Formation and reaction of N-acyl- and N-methanesulfonyl-1-(3,4-dimethoxy)benzyl-7-acetoxy-1,2,3,4,6,7-hexahydro- 7-methoxy-6-oxoisoquinolines (o-quinol acetates)

Article abstract of DOI:10.1016/S0040-4020(00)00934-0

Oxidation of N-acyl- and N-methanesulfonyl-1,2,3,4-tetrahydro-7-methoxyisoquinolin-6-ols (7) with lead tetraacetate in dichloromethane produced quantitatively title compounds (o-QAs) (8). Treatment of N-trifluoroacetyl and N-formyl o-QAs (8a,b) with aceti

Full text of DOI:10.1016/S0040-4020(00)00934-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 265±271
Formation and reaction of N-acyl- and
N-methanesulfonyl-1-(3,4-dimethoxy)benzyl-7-acetoxy-
1,2,3,4,6,7-hexahydro-7-methoxy-6-oxoisoquinolines
(o-quinol acetates)
*
Osamu Hoshino, Masaji Suzuki and Hiromichi Ogasawara
Faculty of Pharmaceutical Sciences, Science University of Tokyo, 12 Ichigaya Funagwara-machi, Shinjuku-ku, Tokyo 162-0826, Japan
Received 24 March 2000; revised 30 May 2000; accepted 10 July 2000
AbstractÐOxidation of N-acyl- and N-methanesulfonyl-1,2,3,4-tetrahydro-7-methoxyisoquinolin-6-ols (7) with lead tetraacetate in
dichloromethane produced quantitatively title compounds (o-QAs) (8). Treatment of N-tri¯uoroacetyl and N-formyl o-QAs (8a,b) with
acetic acid at 30±408C afforded N-tri¯uoroacetyl and N-formyl p-QAs (9a,b), while that of N-acetyl, N-ethoxycarbonyl and N-methane-
sulfonyl congeners (8c±e) gave N,N-dialkylacetamide (10c), ethyl N,N-dialkylcarbamate (10d), and N,N-dialkylmethanesulfonamide (10e),
which are formed by elimination of a benzylic proton and subsequent cleavage of a C1±C8a bond in 9c±e. q 2000 Elsevier Science Ltd. All
rights reserved.
1. Introduction
gives quantitatively the corresponding o-quinol acetates
(o-QAs) (2), treatment of which with tri¯uoroacetic acid
(CF3CO2H) in CH2Cl2 affords N-acylnoraporphines (3) or
It is known that lead tetraacetate (LTA) oxidation of tetra-
hydroisoquinolinols gives the corresponding acetoxyhexa-
hydrooxoisoquinolines (o- or p-quinol acetates)1 having a
dienone moiety, which are valuable intermediates for
synthesis of isoquinoline alkaloids.2,3 Recently we have
reported that oxidation of N-acyl- and N-methanesulfonyl-
1-(3,4-dimethoxy)benzyl-1,2,3,4-tetrahydro-6-methoxyiso-
quinolin-7-ols (1) with LTA in dichloromethane (CH2Cl2)
N-acyl-
and
N-methanesulfonyl-phenanthrenes
(4)
(Scheme 1).4 These ®ndings focused our attention on a
series of reaction of N-acyl- and N-methanesulfonyl-1-
(3,4-dimethoxy)benzyl-1,2,3,4-tetrahydro-7-methoxyiso-
quinolin-6-ols (7), which are a phenolic regioisomer of 1,
because formation of N-acyl and N-methanesulfonyl o-QAs
from 7 could lead to the development of a novel methodology
Scheme 1.
Keywords: lead tetraacetate oxidation; N-acyltetrahydroisoquinolin-6-ol; N-acyl o- and p-quinol acetate.
* Corresponding author. Tel.: 181-33260-6725; fax: 181-33268-3045; e-mail: hoshino@ps.kagu.sut.ac.jp
0040±4020/01/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00934-0

266
O. Hoshino et al. / Tetrahedron 57 (2001) 265±271
Scheme 2.
using LTA for synthesis in the tetrahydroisoquinolinol ®eld.
The present paper deals with formation and reaction of
N-acyl and N-methanesulfonyl o-QAs (8).
N-tri¯uoroacetyl-1-(3,4-dimethoxy)benzyl-7-acetoxy-1,2,3,
4,6,7-hexahydro-7-methoxy-6-oxoisoquinoline (o-QA) (8a).
