New synthesis of 1-[(3,4-dimethoxyphenyl)methoxymethyl]-6,7-dimethoxyisoquinoline (setigerine), a naturally occurring alkaloid, and some derivatives of papaverine

Article abstract of DOI:10.1016/j.tet.2008.11.077

A novel and improved synthetic route for the preparation of the new alkaloid setigerine, isolated from Papaver setigerum DC, and some new 3,4-dihydropapaverine and papaverine derivatives is reported. This method is based on the side chain chlorination of 1-benzyl-3,4-dihydroisoquinolines using N-chlorosuccinimide (NCS) and subsequent reaction with sodium methoxide in methanol to give the corresponding isoquinolines.

Full text of DOI:10.1016/j.tet.2008.11.077

Tetrahedron 65 (2009) 1188–1192
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Tetrahedron
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New synthesis of 1-[(3,4-dimethoxyphenyl)methoxymethyl]-6,7-
dimethoxyisoquinoline (setigerine), a naturally occurring alkaloid,
and some derivatives of papaverine
Jan Jacobs a, Nguyen van Tuyen a, Peter Markusse a, Christian V. Stevens a, Leendert Maat b,
,
Norbert De Kimpe a
*
a Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, B-9000 Ghent, Belgium
b Laboratory for Biocatalysis and Organic Chemistry, Department of Biotechnology, Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and improved synthetic route for the preparation of the new alkaloid setigerine, isolated from
Papaver setigerum DC, and some new 3,4-dihydropapaverine and papaverine derivatives is reported. This
method is based on the side chain chlorination of 1-benzyl-3,4-dihydroisoquinolines using N-chloro-
succinimide (NCS) and subsequent reaction with sodium methoxide in methanol to give the corre-
sponding isoquinolines.
Received 19 September 2008
Received in revised form 13 November 2008
Accepted 20 November 2008
Available online 27 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Setigerine
Papaverine
Isoquinolines
1-(Dimethoxyaryl)methylisoquinolines
1. Introduction
Since papaverine 1 and some of its derivatives are known to
exhibit interesting biological activities, such as muscle relaxation,6
The isoquinoline nucleus is the core of an important family of
alkaloids.1 1-Substituted isoquinolines are the most important
members of this isoquinoline family, which are either naturally
occurring alkaloids or intermediates in both organic synthesis and
biosynthesis.2 Examples include protoberberines, aporphines, and
papaverines. These kinds of alkaloids have interesting biological
activities and many of them have found a therapeutical use.3 In the
past, several novel naturally occurring papaverine isoquinolines 2
(setigerine) and 3 (setigeridine) have been isolated from Papaver
setigerum DC,4 while isoquinolines 4 (fumaflorine) and 5 were
isolated from Fumaria densiflora DC.5
hepatoxicity, and antimalarial activity,7 the modification of
papaverine has been attractive in organic synthesis.8 In the past,
the naturally occurring papaverine derivative setigerine 2 was
synthesized by methylation of papaverinol with iodomethane
in 18% yield.9 Recently, we identified 1-(1,1-dichloroalkyl)- and
1-(trichloromethyl)-3,4-dihydroisoquinoline to be suitable sources
for the synthesis of functionalized isoquinolines. These promising
results initiated us to develop a new convenient method for the
synthesis of setigerine 2 and 3,4-dihydrodimethoxypapaverine
derivatives from 1-(a,a-dichloroaryl)methyl-3,4-dihydroisoquino-
lines via a 1,4-dehydrochlorination protocol.
MeO
MeO
MeO
MeO
MeO
N
N
N
MeO
COOR
OMe
OMe
O
O
O
R
MeO
O
O
1 R = H (Papaverine)
2 R = OMe (Setigerine)
4 R = H (Fumaflorine)
5 R = Me
3 (Setigeridine)
* Corresponding author. Tel.: þ32 9 264 59 51; fax: þ32 9 264 62 43.
