A synthesis of 3-phenyl-1,2,3,4-tetrahydroisoquinoline and 2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine via Pummerer-type cyclization: Enhancing effect of boron trifluoride diethyl etherate on the cyclization

Article abstract of DOI:10.1248/cpb.49.979

A synthesis of 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and 7,8-dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3,4-dimethoxyphenyl)methyl-1-phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3,4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a,b under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dicationic intermediate, sulfonium-carbenium dication (23).

Full text of DOI:10.1248/cpb.49.979

August 2001
Chem. Pharm. Bull. 49(8) 979—984 (2001)
979
A Synthesis of 3-Phenyl-1,2,3,4-tetrahydroisoquinoline and
2-Phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine via Pummerer-Type
Cyclization: Enhancing Effect of Boron Trifluoride
Diethyl Etherate on the Cyclization
Toshiaki SAITOH, Tsuyoshi ICHIKAWA, Yoshie HORIGUCHI, Jun TODA, and Takehiro SANO*
Showa Pharmaceutical University, 3–3165, Higashi-tamagawagakuen, Machida, Tokyo 194–8543, Japan.
Received February 20, 2001; accepted April 24, 2001
A synthesis of 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and 7,8-dimethoxy-2-phenyl-
1,2,4,5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3,4-dimethoxyphenyl)methyl-1-
phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3,4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-
ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a,b
under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as
a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive
reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose
that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dica-
tionic intermediate, sulfonium-carbenium dication (23).
Key words 1,2,3,4-tetrahydroisoquinoline; 1,2,4,5-tetrahydro-3H-3-benzazepine; Pummerer reaction; boron trifluoride diethyl
etherate; sulfonium-carbenium dication
In a series of papers we reported the syntheses of 1,2,3,4- lamine (1a) and (3,4-dimethoxyphenyl)ethylamine (1b) as
tetrahydroisoquinolines,1) 1,2,3,4-tetrahydroquinolines,2) follows (Chart 2). Condensation of 1a, b with phenylsulfanyl-
2,3,4,5-tetrahydro-1H-3-benzazepines,3) 2-quinolones,4) ery- acetophenone (2) in titanium (IV) isopropoxide10) followed
thrinan,5) homoerythrinan,6) isopavine and pavine alkaloids7) by NaBH4 reduction of the resulting imines (3a, b) afforded
using an aromatic cyclization of the sulfonium ion in situ the secondary amines (4a, b) in good yields. Formylation of
formed from a sulfinyl precursor (Pummerer reaction). The 4a, b and then oxidation of the resulting N-formate (5a, b)
aromatic cyclization in the reaction using trifluoroacetic an- with sodium metaperiodate produced 6a, b in good overall
hydride (TFAA) smoothly proceeded at room temperature yields. All the products were characterized by MS, IR, and
when the reactive center of the cyclizing benzene ring was 1H- and 13C-NMR spectra (see Experimental).
activated by an electron-donating group. Furthermore, we
found that the Pummerer substrate, which lacks an electron- Pummerer Reaction
donating group on the cyclizing benzene ring, requires boron
The sulfoxide (6a) on treatment with TFAA in benzene at
trifluoride diethyl etherate (BF3·Et2O) as an additive reagent room temperature yielded two products, a vinyl sulfide (8a)
to induce the aromatic cyclization.1,2) Thus, the investigations as a major product (53%) and a 1,2,3,4-tetrahydroisoquino-
demonstrated that the Pummerer-type cyclization reaction is line (7a) as a minor one (12%). The relative stereochemistry
highly effective and widely applicable for the construction of of the C3-phenyl and C4-SPh groups of 7a was determined
1
six- and seven-membered nitrogen heterocycles.
as trans by the H-NMR spectral analysis. The spectrum ex-
In order to expand the utility of this methodology, we hibits complex signals attributable to the rotational iso-
designed a synthesis of 1,2,3,4-tetrahydroisoquinoline and merism of the N–CO bond. However, the pair of doublets ap-
1,2,4,5-tetrahydro-3H-3-benzazepine derivatives bearing a pearing at d 4.51 with Jϭ16 Hz and d 5.11 with Jϭ17 Hz
phenyl group on the nitrogen-containing ring. The com- can be assigned to the C3-H, and the other pair of doublets at
pounds are expected to have some biological activities. For d 4.00 with Jϭ17 Hz and d 4.17 with Jϭ16 Hz to the C4-H.
example, 3-substituted 1,2,3,4-tetrahydroisoquinolines are The large coupling constants indicated that the protons of C3
known to possess phencyclidine-like effects.8)
and C4 are arranged in trans-diaxial orientation. Thus, the
Although the synthesis of 2-substituted 3-benzazepine de- C–C bond formation of 6a proceeded in a highly stereo-se-
rivatives was achieved by multi-steps using a ring expansion lective manner.
reaction of 1-substituted 1,2,3,4-tetrahydroisoquinoline de-
The result obtained by the reaction of 6a is in strong con-
rivatives as a key step,9) a simple and short-step method has trast to that of the Pummerer substrate lacking the phenyl
not been developed. The route via the Pummerer-type cy- group, N-(3,4-dimethoxyphenyl)methyl-2-(phenylsulfinyl)eth-
clization reaction shown in Chart 1 should provide a conve- ylformamide (11), which underwent the cyclization to give
nient method for preparing nitrogen heterocycles bearing a
phenyl group because all the starting materials are readily
available.
Results and Discussion
N-Formyl sulfoxides (6a, b), substrates of the Pummerer
reaction, were prepared from (3,4-dimethoxyphenyl)methy-
Chart 1
To whom correspondence should be addressed. e-mail: t-sano@ac.shoyaku.ac.jp
© 2001 Pharmaceutical Society of Japan

980
Vol. 49, No. 8
Chart 2
Chart 3
the 1,2,3,4-tetrahydroisoquinoline (12) in a quantitative constants indicated that the protons of C1 and C2 are
yield.1a) The undesired result, however, was improved when arranged in cis orientation. Thus, the C–C bond formation of
BF3·Et2O was used as an additive reagent of the Pummerer 6b also proceeded in a highly stereo-selective manner, which
reaction. That is, the sulfoxide (6a) was treated with TFAA produced a stereochemical result different from that of 6a.
in benzene at room temperature for 5 min, and then The compound (7b), on treatment with p-toluenesulfonic
BF3·Et2O was added to this solution. This mixture was al- acid (p-TsOH) in benzene under heating for 1 h, gave 9b in
lowed to react for a further 3 h at room temperature. Thus, good yield, thus proving that 9b is an elimination product of
the reaction produced 7a in 62% yield, although 8a still ac- the phenylsulfanyl group from 7b.
companied it as a minor product (3%).
