Library construction of 1-(1H-imidazol-1-yl)-1,2-dihydroisoquinolines via three-component reaction of 2-alkynylbenzaldehyde, amine, and imidazole

Article abstract of DOI:10.1016/j.tet.2011.01.048

Parallel diversity-oriented synthesis of diverse 1-(1H-imidazol-1-yl)-1,2- dihydroisoquinolines via AgOTf-catalyzed three-component reaction of 2-alkynylbenzaldehyde, amine, and imidazole is described. This reaction works efficiently under mild conditions to generate a small library of imidazole-incorporated 1,2-dihydroisoquinolines.

Full text of DOI:10.1016/j.tet.2011.01.048

Tetrahedron 67 (2011) 2060e2065
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Tetrahedron
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Library construction of 1-(1H-imidazol-1-yl)-1,2-dihydroisoquinolines via
three-component reaction of 2-alkynylbenzaldehyde, amine, and imidazole
,
a,
Honglei Lou a, Shengqing Ye a, Jianfeng Zhang b , Jie Wu
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b Obstetrics and Gynecology Hospital, Fudan University, 419 Fangxie Road, Shanghai 200011, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Parallel diversity-oriented synthesis of diverse 1-(1H-imidazol-1-yl)-1,2-dihydroisoquinolines via AgOTf-
catalyzed three-component reaction of 2-alkynylbenzaldehyde, amine, and imidazole is described. This
reaction works efficiently under mild conditions to generate a small library of imidazole-incorporated
1,2-dihydroisoquinolines.
Received 14 December 2010
Accepted 18 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Alkynylbenzaldehyde
Amine
Imidazole
1-(1H-Imidazol-1-yl)-1,2-
dihydroisoquinoline
Silver triflate
1. Introduction
Parallel diversity-oriented synthesis has been recognized as
a powerful and efficient tool for providing a large collection of small
molecules in the field of combinatorial chemistry.1 This strategy has
a great impact on the drug discovery process currently. Among the
scaffolds generated based on the approach, intense interest has
been directed toward the design and synthesis of 1,2-
dihydroisoquinolines,2e4 which serves as a core structure in many
natural alkaloids and pharmaceuticals with diverse biological and
pharmacological activities.5,6 On the other hands, the imidazole
moiety is widely featured in many pharmacologically and bi-
ologically active compounds (including antivirals, antitumor, anti-
fungals, etc.).7 Thus, exploration for the efficient generation of
highly functionalized imidazole-related compounds has drawn
a great deal of attention from both medicinal and organic chemists.
As part of an ongoing program in our laboratory for natural
product-like compounds generation,8,9 we are interested in the
methodology development for accessing 1,2-dihydroisoquinolines.
Recently, we developed an efficient pathway to functionalized 1,2-
dihydroisoquinolines starting from 2-alkynylbenzaldehydes.10
Subsequent biological assay revealed that some of them showed
promising result for PTP1B inhibition (Fig. 1). Protein tyrosine
phosphatase 1B (PTP1B) has been demonstrated as a novel target
Fig. 1. 1,2-Dihydroisoquinoline scaffold.
for diabetes and obesity. Inhibition of PTP1B0s activity could im-
prove the sensitivity of insulin signaling.11 This biological result
prompted us to consider to generate more novel 1,2-dihy-
droisoquinoline-based compounds for further screening. Encour-
aged by the importance of the imidazole skeleton, we conceived
that the 1,2-dihydroisoquinoline with an imidazole substituent
might be a choice for hit evaluation. Based on our previous
reports10 and the advancement of multi-component reactions,12
we envisioned that three-component reaction of 2-alky-
nylbenzaldehyde, amine, and imidazole under suitable conditions
would be a good device to afford the desired imidazole-derived 1,2-
dihydroisoquinolines. Therefore, we started to investigate the
methodology for the synthesis of imidazole-incorporated 1,2-
dihydroisoquinolines.
2. Results and discussion
The initial studies were performed for three-component re-
action of 2-alkynylbenzaldehyde 1a, p-toluidine 2b, and imidazole
3a catalyzed by different Lewis acids in various solvents (Table 1).
* Corresponding authors. E-mail address: jie_wu@fundan.edu.cn (J. Wu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.048

H. Lou et al. / Tetrahedron 67 (2011) 2060e2065
2061
Table 1
might be due to the lower electrophilicity of intermediate ortho-
alkynylaryl aldimine toward nucleophilic attack. We subsequently
tested the reactions of 2-alkynylbenzaldehydes 1fei, anilines, and
imidazole. All reactions worked well to provide the desired prod-
ucts in moderate to good yields.
Initial studies for three-component reaction of 2-alkynylbenzaldehyde 1a, p-tolui-
dine 2b, and imidazole 3a
N
NH2
CHO
Lewis acid
(10 mol %)
solvent, temp.
N
N
+
+
C6H4p-Me
N
H
N
Table 2
Ph
Generation of diverse 1-(1H-imidazol-1-yl)-1,2-dihydroisoquinolines via AgOTf-
catalyzed three-component reaction of 2-alkynylbenzaldehyde, amine, and
imidazole
1a
Ph
3a
2b
I-2
R4
N
Entry
Lewis acid
Solvent
Temp (ꢀC)
Yielda (%)
R3 NH2
2
CHO
1
2
3
4
5
6
7
8
CuI
DCE
DCE
DCE
THF
THF
THF
DCE
DCE
25
25
25
25
25
25
50
50
50
50
50
50
50
50
70
NR
NR
NR
NR
NR
NR
Complex
27
Trace
43
R1
N
AgOTf (10 mol %)
toluene, 70 °C
+
N
R3
R2
AgOTf
PdCl2
CuI
AgOTf
PdCl2
CuI
AgOTf
PdCl2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
R4
N
R1
R2
N
H
1
I
3
R1, R2
R3
R4
Yielda (%)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
H, Ph (1a)
5-F, Ph (1b)
5-F, Ph (1b)
5-F, Ph (1b)
5-F, Ph (1b)
5-F, Ph (1b)
C6H5 (2a)
H (3a)
H (3a)
H (3a)
H (3a)
5-Me (3b)
H (3a)
H (3a)
H (3a)
H (3a)
5-Me (3b)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
5-Me (3b)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
5-Me (3b)
5-Me (3b)
5-Me (3b)
5-Me (3b)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
5-Me (3b)
5-Me (3b)
H (3a)
H (3a)
H (3a)
87 (I-1)
80 (I-2)
d (I-3)
65 (I-4)
67 (I-5)
76 (I-6)
78 (I-7)
68 (I-8)
9
DCE
THF
4-MeC6H4 (2b)
C6H5CH2 (2c)
4-FC6H4 (2d)
C6H5 (2a)
10
11
12
13
14
15
MeCN
EtOH
Toluene
1,4-Dioxane
Toluene
41
27
61
44
C6H5 (2a)
4-MeC6H4 (2b)
4-FC6H4 (2d)
4-ClC6H4 (2e)
4-FC6H4 (2d)
4-MeC6H4 (2b)
4-MeOC6H4 (2f)
C6H5 (2a)
4-FC6H4 (2d)
4-ClC6H4 (2e)
3-NO2C6H4 (2g)
4-MeC6H4 (2b)
4-MeC6H4 (2b)
C6H5 (2a)
4-MeC6H4 (2b)
4-MeOC6H4 (2f)
4-FC6H4 (2d)
4-ClC6H4 (2e)
C6H5 (2a)
4-MeC6H4 (2b)
4-MeOC6H4 (2f)
4-ClC6H4 (2e)
C6H5 (2a)
4-MeC6H4 (2b)
4-MeOC6H4 (2f)
4-FC6H4 (2d)
4-ClC6H4 (2e)
4-MeC6H4 (2b)
4-FC6H4 (2d)
C6H5 (2a)
4-MeC6H4 (2b)
4-FC6H4 (2d)
4-ClC6H4 (2e)
C6H5 (2a)
80
65 (I-9)
a
Isolated yield based on 2-alkynylbenzaldehyde 1a.