The analogous reaction of 7b±e produced N-acyl and
N-methanesulfonyl o-QAs (8b±e), the structures of which
were con®rmed by spectral evidence (IR, H NMR) (see
Experimental). As expected, it was found that oxidation of
7 afforded readily N-acyl and N-methanesulfonyl o-QAs (8)
(Scheme 3) in a manner similar to that observed with 1. The
stability of o-QAs (8) was similar to that of o-QAs (2).
1
2. Results and discussion
2.1. Formation of N-acyl and N-methanesulfonyl o-QAs (8)
The starting materials, N-acyl- and N-methanesulfonyl-1-
(3,4-dimethoxy)benzyl-1,2,3,4-tetrahydro-7-methoxyiso-
quinolin-6-ols (7) are prepared as follows. N-Acylation
and N-methanesulfonylation of 6-benzyloxytetrahydroiso-
quinoline (5)5 with tri¯uoroacetic anhydride, acetic anhy-
dride, ethyl chloroformate, and methanesulfonyl chloride
under basic conditions gave the corresponding N-acyl- and
N-methanesulfonyl-tetrahydroisoquinolines (6a,c±e). The
N-formyl congener (6b) was obtained by re¯uxing 5 in
ethyl formate. Furthermore, their debenzylation with cata-
lytic hydrogenation produced 7 in good yields (Scheme 2).
2.2. Reaction of N-acyl and N-methanesulfonyl o-QAs (8)
Treatment of 2 with CF3CO2H in CH2Cl2 at room tempera-
ture is found to produce N-acylnoraporphines (3a±c) or
N-ethoxycarbonyl- and N-methanesulfonyl-phenanthrenes
(4d,e) (Scheme 1).4 Thus, the reaction of 8a with
CF3CO2H in CH2Cl2 or CH3CN at room temperature was
examined. Surprisingly, each reaction afforded a complex
reaction mixture. With Ac2O-concentrated H2SO4,6 the
reaction was also unsuccessful. The reaction of 8a in re¯ux-
ing CH2Cl2 and CHCl3,or at 608C (neat),7 did not proceed.
With 7 in hand, LTA oxidation in a manner similar to that
reported previously3a was carried out. Oxidation of 7a with
LTA (1.1±1.2 equiv.) in CH2Cl2 at room temperature for
0.5 h gave quantitatively an oily product, IR (CHCl3) and
1H NMR spectra of which showed absorption bands at 1740
and 1680 cm21 and two peaks due to an acetoxyl group at d
2.05, 2.08 (3H, each s) and two peaks due to a methoxyl
group at d 3.28, 3.40 (3H, each s). The spectral data
supported the assignment of the products as a diastereomeric
mixture as well as the assignment of overall structure as
After several unfruitful attempts, treatment of 8a with
AcOH8,9 at 30±408C for 3 h gave a crystalline product
1
(mp 165±1678C), the IR (CHCl3) and the H NMR spectra
showed absorption bands at 1745, 1675, 1650, 1625 cm21
and a peak due to an acetoxyl group at d 2.01 (3H, s) and
two peaks due to a methoxyl group at d 3.26, 3.52 (3H, each
s), respectively. The spectral and microanalytical data
supported the assignment of the products as a diastereomeric
Scheme 3.

O. Hoshino et al. / Tetrahedron 57 (2001) 265±271
267
Scheme 4.
Scheme 5.
mixture, the structure of which was N-tri¯uoroacetyl-1-(3,4-
dimethoxy)benzyl-8a-acetoxy-1,2,3,4,6,8a-hexahydro-7-
methoxy-6-oxoisoquinoline (p-QA) (9a) (Scheme 3).
Furthermore, the structure was con®rmed chemically by
conversion of 9a into 7a by reduction with NaBH4 in
MeOH10 (Scheme 4).
The similar reaction of 8b produced p-QA (9b). Unexpect-
edly, however, the reaction of 8c in warm AcOH did not
give p-QA (9c), but rather an N,N-dialkylacetamide contain-
ing product. The IR spectrum exhibited absorption bands at
3550, 1760, 1670 cm21. Furthermore, the 1H NMR spectrum
showed two pairs of two peaks due to two acetyl groups at d
2.08, 2.24, 2.29, 2.32 (6H, each s) and four pairs of two peaks
at d 5.90, 5.93 (1H, Jˆ14.3 Hz, each d) and 7.00, 7.86 (1H,
Jˆ14.3 Hz, each d) due to trans-ole®nic protons. Thus, the
spectral data supported the structure N-[2-(2-acetoxy-5-
It is notable that N-tri¯uoroacetyl p-QA (9a) was obtained,
in contrast to the ®ndings7 that N-methyl p-QA (15) cannot
be isolated in the case of N-methyl o-QA (12) (Scheme 6).
