A facile synthesis of 1-alkyl-5-arylalkoxy-6-methoxy-3,4- dihydroisoquinolines

Article abstract of DOI:10.1002/jhet.5570440426

(Chemical Equation Presented) 1-Alkyl-5-arylalkoxy-6-methoxy-3,4- dihydroisoquinolines were synthesized by the alkylation of 1-alkyl-5-hydroxy-6- methoxy-3,4-dihydroisoquinolines with arylalkyl halide in the presence of potassium carbonate. 1-Alkyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolines as key precursor prepared from o-vaniline via 6 steps.

Full text of DOI:10.1002/jhet.5570440426

Jul-Aug 2007
909
A Facile Synthesis of 1-Alkyl-5-arylalkoxy-6-methoxy-3,4-
dihydroisoquinolines
Heong-Seup Yim,a Ho-Kyun Kim,a Jeum-Jong Kim,a Deok-Heon Kweon,a Sang-Gyeong
Lee,*b Jung-Ho Kimc and Yong-Jin Yoon*a
aDepartment of Chemistry, Environmental Biotechnology National Core Research center, Research Institute of
Natural Science, Graduate School for Molecular Materials and Nanochemistry, Gyeongsang National University,
Jinju 660-701, Korea
bDepartment of Chemistry &Research Institute of Life Science, Graduate School for Molecular Materials and
Nanochemistry, Gyeongsang National University, Jinju 660-701, Korea
cHanwha Chemical R & D center, 6 Shinsung-Dong, Yusung-Gu, Taejon 305-345, Korea
yjyoon@gnu.ac.kr
Received December 26, 2006
OH
OH
O(CH2)nAr
MeO
MeO
CHO
MeO
6 steps
Ar(CH2)nX
N
N
R
R
Ar = Phenyl or Heteroaryl
R = n-Hexyl or n-Decyl
1-Alkyl-5-arylalkoxy-6-methoxy-3,4-dihydroisoquinolines were synthesized by the alkylation of 1-
alkyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolines with arylalkyl halide in the presence of potassium
carbonate. 1-Alkyl-5-hydroxy-6-methoxy-3,4-dihydroisoquinolines as key precursor prepared from o-
vaniline via 6 steps.
J. Heterocyclic Chem., 44, 909 (2007).
According to the retrosynthesis as shown Scheme 1, the
two routes are possible for the synthesis of 1-alkyl-5-
arylalkoxy-3,4-dihydroisoquinolines; the first is the
method using the alkylation of 1-alkyl-5-hydroxy deriv-
ative with arylalkyl halide (method A), and the second is
the method using the cyclization of N-(2-alkoxy-3-
methoxyphenethyl)alkanamide (method B).
The method A is more useful than the method B for the
introduction of various arylalkoxy groups at C-5 position
(Scheme 2). When 2-heteroalkoxy-3-methoxybenzal-
dehyde is used as the starting material (method B),
unexpected side reactions may occur during the coupling
reaction and the cyclization. Actually, we detected the
unknown products on tlc during these reaction. Therefore,
we attempted to synthesize the 1-alkyl-5-arylalkoxy-3,4-
dihydroisoquinolines according to method A.
INTRODUCTION
Isoquinoline alkaloids are often selected as synthetic
targets due to their various physiological activities and
structural properties [1]. In previous papers [2], we
reported the pharmacological effect and chemistry for
some isoquinoline derivatives. In connection with the
SAR study and the evaluation of biological activity such
as cardiovascular activity or immunosuppressive activity,
we required especially some 1-alkyl-5-arylalkoxy (or
heteroarylalkoxy)-6-methoxy-3,4-dihydroisoquinoline
derivatives. Although the synthetic methods of the
interesting isoquinolines have been reported [1-3], there
are no general synthetic methods to obtain 1-alkyl-5-
arylalkoxy-6-methoxy-3,4-dihydroisoquinolines. The
Bischler-Napieralski [2-4] condensation is a common
method for the formation of 3,4-dihydroisoquinoline ring
system.
From the retrosynthesis of target molecules (Scheme 1),
we chose o-vaniline (1) as the starting material for the
Scheme 1
OH
O(CH2) Ar
n
CH2Ph
CH2Ph
O
O
MeO
MeO
MeO
NH2
MeO
NHCOR
N
N
R
R
CH2Ph
O
OH
MeO
CHO
MeO
CHO

910
H.-S. Yim, H.-K. Kim, J.-J. Kim, D.-H. Kweon, S.-G. Lee, J.-H. Kim and Y.-J. Yoon
Vol 44
Scheme 2
O(CH2)nAr
OH
O(CH2)nAr
MeO
MeO
alkylation
Method A
MeO
cyclization
Method B
N
R
N
NHCOR
R
synthesis of 1-alkyl-5-hydroxy-6-methoxy derivatives as a
key precursor.
In this paper, we would like to report on synthesis of
Cyclization of 5 with phosphorus oxychloride in
acetonitrile at room temperature also furnished the
corresponding 3,4-dihydroisoquinolines 6a and 6b. The
infrared spectra of 6 did not show absorption bands of the
carbonyl and NH bonds. The 1H nmr spectra of 6 revealed
proton signals of one OCH3, two CH2 of C-3 and C-4
positions and one benzylic CH2 at C-5 involving aromatic
and alkyl chain protons at C-1 position.
some
1-alkyl-5-arylalkoxy-6-methoxy-3,4-dihydroiso-
quinolines from o-vaniline.
RESULTS AND DISCUSSION
Compound 7 as key precursor was prepared from o-
vaniline (1) via six steps according to Scheme 3. Reaction
of o-vaniline (1) with benzyl chloride in the presence of
potassium carbonate in methanol gave compound 2 in
93% yield. Treatment of 2 with nitromethane in the
presence of potassium fluoride and dimethylamine
hydrochloride in toluene afforded ꢀ-nitrostyrene 3 in
excellent yield. Compound 3 was reduced selectively to
the corresponding amine 4 using lithium aluminum
hydride in diethyl ether. Reaction of 4 with acyl chloride
in the presence of triethylamine in acetonitrile gave the
corresponding amides 5a and 5b in excellent yields.
