CuI-catalyzed Sonogashira reaction for the efficient synthesis of 1H-imidazo[2,1-a]isoquinoline derivatives

Article abstract of DOI:10.1016/j.tet.2017.06.043

The Sonogashira reaction first, and then intra-molecular hydroamination of alkyne catalyzed by CuI/o-phen was proved to be an efficient method for the synthesis of imidazo[2,1-a]isoquinoline, phenanthro[9′,10′:4,5]imidazo[2,1-a]isoquinoline and acenaphtho[1′,2′:4,5]imidazo [2,1-a]isoquinoline derivatives in the presence of Cs₂CO₃.

Full text of DOI:10.1016/j.tet.2017.06.043

Accepted Manuscript
CuI-catalyzed Sonogashira reaction for the efficient synthesis of 1H-
imidazo[2,1-a]isoquinoline derivatives
Ma-Yong Gang, Jian-Quan Liu, Xiang-Shan Wang
PII:
S0040-4020(17)30676-2
10.1016/j.tet.2017.06.043
TET 28808
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 April 2017
Revised Date: 17 June 2017
Accepted Date: 20 June 2017
Please cite this article as: Gang M-Y, Liu J-Q, Wang X-S, CuI-catalyzed Sonogashira reaction for the
efficient synthesis of 1H-imidazo[2,1-a]isoquinoline derivatives, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.06.043.
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ACCEPTED MANUSCRIPT
CuI-catalyzed Sonogashira Reaction for the Efficient Synthesis of
1H-Imidazo[2,1-a]isoquinoline Derivatives
Ma-Yong Gang, Jian-Quan Liu*, Xiang-Shan Wang*
The Sonogashira reaction first, and then intra-molecular hydroamination of alkyne catalyzed by
CuI/o-phen was proved to be an efficient method for the synthesis of imidazo[2,1-a]isoquinoline
derivatives in the presence of Cs2CO3.

ACCEPTED MANUSCRIPT
CuI-catalyzed Sonogashira Reaction for the Efficient Synthesis of
1H-Imidazo[2,1-a]isoquinoline Derivatives
Ma-Yong Gang, Jian-Quan Liu*, Xiang-Shan Wang*
School of Chemistry and Materials Science, Jiangsu Key Laboratory of Green Synthesis for
Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. China
xswang1974@yahoo.com
Abstract: The Sonogashira reaction first, and then intra-molecular hydroamination of alkyne
catalyzed by CuI/o-phen was proved to be an efficient method for the synthesis of imidazo[2,1-a]
isoquinoline, phenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline and acenaphtho[1',2':4,5]imidazo
[2,1-a]isoquinoline derivatives in the presence of Cs2CO3.
Keywords: Sonogashira reaction, hydroamination, imidazoisoquinoline, CuI/o-phen
1. Introduction
Sonogashira reaction is such a well-known cross-coupling for the formation of
C(sp)-C(sp2) bond that terminal alkyne with aryl halide or vinyl halide conventionally
perform with the treatment of Pd-Cu co-catalyst and a base, such as well-established
Pd(PPh3)2Cl2-CuI-Et3N system (Scheme 1, path a).1 In recent years, 2-halogenated
benzamides have been applied to the Sonogashira reaction which in turn underwent an
alkyne hydroamination to deliver the resulting isoquinoline or isoindole derivatives
(Scheme 1, path b).2-4 In 2016, Chen et al. reported the CuI-catalysed tandem
Sonogashira coupling/6-endo cyclization protocol for the assembly of fused
triazolo[5,1-a]isoquinolines in good to excellent yields.5 Of which, the triazole moiety
on 4-(2-bromophenyl)-2H-1,2,3-triazole was utilized as a N-base nucleophilic
component for alkyne hydroamination. Hence, the merge Sonogashira reaction into a
tandem manner provided an efficient access for the synthesis of fused polycyclic
heterocycles. For instance, imidazoisoquinolines possess good pharmacological and
biological activities, such as antimalarial, anti-thrombotic, antisecretory and antitumor
activities.6-9
1

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Scheme 1. Sonogashira approaches for the synthesis of alkynes and N-containing heterocycles
A range of imidazo[2,1-a]isoquinoline derivatives, including 2-(2-bromophenyl)-
4,5-diphenyl-1H-imidazole (2), 2-(2-bromophenyl)-1H-phenanthro[9,10-d]imidazole
(4) and 8-(2-bromophenyl)-7H-acenaphtho[1,2-d] imidazole (6) were synthesized first
in our lab, and then they were submitted to react with phenylacetylenes, respectively.
It is reasonable that the imino group on 1H-imidazole attacks the alkynyl functions
delivering a new C–N single bond after the Sonogashira reaction. To our delight, the
resulting annulation products imidazo[2,1-a]isoquinolines were obtained in good
yields, respectively. As our continious study on the construction of polycyclic
heterocycles catalyzed by copper,10 herein, we present the tandem Sonogashira
approach for the generation of imidazo[2,1-a]isoquinolines with the corresponding
N-heteroaryl bromides and terminal alkynes which undergoes in the presenc of
CuI/o-phen as catalyt and Cs2CO3 as the base (Scheme 1, path c).
2. Results and discussion
The hypothesis was first examined using phenylacetylene (1a) and
2-(2-bromophenyl)-4,5-diphenyl-1H-imidazole (2a) as the model substrate to screen
the reaction conditions involving different transition-metal catalysts, ligands and
bases (Scheme 2).
2

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Ph
Ph
Ph
N
N
N
Transition-M
Base, L
+ Ph
N
H
Ph
Br
Ph
1a
3a
2a
Scheme 2. The model reaction catalyzed by transition-metals
Initially, the model reaction of 1a and 2a was conducted under the available
Sonogashira reaction using 5 mol% Pd(PPh3)2Cl2 and 10 mol% CuI as co-catalyst,
Et3N as a base in refluxing THF, leading to the corresponding product 3a in high
yields (89%) (Table 1, entry 1). When reducing the ammount of palladium catalyst to
1 mol%, the yield is silightly lower to 79%. While in the absence of Pd(PPh3)2Cl2 3a
was still obtained in 32% yield (Table 1, entry 2). Thus, a further exploration of
palladium-free conditions was conducted. First, in the presence of CuI (10mol%) as
the catalyst, several ligands such as PPh3, L-proline, o-phenanthroline (o-phen) and
MeNHCH2CO2H (Figure 1) were evaluated and displayed that o-phen resulted in the
best results with 79% yield of 3a (Table 1, entry 5). When using copper(I) salts e.g.,
CuBr and CuCl as the catalyst with o-phen, the reaction still underwent smoothly but
furnished slightly lower yields (Table 1, entries 7 and 8). Whereas, copper(II) salts
such CuBr2 and CuCl2 were unreactive to promote the desired reaction (Table 1,
entries 9 and 10). Other organic base (e.g., DBU), or inorganic bases including K2CO3,
Cs2CO3, and NaHCO3 were also tested with the combination of CuI and o-phen, and
Cs2CO3 (100 mol%) provided the best result (82%, Table 1, entry 13). Screening
numerous solvents such as such as DME, toluene, DMF and DMSO showed that
dioxane performed better, generating the desired product in 88% yield at 100 °C (88%,
Table 1, entry 16). After attempting various conditions, we obtained the expected
result by using CuI (10 mol%), o-phen (20 mol%), Cs2CO3 (1.0 equiv.), in dioxane at
3

