Facile synthesis of 3-substituted isoquinolines derivatives via microwave-assisted tandem three-component coupling cyclization

Article abstract of DOI:10.1002/cjoc.201100560

A novel three-component reaction of o-bromobenzaldehyde, terminal alkynes and tert-butyl amine has been established, which proceeded smoothly to give 3-substituted isoquinolines in good yields in the presence of palladium/copper catalysts under microwave irradiation.

Full text of DOI:10.1002/cjoc.201100560

FULL PAPER
DOI: 10.1002/cjoc.201100560
Facile Synthesis of 3-Substituted Isoquinolines Derivatives via
Microwave-assisted Tandem Three-component
Coupling Cyclization
Lin, Long(林龙)
Wu, Qiongyou*(吴琼友)
Huang, Shaowei(黄绍维)
Yang, Guangfu*(杨光富)
Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry,
Central China Normal University, Hubei, Wuhan 430079, China
A novel three-component reaction of o-bromobenzaldehyde, terminal alkynes and tert-butyl amine has been es-
tablished, which proceeded smoothly to give 3-substituted isoquinolines in good yields in the presence of palla-
dium/copper catalysts under microwave irradiation.
Keywords palladium/copper-catalyst, microwave, isoquinolines, tandem reaction, coupling cyclization
Introduction
ful for treatment and prevention of cardiovascular dis-
eases and related disease states.[5] Similarly, structur
type C has been reported with potential for treatment of
inflammation.[6] In addition, a number of synthetic
3-substituted isoquinolines with potent antitumor cyto-
toxicities and topoisomerase I inhibitory activities have
also been reported.[7]
Isoquinoline is an important heterocyclic skeleton
that serves as key structural units in a broad range of
natural products as well as building block in important
pharmaceuticals.[1] Isoquinoline species are also utilized
as chiral ligands for transition metal catalysts,[2] and
their iridium complexes are used in organic light-emitt-
ing diodes.[3] In recent years, 3-substituted isoquinoline
derivatives are becoming inspiring owing to their
prominent biological activities. Decumbenine B (Figure
1, structure A), a 3-arylisoquinoline alkaloid isolated
from plant tubers of Coridalis decumbens, has been
recognized as a promising inhibitor for controlling
spontaneous contraction of the intestine.[4] Another kind
of 3-arylisoquinoline derivatives with structure type B
has been concluded to be useful for regulating the ex-
pression of apolipoprotein A-I (ApoA-I), and thus use-
Because of their biological and/or physical proper-
ties, the efficient synthesis of the isoquinoline ring sys-
tem has received considerable attention of synthetic
chemists. Although many methods for the synthesis of
this important ring system are known, the traditional
methods such as the Bischler-Napieralski reaction,[8] the
Pomeranz-Fritsch reaction,[9] and the Pictet-Spengler
reaction[10] suffered from some drawbacks such as the
harsh reaction conditions, tedious reaction procedures,
low yield, which hampered their general utilization, es-
pecially for those with more substituents in 3-aryl group.
In recent years, some mild and efficient synthesis of
isoquinoline has been developed. For instance, Pfeffer[11]
and Heck[12] have reported a methodology to synthesize
substituted isoquinoline utilizing stoichiometric amount
of palladium salts. Moreover, Larock and co-workers
have developed an extremely efficient metal-mediated
method using 2-iodobenzaldimine and substituted ter-
minal acetylenes as starting materials in the syntheis of
a wide variety of 3,4-disubstituted isoquinolines.[13]
Tandem reactions and multicomponent reactions[14]
in which several bond-forming steps take place in one
pot are powerful tools for the construction of some bio-
logically interesting molecules from readily accessible
components. Recently, considerable efforts have been
R2
O
O
OH
R2
O
O
R1
N
OH
N
A
R3
R1
B
OH
N
R2
OR1 C
Figure 1 Selected biologically active 3-substituted isoquinoline
derivatives.
*
E-mail: qywu@mail.ccnu.edu.cn, gfyang@mail.ccnu.edu.cn
Received November 7, 2011; accepted January 3, 2012; published online May 7, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100560 or from the author.
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Lin et al.