E-mail address: norbert.dekimpe@ugent.be (N. De Kimpe).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.11.077

J. Jacobs et al. / Tetrahedron 65 (2009) 1188–1192
1189
2. Results and discussion
(Scheme 2). The mechanism of the aromatization of 1-(alkyl-
dichloromethyl)-3,4-dihydroisoquinolines to isoquinolines
8
9
3,4-Dihydroisoquinolines 7a–c10 were synthesized in 69–76%
yield from N-2-arylethyl amides 6a,b by the Bischler–Napieralski
reaction involving a cyclocondensation with polyphosphoric acid in
toluene under reflux for 3–10 h (Scheme 1). The cyclization of
amide 6c was performed with an excess of POCl3 in boiling
dichloromethane for 16 h, followed by treatment with a 40 wt %
aqueous solution of sodium hydroxide to give 3,4-dihydro-
isoquinoline 7c in 73% yield. Isoquinolines 7a–c were treated
with 2 equiv of N-chlorosuccinimide (NCS) in a 1:1 mixture of
dichloromethane and carbon tetrachloride at room temperature for
concerns a 1,4-dehydrochlorination, followed by tautomerization
and subsequent nucleophilic substitution of the remaining chlorine
by methoxide (Scheme 3). However, under the above mentioned
reaction conditions substrates 8a–c underwent also double
nucleophilic substitution to iminoacetals 10a–c in a competitive
reaction.
In order to increase the yield of setigerin 2, 1-[dichloro-(3,4-
dimethoxyphenyl)methyl]-3,4-dihydro-6,7-dimethoxyisoquinoline
8c was reacted with 3 equiv of 5 M sodium methoxide in methanol
under reflux for 3 h, resulting in the isolation of setigerin 2 in 60%
yield. 3,4-Dihydroisoquinoline 10c was also obtained in 10% yield,
showing the pronounced tendency of such double benzylic and
heteroallylic dichlorides 8c to solvolyse (Scheme 4).
1–4 h to give 1-(a,a-dichloroarylmethyl)-3,4-dihydroisoquinolines
8a–c in excellent yield (77–97%). These novel compounds 8a–c
decomposed rapidly upon contact with silica gel during column
chromatography, therefore they were immediately used in the next
step without purification.
In order to underline the necessary role of the base in the aro-
matization reaction to isoquinolines 2 and 9a,b and to prove the
Since we found that 1-(
a,
a
-dichloroalkyl)-3,4-dihydroiso-
tendency of
a,a-dichloroimines 8a–c for methanolysis, 1-(aryldi-
quinolines can be conveniently converted into functionalized
isoquinolines by treatment with different bases, this method was
applied for the synthesis of the natural product setigerine 2. In
order to develop this method for the functionalization of 1-(aryl-
dichloromethyl)-3,4-dihydroisoquinolines, compounds 8a,b were
treated with 5 equiv of a 2 M solution of sodium methoxide in
methanol under reflux for 3 h. Under these reaction conditions, the
isoquinoline derivatives 9a,b were obtained in 60–81% yield and
setigerine 2 was obtained in only 15% yield. In addition, some
1-(aryldimethoxymethyl)-3,4-dihydropapaverine derivatives 10a,b
were also obtained in 10–16% yield, and 10c in 74% yield
chloromethyl)-3,4-dihydroisoquinolines 8a,b were treated with
2 equiv of triethylamine in boiling methanol for 3 h. Products 10a,b
were obtained in excellent yield (82–96%) (Scheme 5), proving the
methanolysis tendency and the absence of aromatization products
9a,b.
In conclusion, based on the Bischler–Napieralski reaction and
subsequent dichlorination, several 3,4-dihydroisoquinolines 8a–c
were either converted into isoquinolines 9 or iminoacetals 10
depending on the concentration of sodium methoxide in methanol.
This reaction was applied to an efficient synthesis of the isolated
natural product setigerine 2.
