An efficient synthesis of (±)-6,7-dimethoxy-1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline

Article abstract of DOI:10.1081/SCC-100000530

The synthesis of (±)-6,7-dimethoxy-1-oxo-2-(3-piperidyl)-1, 2,3,4-tetrahydroisoquinoline (1) via the cyclization of dimethyl-acetal (3) under acidic condition is described.

Full text of DOI:10.1081/SCC-100000530

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AN EFFICIENT SYNTHESIS OF (±)-6,7-
DIMETHOXY-1-OXO-2-(3-PIPERIDYL)-1,2,3,4-
TETRAHYDROISOQUINOLINE
Akio Kakefuda a , Toshihiro Watanabe a , Takumi Takahashi b , Shuichi Sakamoto a & Shin-
Ichi Tsukamoto a
a Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd. , 21
Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan
b Bulk Manufacturing and Technology Division, Yamanouchi Pharmaceutical Co., Ltd. ,
160-2 Akahama, Takahagi, Ibaraki, 318-0001, Japan
Published online: 09 Nov 2006.
To cite this article: Akio Kakefuda , Toshihiro Watanabe , Takumi Takahashi , Shuichi Sakamoto & Shin-Ichi Tsukamoto
(2001) AN EFFICIENT SYNTHESIS OF (±)-6,7-DIMETHOXY-1-OXO-2-(3-PIPERIDYL)-1,2,3,4-TETRAHYDROISOQUINOLINE,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:3,
401-408, DOI: 10.1081/SCC-100000530
To link to this article: http://dx.doi.org/10.1081/SCC-100000530
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SYNTHETIC COMMUNICATIONS, 31(3), 401–408 (2001)
AN EFFICIENT SYNTHESIS OF ( )-6,7-
DIMETHOXY-1-OXO-2-(3-PIPERIDYL)-
1,2,3,4-TETRAHYDROISOQUINOLINE
Akio Kakefuda,1,∗ Toshihiro Watanabe,1
Takumi Takahashi,2 Shuichi Sakamoto,1
and Shin-Ichi Tsukamoto1
1Institute for Drug Discovery Research, Yamanouchi
Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba,
Ibaraki 305-8585, Japan
2Bulk Manufacturing and Technology Division, Yamanouchi
Pharmaceutical Co., Ltd., 160-2 Akahama, Takahagi,
Ibaraki 318-0001, Japan
ABSTRACT
The synthesis of ( )-6,7-dimethoxy-1-oxo-2-(3-piperidyl)-
1,2,3,4-tetrahydroisoquinoline (1) via the cyclization of dimethyl-
acetal (3) under acidic condition is described.
As part of our research program, the practical preparation of 6,7-dimethoxy-
1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline 1 (Fig. 1) was required. In
previous reports, 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydroisoquinolines have been
prepared by the Bischler–Napieralski reaction involving the ring-closure of
isocyanate with phosphorus oxychloride (POCl3) (1), as well as cyclization of
carbamate with polyphosphoric acid (PPA) (2). However, there are few reports
∗Corresponding author.
401
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

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KAKEFUDA ET AL.
O
O
N
O
Route A
Route B
N
O
O
O
2
N
NH
O
O
O
O
O
1
N
N
O
3
Figure 1.
on the synthesis of 2-substituted derivatives (3) and to our knowledge, for the
derivatives bearing directly cyclic amine at 2-position such as 1 have never been
reported. Hence, we investigated ring-closing processes of the compounds having
piperidine moiety. In this communication, we describe an efficient synthesis of
compound 1 via the cyclization of dimethylacetal 3.
Initially, we tried the synthesis of compound 1 from phenethylcarbamate 2
by the Bischler–Napieralski reaction (Fig. 1, Route A). Phenethylcarbamate 2 was
prepared in two steps from 1-benzyl-3-piperidone hydrate 4 available from Aldrich
(Scheme 1). Compound 4 was condensed with phenethylamine 5 by reductive
O
O
O
O
HCl
N
HO
HO
HN
a
b
N
N
N
O
O
2
6
4
O
O
O
O
H+
O
O
N
N
S
N
N
CF3
O
O
7
8
Condition
Yield of 7
PPA, 145°C 15 min
- (decomposed)
- (no reaction)
19 – 53%
POCl3, reflux 1h
Tf2O, DMAP, CH2Cl2, r.t. 3 days
Conditions; (a) 3,4-dimethoxyphenethylamine (5), NaBH(OAc)3, AcOH, THF;
(b) ClCO2Me, Et3N, THF
Scheme 1.