Table 1 Optimization of temperature and MW powera
FULL PAPER
made to develop efficient methods for the synthesis of
isoquinoline analogues using multicomponent reaction
manner.[15] However, to the best of our knowledge, the
multicomponent synthetic approach to isoquinoline us-
ing the o-bromobenzaldehyde as starting material in-
volving a Sonogashira coupling reaction as a key step is
scarce. Although, the example reported by Abbiati
starting from o-bromobenzaldehyde, terminal alkynes
and aqueous ammonia via the Sonogashira coupling
and/or imination-cyclization tandem procedure achieved
the isoquinolines successfully.[16] this three-component
method needed a comparable high reaction temperature
and a long time microwave irradiation to achieve a low
or moderate product yield, moreover, the scope of the
substrate was confined to the aromatic alkynes, not
suitable for the aliphatic linear alkynes. We were in-
trigued to further simplify and optimize the approach
using an economic multicomponent manner. Herein, we
wish to report a palladium/copper co-catalyzed tandem
three-component coupling-cyclization reaction for the
synthesis of 3-substituted isoquinolines with the readily
available materials of o-bromobenzaldehyde, a terminal
alkyne, and a primary amine under microwave irradia-
tion conditions. Our multicomponent strategy provided
a highly efficient approach to the preparation of isoqui-
noline derivatives with reduced reaction times and im-
proved yields. Furthermore, the tandem reaction se-
quence was evidenced by NMR spectrum. Notably, the
substrate scope is quite broad, which makes this method
an inspiring approach to the isoquinolines library with
structural diversity.
Br
PdCl2(PPh3)2, CuI
MW
t-BuNH2
+
+
CHO
1a
2a
N
3a
Entry
Temp./℃
Power/W
Yieldc/%
19
1b
2
3
4
5
6
7
8
130
100
120
140
160
—
—
—
—
—
—
20
32
41
18
100
120
140
160
40
—
49
—
65
9
a
59
All reactions were run by employing 1.0 equiv. 1a, 1.2 equiv.
2a, 3 equiv. t-butyl amine, 3 equiv. Et3N in 2 mL DMF with 5%
PdCl2(PPh3)2 and 10% CuI catalyst under microwave irradiation
for 15 min. b Conventional heating for 24 h. c Isolated yield.
20% to 41% under microwave irradiation for 15 min
(Table 1, Entries 2 and 4). However, the product yield
decreased dramatically when the reaction temperature
was further increased to 160 ℃ (Table 1, Entry 5). It is
interesting that microwave power is more efficacious
for increasing product yield than the temperature ad-
justment. When the reactant was irradiated at 100 W, a
comparable yield was observed as the irradiation tem-
perature fixed at 140 ℃ (Table 1, Entry 6), whereas
the maximum reaction temperature only reached to 100
℃ during the microwave irradiation. By increasing the
microwave power to 140 W the desired product was
obtained in a satisfying 65% yield in 15 min. Corre-
spondingly, the maximum temperature of the reaction
system was about 135 ℃ at the fixed microwave
power 140 W. A further increase of microwave power
gave a worse result (Table 1, Entry 9). From these re-
sults, it was clearly indicated that microwave irradiation
at 140 W was more suitable for our further reaction op-
timization.
The effect of various palladium catalysts on the re-
action was then investigated in the presence of 10 mol%
of CuI co-catalyst with Et3N as base under microwave
irradiation. The catalyst Pd(PPh3)4 and PdCl2(PPh3)2
afford comparable desired product under this reaction
conditions (Table 2, compare Entry 2 with Entry 4).
Considering the easy handle of PdCl2(PPh3)2, we select
catalyst PdCl2(PPh3)2 for further reaction optimization.
In an effort to reduce the amount of the palladium cata-
Results and Discussion
We initially examined the possibility of achieving a
three-component tandem reaction using a model reac-
tion that included 1.0 equiv. 2-bromobenzaldehyde, 1.2
equiv. phenylacetylene, 3 equiv. tert-butyl amine with
5% PdCl2(PPh3)2 and 10% CuI as the catalyst in 2 mL
DMF (Table 1). We isolated the desired 3-substituted
isoquinoline product in quite low yield when we mixed
the three components in one pot at elevated temperature
with a long reaction time under conventional heating
(Table 1, Entry 1). Microwave-assisted organic synthe-
sis (MAOS) has gained acceptance as a valuable tool for
accelerating organic reaction rates and highly improving
yields.[17] One of the most extensively studied reaction
types in MAOS are transition-metal catalyzed reactions.
Carbon-carbon and carbon-heteroatom bond-forming
reactions, which typically require hours or days to reach
completion, can be significantly accelerated by em-
ploying microwave heating in a sealed vial.[18] We thus
examined the effect of microwave irradiation on our
three-component reaction by using a single-mode
smithsynthesizerTM microwave system with optic fiber
for detecting their temperature (Table 1, Entries 2—9).