65 (I-10)
76 (I-11)
65 (I-12)
67 (I-13)
83 (I-14)
83 (I-15)
55 (I-16)
55 (I-17)
41 (I-18)
83 (I-19)
87 (I-20)
89 (I-21)
80 (I-22)
78 (I-23)
50 (I-24)
55 (I-25)
56 (I-26)
52 (I-27)
60 (I-28)
62 (I-29)
48 (I-30)
55 (I-31)
65 (I-32)
45 (I-33)
35 (I-34)
60 (I-35)
62 (I-36)
47 (I-37)
56 (I-38)
73 (I-39)
76 (I-40)
78 (I-41)
69 (I-42)
66 (I-43)
5-F, cyclopropyl (1c)
5-F, cyclopropyl (1c)
5-F, cyclopropyl (1c)
5-F, cyclopropyl (1c)
5-F, cyclopropyl (1c)
5-F, n-Bu (1d)
4,5-(OMe)2, Ph (1e)
4,5-(OMe)2, Ph (1e)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
5-Me, Ph (1f)
H, cyclopropyl (1g)
H, cyclopropyl (1g)
H, cyclopropyl (1g)
H, cyclopropyl (1g)
H, cyclopropyl (1g)
H, cyclopropyl (1g)
H, cyclopropyl (1g)
H, n-Bu (1h)
Since Pd, Cu, and Ag salts have been demonstrated effectively for
activation of triple bond,10 the reaction was carried out in the
presence of PdCl2, CuI, or AgOTf (10 mol %) in dichloroethane at
room temperature (Table 1, entries 1e3). However, no desired
product was detected and only the intermediate ortho-alkynylaryl
aldimine was observed. The same result was displayed when the
reaction took place in THF (Table 1, entries 4e6). When the reaction
occurred at 50 ꢀC in dichloroethane, complex result was obtained
when CuI was utilized as the catalyst (Table 1, entry 7). Gratifyingly,
the corresponding product I-2 was isolated in 27% yield when the
reaction was catalyzed by AgOTf (Table 1, entry 8). Only a trace
amount of product was formed when PdCl2 was used as a catalyst
(Table 1, entry 9). We further tested the AgOTf-catalyzed reaction in
different solvents at 50 ꢀC. It was found that the reaction worked
the most efficiently in toluene, which furnished the 1,2-dihy-
droisoquinoline I-2 in 61% yield (Table 1, entry 13). The result could
be improved when the reaction occurred at 70 ꢀC, with an isolated
80% yield (Table 1, entry 15). However, reducing the amount of
catalyst resulted in lower reactivity (data not shown in Table 1).
With an expectation to generate a small library of imidazole-
incorporated 1,2-dihydroisoquinolines I, we next investigate the
scope of this three-component reaction of 2-alkynylbenzaldehyde
1, amine 2, and imidazole 3 under the optimized conditions [AgOTf
(10 mol %), toluene, 70 ꢀC]. This silver-catalyzed three-component
reaction was shown to be effective for a number of substrates
(Table 2). However, it seemed that the aniline was crucial for the
transformation. No reaction took place when aliphatic amine, such
as benzylic amine 2c was used as a partner in the reaction of
2-alkynylbenzaldehyde 1a with imidazole 3a. Reaction of 2-alky-
nylbenzaldehyde 1a with aniline, 5-methylimidazole 3b proceeded
smoothly as well under the standard conditions. Other 2-alky-
nylbenzaldehydes were examined meanwhile. As expected, the
fluoro-substituted 2-alkynylbenzaldehyde 1b reacted with various
anilines and imidazole 3a or 3b, leading to the desired imidazole-
incorporated 1,2-dihydroisoquinolines in moderate to good yield.
No difference was observed when the phenyl group attached on the
triple bond of 2-alkynylbenzaldehyde 1b was changed to cyclo-
propyl (1c) or n-butyl group (1d). However, inferior results were
obtained for the reaction of 2-alkynylbenzaldehyde 1e with an
electron-donating group attached on the aromatic ring, which
H, n-Bu (1h)
H, n-Bu (1h)
H, n-Bu (1h)
4-OMe, Ph (1i)
4-OMe, Ph (1i)
4-OMe, Ph (1i)
4-OMe, Ph (1i)
4-OMe, Ph (1i)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
4-MeC6H4 (2b)
4-MeOC6H4 (2f)
4-FC6H4 (2d)
4-ClC6H4 (2e)
a
Isolated yield based on 2-alkynylbenzaldehyde 1.
3. Conclusions
In conclusion, we have described a parallel diversity-oriented
synthesis of diverse 1-(1H-imidazol-1-yl)-1,2-dihydroisoquino-
lines via AgOTf-catalyzed three-component reaction of 2-alky-
nylbenzaldehyde, amine, and imidazole. This reaction works
efficiently under mild conditions to generate a small library of
imidazole-incorporated 1,2-dihydroisoquinolines. Various 2-alky-
nylbenzaldehydes and anilines bearing electron-rich and electron-
poor groups attached on the aromatic ring are suitable partners in
the transformation. However, aliphatic amines are not workable as
substrates in the reaction, which might be due to the stability issue

2062
H. Lou et al. / Tetrahedron 67 (2011) 2060e2065
of intermediate ortho-alkynylaryl aldimines. The imidazole-deriv-
atized 1,2-dihydroisoquinoline small library would be attractive
and beneficial for the further biological screening.
(s, 1H), 6.44 (s, 1H), 6.56 (s, 1H), 6.87e6.99 (m, 6H), 7.14e7.17 (m,
4H), 7.45e7.47 (m, 2H), 7.55 (s, 1H); 13C NMR (100 MHz, CDCl3)
2
2
d
20.6, 62.1, 109.8, 113.2 (d, JCF¼21.9 Hz), 114.5 (d, JCF¼21.0 Hz),
116.0,122.4,125.5 (d, 3JCF¼8.6 Hz),127.5,127.8,128.1,128.2,128.4 (d,
4JCF¼2.9 Hz), 129.2, 129.8, 131.6, 132.2 (d, 3JCF¼6.7 Hz), 135.2, 137.4,
4. Experimental section
1
140.4, 144.6, 161.5 (d, JCF¼244.1 Hz); HRMS calcd for C25H20FN3
4.1. General procedure for AgOTf-catalyzed three-component
reactions of 2-alkynylbenzaldehyde 1, amine 2, and imidazole 3
(MþþH): 382.1720, found: 382.1730.
4.1.7. 7-Fluoro-2-(4-fluorophenyl)-1-(1H-imidazol-1-yl)-3-phenyl-
Imidazole 3 (1.0 mmol, 2.0 equiv) and AgOTf (0.025 mmol,
5 mol %) were added to a mixture of 2-alkynylbenzaldehyde 1
(0.5 mmol) and amine 2 (0.5 mmol, 1.0 equiv) in toluene (2.0 mL).
The reaction mixture was stirred at 70 ꢀC vigorously until com-
pletion of the reaction. Subsequently, the mixture was diluted with
ethyl acetate (5.0 mL), and quenched with water (5.0 mL). The or-
ganic layer was washed with brine, dried over Na2SO4, and con-
centrated in vacuo. The residue was purified by column
chromatography on silica gel to provide the desired product I.
1,2-dihydroisoquinoline (I-8). 1H NMR (400 MHz, CDCl3)
d 6.02 (s,
1H), 6.46 (s, 1H), 6.51 (s, 1H), 6.78 (t, J¼8.24, 2H), 6.90e6.99 (m, 2H),
7.05e7.08 (m, 2H), 7.15e7.22 (m, 4H), 7.43e7.46 (m, 2H), 7.63 (s,
1H); 13C NMR (100 MHz, CDCl3)
d
62.2,110.0,113.2 (d, 2JCF¼22.9 Hz),
114.7 (d, 2JCF¼21.9 Hz),115.3 (d, 2JCF¼22.9 Hz),123.9 (d, 3JCF¼7.6 Hz),
3
125.7 (d, JCF¼8.6 Hz), 127.5, 128.0, 128.2, 128.3, 129.7, 131.9 (d,
3JCF¼7.6 Hz), 135.2, 137.0, 140.3, 140.5 (d, JCF¼3.8 Hz), 143.1 (d,
4
1
1
4JCF¼2.9 Hz), 158.3 (d, JCF¼240.3 Hz), 161.6 (d, JCF¼245.0 Hz);
HRMS calcd for C24H17F2N3 (MþþH): 386.1469, found: 386.1458.
4.1.1. 1-(1H-Imidazol-1-yl)-2,3-diphenyl-1,2-dihydroisoquinoline (I-1).
4.1.8. 2-(4-Chlorophenyl)-7-fluoro-1-(1H-imidazol-1-yl)-3-phenyl-
1H NMR (400 MHz, CDCl3)
d
6.13 (s, 1H), 6.48 (s, 1H), 6.54 (s, 1H),
1,2-dihydroisoquinoline (I-9). 1H NMR (400 MHz, CDCl3)
d 6.03 (s,
6.79e6.82 (m,1H), 7.07e7.11 (m, 4H), 7.14e7.16 (m, 6H), 7.22e7.23 (m,
1H), 6.46 (s, 1H), 6.47 (s, 1H), 6.88e6.97 (m, 2H), 7.02 (s, 4H),
2H), 7.45e7.48 (m, 2H), 7.52 (d, J¼0.88 Hz, 1H); 13C NMR (100 MHz,
7.15e7.20 (m, 5H), 7.41e7.43 (m, 2H), 7.57 (s, 1H); 13C NMR
2
CDCl3)
d
61.8, 111.2, 116.5, 121.9, 122.4, 124.3, 126.2, 126.4, 127.5, 127.7,
(100 MHz, CDCl3)
d
62.0, 110.8, 113.3 (d, JCF¼21.9 Hz), 114.8 (d,
127.9, 128.3, 128.5, 130.5, 132.0, 135.0, 137.4, 140.1, 140.8, 146.9; HRMS
2JCF¼21.9 Hz), 115.7, 123.5, 126.0 (d, 3JCF¼8.6 Hz), 127.1, 127.5, 128.1,
calcd for C24H19N3 (MþþH): 350.1657, found: 350.1663.