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DIMETHYLACETAL CYCLIZATION
403
alkylation in the presence of sodium triacetoxyborohydride (NaBH(OAc)3 (4) to
obtain amine 6. Subsequently, amine 6 was converted to the carbamate 2 by using
methyl chloroformate. The Bischler–Napieralski reaction with the carbamate 2
was attempted under the same conditions (Scheme 1). However, the cyclized com-
pound 7 was only obtained by using trifluoromethanesulfonic anhydride (Tf2O)
and 4-dimethylaminopyridine (DMAP) in CH2Cl2 (5) in low to moderate yields.
Moreover, this reaction needed both a long reaction time (3 days) and column
purification to obtain pure 7 due to the formation of by-product 8.
In the search for a more efficient method to prepare 1, we then examined the
cyclization of dimethylacetal 3 under acidic conditions (Fig. 1, Route B) (6). Com-
pound 4 was condensed with aminoacetaldehyde dimethylacetal 9 by reductive
alkylationfollowed by benzoylation to affordacetal 3 in 92%yield(Scheme2). The
acetal 3 was successfully cyclized to 1,2-dihydro-1-oxo-isoquinoline 11 when con-
centrated hydrogen chloride (conc. HCl) and acetic acid (AcOH) were employed,
although 11 was obtained in moderate yield (47%) as a hydrochloride salt (Table 1,
entry 1). We then attempted to improve the yield of 11 by using other acids. When
trifluoroacetic acid (TFA) or methanesulfonic acid (MsOH) was used, the yield of
11 was improved (73% entry 2, 74% entry 3, respectively). Furthermore, the re-
action with concentrated sulfuric acid (conc. H2SO4) gave 11 in better yield (78%
entry 4). Studies of the amount of conc. H2SO4 and the reaction temperature were
performed (entries 5–10). As a result, the condition using 0.2 times (mL/mmol)
of conc. H2SO4 at 80◦C was optimum (entries 8 and 10), because it allowed the
reaction to be completed within an hour and the sulfate of 11 to be crystallized from
the resulting reaction mixture. This condition abridged the work-up procedures of
the reaction and furnished 11 in excellent reproducibility. Some kilograms of 11
were also synthesized using this condition with minimal modifications.
O
O
O
O
H
HCl
N
HO
HO
N
O
a
b
N
N
O
N
O
4
10
3
O
O
O
O
HCl
H+
c
N
N
N
NH
O
O
11
1
Conditions; (a) aminoacetaldehyde dimethylacetal (9), NaBH(OAc)3, AcOH, THF;
(b) 3,4-dimethoxybenzoylchloride, CH3CN; (c) H2(3-4kg/cm2), 20%Pd(OH)2/C, AcOH, 90°C
Scheme 2.

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KAKEFUDA ET AL.
Table 1. Cyclization of 3 Under Acidic Conditions
Scale
Entry (mmol)
Isolated Yield
of 11 (%)
Condition
Time (h)
1
2
3
4
5
6
7
8
9
5.0 conc. HCl 5 mL, AcOH 5 mL, 60◦C
5.0 TFA 10 mL, 50◦C
4
24
20
8
3
1
2
1
2
1
47a
73b
74b
78b
82b
65b
83b
85c
5.0 MsOH 2 Eq, AcOH 5 mL, 60◦C
5.0 conc. H2SO4 5 mL, AcOH 5 mL, 60◦C
5.0 conc. H2SO4 5 mL, AcOH 5 mL, 80◦C
5.0 conc. H2SO4 5 mL, AcOH 5 mL, 100◦C
5.0 conc. H2SO4 2.5 mL, AcOH 5 mL, 80◦C
5.0 conc. H2SO4 1 mL, AcOH 5 mL, 80◦C
5.0 conc. H2SO4 0.5 mL, AcOH 5 mL, 80◦C
d
—
10
189
conc. H2SO4 37.8 mL, AcOH 189 mL, 80◦C
82c
aAfter column purification, the hydrochloride was obtained.
bThe hydrochloride was obtained without column purification.
cThe sulfate was obtained from the resulting reaction mixture, then was converted to the
hydrochloride.
d The reaction was complicated.
Finally, the resulting 11 was hydrogenated over palladium hydroxide in
AcOH to give 1-oxo-1,2,3,4-tetrahydroisoquinoline 1 in 82% yield. In
conclusion, we demonstrated an efficient synthesis of ( )-6,7-dimethoxy-1-oxo-2-
(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline. This method can offer a useful path-
way for the synthesis of various 2-substituted-6,7-dimethoxy-1-oxo-1,2,3,
4-tetrahydroisoquinolines.
EXPERIMENTAL
Melting points were measured with a Yanaco MP-500D melting point appa-
ratus without correction. 1H NMR spectra were obtained on a JEOL JNM-LA300
or a JEOL JNM-EX400 spectometer and the chemical shifts are expressed in
δ (ppm) values with tetramethylsilane as an internal standard. Mass spectra were
obtained on a JEOL JMS-LX2000 mass spectrometer. The elemental analyses
were performed with a Yanaco MT-5 microanalyzer (C, H, N) and a Yokogawa
IC-7000S ion chromatographic analyzer.
Methyl
(
)-N-(1-Benzyl-3-piperidyl)-Nꢀ-(3,4-dimethoxyphenethyl)
Carbamate (2). To a suspension of 1-benzyl-3-piperidone monohydrochloride
monohydrate 4 (10.0 g, 44.3 mmol) and 3,4-dimethoxyphenethylamine 5 (8.03 g,
44.3 mmol) in tetrahydrofuran (THF, 100 mL) were added AcOH (2.54 mL,
44.3 mmol) and NaBH(OAc)3 (10.3 g, 48.7 mmol), and the mixture was stirred
at room temperature for 1 h. The reaction mixture was made alkaline with 5 N