Scheme 6.

268
O. Hoshino et al. / Tetrahedron 57 (2001) 265±271
hydroxy-4-methoxyphenyl)ethyl]-N-[2-(3,4-dimethoxy-
phenyl)ethenyl]acetamide (10c). The analogous reactions of
8d,e gave also the corresponding amides (10d,e) (Scheme
3), the IR and H NMR spectra of which indicated the
presence of hydroxyl and acetoxyl groups and a trans-ole®n
moiety in the case of 10c (Scheme 3).
3.1.1. N-Tri¯uoroacetyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-6-benzyloxy-7-methoxyisoquinoline (6a).
5
(1.08 g, 2.6 mmol), tri¯uoroacetic anhydride (1.0 mL,
3.2 mmol), K2CO3 (0.524 g, 3.8 mmol), and CH2Cl2
(20 mL) were used (reaction time: 0.5 h): 6a (1.07 g, 82%),
mp 139±1418C (EtOH). Anal. Calcd for C28H28NO5F3: C,
65.23; H, 5.47; N, 2.72; F, 11.06. Found: C, 65.37; H, 5.52;
1
1
A reaction pathway for formation of 10c±e is depicted in
Scheme 5. Namely, N-acyl and N-methanesulfonyl p-QAs
(9c±e), which would be formed initially by the reaction of
N-acyl and N-methanesulfonyl o-QAs (8c±e) in warm
AcOH, undergo elimination of a benzylic proton and subse-
quent cleavage of the C1±C8a bond to give rise to amides
(10c±e). This transformation appears to be remarkably
dependent on the nature (probably the inductive effect) of
the N-substituents.
N, 2.79; F, 10.92. MS m/z: 515 (M1); IR n: 1675 cm21; H
NMR d: 3.68, 3.76, 3.82 (each 3H, s), 5.55 (1H, t, Jˆ7.4 Hz),
6.24±6.84, 7.10±7.60 (each 5H, m).
3.1.2. N-Formyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-tetra-
hydro-6-benzyloxy-7-methoxyisoquinoline (6b). A solu-
tion of 5 (1.0 g, 2.4 mmol) in ethyl formate (20 mL) was
re¯uxed for 3 h. Removal of excess ethyl formate in vacuo
gave 6b (0.89 g, 83%), mp 106±1088C (EtOH). Anal. Calcd
for C27H29NO5: C, 72.46; H, 6.53; N, 3.13. Found: C, 72.53;
1
H, 6.59; N, 3.24. MS m/z: 447 (M1); IR n: 1650 cm21; H
It is noteworthy that the present reaction of N-acyl and
N-methanesulfonyl o-QAs showed chemical behavior
different from that of the N-methyl o-QAs (12) (derived
from 11), in which 4-acetoxy product (13)7or O-acetyl-
aporphines (14)6 are formed under warming or acidic condi-
tions (Scheme 6). The results would be attributable to the
inductive effect of N-substituents, because elimination of a
benzylic proton takes place more readily.
NMR d: 3.68, 3.72, 3.82, 3.84 (9H, each s,), 4.28±4.64 (2H,
m), 5.08, 5.10 (2H, each s), 6.22±6.86, 7.04±7.50 (each 5H,
m), 7.64, 8.07 (1H, each s).
3.1.3. N-Acetyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-tetra-
hydro-6-benzyloxy-7-methoxyisoquinoline (6c). 5 (0.69 g,
1.6 mmol), acetic anhydride (1.68 g, 16.5 mmol), K2CO3
(2.28 g, 16.5 mmol), and CH2Cl2 (10 mL) were used (reac-
tion time: 1 h): 6c (0.39 g, 51%), mp 174±1758C (benzene).
Anal. Calcd for C28H31NO5: C, 72.86; H, 6.77; N, 3.03.