MeO
H
A: 3 equiv. P2O5
MeO
MeO
N
R1
R2
Toluene, Δ, 3-10 h
N
MeO
O
B: (1) 27 equiv. POCl3
CH2Cl2, Δ, 16 h
R1
R2
(2) excess 40 wt% aq. NaOH
Δ, 30 min
7a R1 = R2 = H (A, 76%)
6a R1 = R2 = H
7b R1 = OMe, R2 = H (A, 69%)
6b R1 = OMe, R2 = H
6c R1 = OMe, R2 = OMe
7c R1 = OMe, R2 = OMe (B, 73%)
2 equiv. NCS
CH2Cl2/CCl4 (1:1),
rt, 1-4 h
MeO
N
MeO
R1
R2
Cl
Cl
8a R1 = R2 = H (93%)
8b R1 = OMe, R2 = H (97%)
8c R1 = OMe, R2 = OMe (77%)
Scheme 1.
MeO
MeO
MeO
MeO
MeO
5 equiv. NaOMe 2 M
+
N
N
N
MeOH, Δ, 3 h
MeO
R1
R1
R1
R2
Cl
MeO
MeO
MeO
Cl
R2
R2
8a R1 = R2 = H
9a ( 60%)
9b (81%)
2 (15%)
10a (11%)
10b (16%)
10c (74%)
8b R1 = OMe, R2 = H
8c R1 = OMe, R2 = OMe
Scheme 2.

1190
J. Jacobs et al. / Tetrahedron 65 (2009) 1188–1192
MeO
MeO
H
MeO
MeO
MeO
MeO
MeO
NaOMe
2 equiv. Et3N
MeOH, Δ, 3 h
N
N
N
N
MeO
R1
R2
R1
R1
R1
R2
MeO
MeO
Cl
Cl
Cl
11
Cl
Cl
R2
R2
8
8a R1 = R2 = H
10a (96%)
10b (82%)
8b R1 = OMe, R2 = H
2 x SN
MeOH
tautomerization
MeO
Scheme 5.
MeO
MeO
N
N
N
MeO
was added cautiously until the pH of the aqueous phase was basic
and the resulting mixture was boiled under reflux for 30 min. The
reaction mixture was poured in water and extracted with
dichloromethane. The combined extracts were washed with water,
dried (MgSO4), and evaporated in vacuo to give 400 mg (80%) of the
crude product 7c, which was purified by column chromatography
on silica gel using 4% triethylamine in ethyl acetate in 73% yield. The
spectral data of 3,4-dihydroisoquinoline 7c were in accordance
with the data in the literature.11
R1
R2
R1
R2
MeO
MeO
Cl
12
10
SN
MeO
MeOH
MeO
R1
R2
MeO
3.2.2.1. 1-(3-Methoxyphenyl)methyl-3,4-dihydro-6,7-dimethoxyiso-
9
quinoline (7b). White powder, mp 75–78 ꢀC. 1H NMR (CDCl3):
Scheme 3.
d
2.65 (2H, t, J¼7.6 Hz, H-4), 3.71–3.77 (2H, m, CH2–N]), 3.73 (3H, s,
OMe), 3.77 (3H, s, OMe), 3.87 (3H, s, OMe), 4.02 (2H, s, CH2), 6.65
(1H, s, H-5), 6.73 (1H, dd, J¼8.3, 2.3 Hz, H-40), 6.86 (1H, s, H-20), 6.90
(1H, dd, J¼7.6, 2.3 Hz, H-60), 6.97 (1H, s, H-8), 7.19 (1H, dd, J¼8.3,
3. Experimental part
3.1. General
7.6 Hz, H-50). 13C NMR (CDCl3):
d 25.8 (C-4), 43.6 (CH2–Ar), 47.2
(CH2–N¼), 55.1 (OMe), 55.9 (OMe), 56.0 (OMe), 109.6 (C-5), 110.2
(C-8), 111.8 (C-20), 114.2 (C-40), 121.1 (C-60), 121.6 (C-8a), 129.5 (C-50),
131.8 (C-4a), 139.8 (C-10), 147.2 (C-7), 150.7 (C-6), 159.8 (C-30), 165.3
(C-1). IR (NaCl): nmax 1640, 1600, 1561, 1514, 1460, 1340, 1300, 1280,
1150, 1040 cmꢁ1. MS m/z (%): 311 (Mþ, 70), 310 (100), 296 (21), 280
(37), 265 (9), 156 (7), 140 (10). Anal. Calcd for C19H21NO3: C 73.29%,
H 6.80%, N 4.50%; found: C 73.18%, H 6.88%, N 4.36%.