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100 °C. In contrast, an attempt with the previous conditions5 in the presence of CuI
and K2CO3 at 110 °C in DMSO was conducted, however, affording 3a in 46% yield.
H
O
N
H
P
N
CO2H
N
N
OH
L2
L1
L3
L4
Figure 1. The structures of ligands
Table 1. Optimization of Reaction Conditions for 1a and 2aa
Entry
1
Cat./mol%
Pd-Cuc
L/mol%
_
Base
Et3N
solvent
THF
T/°C
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
100
Yields/%b
89
32
52
65
79
62
72
65
-
2
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuBr(10)
CuCl(10)
CuBr2(10)
CuCl2(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
CuI(10)
_
Et3N
THF
3
L1(20)
L2(20)
L3(20)
L4(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
L3(20)
Et3N
THF
4
Et3N
THF
5
Et3N
THF
6
Et3N
THF
7
Et3N
THF
8
Et3N
THF
9
Et3N
THF
10
11
12
13
14
15
16
17
18
Et3N
THF
-
DBU
THF
73
75
82
65
79
88
64
75
78
K2CO3
Cs2CO3
NaHCO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
d
THF
DME
Dioxane
Toluene
DMF
DMSO
19
100
a
Reaction condition: 1a (374 mg, 1.0 mmol), 2a (122 mg, 1.2 mmol), base (1.0 mmol),
solvent (10.0 mL); b isolated yields; c Pd(PPh3)2Cl2 (5 mol%) and CuI (10 mol%); d 2.0 mmol.
4

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Scheme 3. The Sonogashira reaction and cyclization of 1 and 2
Table 2. The reaction time and yields of the products 3
Entry
1
R
H
R’
C6H5
Products
3a
Time/h
24
Yields/%
88
2
8-Cl
C6H5
3b
3c
22
79
3
9-Cl
C6H5
20
80
4
9-F
C6H5
3d
3e
26
86
5
9-MeO
8,9-OCH2O
9-F
C6H5
22
78
6
C6H5
3f
26
82
7
4-EtC6H4
4-EtC6H4
4-EtC6H4
4-EtC6H4
4-MeOC6H4
Cyclopropyl
Cyclopropyl
3g
26
81
8
8-Me
3h
3i
24
84
9
9-MeO
8,9-OCH2O
9-Cl
26
68
10
11
12
13
3j
22
78
3k
3l
24
80
9-Cl
26
78
8,9-(MeO)2
3m
24
82
Reaction condition: 1 (1.0 mmol), 2 (1.0 mmol), CuI (20 mg, 0.1 mmol), o-phen (36 mg, 0.2
mmol), Cs2CO3 (325 mg, 1.0 mmol), dioxane (10.0 mL), 100 °C.
With the optimized conditions, we examined the scope of this tandem protocol
by using functionalized phenylacetylene with 2-(2-bromophenyl)-4,5-diphenyl-1H-
imidazole (Scheme 3). The results are summarized in Table 2. Both electron-donating
groups (e.g., Me, Et, MeO) and electron-withdrawing groups (e.g., F and Cl) in the
benzene moieties were applicable and delivered the desired imidazo[2,1-a]
isoquinoline derivatives 3a-3k in good yield. To our delight, cyclopropyl acetylene
were also tolerant under the same reaction conditions and afforded the resulting
3-cyclopropylimidazo[2,1-a]isoquinolines (3l-3m) in 78% and 82% yields,
respectively. The molecular structure of 3d was further confirmed by X-ray
diffraction analysis, and its crystal structure was shown in Figure 2.
X-ray diffraction analysis of 3d reveals that all the ring including the central
pyridine are coplanar. The imidazole moiety is nearly parallel to the isoquinoline ring,
forming a dihedral angle of 6.8 (1)°. The dihedral angles between the imidazole and
two benzene rings (C12-C17, and C18-C23) are 37.2 (1) and 60.2 (1)°, respectively.
5

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Another benzene ring (C24-C29) makes a dihedral angle of 54.5 (1)° to the
isoquinoline moiety.
Figure 2. The crystal structure of 3d
A range of modified 2-(2-bromophenyl) imidazole substrates, 2-(2-bromo
phenyl)-1H-phenanthro[9,10-d]imidazoles (4) were synthesized by a three-component
reaction of 9,10-phenanthrenequinone, ammonium acetate and 2-bromobenzaldehyde.
Sequently, the materials (4) were submitted to react with phenylacetylene under the
same reaction conditions (Scheme 4). To our great delight, all of the
2-(2-bromophenyl)-1H-phenanthro[9,10-d]imidazoles were applicable and afforded
the corresponding 5a-5l in good yields (Table 3). Both aryl- and cyclopropyl
substituted alkynes were well efficient under the reaction conditions.
6

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Scheme 4. The Sonogashira reaction and cyclization of 1 and 4
Table 3. The reaction time and yields of the products 5
Entry
1
R
R’
Products
5a
Time/h
20
Yields/%
80
H
C6H5
2
3-Cl
C6H5
5b
5c
22
89
3
2-Cl
C6H5
22
88
4
2-MeO
3-Cl
C6H5
5d
5e
24
86
5
4-MeC6H4
4-MeC6H4
4-EtC6H4
4-EtC6H4
4-EtOC6H4
4-(n-Pr)C6H4
Cyclopropyl
Cyclopropyl
26
78
6
2-Cl
5f
22
88
7
2-Cl
5g
24
85
8
2-MeO
2-MeO
2-MeO
3-Cl
5h
5i
26
88
9
24
84
10
11
12
5j
24
85
5k
5l
26
91
2-Cl
26
82
Reaction condition: 1 (1.0 mmol), 4 (1.0 mmol), CuI (20 mg, 0.1 mmol), o-phen (36 mg, 0.2
mmol), Cs2CO3 (325 mg, 1.0 mmol), dioxane (10.0 mL), 100 °C.
Analogously, 2-(2-bromophenyl)imidazole compounds, 8-(2-bromophenyl)-7H-
acenaphtho[1,2-d] imidazole (6) were also treated with phenylacetylene under similar
conditions (Scheme 5), albeit all reactions required slightly longer time to complete
the intermolecular coupling and subsequent intramolecular cyclization. As a result,
the 8-(2-bromophenyl)-7H-acenaphtho[1,2-d]imidazole substrates proved to be
reactive and led to the corresponding 13-arylacenaphtho[1',2':4,5]imidazo[2,1-a]
isoquinoline derivatives 7a-g in moderate to good yields (Table 4).
7

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Scheme 5. The Sonogashira reaction and cyclization of 1 and 6
Table 4. The reaction time and yields of the products 7
Entry
R
R’
Products
7a
Time/h
28
Yields/%
1
2
3
4
5
6
7
H
H
H
Ph
76
78
80
68
79
82
80
4-EtC6H4
7b
26
4-(n-Pr)C6H4
Cyclopropyl
4-EtC6H4
7c
30
9-F
9-F
9-F
9-Cl
7d
26
7e
29
4-(n-Pr)C6H4
Cyclopropyl
7f
30
7g
32
Reaction condition: 1 (1.0 mmol), 6 (1.0 mmol), CuI (20 mg, 0.1 mmol), o-phen (36 mg, 0.2
mmol), Cs2CO3 (325 mg, 1.0 mmol), dioxane (10.0 mL), 100 °C.
3. Conclusion
In summary, we have developed a CuI/o-phen catalysed tandem Sonogashira
coupling/hydroamination approach of 2-(2-bromophenyl)imidazoles and terminal
alkynes affording a variety of imidazo[2,1-a]isoquinoline-based fused polycyclic
compounds in good yields. A range of 2-(2-bromophenyl)imidazole derivatives with
highly polycyclic aromatics were applicable under the optimal conditions.
4. Experimental
Melting points were determined in open capillaries and are uncorrected. IR
spectra were recorded on a TENSOR 27 spectrometer in KBr. NMR spectra were
obtained from solution in CDCl3 with Me4Si as internal standard using a
BRUKER-400 spectrometer. HRMS analyses were carried out using
Bruker-micro-TOF-Q-MS analyzer.
a
4.1. General procedure for the preparation of the substates 2, 4 and 6 (Using
2a as a model)11,12
Benzil (4.204 g, 20 mmol), 2-bromobenzaldehyde (3.700 g, 20 mmol) and
NH4OAc (6.160 g, 80 mmol) were added to a mixture of ethyl alcohol (50.0 mL) and
glacial acetic acid (5.0 mL). The mixture was refluxing until all the benzil was
consumed which was monitoried by TLC. After the completion of the reaction, the
8