Debenzylation of compound 6 with hydrogen in the
presence of Pd/C in methanol gave the corresponding 5-
hydroxy-3,4-dihydroisoquinolines 7a and 7b in good
yield, respectively. The infrared spectra of 7a and 7b
1
showed absorption band of the hydroxyl bond. The H
nmr spectra of 7a and 7b also detected proton signals of
one OCH3 and two CH2 of C-3 and C-4 positions
involving aromatic and alkyl chain protons at C-1
position.
On the other hand, we attempted to synthesize some
5-arylalkoxy (or heteroarylalkoxy)-3,4-dihydroxyiso-
Scheme 3
OH
O
OBn O
OBn
benzyl chloride
K2CO3, MeOH
(CH3)2NH2Cl, KF
CH3NO2, toluene
MeO
MeO
NH2
MeO
NO2
H
H
1
2
3
OBn
MeO
OBn
MeO
LiAlH4
RCOCl
3
NHCOR
diethyl ether
Et3N, CH3CN
4
5
OBn
POCl3
OH
OAr
H2, Pd/C
MeOH
5
MeO
MeO
ArX
CH3CN
MeO
N
K2CO3, MeOH
(or CH3CN, THF)
N
5,6,7a R= n-C6H13
5,6,7b R= n-C10H21
N
6
R
7
R
8
R
a
c
e
8
b
d
f
R
n-C6H13
n-C6H13 n-C6H13 n-C6H13
n-C6H13
n-C10H21
O
Br NO2
Ar
N
O
N
N
N
g
i
k
8
h
j
R
n-C10H21 n-C10H21 n-C10H21
n-C10H21
O
n-C10H21
O
N
Cl
N
Cl
Cl
Ar
N
-(H2C)4
N
O
N
O
O

Jul-Aug 2007
A Facile Synthesis of 1-Alkyl-5-arylalkoxy-6-methoxy-3,4-dihydroisoquinolines
911
stirred for 5 minutes. After separating the organic layer, this
layer was washed with sodium hydroxide solution (100 mL,
25%) and water (150 mL) and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure to
give compound 2 as yellowish liquid in 93% yield. mp oil (lit.[6]
mp 58 - 59 °C). IR (KBr): 3060, 3030, 2940, 2870, 1690, 1590,
1480, 1450, 1370, 1310, 1270, 1220, 1180, 1070, 970, 910, 670
cm-1; 1H NMR (CDCl3): ꢀ 3.79 (s, 3H), 5.21 (s, 2H), 7.02 – 7.09
(m, 2H), 7.27 – 7.35 (m, 6H), 10.23 ppm (s, 1H); 13C NMR
(CDCl3): ꢀ 118.1, 118.9, 124.3, 128.4, 128.5, 128.6, 128.7,
130.3, 136.6, 153.1, 190.1 ppm; Anal. Calcd. for C15H14O3: C ,
74.36; H 5.82. Found: C, 74.40; H 5.89.
2-(Benzyloxy)-1-methoxy-3-(2-nitrovinyl)benzene (3).
Compound 2 (2 g, 8.3 mmol) was dissolved in toluene/
nitromethane (20 mL: 20 mL). N,N-Dimethylammonium
chloride (1.4 g, 16.6 mmol) and potassium fluoride (0.1 g, 1.3
mmol) were added to the solution. The mixture was refluxed for
3-4 hours. And during the reaction, water was removed using
Dean-Stark tube. After cooling to room temperature, the
solution was filtrated and evaporated under reduced pressure.
The resulting residue was dissolved in diethyl ether (30 mL)
after which the solution was filtrated. The solvent was
evaporated under reduced pressure to give the product 3 as
yellow crystals in 89% yield, mp 64-65°C (lit.[6] mp 72 –
73°C). IR (KBr): 3110, 3080, 3010, 2940, 2880, 2840, 1680,
1630, 1580, 1510, 1450, 1340, 1270, 1060, 970, 790, 740 cm-1;
1H NMR (CDCl3): ꢀ 3.96 (s, 3H), 5.13 (s, 2H), 7.02 – 7.15 (m,
3H), 7.34 - 7.40 (m, 6H), 7.57 (d, 1H, J = 13.7 Hz), 8.11 ppm (d,
1H, J = 13.7 Hz); 13C NMR (CDCl3): ꢀ 56.0, 75.7, 115.7, 120.7,
124.6, 125.0, 127.0, 128.6, 128.9, 134.7, 136.3, 138.1, 147.7,
153.3 ppm. Anal. Calcd. for C16H15NO4(285.29): C, 67.36; H,
5.30; N 4.91. Found: C, 67.41; H, 5.39; N, 5.02.
quinolines. Alkylation of compound 7 with benzyl
chlorides or heteroarylalkyl chlorides (or bromides) in the
presence of potassium carbonate in methanol except for
8c (CH3CN), 8h (CH3CN) and 8k (THF) afforded the
corresponding 1-hexyl (or decyl)-5-arylalkoxy-6-meth-
oxy-3,4-dihydroisoquinolines in moderate to good yield,
respectively. When the reaction of 7 with 4,5-dichloro-1-
chloromethylpyridazin-3(2H)-one in the presence of
potassium carbonate in methanol, 4-chloro-5-methoxy-1-
methoxymethylpyridazin-3(2H)-one as the main product
was obtained instead of the expected product 8k. This
result is similar to Chung’s result for the methoxylation of
4,5-dichloropyridazin-3(2H)-one with potassium carbo-
nate in methanol [5]. Therefore, we used tetrahydrofuran
as solvent for the alkylation of compound 7 with
4,5-dichloro-1-chloromethylpyridazin-3(2H)-one in the
presence of potassium carbonate. The infrared spectra of 8
1
did not show absorption band of the OH bond. The H
nmr spectra of 8 revealed proton signals of one OCH3 (ꢀ
3.58 – 3.92 ppm as singlet) and two CH2 of C-3 and C-4
positions (ꢀ 2.43 – 2.75 ppm as triplets or multiplets for
C-3 and ꢀ 2.33- 2.66 ppm as triplets or multiplets for C-4)
involving aromatic, arylalkyl chain at C-5 and alkyl chain
protons at C-1 position. The structures of all synthetic
compounds were established by ir, nmr and elemental
analyses.