1H HMR (270 MHz) and 13C NMR (67 MHz) spectra were recor-
ded with a Jeol JNM-EX 270 NMR spectrometer. IR spectra were
measured with a Perkin Elmer model 983 spectrophotometer. Mass
spectra were recorded with a Varian-MAT 112 mass spectrometer
(70 eV). Melting points were measured with a Buchi 535 apparatus.
3.2. Synthesis of 1-(arylmethyl)-3,4-dihydro-6,7-
dimethoxyisoquinolines 7a–c
3.3. Synthesis of 1-(aryldichloromethyl)-3,4-dihydro-6,7-
dimethoxyisoquinolines 8a–c
3.2.1. Procedure A
Polyphosphoric acid was obtained from 85% phosphoric acid
and P2O5 (1:1 w/w). To a solution of 1.0 mmol of carboxylic amides
6a and 6b in 30 ml of toluene, 3 mmol of polyphosphoric acid was
added dropwise. The reaction mixture was refluxed for 3–10 h.
Then, this mixture was poured into ice water and extracted three
times with CH2Cl2. The combined extracts were washed with
NaHCO3 (5%), dried (MgSO4), and evaporated in vacuo to give 3,4-
dihydroisoquinolines 7a and 7b in 76% and 69% yield, respectively.
The spectral data of 3,4-dihydroisoquinoline 7a were in accordance
with the literature.10a
3.3.1. General procedure
A vigorously stirred solution of 1.78 mmol of compound 7 in
40 ml of a 1:1 mixture of CH2Cl2 and CCl4 was treated with 473 mg
(3.56 mmol) of N-chlorosuccinimide, after which the reaction
mixture was stirred at room temperature for 1–4 h. The reaction
mixture was poured in water and extracted three times with
CH2Cl2. The combined extracts were washed with NaHCO3 (5%) and
brine, dried (MgSO4), and evaporated in vacuo to give crude
products 8a–c (purity >95%). Compounds 8a–c decomposed upon
contact with silica gel during column chromatography and were
used as such in the next step.
3.2.2. Procedure B
A solution of 1.0 g (2.8 mmol) of carboxylic amide 6c10b in 60 ml
of CH2Cl2 was treated with an excess of POCl3 (7.0 ml, 75.2 mmol) at
reflux for 16 h. Then, a 40 wt % aqueous sodium hydroxide solution
3.3.1.1. 1-(
a
,
a
-Dichlorobenzyl)-3,4-dihydro-6,7-dimethoxyisoquino-
2.64–
line (8a). Crude yield: 93%, colorless oil. 1H NMR (CDCl3):
d
2.80 (2H, m, CH2), 3.39 (3H, s, OMe), 3.83 (3H, s, OMe), 3.96 (2H, t,
MeO
+
MeO
OMe
MeO
MeO
MeO
MeO
3 equiv. NaOMe 5 M
N
N
N
MeOH, Δ, 3 h
OMe
OMe
OMe
OMe
MeO
MeO
Cl
MeO
Cl
OMe
2 (60%)
10c (10%)
8c
(Setigerine)
Scheme 4.

J. Jacobs et al. / Tetrahedron 65 (2009) 1188–1192
1191
J¼7.6 Hz, CH2–N), 6.57 (1H, s, H-5), 6.67 (1H, s, H-8), 7.19–7.37 (3H,
m, H-30, H-40, and H-50), 7.68 (2H, d, J¼7.6 Hz, H-20 and H-60). 13C
CH2Cl2. The combined extracts were washed with 2 M hydrochloric
acid, brine, water, and dried (MgSO4). The solvent was removed in
vacuo and the reaction crudes were purified by flash chromatog-
raphy on silica gel (EtOAc/MeOH 4:1) to give pure compounds
10a,b.
