A convenient synthesis of 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines via Pictet-Spengler reaction using titanium(IV) isopropoxide and acetic-formic anhydride.

Article abstract of DOI:10.1248/cpb.50.253

A synthesis of 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines (6) was achieved in a highly efficient manner via Pictet-Spengler reaction of arylethylamines (1) and acyclic and cyclic ketones (2) using titanium (IV) isopropoxide and acetic-formic anhydride. The cyclization of the in situ formed acyliminium ion (4) to N-formyl 1,2,3,4-tetrahydroisoquinoline (5) was greatly facilitated by using trifluoroacetic acid as an additional reagent. The Pictet-Spengler reaction was carried out by one pot procedure, providing a convenient and effective method for preparing various 1,2,3,4-tetrahydroisoquinolines.

Full text of DOI:10.1248/cpb.50.253

February 2002
Chem. Pharm. Bull. 50(2) 253—257 (2002)
253
A Convenient Synthesis of 1,1-Disubstituted 1,2,3,4-Tetrahydroisoquinolines
via Pictet–Spengler Reaction Using Titanium(IV) Isopropoxide and
Acetic-Formic Anhydride
Yoshie HORIGUCHI,* Hirokazu KODAMA, Masayoshi NAKAMURA, Tsuyoshi YOSHIMURA, Kaori HANEZI,
Hiroko HAMADA, Toshiaki SAITOH, and Takehiro SANO
Showa Pharmaceutical University, 3–3165 Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received September 13, 2001; accepted October 21, 2001
A synthesis of 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines (6) was achieved in a highly efficient manner
via Pictet–Spengler reaction of arylethylamines (1) and acyclic and cyclic ketones (2) using titanium (IV) iso-
propoxide and acetic-formic anhydride. The cyclization of the in situ formed acyliminium ion (4) to N-formyl
1,2,3,4-tetrahydroisoquinoline (5) was greatly facilitated by using trifluoroacetic acid as an additional reagent.
The Pictet–Spengler reaction was carried out by one pot procedure, providing a convenient and effective method
for preparing various 1,2,3,4-tetrahydroisoquinolines.
Key words Pictet–Spengler reaction; titanium(IV) isopropoxide; 1,2,3,4-tetrahydroisoquinoline; N-formylation; acyliminium ion
The Pictet–Spengler reaction is one of the key reactions at 80 °C for 3 h and then treated with sodium borohydride to
for construction of the isoquinoline skeleton, which consti- yield the secondary amine (7) in 99% yield.
tutes an important class of naturally occurring bioactive sub-
Then, we found that the imines (3) thus formed in situ, on
stances.1) The reaction utilizes an acid-catalyzed cyclization heating in a solution of acetic-formic anhydride, induced the
of the intermediate imine formed by condensation of Pictet–Spengler cyclization (Table 1). For example, a solu-
arylethylamine with a carbonyl compound. Aldehydes or ac- tion containing 10 eq of acetic-formic anhydride which was
tivated ketone such as a 1,2-carbonyl compound are pre- prepared from 10 eq of acetic anhydride and 30 eq of formic
ferred for the carbonyl compound. Generally speaking, the acid (the ratio of Ac2O and HCOOHϭ1 : 3), was added to the
Pictet–Spengler reaction of simple ketones using as the car- titanium(IV) isopropoxide solution of 3a. The mixture was
bonyl compounds is known to be difficult.2) This retardation then heated at 70 °C for 3 h to yield two products, the desired
of the reaction can be ascribed to the difficulty in the forma- N-formyl tetrahydroisoquinoline (5a) in 12% yield and the
tion of imines by conventional methods, and also to the steric uncyclized N-formyl enamine (8) in 8% yield (run 1). On the
inhibition in the cyclization of the imine, which produces a other hand, the Pictet–Spengler cyclization did not occur
congested quarternary carbon at C1 of the isoquinoline when a solution of acetic-formic anhydride prepared from
skeleton.
the equimolar amount of Ac2O (10 eq) and HCOOH (10 eq)
Recently, Bhattacharyya et al.3) reported that titanium(IV) was used. The reaction gave only the uncyclized 8 in 16%
isopropoxide is an excellent reagent that catalyzes the con- yield (run 2). The difference between the two reactions (runs
densation reaction of ketones with amines. They successfully 1, 2) is the amount of formic acid used. The reaction of run
applied this reaction to the preparation of higher various 1, where the acetic formic anhydride solution contains dou-
amines in a highly effective manner through the reduction of ble the excess of formic acid of acetic-formic anhydride,
intermediary formed imines. This and also our experiments4) caused the cyclization. This result suggested that the cycliza-
of the reductive amination reaction using the titanium tion of 3a to 5a required the increased acidity in the reaction
reagent demonstrates that the imines, although not isolable medium. However, the concomitant use of p-toluenesulfonic
from the reaction mixture, are quantitatively produced from acid (1 eq) and acetic-formic anhydride (10 eq) produced 5a
ketones. In this paper we describe the Pictet–Spengler reac- only in 7% yield (run 3). This result was very poor when
tion of the imines formed by the condensation of arylethyl- compared with the fact that the treatment of 8 with p-tolue-
amines with various ketones using the titanium reagent. This nesulfonic acid in boiling benzene for 30 min produced 5a in
reaction should provide a general and convenient method for 72% yield. The longer reaction time (48 h) slightly improved
preparing 1,1-disubstituted 1,2,3,4-tetrahydroisoquinolines the yield of the cyclized 5a (21%) (run 4).