Found: C, 72.84; H, 6.68; N, 2.87. MS m/z: 418 (M1243);
IR n: 1620 cm21; 1H NMR d: 1.62, 2.12 (3H, each s), 3.62,
3.74, 3.83 (each 3H, s,), 4.52±4.86 (1H, m), 5.08, 5.10 (2H,
each s), 6.14±6.88, 7.08±7.50 (each 5H, m).
In conclusion, it was found that LTA oxidation of N-acyl-
and N-methanesulfonyl-tetrahydroisoquinolin-6-ols (7)
gave corresponding o-QAs (8) similar to that of N-acyl-
and N-methanesulfonyl-tetrahydroisoquinolin-7-ols (1) and
their reaction in warm AcOH produced novel N-tri¯uoro-
acetyl and N-formyl p-QAs (9a,b) or N-acetyl-, N-ethoxycar-
bonyl-, and N-methanesulfonylamides (10c±e) depending on
the nature of the N-substituents in the o-QAs. Furthermore,
the chemical behavior of N-acyl o-QAs (8a±d) was
distinctly different from that of N-methyl o-QA (12).11
3.1.4. N-Ethoxycarbonyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-6-benzyloxy-7-methoxyisoquinoline (6d). 5
(1.08 g, 2.8 mmol), ethyl chloroformate (0.56 g,
5.2 mmol), K2CO3 (0.71 g, 5.2 mmol), and CH2Cl2
(20 mL) were used (reaction time: 1 h): 6d (1.03 g, 82%),
mp 174±1758C (EtOH). Anal. Calcd for C29H33NO6: C,
70.86; H, 6.77; N, 2.85. Found: C, 70.88; H, 6.73; N,
Further examination on the effect of N-acyl groups in the
reactions of o-QAs is in progress.
1
3.07. MS m/z: 446 (M1245); IR n: 1670 cm21; H NMR
d: 1.13, 1.24 (3H, each t, Jˆ7.1 Hz), 3.62, 3.82, 3.87, 3.93
3. Experimental
(9H, each s), 4.88±5.34 (3H, m), 6.08±7.48 (10H, m).
All melting points were measured on BuÈchi melting point
measuring apparatus and are uncorrected. H NMR spectra
1
3.1.5. N-Methanesulfonyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-6-benzyloxy-7-methoxyisoquinoline (6e). 5
(0.94 g, 2.2 mmol), methanesulfonyl chloride (1.9 mL,
11.4 mmol), K2CO3 (3.37 g, 24.4 mmol), and CH2Cl2
(20 mL) were used (reaction time: 2 h): 6e (1.04 g, 95%),
mp 163±1658C (EtOH). Anal. Calcd for C27H31NO6S: C,
65.17; H, 6.28; N, 2.81; S, 6.43. Found: C, 65.24; H, 6.45;
N, 2.84; S, 6.48. MS m/z: 346 (M12151); IR n: 1310,
were recorded on a JOEL JNM-FX 100 (100 MHz) instru-
ment in CDCl3 solution using tetramethylsilane as internal
standard. IR spectra were measured on a Hitachi model 260-
10 spectrophotometer in CHCl3 solution. Mass spectra were
taken with a Hitachi RMU-7M or M-80 instrument. Prepara-
tive TLC was performed on Merck Kieselgel 60F254 plates
(20£20£0.5 cm).
1140 cm21 1H NMR d: 2.47 (3H, s), 3.71, 3.80, 3.84
;
(each 3H, s), 4.96 (1H, t, Jˆ7.1 Hz), 5.08 (2H, s), 6.32±
3.1. A general procedure for preparation of N-acyl- and
N-methanesulfonyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-6-benzyloxy-7-methoxyisoquinolines (6)
6.86, 7.04±7.50 (each 5H, m).
3.2. A general procedure for preparation of N-acyl- and
N-methanesulfonyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-7-methoxyisoquinolin-6-ols (7)
A mixture of 5,5 acetic anhydride or ethyl chloroformate or
methanesulfonyl chloride, and K2CO3 in CH2Cl2 was stirred
at room temperature for 0.5±2 h (except for 6b). After addi-
tion of water to the reaction mixture, the product was taken
up in CH2Cl2. Usual work-up of the organic layer gave solid
product, which was puri®ed by recrystallization.
A mixture of 6 and 10% Pd±C in AcOEt (for 6a,b,d,e) or
AcOEt±CHCl3 (for 6c) was shaken with hydrogen (1 atm)
at room temperature for 2 h. After ®ltration of catalyst

O. Hoshino et al. / Tetrahedron 57 (2001) 265±271
269
followed by removal of the solvent gave a solid, which was
puri®ed by recrystallization.