NMR (CDCl3):
d 25.8 (C-4), 48.0 (C-3), 55.4 (OMe), 55.7 (OMe), 91.2
(ArCCl2), 110.0 (C-5), 111.5 (C-8), 117.7 (C-8a), 125.8 (C-20 and C-60),
128.7 (C-30 and C-50), 129.2 (C-40), 132.9 (C-4a), 142.2 (C-10), 146.2
(C-7), 150.6 (C-6), 162.1 (C-1). IR (NaCl): nmax 1604, 1570, 1520,
1280 cmꢁ1. MS m/z (%): 349/351/353 (Mþ, 8), 314/316 (100), 264
(18), 186 (17), 139 (36).
3.4.3.1. 1-(
a
-Methoxybenzyl)-6,7-dimethoxyisoquinoline
(9a).
Compound 9a was synthesized in 60% yield according to method
A (Section 3.4.1); white powder, mp 94–96 ꢀC. 1H NMR (CDCl3):
3.3.1.2. 1-[
dimethoxyisoquinoline (8b). Crude yield 97%, colorless oil. 1H NMR
(CDCl3):
a
,
a
-Dichloro-(3-methoxyphenyl)methyl]-3,4-dihydro-6,7-
d 3.49 (3H, s, OMe), 3.84 (3H, s, OMe), 3.94 (3H, s, OMe), 5.92 (1H,
s, CHOMe), 7.01 (1H, s, H-5), 7.16–7.21 (1H, m, H-40), 7.25–7.30 (2H,
d
2.74 (2H, t, J¼7.8 Hz, CH2), 3.40 (3H, s, OMe), 3.77 (3H, s,
m, H-30and H-50), 7.45–7.49 (3H, m, H-20, H-4, and H-60), 7.70 (1H, s,
OMe), 3.87 (3H, s, OMe), 3.98 (2H, t, J¼7.8 Hz, CH2–N), 6.62 (1H, s,
H-8), 8.41 (1H, m, H-3). 13C NMR (CDCl3):
d 55.8 (OMe), 55.9
H-5), 6.68 (1H, s, H-8), 6.68–6.90 (1H, m, H-40), 7.23–7.30 (2H, m, H-
(OMe), 57.4 (OMe), 87.7 (CHOMe), 104.8 (C-5), 105.0 (C-8), 119.8
(C-4),122.0 (C-8a),126.0 (C-20 and C-60), 127.2 (C-40),128.1 (C-30 and
C-50), 134.1 (C-4a), 140.5 (C-3), 140.9 (C-10), 149.4 (C-7), 152.4 (C-6),
60 and H-50), 7.27 (1H, m, H-20). 13C NMR (CDCl3):
d 25.8 (C-4), 48.0
(C-3), 55.3 (OMe), 55.5 (OMe), 58.8 (OMe), 90.8 (ArCCl2), 109.9 (C-
5), 111.4 (C-8), 111.9 (C-20), 114.6 (C-40), 117.8 (C-8a), 118.1 (C-60),
129.8 (C-50), 133.0 (C-4a), 143.6 (C-10), 146.3 (C-7), 150.7 (C-6), 159.8
(C-30), 162.1 (C-1). IR (NaCl): nmax 1600, 1515, 1257, 1150 cmꢁ1. MS
m/z (%): no Mþ, 344/346 (MþꢁCl, 100), 309 (79), 294 (29), 266 (12),
265 (11), 172 (16), 133 (18).
157.1 (C-1). IR (KBr): nmax 2940, 1560, 1505, 1480, 1255, 1160 cmꢁ1
.
MS m/z (%): 309 (Mþ, 59), 294 (82), 297 (100), 262 (18), 188 (15).
Anal. Calcd for C19H19NO3: C 73.77%, H 6.19%, N 4.53%; found: C
73.65%, H 6.08%, N 4.66%.