including 1-methyl-1-phenyl derivatives (6a, b), non-compet-
Judging from the results described above, this Pictet–
Spengler cyclization might be improved by using a large ex-
cess amount of a solution of acetic-formic anhydride contain-
ing an excess of formic acid. Recently, T. Ohwada and his
itive N-methyl-D-aspartate (NMDA) antagonists.5,6)
Results and Discussion
The condensation reaction of arylethylamines (1) and ke- colleagues7) clearly demonstrated in their investigations of
tones (2) to imines (3) was carried out by heating in tita- dication chemistry that the Pictet–Spengler cyclization was
nium(IV) isopropoxide without using any solvent. Although enormously facilitated by increasing acidity in the reaction
the isolation of 3 from the reaction mixture was unsuccess- media. Thus, the imine (3a) prepared in neat titanium(IV)
ful, this condensation was proved to proceed quantitatively as isopropoxide was treated with 100 eq of acetic-formic anhy-
shown by the following experiment: A mixture of 2-(3,4- dride containing 200 eq of formic acid under heating at 70 °C
dimethoxyphenyl)ethylamine (1a) (1.2 eq), acetophenone for 18 h. This reaction produced 5a in 56% yield (run 5).
(2a) (1 eq) and titanium(IV) isopropoxide (1.5 eq) was heated
Next, we proved that this Pictet–Spengler cyclization pro-
To whom correspondence should be addressed. e-mail: horiguti@ac.shoyaku.ac.jp
© 2002 Pharmaceutical Society of Japan

254
Vol. 50, No. 2
Chart 1
Table 1. Pictet–Spengler Reaction of 3a under Various Conditions
Reagents
Conditions
Products
Run
Ac2O
(mol eq)
HCOOH
(mol eq)
Other acid
(mol eq)
Temp.
(°C)
Time
(h)
5a
(yield %)
8
(yield %)
1
2
3
4
5
6
7
8
10
10
10
10
100
—
30
10
30
—
—
70
70
70
70
70
70
70
70
3
18
18
48
18
18
18
18
12
—
7
21
56
—
—
99
8
16
—
—
—
—
—
—
p-TsOH (1)
30
—
—
—
300
300
—
—
100
CF3COOH (300)
CF3COOH (200)
100
Table 2. Synthesis of 1,1-Disubstituted 1,2,3,4-Tetrahydroisoquinolines (6)
Pictet–Spengler reaction
Hydrolysis of 5
N-Formyl
Arylamines
Ketones
Reagenta)
TIQb) (5)
Yield (%)
TIQb) (6)
Yield (%)
1a
1a
1b
1b
1a
1a
1b
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2c
2d
2d
2f
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
56
99
34
99
55
96
38
73
48
92
51
76
53
92
20
87
11
60
6a
6b
6c
6d
6e
6f
78
82
90
94
92
75
87
84
90
5f
5h
5h
5i
5i
5j
6h
6i
2f
2g
2g
2h
2h
6j
5j
a) Reagent A: Ti(O-isoPr)4 (1.5 mol eq), Ac2O (100 mol eq), HCOOH (300 mol eq), B: Ti(O-isoPr)4 (1.5 mol eq), Ac2O (100 mol eq), HCOOH (100 mol eq) and CF3COOH
(200 mol eq). b) TIQ: 1,2,3,4-Tetrahydroisoquinoline.

February 2002
255
reactant gas: iso-butane] using a direct inlet system. Elemental analyses
were recorded on a Yanaco CHN-corder MT-3. For column chromatography,
silica gel (Mallinckrodt type 150A or Wako-Gel C-200) was used.
ceeded via the acyliminium ion 4, not the iminium ions pro-
duced by protonation of the imine 3. That is, when a solution
of 3a in formic acid (run 6) or in trifluoroacetic acid (run 7)
without acetic-formic anhydride was heated at 70 °C for 18 h,
no cyclization occurred to any extent.
Reductive Amination of 2-(3,4-Dimethoxyphenyl)ethylamine (1a) and
Acetophenone (2a) A mixture of 1a (1 g, 5.52 mmol), 2a (552 mg, 4.60
mmol) and Ti(O-isoPr)4 (1.96 g, 6.9 mmol) was heated at 80 °C for 3 h under
an argon atmosphere. The reaction mixture was diluted with MeOH
(100 ml), and NaBH4 (0.3 g, 8 mmol) was added slowly at 0 °C and stirred
for 1 h at room temperature Water (10 ml) was added to the reaction mixture.
After removal of the solvent in vacuo, the residue was extracted with CHCl3,
washed with brine and dried over Na2SO4. After removal of the solvent in
vacuo, the residual oil was chromatographed over SiO2 (hexane/ethyl acetate
1 : 1) to give N-(1-phenylethyl)-2-(3,4-dimethoxyphenyl)ethylamine (7)
The Pictet–Spengler reaction of other acyclic ketones
(2b—d) under conditions similar to those of the run 5
(method A) also provided the corresponding N-formyl 1,1-
disubstituted 1,2,3,4-tetrahydroisoquinolines (5c, e, f) in
moderate yields as shown in Table 2. The reaction of the
cyclic ketones cyclopentanone (2f), cyclohexanone (2g), and
1-indanone (2h) yielded the corresponding 1-spirocycloalky-
lated 1,2,3,4-tetrahydroisoquinolines (5h—j), in 53, 20, 11%
yields, respectively. This gradually decreased yields were ob-
served in the reactions of cyclic ketones and suggesed that
the cyclization, as anticipated, is sensitive to the steric con-
gestion. In fact, the Pictet–Spengler reaction of benzophe-
none (2e) did not yield 1,1-diphenyl-1,2,3,4-tetrahydroiso-
quinoline (5g).