In summary, a efficient and facile route for the prepar-
ation of 1-alky-5-arylalkoxy-6-methoxy-3,4-dihydroiso-
quinolines has been developed. The most advantageous
feature of the synthesis reported here is the fact that the
target molecules can be obtained with various arylalkoxy
group at C-5 position in 3,4-dihydroisoquinoline ring.
Further work including the biological activity and the
chemical transformation of the products to 2-substituted-
1,2,3,4-tetraisoquinolinium salts are under way in our
laboratory.
2-[2-(Benzyloxy)-3-methoxyphenyl]ethanamine (4). A ether
solution of compound 3 (10 g, 25.1 mmol in 100 mL of diethyl
ether ) was added slowly to ether solution of lithium aluminum
hydride (6.7 g, 0.18 mol in 200 mL of diethyl ether) for 30
minutes with stirring. The mixture was refluxed for 44 - 46
hours. After cooling the reaction mixture to room temperature,
water (50 mL) was added slowly in an ice bath. And potassium
hydroxide aqueous solution (20 mL, 20%) was then added to the
mixture. The mixture was stirred for 5 minutes, and neutralized
by adding hydrochloric acid (50%) to pH 7. The product was
extracted with diethyl ether (2 x 250 mL). The resulting ether
solution was washed with water (250 mL) and dried over
anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure to give compound 4 as liquid in 77%
yield. IR (KBr): 3370, 3300, 3060, 2940, 2870, 2840, 1590,
EXPERIMENTAL
Melting points were determined with a capillary apparatus
and uncorrected.1H and 13C NMR spectra were recorded on a
300 MHz spectrophotometer with chemical shift values reported
in ꢀ units (ppm) relative to an internal standard (TMS). IR
spectra were obtained on an IR spectrophotometer. Elemental
analyses were performed with a CHNS-932 (Leco). High
resolution mass spectra (HRMS) were obtained on a JEOL JMS-
700 (Japan) system. Open-bed chromatography was carried out
on silica gel (70-230 mesh, Merck) using gravity flow. The
column was packed as slurries with the elution solvent.
1
1470, 1380, 1270, 1210, 1080, 1010, 990, 750, 700 cm-1; H
NMR (CDCl3): ꢀ 2.13 (bs, 2H), 2.70 (t, 2H, J = 6.8 Hz), 2.85 (t,
2H, J = 6.8 Hz), 3.85 (s, 3H), 4.99 (s, 2H), 6.75-6.82 (m, 2H),
6.99 (t, 1H, J = 7.9 Hz), 7.30 – 7.38 (m, 3H), 7.45 ppm (d, 2H, J
= 7.2 Hz); 13C NMR (CDCl3): ꢀ 34.2, 42.6, 55.7, 74.7 110.7,
122.3, 124.0, 127.9, 128.1, 128.4, 133.8, 138.0, 146.2, 152.9
ppm. Anal. Calcd. for C16H19NO2: C, 74.68; H ,7.44; N, 5.44.
Found: C, 74.71; H, 7.49; N, 5.47.
N-(2-Benzyloxy-3-methoxyphenethyl)alkanamide (5).
A
2-(Benzyloxy)-3-methoxybenzaldehyde (2). A solution of o-
vaniline (1, 10 g, 66 mmol), potassium carbonate (11 g, 79
mmol) and benzyl chloride (11.4 mL, 99 mmol) in methanol
(200 mL) was refluxed for 17-19 hours. After cooling to room
temperature, the mixture was filtrated and evaporated under
reduced pressure. Water (150 mL) and diethyl ether (150 mL)
was added to the resulting residue and the mixture was then
solution of compound 4 (5 g, 19.4 mmol), triethyl amine (3.3
mL, 23.28 mmol), alkanoyl chloride (23.28 mmol) and
acetonitrile (150 mL) was stirred for 1 -1.5 hours at room
temperature. After filtering the mixture, the solvent was
evaporated under reduced pressure. Diethyl ether/ water (100
mL: 100 mL) was added to the residue. The resulting solution

912
H.-S. Yim, H.-K. Kim, J.-J. Kim, D.-H. Kweon, S.-G. Lee, J.-H. Kim and Y.-J. Yoon
Vol 44
was stirred for 5 minute. After separating the organic layer, the
solution was dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure to give the
product 5.
Anal. Calcd. for C27H37NO2: C, 79.56; H, 9.15; N, 3.44. Found:
C, 79.61; H, 9.21; N, 3.50.
1-Alkyl-6-methoxy-3, 4-dihydroisoquinolin-5-ol (7). A
solution of compound 6 (28.5 mmol), Pd/C (0.5 g) and methanol
(150 mL) was stirred for 4 – 8 hours under a hydrogen
atmosphere (using toy balloon) at room temperature. After
filtering using Celite -545 pad, the filtrate was evaporated under
reduced pressure. The resulting residue was applied to the top of
an open-bed silica gel column (3.5 x 14 cm). The column was
eluted with ethyl acetate. Fractions containing the product were
combined and evaporated under reduced pressure to give the
corresponding phenol 7.