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desired 2a was obtained as the yellow crystals by a filtration when the mixture was
allowed to cool down to room temperarure, 92% yield, m.p. 202-203 °C (Lit.11
201-202 °C). The 4 and 6 were prepared by the same procedure using
phenanthrene-9,10-dione and acenaphthylene-1,2-dione as the o-diketones,
respectively.
4.2. General procedure for the syntheses of imidazo[2,1-a]isoquinoline 3
A dry 50 mL flask was charged with phenylacetylene 1 (1.0 mmol),
2-(2-bromoaryl)-4,5-diphenyl-1H-imidazole 2 (1.0 mmol), CuI (20 mg, 0.1 mmol),
o-phen (36 mg, 0.2 mmol), Cs2CO3 (325 mg, 1.0 mmol), dioxane (10.0 mL). The
reaction mixture was stirred at 100 °C for 20-26 h under N2 atmosphere until all the 2
was consumed. The insoluble substance was romoved by a fast hot filtration, and the
filtrate was concentrated under reduced pressure. The residue was purified by a
column chromatography to give 3 using a mixture of ethyl acetate and petroleum ether
(1 : 8) as an eluant.
1
2,3,5-Triphenylimidazo[2,1-a]isoquinoline (3a): M.p. 212~214 °C; H NMR (CDCl3,
400 MHz): δH 6.90~7.10 (m, 11H, ArH), 7.17~7.25 (m, 3H, ArH), 7.50~7.52 (m, 2H,
ArH), 7.57~7.61 (m, 1H, ArH), 7.65~7.71 (m, 2H, ArH), 8.88 (d, J = 8.0 Hz, 1H,
ArH). 13C NMR (CDCl3, 100 MHz): δC 115.7, 123.3, 123.7, 124.5, 126.5, 126.9,
127.3, 127.4, 127.77, 127.82, 128.0, 128.3, 128.5, 129.2, 129.3, 131.4, 134.4, 134.7,
137.0, 141.7, 143.8. IR (KBr):
ν 3056, 1716, 1684, 1653, 1635, 1559, 1540, 1507,
1489, 1473, 1418, 1396, 1379, 1339, 1025, 915, 846, 777, 763 cm-1. HRMS (ESI,
m/z): Calcd for C29H21N2 [M + H]+ 397.1704, found 397.1708.
8-Chloro-2,3,5-triphenylimidazo[2,1-a]isoquinoline (3b): M.p. 208~210 °C; 1H NMR
(CDCl3, 400 MHz): δH 6.83 (s, 1H, ArH), 6.89~7.10 (m, 10H, ArH), 7.17~7.25 (m,
3H, ArH), 7.47~7.50 (m, 2H, ArH), 7.60 (dd, J = 8.8 Hz, J’ = 2.0 Hz, 1H, ArH), 7.67
9

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(d, J = 2.0 Hz, 1H, ArH), 8.80 (d, J = 8.8 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz):
δC 114.5, 121.6, 124.7, 125.4, 125.6, 127.1, 127.44, 127.47, 127.8, 128.1, 128.3,
128.5, 129.1, 130.4, 131.2, 131.4, 133.97, 134.04, 134.5, 138.3, 142.0, 143.3. IR
(KBr):
ν 3057, 1632, 1598, 1526, 1498, 1472, 1446, 1422, 1379, 1336, 1323, 1235,
1197, 1158, 1116, 1081, 1027, 942, 915, 887, 820, 763, 753, 701 cm-1. HRMS (ESI,
m/z): Calcd for C29H20ClN2 [M + H]+ 431.1315, found 431.1318.
1
9-Chloro-2,3,5-triphenylimidazo[2,1-a]isoquinoline (3c): M.p. 193~195 °C; H NMR
(CDCl3, 400 MHz): δH 6.88~7.00 (m, 7H, ArH), 7.02~7.10 (m, 4H, ArH), 7.17~7.25
(m, 3H, ArH), 7.48~7.53 (m, 3H, ArH), 7.63 (d, J = 8.8 Hz, 1H, ArH), 8.87 (d, J = 2.4
Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 115.0, 123.1, 124.3, 124.9, 127.1,
127.45, 127.52, 127.8, 128.0, 128.1, 128.2, 128.4, 128.7, 129.1, 131.1, 131.3, 133.7,
134.1, 134.4, 137.3, 142.0, 142.8. IR (KBr):
ν 3031, 2964, 1540, 1507, 1490, 1473,
1442, 1419, 1375, 1302, 1095, 1020, 917, 879, 868, 858, 815, 764, 749, 709 cm-1.
HRMS (ESI, m/z): Calcd for C29H20ClN2 [M + H]+ 431.1315, found 431.1315.
1
9-Fluoro-2,3,5-triphenylimidazo[2,1-a]isoquinoline (3d): M.p. 192~193 °C; H NMR
(CDCl3, 400 MHz): δH 6.90~7.10 (m, 11H, ArH), 7.17~7.25 (m, 3H, ArH), 7.29~7.34
(m, 1H, ArH), 7.48~7.51 (m, 2H, ArH), 7.69 (dd, J = 8.8 Hz, J’ = 5.2 Hz, 1H, ArH),
13
8.51 (dd, J = 9.6 Hz, J’ = 2.8 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 108.9
(d, J(F-C) = 23.0 Hz), 115.0, 117.1 (d, J(F-C) = 24.0 Hz), 124.8, 124.9, 125.9 (d, J(F-C)
=
1.8 Hz), 127.1, 127.5, 127.8, 128.07, 128.11, 128.5, 128.8 (d, J(F-C) = 8.0 Hz), 129.2,
131.2, 131.4, 134.2, 134.5, 136.3 (d, J(F-C) = 2.7 Hz), 141.9, 143.1 (d, J(F-C) = 4.7 Hz),
162.1 (d, J(F-C) = 246.0 Hz). IR (KBr):
ν 3056, 3005, 2960, 2836, 1599, 1508, 1473,
1441, 1375, 1303, 1247, 1174, 1108, 1073, 1031, 918, 862, 834, 811, 775, 750, 702
cm-1. HRMS (ESI, m/z): Calcd for C29H20FN2 [M + H]+ 415.1610, found 415.1604.
10

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1
9-Methoxy-2,3,5-triphenylimidazo[2,1-a]isoquinoline (3e): M.p. 198~200 °C; H
NMR (CDCl3, 400 MHz): δH 4.08 (m, 3H, OCH3), 6.90~7.09 (m, 11H, ArH),
7.18~7.24 (m, 4H, ArH), 7.50~7.52 (m, 2H, ArH), 7.62 (d, J = 8.4 Hz, 1H, ArH), 8.32
(d, J = 2.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 56.1, 103.7, 115.8, 119.5,
123.7, 124.4, 124.6, 127.1, 127.3, 127.4, 127.7, 127.9, 128.1, 128.2, 128.6, 129.2,
131.2, 131.4, 134.5, 134.6, 134.7, 141.6, 143.6, 159.5. IR (KBr):
ν 3055, 2967, 1601,
1523, 1495, 1436, 1380, 1355, 1245, 1217, 1193, 1103, 1027, 912, 860, 816, 773, 757
cm-1. HRMS (ESI, m/z): Calcd for C30H23N2O [M + H]+ 427.1810, found 427.1807.
2,3,5-Triphenyl-[1,3]dioxolo[4,5-g]imidazo[2,1-a]isoquinoline (3f): M.p. 230~231
1
°C; H NMR (CDCl3, 400 MHz): δH 6.13 (s, 2H, CH2), 6.79 (s, 1H, ArH), 6.89~7.08
(m, 11H, ArH), 7.16~7.24 (m, 3H, ArH), 7.48~7.51 (m, 2H, ArH), 8.24 (s, 1H, ArH).
13C NMR (CDCl3, 100 MHz): δC 101.5, 102.2, 104.3, 115.4, 119.2, 123.8, 125.6,
126.9, 127.2, 127.4, 127.7, 127.9, 128.0, 128.5, 128.6, 129.0, 129.2, 131.4, 131.5,
134.4, 134.8, 135.5, 141.5, 144.0, 148.5, 149.0. IR (KBr):
ν 3053, 2909, 1521, 1501,
1476, 1442, 1382, 1311, 1249, 1196, 1141, 1118, 1040, 944, 911, 886, 863, 833, 773,
756, 722 cm-1. HRMS (ESI, m/z): Calcd for C30H21N2O2 [M + H]+ 441.1603, found
441.1603.
5-(4-Ethylphenyl)-9-fluoro-2,3-diphenylimidazo[2,1-a]isoquinoline
(3g):
M.p.
211~213 °C; 1H NMR (CDCl3, 400 MHz): δH 1.17 (t, J = 7.6 Hz, 3H, CH3), 2.51 (q, J
= 7.6 Hz, 2H, CH2), 6.79 (d, J = 7.6 Hz, 2H, ArH), 6.88~6.97 (m, 7H, ArH),
7.02~7.05 (m, 1H, ArH), 7.19~7.25 (m, 3H, ArH), 7.28~7.33 (m, 1H, ArH), 7.49~7.51
(m, 2H, ArH), 7.68 (dd, J = 8.8 Hz, J’ = 5.2 Hz, 1H, ArH), 8.50 (dd, J = 9.6 Hz, J’ =
2.4 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 15.7, 28.7, 108.9 (d, J(F-C) = 23.6
Hz), 114.6, 117.1 (d, J(F-C) = 23.9 Hz), 124.7 (d, J(F-C) = 9.8 Hz), 124.9, 126.0 (d, J(F-C)
= 1.9 Hz),126.9, 127.0, 127.3, 127.7, 128.1, 128.5, 128.7 (d, J(F-C) = 8.7 Hz), 129.2,
11