1
(1.3 g, 99%) as a pale yellow gum. IR: 2830, 2364, 1591, 1516. H-NMR:
1.32 (3H, d, Jϭ7 Hz, CH3), 2.68—2.75 (4H, m, NCH2CH2), 3.73—3.79
(1H, m, CHCH3), 3.83 (3H, s, OCH3), 3.85 (3H, s, OCH3), 6.67—6.80 (3H,
m, Ar-H), 7.23—7.33 (5H, m, Ph). 13C-NMR: 24.1 (CH3), 35.7 (C2), 48.7
(C1), 55.5 (OCH3), 55.6 (OCH3), 58.0 (C1Ј), 111.6 (C2Љ and C5Љ), 120.4
(C6Љ), 128.6 (2ϫPhCH), 126.3 (2ϫPhCH), 126.6 (PhCH), 128.2
(2ϫPhCH), 132.4 (PhC), 145.4 (C1Љ), 147.1 (C3Љ or C4Љ), 148.6 (C3Љ or
C4Љ). LR-MS m/z: 285 (Mϩ). HRMS m/z Calcd for C18H23NO2: 285.1729.
Found: 285.1765.
The Pictet–Spengler Reaction of 2-(3,4-Dimethoxyphenyl)ethylamine
(1a) with Acetophenone (2a) A mixture of 1a (1 g, 5.52 mmol), 2a
(0.552 g, 4.60 mmol) and Ti(O-isoPr)4 (1.96 g, 6.90 mmol) was heated at
80 °C for 3 h under an argon atmosphere. To the reaction mixture was added
a solution of acetic-formic anhydride [prepared from HCOOH (6.35 g,
0.138 mol) and Ac2O (4.7 g, 46 mmol)] at 0 °C, then the mixture was heated
Next, we found that the use of trifluoroacetic acid as an
additional reagent greatly improved the yields of the cyclized
5. That is, 200 eq of trifluoroacetic acid was added to the
acyliminium ion (4a) in situ prepared from 3a in a solution
containing 100 eq of acetic-formic anhydride prepared from at 70 °C for 3 h. The reaction mixture was diluted with MeOH (100 ml) and
passed through a short SiO2 column chromatography (CHCl3–MeOH) to re-
move TiO2. The eluent was concentrated in vacuo to ca. 50 ml and diluted
with CHCl3. The extract was washed with brine and dried over Na2SO4.
After removal of the solvent in vacuo, the residue was purified by chro-
Ac2O (100 eq) and HCOOH (100 eq). Then, the reaction
mixture was heated at 70 °C for 18 h. This treatment caused
the cyclization quantitatively, thus producing 5a in 99% yield
(run 8). The reaction of other acyclic ketones (2b—d) and
cyclic ketones (2f—h) by this treatment (method B) also pro-
vided the tetrahydroisoquinolines (5c, e, f) and (5h—j) in ex-
cellent yields. The results are summarized in Table 2.
Finally, we wish to note that this Pictet–Spengler reaction,
as generally observed in the conventional Pictet–Spengler re-
action,7) requires electron-rich aromatics of the arylethyl
moiety. Thus, the reaction of 2-(3-methoxyphenyl)ethyl-
amine (1b) with 2a or 2b under the conditions using a large
excess of acetic-formic anhydride and trifluoroacetic acid
afforded the corresponding N-formyl-6-methoxy-1,2,3,4-
tetrahydroisoquinoline (5b, d) in 99% and 73% yield, respec-
tively. The reaction of 2-(4-methoxyphenyl)ethylamine and
phenylethylamine in which the nucleophilic center is not
electronically activated, induced no expected cyclizations,
however.
Alkaline hydrolysis of the N-formyl-1,2,3,4-tetrahydroiso-
quinoline (5) afforded the 1,1-disubstituted 1,2,3,4-tetrahy-
droisoquinoline (6) in good yields as shown in Table 2.
Thus, the Pictet–Spengler reaction of arylethylamines and
ketones using titanium(IV) isopropoxide and acetic-formic
anhydride provides a convenient method of synthesizing
various 1,1-disubstitued 1,2,3,4-tetrahydroisoquinolines. This
method is particularly highly effective when trifluoroacetic
acid is used as an additional reagent for the cyclization.
matography over SiO2 (hexane/ethyl acetate 1 : 1) to give 5a (205 mg, 12%)
and 8 (137 mg, 8%). Other reaction conditions and results are summarized in
Table 1.
2-Formyl-6,7-dimethoxy-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquino-
line (5a): Pale yellow needles, crystallized from MeOH–hexane, mp 100—
101 °C. IR: 2935, 1664, 1612, 1515 cmϪ1 1H-NMR: 2.04 (3H, s, CH3),
.
2.80—2.97 (2H, m, 4-H), 3.54—3.60 (1H, m, 3-H), 3.64 (3H, s, OCH3),
3.86 (3H, s, OCH3), 4.11—4.22 (1H, m, 3-H), 6.26 (1H, s, 8-H), 6.62 (1H, s,
5-H), 7.2—7.4 (5H, m, Ph), 8.10 (1H, s, CHO). 13C-NMR: d 28.5 (C4), 29.2
(CH3), 36.0 (C3), 55.8 (OCH3), 56.0 (OCH3), 62.7 (C1), 110.7 (C5), 110.9
(C8), 126.4 (C4a), 127.3 (C2Ј and C6Ј), 127.6 (C4Ј), 128.7 (C3Ј and C5Ј),
133.4 (C8a), 145.5 (C1Ј), 147.7 (C6 or C7), 147.8 (C6 or C7), 163.0 (CHO).
LR-MS m/z: 311 (Mϩ, base peak). HR-MS m/z Calcd for C19H21NO3:
311.1522. Found: 311.1552. Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80;
N, 4.50. Found: C, 73.35; H, 6.88; N, 4.30.