We noticed that when the reaction temperature was im-
proved from 100 to 140 ℃ the yield increased from
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Facile Synthesis of 3-Substituted Isoquinolines Derivatives
lyst, one reaction was run in which the amount of
PdCl2(PPh3)2 was reduced from 5 to 2.5 mol%. How-
ever, a significant decrease in the product yield was ob-
served (Table 2, Entry 5). CuI is a very important
co-catalyst in the Sonogashira coupling reaction and it
also plays a key role in the cyclizaiton step for the for-
mation of isoquinoline. We noticed that the yield of 3a
was improved by increasing the amount of CuI. For
example, when CuI was increased from the catalytic
amount (10 mol%) to a substoichiometric amount (40
mol%), the yield of product 3a was dramatically im-
proved from 65% to 82%. However, further improve the
amount of CuI to 60 mol%, a much lower yield was
obtained, beside a mixture of unidentified products. For
comparison purpose, a reaction without the palladium
catalyst was carried out in the presence of 40 mol% CuI,
a scarce result was observed (Table 2, Entry 16).
PdCl2(PPh3)2, 40 mol% CuI, 3 equiv. Et3N under mi-
crowave irradiation at 140 W for 5 min.
With the optimized conditions in hand, the scope of
the three-component tandem coupling-cyclization reac-
tion was then investigated, and the results are summa-
rized in Table 3. The scope of this reaction is quite gen-
eral. A variety of functionalized terminal acetylenes
have been employed in this palladium/copper-catalyzed
process. For instance, the aryl-, alkenyl- and alkyl-
substituted acetylenes all tolerated the reaction condi-
tions and afforded the desired isoquinolines in good
yields. The phenylacetylenes bearing electron-with-
drawing fluorine substituent on both ortho and para
position afforded the corresponding isoquinolines in
moderate yield under the standard reaction condition
(Table 3, Entry 2). Interestingly, the less steric hindered
p-fluoro substituted phenylacetylene required a twofold
reaction time to give a slightly higher yield (Table 3,
Entry 3). In comparison, when an electron-donating
methyl group was introduced on the phenylacetylene,
despite a longer reaction time required for the sterically
crowded o-methyl phenylacetylene substrate, the reac-
tion yields are higher (Table 3, Entries 5 and 6). How-
ever, when a methoxyl group appeared on the
meta-position of phenylacetylene, only a 58% isolated
yield was obtained. Moreover, an alkyne bearing a
bulky substituent such as a naphthalene group can also
participate in this reaction and afforded the isoquinoline
in moderate yield (Table 3, Entry 7). The reactions pro-
ceed smoothly when the terminus of the carbon-carbon
triple bond is substituted by an alkyl group. The ali-
phatic linear alkyne, which failed to participate in the
three component synthesis of isoquinolines elsewhere,[16]
was successfully converted to the corresponding iso-
quinoline (Table 3, Entry 9). In addition, when cyclic
aliphatic alkyne such as ethynylcyclohexane was em-
ployed as the substrate, the 3-position cyclohexyl sub-
stituted isoquinoline 3j was prepared in good yield in a
prolonged irradiation time. Furthermore, 1-ethynyl-
cyclohex-1-ene can also take part in this three-comp-
onent coupling cyclization to give the alkenyl substi-
tuted product 3k in good yield.
Table 2 Optimization of the reaction conditionsa
Entry Catalyst (5 mol%) CuI/mol% Base
Time/min Yieldb/%
1
2
3
4
5c
6
7
8
9
Pd(OAc)2
10
10
10
10
10
20
40
60
40
40
40
40
40
40
40
40
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
15
15
15
15
15
15
15
15
34
67
trace
65
52
72
82
51
30
51
63
32
61
81
79
44
Pd(PPh3)4
PdCl2(PhCN)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
K3PO4 15
K2CO3 15
Na2CO3 15
t-BuNH2 15
10 PdCl2(PPh3)2
11 PdCl2(PPh3)2
12d PdCl2(PPh3)2
13 PdCl2(PPh3)2
14 PdCl2(PPh3)2
15 PdCl2(PPh3)2
Et3N
Et3N
Et3N
Et3N
30
10
5
16
a
—
15
All reactions were run by employing 1.0 equiv. 1a, 1.2 equiv.
2a, 3 equiv. t-butyl amine and 3 equiv. base in 2 mL DMF under
microwave irradiation. b Isolated yield. c 2.5 mol% PdCl2(PPh3)2.
d The reaction was run in 2 mL t-BuNH2.
The scope of the tandem three-component synthesis
approach to the 3-substituted isoquinoline by changing
the substituted pattern on the 2-bromobenzaldehyde
framework was next investigated. The highly substi-
tuted benzaldehyde (1b) substrate provided the desired
isoquinoline derivative 3l in moderate yield. While in
the presence of an electron-withdrawing fluorine sub-
stituent (1c) the best results were obtained in a three-
fold irradiation time. In addition, the benzodioxole can
be converted to the desired isoquinoline 3n in a slightly
lower yield under our standard experimental conditions.