ACCEPTED MANUSCRIPT
131.3, 131.4, 131.5, 134.6, 136.5 (d, J(F-C) = 2.8 Hz), 141.8, 143.1 (d, J(F-C) = 4.6 Hz),
144.3, 162.0 (d, J(F-C) = 245.9 Hz). IR (KBr):
ν 3058, 2965, 1601, 1532, 1508, 1483,
1444, 1377, 1309, 1233, 1189, 1142, 1098, 1020, 916, 833, 805, 774, 700 cm-1.
HRMS (ESI, m/z): Calcd for C31H24FN2 [M + H]+ 443.1923, found 443.1920.
5-(4-Ethylphenyl)-9-methyl-2,3-diphenylimidazo[2,1-a]isoquinoline
(3h):
M.p.
166~168 °C; 1H NMR (CDCl3, 400 MHz): δH 1.17 (t, J = 7.6 Hz, 3H, CH3), 2.51 (q, J
= 7.6 Hz, 2H, CH2), 2.54 (s, 3H, CH3), 6.78 (d, J = 8.0 Hz, 2H, ArH), 6.84 (s, 1H,
ArH), 6.88~7.03 (m, 7H, ArH), 7.15~7.24 (m, 3H, ArH), 7.47~7.51 (m, 4H, ArH),
8.75 (d, J = 8.8 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 15.7, 21.8, 28.7,
115.2, 121.1, 123.7, 124.3, 126.1, 126.8, 126.9, 127.1, 127.6, 128.0, 128.5, 129.2,
129.4, 129.6, 131.5, 131.6, 131.8, 134.9, 137.2, 138.2, 141.4, 144.0, 144.2. IR (KBr):
ν
3025, 2958, 1559, 1540, 1507, 1473, 1457, 1375, 1327, 911, 894, 836, 773, 747,
717, 701 cm-1. HRMS (ESI, m/z): Calcd for C32H27N2 [M + H]+ 439.2174, found
439.2175.
5-(4-Ethylphenyl)-9-methoxy-2,3-diphenylimidazo[2,1-a]isoquinoline (3i): M.p.
175~176 °C; 1H NMR (CDCl3, 400 MHz): δH 1.17 (t, J = 7.6 Hz, 3H, CH3), 2.51 (q, J
= 7.6 Hz, 2H, CH2), 4.07 (s, 3H, OCH3), 6.78 (d, J = 8.0 Hz, 2H, ArH), 6.87~6.97 (m,
7H, ArH), 7.00~7.02 (m, 1H, ArH), 7.16~7.25 (m, 4H, ArH), 7.50~7.52 (m, 2H, ArH),
7.61 (d, J = 8.8 Hz, 1H, ArH), 8.25 (d, J = 2.4 Hz, 1H, ArH). 13C NMR (CDCl3, 100
MHz): δC 15.8, 28.7, 55.9, 103.7, 115.1, 119.2, 123.7, 124.5, 124.6, 126.9, 127.1,
127.6, 128.0, 128.1, 128.6, 129.3, 131.4, 131.5, 131.8, 134.8, 134.9, 141.6, 143.6,
144.0, 159.4. IR (KBr):
ν 3026, 2965, 1559, 1541, 1508, 1490, 1473, 1465, 1457,
1438, 1250, 1218, 1153, 1103, 1023, 867, 837, 776, 702 cm-1. HRMS (ESI, m/z):
Calcd for C32H27N2O [M + H]+ 455.2123, found 455.2120.
12

ACCEPTED MANUSCRIPT
5-(4-Ethylphenyl)-2,3-diphenyl-[1,3]dioxolo[4,5-g]imidazo[2,1-a]isoquinoline (3j):
M.p. 188~190 °C; 1H NMR (CDCl3, 400 MHz): δH 1.16 (t, J = 7.6 Hz, 3H, CH3), 2.50
(q, J = 7.6 Hz, 2H, CH2), 6.11 (s, 2H, CH2), 6.77 (d, J = 8.0 Hz, 3H, ArH), 6.87~6.95
(m, 6H, ArH), 6.99~7.03 (m, 2H, ArH), 7.15~7.24 (m, 3H, ArH), 7.49~7.51 (m, 2H,
13
ArH), 8.23 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 15.8, 28.7, 101.5, 102.1,
104.3, 115.0, 119.1, 123.8, 125.6, 126.8, 126.9, 127.0, 127.6, 128.0, 128.5, 128.6,
129.0, 129.2, 131.4, 131.6, 131.7, 134.8, 135.7, 141.4, 144.0, 144.1, 148.4, 148.9. IR
(KBr):
ν 3051, 2958, 1507, 1470, 1448, 1379, 1316, 1244, 1196, 1144, 1116, 1034,
950, 910, 965, 881, 869, 833, 789, 773, 700 cm-1. HRMS (ESI, m/z): Calcd for
C32H25N2O2 [M + H]+ 469.1916, found 469.1915.
9-Chloro-5-(4-methoxyphenyl)-2,3-diphenylimidazo[2,1-a]isoquinoline (3k): M.p.
220~222 °C; 1H NMR (CDCl3, 400 MHz): δH 3.73 (s, 3H, OCH3), 6.49 (d, J = 8.8 Hz,
2H, ArH), 6.86~6.91 (m, 3H, ArH), 6.96~7.00 (m, 4H, ArH), 7.06~7.10 (m, 1H, ArH),
7.19~7.24 (m, 3H, ArH), 7.48~7.53 (m, 3H, ArH), 7.62 (d, J = 8.4 Hz, 1H, ArH), 8.86
(d, J = 1.6 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 55.3, 112.9, 114.5, 123.1,
124.2, 124.9, 126.5, 127.0, 127.2, 127.6, 127.75, 127.83, 128.0, 128.5, 128.7, 130.4,
131.3, 131.4, 133.4, 134.5, 137.1, 142.0, 142.7, 159.4. IR (KBr):
ν 3052, 1602, 1541,
1494, 1473, 1445, 1376, 1340, 1307, 1235, 1190, 1144, 1117, 1100, 1073, 1027, 886,
864, 818, 778, 760, 706 cm-1. HRMS (ESI, m/z): Calcd for C30H22ClN2O [M + H]+
461.1420, found 461.1416.
9-Chloro-5-cyclopropyl-2,3-diphenylimidazo[2,1-a]isoquinoline (3l): M.p. 173~174
1
°C; H NMR (CDCl3, 400 MHz): δH 0.36~0.41 (m, 2H, CH2), 0.62~0.66 (m, 2H,
CH2), 1.54~1.61 (m, 1H, CH), 6.70 (s, 1H, ArH), 7.17~7.26 (m, 3H, ArH), 7.39~7.47
(m, 4H, ArH), 7.51~7.56 (m, 5H, ArH), 8.77 (d, J = 2.0 Hz, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): δC 8.7, 15.9, 110.1, 123.0, 124.1, 124.7, 127.0, 127.5, 127.7,
13