Reductive removal of the phenylsulfanyl group of 7a, b
The sulfoxide (6b), a homologous substrate of 6a, when proceeded on treatment with NiCl2–NaBH4 in MeOH–THF
treated with TFAA in benzene at room temperature for 5.5 h, to give N-formyl derivatives (13a, b) in good yields. Depro-
only produced the vinyl sulfide (8b) in 46% yield. No ben- tection of the N-formyl group was readily achieved by con-
zazepine derivative was obtained. However, this situation ventional methods. Alkaline hydrolysis of 13a, b gave the 3-
also changed when BF3·Et2O was used as an additive reagent phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and the 2-phenyl-
as described above. Thus, the sulfoxide (6b) underwent the 3-benzazepine (14b), respectively. Reduction of 13a, b with
cyclization to give 2-phenyl-1-phenylsulfanyl-3-benzazepine LiAlH4 gave the corresponding N-methyl derivatives (15a,
(7b) in 46% yield and 2-phenyl-4,5-dihydro-3-benzazepine b), respectively.
(9b) in 8% yield. The relative stereochemistry of the C1-SPh
The results clearly demonstrated that the reaction induced
and C2-phenyl groups of 7b was determined as cis by the 1H- two irreversible pathways, the cyclization or the double bond
NMR spectral analysis. The spectrum also exhibits complex migration, via the initially formed sulfonium ion (10) in a
signals attributable to the rotational isomerism of the N–CO competitive manner (Chart 3). The phenyl group present at b
bond. But the pair of doublets appearing at d 4.48 with position of the phenylsulfinyl group facilitated the double
Jϭ4.3 Hz and d 4.93 with Jϭ3.6 Hz can be assigned to the bond migration of 10 into 8 since the double bond is stabi-
C1-H, and the other pair of doublets at d 4.73 with Jϭ4.3 Hz lized by conjugation with the phenyl group. As a result, the
and d 5.04 with Jϭ3.6 Hz to the C2-H. The small coupling reaction retarded the aromatic cyclization leading to either

August 2001
981
Chart 4
Chart 5
isoquinoline ring or benzazepine ring.
cyclized product is a congested isoindole derivative with
To examine whether the cyclized products (7) are formed bulky groups. On the other hand, the immonium ion (17b)
through the corresponding vinyl sulfides (8) under the acidic generated from 8b induced a cyclization reaction different
conditions, we carried out acid-catalyzed reactions of 8 from the Pummerer-type cyclization to give the 1,2,3,4-
(Chart 4). Treatment of 8a or 8b with BF3·Et2O in benzene tetrahydroisoquinoline derivative (18). The steric congestion
at room temperature (the Pummerer reaction condition) for in 19 due to two bulky substituents positioned at C-1 proba-
24 h did not induce any reaction and the starting material was bly causes the ring cleavage to give the seco-derivative (19)
recovered almost quantitatively. Treatment of 8a with p- as shown in Chart 4.
TsOH in benzene under reflux yielded two products, an iso-
The stereo-structures of the vinyl sulfide (8a) and its geo-
meric vinyl sulfide (16a) (50%) and 2 (36%), with recovery metric isomer (16a) were deduced as follows. The compound
of the starting vinyl sulfide (8a) (6%). Compound 7a was not (8a) is a kinetic product of the Pummerer reaction since this
yielded to any extent.
was formed exclusively from the sulfonium ion (10a). On the
The vinyl sulfide (8b) on similar treatment with p-TsOH other hand, the isomer (16a) is a thermodynamic product of
in benzene under reflux, produced the 1,2,3,4-tetrahydroiso- the acid-catalyzed E–Z isomerization reaction since 8a and
quinoline derivative (18) (21%) and the seco-product (19) 16a are equilibrated in favor of the latter isomer. The heat of
(53%), with recovery of the starting vinyl sulfide (8b) (21%). formation calculated by MNDO-PM3 showed that the Z-
Neither benzazepine (7b) nor the isomeric vinyl sulfide (16b) form (Ϫ5.12720 kcal/mol) is more stable than the corre-
was formed in this reaction. The structure of 18 was con- sponding E-form (Ϫ4.02976 kcal/mol), thus the stereo-struc-
firmed by the conversion to the 1-methyl-1-phenyl-1,2,3,4- ture of 8a and 16a was assigned as E-and Z-form, respec-
tetrahydroisoquinoline (21)11) by reductive elimination of the tively.
phenylsulfanyl group followed by hydrolysis of 20. LiAlH4
Finally, we wish to discuss the role of BF3·Et2O on the
reduction of 20 yielded the corresponding N-methyl deriva- Pummerer-type cyclization reaction (Chart 5). This and pre-
tive (22). Thus, the results clearly demonstrated that the cy- vious results of our investigations1a—d,2,3) showed that the
clized products (7) were not produced via the acid-catalyzed Lewis acid of the additive reagent dramatically enhanced the
cyclization reaction of 8.
cationic cyclization in the Pummerer reaction, in particular,
The acid-catalyzed reactions of 8 are rationalized in terms when the nucleophilic benzene ring is not activated by the
of the intervention of immonium ions (17). The E–Z isomer- electron-donating group. This situation is reminiscent of su-
ization between 8a and 16a apparently occurs via the inter- peracid-catalyzed Friedel–Craft12) and Pictet–Spengler reac-
mediate (17a). Compound 2 is produced by hydrolysis of the tions13) reported by Shudo and his collaborators. In their ki-
immonium moiety of 17a. The aromatic cyclization of 17a netic studies, they clearly proved that the acceleration in the
may be prohibited by steric hindrance since the anticipated superacid-catalyzed reactions can be attributed to the in-

982
Vol. 49, No. 8
hexane/ethyl acetate (3 : 1) to give 5a (16.4 g, 96%) as a pale yellow gum.