128.2, 128.4 (d, JCF¼2.9 Hz), 128.5, 128.7, 132.6 (d, JCF¼6.7 Hz),
135.4, 137.1, 139.8, 140.6, 145.6, 161.7 (d, 1JCF¼245.0 Hz); HRMS calcd
for C24H17ClFN3 (MþþH): 402.1173, found: 402.1178.
4
3
4.1.2. 1-(1H-Imidazol-1-yl)-3-phenyl-2-p-tolyl-1,2-dihydroisoquino-
line (I-2). 1H NMR (400 MHz, CDCl3)
d 2.15 (s, 3H), 6.07 (s, 1H), 6.46
(s, 1H), 6.54 (s, 1H), 6.86 (d, J¼8.24 Hz, 2H), 6.96 (d, J¼8.72 Hz, 2H),
4.1.9. 7-Fluoro-2-(4-fluorophenyl)-1-(4-methyl-1H-imidazol-1-yl)-
3-phenyl-1,2-dihydroisoquinoline (I-10). 1H NMR (400 MHz, CDCl3)
7.11e7.15 (m, 6H), 7.21e7.22 (m, 2H), 7.46e7.50 (m, 3H); 13C NMR
(100 MHz, CDCl3)
d
20.6, 62.1, 110.6, 116.6, 122.5, 124.2, 126.2, 126.3,
d 2.17 (s, 3H), 6.13 (s, 1H), 6.45 (s, 1H), 6.61 (s, 1H), 6.77e6.82 (m,
127.5,127.6, 127.8, 128.2, 129.2, 130.1, 131.5,132.0, 135.0, 137.5, 139.9,
141.0, 144.6; HRMS calcd for C25H21N3 (MþþH): 364.1814, found:
364.1815.
2H), 6.93e7.08 (m, 4H), 7.21e7.28 (m, 5H), 7.40e7.42 (m, 2H); 13C
2
NMR (100 MHz, CDCl3)
d
14.2, 62.4, 108.9, 113.6 (d, JCF¼21.9 Hz),
2
2
115.3 (d, JCF¼21.9 Hz), 115.4 (d, JCF¼21.9 Hz), 115.4, 124.2 (d,
3
3
3JCF¼7.6 Hz), 126.1 (d, JCF¼7.6 Hz), 127.6, 128.4 (d, JCF¼6.7 Hz),
3
4
4.1.3. 2-(4-Fluorophenyl)-1-(1H-imidazol-1-yl)-3-phenyl-1,2-dihy-
128.5, 129.4, 130.3 (d, JCF¼6.7 Hz), 136.6, 141.3 (d, JCF¼1.9 Hz),
4 1
droisoquinoline (I-4). 1H NMR (400 MHz, CDCl3)
d
6.05 (s, 1H), 6.45
142.7 (d, JCF¼2.9 Hz), 147.8, 158.6 (d, JCF¼241.2 Hz), 161.9 (d,
1JCF¼246.0 Hz); HRMS calcd for C25H19F2N3 (MþþH): 400.1625,
found: 400.1609.
(s, 1H), 6.51 (s, 1H), 6.75e6.80 (m, 2H), 7.07e7.10 (m, 2H), 7.16e7.18
(m, 5H), 7.25e7.26 (m, 2H), 7.44e7.46 (m, 2H), 7.57 (d, J¼0.92 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d
62.4, 110.6, 115.2 (d, 2JCF¼21.9 Hz),
3
116.0, 123.9 (d, JCF¼7.6 Hz), 124.3, 126.2, 126.4, 127.6, 127.7, 127.9,
4.1.10. 3-Cyclopropyl-7-fluoro-1-(1H-imidazol-1-yl)-2-p-tolyl-1,2-
128.3, 129.7, 130.2, 132.1, 135.1, 137.3, 140.8, 143.3 (d, 4JCF¼2.86 Hz),
dihydroisoquinoline (I-11). 1H NMR (400 MHz, CDCl3)
d 0.56e0.64
1
158.1 (d, JCF¼220.5 Hz); HRMS calcd for C24H18FN3 (MþþH):
(m, 3H), 0.72e0.78 (m, 1H), 1.30e1.38 (m, 1H), 2.29 (s, 3H), 5.62 (s,
1H), 5.79 (s, 1H), 6.63 (s, 1H), 6.70e6.85 (m, 2H), 6.92 (dd, J¼5.5,
8.7 Hz, 1H), 7.06 (d, J¼8.24 Hz, 2H), 7.17 (d, J¼8.68 Hz, 2H), 7.46 (d,
368.1563, found: 368.1574.
4.1.4. 1-(4-Methyl-1H-imidazol-1-yl)-2,3-diphenyl-1,2-dihy-
J¼1.4 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 7.7, 10.7, 13.9, 20.7, 62.0,
droisoquinoline (I-5). 1H NMR (400 MHz, CDCl3)
d
2.17 (s, 3H), 6.28
99.7, 112.8 (d, 2JCF¼21.9 Hz), 114.2 (d, JCF¼21.0 Hz), 123.7, 124.1 (d,
2
4
3
(s, 1H), 6.49 (s, 1H), 6.61 (s, 1H), 6.84e6.88 (m, 1H), 7.08e7.13 (m,
3JCF¼7.63 Hz), 128.5 (d, JCF¼2.9 Hz), 129.2, 130.6 (d, JCF¼6.7 Hz),
132.7, 135.9, 143.8, 144.6, 160.6 (d, 1JCF¼243.1 Hz); HRMS calcd for
C22H20FN3 (MþþH): 346.1720, found: 346.1726.
5H), 7.19e7.23 (m, 6H), 7.29e7.31 (m, 2H), 7.43e7.46 (m, 2H); 13C
NMR (100 MHz, CDCl3)
d 29.7, 62.3, 110.2, 112.5, 112.8, 124.7, 126.7,
127.1, 127.8, 128.3, 128.4, 128.5, 128.6, 128.7, 129.1, 129.9, 131.6, 137.2,
142.0, 146.7, 148.6, 148.7; HRMS calcd for C25H21N3 (MþþH):
364.1814, found: 364.1802.
4.1.11. 3-Cyclopropyl-7-fluoro-1-(1H-imidazol-1-yl)-2-(4-methoxy-
phenyl)-1,2-dihydroisoquinoline (I-12). 1H NMR (400 MHz, CDCl3)
d
0.56e0.72 (m, 4H), 1.24e1.30 (m, 1H), 3.75 (s, 3H), 5.56 (s, 1H),
4.1.5. 7-Fluoro-1-(1H-imidazol-1-yl)-2,3-diphenyl-1,2-dihy-
5.74 (s, 1H), 6.64 (s, 1H), 6.76e6.86 (m, 5H), 6.90e6.94 (m, 1H),
droisoquinoline (I-6). 1H NMR (400 MHz, CDCl3)
d
6.11 (s,1H), 6.46 (s,
7.20e7.21 (m, 2H), 7.46 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 7.2,
1H), 6.56 (s, 1H), 6.82e6.84 (m, 1H), 6.90e6.98 (m, 2H), 7.09e7.10 (d,
10.5, 13.9, 55.4, 62.2, 98.4, 112.7 (d, 2JCF¼21.9 Hz), 113.7, 113.9, 114.2
J¼4.56 Hz, 4H), 7.14e7.22 (m, 5H), 7.45e7.47 (m, 2H), 7.58 (s, 1H); 13C
(d, 2JCF¼21.9 Hz), 124.0 (d, 3JCF¼7.6 Hz), 125.9, 127.9, 128.7, 130.3 (d,
1
NMR (100 MHz, CDCl3)
d
62.0, 110.3, 113.3 (d, 2JCF¼21.9 Hz), 114.7 (d,
3JCF¼6.7 Hz), 135.0, 139.6, 145.1, 156.1, 160.6 (d, JCF¼242.2 Hz);
2JCF¼21.9 Hz), 122.0, 122.4, 125.8 (d, 3JCF¼7.6 Hz), 127.6, 128.0, 128.4,
128.5, 128.7, 132.7, 135.3, 137.5, 140.3, 147.0, 161.6 (d, 1JCF¼244.1 Hz);
HRMS calcd for C24H18FN3 (MþþH): 368.1563, found: 368.1543.
