Gajare, K. Toyota, M. Yoshifuji and
F. Yoshifuji, Chem. Commun., 2004, 1994; (i) H. Rao, Y. Jin,
H. Fu, Y. Jiang and Y. Zhao, Chem.–Eur. J., 2006, 12, 3636;
(j) X. Guo, H. Rao, Y. Jin, H. Fu, Y. Jiang and Y. Zhao, Adv.
Synth. Catal., 2006, 348, 2197; (k) L. Zhu, L. Cheng,
Y. Zhang, R. Xie and J. You, J. Org. Chem., 2007, 72, 2737;
(l) D. Jiang, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem.,
Angew. Chem., Int. Ed, 2008, 47, 6411; (b) G. Brasche and
S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 1932; (c)
S. Ueda and H. Nagasawa, J. Am. Chem. Soc., 2009, 131,
15080; (d) P. Saha, T. Ramana, N. Purkait, M. A. Ali,
R. Paul and T. Punniyamurthy, J. Org. Chem., 2009, 74,
8719; (e) C. Wan, J. Zhang, S. Wang, J. Fan and Z. Wang,
Org. Lett., 2010, 12, 2338; (f) H. Wang, Y. Wang, D. Liang,
L. Liu, J. Zhang and Q. Zhu, Angew. Chem., Int. Ed., 2011,
50, 5678; (g) Y.-F. Wang, H. Chen, X. Zhu and S. Chiba,
J. Am. Chem. Soc., 2012, 134, 11980; (h) Z. Wu, Q. Huang,
X. Zhou, L. Yu, Z. Li and D. Wu, Eur. J. Org. Chem., 2011,
5242; For a review: see: ; (i) T. Liu and H. Fu, Synthesis,
2012, 44, 2805.
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