(8a). 7a (100 mg, 0.24 mmol), Pb(OAc)4 (127 mg,
0.29 mmol), and CH2Cl2 (1 mL) were used: 8a (oil); IR n:
1740, 1680 cm21; 1H NMR d: 2.05, 2.08 (3H, each s), 3.28,
3.40 (3H, each s), 3.84 (6H, s), 4.92±5.18 (1H, m), 5.60±
5.74, 5.86±6.07 (each 1H, m), 6.52±6.84 (3H, m).
3.2.1. N-Tri¯uoroacetyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-7-methoxyisoquinolin-6-ol (7a). 6a (1.02 g,
2.0 mmol), 10% Pd±C (0.42 g), and AcOEt (50 mL) were
used: 7a (0.784 g, 93%), mp 148±1498C (benzene). Anal.
Calcd for C21H22NO5F3: C, 59.29; H, 5.21; N, 3.29; F, 13.40.
Found: C, 59.29; H, 5.19; N, 3.40; F, 13.46. MS m/z: 425
(M1); IR n: 3530, 1675 cm21; 1H NMR d: 3.68, 3.76, 3.83
(each 3H, s), 5.36±5.60 (2H, m), 6.20±6.84 (5H, m).
3.3.2. N-Formyl-1-(3,4-dimethoxy)benzyl-7-acetoxy-1,2,3,
4,6,7-hexahydro-7-methoxy-6-oxoisoquinoline (8b). 7b
(100 mg, 0.28 mmol), Pb(OAc)4 (149 mg, 0.34 mmol),
and CH2Cl2 1 (5 mL) were used: 8b (oil); IR n: 1740,
1670 cm21; H NMR d: 2.05, 2.08, 2.10 (3H, each s),
3.32, 3.40, 3.42 (3H, each s), 3.84 (6H, s), 5.00±5.32 (1H,
m), 5.60±6.04 (2H, m), 6.50±6.84 (3H, m), 7.69, 8.78, 8.12
(1H, each s).
3.2.2. N-Formyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-tetra-
hydro-7-methoxyisoquinolin-6-ol (7b). 6b (1.3 g,
2.9 mmol), 10% Pd±C (0.62 g), and AcOEt (50 mL) were
used: 7b (0.9 g, 86%), mp 177±1798C (benzene). HRMS
m/z Calcd for C20H23NO5 (M1): 357.1574. Found: C,
3.3.3. N-Acetyl-1-(3,4-dimethoxy)benzyl-7-acetoxy-1,2,3,
4,6,7-hexahydro-7-methoxy-6-oxoisoquinoline (8c). 7c
(100 mg, 0.27 mmol), Pb(OAc)4 (143 mg, 0.32 mmol),
and CH2Cl2 (5 mL) were used: 8c (oil); IR n: 1740, 1685,
357.1552. MS m/z: 357 (M1); IR n: 3530, 1650 cm21; 1
H
NMR d: 3.66, 3.76, 3.84 (each 3H, s), 6.22±6.83 (5H, m),
7.66, 8.08 (1H, each s).
1640 cm21 1H NMR d: 2.02, 2.04, 2.08, 2.12, 2.14
;
(6H, each s), 3.20, 3.32 (3H, each s), 3.83, 3.85 (each
3H, s), 4.98±5.32 (1H, m), 5.48±6.02 (2H, m), 6.48±
6.88 (3H, m).
3.2.3. N-Acetyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-tetra-
hydro-7-methoxyisoquinolin-6-ol (7c). 6c (1.06 g,
2.3 mmol), 10% Pd±C (0.42 g), and AcOEt (20 mL)-
CHCl3 (30 mL) were used: 7c (0.734 g, 86%), mp 141±
1428C (benzene±ether). Anal. Calcd for C21H25NO5: C,
67.91; H, 6.78; N, 3.77. Found: C, 67.81; H, 6.74; N, 3.84.
MS m/z: 371 (M1); IR n: 3530, 1620 cm21; 1H NMR d: 1.61,
2.12 (3H, each s), 3.60, 3.76, 3.83 (each 3H), 4.56±4.85 (1H,
m), 5.40±5.65 (2H, m), 6.09±6.88 (5H, m).