Interestingly, bicyclic heteropyridine derivative 3o,
which might show interesting biological properties, was
constructed successfully in good yield.
The base effect on the reaction was also evaluated.
Of all the bases we examined, triethyl amine was supe-
rior. The reaction could proceed in the presence of all
kinds of bases including K3PO4, K2CO3, Na2CO3 and
t-BuNH2, although a lower yield was observed (Table 1,
compare Entry 7 with 9—12).
Finally, we optimized the microwave irradiation
time. When the irradiation time was prolonged from 15
to 30 min, the isolated product yield decreased from
82% to 61% due to the product decomposition. How-
ever, there is no significant change in the yield when the
irradiation time was reduced from 15 to 5 min. Thus, we
chose the following reaction conditions as optimum for
all subsequent three-component reaction: 5 mol%
Theoretically speaking, there are two possible routes
to the final desired product isoquinoline because the
Chin. J. Chem. 2012, 30, 1075—1082
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Lin et al.
FULL PAPER
Table 3 Synthesis of 3-substituted isoquinoline derivatives 3aa
Br
R
PdCl2(PPh3)2, CuI
Et3N, MW
R
+
t-BuNH2
+
N
CHO
3
2
1
Entry Aldehyde 1
Alkyne 2
tb/min
Product 3
Yieldc/%
1
5
5
79
61
67
58
76
73
56
N
N
3a
F
2
3
4
F
F
F
F
3b
F
10
N
N
3c
OMe
CH3
10
5
OMe
3d
5
6
7
Br
N
H3C
CHO
3e
1a
10
15
N
CH3
CH3
3f
OMe
N
MeO
3g
N
8
9
10
5
75
57
3h
N
N
3i
3j
10
30
62
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Facile Synthesis of 3-Substituted Isoquinolines Derivatives
Continued
Yieldc/%
Entry Aldehyde 1
Alkyne 2
tb/min
Product 3
11
15
74
N
3k
MeO
Br
MeO
H3C
H3C
CHO
N
12
5
58
OMe
OMe
1b
3l
Br
13
14
15
5
61
46
56
F
CHO
N
F
1c
1d
3m
Br
O
O
O
O
CHO
N
3n
Br
15
5
N
CHO
N
N
1d
3o
a
All reactions were conducted using 1.0 equiv. aldehyde 1, 1.2 equiv. alkyne 2, 5 mol% PdCl2(PPh3)2, 40 mol% CuI, 3 equiv. t-butyl
b
amine and 3 equiv. Base in 2 mL DMF under microwave irradiation. All reactions were monitored by TLC until the disappearance of
the starting aldehyde. c Isolated yield.
starting material 2-bromobenzaldehyde 1a bears two
different functional groups (Scheme 1). In route A, the
formyl group is converted to the tert-butylimine 1aa
firstly, which is subsequently subjected to a Sonogashira
reaction to furnish the iminoalkyne 1ac. Finally, 1ac
was converted to isoquinoline. In an alternative route B,
Sonogashira coupling product 1ab was formed in ad-
vance of butylimine 1aa in the reaction system. To
demonstrate the reaction sequence of this tandem
three-component synthesis of isoquinoline, we have
for 5 min, which indicated the desired transformation
occurred in this tandem three-component reaction sys-
tem.
In conclusion, we have developed a rapid and effi-
cient tandem three-component reaction for the synthesis
of 3-substituted isoquinolines, which formed one car-
bon-carbon and two carbon-nitrogen bonds in one pot.
The reaction scope is quite broad and acceptable and
good yields were achieved by employing the readily
available 2-bromobenzaldehyde and various terminal
alkynes as starting materials. This methodology could
be applied to the construction of a highly potent isoqui-
noline library to provide structural diversity and bio-
logical activity.
1
monitored the reaction process by H NMR (Figure 2).
Samples from the reaction medium were removed at
1
intervals and immediately analyzed by H NMR spec-
1
troscopy. H NMR analysis showed that tert-butylimine
1aa formed very quickly. Starting material 1a coverted
to 1aa after microwave irradiation for 0.5 min and a
small amount iminoalkyne 1ac also appeared at the
same time. After microwave irradiation for 1 min, the
iminoalkyne 1ac became apparent. The desired product
isoquinoline 3a appeared after microwave irradiation for
2 min. The rate of the transformation from the interme-
diate 1ac to 3a was faster than that of intermediate 1aa
to 1ac. All the characteristic peaks assigned to the in-
termediates 1aa and 1ac disappeared by comparison
with the authentic sample after microwave irradiation
Experimental
General
Unless otherwise noted, all materials were commer-
cially available and were used directly without further
purification. All solvents were redistilled before use. 1H
NMR spectra were recorded in CDCl3 on a Varian
Mercury 600 spectrometer and resonances (δ) are given
relative to tetramethylsilane. 13C NMR spectra were
recorded in CDCl3 on a Varian Mercury 600 (150
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Lin et al.