HRMS calcd for C22H20FN3O (MþþH): 362.1669, found: 362.1673.
4.1.12. 3-Cyclopropyl-7-fluoro-1-(1H-imidazol-1-yl)-2-phenyl-1,2-
dihydroisoquinoline (I-13). 1H NMR (400 MHz, CDCl3)
d 0.57e0.66
4.1.6. 7-Fluoro-1-(1H-imidazol-1-yl)-3-phenyl-2-p-tolyl-1,2-dihy-
(m, 3H), 0.75e0.81 (m, 1H), 1.34e1.41 (m, 1H), 5.67 (s, 1H), 5.85 (s,
1H), 6.61 (s, 1H), 6.80e6.82 (m, 1H), 6.86 (dd, J¼2.76, 8.72 Hz, 1H),
droisoquinoline (I-7). 1H NMR (400 MHz, CDCl3)
d 2.16 (s, 3H), 6.05

H. Lou et al. / Tetrahedron 67 (2011) 2060e2065
2063
6.95 (dd, J¼5.52, 8.24 Hz, 1H), 7.00e7.02 (m, 1H), 7.24e7.32 (m, 5H),
7.00e7.15 (m, 9H), 7.42e7.44 (m, 3H); 13C NMR (100 MHz, CDCl3)
21.2, 62.1, 111.3, 121.6, 122.1, 124.2, 126.8, 127.3, 127.6, 128.2, 128.3,
7.49 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
7.9, 10.8, 13.8, 61.8, 100.7,
d
112.8 (d, 2JCF¼21.9 Hz), 114.3 (d, 2JCF¼21.9 Hz), 122.9, 123.4, 124.3(d,
128.5, 129.3, 130.9, 135.0, 136.2, 137.6, 139.8, 147.1; HRMS calcd for
4
3
3JCF¼7.6 Hz), 128.4 (d, JCF¼1.9 Hz), 128.7, 130.9 (d, JCF¼6.7 Hz),
C25H21N3 (MþþH): 364.1814, found: 364.1830.
1
135.0, 144.3, 146.3, 160.7 (d, JCF¼242.2 Hz); HRMS calcd for
C21H18FN3 (MþþH): 332.1563, found: 332.1560.
4.1.19. 1-(1H-Imidazol-1-yl)-7-methyl-3-phenyl-2-p-tolyl-1,2-dihy-
droisoquinoline (I-20). 1H NMR (400 MHz, CDCl3)
d 2.13 (s, 3H), 2.22
4.1.13. 3-Cyclopropyl-7-fluoro-2-(4-fluorophenyl)-1-(1H-imidazol-1-
yl)-1,2-dihydroisoquinoline (I-14). 1H NMR (400 MHz, CDCl3)
(s, 3H), 6.02 (s, 1H), 6.45 (s, 1H), 6.58 (s, 1H), 6.84 (d, J¼8.68 Hz, 2H),
6.94 (d, J¼8.24 Hz, 3H), 7.01 (d, J¼8.24 Hz, 1H), 7.08e7.15 (m, 5H),
d
0.54e0.63 (m, 3H), 0.71e0.76 (m, 1H), 1.23e1.28 (m, 1H), 5.64 (s,
7.41e7.46 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 20.5, 21.2, 62.4,
1H), 5.75 (s, 1H), 6.56 (s, 1H), 6.77e6.87 (m, 2H), 6.90e6.96 (m,
110.8, 116.3, 122.2, 124.1, 126.8, 127.4, 127.5, 128.1, 128.3, 129.1, 129.4,
130.6, 131.1, 135.0, 136.1, 137.7, 140.1, 144.8; HRMS calcd for
C26H23N3 (MþþH): 378.1970, found: 378.1963.
3H), 7.22e7.26 (m, 2H), 7.48 (s, 1H); 13C NMR (100 MHz, CDCl3)
2
d
7.4, 10.7, 13.8, 62.2, 100.3, 112.8 (d, JCF¼21.9 Hz), 114.3 (d,
2JCF¼21.0 Hz), 115.3 (d, JCF¼21.9 Hz), 124.3 (d, JCF¼7.6 Hz), 125.4
2
3
(d, 3JCF¼7.6 Hz), 128.5 (d, 4JCF¼2.8 Hz), 130.6 (d, 3JCF¼7.6 Hz), 135.1,
4.1.20. 1-(1H-Imidazol-1-yl)-2-(4-methoxyphenyl)-7-methyl-3-phe-
2
1
142.5 (d, JCF¼1.9 Hz), 144.3, 159.1 (d, JCF¼241.2 Hz), 160.7 (d,
1JCF¼242.2 Hz); HRMS calcd for C21H17F2N3 (MþþH): 350.1469,
found: 350.1464.
nyl-1,2-dihydroisoquinoline (I-21). 1H NMR (400 MHz, CDCl3)
d 2.26
(s, 3H), 3.64 (s, 3H), 5.97 (s,1H), 6.43 (s,1H), 6.60e6.63 (m, 3H), 6.95
(s, 1H), 6.95e7.05 (m, 3H), 7.11e7.16 (m, 4H), 7.45e7.48 (m, 3H); 13C
NMR (100 MHz, CDCl3)
d 21.2, 55.3, 62.7, 110.0, 113.9, 123.8, 124.1,
4.1.14. 2-(4-Chlorophenyl)-3-cyclopropyl-7-fluoro-1-(1H-imidazol-
1-yl)-1,2-dihydroisoquinoline (I-15). 1H NMR (400 MHz, CDCl3)
126.8, 127.5, 127.6, 128.2, 128.3, 129.4, 130.3, 134.9, 136.1, 137.7,
140.4, 140.9, 154.8; HRMS calcd for C26H23N3O (MþþH): 394.1919,
found: 394.1911.
d
0.55e0.60 (m, 3H), 0.74e0.78 (m, 1H), 1.28e1.32 (m, 1H), 5.70 (s,
1H), 5.77 (s, 1H), 6.53 (s, 1H), 6.78 (dd, J¼2.28, 8.72 Hz, 1H),
6.83e6.88 (m, 1H), 6.95 (dd, J¼5.52, 8.72 Hz, 1H), 7.18e7.24 (m, 4H),
4.1.21. 2-(4-Fluorophenyl)-1-(1H-imidazol-1-yl)-7-methyl-3-phenyl-
7.48 (d, J¼0.92 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d
7.8, 10.8, 13.8,
1,2-dihydroisoquinoline (I-22). 1H NMR (400 MHz, CDCl3)
d 2.25 (s,
2
2
61.9, 101.7, 112.8 (d, JCF¼21.9 Hz), 114.3 (d, JCF¼21.0 Hz), 124.4,
3H), 5.98 (s, 1H), 6.46 (s, 1H), 6.53 (s, 1H), 6.74 (t, J¼8.72 Hz, 2H),
4
3
124.5, 127.9, 128.3 (d, JCF¼2.9 Hz), 128.6, 130.9 (d, JCF¼6.7 Hz),
6.95 (s, 1H), 7.01e7.06 (m, 3H), 7.11e7.15 (m, 4H), 7.41e7.48 (m, 3H);
1
135.1, 143.6, 144.9, 160.7 (d, JCF¼243.1 Hz); HRMS calcd for
13C NMR (100 MHz, CDCl3)
d
21.2, 62.5, 111.0, 115.1 (d, 2JCF¼21.9 Hz),
C21H17ClFN3 (MþþH): 366.1173, found: 366.1165.
123.6 (d, 3JCF¼8.6 Hz), 124.3, 126.8, 127.4, 127.7, 128.2, 128.4, 129.3,
4
130.5, 135.0, 136.3, 137.4, 139.9, 143.4 (d, JCF¼1.9 Hz), 158.0 (d,
4.1.15. 3-Butyl-7-fluoro-1-(1H-imidazol-1-yl)-2-(3-nitrophenyl)-1,2-
1JCF¼240.3 Hz); HRMS calcd for C25H20FN3 (MþþH): 382.1720,
dihydroisoquinoline (I-16). 1H NMR (400 MHz, CDCl3)
d
0.65 (t,
found: 382.1715.