3.4.3.2. 1-[Methoxy-(3-methoxyphenyl)methyl]-6,7-dimethoxyiso-
quinoline (9b). Compound 9b was synthesized in 81% yield
according to method A (Section 3.4.1); colorless oil. 1H NMR
3.3.1.3. 1-[
6,7-dimethoxyisoquinoline (8c). Crude yield 77%, colorless oil. 1H
NMR (CDCl3): 2.69–2.74 (2H, m, CH2), 3.45 (3H, s, OMe), 3.81
a,a-Dichloro-(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-
d
(CDCl3): d 3.48 (3H, s, OMe), 3.72 (3H, s, OMe), 3.86 (3H, s, OMe),
(3H, s, OMe), 3.86 (3H, s, OMe), 3.96 (3H, s, OMe), 3.87–3.96 (2H,
3.95 (3H, s, OMe), 5.89 (1H, s, CHOMe), 6.72–6.76 (1H, m, H-40), 7.01
(1H, s, H-5), 7.04–7.07 (1H, m, H-60), 7.07–7.11 (1H, m, H-20), 7.16–
7.22 (1H, m, H-50), 7.46 (1H, m, H-4), 7.73 (1H, s, H-8), 8.41 (1H, m,
m, CH2–N), 6.64–6.75 (4H, m, 4ꢂ]CH), 7.88 (1H, s, ]CH). 13C
NMR (CDCl3):
d 25.2 (C-4), 47.4 (C-3), 55.5 (OMe), 55.7 (OMe), 56.1
(OMe), 56.3 (OMe), 89.7 (ArCCl2), 110.0 (]CH), 110.2 (]CH), 111.2
(]CH), 114.1 (]CH), 117.1 (]CH), 130.6 (]Cquat), 133.6 (]Cquat),
137.7 (]Cquat), 146.1 (]Cquat), 147.1 (]Cquat), 149.9 (]Cquat), 151.1
(]Cquat), 163.2 (C-1). IR (NaCl): nmax 1639, 1601, 1510, 1275,
1215 cmꢁ1. MS m/z (%): 409/411/413 (Mþ, 9), 407 (13), 373 (9), 372
(16), 134 (14), 133 (12), 120 (9), 119 (31), 105 (24), 99 (96), 56
(100).
H-3). 13C NMR (CDCl3):
d
55.1 (OMe), 55.9 (2ꢂOMe), 57.4 (OMe),
87.5 (CHOMe), 104.5 (C-5), 105.0 (C-8), 111.8 (C-20), 112.6 (C-40),
118.4 (C-60), 119.8 (C-4),122.0 (C-8a),129.1 (C-50),134.1 (C-4a),140.5
(C-3), 142.6 (C-10), 149.4 (C-7), 152.4 (C-6), 157.0 (C-30), 159.6 (C-1).
IR (NaCl): nmax 2930, 1590, 1505, 1480, 1255, 1160 cmꢁ1. MS m/z (%):
339 (Mþ, 84), 324 (100), 309 (88), 294 (26), 262 (18), 188 (18), 119
(28). Anal. Calcd for C20H21NO4: C 70.78%, H 6.24%, N 4.13%; found:
C 70.65%, H 6.16%, N 4.28%.
3.4. Reaction of 1-(aryldichloromethyl)-3,4-dihydro-6,7-
dimethoxyisoquinolines 8 with sodium methoxide:
general procedure
3.4.3.3. 1-[Methoxy-(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyiso-
quinoline (Setigerin) (2). Compound 2 was obtained in 15% and
60% yield according to method A and method B (Sections 3.4.1
and 3.4.2), respectively. Mp 148–150 ꢀC (from MeOH) (Ref. 4: 151 ꢀC
and Ref. 9: 145 ꢀC). 1H NMR data were in accordance with the data
reported in the literature.9 Other experimental properties are as
follows.
3.4.1. Method A
A solution of 1 mmol of crude compounds 8 was reacted with
2.5 ml (5 mmol) of 2 M NaOMe in methanol at reflux for 3 h. The
reaction mixture was poured in water and extracted with CH2Cl2.
The combined extracts were washed with 2 M hydrochloric acid,
brine, and water, respectively, and dried (MgSO4). After filtration,
the solvent was removed in vacuo and the reaction crudes were
purified by flash chromatography on silica gel (EtOAc/MeOH 9:1) to
give pure products 9 and 10.