FULL PAPER
Scheme 1 Two possible pathways to target 3a
Br
N
Bu-t
A
Ph
1aa
Br
Ph
N
N
Bu-t
CHO
Ph
B
1ac
1a
3a
CHO
1ab
was removed under vacuum and the residue was puri-
fied by flash column chromatography on silica gel
eluting with ethyl acetate and petroleum ether.
3-Phenylisoquinoline[3a,16] (3a) Yield 79%, yel-
low solid, m.p. 99—101 ℃; 1H NMR (600 MHz,
CDCl3) δ: 9.34 (s, 1H), 8.14 (d, J＝7.8 Hz, 2H), 8.06 (s,
1H), 7.97 (d, J＝8.4 Hz, 1H), 7.85 (d, J＝8.4 Hz, 1H),
7.68 (t, J＝7.2 Hz, 1H), 7.57 (t, J＝7.2 Hz, 1H), 7.54—
7.43 (m, 2H), 7.42 (t, J＝9.0 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ: 152.3, 151.2, 139.5, 136.5, 130.4,
128.7, 128.4, 127.7, 127.5, 127.0, 126.9, 126.8, 116.4;
HRMS (ESI) calcd for C15H12N [M＋H]＋ 206.0970,
found 206.0979.
3-(2,4-Difluorophenyl)isoquinoline (3b)
Yield
1
61%, yellow solid, m.p. 87—89 ℃; H NMR (600
MHz, CDCl3) δ: 9.32 (s, 1H), 8.17—8.15 (m, 1H), 8.13
(s, 1H), 7.99 (d, J＝8.4 Hz, 1H), 7.86 (d, J＝7.8 Hz,
1H), 7.70 (t, J＝7.5 Hz, 1H), 7.61 (t, J＝7.5 Hz, 1H),
7.03 (t, J＝7.8 Hz, 1H), 6.97—6.94 (m, 1H); 13C NMR
19
Figure 2 1H NMR monitor the reaction process of the three-
component reaction system under MW.
(150 MHz, CDCl3) δ: 163.6 (d, JC- F＝12.3 Hz), 161.9
19
19
(d, JC- F＝12.0 Hz), 161.3 (d, JC- F＝11.7 Hz), 159.7
19
(d, JC- F＝12.0 Hz), 152.3, 145.6, 136.2, 132.2 (d,
19
19
JC- F＝9.3 Hz), 130.6, 127.5 (d, JC- F＝10.8 Hz), 127.0,
MHz) spectrometer and resonances (δ) are given rela-
tive to the center line of a triplet at δ 77.0 of chloro-
form-d. The following abbreviations were used to des-
ignate chemical shift mutiplicities: s＝ singlet, d ＝
doublet, t＝triplet, m＝multiplet, br＝broad. HRMS
were obtained on a WATERS MALDI SYNAPT G2
HDMS equipped with an electrospray source (MA,
USA).
19
123.9 (d, J＝11.4 Hz), 120.6 (d, JC- F＝10.2 Hz), 111.8
19
19
(d, JC- F＝21.9 Hz), 104.4 (t, JC- F＝26.1 Hz); IR (KBr)
ν: 1618, 1599, 1579, 1505, 1443, 1262, 1136, 1106, 964,
－
1
845, 827, 760 cm ; HRMS (ESI) calcd for C15H10F2N
[M＋H]＋ 242.0781, found 242.0814.