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DIMETHYLACETAL CYCLIZATION
405
NaOHaq. at 0◦C, then extracted with CHCl3 (50 mL × 2). The combined extract
was dried over anhydrous Na2SO4 and concentrated in vacuo to give 1-benzyl-3-
[(3,4-dimethoxyphenethyl)amino]piperidine 6 (14.2 g, 90%) as a yellow oil. To a
solution of 6 (14.2 g, 40.1 mmol) and Et3N (6.70 mol, 48.1 mmol) in THF (100 mL)
was added dropwise a solution of methyl chloroformate (3.40 mL, 44.1 mmol) in
THF (10 mL) at 0◦C, and the mixture was stirred at 0◦C for 1 h. The result-
ing mixture was concentrated in vacuo and the residue was dissolved in H2O
(150 mL), then extracted with AcOEt (50 mL × 2). The combined extract was
washed with 1 N NaOHaq. (100 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo to give 2 (16.2 g, 98%) as a yellow oil. This material may be used
in the next cyclization step or converted to its oxalate salt. The oxalate salt was
obtained from MeOH–AcOEt as a colorless powder: m.p. 145–146◦C; 1H NMR
(400 MHz, DMSO-d6) δ 1.68–1.78 (4H, m, 4-H2 and 5-H2 of piperidine), 2.41 (2H,
br s, 1-H2 or 6-H2 of piperidine), 2.66 (2H, br s , 3,4-(OMe)2PhCH2), 2.95–2.97
(2H, m, 1-H2 or 6-H2 of piperidine), 3.27–3.29 (2H, m, MeO2 CNCH2), 3.60 (3H,
s, OMe), 3.72 (3H, s, OMe), 3.74 (3H, s, OMe), 3.95 (3H, br s, CH2Ph and 3-H of
piperidine), 6.70 (1H, d, J = 7.2 Hz, 5- or 6-H of 3,4-(OMe)2Ph), 6.78 (1H, s, 2-H
of 3,4-(MeO)2Ph), 6.86 (1H, d, J = 7.2 Hz, 5- or 6-H of 3,4-(MeO)2Ph), 7.40 (5H,
brs, CH2Ph); MS (FAB) m/z 413 (MH+); Anal. calcd. for C24H32N2O4 · C2H2O4:
C 62.14, H 6.82, N 5.57. Found: C 62.01, H 6.81, N 5.47.
(
)-2-(1-Benzyl-3-piperidyl)-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydroi-
soquinoline(7)and( )-6,7-dimethoxy-1-oxo-2-[1-(trifluoromethanesulfonyl)-
3-piperidyl]-1,2,3,4-tetrahydroisoquinoline (8). To a solution of 2 (6.31 g,
15.3 mmol) and DMAP (4.67 g, 38.2 mmol) in CH2Cl2 (120 mL) was added drop-
wise a solution of Tf2O (10.3 mL, 61.2 mmol) in CH2Cl2 (10 mL) at 0◦C, and
the mixture was stirred at room temperature for 3 days. The reaction mixture was
partitioned between CHCl3 (50 mL × 2) and H2O (150 mL) and the combined
CHCl3 layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give
a mixture of 7 and 8. The mixture can be separated by column chromatography
on silica gel (CHCl3/MeOH = 49/1 for 7, 99/1 for 8) to give 7 (3.11 g, 53%) as a
yellow oil and 8 as a yellow form.
Compound 7 may be converted to its hydrochloride salt. The hydrochloride
salt of 7 was obtained from EtOH–AcOEt as a colorless powder: m.p. 232–238◦C;
1H NMR (400 MHz, DMSO-d6) δ 1.74–1.93 (4H, m, 4-H2 and 5-H2 of piperidine),
2.87 (2H, br s, 4-H2 of isoquinoline), 2.88 (1H, br s, 1-H or 6-H of piperidine),
3.19–3.24 (2H, m, 1-H and 6-H of piperidine), 3.31 (1H, br s, 1-H or 6-H of
piperidine), 3.44 (2H, br s, 3-H2 of isoquinoline), 3.75 (3H, s, OMe), 3.81 (3H, s,
OMe), 4.32 (2H, t, J = 4.8 Hz, CH2Ph), 4.85–4.87 (1H, m, 3-H of piperidine),
6.89 (1H, s, 5-H of isoquinoline), 7.34 (1H, s, 8-H of isoquinoline), 7.46–7.48 (3H,
m, CH2Ph), 7.59–7.61 (2H, m, CH2Ph), 10.64 (1H, brs, HCl); MS (FAB) m/z 381
(MH+); Anal. calcd. for C23H28N2O3 · HCl · 0.3H2O: C 65.41, H 7.06, N 6.63, Cl
8.39. Found: C 65.38, H 7.12, N 6.65, Cl 8.17.