ACCEPTED MANUSCRIPT
127.9, 128.0, 128.1, 128.5, 128.7, 132.6, 133.0, 133.1, 134.5, 139.3, 141.7, 142.3. IR
(KBr):
ν 3015, 1598, 1531, 1473, 1442, 1396, 1300, 1173, 1101, 1075, 1025, 883,
860, 842, 776, 758, 718 cm-1. HRMS (ESI, m/z): Calcd for C26H20ClN2 [M + H]+
395.1315, found 395.1314.
5-Cyclopropyl-8,9-dimethoxy-2,3-diphenylimidazo[2,1-a]isoquinoline (3m): M.p.
264~266 °C; 1H NMR (CDCl3, 400 MHz): δH 0.33~0.38 (m, 2H, CH2), 0.60~0.64 (m,
2H, CH2), 1.55~1.62 (m, 1H, CH), 4.00 (s, 3H, OCH3), 4.13 (m, 3H, OCH3), 6.69 (s,
1H, ArH), 6.99 (s, 1H, ArH), 7.15~7.25 (m, 3H, ArH), 7.37~7.45 (m, 3H, ArH),
7.54~7.58 (m, 4H, ArH), 8.17 (s, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 8.6,
15.9, 56.0, 56.5, 104.2, 106.4, 110.5, 117.3, 123.8, 124.4, 126.8, 127.8, 128.0, 218.47,
128.54, 132.7, 133.4, 137.3, 141.1, 143.3, 149.8, 150.5. IR (KBr):
ν 3054, 2994,
2956, 2832, 1640, 1600, 1533, 1495, 1439, 1394, 1309, 1247, 1225, 1163, 1123,
1103, 1027, 1006, 919, 863, 782, 757, 706 cm-1. HRMS (ESI, m/z): Calcd for
C28H25N2O2 [M + H]+ 421.1916, found 421.1917.
4.3. General procedure for the syntheses of phenanthro[9',10':4,5]
imidazo[2,1-a]isoquinolines 5
A dry 50 mL flask was charged with phenylacetylene 1 (1.0 mmol), 2-(2-
bromophenyl)-1H-phenanthro[9,10-d]imidazole 4 (1.0 mmol), CuI (20 mg, 0.1 mmol),
o-phen (36 mg, 0.2 mmol), Cs2CO3 (325 mg, 1.0 mmol), dioxane (10.0 mL). The
reaction mixture was stirred at 100 °C for 20-26 h under N2 atmosphere until all the 4
was consumed. The aftertreatment and purification of products 5 (The volume ratio of
ethyl acetate and petroleum ether is 1 : 6) were same to those of 3.
1
6-Phenylphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline (5a): M.p. 231~232 °C; H
NMR (CDCl3, 400 MHz): δH 6.92~6.96 (m, 1H, ArH), 7.02 (dd, J = 8.4 Hz, J’ = 0.8
Hz, 1H, ArH), 7.28 (s, 1H, ArH), 7.32~7.42 (m, 4H, ArH), 7.48~7.50 (m, 2H, ArH),
14

ACCEPTED MANUSCRIPT
7.67~7.85 (m, 5H, ArH), 8.67~8.71 (m, 2H, ArH), 9.03~9.06 (m, 2H, ArH). 13C NMR
(CDCl3, 100 MHz): δC 116.3, 123.0, 123.1, 123.3, 123.6, 124.0, 124.5, 124.65, 124.67,
126.56, 126.60, 126.7, 127.2, 128.1, 128.3, 129.0, 129.1, 129.3, 129.7, 130.6, 137.0,
137.8, 140.6, 148.1. IR (KBr):
ν 3051, 1577, 1559, 1518, 1470, 1456, 1416, 1380,
1337, 1304, 1278, 1237, 1146, 1128, 1025, 950, 876, 842, 778, 770, 750, 725 cm-1.
HRMS (ESI, m/z): Calcd for C29H19N2 [M + H]+ 395.1548, found 395.1557.
3-Chloro-6-phenylphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline
(5b):
M.p.
1
269~270 °C; H NMR (CDCl3, 400 MHz): δH 6.90~6.95 (m, 2H, ArH), 7.12 (s, 1H,
ArH), 7.30~7.44 (m, 6H, ArH), 7.64 (dd, J = 8.4 Hz, J’ = 1.6 Hz, 1H, ArH), 7.69~7.72
(m, 1H, ArH), 7.76~7.80 (m, 2H, ArH), 8.65~8.69 (m, 2H, ArH), 8.92 (d, J = 8.8 Hz,
1H, ArH), 8.99 (dd, J = 8.0 Hz, J’ = 0.4 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz):
δC 115.0, 121.6, 122.96, 123.01, 123.4, 123.6, 124.2, 124.6, 124.7, 125.9, 126.3,
126.6, 126.7, 127.1, 127.3, 128.4, 128.5, 129.1, 129.4, 129.8, 131.6, 135.1, 136.6,
139.0, 140.7, 147.5. IR (KBr):
ν 3052, 1559, 1540, 1507, 1458, 1447, 1412, 1377,
1321, 1277, 1255, 1197, 1152, 1077, 1039, 938, 869, 834, 773, 752, 722, 708 cm-1.
HRMS (ESI, m/z): Calcd for C29H18ClN2 [M + H]+ 429.1158, found 429.1158.
2-Chloro-6-phenylphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline
(5c):
M.p.
1
266~268 °C; H NMR (CDCl3, 400 MHz): δH 6.91~6.98 (m, 2H, ArH), 7.22 (s, 1H,
ArH), 7.31~7.39 (m, 4H, ArH), 7.40~7.47 (m, 2H, ArH), 7.61 (dd, J = 8.4 Hz, J’ = 2.0
Hz, 1H, ArH), 7.69~7.81 (m, 3H, ArH), 8.66~8.70 (m, 2H, ArH), 9.00~9.02 (m, 2H,
ArH). 13C NMR (CDCl3, 100 MHz): δC 115.5, 123.0, 123.1, 123.4, 123.6, 124.1,
124.2, 124.3, 124.6, 124.8, 126.6, 126.8, 127.1, 127.4, 128.2, 128.5, 128.8, 129.1,
129.3, 129.7, 129.8, 133.9, 136.7, 138.0, 140.7, 146.9. IR (KBr):
ν 3058, 1653, 1636,
1559, 1540, 1507, 1490, 1472, 1457, 1448, 1410, 1386, 1277, 1072, 1021, 874, 865,
15

ACCEPTED MANUSCRIPT
807, 772 cm-1. HRMS (ESI, m/z): Calcd for C29H18ClN2 [M + H]+ 429.1158, found
429.1158.
2-Methoxy-6-phenylphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline (5d): M.p.
245~247 °C; 1H NMR (CDCl3, 400 MHz): δH 4.13 (s, 3H, OCH3), 6.91~6.95 (m, 1H,
ArH), 7.03 (d, J = 8.0 Hz, 1H, ArH), 7.23 (s, 1H, ArH), 7.27~7.38 (m, 5H, ArH),
7.44~7.46 (m, 2H, ArH), 7.68~7.81 (m, 3H, ArH), 8.41 (d, J = 2.4 Hz, 1H, ArH),
8.66~8.71 (m, 2H, ArH), 9.05 (dd, J = 8.0 Hz, J’ = 1.2 Hz, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): δC 55.9, 104.7, 116.3, 120.2, 122.97, 123.00, 123.2, 123.3, 123.6,
123.9, 124.5, 124.6, 124.7, 124.8, 126.47, 126.52, 127.2, 127.3, 128.3, 128.4, 128.8,
129.0, 129.7, 135.5, 137.2, 140.5, 147.9, 159.6. IR (KBr):
ν 3064, 1612, 1559, 1533,
1507, 1497, 1447, 1436, 1413, 1355, 1280, 1196, 1092, 1030, 867, 848, 814, 771,
763, 751, 725 cm-1. HRMS (ESI, m/z): Calcd for C30H21N2O [M + H]+ 425.1654,
found 425.1660.
3-Chloro-6-(p-tolyl)phenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline
(5e):
M.p.
1
247~248 °C; H NMR (CDCl3, 400 MHz): δH 2.39 (s, 3H, CH3), 6.93~6.97 (m, 1H,
ArH), 7.02 (d, J = 8.0 Hz, 1H, ArH), 7.13~7.16 (m, 3H, ArH), 7.34~7.40 (m, 3H,
ArH), 7.65 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 7.69~7.73 (m, 1H, ArH), 7.77~7.80
(m, 2H, ArH), 8.67~8.71 (m, 2H, ArH), 8.94 (d, J = 8.4 Hz, 1H, ArH), 9.00 (d, J = 8.0
Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 21.4, 114.6, 121.5, 123.0, 123.06,
123.08, 123.4, 123.6, 124.1, 124.5, 125.0, 125.8, 126.2, 126.5, 126.7, 127.1, 127.3,
128.3, 128.4, 129.7, 129.8, 131.7, 133.8, 135.1, 139.2, 139.6, 140.7, 147.5. IR (KBr):
ν
3031, 1559, 1540, 1521, 1490, 1465, 1414, 1374, 1323, 1278, 1238, 1182, 1078,
894, 881, 817, 751, 726 cm-1. HRMS (ESI, m/z): Calcd for C30H20ClN2 [M + H]+
443.1315, found 443.1315.
16