Compound 5a. Yield: 93%; mp 49-50°C. IR (KBr): 3300,
3070, 3030, 2950, 2930, 2860, 1640, 1570, 1550, 1470, 1370,
1270, 1210, 1080, 990, 750, 700 cm-1; 1H NMR (CDCl3): ꢀ 0.88
(t, 3H, J = 6.6 Hz), 1.21 – 1.29 (m, 6H), 1.50 (m, 2H), 2.00 (t,
2H, J = 7.4 Hz), 2.78 (t, 2H, J = 6.7 Hz), 3.42 (q, 2H, J = 6.3
and 6.1 Hz), 3.90 (s, 3H), 5.04 (s, 2H), 5.95 (s, NH), 6.77 (d,
1H, J = 7.6 Hz), 6.86 (d, 1H, J = 8.0 Hz), 7.03 (t, 1H, J = 7.9
Hz), 7.32 – 7.42 (m, 3H), 7.48 ppm (d, 2H, J = 7.3 Hz); 13C
NMR (CDCl3): ꢀ 14.1, 22.5, 25.6, 28.9, 30.0, 31.5, 36.7, 40.6,
55.7, 74.8, 111.0, 122.4, 124.4, 128.1, 128.3, 128.5, 133.4,
137.7, 145.9, 152.8, 173.3 ppm. Anal. Calcd. for C23H31NO3: C,
74.76; H, 8.46; N, 3.79. Found: C, 74.80; H, 8.60; N 3.83.
Compound 5b. Yield: 89%; mp 70-71°C. IR (KBr): 3320,
3080, 3040, 3000, 2920, 2850, 1640, 1580, 1550, 1470, 1380,
1360, 1310, 1270, 1210, 1090, 1040, 1000, 980, 920, 750, 700
Compound 7a. Yield 85%; mp 115 - 116°C. IR (KBr): 3500,
3080, 2950, 2920, 2850, 1620, 1590, 1500, 1460, 1430, 1290,
1
1240, 1070, 870, 790 cm-1; H NMR (CDCl3): ꢀ 0.84 (t, 3H, J =
6.8 Hz), 1.23 – 1.36 (m, 6H), 1.55 – 1.65 (m, 2H), 2.67 – 2.76
(m, 4H), 3.62 (t, 2H, J = 7.4 Hz), 3.87 (s, 3H), 6.74 (d, 1H, J =
8.4 Hz), 7.06 (d, 1H, J = 8.4 Hz), 7.25 ppm (bs, 1H, D2O
exchangeable); 13C NMR (CDCl3): ꢀ 14.1, 19.5, 22.6, 27.8, 29.3,
31.6, 35.9, 46.0, 55.7, 107.9, 117.6, 122.8, 124.6, 142.3, 149.0,
168.0 ppm. Anal. Calcd. for C16H23NO2: C, 73.53; H, 8.87; N,
5.36. Found: C, 73.60; H, 8.91; N, 5.50.
1
cm-1; H NMR (CDCl3): ꢀ 0.88 (t, 3H, J = 6.9 Hz), 1.20 – 1.32
(m, 14H), 1.43 – 1.52 (m, 2H), 1.98 (t, 2H, J = 7.4 Hz), 2.76 (t,
2H, J = 6.5 Hz), 3.38 – 3.44 (m, 2H), 3.90 (s, 3H), 5.02 (s, 2H),
5.85 (bs, 1H, D2O exchangeable), 6.76 (d, 1H, J = 7.6 Hz), 6.85
(d, 1H, J = 8.1 Hz), 7.03 (t, 1H, J = 8.1 Hz), 7.31 – 7.41 (m, 3H),
7.46 ppm (d, 2H, J = 6.7 Hz); 13C NMR (CDCl3): ꢀ 14.1, 22.7,
25.7, 29.2, 29.3, 29.4, 29.5, 29.6, 30.0, 31.9, 36.8, 40.6, 55.7,
74.8, 110.9, 122.4, 124.4, 128.1, 128.3, 128.5, 133.5, 137.6,
145.9, 152.8, 173.2 ppm. Anal. Calcd. for C27H39NO3: C, 76.20;
H, 9.24; N, 3.29. Found: C, 76.28; H, 9.31; N, 3.30.
1-Alkyl-5-benzyloxy-6-methoxy-3,4-dihydroisoquinoline
(6). A solution of compound 5 (0.027 mol), phosphorus
oxychloride (10.1 mL, 0.108 mol) and acetonitrile (150 mL) was
stirred for 18 hours at room temperature. After evaporating the
solvent under reduced pressure, water (100 mL) was added to
the residue. And the mixture was then neutralized with sodium
hydroxide solution (20%) to pH 7. The product was extracted
with diethyl ether (100 mL x 2). After drying over anhydrous
magnesium sulfate, the solvent was evaporated under reduced
pressure to give the product 6.
Compound 6a. Yield 74%; mp 137 - 138°C. IR (KBr): 3070,
3020, 2930, 2850, 1600, 1570, 1470, 1280, 1220, 1080, 980,
750, 700 cm-1; 1H NMR (CDCl3): ꢀ 0.87 (t, 3H, J = 6.8 Hz), 1.27
– 1.32 (m, 4H), 1.38 – 1.48 (m, 2H), 1.70 – 1.79 (m, 2H), 2.75
(t, 2H, J = 7.7 Hz), 3.21 (t, 2H, J = 7.7 Hz), 3.60 (t, 2H, J = 7.6
Hz), 4.08 (s, 3H), 5.06 (s, 2H), 7.12 (d, 1H, J = 8.8 Hz), 7.30 –
7.36 (m, 5H), 7.67 ppm (d, 1H, J = 8.8 Hz); 13C NMR (CDCl3):
ꢀ 13.9, 19.7, 22.2, 28.8, 29.1, 31.2, 32.4, 40.3, 56.5, 74.9, 111.3,
117.6, 127.9, 128.5, 128.6, 128.7, 132.1, 136.2, 143.9, 159.8,
177.4 ppm; HRMS Calcd. for C23H29NO2: 351.2198; Found:
351.2194. Anal. Calcd. for C23H29NO2: C, 78.59; H, 8.32; N,
3.99. Found: C, 78.62; H, 8.40; N, 4.06.
Compound 6b. Yield: 72%; mp liquid. IR (KBr): 3060, 3030,
2930, 2850, 1620, 1600, 1570, 1490, 1450, 1370, 1330, 1270,
1210, 1150, 1080, 990, 810, 750, 700 cm-1; 1H NMR (CDCl3): ꢀ
0.87 (t, 3H, J = 6.2 Hz), 1.21 – 1.32 (m, 14H), 1.57 – 1.67 (m,
2H), 2.55 (t, 2H, J = 7.6 Hz), 2.66 (t, 2H, J = 7.6 Hz), 3.47 (t,
2H, J = 7.2 Hz), 3.88 (s, 3H), 4.97 (s, 2H), 6.80 (d, 1H, J = 8.5
Hz), 7.24 (d, 1H, J = 8.5 Hz), 7.28 – 7.35 (m, 3H), 7.39 ppm (d,
2H, J = 7.3 Hz); 13C NMR (CDCl3): ꢀ 14.1, 20.2, 22.7, 27.4,
29.3, 29.4, 29.5, 29.6, 31.9, 36.1, 46.4, 55.6, 60.3, 74.7, 109.3,
121.9, 123.0, 128.1, 128.4, 132.5, 137.4, 143.7, 154.3, 167.1
ppm; HRMS Calcd. for C27H37NO2: 407.2824; Found: 407.2829.