J¼7.32 Hz, 3H), 0.89e0.96 (m, 2H), 1.07e1.15 (m, 2H), 2.09e2.17 (m,
1H), 2.34e2.39 (m, 1H), 5.87 (s, 1H), 6.10 (s, 1H), 6.38 (s, 1H), 6.80
(dd, J¼2.72, 8.68 Hz, 1H), 6.95 (td, J¼2.32, 8.24 Hz, 1H), 7.10 (dd,
J¼5.52, 8.28 Hz, 1H), 7.45 (t, J¼7.80 Hz, 1H), 7.63 (s, 1H), 7.77 (dd,
J¼1.4, 7.8 Hz, 1H), 7.84 (dd, J¼2.28, 7.8 Hz, 1H), 8.08 (t, J¼1.84 Hz,
4.1.22. 2-(4-Chlorophenyl)-1-(1H-imidazol-1-yl)-7-methyl-3-phe-
nyl-1,2-dihydroisoquinoline (I-23). 1H NMR (400 MHz, CDCl3)
d 2.26
(s, 3H), 6.02 (s,1H), 6.48 (s,1H), 6.52 (s,1H), 6.96 (s,1H), 7.00 (s, 4H),
7.04e7.06 (m, 1H), 7.12e7.15 (m, 4H), 7.40e7.42 (m, 2H), 7.49 (d,
1H); 13C NMR (100 MHz, CDCl3)
d
13.7, 21.7, 29.9, 32.1, 61.7, 110.5,
J¼0.92 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 21.2, 62.2, 111.7, 123.2,
112.9 (d, 2JCF¼21.9 Hz), 114.7 (d, 2JCF¼21.0 Hz), 116.0 (d, 4JCF¼2.9 Hz),
124.4, 126.6, 126.8, 127.3, 127.8, 128.3, 128.5, 129.2, 130.8, 135.1,
136.5, 137.2, 139.4, 141.0, 145.7; HRMS calcd for C25H20ClN3
(MþþH): 398.1424, found: 398.1426.
3
4
116.9, 117.1, 125.2 (d, JCF¼7.6 Hz), 128.1 (d, JCF¼2.9 Hz), 128.4,
3
4
129.6, 131.3 (d, JCF¼6.7 Hz), 135.2, 140.0 (d, JCF¼1.9 Hz), 147.2,
148.7, 155.5, 161.2 (d, 1JCF¼244.2 Hz); HRMS calcd for C22H21FN4O2
(MþþH): 393.1727, found: 393.1739.
4.1.23. 7-Methyl-1-(4-methyl-1H-imidazol-1-yl)-2,3-diphenyl-1,2-
dihydroisoquinoline (I-24). 1H NMR (400 MHz, CDCl3)
d 2.24 (s, 3H),
4.1.16. 1-(1H-Imidazol-1-yl)-6,7-dimethoxy-3-phenyl-2-p-tolyl-1,2-
2.28 (s, 3H), 6.10 (s, 1H), 6.53 (s, 1H), 6.82e6.88 (m, 2H), 6.96e7.20
dihydroisoquinoline (I-17). 1H NMR (400 MHz, CDCl3)
d 2.17 (s, 3H),
(m, 10H), 7.35 (s, 1H), 7.38e7.42 (m, 2H); 13C NMR (100 MHz, CDCl3)
3.78 (s, 3H), 3.89 (s, 3H), 6.02 (s, 1H), 6.43 (s, 1H), 6.61(s, 1H), 6.70 (s,
1H), 6.79 (s, 1H), 6.90 (d, J¼8.24 Hz, 2H), 6.99 (d, J¼8.24 Hz, 2H),
7.12e7. 18 (m, 3H), 7.45e7.47 (m, 2H), 7.55 (s, 1H); 13C NMR
d 11.8, 21.3, 60.2, 110.9, 122.1, 122.3, 124.4, 126.6, 127.4, 127.9, 128.3,
128.6, 128.9, 129.6, 130.6, 133.3, 136.9, 137.4, 141.4, 147.1; HRMS
calcd for C26H23N3 (MþþH): 378.1970, found: 378.1987.
(100 MHz, CDCl3)
d 20.6, 55.8, 55.9, 61.9, 107.4, 109.6, 110.6, 122.3,
122.9, 125.2, 127.3, 127.5, 128.2, 129.2, 131.2, 135.0, 137.6, 139.4,
144.8, 147.9, 148.4; HRMS calcd for C27H25N3O2 (MþþH): 424.2025,
found: 424.2029.
4.1.24. 7-Methyl-1-(4-methyl-1H-imidazol-1-yl)-3-phenyl-2-p-tolyl-
1,2-dihydroisoquinoline (I-25). 1H NMR (400 MHz, CDCl3)
d 2.16 (s,
3H), 2.22 (s, 3H), 2.27 (s, 3H), 6.03 (s,1H), 6.50 (s,1H), 6.82e6.90 (m,
5H), 7.04e7.07 (m, 1H), 7.12e7.20 (m, 5H), 7.35 (s, 1H), 7.40e7.46
4.1.17. 6,7-Dimethoxy-1-(4-methyl-1H-imidazol-1-yl)-3-phenyl-2-p-
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 11.6, 20.6, 21.2, 60.4, 110.4,
tolyl-1,2-dihydroisoquinoline (I-18). 1H NMR (400 MHz, CDCl3)
122.5, 124.4, 126.7, 127.4, 127.9, 128.3, 128.6, 129.1, 129.2, 129.6,
129.8, 130.1, 131.8, 133.1, 136.8, 137.4, 141.6, 144.7; HRMS calcd for
C27H25N3 (MþþH): 393.2127, found: 393.2153.
d
2.18 (s, 3H), 2.23 (s, 3H), 3.80 (s, 3H), 3.91 (s, 3H), 6.01 (s, 1H), 6.49
(s, 1H), 6.56 (s, 1H), 6.81 (s, 1H), 6.92 (s, 5H), 7.14e7.20 (m, 6H), 7.36
(s, 1H), 7.42e7.47 (m, 2H); 13C NMR (100 MHz, CDCl3)
20.6, 29.7,
d
55.9, 56.0, 60.2, 107.4, 107.5, 109.3, 110.3, 122.3, 122.4, 124.8, 127.3,
127.8, 129.3, 131.8, 137.4, 140.8, 144.8; HRMS calcd for C28H27N3O2
(MþþH): 438.2182, found: 438.2186.
4.1.25. 2-(4-Methoxyphenyl)-7-methyl-1-(4-methyl-1H-imidazol-1-
yl)-3-phenyl-1,2-dihydroisoquinoline (I-26). 1H NMR (400 MHz,
CDCl3)
d 2.22 (s, 3H), 2.27 (s, 3H), 3.65 (s, 3H), 5.97 (s, 1H), 6.46 (s,
1H), 6.62e6.64 (m, 2H), 6.85 (s, 1H), 6.92e6.95 (m, 2H), 7.06 (m,
4.1.18. 1-(1H-Imidazol-1-yl)-7-methyl-2,3-diphenyl-1,2-dihy-
1H), 7.14e7.20 (m, 4H), 7.35 (s, 1H), 7.39e7.44 (m, 2H); 13C NMR
droisoquinoline (I-19). 1H NMR (400 MHz, CDCl3)
d
2.23 (s, 1H), 6.08
(100 MHz, CDCl3)
d 11.8, 21.3, 55.3, 60.7, 109.5, 113.9, 124.1, 124.3,
(s, 1H), 6.47 (s, 1H), 6.57 (s, 1H), 6.75e6.79 (m, 1H), 6.95 (s, 1H),
126.7, 127.6, 127.8, 127.9, 128.2, 128.5, 128.6, 129.1, 129.5, 129.9,

2064
H. Lou et al. / Tetrahedron 67 (2011) 2060e2065
133.2, 136.7, 137.5, 140.8, 142.0, 155.2; HRMS calcd for C27H25N3O
d 0.60e0.69 (m, 4H), 1.15e1.20 (m, 1H), 2.04 (s, 3H), 5.54 (s, 1H),
(MþþH): 408.2076, found: 408.2072.
5.76 (s, 1H), 6.84e7.15 (m, 9H), 7.27 (s, 1H); 13C NMR (100 MHz,
2
CDCl3)
d
7.25, 10.0, 14.2, 20.6, 60.2, 97.5, 115.4 (d, JCF¼21.9 Hz),
3
4.1.26. 2-(4-Chlorophenyl)-7-methyl-1-(4-methyl-1H-imidazol-1-
123.1, 125.2, 125.8, 127.1, 127.7 (d, JCF¼8.6 Hz), 128.5 (d,
3JCF¼6.7 Hz), 129.4, 132.2, 133.3, 141.9, 147.0, 159.8 (d,
1JCF¼227.4 Hz); HRMS calcd for C22H20FN3 (MþþH): 346.1720,
found: 346.1729.
yl)-3-phenyl-1,2-dihydroisoquinoline (I-27). 1H NMR (400 MHz,
CDCl3)
(s, 1H), 6.95e7.22 (m, 9H), 7.34 (s, 1H), 7.38e7.42 (m, 2H); 13C
NMR (100 MHz, CDCl3) 11.5, 21.3, 60.6, 111.4, 123.3, 124.5, 126.7,
d 2.12 (s, 3H), 2.29 (s, 3H), 6.04 (s, 1H), 6.53 (s, 1H), 6.89
d
127.1, 127.4, 128.1, 128.4, 128.6, 128.7, 133.3, 137.1, 137.1, 140.9,
145.8; HRMS calcd for C26H22ClN3 (MþþH): 412.1581, found:
412.1565.