N-(3,4-Dimethoxyphenyl)methyl-1-phenyl-(2-phenylsulfanyl)ethylfor-
mamide (5a) IR (film): 1668. H-NMR: 3.0—4.2 (total 4H, m, ArCH2–,
PhSCH2CHϽ), 3.74, 3.81, 3.86 (total 6H, each s, OCH3ϫ2), 4.3—4.7,
5.2—5.4 (total 1H, m, PhSCH2CHϽ), 6.5—6.8 (total 3H, m, ArH), 7.0—7.5
volvement of dicationic intermediates, and revealed that the
true electrophiles inducing the cyclizations are dicationic
super-electrophiles.
1
Thus, as a possible pathway we postulate that the
BF3·Et2O-catalyzed cyclization of the Pummerer reaction (total 10H, m, PhHϫ2), 8.36, 8.44 (total 1H, each s, CHO). HR-EIMS m/z
(Mϩ): Calcd for C24H25NO3S: 407.1555. Found: 407.1565.
N-2-(3,4-Dimethoxyphenyl)ethyl-1-phenyl-(2-phenylsulfanyl)-
ethylformamide (5b) From 4a (8.9 g, 22.6 mmol); column chromatography
can involve a dicationic intermediate. For example, the sulfo-
nium-carbenium dication (23) can be generated by the coor-
dination of the Lewis acid to the cationic sulfur atom of the
sulfonium ion (10). The dicationic species that can act as a
super-electrophile may be a true electrophile in the
BF3·Et2O-catalyzed cyclization of the Pummerer reaction.
Mechanistic studies of this cyclization are now under way.
(CHCl3) gave 5b (9.6 g, 99%) as a pale yellow gum. IR (film): 1652, 1515.
1H-NMR: 2.0—3.8 (total 6H, m, ArCH2CH2–, PhSCH2CHϽ), 3.79, 3.82
(total 6H, each s, OCH3ϫ2), 4.5—4.8, 5.3—5.6 (total 1H, each m,
PhSCH2CHϽ), 6.4—6.8 (total 3H, m, ArH), 7.2—7.5 (total 10H, m,
PhHϫ2), 8.01, 8.29 (total 1H, each s, CHO). HR-EIMS m/z (Mϩ): Calcd for
C25H27NO3S: 421.1709. Found: 421.1701.
Oxidation of 5a with NaIO4. Typical Procedure A solution of 5a
(15.6 g, 38.3 mmol) and NaIO4 (13.0 g, 57.45 mmol) in MeOH (200 ml) and
Experimental
General Notes Unless otherwise noted, the following procedures were H2O (50 ml) was stirred at room temperature for 1.5 h. After removal of in-
adopted. Melting points were taken on a YANACO SP-M1 hot-stage melting organic precipitates by filtration, the filtrate was concentrated in vacuo. The
point apparatus and are uncorrected. IR spectra were obtained as films for residue was extracted with CHCl3. The product was chromatographed with
oils and gums, and KBr disks for solids with a HORIBA FT-710 spectropho-
hexane/ethyl acetate (1 : 3) to give 6a (15.8 g, 97%) as a yellow gum.
N-(3,4-Dimethoxyphenyl)methyl-1-phenyl-(2-phenylsulfinyl)ethylform-
tometer, and are given in cmϪ1. NMR spectra were measured on a JEOL
JNM-AL 300 (1H, 300 MHz; 13C, 75 MHz) or a JEOL JNM-a500 (1H, 500 amide (6a) IR: 1670, 1515. 1H-NMR: 2.9—4.6 (total 4H, m, ArCH2–,
MHz; 13C, 125 MHz) spectrometer in CDCl3 with tetramethylsilane as an in- PhS(O)CH2CHϽ), 3.72, 3.75, 3.77, 3.85, 3.86, 3.87, 3.91 (total 6H, each s,
ternal standard, and the chemical shifts are given in d values. LR-EIMS was OCH3ϫ2), 4.9—5.6 (total 1H, m, PhS(O)CH2CHϽ), 6.4—7.8 (total 13H,
obtained with a JEOL JMS-AM20 at 70 eV using a direct inlet system, and
m, ArH, PhHϫ2), 8.22, 8.46, 8.50, 8.75 (total 1H, each s, CHO). HR-EIMS
figures in parentheses indicate the relative intensities. HR-EIMS was taken m/z (Mϩ): Calcd for C24H25NO4S: 423.1501. Found: 423.1483.
on a JEOL JMS-D300 spectrometer at 70 eV using a direct inlet system.
HR-FABMS was measured with a JEOL JMS-HX110A spectrometer (reac-
N-2-(3,4-Dimethoxyphenyl)ethyl-1-phenyl-(2-phenylsulfinyl)ethylform-
amide (6b) From 5b (9.6 g, 22.8 mmol); column chromatography (hexane/
tant gas: xenon, matrix: glycerol). Elemental analysis was recorded on a ethyl acetate 1 : 1) gave 6b (9.6 g, 97%) as a yellow gum. IR: 1670, 1515.
YANACO CHN Corder MT-3. The organic extract from each reaction mix-
1H-NMR: 2.1—4.7 (total 6H, m, ArCH2CH2–, PhSCH2CH–), 3.78, 3.81, 3.83,
ture was washed with brine, dried over anhydrous Na2SO4, and concentrated 3.85 (total 6H, each s, OCH3ϫ2), 4.3—5.5 (total 1H, m, PhSCH2CH–),
in vacuo to dryness.