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-(1-phenylvinyl)formamide (8):
A
pale yellow gum. IR: 2935, 1676, 1610, 1516. 1H-NMR: 2.75 (2H, t, Jϭ
8 Hz, 2-H), 3.68 (2H, t, Jϭ8 Hz, 1-H), 3.81 (3H, s, OCH3), 3.84 (3H, s,
OCH3), 4.92 (1H, s, 2Ј-H), 5.20 (1H, s, 2Ј-H), 6.62—6.75 (3H, m, Ar-H),
7.3—7.4 (5H, m, Ph), 8.35 (1H, s, CHO). 13C-NMR: 33.1 (C2), 44.3 (C1),
55.6 (OCH3), 55.7 (OCH3), 108.7 (C2Љ), 110.9 (C5Љ), 120.6 (C6Љ), 128.6 (2ϫ
PhCH), 128.6 (2ϫPhCH), 129.1 (PhCH), 130.6 (C1Ј), 135.3 (PhC), 145.9
(C1Љ), 147.3 (C3Љ or C4Љ), 148.6 (C3Љ or C4Љ), 162.3 (CHO). LR-MS m/z:
311 (Mϩ). HR-MS m/z Calcd for C19H21NO3: 311.1521. Found: 311.1526.
Cyclization Reaction of 8 A solution of 8 (218 mg, 0.7 mmol) and p-
TsOH (360 mg, 2.1 mmol) in benzene (20 ml) was refluxed for 30 min. The
reaction mixture was diluted with benzene (50 ml) and washed with 5%
NaOH and H2O. After removal of the solvent in vacuo, the product was puri-
fied by column chromatography over SiO2 (ethyl acetate/hexane 1 : 1) to give
5a (164 mg, 75%).
The Pictet–Spengler Reaction of Arylethylamines (1) with Ketones
(2). General Procedure i) Method A: A mixture of 1 (5.52—9.20 mmol),
Experimental
Unless otherwise stated, the following procedures were adopted. All melt- 2 (4.60 mmol) and Ti(O-isoPr)4 (6.90 mmol) was heated at 80 °C for 3 h
ing points were measured on a Yanagimoto micro hot-stage melting point under an argon atmosphere. To this reaction mixture a solution of acetic-
apparatus (Yanagimoto MP type) and are uncorrected. IR spectra were mea- formic anhydride [prepared from HCOOH (63.6 g, 1.38 mol) and Ac2O
sured with a HORIBA FT-710 as KBr disks and values are given in cmϪ1
.
(47 g, 0.46 mol)] was added at 0 °C and the mixture was heated at 70 °C for
NMR spectra were recorded on a JNM-AL300 (1H, 300 MHz; 13C, 75 MHz) 18 h. The work-up of the reaction mixture as described above gave 5.
NMR spectrometer in CDCl3 solution using tetramethylsilane (TMS) as an
Method B: A mixture of 1 (5.52—9.20 mmol), 2 (4.60 mmol) and Ti(O-
internal standard. Low-resolution MS spectra (LR-MS) were taken on a isoPr)4 (6.90 mmol) was heated at 80 °C for 3 h under an argon atmosphere.
JMS-AM20, and high-resolution MS spectra (HR-MS) was taken on a JMS-
To this reaction mixture acetic-formic anhydride [prepared from HCOOH
D300 spectrometer at 70 eV or at 270 eV [chemical ionization MS (CI-MS), (21.2 g, 0.46 mol) and Ac2O (47 g, 0.46 mol)] was added at 0 °C and heated

256
Vol. 50, No. 2
at 70 °C for 2 h. To this reaction mixture CF3COOH (105 g, 0.92 mol) was mmol) as colorless prisms, crystallized from MeOH–hexane, mp 123—
added and heated at 70 °C for 18 h. The work-up of the reaction mixture as
described above gave 5. Yields are summarized in Table 1.
2-Formyl-6-methoxy-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoloine
(5b) was obtained from 2-(3-methoxyphenyl)ethylamine (1b) (830 mg,
126 °C. IR: 1641, 1523. 1H-NMR: 1.42—1.99 (8H, m, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-
H), 2.29 (2H, d, Jϭ14 Hz, 2Ј-H), 2.82 (2H, t, Jϭ6 Hz, 4-H), 3.82 (2H, t,
Jϭ6 Hz, H-3), 3.84 (3H, s, OCH3), 3.89 (3H, s, –OCH3), 6.55 (1H, s, 5-H),
6.75 (1H, s, 8-H), 8.54 (1H, s, CHO). 13C-NMR: 21.8 (C3Ј and C5Ј), 25.6
5.52 mmol) and 2a (552 mg, 4.60 mmol) as a pale yellow gum. IR: 1664, (C4), 27.9 (C4Ј), 34.3 (C3), 36.1 (C2Ј and C6Ј), 55.7 (OCH3), 56.2 (OCH3),
1610 cmϪ1. 1H-NMR: 2.02, 2.04 (total 3H, each s, CH3), 2.86—2.96 (2H, m, 59.8 (C1), 108.1 (C5), 111.8 (C8), 126.7 (C4a), 135.2 (C8a), 147.1 (C6 or
4-H), 3.58—3.67 (1H, m, 3-H), 3.77 (3H, s, OCH3), 4.11—4.18 (1H, m, 3- C7), 147.8 (C6 or C7), 162.4 (CHO). LM-RS: 289 (Mϩ), 205 (base peak).
H), 6.66—6.78 (3H, s, Ar-H), 7.2—7.4 (5H, m, Ph), 8.12 (s, 1H, CHO). 13C- HM-RS m/z Mϩ Calcd for C17H23NO3: 289.1678. Found: 289.1683.