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KAKEFUDA ET AL.
Compound 8: 1H NMR (300 MHz, CDCl3) δ 1.79–1.96 (4H, m, 4-H2 and 5-
H2 of piperidine), 2.89–2.93 (2H, m, 4-H2 of isoquinoline), 2.98–3.02 (1H, m, 1-H
or 6-H of piperidine), 3.25–3.33 (1H, m, 1-H or 6-H of piperidine), 3.38–3.57 (2H,
m, 3-H2 of isoquinoline), 3.92 (6H, s, (OMe)2), 3.94–4.01 (2H, m, 1-H and 6-H of
piperidine), 4.47 (1H, br s, 3-H of piperidine), 6.63 (1H, s, 5-H of isoquinoline),
7.58 (1H, s, 8-H of isoquinoline); MS (FAB) m/z 423 (MH+).
(
)-N-(1-Benzyl-3-piperidyl)-N-(2,2-dimethoxyethyl)-3,4-dimethoxy-
benzamide (3). To a suspension of 1-benzyl-3-piperidonemonohydrochloride
monohydrate 4 (46.4 g, 205 mmol) in THF (380 mL) were added aminoac-
etaldehyde dimethylacetal (21.6 g, 205 mmol), AcOH (11.8 mL, 205 mmol), and
NaBH(OAc)3 (47.9 g, 226 mmol), and the mixture was stirred at room tempera-
ture for 2 h. The reaction mixture was made alkaline with 5 N NaOHaq. at 0◦C,
then extracted with AcOEt (200 mL × 2). The combined extract was washed with
saturated NaClaq. (200 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo to give 1-benzyl-3-[(2,2-dimethoxyethyl)amino]piperidine 10 (52.7 g, 92%)
as a yellow oil. To a solution of 10 (52.7 g, 189 mmol) in CH3CN (400 mL) was
added dropwise a solution of 3,4-dimethoxybenzoylchloride (39.9 g, 199 mmol)
in CH3CN (100 mL) at 0◦C, and the mixture was stirred at room temperature for
0.5 h. The reaction mixture was made alkaline with 5 N NaOHaq. at 0◦C, then
extracted with AcOEt (250 mL × 2). The combined extract was washed with
0.5 N NaOHaq. (200 mL × 2), saturated NaClaq. (200 mL), and dried over an-
hydrous Na2SO4, then concentrated in vacuo to give 3 (97.4 g, 99%) as a brown
oil. This material may be used in the next cyclization step: 1H NMR (300 MHz,
CDCl3) δ 1.51–1.89 (4H, m, 4-H2 and 5-H2 of piperidine), 2.10 (2H, br s, 1-H
and 6-H of piperidine), 2.74–2.84 (2H, m, 1-H and 6-H of piperidine), 3.34–3.68
(10H, m, (OMe)2 and CONCH2 and CH2Ph), 3.80 (3H, s, OMe), 3.91 (1H, brs,
CH(OMe)2), 3.92 (3H, s, OMe), 4.65 (1H, br s, 3-H of piperidine), 6.81–6.88
(3H, m, 3,4-(MeO)2Ph), 7.24–7.33 (5H, m, CH2Ph); MS (FAB) m/z 443 (MH+);
HRMS calcd. for C25H34N2O5:443.2521. Found: 443.2545.
(
)-2-(1-Benzyl-3-piperidyl)-6,7-dimethoxy-1-oxo-1,2-dihydroisoquin-
oline (11). To a solution of 3 (97.4 g, 196 mmol) in AcOH (196 mL) was added
conc. H2SO4 (39.2 mL), and the mixture was stirred at 80◦C for 1 h. The mixture
was cooled to room temperature to allow crystallization from the resulting solu-
tion. To the mixture was added acetone (300 mL) and the mixture was further
stirred at 4◦C for 4 h, then the resulting crystals were collected and washed with
acetone to give the sulfate salt of 11 as a slightly brown powder. The sulfate salt
of 11 was dissolved in H2O (200 mL) and made alkaline with 5 N NaOHaq. at
0◦C, then extracted with CHCl3 (200 mL × 2). The combined extract was dried
over anhydrous Na2SO4 and concentrated in vacuo to give 11 as a brown foam.