13C NMR (CDCl3):
d
55.7 (4ꢂOMe), 55.8 (OMe), 86.9 (CHOMe),
104.3 (C-5), 104.9 (C-8), 109.5 (C-20), 110.5 (C-60), 118.5 (C-50), 119.54
(C-4), 121.9 (C-4a), 133.4 (C-8a), 133.9 (C-10), 140.4 (C-30), 148.1
(]Cquat), 148.7 (]Cquat), 149.3 (]Cquat), 152.3 (]Cquat), 156.9 (C-1).
IR (KBr): nmax 1613, 1585, 1560, 1502, 1473, 1458, 1428, 1413, 1368,
1156, 1096, 1026 cmꢁ1. MS m/z (%): 369 (Mþ, 10), 354 (16), 339 (8),
235 (11), 220 (10), 189 (14), 119 (16), 103 (21), 73 (26), 59 (100).
Anal. Calcd for C21H23NO5: C 68.28%, H 6.28%, N 3.79%; found: C
68.14%, H 6.31%, N 3.75%.
3.4.2. Method B
A solution of 1 mmol of the crude a,a-dichloro-3,4-dihydro-6,7-
dimethoxyisoquinoline 8c in 0.6 ml (3 mmol) of 5 M NaOMe in
methanol was boiled under reflux for 3 h. The reaction mixture was
extracted three times with CH2Cl2 and the combined extracts were
subsequently washed with 2 M hydrochloric acid, brine, and water.
After drying over MgSO4 and filtration, the solvent was removed in
vacuum. The reaction crude was purified by flash chromatography
on silica gel (EtOAc/MeOH 4:1) to give compound 2 (60% yield) and
compound 10c (10% yield).
3.4.3.4. 1-[(a,a-Dimethoxybenzyl)]-3,4-dihydro-6,7-dimethoxyiso-
quinoline (10a). Compound 10a was synthesized in 11% and 96%
yield according to method A and method C (Sections 3.4.1 and
3.4.3), respectively; colorless oil. 1H NMR (CDCl3):
d 2.63 (2H, t,
J¼7.5 Hz, CH2), 3.17 (6H, s, C(OMe)2), 3.63 (3H, s, OMe), 3.83 (3H, s,
OMe), 3.85–3.91 (2H, m, CH2N), 6.59 (1H, s, H-5), 7.26 (1H, s, H-8),
7.25–7.34 (3H, m, 3ꢂ]CH), 7.66–7.69 (2H, m, 2ꢂ]CH). 13C NMR
3.4.3. Method C
(CDCl3):
d
25.9 (C-4), 47.6 (C-3), 49.4 (2ꢂOMe), 55.8 (2ꢂOMe), 101.9
To a solution of 1 mmol of the crude products 8a,b in 3 ml of
methanol was added dropwise 0.21 g (3 mmol) of triethylamine
and the reaction mixture was refluxed for 3 h. This mixture was
poured in cold water, after which it was extracted three times with
(C(OMe)2), 109.7 (C-5), 111.6 (C-8), 119.5 (C-8a), 126.9 (2ꢂ]CH),
128.1 (2ꢂ]CH), 128.3 (]CH), 132.2 (C-4a), 139.6 (C-10), 146.6 (C-7),
150.2 (C-6), 163.8 (C-1). IR (NaCl): nmax 1607, 1570, 1516, 1467,
1275,1213, 1018 cmꢁ1. MS m/z (%): 341 (Mþ, 7), 326 (23), 311 (12),

1192
J. Jacobs et al. / Tetrahedron 65 (2009) 1188–1192
396 (11), 151 (100), 105 (21). Anal. Calcd for C20H23NO4: C 70.36%, H
6.79%, N 4.10%; found: C 70.52%, H 6.92%, N 4.29%.
1564, 1507, 1457, 1402, 1265, 1207, 1109, 1025 cmꢁ1. MS m/z (%): 401
(Mþ, 9), 386 (22), 369 (26), 355 (22), 354 (56), 324 (25), 336 (11),
212 (12), 211 (100), 196 (20), 165 (34), 151 (23). Anal. Calcd for
C22H27NO6: C 65.82%, H 6.78%, N 3.49%; found: C 65.68%, H 6.65%,
N 3.63%.