NMR: 29.2 (C4), 29.5 (CH3), 36.1 (C3), 55.2 (OCH3), 62.7 (C1), 113.0
2-Formyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-spiro-1Ј-indane
(C7), 113.1 (C5), 127.3 (C3Ј and C5Ј), 127.5 (C4Ј), 128.7 (C2Ј and C6Ј), (5j) was obtained from 1a (2 g, 11 mmol) and 2h (660 mg, 5.5 mmol) as col-
128.9 (C8), 134.0 (C1Ј), 135.4 (C4a), 145.8 (C7a), 158.0 (C6), 163.0 orless prisms, crystallized from MeOH–hexane, mp 124—127 °C. IR: 1646,
(CHO). LR-MS m/z: 281 (Mϩ), 266 (base peak). HR-MS m/z Calcd for 1521. 1H-NMR: 2.43, 2.48 (total 1H, each t, Jϭ8 Hz, 3Ј-H), 2.60, 2.65 (total
C18H19NO3: 281.1416. Found: 281.1423.
1H, each t, Jϭ8 Hz, 3Ј-H), 2.75, 2.80 (total 1H, each t, Jϭ3 Hz, 4-H), 2.96,
2-Formyl-6,7-dimethoxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (5c) 3.70 (total 3H, each dd, Jϭ5, 12Hz, 3-H, 4-H), 3.21, 3.25 (total 1H, each dd,
was obtained from 1a (1 g, 5.52 mmol) and 2b (267 mg, 4.6 mmol) as pale Jϭ3, 8 Hz, 2Ј-H), 3.60 (3H, s, OCH3), 3.88 (3H, s, –OCH3), 4.64, 4.69 (total
yellow plates, crystallized from MeOH–hexane, mp 96—98 °C. IR: 1653, 1H, each q, Jϭ3 Hz, 2Ј-H), 6.16 (1H, s, 5-H), 6.63 (1H, s, 8-H), 6.87 (1H,
1517 cmϪ1
.
1H-NMR: 1.73 (3H, s, CH3), 1.81 (3H, s, CH3), 2.75 (1H, t,
d, Jϭ8 Hz, 4Ј-H), 7.19—7.37 (3H, m, 5Ј-H, 6Ј-H, 7Ј-H), 7.51 (1H, s, CHO).
Jϭ6Hz, 4-H), 2.81 (1H, t, Jϭ6Hz, 4-H), 3.49 (1H, t, Jϭ6Hz, 3-H), 3.83 13C-NMR: 28.6 (C4), 29.8 (C3Ј), 36.5 (C3), 43.8 (C2Ј), 55.8 (OCH3), 56.0
(1H, t, Jϭ6 Hz, 3-H), 3.87 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.58 (1H, s,
(OCH3), 71.8 (C1), 110.59 (C5), 110.61 (C8), 125.0 (C4Ј), 126.2 (C5Ј),
127.4 (C6Ј), 127.7 (C7aЈ), 129.1 (C7Ј), 132.5 (C3aЈ), 143.9 (C4a), 145.1
5-H), 6.72 (1H, s, 8-H), 8.21, 8.62 (total 1H, each s, CHO). 13C-NMR: 29.0
(C4), 31.1 (2ϫCH3), 35.2 (C3), 55.8 (OCH3), 56.1 (OCH3), 57.4 (C1), 108.8 (C8a), 147.6 (C6 or C7), 148.0 (C6 or C7), 161.3 (CHO). LM-RS: 323
(C5), 111.3 (C8), 126.6 (C4a), 133.4 (C8a), 147.7 (C6 and C7), 160.1 (Mϩ), 278 (base peak). HM-RS m/z Mϩ Calcd for C20H21NO3: 323.1521.
(CHO). LR-MS m/z: 249 (Mϩ), 234 (base peak). HR-MS m/z Calcd for Found: 323.1526.
C14H19NO3: 249.1362. Found: 249.1351. Anal. Calcd for C14H19NO3: C,
69.45; H, 7.68; N, 5.62. Found: C, 67.37; H, 7.81; N, 5.43.
2-Formyl-6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (5d) was
Hydrolysis of 5. General Pocedure A solution of 5 (0.35 mmol) in
EtOH (20 ml) and 20% NaOH (20 ml) was refluxed for 18 h. The reaction
mixture was concentrated in vacuo, and the residue was extracted with
obtained from 1b (692 mg, 5.52 mmol) and 2b (266 mg, 4.60 mmol) as a CHCl3. The extract was washed with brine and dried over Na2SO4. After re-
pale yellow gum. IR: 1630, 1548 cmϪ1 1H-NMR: 1.71 (3H, s, CH3), 2.80 moval of the solvent in vacuo, the residue was purified by chromatography
(2H, t, Jϭ6Hz, 4-H), 3.79 (3H, s, OCH3), 3.83 (2H, t, Jϭ6Hz, 3-H), 6.62 over SiO2 (hexane/ethyl acetate 1 : 4) to give 6. Yields are summarized in
.
(1H, d, Jϭ3 Hz, 5-H), 6.80 (1H, dd, Jϭ9, 3 Hz, 7-H), 7.18 (1H, d, Jϭ9 Hz, Table 2.
8-H), 8.61 (1H, s, CHO). 13C-NMR: 29.8 (C4), 31.3 (2ϫCH3), 35.2 (C3),
6,7-Dimethoxy-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (6a):
Colorless prisms, crystallized from ethyl acetate–hexane, mp 94—96 °C.
55.3 (OCH3), 57.5 (C1), 111.3 (C8), 113.2 (C5), 126.8 (C7), 134.0 (C4a),
135.7 (C8a), 157.9 (C6), 160.7 (CHO). LR-MS m/z: 219 (Mϩ), 204 (base [Hydrochloride salt: colorless prisms crystallized from MeOH–Et2O, mp
peak). HR-MS m/z Calcd for C13H17NO2: 219.1259. Found: 219.1230.
220—221 °C (lit.,6) mp 260—262 °C)]. IR: 2952, 1610, 1512 cmϪ1 1H-
.