6.4—6.9 (total 3H, m, ArH), 7.2—7.8 (total 10H, m, PhHϫ2), 7.79, 8.08,
Materials Pre-coated silica gel glass plates [Merck Silica gel, Art5715] 8.36, 8.61 (total 1H, each s, CHO). HR-EIMS m/z (Mϩ): Calcd for
were used for analytical thin layer chromatography (TLC). Wakogel C-200 C25H27NO4S: 437.1661. Found: 437.1684.
was used for column chromatography. 1-Phenylsulfanylacetophenone (2)
was prepared according to the known method from phenacyl bromide and
diphenyl disulfide.14)
Pummerer Reaction of 6a i) Method A: A solution of TFAA (2.59 g,
12.33 mmol) in benzene (5 ml) was added to a solution of 6a (1.043 g, 2.47
mmol) in benzene (45 ml) at room temperature, and the mixture was stirred
Preparation of 4a. Typical Procedure A mixture of 1a (9 g, 53.9 for 24 h under an argon atmosphere at room temperature. The reaction mix-
mmol), 2 (12.3 g, 53.9 mmol), and titanium (IV) isopropoxide (20 g, 81 ture was concentrated in vacuo, and the product was chromatographed with
mmol) was heated at 80 °C for 3 h under an argon atmosphere. After cool-
ing, the reaction mixture was diluted with MeOH (100 ml). To this solution,
hexane/ethyl acetate (4 : 1) to give 7a (124 mg, 12%) and 8a (530 mg, 53%).
ii) Method B: A solution of TFAA (2.53 g, 12 mmol) in benzene (5 ml)
NaBH4 (2 g, 53.9 mmol) was added in small portions under ice-cooling. The was added to a solution of 6a (1.02 g, 2.4 mmol) in benzene (40 ml), and the
reaction mixture was stirred at room temperature for 1 h and concentrated in mixture was stirred at room temperature for 5 min under an argon atmos-
vacuo. Water (ca. 40 ml) was added to the residue, and the mixture was di- phere. To this mixture was slowly added BF3·Et2O (1.03 g, 7.3 mmol) and
luted with MeOH (ca. 500 ml). After removal of precipitated inorganic ma- the mixture was further stirred for 3 h. The reaction mixture was neutralized
terials by filtration, the filtrate was concentrated in vacuo. The residue was with 5% NaOH and extracted with CHCl3. The product was chro-
dissolved in water and extracted with CHCl3. Column chromatography of matographed with hexane/ethyl acetate (6 : 1) to give 7a (602 mg, 62%) and
the product with hexane/ethyl acetate (6 : 1) gave 4a (16 g, 79%) as a yellow 8a (33 mg, 2%).
*
*
gum.
N-(3,4-Dimethoxyphenyl)methyl-(1-phenyl-2-phenylsulfanyl)ethyl-
(3S ,4R )-2-Formyl-6,7-dimethoxy-3-phenyl-4-phenylsulfanyl-1,2,3,4-
tetrahydroisoquinoline (7a) A pale yellow gum. IR (film): 1675, 1517.
1
amine (4a) IR (film): 3309, 1513. H-NMR: 1.96 (1H, br s, ϾNH), 2.8— 1H-NMR: 3.83, 3.84, 3.87 (total 6H, each s, OCH3ϫ2), 4.00, 4.17 (total 1H,
4.1 (5H, m, ArCH2–, PhSCH2CHϽ), 3.84 (3H, s, OCH3), 3.86 (3H, s,
each d, Jϭ17, 16 Hz, C3-H), 4.51, 5.11 (total 1H, each d, Jϭ16, 17 Hz, C4-
OCH3), 6.77 (3H, s, ArH), 7.0—7.5 (10H, m, PhHϫ2). 13C-NMR: 42.5 (t), H), 4.87, 4.90 (total 2H, each s, C1-H), 6.50, 6.55, 6.70, 6.81 (total 2H, each
51.0 (t), 55.8 (q), 55.9 (q), 60.3 (d), 111.2 (d), 111.5 (d), 120.1 (d), 126.3 s, ArH), 6.9—7.7 (total 10H, m, Phϫ2), 8.28, 8.46 (total 1H, each s, CHO).
(d), 127.3 (dϫ2), 127.6 (d), 128.6 (dϫ2), 128.9 (dϫ2), 129.9 (dϫ2), 132.9
(s), 135.6 (s), 142.6 (s), 148.0 (s), 148.9 (s). HR-EIMS m/z (Mϩ): Calcd for
C23H25NO2S: 379.1607. Found: 379.1645.
HR-EIMS m/z (Mϩ): Calcd for C24H23NO3S: 405.1396. Found: 405.1363.
N-(3,4-Dimethoxyphenyl)methyl-N-[(E)-1-phenyl-2-(phenylsulfanyl)-
ethenyl]formamide (8a) A colorless gum. IR (film): 1683, 1515. 1H-
N-2-(3,4-Dimethoxyphenyl)ethyl-1-phenyl-(2-phenylsulfanyl)ethyl- NMR: 3.80 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.52 (2H, s, ArCH2–), 6.10
amine (4b) From 1b (4.76 g, 26.3 mmol) and 2 (6.0 g, 26.3 mmol); column (1H, s, PhSCHϭ), 6.6—6.9 (3H, m, ArH), 7.0—7.5 (10H, m, PhHϫ2), 8.47
chromatography (hexane/ethyl acetate 6 : 1) gave 4b (8.92 g, 86%) as a yel- (1H, s, CHO). 13C-NMR: 46.5 (t), 55.79 (q), 55.82 (q), 110.9 (d), 111.9 (d),
low gum. IR (film): 3297, 1589, 1515. 1H-NMR: 1.78 (1H, br s, >NH),
121.3 (d), 121.4 (d), 127.0 (d), 128.68 (dϫ2), 128.70 (dϫ2), 128.8 (s),
2.5—3.4 (6H, m, ArCH2CH2–, PhSCH2CHϽ), 3.68 (1H, dd, Jϭ4, 9 Hz, 128.9 (dϫ2), 129.2 (dϫ2), 129.4 (d), 133.4 (s), 135.3 (s), 137.6 (s), 148.5
PhSCH2CHϽ), 3.84 (3H, s, OCH3), 3.85 (3H, s, OCH3), 6.6—6.9 (3H, m, (s), 148.9 (s), 162.0 (d). HR-EIMS m/z (Mϩ): Calcd for C24H23NO3S:
ArH), 7.2—7.3 (10H, m, PhHϫ2). 13C-NMR: 35.7 (t), 42.3 (t), 48.9 (t), 55.7
(q), 55.9 (q), 61.5 (d), 111.3 (d), 112.0 (d), 120.6 (d), 126.3 (d), 127.1
(dϫ2), 127.4 (d), 128.4 (dϫ2), 128.8 (dϫ2), 129.9 (dϫ2), 132.6 (s), 135.5
405.1395. Found: 405.1379.
Pummerer Reaction of 6b i) Method A: A solution of TFAA (204 mg,
0.97 mmol) in benzene (5 ml) was added to a solution of 6b (85 mg, 0.195
(s), 142.6 (s), 147.4 (s), 148.9 (s). HR-FABMS m/z (MHϩ): Calcd for mmol) in benzene (10 ml) at room temperature, and the mixture was stirred
C24H28NO2S: 394.1841. Found: 394.1819.