ACCEPTED MANUSCRIPT
2-Chloro-6-(p-tolyl)phenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline
(5f):
M.p.
1
199~201 °C; H NMR (CDCl3, 400 MHz): δH 2.39 (m, 3H, CH3), 6.93~6.97 (m, 1H,
ArH), 7.03 (d, J = 7.2 Hz, 1H, ArH), 7.14 (d, J = 8.4 Hz, 2H, ArH), 7.19 (s, 1H, ArH),
7.34~7.40 (m, 3H, ArH), 7. 7.61 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 7.70~7.75 (m,
2H, ArH), 7.78~7.81 (m, 1H, ArH), 8.67~8.70 (m, 2H, ArH), 8.99~9.02 (m, 2H, ArH).
13C NMR (CDCl3, 100 MHz): δC 21.4, 115.0, 122.96, 123.04, 123.2, 123.4, 123.6,
124.0, 124.17, 124.20, 124.5, 125.1, 126.5, 126.7, 127.1, 127.3, 128.1, 128.5, 128.9,
129.6, 129.7, 129.8, 133.7, 133.9, 138.2, 139.5, 140.7, 146.9. IR (KBr):
ν 3027, 1595,
1533, 1511, 1467, 1449, 1413, 1381, 1337, 1307, 1277, 1235, 1188, 1111, 1071, 1020,
952, 875, 864, 822, 771, 748, 727, 707 cm-1. HRMS (ESI, m/z): Calcd for C30H20ClN2
[M + H]+ 443.1315, found 443.1318.
2-Chloro-6-(4-ethylphenyl)phenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline
(5g):
M.p. 270~272 °C; 1H NMR (CDCl3, 400 MHz): δH 1.24 (t, J = 7.6 Hz, 3H, CH3), 2.67
(q, J = 7.6 Hz, 2H, CH2), 6.88~6.96 (m, 2H, ArH), 7.14~7.17 (m, 3H, ArH),
7.34~7.38 (m, 3H, ArH), 7.59 (dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 7.68~7.72 (m,
2H, ArH), 7.76~7.80 (m, 1H, ArH), 8.65~8.68 (m, 2H, ArH), 8.97~9.01 (m, 2H, ArH).
13C NMR (CDCl3, 100 MHz): δC 15.9, 28.8, 114.9, 122.92, 123.02, 123.2, 123.3,
123.6, 124.0, 124.1, 124.2, 124.5, 125.1, 126.7, 127.1, 127.3, 128.0, 128. 44, 128.52,
128.8, 129.6, 129.8, 133.6, 134.1, 138.2, 140.6, 146.0, 146.9. IR (KBr):
ν 3063, 2962,
2927, 2872, 1540, 1508, 1466, 1418, 1411, 1380, 1338, 1320, 1277, 1072, 968, 864,
832, 804, 754, 725, 700 cm-1. HRMS (ESI, m/z): Calcd for C31H22ClN2 [M + H]+
457.1471, found 457.1468.
6-(4-Ethylphenyl)-2-methoxyphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline (5h):
M.p. 244~245 °C; 1H NMR (CDCl3, 400 MHz): δH 1.25 (t, J = 7.6 Hz, 3H, CH3), 2.67
(q, J = 7.6 Hz, 2H, CH2), 4.13 (s, 3H, OCH3), 6.91~6.94 (m, 1H, ArH), 7.04 (d, J =
17

ACCEPTED MANUSCRIPT
8.0 Hz, 1H, ArH), 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.23 (s, 1H, ArH), 7.29 (dd, J = 8.8
Hz, J’ = 2.8 Hz, 1H, ArH), 7.35~7.38 (m, 3H, ArH), 7.69~7.81 (m, 3H, ArH), 8.42 (d,
13
J = 2.8 Hz, 1H, ArH), 8.67~8.72 (m, 2H, ArH), 9.05~9.07 (m, 1H, ArH). C NMR
(CDCl3, 100 MHz): δC 16.0, 28.8, 55.9, 104.7, 115.8, 120.1, 123.0, 123.1, 123.3,
123.6, 123.9, 124.46, 124.51, 125.0, 126.5, 126.6, 127.2, 127.3, 128.28, 128.32,
128.5, 129.7, 134.6, 135.7, 140.4, 145.5, 147.9, 159.5. IR (KBr):
ν 3013, 2956, 2867,
1609, 1533, 1508, 1488, 1437, 1381, 1355, 1254, 1196, 1186, 1145, 1030, 868, 848,
836, 811, 754, 724, 705 cm-1. HRMS (ESI, m/z): Calcd for C32H25N2O [M + H]+
453.1967, found 453.1957.
6-(4-Ethoxyphenyl)-2-methoxyphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline (5i):
M.p. 249~250 °C; 1H NMR (CDCl3, 400 MHz): δH 1.41 (t, J = 7.2 Hz, 3H, CH3), 4.03
(q, J = 7.6 Hz, 2H, CH2), 4.13 (s, 3H, OCH3), 6.83 (d, J = 8.4 Hz, 2H, ArH),
6.99~7.03 (m, 1H, ArH), 7.14 (d, J = 8.4 Hz, 1H, ArH), 7.18 (s, 1H, ArH), 7.29 (dd, J
= 8.8 Hz, J’ = 2.8 Hz, 1H, ArH), 7.37~7.40 (m, 3H, ArH), 7.69~7.74 (m, 2H, ArH),
7.77~7.81 (m, 1H, ArH), 8.41 (d, J = 2.4 Hz, 1H, ArH), 8.67~8.71 (m, 2H, ArH), 9.05
13
(d, J = 8.0 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 16.0, 28.8, 55.9, 100.0,
104.6, 115.8, 120.2, 123.0, 123.1, 123.3, 123.6, 123.9, 124.46, 124.47, 125.0, 126.5,
126.6, 127.2, 127.3, 128.26, 128.32, 128.5, 129.7, 134.5, 135.7, 140.4, 145.4, 147.9,
159.5. IR (KBr):
ν 3033, 2981, 1541, 1508, 1489, 1473, 1418, 1283, 1248, 1230,
1178, 1092, 1039, 923, 964, 835, 752, 727 cm-1. HRMS (ESI, m/z): Calcd for
C32H25N2O2 [M + H]+ 469.1916, found 469.1917.
2-Methoxy-6-(4-n-propylphenyl)phenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline
(5j): M.p. 231~232 °C; 1H NMR (CDCl3, 400 MHz): δH 0.96 (t, J = 8.0 Hz, 3H, CH3),
1.60~1.69 (m, 2H, CH2), 2.60 (t, J = 7.2 Hz, 2H, CH2), 4.12 (s, 3H, OCH3), 6.90~6.94
(m, 1H, ArH), 7.05 (d, J = 8.0 Hz, 1H, ArH), 7.12 (d, J = 8.0 Hz, 2H, ArH), 7.21 (s,
18