3.4.3.5. 1-[Dimethoxy-(3-methoxyphenyl)methyl]-3,4-dihydro-6,7-di-
methoxyisoquinoline (10b). Compound 10b was synthesized in
16% and 82% yield according to method A and method C (Sections
3.4.1 and 3.4.3), respectively; colorless oil. 1H NMR (CDCl3):
d 2.62
Acknowledgements
(2H, t, J¼7.5 Hz, CH2), 3.17 (6H, s, C(OMe)2), 3.66 (3H, s, OMe), 3.76
(3H, s, OMe), 3.84 (3H, s, OMe), 3.85–3.90 (2H, m, CH2N), 6.59 (1H, s,
H-5), 6.78–6.82 (1H, m, H-40), 7.19–7.26 (3H, m, 3ꢂ]CH), 7.30 (1H,
The authors are indebted to the ‘Research FoundationdFlanders
(FWO-Vlaanderen)’ for financial support of this research.
s, H-8). 13C NMR (CDCl3):
d
25.9 (C-4), 47.5 (C-3), 49.4 (2ꢂOMe),
55.2 (OMe), 55.8 (2ꢂOMe), 101.7 (C(OMe)2), 109.7 (C-5), 110.6 (C-8),
112.5 (C-20), 113.8 (C-40), 119.4 (C-60), 119.6 (C-8a), 129.1 (C-50), 132.2
(C-4a), 141.3 (C-10), 146.6 (C-7), 150.2 (C-6), 159.5 (C-30), 163.8 (C-1).
IR (NaCl): nmax 1605,1570,1516,1470,1402,1275,1018 cmꢁ1. MS m/z
(%): 371 (Mþ, 14), 356 (29), 341 (11), 326 (14), 207 (15), 196 (25), 181
(100), 165 (23), 135 (19). Anal. Calcd for C21H25NO5: C 67.91%, H
6.78%, N 3.77%; found: C 67.78%, H 6.68%, N 3.89%.
References and notes
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1972.
2. Meuzelaar, G. J.; Neeleman, E.; Maat, L.; Sheldon, R. A. Eur. J. Org. Chem. 1998,
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3. Brochmann-Hanssen, E. Pharmacognosy and Phytochemistry; Springer: Berlin,
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Bochorakova, H.; Sousek, J.; Sedmera, P.; Havlicek, V.; Simanek, V. Heterocycles
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6. Reddy, G. C. Tetrahedron Lett. 1995, 36, 1001–1002.
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9. Mahboobi, S.; Pongratz, H.; Wiegrebe, W. Pharmazie 1997, 52, 399.
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3.4.3.6. 1-[Dimethoxy-(3,4-dimethoxyphenyl)methyl]-3,4-dihydro-6,7-
dimethoxyisoquinoline (10c). Compound 10c was synthesized in
74% and 10% yield according to method A and method B (Sections
3.4.1 and 3.4.2), respectively; colorless oil. 1H NMR (CDCl3):
d 2.59
(2H, t, J¼7.6 Hz, CH2), 3.14 (6H, s, C(OMe)2), 3.65 (3H, s, OMe), 3.81–
3.92 (2H, m, CH2N), 3.81 (3H, s, OMe), 3.82 (6H, s, 2ꢂOMe), 6.57
(1H, s, H-5), 6.78 (1H, d, J¼8.6 Hz, H-60), 7.11 (1H, m, H-20), 7.23 (1H,
d, J¼8.6 Hz, H-50), 7.27 (1H, s, H-8). 13C NMR (CDCl3):
d 25.8 (C-4),
47.5 (C-3), 49.2 (2ꢂOMe), 55.6 (2ꢂOMe), 55.7 (2ꢂOMe), 101.6
(C(OMe)2), 109.5 (C-5), 109.7 (C-8), 110.2 (C-50), 110.5 (C-10), 119.4
(C-60), 131.9 (C-4a), 132.0 (C-5a), 146.5 (]Cquat), 148.5 (]Cquat),
148.7 (]Cquat), 150.0 (]Cquat), 167.7 (C-1). IR (NaCl): nmax 1599,
11. (a) Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689–2693; (b) Ajzert, K. I.;
Takacs, K. Liebigs Ann. Chem. 1987, 1061–1063.