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DIMETHYLACETAL CYCLIZATION
407
Compound 11 was converted to its hydrochloride salt. The hydrochloride salt of
11 was obtained from EtOH–AcOEt as a slightly brown powder (64.5 g, 82%):
m.p. 256–259◦C; 1H NMR (400 MHz, DMSO-d6) δ 1.86–1.88 (4H, m, 4-H2 and
5-H2 of piperidine), 2.03–2.08 (3H, m, 1-H and 6-H of piperidine), 2.97 (1H, br
s, 1-H or 6-H of piperidine), 3.85 (3H, s, OMe), 3.88 (3H, s, OMe), 4.30–4.39
(2H, m, CH2Ph), 5.30 (1H, brs, 3-H of piperidine), 6.63 (1H, d, J = 7.2 Hz, 3-H
of isoquinoline), 7.16 (1H, s, 5-H of isoquinoline), 7.37 (1H, d, J = 7.2 Hz, 4-H
of isoquinoline), 7.45–7.46 (3H, m, CH2Ph), 7.61 (1H, s, 8-H of isoquinoline),
7.76–7.78 (2H, m, CH2Ph), 11.07 (1H, brs, HCl); MS (FAB) m/z 379 (MH+);
Anal. calcd. for C23H26N2O3 · HCl: C 66.58, H 6.56, N 6.75, Cl 8.54. Found: C
66.70, H 6.58, N 6.70, Cl 8.48.
(
)-6,7-Dimethoxy-1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquino-
line (1). To a solution of the hydrochloride salt of 11 (21.2 g, 51.0 mmol) in
AcOH (106 mL) was added palladium hydroxide on carbon (20 wt% 10.6 g), and
the mixture was stirred under hydrogen pressure (3–4 kg/cm2) at 90◦C for 2 days.
The catalyst was removed by filtration and the filtrate was concentrated in vacuo.
The residue was dissolved in H2O (100 mL) and made alkaline with 5 N NaOHaq.
at 0◦C, then extracted with CHCl3 (100 mL × 2). The combined extract was dried
over anhydrous Na2SO4 and concentrated in vacuo. The residual solid was recrys-
tallizedfromAcOEttogive 1(12.4g, 84%)asacolorlesspowder:m.p. 139–140◦C;
1H NMR (400 MHz, CDCl3) δ 1.58–1.73 (2H, m, 4-H2 of piperidine), 1.80–1.90
(2H, m, 5-H2 ofpiperidine), 2.46–2.53(1H, m, 1-Hor6-Hofpiperidine), 2.66–2.72
(1H, m, 1-H or 6-H of piperidine), 2.84–2.87 (2H, m, 4-H2 of isoquinoline),
3.02–3.09 (2H, m, 1-H and 6-H of piperidine), 3.41–3.53 (2H, m, 3-H2 of
isoquinoline), 3.73 (3H, s, OMe), 3.74 (3H, s, OMe), 4.59–4.66 (1H, m, 3-H
of piperidine), 6.63 (1H, s, 5-H of isoquinoline), 7.60 (1H, s, 8-H of isoquinoline);
MS (FAB) m/z 291 (MH+); Anal. calcd. for C16H22N2O3: C 66.18, H 7.64, N 9.65.
Found: C 65.98, H 7.62, N 9.61.
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5. Banwell, M.G.; Bissett, B.D.; Busato, S.; Cowden, C.J.; Hockless, D.C.;
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Received in Japan March 6, 2000

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