4.1.34. 3-Butyl-1-(1H-imidazol-1-yl)-2-phenyl-1,2-dihydroisoquino-
line (I-35). 1H NMR (400 MHz, CDCl3)
d
0.69 (t, J¼7.32 Hz, 3H),
0.96e1.08 (m, 2H), 1.20e1.30 (m, 2H), 2.08e2.15 (m, 1H),
2.36e2.45 (m, 1H), 5.85 (s, 1H), 5.97 (s, 1H), 6.51 (s, 1H), 7.01e7.30
4.1.27. 3-Cyclopropyl-1-(1H-imidazol-1-yl)-2-phenyl-1,2-dihy-
(m, 10H), 7.47 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 13.8, 21.9, 30.1,
droisoquinoline (I-28). 1H NMR (400 MHz, CDCl3)
d
0.56e0.66 (m,
3H), 0.75e0.82 (m, 1H), 1.35e1.42 (m, 1H), 5.67 (s, 1H), 5.89 (s, 1H),
6.62 (s, 1H), 6.98e7.43 (m, 11H); 13C NMR (100 MHz, CDCl3)
8.0,
32.5, 61.9, 107.7, 122.9, 123.2, 123.7, 125.3, 125.9, 127.5, 128.7, 132.2,
134.8, 142.8, 146.3; HRMS calcd for C22H23N3 (MþþH): 330.1970,
found: 330.1978.
d
10.9, 13.9, 61.9, 100.9, 122.7, 123.0, 123.5, 125.0, 125.8, 127.4, 128.6,
129.3, 132.1, 134.9, 145.0, 146.3; HRMS calcd for C21H19N3 (MþþH):
314.1657, found: 314.1652.
4.1.35. 3-Butyl-1-(1H-imidazol-1-yl)-2-p-tolyl-1,2-dihydroisoquino-
line (I-36). 1H NMR (400 MHz, CDCl3)
d
0.70 (t, J¼6.88 Hz, 3H),
1.00e1.07 (m, 2H), 1.21e1.28 (m, 2H), 2.07e2.13 (m, 2H), 2.30 (s,
3H), 5.79 (s, 1H), 5.91 (s, 1H), 6.55 (s, 1H), 6.98e7.18 (m, 9H), 7.47
4.1.28. 3-Cyclopropyl-1-(1H-imidazol-1-yl)-2-p-tolyl-1,2-dihy-
droisoquinoline (I-29). 1H NMR (400 MHz, CDCl3)
d
0.61e0.78 (m,
(s, 1H); 13C NMR (100 MHz, CDCl3)
d 13.8, 20.8, 21.9, 30.1, 32.6,
4H), 1.30e1.40 (m, 1H), 2.30 (s, 3H), 5.62 (s, 1H), 5.85 (s, 1H), 6.69 (s,
59.9, 106.6, 123.0, 124.0, 125.1, 125.9, 127.4, 129.3, 132.3, 134.7,
143.3, 143.9; HRMS calcd for C23H25N3 (MþþH): 344.2127, found:
344.2127.
1H), 6.98e7.26 (m, 9H), 7.49 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
7.7, 10.9, 14.0, 20.8, 61.9, 99.8, 122.9, 124.0, 124.9, 125.8, 127.5,
129.2, 130.5, 132.2, 132.8, 143.9; HRMS calcd for C22H21N3 (MþþH):
328.1814, found: 328.1819.
4.1.36. 3-Butyl-2-(4-fluorophenyl)-1-(1H-imidazol-1-yl)-1,2-dihy-
droisoquinoline (I-37). 1H NMR (400 MHz, CDCl3)
d 0.69 (t,
4.1.29. 3-Cyclopropyl-1-(1H-imidazol-1-yl)-2-(4-methoxyphenyl)-
J¼7.36 Hz, 3H), 0.94e1.00 (m, 2H), 1.16e1.22 (m, 2H), 2.04e2.12
1,2-dihydroisoquinoline (I-30). 1H NMR (400 MHz, CDCl3)
(m, 1H), 2.28e2.36 (m, 1H), 5.76 (s, 1H), 5.93 (s, 1H), 6.93e7.22 (m,
d
0.58e0.76 (m, 4H),1.26e1.28 (m,1H), 3.78 (s, 3H), 5.56 (s,1H), 5.78
9H), 7.51 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
13.8, 21.8, 30.0, 32.5,
2
(s, 1H), 6.66 (s, 1H), 6.81 (d, J¼9.2 Hz, 2H), 6.95e7.04 (m, 4H),
62.2, 107.1, 115.4 (d, JCF¼22.9 Hz), 123.2, 125.3, 125.6 (d,
3JCF¼8.6 Hz), 125.9, 127.5, 128.7, 132.2, 134.8, 142.5, 142.8, 159.1 (d,
1JCF¼241.2 Hz); HRMS calcd for C22H22FN3 (MþþH): 348.1876,
found: 348.1875.
7.13e7.17 (m, 1H), 7.23 (d, J¼9.2 Hz, 2H), 7.44 (s, 1H); 13C NMR
(100 MHz, CDCl3) d 7.3,10.7,14.0, 55.4, 98.5,113.8,122.8,124.7,125.8,
126.1, 127.4, 128.5, 132.4, 134.9, 145.8; HRMS calcd for C22H21N3O
(MþþH): 344.1763, found: 344.1752.
4.1.37. 3-Butyl-2-(4-chlorophenyl)-1-(1H-imidazol-1-yl)-1,2-dihy-
4.1.30. 3-Cyclopropyl-2-(4-fluorophenyl)-1-(1H-imidazol-1-yl)-1,2-
droisoquinoline (I-38). 1H NMR (400 MHz, CDCl3)
d 0.68 (t,
dihydroisoquinoline (I-31). 1H NMR (400 MHz, CDCl3)
d
0.59e0.79
J¼7.36 Hz, 3H), 0.94e1.02 (m, 2H), 1.14e1.20 (m, 2H), 2.07e2.11 (m,
1H), 2.35e2.39 (m, 1H), 5.80 (s, 1H), 6.99 (s, 1H), 6.44 (s, 1H),
7.02e7.10 (m, 4H), 7.18e7.26 (m, 6H), 7.53 (s, 1H); 13C NMR
(m, 4H), 1.24e1.30 (m, 1H), 5.65 (s, 1H), 5.80 (s, 1H), 6.57 (s, 1H),
6.93e7.05 (m, 6H), 7.14e7.18 (m, 1H), 7.25e7.29 (m, 2H), 7.47 (s,
1H); 13C NMR (100 MHz, CDCl3)
d
7.5, 10.9, 13.9, 62.3, 100.4, 115.2
(100 MHz, CDCl3) d 13.8, 21.8, 30.0, 32.4, 62.0, 108.6, 123.3, 124.6,
2
3
(d, JCF¼21.9 Hz), 123.0, 125.0, 125.5 (d, JCF¼7.6 Hz), 125.8, 127.5,
124.7, 125.5, 127.6, 127.9, 128.7, 129.0, 132.1, 134.8, 142.1, 144.9;
4
128.9, 132.2, 134.9, 142.5 (d, JCF¼2.9 Hz), 145.1, 159.1 (d,
HRMS calcd for C22H22ClN3 (MþþH): 364.1581, found: 364.1592.
1JCF¼241.2 Hz); HRMS calcd for C21H18FN3 (MþþH): 332.1563,
found: 332.1568.
4.1.38. 1-(1H-Imidazol-1-yl)-6-methoxy-2,3-diphenyl-1,2-dihy-
droisoquinoline (I-39). 1H NMR (400 MHz, CDCl3)
d 3.78 (s, 3H),
6.08 (s, 1H), 6.40 (s, 1H), 6.54 (s, 1H), 6.68e6.70 (m, 1H),
4.1.31. 2-(4-Chlorophenyl)-3-cyclopropyl-1-(1H-imidazol-1-yl)-1,2-
6.77e6.80 (m, 2H), 7.04e7.13 (m, 9H), 7.43e7.48 (m, 3H); 13C NMR
dihydroisoquinoline (I-32). 1H NMR (400 MHz, CDCl3)
d
0.60e0.79
(m, 4H), 1.25e1.33 (m, 1H), 5.71 (s, 1H), 5.82 (s, 1H), 6.52 (s, 1H),
7.00e7.24 (m, 9H), 7.45 (s, 1H); 13C NMR (100 MHz, CDCl3)
7.8,
(100 MHz, CDCl3)
d 55.2, 61.6, 109.0, 110.9, 112.1, 121.7, 122.3,
123.4, 127.0, 127.5, 127.9, 128.2, 128.5, 133.2, 135.1, 137.5, 141.2,
147.0, 159.1; HRMS calcd for C25H21N3O (MþþH): 380.1763, found:
380.1749.
d
11.0, 13.9, 62.1, 102.0, 123.2, 124.5, 125.2, 125.8, 127.6, 127.8, 128.6,
129.2, 131.9, 135.0, 144.3, 144.9; HRMS calcd for C21H18ClN3
(MþþH): 348.1268, found: 348.1263.