for 5.5 h under an argon atmosphere. The reaction mixture was concentrated
Formylation of 4a. Typical Procedure To a solution of 4a (15.8 g, 41.7 in vacuo, and the product was chromatographed with CHCl3 to give 8b (37
mmol) in formic acid (20 ml) was slowly added at 0 °C the mixed anhydride mg, 46%) as a pale yellow gum.
prepared from formic acid (50 ml) and acetic anhydride (66 ml), and then the
ii) Method B: A solution of TFAA (4.77 g, 22.7 mmol) in benzene (5 ml)
mixture was heated at 60 °C for 1 h. The reaction mixture was concentrated was added to a solution of 6b (1.98 g, 4.53 mmol) in benzene (40 ml), and
in vacuo and extracted with CHCl3. The residue was chromatographed with the mixture was stirred at room temperature for 5 min under an argon atmos-

August 2001
983
phere. To this mixture was slowly added BF3·Et2O (1.93 g, 13.6 mmol) and
7,8-Dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine (14b)
the mixture was further stirred for 1.5 h. The reaction mixture was neutral- From 13b (200 mg, 0.64 mmol); heating for 25 h under reflux and chro-
ized with 5% NaOH and extracted with CHCl3. The product was chro- matography with hexane/ethyl acetate (1 : 10) gave 14b (131 mg, 72%) as a
matographed with hexane/ethyl acetate (5 : 1) to give 7b (870 mg, 46%) and
9b (115 mg, 8%).
colorless gum (lit.,9a) HCl salt, mp 172—174 °C). IR (film): 3320, 1517. 1H-
NMR: 1.87 (1H, br s, ϾNH), 2.6—4.0 (7H, m, C1, 2, 4, 5-H), 3.84 (3H, s,
N-2-(3,4-Dimethoxyphenyl)ethyl-N-[(E)-1-phenyl-2-(phenylsulfanyl)- OCH3), 3.87 (3H, s, OCH3), 6.64 (1H, s, C6 or 9-H), 6.68 (1H, s, C6 or 9-
1
ethenyl]formamide (8b) IR: 1673, 1515. H-NMR: 2.77 (2H, t, Jϭ7 Hz, H), 7.2—7.5 (5H, m, PhH). 13C-NMR: 38.5 (t), 46.6 (t), 49.0 (t), 55.9
ArCH2CH2–), 3.62 (2H, t, Jϭ7 Hz, ArCH2CH2–), 3.79 (3H, s, OCH3), 3.82 (qϫ2), 63.8 (d), 113.3 (d), 113.7 (d), 126.3 (dϫ2), 127.0 (d), 128.4 (dϫ2),
(3H, s, OCH3), 6.15 (1H, s, PhSCHϭCϽ), 6.6—6.8 (3H, m, ArH), 7.2—7.7
132.9 (s), 134.5 (s), 146.1 (s), 146.6 (s), 146.8 (s). HR-EIMS m/z (Mϩ):
(10H, m, PhHϫ2), 8.40 (1H, s, CHO). 13C-NMR: 33.4 (t), 44.4 (t), 55.8 Calcd for C18H21NO2: 283.1572. Found: 283.1582.
(qx2), 111.1 (d), 111.9 (d), 120.7 (d), 121.1 (d), 127.3 (d), 128.6 (dϫ2),
LiAlH4 Reduction of 13a. Typical Procedure LiAlH4 (26 mg, 0.68
128.7 (dϫ2), 128.9 (d), 129.3 (dϫ2), 129.4 (dϫ2), 130.7 (s), 133.4 (s), mmol) was added to a solution of 13a (100 mg, 0.34 mmol) in dry THF (15
135.1 (s), 137.1 (s), 147.6 (s), 148.8 (s), 162.3 (d). HR-EIMS m/z (Mϩ):
Calcd for C25H25NO3S: 419.1552. Found: 419.1537.
ml), and the mixture was heated under reflux for 30 min. Et2O, saturated
with water, was added to the reaction mixture and insoluble material was fil-
*
*
(1S ,2S )-3-Formyl-7,8-dimethoxy-2-phenyl-1-phenylsulfanyl-1,2,4,5- tered off. The product was chromatographed with CHCl3 to give 15a (86 mg,
tetrahydro-3H-3-benzazepine (7b) A pale yellow gum. IR: 1670. 1H- 91%) as a pale yellow gum.
NMR: 2.64—3.33 (total 2H, m, C4-H, C5-H), 3.50—4.53 (total 2H, m, C4-
H, C5-H), 4.48, 4.93 (total 1H, each d, Jϭ4.3, 3.6 Hz, C1-H), 4.73, 5.04
6,7-Dimethoxy-2-methyl-3-phenyl-1,2,3,4-tetrahydroisoquinoline
(15a) IR (film): 1519. H-NMR: 2.17 (3H, s, ϾNCH3), 2.8—4.1 (5H, m,
1
(total 1H, each d, Jϭ4.3, 3.6 Hz, C2-H), 3.63, 3.72, 3.85 (total 6H, each s, C1, C3, C4-H), 3.83 (3H, s, OCH3), 3.85 (3H, s, OCH3), 6.57 (2H, s, ArH),
OCH3ϫ2), 6.31, 6.37, 6.50, 6.60 (total 2H, each s, C6 or 9-H), 7.0—7.6
7.2—7.5 (5H, m, PhH). 13C-NMR: 37.7 (t), 43.3 (q), 55.85 (q), 55.92 (q),
(total 10H, m, PhHϫ2), 8.28, 8.38 (total 1H, each s, CHO). HR-EIMS m/z 58.2 (t), 66.5 (d), 108.9 (d), 110.7 (d), 126.20 (s), 126.24 (s), 127.3 (d),
(Mϩ): Calcd for C25H25NO3S: 419.1552. Found: 419.1514.