Compound 7b. Yield: 70%; mp 108 – 109 °C. IR (KBr):
3450, 3010, 2930, 2850, 1640, 1610, 1570, 1490, 1460, 1440,
1
1290, 1240, 1150, 1080, 910, 740 cm-1; H NMR (CDCl3): ꢀ
0.86 (t, 3H, J = 6.3 Hz), 1.19 – 1.34 (m, 12H), 1.42 – 1.51 (m,
2H), 1.73 – 1.81 (m, 2H), 3.08 (t, 2H, J = 6.9 Hz), 3.20 (t, 2H, J
= 7.3 Hz), 3.83 (t, 2H, J = 6.7Hz), 4.05 (s, 3H), 6.97 (d, 1H, J =
8.6 Hz), 7.43 (d, 1H, J = 8.6 Hz), 8.04 ppm (bs, 1H, D2O
exchangeable); 13C NMR (CDCl3): ꢀ 14.0, 19.0, 22.6, 29.0, 29.1,
29.2, 29.3, 29.4, 29.5, 31.7, 32.7, 40.6, 56.5, 109.5, 117.8, 123.1,
123.6, 143.2, 154.3, 177.6 ppm. Anal. Calcd. for C20H31NO2: C,
75.67; H, 9.84; N, 4.41. Found: C, 75.73; H, 9.90; N, 4.48.
1-Alkyl-5-arylalkoxy-6-methoxy-3,4-dihydroisoquinoline
(8). A solution of compound 7 (11.5 mmol), potassium
carbonate (13.8 mmol, 1.2 equiv), arylalkyl halide (16.1 mmol,
1.4 equiv) and methanol was refluxed until compound 7 was
disappeared. After cooling to room temperature, the mixture was
filtered. The filtrate was evaporated under reduced pressure. The
resulting residue was applied to the top of an open-bed silica gel
column. The column was eluted with ethyl acetate. Fractions
containing the product were combined and evaporated under
reduced pressure to give the product 8.
Compound 8a. Yield 75%; mp 87 - 88°C. IR (KBr): 3050,
3010, 2950, 2920, 2850, 1630, 1600, 1570, 1490, 1450, 1430,
1370, 1330, 1270, 1220, 1140, 1080, 1050, 1040, 990, 820, 780,
1
730 cm-1; H NMR (CDCl3): ꢀ 0.88 (t, 3H, J = 6.5 Hz), 1.30 –
1.40 (m, 6H), 1.59 – 1.69 (m, 2H), 2.66 – 2.75 (m, 4H), 3.57 (t,
2H, J = 7.1 Hz), 3.87 (s, 3H), 5.30 (s, 2H), 6.82 (d, 1H, J = 8.5
Hz), 7.28 (d, 1H, J = 8.5 Hz), 7.51 (t, 1H, J = 7.4 Hz), 7.70 (t,
1H, J = 7.1 Hz), 7.81 (d, 1H, J = 8.1 Hz), 7.85 (d, 1H, J = 8.5
Hz), 8.06 (d, 1H, J = 8.4 Hz), 8.20 ppm (d, 1H, J = 8.5 Hz); 13C
NMR (CDCl3): ꢀ 14.1, 20.2, 22.6, 27.4, 29.3, 31.7, 36.1, 46.4,
55.6, 75.9, 109.4, 119.7, 122.1, 123.0, 126.4, 127.5, 127.6,
129.0, 129.6, 132.0, 136.7, 143.9, 147.4, 154.1, 158.3, 167.1
ppm; HRMS Calcd. for C26H30N2O2: 402.2307; Found:
402.2298. Anal. calcd. for C26H30N2O2: C, 77.58; H, 7.51; N,
6.96. Found: C, 77.62; H, 7.57; N, 7.02.
Compound 8b. Yield: 76%; mp oil. IR (KBr): 3090, 3030,
2920, 2850, 1620, 1600, 1570, 1490, 1450, 1370, 1330, 1280,
1
1220, 1150, 1080, 1000, 940, 870, 800, 710, 670 cm-1; H NMR
(CDCl3): ꢀ 0.61, (t, 3H, J = 6.2 Hz), 0.98 – 1.11 (m, 6H), 1.32 –

Jul-Aug 2007
A Facile Synthesis of 1-Alkyl-5-arylalkoxy-6-methoxy-3,4-dihydroisoquinolines
913
1.38 (m, 2H), 2.33 (t, 2H, J = 7.3 Hz), 2.43 (t, 2H, J = 7.0 Hz),
3.25 (t, 2H, J = 7.5 Hz), 3.63 (s, 3H), 6.57 – 6.61 (m, 1H), 6.99 –
7.04 (m, 2H), 7.51 (d, 1H, J = 7.8 Hz), 8.27 – 8.29 Hz (m, 1H),
8.39 ppm (s, 1H); 13C NMR (CDCl3): ꢀ 13.9, 19.9, 22.3, 25.2,
27.3, 28.8, 28.9, 31.2, 31.4, 35.2, 35.4, 45.5, 55.4, 71.7, 109.3,
122.4, 123.2, 131.8, 132.8, 135.9, 143.0, 148.0, 149.0, 149.2,
154.2, 167.4 ppm; HRMS Calcd. for C22H28N2O2: 352.2151;
Found: 352.2147. Anal. calcd. for C22H28N2O2: C, 74.97; H,
8.01; N, 7.95. Found: C, 75.02; H, 8.04; N, 7.98.