4.1.39. 1-(1H-Imidazol-1-yl)-6-methoxy-3-phenyl-2-p-tolyl-1,2-di-
hydroisoquinoline (I-40). 1H NMR (400 MHz, CDCl3)
d 2.15 (s, 3H),
4.1.32. 3-Cyclopropyl-1-(4-methyl-1H-imidazol-1-yl)-2-p-tolyl-1,2-
3.78 (s, 3H), 6.03 (s, 1H), 6.38 (s, 1H), 6.57 (s, 1H), 6.67e6.70 (m, 1H),
6.77 (d, J¼2.32 Hz, 1H), 6.87 (d, J¼8.28 Hz, 2H), 6.98 (d, J¼8.28 Hz,
2H), 7.05 (d, J¼8.24 Hz, 1H), 7.11e7.15 (m, 3H), 7.44e7.48 (m, 3H);
dihydroisoquinoline (I-33). 1H NMR (400 MHz, CDCl3)
d
0.61e0.73
(m, 4H), 1.23e1.26 (m, 1H), 2.13 (s, 1H), 2.31 (s, 1H), 5.52 (s, 1H), 5.80
(s, 1H), 6.99e7.26 (m, 10H); 13C NMR (100 MHz, CDCl3)
7.4, 10.4,
13C NMR (100 MHz, CDCl3)
d 20.6, 55.2, 61.9, 108.9, 110.4, 112.0,
d
11.9, 14.1, 20.8, 60.0, 96.9, 116.4, 122.9, 125.0, 125.7, 127.6, 128.6,
129.3, 132.2, 133.1, 133.2, 134.3, 143.3, 147.4; HRMS calcd for
C23H23N3 (MþþH): 342.1970, found: 342.1956.
122.4, 123.2, 127.1, 127.6, 127.8, 128.2, 129.1, 131.3, 133.3, 135.0, 137.6,
141.5, 144.7; HRMS calcd for C26H23N3O (MþþH): 394.1919, found:
394.1938.
4.1.33. 3-Cyclopropyl-2-(4-fluorophenyl)-1-(4-methyl-1H-imidazol-
1-yl)-1,2-dihydroisoquinoline (I-34). 1H NMR (400 MHz, CDCl3)
4.1.40. 1-(1H-Imidazol-1-yl)-6-methoxy-2-(4-methoxyphenyl)-3-
phenyl-1,2-dihydroisoquinoline (I-41). 1H NMR (400 MHz, CDCl3)

H. Lou et al. / Tetrahedron 67 (2011) 2060e2065
2065
D.; Gupta, A.-K.; Oh, C.-H. Org. Lett. 2005, 7, 5289; (e) Sato, K.; Asao, N.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 8977; (f) Asao, N.; Sato, K.; Menggenbateer;
Yamamoto, Y. J. Org. Chem. 2005, 70, 3682; (g) Kusama, H.; Funami, H.; Takaya, J.;
Iwasawa, N. Org. Lett. 2004, 6, 605; (h) Asao, N.; Aikawa, H.; Yamamoto, Y. J. Am.
Chem. Soc. 2004, 126, 7458; (i) Asao, N.; Salprima, Y. S.; Nogami, T.; Yamamoto, Y.
Heterocycles 2008, 76, 471; (j) Yadav, J. S.; Reddy, B. V. S.; Yadav, N. N.; Gupta, M. K.
Tetrahedron Lett. 2008, 49, 2815.
5. For selected examples, see: (a) Bentley, K. W. The Isoquinoline Alkaloids; Har-
wood Academic: Australia, 1998; Vol 1; (b) Trotter, B. W.; Nanda, K. K.; Kett, N.
R.; Regan, C. P.; Lynch, J. J.; Stump, G. L.; Kiss, L.; Wang, J.; Spencer, R. H.; Kane,
S. A.; White, R. B.; Zhang, R.; Anderson, K. D.; Liverton, N. J.; McIntyre, C. J.;
Beshore, D. C.; Hartman, G. D.; Dinsmore, C. J. J. Med. Chem. 2006, 49, 6954; (c)
Ramesh, P.; Reddy, N. S.; Venkateswarlu, Y. J. Nat. Prod. 1999, 62, 780; (d) Ka-
neda, T.; Takeuchi, Y.; Matsui, H.; Shimizu, K.; Urakawa, N.; Nakajyo, S. J. Pharm.
Sci. 2005, 98, 275; (e) Marchand, C.; Antony, S.; Kohn, K. W.; Cushman, M.;
Ioanoviciu, A.; Staker, B. L.; Burgin, A. B.; Stewart, L.; Pommier, Y. Mol. Cancer
Ther. 2006, 5, 287.
6. (a) Kletsas, D.; Li, W.; Han, Z.; Papadopoulos, V. Biochem. Pharmacol. 2004, 67,
1927; (b) Mach, U. R.; Hackling, A. E.; Perachon, S.; Ferry, S.; Wermuth, C. G.;
Schwartz, J.-C.; Sokoloff, P.; Stark, H. ChemBioChem 2004, 5, 508; (c) Mus-
carella, D. E.; O’Brian, K. A.; Lemley, A. T.; Bloom, S. E. Toxicol. Sci. 2003, 74, 66;
(d) Dzierszinski, F.; Coppin, A.; Mortuaire, M.; Dewally, E.; Slomianny, C.;
Ameisen, J.-C.; Debels, F.; Tomavo, S. Antimicrob. Agents Chemother. 2002, 46,
3197.
7. For selected examples, see: (a) Erhardt, P. W. J. Med. Chem. 1987, 30, 231;
(b) Tomczuk, B. E.; Taylor, C. R., Jr.; Moses, L. M.; Sutherland, D. B.; Lo, Y. S.;
Johnson, D. N.; Kinnier, W. B.; Kilpatrick, B. F. J. Med. Chem. 1991, 34, 2993; (c)
Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A. Pharm. Chem. J. 1999,
33, 232; (d) Gravatt, G. L.; Baguley, B. C.; Wilson, W. R.; Denny, W. A. J. Med.
Chem. 1994, 37, 4338; (e) Soderlind, K.-J.; Gorodetsky, B.; Singh, A. K.; Bachur,
N.; Miller, G. G.; Lown, J. W. Anticancer Drug Des. 1999, 14, 19; (f) Kim, J. S.; Gatto,
B.; Yu, C.; Liu, A.; Liu, L. F.; Lavoie, E. J. J. Med. Chem. 1996, 39, 992; (g) Chen, A. Y.;
Yu, C.; Gatto, B.; Liu, L. F. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 8131; (h) Roth, T.;
Morningstar, M. L.; Boyer, P. L.; Hughes, S. H.; Buckheit, R. W.; Michejda, C. J. J.
Med. Chem. 1997, 40, 4199.
d
3.64 (s, 3H), 3.79 (s, 3H), 5.97 (s, 1H), 6.36 (s, 1H), 6.58 (s, 1H),
6.61e6.63 (m, 2H), 6.68e6.71 (m, 1H), 6.77 (d, J¼2.28 Hz, 1H),
7.02e7.15 (m, 7H), 7.45e7.49 (m, 3H); 13C NMR (100 MHz, CDCl3)
d
55.2, 55.3, 62.2, 108.8, 109.7, 112.0, 113.8, 122.8, 124.0, 127.1, 127.7,
127.8, 128.2, 133.4, 135.0, 137.6, 140.8, 141.7, 154.9, 159.1; HRMS
calcd for C26H23N3O2 (MþþH): 410.1869, found: 410.1851.
4.1.41. 2-(4-Fluorophenyl)-1-(1H-imidazol-1-yl)-6-methoxy-3-phe-
nyl-1,2-dihydroisoquinoline (I-42). 1H NMR (400 MHz, CDCl3)
d 3.80
(s, 3H), 5.99 (s, 1H), 6.39 (s, 1H), 6.52 (s, 1H), 6.70e6.79 (m, 4H),
7.05e7.08 (m, 4H), 7.14e7.16 (m, 3H), 7.42e7.44 (m, 2H), 7.53 (s,
1H); 13C NMR (100 MHz, CDCl3)
d
55.3, 62.0, 109.0, 110.6,112.2,115.1
2
3
(d, JCF¼21.9 Hz), 123.0, 123.9 (d, JCF¼7.6 Hz), 127.1, 127.7, 127.9,
128.2, 133.2, 135.1, 137.3, 141.3,143.3 (d, 4JCF¼2.9 Hz),159.2, 158.2 (d,
1JCF¼239.3 Hz); HRMS calcd for C25H20FN3O (MþþH): 398.1669,
found: 398.1672.