127.9 (dϫ2), 128.5 (dϫ2), 142.6 (s), 147.3 (s), 147.6 (s). HR-EIMS m/z
3-Formyl-7,8-dimethoxy-2-phenyl-4,5-dihydro-3H-3-benzazepine (9b) (Mϩ): Calcd for C18H21NO2: 283.1570. Found: 283.1565.
Colorless prisms crystallized from Et2O, mp 154—156 °C. IR: 1670, 1521.
7,8-Dimethoxy-3-methyl-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine
(15b) From 13b (200 mg, 0.64 mmol); chromatography with hexane/ethyl
1H-NMR: 3.15 (2H, t, Jϭ5 Hz, C5-H), 3.89 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 4.03 (2H, t, Jϭ5 Hz, C4-H), 6.14 (1H, s, C1-H), 6.71 (1H, s, C6 or acetate (1 : 4) gave 15b (166 mg, 87%) as colorless plates crystallized from
C9-H), 6.76 (1H, s, C6 or C9-H), 7.3—7.6 (5H, m, PhH), 8.22 (1H, s,
hexane–Et2O, mp 112–114 °C (lit.,9b) mp 156—157 °C from MeOH). IR:
CHO). 13C-NMR: 36.6 (t), 42.0 (t), 55.9 (q), 56.0 (q), 113.2 (d), 115.3 (d), 1517. 1H-NMR: 2.06 (3H, s, ϾNCH3), 2.2—4.0 (7H, m, C1, C2, C4, C5-H),
118.4 (d), 126.2 (s), 127.8 (dϫ2), 128.6 (d), 128.8 (dϫ2), 131.2 (s), 138.1 3.81 (3H, s, OCH3), 3.87 (3H, s, OCH3), 6.59 (1H, s, C6 or C9-H), 6.68 (1H,
(s), 138.7 (s), 147.1 (s), 147.9 (s), 162.4 (d). LR-EIMS m/z: 309 (Mϩ, 100).
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.58; H,
6.30; N, 4.47.
s, C6 or C9-H), 7.2—7.4 (5H, m, PhH). 13C-NMR: 35.1 (t), 44.1 (t), 45.5
(q), 56.0 (qx2), 57.8 (t), 71.0 (d), 112.4 (d), 113.4 (d), 127.0 (d), 127.1
(dϫ2), 128.5 (dϫ2), 132.4 (s), 134.2 (s), 145.7 (s), 146.9 (s), 147.2 (s). HR-
Treatment of 7b with p-TsOH A solution of 7b (176 mg, 0.42 mmol) EIMS m/z (Mϩ): Calcd for C19H23NO2: 297.1729. Found: 297.1755.
and p-TsOH·H2O (360 mg, 2.1 mmol) in benzene (20 ml) was heated under
reflux for 1 h. The product was chromatographed with hexane/ethyl acetate and p-TsOH·H2O (187 mg, 1.1 mmol) in benzene (15 ml) was heated under
(5 : 1) to give 9b (99 mg, 76%). reflux for 7 h using a Dean-Stark water separator. The reaction mixture was
Reaction of 8a with p-TsOH A solution of 8a (108 mg, 0.27 mmol)
Reductive Desulfurization of 7a. Typical Procedure NaBH4 (980 mg, concentrated in vacuo, and the residue was extracted with CHCl3. The prod-
25.79 mmol) was added in small portions to a stirred solution of 7a (500 mg, uct was chromatographed with hexane/ethyl acetate (1 : 1) to give 2 (22 mg,
1.23 mmol) and NiCl2·6H2O (980 mg, 25.79 mmol) in MeOH–THF (3 : 1) 36%), 16a (54 mg, 50%), and the starting material 8a (7 mg, 6%).
(30 ml) under ice-cooling. The mixture was stirred at room temperature for 1
N-(3,4-Dimethoxyphenyl)methyl-N-[(Z)-1-phenyl-2-phenylsul-
h. After removal of inorganic materials by filtration, the filtrate was concen- fanylethenyl]formamide (16a) A pale yellow gum. IR (film): 1670, 1515.
trated in vacuo. The residue was extracted with CHCl3. The product was 1H-NMR: 3.74 (3H, s, OCH3), 3.83 (3H, s, OCH3), 4.60 (2H, s, ArCH2–),
chromatographed with hexane/ethyl acetate (1 : 1) to give 13a (317 mg, 6.54 (1H, s, PhSCHϭ), 6.6—6.9 (3H, s, ArH), 7.0—7.5 (10H, m, PhHϫ2),
86%) as colorless prisms crystallized from Et2O, mp 128—130 °C.
8.38 (1H, s, CHO). 13C-NMR: 46.3 (t), 55.7 (q), 55.8 (q), 110.6 (d), 112.5
2-Formyl-6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (d), 121.7 (d), 123.1 (d), 126.3 (dϫ2), 127.3 (d), 128.3 (s), 128.91 (dϫ2),
(13a) IR: 1664, 1517. 1H-NMR: 3.1—3.4 (total 2H, m, C4-H), 3.83, 3.87, 128.92 (d), 129.2 (dϫ2), 129.6 (dϫ2), 134.6 (s), 135.6 (s), 138.6 (s), 148.5
3.90 (total 6H, each s, OCH3ϫ2), 3.9—4.5, 4.9—5.2, 5.9—6.1 (total 3H, m,
(s), 148.6 (s), 163.1 (d). HR-EI-MS m/z (Mϩ): Calcd for C24H23NO3S:
C1, C3-H), 6.50, 6.56, 6.66, 6.73 (total 2H, each s, ArH), 7.0—7.5 (total 5H, 405.1399. Found: 405.1411.
m, PhH), 8.34, 8.37 (total 1H, each s, CHO). LR-EIMS m/z: 297 (Mϩ, 33),
Reaction of 8b with p-TsOH A solution of 8b (91 mg, 0.22 mmol) and
91 (100). Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, p-TsOH·H2O (187 mg, 1.1 mmol) in benzene (15 ml) was heated under re-
72.62; H, 6.49; N, 4.70.
flux for 2.5 h using a Dean-Stark water separator. The reaction mixture was
3-Formyl-7,8-dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine
concentrated in vacuo, and the residue was extracted with CHCl3. The prod-
(13b) From 7b (785 mg, 1.87 mmol); chromatography with hexane/ethyl uct was chromatographed with hexane/ethyl acetate (1 : 1) to give 18 (19 mg,
1
acetate (1 : 3) gave 13b (407 mg, 70%) as a pale yellow gum. IR: 1670. H- 21%), 19 (48 mg, 53%), and the starting material (8b) (19 mg, 21%).