ACCEPTED MANUSCRIPT
1H, ArH), 7.29 (dd, J = 8.8 Hz, J’ = 2.8 Hz, 1H, ArH), 7.33~7.37 (m, 3H, ArH),
7.68~7.74 (m, 2H, ArH), 7.77~7.80 (m, 1H, ArH), 8.41 (d, J = 2.8 Hz, 1H, ArH),
13
8.66~8.71 (m, 2H, ArH), 9.04~9.06 (m, 1H, ArH). C NMR (CDCl3, 100 MHz): δC
13.7, 24.6, 37.8, 55.9, 104.6, 115.8, 120.1, 123.0, 123.1, 123.3, 123.5, 123.8, 124.45,
124.47, 124.9, 125.0, 126.4, 126.5, 127.2, 127.3, 128.2, 128.3, 129.1, 129.7, 134.6,
135.7, 140.4, 143.7, 147.9, 159.5. IR (KBr):
ν 3058, 2959, 2870, 2827, 1614, 1533,
1511, 1488, 1436, 1417, 1382, 1354, 1280, 1232, 1200, 1146, 1092, 1032, 867, 846,
819, 770, 750, 725 cm-1. HRMS (ESI, m/z): Calcd for C33H27N2O [M + H]+ 467.2123,
found 467.2133.
3-Chloro-6-cyclopropylphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline (5k): M.p.
216~217 °C; 1H NMR (CDCl3, 400 MHz): δH 1.01~1.05 (m, 2H, CH2), 1.25~1.30 (m,
2H, CH2), 2.55~2.61 (m, 1H, CH), 6.66 (s, 1H, ArH), 7.54~7.61 (m, 3H, ArH), 7.64
(d, J = 1.6 Hz, 1H, ArH), 7.70~7.73 (m, 1H, ArH), 7.76~7.79 (m, 1H, ArH),
8.58~8.60 (m, 1H, ArH), 8.72 (d, J = 8.4 Hz, 1H, ArH), 8.76~8.78 (m, 1H, ArH), 8.82
(d, J = 8.4 Hz, 1H, ArH), 8.95 (d, J = 8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz):
δC 12.3, 16.3, 107.4, 121.1, 122.9, 123.0, 123.5, 124.16, 124.20, 124.5, 124.9, 125.0,
125.2, 126.1, 126.7 127.1, 127.4, 127.5, 128.6, 129.7, 131.9, 134.9, 141.2, 142.6,
147.5. IR (KBr):
ν 3043, 1539, 1463, 1448, 1414, 1324, 1257, 1238, 1172, 1161,
1102, 1072, 1041, 1023, 980, 946, 921, 869, 824, 809, 724, 711 cm-1. HRMS (ESI,
m/z): Calcd for C26H18ClN2 [M + H]+ 393.1158, found 393.1151.
2-Chloro-6-cyclopropylphenanthro[9',10':4,5]imidazo[2,1-a]isoquinoline (5l): M.p.
229~230 °C; 1H NMR (CDCl3, 400 MHz): δH 1.00~1.04 (m, 2H, CH2), 1.23~1.28 (m,
2H, CH2), 2.54~2.61 (m, 1H, CH), 6.72 (s, 1H, ArH), 7.53 (dd, J = 8.8 Hz, J’ = 2.0 Hz,
1H, ArH), 7.56~7.61 (m, 3H, ArH), 7.69~7.73 (m, 1H, ArH), 7.77~7.79 (m, 1H, ArH),
8.57~7.61 (m, 1H, ArH), 8.71 (d, J = 8.0 Hz, 1H, ArH), 8.74~8.78 (m, 1H, ArH), 8.87
19

ACCEPTED MANUSCRIPT
(d, J = 1.6 Hz, 1H, ArH), 8.94 (d, J = 8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz):
δC 12.2, 16.3, 107.9, 122.96, 123.04, 123.5, 123.8, 123.9, 124.16, 124.19, 124.6,
125.0, 125.1, 126.7, 127.1, 127.2, 127.4, 128.6, 129.0, 129.5, 129.7, 132.8, 141.1,
141.5, 146.9. IR (KBr):
ν 3074, 3006, 1636, 1596, 1571, 1544, 1532, 1471, 1448,
1404, 1323, 1259, 1237, 1175, 1108, 1068, 1041, 986, 949, 901, 883, 846, 821, 773,
754, 727 cm-1. HRMS (ESI, m/z): Calcd for C26H18ClN2 [M + H]+ 393.1158, found
393.1155.
4.4. General procedure for the syntheses of acenaphtho[1',2':4,5]
imidazo[2,1-a]isoquinolines 7
A dry 50 mL flask was charged with phenylacetylene 1 (1.0 mmol),
8-(2-bromoaryl)-7H-acenaphtho[1,2-d]imidazole 6 (1.0 mmol), CuI (20 mg, 0.1
mmol), o-phen (36 mg, 0.2 mmol), Cs2CO3 (325 mg, 1.0 mmol), dioxane (10.0 mL).
The reaction mixture was stirred at 100 °C for 26-32 h under N2 atmosphere until all
the 6 was consumed. The aftertreatment and purification of products 7 (The volume
ratio of ethyl acetate and petroleum ether is 1 : 5) were the same as those of 3.
13-Phenylacenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline (7a): M.p. 290~292 °C; 1H
NMR (CDCl3, 400 MHz): δH 5.05 (d, J = 6.8 Hz, 1H, ArH), 7.05~7.08 (m, 2H, ArH),
7.54~7.75 (m, 11H, ArH), 8.10 (d, J = 7.2 Hz, 1H, ArH), 8.81 (d, J = 8.0 Hz, 1H,
ArH). 13C NMR (CDCl3, 100 MHz): δC 114.5, 121.1, 121.2, 123.6, 123.8, 125.9,
126.9, 127.2, 127.3, 127.5, 127.8, 128.1, 128.2, 129.18, 129.21, 129.5, 129.8, 130.0,
130.6, 131.9, 135.57, 135.64, 148.3, 151.5. IR (KBr):
ν 3044, 1528, 1492, 1474,
1438, 1282, 1224, 1180, 1123, 1040, 903, 870, 816, 781, 765, 749 cm-1. HRMS (ESI,
m/z): Calcd for C27H17N2 [M + H]+ 369.1391, found 369.1390.
13-(4-Ethylphenyl)acenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline
(7b):
M.p.
218~220 °C; 1H NMR (CDCl3, 400 MHz): δH 1.42 (t, J = 7.6 Hz, 3H, CH3), 2.88 (q, J
20