1-Ethyl-2-formyl-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline NMR: 1.84 (3H, s, CH3), 2.65—3.02 (4H, m, 3-H, 4-H), 3.75 (3H, s,
(5e) was obtained from 1a (1 g, 5.52 mmol) and 2c (331 mg, 4.60 mmol) as a OCH3), 3.89 (3H, s, OCH3), 6.54 (1H, s, 8-H), 6.62 (1H, s, 5-H), 7.2—7.3
pale yellow gum. IR: 1678, 1626, 1514 cmϪ1. 1H-NMR: 0.47, 0.61 (total 3H, (5H, m, Ph). 13C-NMR: 29.6 (C4), 30.3 (CH3), 39.0 (C3), 55.7 (OCH3), 56.0
each t, Jϭ7 Hz, CH2CH3), 1.59, 1.66 (total 3H, each s, CH3), 1.80—2.04,
3.06—3.13 (2H, m, –CH2CH3), 2.62—2.74 (2H, m, 4-H), 3.59—3.67, 3.72—
3.79 (2H, m, H-3), 3.78 (3H, s, OCH3), 3.79 (3H, s, OCH3), 6.51 (1H, s, 5-
(OCH3), 58.8 (C1), 110.9 (C5), 111.6 (C8), 126.4 (C4a), 127.1 (C2Ј and
C6Ј), 127.5 (C1Ј), 127.9 (C3Ј and C5Ј), 133.9 (C4a), 147.0 (C8a), 147.6 (C6
or C7), 148.3 (C6 or C7). LR-MS m/z: 283 (Mϩ), 268 (base peak). HR-MS
H), 6.60 (1H, s, 8-H), 8.14, 8.43 (1H, s, CHO). 13C-NMR: 7.6 (CH2CH3), m/z Calcd for C18H21NO2: 283.1572. Found: 283.1572.
28.6 (C4), 29.9 (CH3), 35.1 (CH2CH3), 35.4 (C3), 55.5 (OCH3), 55.9
6-Methoxy-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (6b): A
(OCH3), 60.4 (C1), 108.4 (C5), 110.9 (C8), 127.5 (C4a), 131.9 (C8a), 147.4 pale yellow gum. (lit.,6) Hydrochloride salt, mp 284—286 °C). IR: 1608,
(C6), 147.7 (C7), 161.0 (CHO). LR-MS m/z: 263 (Mϩ), 234 (base peak). 1577, 1500 cmϪ1. H-NMR: 1.82 (3H, s, CH3), 2.67—3.04 (4H, m, 3-H, 4-
1
HR-MS m/z Calcd for C15H21NO3: 263.1519. Found: 263.1496.
H), 3.80 (3H, s, OCH3), 6.67 (1H, d, Jϭ3Hz, 5-H), 6.72 (1H, dd, Jϭ9, 3 Hz,
2-Formyl-6,7-dimethoxy-1-methyl-1-phenylsulfanylmethyl-1,2,3,4- 7-H), 6.99 (1H, d, Jϭ9 Hz, 8-H), 7.16—7.29 (5H, m, Ph). 13C-NMR: 30.4
tetrahydroisoquinoline (5f) was obtained from 1a (1.2 g, 5.52 mmol) and 2d (C4), 30.5 (CH3), 39.0 (C3), 55.1 (OCH3), 58.7 (C1), 112.1 (C7), 113.4
(763 mg, 4.60 mmol) as pale yellow plates, crystallized from MeOH– (C5), 126.4 (C8), 127.1 (C2Ј and C6Ј), 127.9 (C3Ј and C5Ј), 128.9 (C4Ј),
hexane, mp 86—88 °C. IR: 1657, 1518 cmϪ1. 1H-NMR: 1.80, 1.83 (total 3H,
134.4 (C1Ј), 136.5 (C4a), 149.0 (C8a), 157.7 (C6). LR-MS m/z: 253 (Mϩ,
each s, CH3), 2.63—2.79, 2.98—3.07 (2H, m, 4-H), 3.36—3.57 (2H, m, 3- base peak). HR-MS m/z Calcd for C17H19NO: 253.1467. Found: 253.1475.
H), 3.84 (3H, s, OCH3), 3.86 (3H, s, OCH3), 6.55, 6.57 (total 1H, each s, 5-
H), 6.60, 6.65 (total 1H, each s, 8-H), 7.1—7.3 (5H, m, Ar-H), 8.16, 8.59
6,7-Dimethoxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (6c): A color-
less gum. IR: 1620, 1579 cmϪ1. 1H-NMR: 1.48 (6H, s, 2ϫCH3), 2.74 (2H, t,
(total 1H, each s, CHO). 13C-NMR: 26.4, 27.0 (CH3), 28.6, 30.0 (C4), 34.9, Jϭ6 Hz, 4-H), 3.12 (2H, t, Jϭ6 Hz, 3-H), 3.84 (3H, s, OCH3), 3.86 (3H, s,
44.4 (C3), 44.6, 47.6 (CH2–S–), 55.6 (OCH3), 55.8, 56.0 (OCH3), 60.1, 61.7
(C1), 108.3, 108.6 (C5), 110.6, 111.3 (C8), 125.8, 126.8 (C4Љ), 127.3, 127.7 (2ϫCH3), 38.8 (C3), 52.6 (C1), 55.5 (OCH3), 55.8 (OCH3), 108.8 (C5),
OCH3), 6.54 (1H, s, 8-H), 6.67 (1H, s, 5-H). 13C-NMR: 29.7 (C4), 30.9
(C4a), 128.3, 128.8 (C3Љ and C5Љ), 129.9, 130.9 (C2Љ and C6Љ), 130.0, 131.5
111.4 (C8), 125.9 (C4a), 135.5 (C8a), 147.0 (C6 and C7). LRMS m/z: 221
(C8a), 133.6, 136.5 (C1Љ), 147.5, 147.6 (C6 or C7), 147.8, 148.0 (C6 or C7), (Mϩ), 207 (base peak). HRMS m/z Calcd for C13H19NO2: 221.1413. Found:
160.8, 162.6 (CHO). LR-MS m/z: 357 (Mϩ, base peak). HR-MS m/z Calcd 221.1410.
for C20H23NO3S: 357.1399. Found: 357.1427. Anal. Calcd for C20H23NO3S:
C, 67.20; H, 6.49; N, 3.92. Found: C, 66.94; H, 6.43; N, 3.75.