3-(4-Fluorophenyl)isoquinoline (3c) Yield 67%,
1
yellow solid, m.p. 125—127 ℃; H NMR (600 MHz,
CDCl3) δ: 9.32 (s, 1H), 8.12—8.10 (m, 2H), 8.02 (s,
1H), 7.99 (d, J＝8.4 Hz, 1H), 7.87 (d, J＝8.4 Hz, 1H),
7.71 (t, J＝7.5 Hz, 1H), 7.59 (t, J＝7.5 Hz, 1H), 7.19 (t,
General procedure for the microwave assisted syn-
thesis of 3-substituted isoquinoline 3
J＝8.4 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ: 164.0,
2-Bromobenzaldehyde 1 (0.50 mmol), a terminal
alkyne 2 (0.60 mmol), PdCl2(PPh3)2 (0.025 mmol), CuI
(0.20 mmol), t-BuNH2 (1.5 mmol) and Et3N (1.5 mmol)
in DMF (2 mL) were mixed in a sealed 10 mL micro-
wave vial. The reaction mixture was irradiated in a
SmithsynthesizerTM microwave system at 140 W for 5
min or until disappearance of the starting aldehyde as
monitored by thin layer chromatography. The reaction
mixture was poured into water and neutralized with 1
mol/L HCl. The aqueous phase was extracted with di-
ethyl ether (10 mL×3). The organic layers were com-
bined and dried over anhydrous MgSO4. The solvent
19
162.3, 152.3, 150.1, 136.5, 135.6, 130.5, 128.6 (d, JC-
F
19
＝9.2 Hz), 127.5 (d, JC- F＝9.2 Hz), 127.0, 126.7,
19
116.1, 115.6 (d, JC- F＝21.3 Hz); IR (KBr) ν: 1622,
－
1
1600, 1579, 1508, 1448, 1226, 1156, 1128, 836 cm .
HRMS (ESI) calcd for C15H11FN [M＋H]＋ 224.0876,
found 224.0899.
3-(3-Methoxyphenyl)isoquinoline[19] (3d) Yield
1
58%, yellow solid, m.p. 80—82 ℃; H NMR (600
MHz, CDCl3) δ: 9.31 (s, 1H), 8.03 (s, 1H), 7.95 (d, J＝
7.8 Hz, 1H), 7.83 (d, J＝7.8 Hz, 1H), 7.72 (s, 1H),
7.69—7.65 (m, 2H), 7.55 (t, J＝7.5 Hz, 1H), 7.41 (t,
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Chin. J. Chem. 2012, 30, 1075—1082

Facile Synthesis of 3-Substituted Isoquinolines Derivatives
J＝7.8 Hz, 1H), 6.97—6.96 (m, 1H), 3.91 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ: 160.0, 152.2, 150.9, 141.0,
136.5, 130.4, 129.7, 127.7, 127.4, 127.0, 126.8, 119.3,
116.6, 114.5, 112.0, 55.3; HRMS (ESI) calcd for
C16H14NO [M＋H]＋ 236.1075, found 236.1093.
2.88—2.83 (m, 1H), 2.08—2.06 (m, 2H), 1.91—1.88
(m, 2H), 1.79—1.77 (m, 1H), 1.64—1.57 (m, 2H),
1.50—1.44 (m, 2H), 1.36—1.29 (m, 1H); 13C NMR
(150 MHz, CDCl3) δ: 159.9, 151.7, 136.6, 130.1, 127.4,
127.1, 126.2, 116.1, 116.0, 45.9, 33.1, 26.6, 26.1;
HRMS (ESI) calcd for C15H18N [M＋H]＋ 212.1439,
found 212.1449.
3-p-Tolylisoquinoline[16,20] (3e) Yield 76%,
1
yellow solid, m.p. 69—71 ℃; H NMR (600 MHz,
3-Cyclohexenylisoquinoline[13a,13e,13f] (3k) Yield
CDCl3) δ: 9.33 (s, 1H), 8.04—8.02 (m, 3H), 7.98 (d,
J＝7.8 Hz, 1H), 7.86 (d, J＝8.4 Hz, 1H), 7.69 (t, J＝7.2
Hz, 1H), 7.57 (t, J＝7.2 Hz, 1H), 7.32 (d, J＝7.8 Hz,
2H), 2.43 (s, 3H); 13C NMR (150 MHz, CDCl3) δ: 152.3,
151.2, 138.4, 136.7, 136.6, 130.4, 129.5, 129.4, 127.5,
127.4, 126.8, 126.7, 115.9, 21.2; HRMS (ESI) calcd for
C16H14N [M＋H]＋ 220.1126, found 220.1126.
1
74%, yellow solid, m.p. 107—109 ℃; H NMR (600
MHz, CDCl3) δ: 9.20 (s, 1H), 7.93 (d, J＝8.4 Hz, 1H),
7.78 (d, J＝8.4 Hz, 1H), 7.64 (t, J＝7.5 Hz, 1H), 7.60 (s,
1H), 7.52 (t, J＝7.5 Hz, 1H), 7.01 (br, 1H), 2.59 (br,
2H), 2.33—2.32 (m, 2H), 1.87—1.85 (m, 2H),
1.74—1.71 (m, 2H); 13C NMR (150 MHz, CDCl3) δ:
152.3, 151.5, 136.5, 135.5, 130.2, 128.3, 127.4, 127.3,
126.6, 126.3, 114.1, 26.1, 25.9, 22.9, 22.1; HRMS (ESI)
calcd for C15H16N [M＋H]＋ 210.1283, found 210.1288.