NMR: 2.8—4.7 (total 6H, m, C1, C4, C5-H), 3.84, 3.87 (total 6H, each s,
2-Formyl-6,7-dimethoxy-1-phenyl-1-phenylsulfanylmethyl-1,2,3,4-
1
OCH3ϫ2), 4.8—5.0, 5.8—6.0 (total 1H, each m, C2-H), 6.62 (1H, d, Jϭ2 tetrahydroisoquinoline (18) A colorless gum. IR (film): 1652, 1515. H-
Hz, C6 or C9-H), 6.74 (1H, d, Jϭ2 Hz, C6 or C9-H), 7.2—7.4 (total 5H, m, NMR (500 MHz): 2.78, 2.82 (total 1H, each t, Jϭ4 Hz, C4-H), 2.96, 2.99
PhH), 8.16, 8.20 (total 1H, each s, CHO). HR-EIMS m/z (Mϩ): Calcd for (total 1H, each dd, Jϭ5, 10 Hz, C4-H), 3.0—3.2 (total 1H, m, C3-H), 3.53,
C19H21NO3: 311.1519. Found: 311.1499.
3.57, 3.85, 3.86 (total 6H, each s, OCH3ϫ2), 3.74 (1H, d, Jϭ14 Hz,
Hydrolysis of 13a. Typical Procedure A 10% NaOH solution (6 ml) PhSCH2–), 4.13 (1H, d, Jϭ14 Hz, PhSCH2–), 4.26, 4.29 (total 1H, each t,
was added to a solution of 13a (100 mg, 0.34 mmol) in EtOH (12 ml), and Jϭ5 Hz, C3-H) 6.13, 6.17 (total 1H, each s, ArH), 6.58, 6.59 (total 1H, each
the mixture was heated under reflux for 20 h. The reaction mixture was con- s, ArH), 7.1—7.6 (total 10H, m, PhHϫ2), 8.08, 8.16 (total 1H, each s,
centrated in vacuo, and the residue was diluted with water, then extracted CHO). HR-EIMS m/z (Mϩ): Calcd for C25H25NO3S: 419.1553. Found:
with CHCl3. The product was chromatographed with hexane/ethyl acetate (1 :
419.1511.
N-2-{4,5-Dimethoxy-2-[1-phenyl-2-(phenylsulfanyl)ethenyl]phenyl}-
5) to give 14a (90 mg, 99%) as pale yellow prisms from Et2O, mp 170—172
°C (lit.15), mp 93—94 °C). The reason for the big difference in the melting ethylformamide (19) A pale yellow gum. IR (film): 3355, 1683, 1511. 1H-
point with that reported is unclear.
NMR: 2.5—2.7 (total 2H, m, ArCH2CH2–), 3.0—3.7 (total 2H, m,
6,7-Dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) IR: 3397,
ArCH2CH2–), 3.88, 3.89, 3.92 (total 6H, each s, OCH3ϫ2), 6.53, 6.70, 6.79,
1
1517. H-NMR: 1.80 (1H, s, ϾNH), 2.88 (2H, br d, Jϭ4 Hz, C4-H), 3.6— 6.83 (total 2H, each s, ArH), 7.07 (1H, s, PhSCHϭCϽ), 7.2—7.5 (total
4.4 (3H, m, C1, C3-H), 3.85 (3H, s, OCH3), 3.86 (3H, s, OCH3), 6.59 (2H, 10H, m, PhHϫ2), 7.92 (1H, br s, CHO). HR-EIMS m/z (Mϩ): Calcd for
br s, ArH), 7.1—7.6 (5H, m, PhH). 13C-NMR: 37.1 (t), 48.8 (t), 56.0 (qϫ2), C25H25NO3S: 419.1555. Found: 419.1577.
58.6 (d), 109.2 (d), 111.9 (d), 126.5 (dϫ2), 126.8 (s), 127.0 (s), 127.3 (d),
128.5 (dϫ2), 144.3 (s), 147.5 (s), 147.6 (s). HR-EIMS m/z (Mϩ): Calcd for added in small portions to a stirred solution of 18 (480 mg, 1.15 mmol) and
C17H19NO2: 269.1414. Found: 269.1414. NiCl2·6H2O (1.9 g, 23.7 mmol) in MeOH–THF (3 : 1) (30 ml) under ice-
Reductive Desulfurization of 18 NaBH4 (900 mg, 23.7 mmol) was

984
Vol. 49, No. 8
cooling. The mixture was stirred at room temperature for 1 h. After removal
Acknowledgment This work was supported by a Grant-in-Aid for Sci-
of inorganic materials by filtration, the filtrate was concentrated in vacuo.
entific Research (No. 11672115) from the Ministry of Education, Science,
The residue was extracted with CHCl3. The product was chromatographed Sports, Culture and Technology of Japan.
with hexane/ethyl acetate (3 : 1) to give 20 (346 mg, 97%) as colorless
prisms from hexane, mp 109—111 °C.
References and Notes
2-Formyl-6,7-dimethoxy-1-methyl-1-phenyl-1,2,3,4-tetrahydroiso-
quinoline (20) IR: 1654. H-NMR: 2.04 (3H, s, CH3), 2.7—3.0 (2H, m,
1) a) Shinohara T., Toda J., Sano T., Chem. Pharm. Bull., 45, 813—819
(1997); b) Shinohara T., Takeda A., Toda J., Terasawa N., Sano T., Het-
erocycles, 46, 555—565 (1997); c) Shinohara T., Takeda A., Toda J.,
Ueda Y., Kohno M., Sano T. Chem. Pharm. Bull., 46, 918—927
(1998); d) Shinohara T., Takeda A., Toda J., Sano T., ibid., 46, 430—
433 (1998); e) Toda J., Matsumoto S., Saitoh T., Sano T., ibid., 48,
91—98 (2000).
2) Toda J., Sakagami M., Sano T., Chem. Pharm. Bull., 47, 1269—1275
(1999).