6-Methoxy-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (6d): A pale yel-
1
low gum. IR: 1608, 1576, 1500 cmϪ1. H-NMR: 1.43 (6H, s, 2ϫCH3), 2.75
2-Formyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-spirocyclopen- (2H, t, Jϭ6 Hz, 4-H), 3.12 (2H, t, Jϭ6 Hz, 3-H), 3.77 (3H, s, OCH3), 6.58
tane (5h) was obtained from 1a (2 g, 11 mmol) and 2f (462 mg, 5.5 mmol) as (1H, d, Jϭ3 Hz, 5-H), 6.73 (1H, dd, Jϭ9, 3 Hz, 7-H), 7.12 (1H, d, Jϭ9 Hz,
pale yellow plates crystallized from MeOH–hexane, mp 75—78 °C. IR: 8-H). 13C-NMR: 31.1 (C4), 31.5 (2ϫCH3), 39.1 (C3), 52.5 (C1), 55.1
1639, 1517. 1H-NMR: 1.8—2.3 (8H, m, 2Ј-H, 3Ј-H, 4Ј-H and 5Ј-H), 2.77 (OCH3), 112.4 (C7), 113.4 (C5), 127.0 (C8), 135.5 (C4a), 136.5 (C8a),
(2H, t, Jϭ6 Hz, 4-H), 3.82 (2H, t, Jϭ6 Hz, 3-H), 3.86 (3H, s, OCH3), 3.88 157.3 (C6). LR-MS m/z: 191 (Mϩ). HR-MS m/z Calcd for C12H17NO:
(3H, s, –OCH3), 6.57 (1H, s, 5-H), 6.70 (1H, s, 8-H), 8.36 (1H, s, CHO). 191.1310. Found: 191.1290.
13C-NMR: 24.0 (C3Ј and C4Ј), 28.8 (C4), 35.9 (C3), 40.8 (C2Ј and C5Ј),
55.7 (OCH3), 56.1 (OCH3), 69.1 (C1), 108.5 (C5), 111.2 (C8), 127.6 (C4a),
132.0 (C8a), 147.58 (C6 or C7), 147.64 (C6 or C7), 160.2 (CHO).
1-Ethyl-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline (6e):
colorless gum. IR: 1520 cmϪ1 1H-NMR: (3H, t, Jϭ7 Hz, CH2CH3), 1.39
(3H, s, CH3), 1.59—1.75 (1H, m, CH2CH3), 1.81—1.96 (1H, m, CH2CH3),
A
.
LM-RS: 275 (Mϩ), 205 (base peak). HM-RS m/z Mϩ Calcd for C16H21NO3: 2.621—2.77 (2H, m, H-4), 3.02—3.16 (2H, m, H-3), 3.85 (6H, s, 2ϫOCH3),
275.1521. Found: 275.1559.
6.54 (1H, s, H-5), 6.63 (1H, s, H-8). 13C-NMR: 8.1 (CH2CH3), 28.9 (CH3),
2-Formyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-spirocyclo- 30.1 (C4), 35.1 (CH2CH3), 38.9 (C3), 55.2 (C1), 55.6 (OCH3), 56.0 (OCH3),
hexane (5i) was obtained from 1a (2 g, 11 mmol) with 2g (528 mg, 5.5 109.1 (C5), 111.5 (C8), 127.1 (C4a), 135.1 (C8a), 146.9 (C6), 147.1 (C7).

February 2002
257
LR-MS m/z 235. HR-MS m/z Calcd for C14H21NO2: 235.1572. Found
295 (base peak). HR-MS m/z: Calcd for C19H21NO2: 295.1572. Found:
235.1545.
295.1578.
6,7-Dimethoxy-1-methyl-1-phenylsulfanylmethyl-1,2,3,4-tetrahydroiso-
1
quinoline (6f): A colorless gum. IR: 1582, 1574 cmϪ1. H-NMR: 1.51 (3H, References and Notes
s, CH3), 2.66—2.75 (2H, m, 4-H), 3.00—3.04 (2H, m, 3-H). 3.25 (1H, d,
Jϭ13 Hz, SCH2), 3.56 (1H, d, Jϭ13 Hz, SCH2), 3.81 (3H, s, OCH3), 3.85
(3H, s, OCH3), 6.55 (1H, s, 5-H), 6.60 (1H, s, 8-H), 7.1—7.4 (5H, m, SPh).
13C-NMR: 28.6 (CH3), 29.7 (C4), 38.6 (C3), 47.2 (SCH2), 55.5 (OCH3),
55.8 (OCH3), 60.1 (C1), 108.7 (d, C5), 111.4 (C8), 125.8 (C4Љ), 127.1 (C1Љ),
128.6 (C2Љ and C6Љ), 129.7 (C3Љ and C5Љ), 133.1 (C4a), 137.0 (C8a), 146.9
(C6 or C7), 147.3 (C6 or C7). CIMS m/z: 330 (MHϩ, base peak).
1) Lundström J., “The Alkaloids,” Vol. 21, ed. by Brossi A., Academic
Press, New York, 1893, pp. 255—327; Collins M. A., “The Alka-
loids,” Vol. 21, ed. by Brossi A., Academic Press, New York, 1893, pp.
329—358; Brossi A., “The Alkaloids,” Vol. 43, ed. by Cordell G. A.,
Academic Press, New York, 1993, pp. 119—183; Nagatsu T., Neuro-
science Res., 29, 99—111 (1997).