6,8-Dimethoxy-7-methyl-3-phenylisoquinoline (3l)
3-o-Tolylisoquinoline[20] (3f) Yield 73%, yellow
1
solid, m.p. 73—75 ℃; H NMR (600 MHz, CDCl3) δ:
9.34 (s, 1H), 8.02 (d, J＝7.8 Hz, 1H), 7.86 (d, J＝7.8
Hz, 1H), 7.75 (s, 1H), 7.72 (t, J＝7.8 Hz, 1H), 7.62 (t,
J＝7.5 Hz, 1H), 7.50 (d, J＝6.6 Hz,1H), 7.32—7.30 (m,
3H), 2.42 (s, 3H); 13C NMR (150 MHz, CDCl3) δ: 153.6,
151.7, 140.4, 136.1, 136.0, 130.6, 130.3, 130.0, 128.0,
127.4, 127.1, 127.0, 126.6, 125.8, 120.0, 20.4; HRMS
(ESI) calcd for C16H14N [M＋H]＋ 220.1126, found
220.1137.
1
Yield 58%, yellow oil; H NMR (600 MHz, CDCl3) δ:
9.43 (s, 1H), 8.11 (d, J＝7.2 Hz, 2H), 7.96 (s, 1H), 7.50
(t, J＝7.5 Hz, 2H), 7.42—7.41 (m, 1H), 6.92 (s, 1H),
3.99—3.98 (m, 6H), 2.32 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ: 160.9, 155.2, 151.2, 146.7, 139.7, 137.3,
128.6, 128.3, 126.8, 121.1, 118.1, 115.6, 99.8, 62.2,
55.7, 9.3; IR (KBr) ν: 1623, 1572, 1484, 1485, 1400,
1248, 1227, 1192, 1149, 1119, 1022, 959, 880, 765,694
cm－1; HRMS (ESI) calcd for C18H18NO2 [M＋H]＋
280.1338, found 280.1326.
3-(6-Methoxynaphthalen-2-yl)isoquinoline (3g)
1
Yield 56%, yellow solid, m.p. 161—163 ℃; H NMR
(600 MHz, CDCl3) δ: 9.38 (s, 1H), 8.59 (s, 1H), 8.22 (d,
J＝7.8 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J＝7.8 Hz, 1H),
7.91—7.87 (m, 3H), 7.71 (t, J＝7.5 Hz, 1H), 7.59 (t,
J＝7.2 Hz, 1H), 7.20—7.19 (m, 2H), 3.96 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ: 158.0, 152.4, 151.2, 136.7,
134.6, 130.5, 130.2, 129.1, 127.6, 127.5, 127.2, 126.9,
126.8, 126.1, 125.1, 119.1, 116.2, 105.6, 95.3, 55.3; IR
(KBr) ν: 1621, 1570, 1483, 1461, 1386, 1261, 1227,
7-Fluoro-3-phenylisoquinoline[13a] (3m)
Yield
1
61%, yellow solid, m.p. 124—126 ℃; H NMR (600
MHz, CDCl3) δ: 9.30 (s, 1H), 8.11 (d, J＝7.2 Hz, 2H),
8.07 (s, 1H), 7.90—7.88 (m, 1H), 7.62—7.60 (m, 1H),
7.53—7.47 (m, 3H), 7.43 (t, J＝7.2 Hz, 1H); 13C NMR
19
－
(150 MHz, CDCl3) δ: 161.5, 159.9, 151.5 (d, JC- F＝6.9
1
1185, 1160, 1119, 855 cm ; HRMS (ESI) calcd for
C20H16NO [M＋H]＋ 286.1232, found 286.1218.
3-Benzylisoquinoline[21] (3h) Yield 75%, yellow
19
Hz), 150.9, 139.2, 133.6, 129.5 (d, JC- F＝6.9 Hz),
19
19
128.7 (d, JC- F＝34.5 Hz), 128.1, 126.8, 121.1 (d, JC-
F
19
1
＝25.4 Hz), 116.2, 110.5 (d, JC- F＝20.7 Hz). HRMS
(ESI) calcd for C15H11FN [M＋H]＋ 224.0876, found
224.0885.
solid, m.p. 57—59 ℃; H NMR (600 MHz, CDCl3) δ:
9.22 (s, 1H), 7.93 (d, J＝8.4 Hz, 1H), 7.72 (d, J＝8.4
Hz, 1H), 7.64 (t, J＝7.5 Hz, 1H), 7.54 (t, J＝7.2 Hz,
1H), 7.43(s, 1H), 7.33—7.32 (m, 4H), 7.25—7.23 (m,
1H), 4.32 (s, 2H); 13C NMR (150 MHz, CDCl3) δ: 154.3,
152.2, 139.7, 136.3, 130.2, 129.1, 128.4, 127.3, 127.0,
126.5, 126.2, 126.1, 118.6, 44.2; HRMS (ESI) calcd for
C16H14N [M＋H]＋ 220.1126, found 220.1144.