3) Toda J., Ichikawa T., Saitoh T., Horiguchi Y., Sano T., Heterocycles,
53, 2009—2018 (2000).
4) Toda J., Sakagami M., Goan Y., Shimakata M., Saitoh T., Horiguchi
Y., Sano T., Chem. Pharm. Bull., 48, 1854—1861 (2000).
5) Toda J., Niimura Y., Takeda K., Sano T., Tsuda Y., Chem. Pharm.
Bull., 46, 906—912 (1998).
6) Toda J., Niimura Y., Sano T., Tsuda Y., Heterocycles, 48, 1599—1607
(1998).
7) Shinohara T., Takeda A., Toda J., Sano T., Heterocycles, 48, 981—992
(1998).
8) Gray N. M., Cheng B. K., Mick S. J., Lair C. M., Contreras P. C., J.
Med. Chem., 32, 1242—1248 (1989).
1
C4-H), 3.4—3.6 (1H, m, C3-H), 3.64 (3H, s, OCH3), 3.87 (3H, s, OCH3),
4.1—4.2 (1H, m, C3-H), 6.26 (1H, s, C5 or C8-H), 6.62 (1H, s, C5 or C8-
H), 7.2—7.5 (5H, m, PhH), 8.11 (1H, s, CHO). 13C-NMR: 28.5 (t), 29.2 (q),
36.0 (t), 55.8 (q), 56.0 (q), 62.7 (s), 110.7 (d), 110.9 (d), 126.4 (s), 127.3
(dϫ2), 127.6 (d), 128.7 (dϫ2), 133.5 (s), 145.5 (s), 147.7 (s), 147.9 (s),
163.0 (d). LR-EIMS m/z: 311 (Mϩ, 30), 296 (100). Anal. Calcd for
C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C, 73.08; H, 6.91; N, 4.43.
Hydrolysis of 20 A 10% NaOH solution (5 ml) was added to a solution
of 20 (100 mg, 0.32 mmol) in EtOH (10 ml), and the mixture was heated
under reflux for 45 h. The reaction mixture was concentrated in vacuo, and
the residue was diluted with water, then extracted with CHCl3. The product
was chromatographed with hexane/ethyl acetate (4 : 1) to give 21 (73 mg,
80%) as colorless prisms from Et2O, mp 101—103 °C (lit.,11) HCl salt, mp
260—262 °C).
6,7-Dimethoxy-1-methyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline (21)
1
IR: 3326, 1513. H-NMR: 1.86 (3H, s, CH3), 2.04 (1H, br s, ϾNH), 2.6—
3.1 (4H, m, C3, C4-H), 3.75 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.53 (1H, s,
C5 or C8-H), 6.62 (1H, s, C5 or C8-H), 7.1—7.3 (5H, m, PhH). 13C-NMR:
29.5 (t), 30.3 (q), 39.0 (t), 55.8 (q), 56.0 (q), 58.9 (s), 110.9 (d), 111.6 (d),
126.5 (d), 127.2 (dϫ2), 127.4 (s), 127.9 (dϫ2), 133.8 (s), 147.1 (s), 147.6
(s), 148.6 (s). LR-EIMS m/z: 283 (Mϩ, 100). Anal. Calcd for C18H21NO2: C,
76.29; H, 7.47; N, 4.94. Found: C, 75.99; H, 7.59; N, 4.87.
9) a) Schmidhanner H., Sci. Pharm., 49, 296—304 (1981); b) Pfister J.
R., Heterocycles, 24, 2099—2103 (1986); c) Kessar S. V., Singh P.,
Kaur N. P., Chawla U., Shukla K., Aggarwal P., Venugopal D., J. Org.
Chem., 56, 3908—3912 (1991).
LiAlH4 Reduction of 20 LiAlH4 (24 mg, 0.63 mmol) was added to a so-
lution of 18 (97 mg, 0.31 mmol) in dry THF (15 ml), and the mixture was 10) Bhattacharyya S., Chatterjee A., Williamson J. S., SYNLETT, 1995,
heated under reflux for 2.5 h. Et2O, saturated with water, was added to the
reaction mixture and insoluble material was filtered off. The product was
chromatographed with CHCl3 to give 22 (82 mg, 88%) as a colorless gum.
1079—1080; Bhattacharyya S., J. Org. Chem., 60, 4928—4929
(1995); Neidigh K. A., Avery M. A., Willamson J. S., Bhattacharyya
S., J. Chem. Soc., Perkin Trans. 1, 1998, 2527—2531.
6,7-Dimethoxy-1,2-dimethyl-1-phenyl-1,2,3,4-tetrahydroisoquinoline 11) Ohkubo M., Kuno A., Katsuta K., Ueda Y., Shirakawa K., Nakanishi
(22) IR (film): 1511. 1H-NMR: 1.70 (3H, s, C-CH3), 2.15 (3H, s, ϾNCH3),
H., Nakanishi I., Kinoshita T., Takasugi H., Chem. Pharm. Bull., 44,
2.7—3.2 (4H, m, C3, C4-H), 3.59 (3H, s, OCH3), 3.84 (3H, s, OCH3), 6.18
95—102 (1996).
(1H, s, C5 or C8-H), 6.56 (1H, s, C5 or C8-H), 7.1—7.4 (5H, m, PhH). 13C- 12) Saito S., Sato Y., Ohwada T., Shudo K., J. Am. Chem. Soc., 116,
NMR: 20.0 (q), 28.8 (t), 38.5 (q), 47.0 (t), 55.6 (q), 55.8 (q), 63.3 (s), 110.5
2312—2317 (1994).
(d), 111.8 (d), 126.0 (s), 126.4 (d), 127.6 (dϫ2), 128.1 (dϫ2), 135.8 (s), 13) Yokoyama A., Ohwada T., Shudo K., J. Org. Chem., 64, 611—617
146.9 (s), 147.1 (s), 147.6 (s). HR-EIMS m/z (Mϩ): Calcd for C19H23NO2:
(1999).
297.1729. Found: 297.1754.
14) Yoon N. M., Choi J., Ahn J. H., J. Org. Chem., 59, 3490—3493 (1994).
15) Aguirre J. M., Alesso E. N., Somoza C., Tombari D. G., Moltrasio G.
Y., Bonafede J. D., An. Asoc. Quim. Argent., 73, 391—399 (1985).