2) Bringmann G., Ewers C. T., Walter R., “Comprehensive Organic Syn-
thesis,” Vol. 6, ed. by Trost B. M., Fleming I., Pergamon Press, Ox-
ford, 1991, pp. 736—739.
3) Bhattacharyya S., Synlett, 1994, 1029—1030; Bhattacharyya S., Chat-
terjiee A., Williamson J. S., ibid., 1995, 1079—1080; Bhattacharyya
S., J. Org. Chem., 60, 4928—4929 (1995); Neidigh K. A., Avery M.
A., Williamson J. S., Bhattacharyya S., J. Chem. Soc., Perkin Trans. 1,
1998, 2527—2531.
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-spirocyclopentane (6h)8):
A colorless gum. IR: 1508. 1H-NMR: 1.85—1.96 (8H, m, 2Ј-H, 3Ј-H, 4Ј-H,
5Ј-H), 2.70 (2H, t, Jϭ6 Hz, 4-H), 3.08 (2H, t, Jϭ6 Hz, 3-H), 3.84 (3H, s,
OCH3), 3.85 (3H, s, OCH3), 6.52 (1H, s, 5-H), 6.66 (1H, s, 8-H). 13C-NMR:
25.2 (C3Ј and C4Ј), 29.9 (C4), 39.9 (C3), 43.0 (C2Ј and C5Ј), 55.7 (OCH3),
56.0 (OCH3), 64.5 (C1), 108.9 (C5), 111.3 (C8), 127.2 (C4a), 135.4 (C8a),
147.0 (C6 or C7), 147.3 (C6 or C7). LR-MS m/z: 247 (Mϩ), 218 (base
peak). HR-MS m/z: Calcd for C15H21NO2 (Mϩ): 247.1571. Found: 247.1571.
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline-1-spirocyclohexane (6i)8):
4) Shinohara T., Takeda A., Toda J., Sano T., Heterocycles, 46, 555—566
(1997); Toda J., Matsumoto S., Saitoh T., Sano T., Chem. Pharm.
Bull., 48, 91—98 (2000).
1
A colorless gum. IR: 1508. H-NMR: 1.25 (1H, m, 2Ј-H), 1.60—1.76 (9H,
m, 2Ј-H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 2.69 (2H, d, Jϭ14 Hz, 4-H), 3.04 (2H, t,
Jϭ6 Hz, 3-H), 3.84 (3H, s, OCH3), 3.87 (3H, s, OCH3), 6.54 (1H, s, 5-H),
6.74 (1H, s, 8-H). 13C-NMR: 21.6 (C3Ј and C5Ј), 25.5 (C4), 30.2 (C4Ј), 37.7
(C2Ј and C6Ј), 38.2 (C3), 54.2 (C1), 55.6 (OCH3), 56.0 (OCH3), 109.0 (C5),
111.4 (C8), 126.6 (C4a), 127.0 (C8a), 146.9 (C6 or C7), 147.0 (C6 or C7).
LR-MS m/z: 261 (Mϩ), 218 (base peak). HR-MS m/z: Calcd for C16H23NO2:
261.1726. Found: 261.1698.
5) Hodgkiss J. P., Sherriffis H. J., Cottrell D. A., Olverman H. J., Shi-
rakawa K., Kelly J. S., Kuno A., Okubo M., Bucher S. P., Ovlverman
H. J., Eur. J. Pharmacol., 240, 219—227 (1993); Sherriffis H. J., Shi-
rakawa K., Kelly J. S., Olverman H. J., Kuno A., Okubo M., Bucher S.
P., ibid., 247, 319—324 (1993).
6) The 1,2,3,4-tetrahydroisoquinlines (6a) and (6b) have been synthe-
sized in multi-steps using methylation at C1-position by the Grignard
reaction of isoquinoline salt prepared by the N-benzylation of 1-aryl-
3,4-dihydroisoquinolines in a good overall yield. [Ohkubo M., Kuno
A., Katsuta K., Ueda Y., Shirakawa K., Nakanishi H., Nakanishi I., Ki-
noshita, T., Takasugi H., Chem. Pharm. Bull., 44, 95—102 (1996).]
7) Yokoyama A., Ohwada T., Shudo K., J. Org. Chem., 64, 611—617
(1999).
6,7-Dimetoxy-1,2,3,4-tetrahydoisoquinoline-1-spiro-1Ј-indane (6j):
A
colorless gum. IR: 1508. 1H-NMR: 2.3—2.5 (2H, m, 4-H), 2.74,(1H, dt,
Jϭ16, 4 Hz, 3Ј-H), 2.9—3.0 (2H, m, 2Ј-H, 3Ј-H), 3.1—3.2 (3H, m, 2Ј-H, 3-
H), 3.62 (3H, s, OCH3), 3.86 (3H, s, OCH3), 6.28 (1H, s, 5-H), 6.60 (1H, s,
8-H), 6.90 (1H, d, Jϭ8 Hz, 4Ј-H), 7.12 (1H, t, Jϭ8 Hz, 5Ј-H), 7.22 (1H, t,
Jϭ8 Hz, 6Ј-H) 13C-NMR: 29.7 (C3Ј), 29.9 (C2Ј), 40.2 (C4), 42.4 (C5), 55.7
(OCH3), 55.8 (OCH3), 68.3 (C1), 110.6 (C5), 110.9 (C8), 124.2 (C4Ј), 124.6
(C5Ј), 126.5 (C6Ј), 127.5 (C7Ј), 127.9 (C7aЈ), 133.5 (C3aЈ), 143.7 (C4a),
147.1 (C8a), 147.4 (C6 or C7), 150.1 (C6 or C7). LR-MS m/z: 295 (Mϩ),
8) Meyers A. I., Du B., Gonzales M. A., J. Org. Chem., 55, 4218—4220
(1990).