Compound 8g. Yield: 83%; mp oil. IR (KBr): 3070, 3030,
2950, 2850, 1620, 1600, 1570, 1490, 1460, 1370, 1330, 1270,
1210, 1080, 1000, 800, 740, 710 cm-1; 1H NMR (CDCl3): ꢀ 0.87
(t, 3H, J = 6.9 Hz), 1.25 – 1.33 (m, 14H), 1.58 – 1.67 (m, 2H),
2.57 (t, 2H, J = 7.2 Hz), 2.67 (t, 2H, J = 7.5 Hz), 3.50 (t, 2H, J =
6.9 Hz), 3.89 (s, 3H), 5.00 (s, 2H), 6.83 (d, 1H, J = 8.4 Hz), 7.26
– 7.29 (m, 2H), 7.76 (d, 1H, J = 7.5 Hz), 8.54 (d, 1H, J = 8.4
Hz), 8. 64 ppm (s,1H); 13C NMR (CDCl3): ꢀ 14.0, 20.0, 22.5,
27.2, 29.1, 29.2, 29.3, 29.4, 29.5, 31.7, 35.8, 46.1, 55.5, 71.8,
109.3, 122.1, 122.8, 123.2, 131.9, 132.9, 135.8, 143.1, 149.2,
149.4, 153.9, 166.9 ppm; HRMS Calcd. for C26H36N2O2:
408.2777; Found: 408.2785. Anal. calcd. for C26H36N2O2: C,
76.43; H, 8.88; N, 6.86. Found: C, 76.51; H, 8.90; N, 6.95.
Compound 8h. Yield: 80%; mp 51 – 52°C. IR (KBr): 3050,
2960, 2930, 1740, 1600, 1490, 1440, 1460, 1410, 1360, 1330,
Compound 8c. Yield: 62%; mp oil. IR (KBr): 3070, 3050,
2950, 2930, 2860, 2650, 1620, 1600, 1570, 1490, 1460, 1400,
1
1370, 1280, 1210, 1080, 1010, 830, 800, 740 cm-1; H NMR
(CDCl3): ꢀ 0.87 (t, 3H, J = 6.7 Hz), 1.20 – 1.35 (m, 6H), 1.53 –
1.61 (m, 2H), 2.54 (t, 2H, J = 7.5 Hz), 2.64 (t, 2H, J = 7.6 Hz),
3.44 (t, 2H, J = 7.1 Hz), 3.85 (s, 3H), 4.90 (s, 2H), 6.79 (d, 1H, J
= 8.6 Hz), 7.26 (d, 2H, J = 8.3 Hz), 7.38 (d, 1H, J = 8.3 Hz),
7.43 ppm (d, 2H, J = 8.6 Hz); 13C NMR (CDCl3): ꢀ 14.1, 20.2,
22.5, 22.6, 27.4, 29.3, 31.7, 36.0, 46.3, 55.7, 73.8, 109.4, 122.0,
122.1, 122.9, 129.9, 131.5, 132.2, 136.5, 143.5, 154.2, 167.2
ppm; HRMS Calcd. for C23H28BrNO2: 429.1303; Found:
429.1299. Anal. calcd. for C23H28BrNO2: C, 64.19; H, 6.56; N,
3.25. Found: C, 64.21; H, 6.60; N, 3.32.
Compound 8d. Yield: 71%; mp 85 - 86°C. IR (KBr): 3090,
3070, 3030, 3000, 2950, 2930, 2890, 2840, 1620, 1600, 1570,
1520, 1490, 1450, 1350, 1270, 1210, 1140, 1080, 990, 850, 810
cm-1; 1H NMR (CDCl3): ꢀ 0.88 (t, 3H, J = 6.9 Hz), 1.27 – 1.40 (m,
6H), 1.59 – 1.68 (m, 2H), 2.63 – 2.71 (m, 4H), 3.56 (t, 2H, J = 7.1
Hz), 3.92 (s, 3H), 5.10 (s, 2H), 6.87 (d, 1H, J = 8.5 Hz), 7.31 (d,
2H, J = 8.5 Hz), 7.64 (d, 2H, J = 8.5 Hz), 8.21 (d, 2H, J = 8.6 Hz);
13C NMR (CDCl3): ꢀ 14.0, 20.1, 22.5, 27.3, 29.2, 31.6, 36.0, 46.3,
55.7, 73.1, 109.4, 122.3, 123.0, 123.5, 131.9, 143.3, 145.1, 147.4,
153.9, 166.9 ppm; HRMS Calcd. for C23H28N2O4: 396.2049;
Found: 396.2056. Anal. calcd. for C23H28N2O4: C, 69.67; H, 7.12;
N, 7.07. Found: C, 69.70; H, 7.22; N, 7.11.
Compound 8e. Yield: 63%; mp oil. IR (KBr): 3060, 2930,
2850, 1770, 1710, 1620, 1600, 1570, 1490, 1430, 1390, 1270,
1220, 1080, 1020, 910, 740, 720 cm-1; 1H NMR (CDCl3): ꢀ 0.86
(t, 3H, J = 6.6 Hz), 1.23 – 1.36 (m, 6H), 1.54 – 1.62 (m, 2H),
2.57 – 2.65 (m, 4H), 3.49 (t, 2H, J = 7.1 Hz), 3.65 (s, 3H), 4.07 –
4.12 (m, 2H), 4.20 (t, 2H, J = 5.3 Hz), 6.71 (d, 1H, J = 8.5 Hz),
7.19 (d, 1H, J = 8.5 Hz), 7.71 – 7.75 (m, 2H), 7.85 - 7.88 ppm
(m, 2H); 13C NMR (CDCl3): ꢀ 14.0, 19.8, 22.5, 27.3, 29.2, 31.6,
36.0, 38.2, 46.2, 55.4, 69.4, 109.2, 121.9, 122.7, 123.2, 131.7,
132.1, 133.9, 143.7, 153.7, 167.0, 168.2 ppm; HRMS Calcd. for
C26H30N2O4: 434.2206; Found: 434.2206. Anal. calcd. for
C26H30N2O4: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.91; H,
7.02; N, 6.50.