4.1.42. 2-(4-Chlorophenyl)-1-(1H-imidazol-1-yl)-6-methoxy-3-phe-
nyl-1,2-dihydroisoquinoline (I-43). 1H NMR (400 MHz, CDCl3)
d 3.80
(s, 3H), 6.02 (s, 1H), 6.42 (s, 1H), 6.50 (s, 1H), 6.71e6.74 (m, 1H), 6.79
(d, J¼2.28 Hz, 1H), 7.03 (s, 5H), 7.14e7.17 (m, 3H), 7.40e7.43 (m, 2H),
7.53 (d, J¼0.88 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 55.3, 61.6,
109.1,111.3,112.3,123.3, 123.4, 126.7,127.0,127.6,128.0, 128.3, 128.5,
133.1, 135.1, 137.2, 140.7, 145.6, 159.2; HRMS calcd for C25H20ClN3O
(MþþH): 414.1373, found: 414.1365.
Acknowledgements
8. (a) Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856; (b) Qiu, G.; Ding, Q.; Ren, H.; Peng,
Y.; Wu, J. Org. Lett. 2010, 12, 3975; (c) Ye, S.; Yang, X.; Wu, J. Chem. Commun.
2010, 46, 5238; (d) Ye, S.; Yang, X.; Wu, J. Chem. Commun. 2010, 46, 2950; (e) Ye,
S.; Gao, K.; Wu, J. Adv. Synth. Catal. 2010, 352, 1746; (f) Yu, X.; Ye, S.; Wu, J. Adv.
Financial support from National Natural Science Foundation of
China (No. 20972030) and the Science and Technology Commission
of Shanghai Municipality (No. 09JC1404902) is gratefully
acknowledged.
Synth.
Catal. 2010, 352, 2050; (g) Yu, X.; Chen, Z.; Yang, X.; Wu, J. J. Comb. Chem.
2010, 12, 374; (h) Ye, S.; Ren, H.; Wu, J. J. Comb. Chem. 2010, 12, 670; (i) Yu, X.;
Ding, Q.; Wu, J. J. Comb. Chem. 2010, 12, 743; (j) Ren, H.; Ye, S.; Liu, F.; Wu, J.
Tetrahedron 2010, 66, 8242.
9. (a) Chen, Z.; Yang, X.; Wu, J. Chem. Commun. 2009, 3469; (b) Ye, S.; Gao, K.;
Zhou, H.; Yang, X.; Wu, J. Chem. Commun. 2009, 5406; (c) Chen, Z.; Yu, X.; Su,
M.; Yang, X.; Wu, J. Adv. Synth. Catal. 2009, 351, 2702; (d) Chen, Z.; Ding, Q.; Yu,
X.; Wu, J. Adv. Synth. Catal. 2009, 351, 1692; (e) Ding, Q.; Wang, Z.; Wu, J. J. Org.
Chem. 2009, 74, 921; (f) Ding, Q.; He, X.; Wu, J. J. Comb. Chem. 2009, 11, 587; (g)
Yu, X.; Wu, J. J. Comb. Chem. 2009, 11, 895; (h) Ding, Q.; Huang, X.; Wu, J. J. Comb.
Chem. 2009, 11, 1047; (i) Gao, K.; Wu, J. Org. Lett. 2008, 10, 2251.
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.01.048.
References and notes
10. (a) Chen, Z.; Yu, X.; Wu, J. Chem. Commun. 2010, 46, 6356; (b) Yu, X.; Wu, J.
J.Comb. Chem. 2010, 12, 238; (c) Ye, S.; Wu, J. Tetrahedron Lett. 2009, 50, 6273;
(d) Zhou, H.; Jin, H.; Ye, S.; He, X.; Wu, J. Tetrahedron Lett. 2009, 50, 4616; (e) Yu,
X.; Ding, Q.; Chen, Z.; Wu, J. Tetrahedron Lett. 2009, 50, 4279; (f) Ding, Q.; Wang,
Z.; Wu, J. Tetrahedron Lett. 2009, 50, 198; (g) Ye, S.; Zhou, H.; Wu, J. Tetrahedron
2009, 65, 1294; (h) Ye, Y.; Ding, Q.; Wu, J. Tetrahedron 2008, 64, 1378; (i) Ding,
Q.; Wu, J. Org. Lett. 2007, 9, 4959; (j) Gao, K.; Wu, J. J. Org. Chem. 2007, 72, 8611;
(k) Ding, Q.; Ye, Y.; Fan, R.; Wu, J. J. Org. Chem. 2007, 72, 5439; (l) Sun, W.; Ding,
Q.; Sun, X.; Fan, R.; Wu, J. J. Comb. Chem. 2007, 9, 690; (m) Ding, Q.; Wang, B.;
Wu, J. Tetrahedron 2007, 63, 12166.
1. (a) Walsh, D. P.; Chang, Y.-T. Chem. Rev. 2006, 106, 2476; (b) Arya, P.; Chou, D. T. H.;
Baek, M.-G. Angew. Chem., Int. Ed. 2001, 40, 339; (c) Schreiber, S. L. Science 2000,
287, 1964; (d) Pinilla, C.; Appel, J. R.; Houghten, R. A. Nat. Med. 2003, 9, 118.
2. For selected examples, see: (a) Balasubramanian, M.; Keay, J. G. Isoquinoline
Synthesis In. Comprehensive Heterocyclic Chemistry II; McKillop, A. E., Katrizky,
A. R., Rees, C. W., Scrivem, E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 5,
pp 245e300; (b) For a review on the synthesis of isoquinoline alkaloid, see:
Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341.
3. (a) Obika, S.; Kono, H.; Yasui, Y.; Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72,
4462 and references cited therein; (b) Asao, N.; Yudha, S.; S.; Nogami, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526; (c) Yanada, R.; Obika, S.;
Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3822; (d) Asao, N.; Iso, K.;
Yudha, S. S. Org. Lett. 2006, 8, 4149; (e) Mori, S.; Uerdingen, M.; Krause, N.;
Morokuma, K. Angew. Chem., Int. Ed. 2005, 44, 4715; (f) Asao, N.; Chan, C. S.;
Takahashi, K.; Yamamoto, Y. Tetrahedron 2005, 61, 11322; (g) Ohtaka, M.; Na-
kamura, H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 7339; (h) Witulski, B.;
Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257; (i) Yavari,
I.; Ghazanfarpour-Darjani, M.; Sabbaghan, M.; Hossaini, Z. Tetrahedron Lett.
2007, 48, 3749; (j) Shaabani, A.; Soleimani, E.; Khavasi, H. R. Tetrahedron Lett.
2007, 48, 4743; (k) Wang, G.-W.; Li, J.-X. Org. Biomol. Chem. 2006, 4, 4063;
(l) Diaz, J. L.; Miguel, M.; Lavilla, R. J. Org. Chem. 2004, 69, 3550.
11. For selected examples, see: (a) Frangioni, J. V.; Beahm, P. H.; Shifrin, V.; Jost, C.
A.; Neel, B. G. Cell 1992, 68, 545; (b) Woodford-Thomas, T. A.; Rhodes, J. D.;
Dixon, J. E. J. Cell Biol. 1992, 117, 401; (c) Haj, F. G.; Verveer, P. J.; Squire, A.; Neel,
B. G.; Bastiaens, P. I. Science 2002, 295, 1708.
12. For selected examples of multi-component reactions, see: (a) Multicomponent
Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005;
(b) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602; (c) Nair, V.;
Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekenth, A. R.; Balagopal, L. Acc. Chem. Res.
2003, 36, 899; (d) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471; (e) Balme,
€
G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem. 2003, 4101; (f) Domling, A.;
ꢀ
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (g) Bienayme, H.; Hulme, C.;
Oddon, G.; Schmitt, P. Chem.dEur. J. 2000, 6, 3321; (h) Sunderhaus, J. D.;
Martin, S. F. Chem.dEur. J. 2009, 15, 1300; (i) Ugi, I.; Domling, A.; Werner, B.
J. Heterocycl. Chem. 2000, 37, 647; (j) Zhu, J. Eur. J. Org. Chem. 2003, 1133; (k)
Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51; (l) Weber, L. Curr. Med. Chem.
2002, 9, 1241.
4. For more selected examples, see: (a) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2007, 129, 1413 and references cited therein; (b) Asao,
N. Synlett 2006, 1645; (c) Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yama-
moto, Y. J. Am. Chem. Soc. 2005, 127, 9844; (d) Kim, N.; Kim, Y.; Park, W.; Sung,