ACCEPTED MANUSCRIPT
= 7.6 Hz, 2H, CH2), 5.03 (d, J = 7.2 Hz, 1H, ArH), 7.02~7.06 (m, 2H, ArH), 7.46 (d, J
= 7.6 Hz, 2H, ArH), 7.53~7.60 (m, 5H, ArH), 7.64~7.74 (m, 3H, ArH), 8.09 (d, J =
13
6.8 Hz, 1H, ArH), 8.80 (d, J = 8.0 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC
16.3, 29.1, 114.2, 121.2, 123.6, 123.7, 125.9, 126.8, 127.05, 127.10, 127.3, 127.4,
127.8, 128.0, 128.1, 128.2, 128.7, 129.2, 129.6, 130.0, 130.1, 131.9, 133.0, 134.5,
135.7, 146.5, 151.4. IR (KBr):
ν 3036, 2954, 2925, 1529, 1509, 1473, 1461, 1438,
1410, 1388, 1280, 1220, 1187, 1121, 1042, 1021, 971, 932, 870, 842, 832, 818, 768,
748, 801 cm-1. HRMS (ESI, m/z): Calcd for C29H21N2 [M + H]+ 397.1704, found
397.1700.
13-(4-Propylphenyl)acenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline
(7c):
M.p.
1
223~225 °C; H NMR (CDCl3, 400 MHz): δH 1.11 (t, J = 7.2 Hz, 3H, CH3),
1.79~1.88 (m, 2H, CH2), 2.81 (t, J = 7.6 Hz, 2H, CH2), 5.07 (d, J = 7.2 Hz, 1H, ArH),
7.01~7.06 (m, 2H, ArH), 7.43 (d, J = 7.6 Hz, 2H, ArH), 7.53~7.60 (m, 5H, ArH),
7.64~7.73 (m, 3H, ArH), 8.09 (d, J = 6.8 Hz, 1H, ArH), 8.80 (d, J = 8.0 Hz, 1H, ArH).
13C NMR (CDCl3, 100 MHz): δC 13.8, 24.9, 38.0, 114.3, 121.2, 123.6, 123.7, 125.9,
126.8, 127.1, 127.3, 127.4, 127.8, 128.0, 128.1, 129.2, 129.3, 129.6, 129.9, 130.0,
130.6, 131.9, 133.0, 135.7, 144.7, 148.3, 151.4. IR (KBr):
ν 3036, 2957, 2925, 2857,
1556, 1508, 1473, 1437, 1410, 1284, 1226, 1186, 1122, 1038, 1022, 947, 932, 909,
844, 818, 768, 746, 721, 701 cm-1. HRMS (ESI, m/z): Calcd for C30H23N2 [M + H]+
411.1861, found 411.1862.
13-Cyclopropyl-9-fluoroacenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline (7d): M.
1
p.252~255 °C; H NMR (CDCl3, 400 MHz): δH 1.04~1.08 (m, 2H, CH2), 1.25~1.30
(m, 2H, CH2), 2.58~2.65 (m, 1H, CH), 6.75 (s, 1H, ArH), 7.17~7.22 (m, 1H, ArH),
7.43~7.46 (m, 1H, ArH), 7.53~7.62 (m, 2H, ArH), 7.67 (d, J = 8.4 Hz, 1H, ArH), 7.73
(d, J = 7.2 Hz, 1H, ArH), 7.76 (d, J = 8.0 Hz, 1H, ArH), 8.08 (d, J = 7.2 Hz, 1H, ArH),
21

ACCEPTED MANUSCRIPT
13
8.29 (d, J = 7.6 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 8.2, 14.7, 108.5 (d,
J(F-C) = 23.7 Hz), 109.5, 116.8 (d, J(F-C) = 24.0 Hz), 120.8, 121.2, 124.7 (d, J(F-C) = 9.8
Hz), 126.0 (d, J(F-C) = 1.7 Hz), 126.3, 127.3, 127.5, 127.7, 128.0, 128.5, 128.6, 129.6,
129.8, 130.5, 132.2, 136.6 (d, J(F-C) = 2.7 Hz), 147.6 (d, J(F-C) = 5.4 Hz), 151.7, 160.3
(d, J(F-C) = 245.6 Hz). IR (KBr):
ν 3041, 2925, 2855, 1534, 1488, 1459, 1280, 1268,
1224, 1200, 1182, 1157, 1123, 1075, 1038, 997, 955, 933, 896, 862, 817, 798, 763,
747 cm-1. HRMS (ESI, m/z): Calcd for C24H16FN2 [M + H]+ 351.1297, found
351.1290.
13-(4-Ethylphenyl)-9-fluoroacenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline
(7e):
M.p. 269~271 °C; 1H NMR (CDCl3, 400 MHz): δH 1.42 (t, J = 7.6 Hz, 3H, CH3), 2.87
(q, J = 7.6 Hz, 2H, CH2), 5.04 (d, J = 7.2 Hz, 1H, ArH), 7.03~7.07 (m, 2H, ArH),
7.28~7.33 (m, 1H, ArH), 7.46 (d, J = 7.6 Hz, 2H, ArH), 7.55~7.58 (m, 4H, ArH),
7.69~7.73 (m, 2H, ArH), 8.09 (d, J = 6.8 Hz, 1H, ArH), 8.42 (dd, J = 9.6 Hz, J’ = 2.4
Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 15.6, 28.7, 107.7 (d, J(F-C) = 22.1 Hz),
117.5, 121.6 (d, J(F-C) = 25.6 Hz), 122.7, 125.7 (d, J(F-C) = 8.7 Hz), 127.1, 127.2, 128.3,
129.0, 130.3 (d, J(F-C) = 8.6 Hz), 131.8, 131.9, 134.7, 136.08, 136.14, 145.0, 148.3,
148.4, 150.9 (d, J(F-C) = 2.7 Hz), 161.5 (d, J(F-C) = 248.8 Hz), 164.3. IR (KBr):
ν 2963,
2926, 2854, 1508, 1483, 1460, 1377, 1350, 1301, 1274, 1262, 1231, 1189, 1154,
1097, 1039, 952, 931, 899, 872, 849, 819, 769, 720 cm-1. HRMS (ESI, m/z): Calcd for
C29H20FN2 [M + H]+ 415.1610, found 415.1614.
9-Fluoro-13-(4-n-propylphenyl)acenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline (7f):
1
M.p. 270~272 °C; H NMR (CDCl3, 400 MHz): δH 1.11 (t, J = 7.2 Hz, 3H, CH3),
1.79~1.88 (m, 2H, CH2), 2.81 (t, J = 7.6 Hz, 2H, CH2), 5.06 (d, J = 7.2 Hz, 1H, ArH),
7.01~7.05 (m, 2H, ArH), 7.27~7.31 (m, 1H, ArH), 7.43 (d, J = 8.0 Hz, 2H, ArH),
7.54~7.58 (m, 4H, ArH), 7.67~7.72 (m, 2H, ArH), 8.08 (d, J = 6.8 Hz, 1H, ArH), 8.42
22

ACCEPTED MANUSCRIPT
13
(dd, J = 9.6 Hz, J’ = 2.4 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 13.8, 24.9,
38.0, 108.6 (d, J(F-C) = 23.7 Hz), 113.6, 117.0 (d, J(F-C) = 23.9 Hz), 121.2, 121.4, 125.1
(d, J(F-C) = 9.7 Hz), 126.0, 126.1 (d, J(F-C) = 2.0 Hz), 127.1, 127.4, 127.5, 127.6, 129.1,
129.19, 129.23, 129.3, 129.8, 129.9, 132.0, 132.8, 135.0 (d, J(F-C) = 2.7 Hz), 144.8,
147.5 (d, J(F-C) = 4.7 Hz), 151.5, 162.1 (d, J(F-C) = 246.4 Hz). IR (KBr):
ν 3039, 2964,
2927, 2867, 1525, 1508, 1460, 1435, 1350, 1299, 1265, 1224, 1144, 1130, 1096,
1067, 1049, 1010, 965, 921, 882, 851, 832, 816, 767, 742, 719 cm-1. HRMS (ESI,
m/z): Calcd for C30H22FN2 [M + H]+ 429.1767, found 429.1759.
9-Chloro-13-cyclopropylacenaphtho[1',2':4,5]imidazo[2,1-a]isoquinoline (7g): M.p.
272~274 °C; 1H NMR (CDCl3, 400 MHz): δH 1.08~1.12 (m, 2H, CH2), 1.29~1.34 (m,
2H, CH2), 2.64~2.71 (m, 1H, CH), 6.78 (s, 1H, ArH), 7.41~7.53 (m, 3H, ArH),
7.60~7.64 (m, 1H, ArH), 7.71 (d, J = 8.0 Hz, 1H, ArH), 7.76~7.80 (m, 2H, ArH), 8.09
13
(d, J = 6.8 Hz, 1H, ArH), 8.67 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 8.2,
14.8, 109.4, 120.9, 121.3, 122.9, 124.3, 126.5, 127.4, 127.6, 127.69, 127.73, 127.8,
128.0, 128.4, 129.7, 129.8, 130.6, 132.2, 133.4, 137.6, 147.3, 151.8. IR (KBr):
ν
3040, 2955, 2928, 2868, 1606, 1559, 1508, 1473, 1437, 11411, 1375, 1300, 1274,
1224, 1187, 1154, 1121, 1041, 952, 906, 819, 769 cm-1. HRMS (ESI, m/z): Calcd for
C24H16ClN2 [M + H]+ 367.1002, found 367.1000.
Acknowledgements
We are grateful to the Major Natural Science Foundation of Jiangsu Province
(14KJA150004), and a project funded by the Priority Academic Program
Development of Jiangsu Higher Education for financial support.
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