Compound 8f. Yield: 77%; mp oil. IR (KBr): 3050, 2920,
2850, 1620, 1600, 1500, 1460, 1330, 1280, 1230, 1090, 880,
830, 790, 740 cm-1; 1H NMR (CDCl3): ꢀ 0.88 (t, 3H, J = 6.9 Hz),
1.16 – 1.30 (m, 14H), 1.46 – 1.62 (m, 3H), 1.79 – 1.89 (m, 1H),
2.57 – 2.63 (m, 1H), 2.85 – 3.00 (m, 2H), 3.18 -3.25 (m, 1H),
3.58 (s, 3H), 4.06 (s, 2H), 6.47 (d, 1H, J = 8.3 Hz), 6.59 (d, 1H, J
= 8.3 Hz), 7.41 (t, 1H, J = 7.7 Hz), 7.59 (t, 1H, J = 7.1 Hz), 7.71
(d, 1H, J = 8.1 Hz), 7.79 (d, 1H, J = 8.5 Hz), 8.06 (d, 1H, J = 8.5
Hz), 8.14 ppm (d, 1H, J = 8.5 Hz); 13C NMR (CDCl3): ꢀ 14.2,
18.6, 20.9, 22.8, 26.7, 29.5, 29.7, 29.8, 32.0, 36.6, 55.6, 60.1,
60.3, 61.1, 108.5, 118.2, 121.3, 121.6, 126.0, 127.4, 127.5,
129.0, 129.2, 132.1, 136.2, 143.2, 144.4, 147.4, 161.5, 170.9
ppm; HRMS Calcd. for C30H38N2O2: 458.2933; Found:
458.2930. Anal. calcd. for C30H38N2O2: C, 78.56; H, 8.35; N,
6.11. Found: C, 78.61; H, 8.39; N, 6.17.
1
1280, 1210, 1130, 1090, 1020, 840, 800, 740 cm-1; H NMR
(CDCl3): ꢀ 0.85 (t, 3H, J = 6.9 Hz), 1.24 – 1.37 (m, 14H), 1.56 –
1.65 (m, 2H), 2.56 (t, 2H, J = 7.1 Hz), 2.65 (t, 2H, J = 7.4 Hz),
3.50 (t, 2H, J = 7.0 Hz), 3.87 (s, 3H), 4.91 (s, 2H), 6.79 (d, 1H, J
= 8.5 Hz), 7.24 (d, 1H, J = 8.5 Hz), 7.26 – 7.34 ppm (m, 4H);
13C NMR (CDCl3): ꢀ 14.1, 20.2, 22.7, 27.4, 29.3, 29.4, 29.5,
29.6, 29.7, 31.9, 36.1, 46.4, 55.6, 73.7, 109.3, 122.0, 123.0,
128.5, 129.6, 132.3, 133.8, 136.0, 143.5, 154.1, 167.0 ppm;
HRMS Calcd. for C27H36ClNO2: 441.2435; Found: 441.2435.
Anal. calcd. for C27H36ClNO2: C, 73.36; H, 8.21; N, 3.17. Found:
C, 73.41; H, 8.42; N, 3.21.
Compound 8i. Yield: 59%; mp 80 – 81°C. IR (KBr): 3080,
3030, 2950, 2920, 2850, 1770, 1710, 1630, 1600, 1490, 1460,
1430, 1400, 1320, 1270, 1200, 1080, 1050, 1020, 990, 720 cm-1;
1H NMR (CDCl3): ꢀ 0.86 (t, 3H, J = 6.9 Hz), 1.24 – 1.35 (m,
14H), 1.54 – 1.63 (m, 2H), 2.57 – 2.65(m, 4H), 3.50 (t, 2H, J =
7.1 Hz), 3.64 (s, 3H), 4.08 (t, 2H, J = 5.5 Hz), 4.20 (t, 2H, J =
5.3 Hz), 6.70 (d, 1H, J = 8.5 Hz), 7.19 (d, 1H, J = 8.5 Hz), 7.75 –
7.69 (m, 2H), 7.83 – 7.87 ppm (m, 2H); 13C NMR (CDCl3):
ꢀ 14.1, 19.8, 22.6, 27.3, 29.3, 29.4, 29.5, 29.6, 29.7, 31.8, 36.0,
38.2, 46.2, 55.3, 69.4, 109.2, 121.8, 122.7, 123.1, 131.7, 132.1,
133.9, 143.7, 153.7, 167.0, 168.1 ppm; HRMS Calcd. for
C30H38N2O4: 490.2832; Found: 490.2828. Anal. calcd. for
C30H38N2O4: C, 73.44; H, 7.81; N, 5.71. Found: C, 73.49; H,
7.93; N, 5.76.
Compound 8j. Yield: 91%; mp oil. IR (KBr): 3060, 2930,
2850, 1770, 1710, 1620, 1600, 1570, 1490, 1440, 1400, 1370,
1
1340, 1270, 1220, 1080, 1050, 940, 900, 800, 720 cm-1; H
NMR (CDCl3): ꢀ 0.87 (t, 3H, J = 6.9 Hz), 1.29 – 1.41 (m, 14H),
1.59 – 1.69 (m, 2H),1.80 – 1.98 (m, 4H), 2.64 – 2.71(m, 4H),
3.58 (t, 2H, J = 7.4 Hz), 3.78 (t, 2H, J = 7.1 Hz), 3.88 (s, 3H),
3.95 (t, 2H, J = 5.9 Hz), 6.79 (d, 1H, J = 8.5 Hz), 7.24 (d, 1H, J
= 8.5 Hz), 7.69 – 7.72 (m, 2H), 7.81 – 7.84 ppm (m, 2H); 13C
NMR (CDCl3): ꢀ 14.1, 19.9, 20.9, 22.6, 25.3, 27.4, 27.6, 29.2,
29.3, 29.4, 31.8, 36.0, 37.6, 46.4, 55.5, 60.2, 72.1, 109.2, 121.7,
122.9, 123.0, 132.0, 132.1, 133.8, 144.0, 154.2, 167.1, 168.3,
170.9 ppm; HRMS Calcd. for C32H42N2O4: 518.3145; Found:
518.3142. Anal. calcd. for C32H42N2O4: C, 74.10; H, 8.16; N,
5.40. Found: C, 74.18; H, 8.21; N, 5.47.
Compound 8k. Yield: 71%; mp 92 – 93 °C. IR (KBr): 3070,
2920, 2850, 1670, 1610, 1570, 1490, 1450, 1390, 1280, 1210,
1
1080, 860, 750 cm-1; H NMR (CDCl3): ꢀ 0.88 (t, 3H, J = 5.6
Hz), 1.26 – 1.36 (m, 14H), 1.58 – 1.67 (m, 2H), 2.64 (t, 2H, J =
7.5 Hz), 2.72 (t, 2H, J = 7.5 Hz), 3.65 (t, 2H, J = 7.2 Hz), 3.87
(s, 3H), 5.85 (s, 2H), 6.94 (d, 1H, J = 8.6 Hz), 7.34 (s, 1H), 7.49
ppm (d, 1H, J = 8.6 Hz); 13C NMR (CDCl3): ꢀ 14.1, 19.7, 22.7,
27.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.9, 36.0, 45.7, 56.2, 58.3,

914
H.-S. Yim, H.-K. Kim, J.-J. Kim, D.-H. Kweon, S.-G. Lee, J.-H. Kim and Y.-J. Yoon
Vol 44
[2a] Cho, S. D.; Park, Y. D.; Kim, J. J.; Joo, W. H.; Shiro M.;
Esser, L.; Falck, J. R.; Ahn, C.; Shin, D. S.; Yoon, Y. J. Tetrahedron
2004, 60, 3763. [b] Cho, S. D.; Song, S. Y.; Hur, U. J.; Joo, W. H.;
Falck, J. R.; Yoon, Y. J.; Shin, D. S. Tetrahedron Lett. 2001, 42, 6251.
[c] Cho, S. D.; Kweon, D. H.; Kang, Y. J.; Lee, S. G.; Lee, W. S.; Yoon,
Y. J. J. Heterocyclic Chem. 1999, 36, 1151. [d] Cho, S. D.; Kim, S. K.;
Chung, H. –A; Kang, Y. J.; Yoon, Y. J. J. Heterocyclic Chem. 1999, 36,
75. [e] Cho, S. D.; Kim, S. K.; Yoon, Y. J. J. Heterocyclic Chem. 1998,
35, 77. [f] Chang, K. C.; Ko, H. J., Cho, S. D.; Yoon, Y. J.; Kim, J. H.
Eur. J. Pharmacol. 1993, 236, 51.
109.8, 117.2, 123.2, 124.9, 129.9, 131.8, 137.5, 152.4, 153.9,
157.8, 166.4 ppm; HRMS Calcd. for C25H33Cl2N3O3: 493.1899;
Found: 493.1899. Anal. calcd. for C25H33Cl2N3O3: C, 60.73; H,
6.73; N, 8.50. Found: C, 60.76; H, 6.80; N, 8.56.
Acknowledgments. This work was supported by a grant from
the Korea Science and Engineering Foundation (KOSEF) to the
Environmental Biotechnology National Core Research Center
(grant #: R15-2003-012-02001-0).
[3a] Samma, M. The Isoquinoline Alkaloids, Chemistry and
Pharmacology, Organic Chemistry A Series of Monographs vol. 25,
Academic Press, New York, 1972. [b] Kametani, T. The Total Syntheses
of Isoquinoline Alkaloids in The Total Synthesis of Natural Products, vol
3. ed. by ApSimon, J. John Wiely & Sons, New York, 1977.
[4a] Ziolkowski, M.; Czarnocki, Z. Tetrahedron Lett. 2000, 41,
1963. [b] Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc. 1989,
111, 4859. [c] Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett.
1995, 36, 6709.
REFERENCES
[1a] Kanemitsu, T.; Yamashita, Y.; Nagata, K.; Itoh, T. Synlett
2006, 1595. [b] Kaufman, T. S. Synthesis, 2005, 339. [c] Bracca, A. B. J.;
Kaufman, T. S. Tetrahedron 2004, 60, 10575. [d] Kaufman T. S.
Tetrahedron Asymmetry 2004, 15, 1203. [e] Chrzanowska, M.;
Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341. [f] Ankabe, E.;
Vicario, J. L.; Badia, D.; Carrillo, L.; Yoldi, V. Eur. J. Org. Chem. 2001,
4343. [g] Rozwadowska, M. D. Heterocycles 1994, 39, 903. [h]
McNaught, K. S.; Carrupt, P. A.; Altomare, C.; Cellamare, S.; Carotti, A.;
Testa, B.; Jenner, P.; Marsden, C. D. Biochem. Pharmacol. 1998, 56, 921.
[i] Yamakawa, T.; Ohta, S. Biochem. Biophys. Res. Commun. 1997, 236,
676. [j] Nagatsu, T. Neurosci. Res. 1997, 29, 99. [k] Thull, U.; Kneubuler,
S.; Gaillard, P.; Carrupt, P. A.; Testa, B.; Altomare, C.; Carotti, A.; Jenner,
P.; McNaught, K. S. P. Biochem. Pharmacol. 1995, 50, 869.
[5] Chung, H. –A; Kweon, D. H.; Kang, Y. J.; Park, J. W.; Yoon,
Y. J. J. Heterocyclic Chem. 1999,
36, 905.
[6] Lin, C.-F.; Yang, J.-S.; Chang, C.-Y.; Kuo, S.-C.; Lee, M.-R.;
Hung, L. –J. Bioorg. Med. Chem.
2005, 13, 1537.