7-Phenyl-[1,3]dioxolo[4,5-g]isoquinoline[13a] (3n)
1
Yield 46%, yellow solid, m.p. 119—121 ℃; H NMR
(600 MHz, CDCl3) δ: 9.07 (s, 1H), 8.07 (d, J＝7.8 Hz,
2H), 7.91 (s, 1H), 7.50—7.48 (m, 2H), 7.41—7.39 (m,
1H), 7.22 (s, 1H), 7.13 (s, 1H), 6.11 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ: 150.9, 150.3, 150.0, 148.2, 139.5,
134.9, 128.6, 128.2, 126.6, 124.8, 116.2, 102.9, 102.6,
101.5; HRMS (ESI) calcd for C16H12NO2 [M＋H]＋
250.0868, found 250.0891.
3-Butylisoquinoline[22] (3i) Yield 57%, yellow oil;
1H NMR (600 MHz, CDCl3) δ: 9.20 (s, 1H), 7.93 (d,
J＝8.4 Hz, 1H), 7.75 (d, J＝8.4 Hz, 1H), 7.65 (t, J＝7.5
Hz, 1H), 7.53 (t, J＝7.8 Hz, 1H), 7.47 (s, 1H), 2.94 (t,
J＝7.8 Hz, 2H), 1.83—1.78 (m, 2H), 1.45—1.41 (m,
2H), 0.97 (t, J＝7.8 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ: 155.7, 152.0, 136.4, 130.1, 127.3, 126.9,
126.1, 125.9, 117.8, 37.7, 32.1, 22.4, 13.9. HRMS (ESI)
calcd for C13H16N [M＋H]＋ 186.1283, found 186.1270.
3-Cyclohexylisoquinoline[13e,13f] (3j) Yield 62%,
Yellow oil; 1H NMR (600 MHz, CDCl3) δ: 9.21 (s, 1H),
7.91 (d, J＝8.4 Hz, 1H), 7.74 (d, J＝8.4 Hz, 1H), 7.62 (t,
J＝7.2 Hz, 1H), 7.50 (t, J＝7.5 Hz, 1H), 7.453 (s, 1H),
6-Phenyl-1,7-naphthyridine[23] (3o) Yield 56%,
1
yellow solid, m.p. 132—134 ℃; H NMR (600 MHz,
CDCl3) δ: 9.37 (s, 1H), 9.11—9.10 (m, 1H), 8.36 (s,
1H), 8.32 (d, J＝8.4 Hz, 1H), 8.18 (d, J＝7.8 Hz, 2H),
7.56—7.51 (m, 3H), 7.48—7.47 (m, 1H); 13C NMR
(150 MHz, CDCl3) δ: 155.0, 154.9, 152.6, 151.2, 138.7,
135.5, 129.1, 128.8, 127.1, 122.5, 122.1, 117.7; HRMS
(ESI) calcd for C14H11N2 [M＋H]＋ 207.0922, found
207.0930.
Chin. J. Chem. 2012, 30, 1075—1082
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1081

Lin et al.
FULL PAPER
T. N.; Kim, T. S. Bioorg. Med. Chem. Lett. 2003, 13, 4451.
Acknowledgement
[8] (a) Kametani, T.; Fukumoto, K. The Chemistry of Heterocyclic
Compounds, Isoquinolines, Vol. 38, Ed.: Grethe, G., Wiley, New
York, 1981, Part 1, Chapter 2, pp. 139—274; (b) Whaley, W. M.;
Govinda-chari, T. R. Organic Reactions, Vol. 6, Ed.: Adams, R.,
Wiley, New York, 1951, pp. 151—190.
This work was supported by the National Natural
Science Foundation of China (No. 21002038) and the
Self-determined Research Funds of CCNU from the
Colleges’ Basic Research and Operation of MOE (No.
CCNU09A01014).
[9] Gensler, W. J. Organic Reaction, Vol. 6, Ed.: Adams, R., Wiley,
New York, 1951, pp. 191—206.
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1082
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1075—1082