3.3.4. N-Ethoxycarbonyl-1-(3,4-dimethoxy)benzyl-7-acet-
oxy-1,2,3,4,6,7-hexahydro-7-methoxy-6-oxoisoquinoline
(8d). 7d (100 mg, 0.25 mmol), Pb(OAc)4 (133 mg,
0.30 mmol), and CH2Cl2 (5 mL) were used: 8d (oil); IR n:
1740, 1680 cm21 1H NMR d: 1.28, 1.29 (3H, each t,
;
Jˆ7.1 Hz), 2.08, 2.28 (3H, each s), 3.20, 3.38 (3H, each
s), 3.84 (6H, s), 5.44±5.68 (1H, m), 5.48±6.00 (2H, m),
6.48±6.92 (3H, m).
3.2.4. N-Ethoxycarbonyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-7-methoxyisoquinolin-6-ol (7d). 6d (0.93 g,
1.9 mmol), 10% Pd±C (0.37 g), and AcOEt (50 mL) were
used: 7d (0.737 g, 99%), mp 80±958C (benzene). Anal.
Calcd for C22H27NO6´0.5H2O: C, 64.38; H, 6.88; N, 3.41.
Found: C, 64.24; H, 6.62; N, 3.51. MS m/z: 400 (M121); IR
3.3.5. N-Methanesulfonyl-1-(3,4-dimethoxy)benzyl-7-acet-
oxy-1,2,3,4,6,7-hexahydro-7-methoxy-6-oxoisoquinoline
(8e). 7e (100 mg, 0.25 mmol), Pb(OAc)4 (139 mg,
0.31 mmol), and CH2Cl2 (1 mL) were used: 8e (oil); IR n:
1740, 1680 cm21; 1H NMR d: 2.04, 2.08 (3H, each s), 2.60,
2.88 (3H, each s), 3.24, 3.40 (3H, each s), 3.84, 3.85 (each
3H, s), 4.48±4.86 (1H, m), 5.64, 5.72 (1H, each s), 5.84±
6.04 (1H, m), 6.56±6.84 (3H, m).
1
n: 3430, 1670 cm21; H NMR d: 1.15, 1.24 (3H, each t,
Jˆ7.1 Hz), 3.60, 3.69, 3.76, 3.78, 3.84 (9H, each s), 4.87±
5.28 (1H, m), 6.07±6.84 (5H, m).
3.2.5. N-Methanesulfonyl-1-(3,4-dimethoxy)benzyl-1,2,3,4-
tetrahydro-7-methoxyisoquinolin-6-ol (7e). 6e (0.91 g,
1.8 mmol), 10% Pd±C (0.39 g), and AcOEt (50 mL) were
used: 7e (0.59 g, 84%), mp 170±1718C (benzene). Anal.
Calcd for C20H25NO6S: C, 58.95; H, 6.18; N, 3.44; S,
7.87. Found: C, 59.10; H, 6.18; N, 3.60; S, 7.87. MS m/z:
3.4. A general procedure for the reaction of o-QAs (8)
with AcOH
A solution of o-QA (8) [prepared from 7] in AcOH was
stirred at 30±408C for 2±3 h. The reaction mixture was
diluted with water and basi®ed with 10% aq. Na2CO3
solution. The product was taken up in CH2Cl2. A residue
obtained on usual work-up of the organic layer was
puri®ed by preparative TLC (developing solvent:
AcOEt:hexaneˆ2:1) or recrystallization.
1
407 (M1); IR n: 3530, 1310, 1140 cm21; H NMR d: 2.49
(3H, s), 3.70, 3.81, 3.84 (each 3H, s), 5.94 (1H, t, Jˆ7.1 Hz),
6.21±6.82 (5H, m).
3.3. A general procedure for formation of N-acyl- and
N-methanesulfonyl-1-(3,4-dimethoxy)benzyl-6-acetoxy-
1,2,3,4,6,7-hexahydro-7-methoxy-6-oxoisoquinolines (8)
(o-quinol acetates)
3.4.1. N-Tri¯uoroacetyl-1-(3,4-dimethoxy)benzyl-8a-acet-
oxy-1,2,3,4,6,8a-hexahydro-7-methoxy-6-oxoisoquino-
line (9a). 8a [prepared from 7a (100 mg)] and AcOH
(10 mL) were used (reaction time: 3 h): 9a (87 mg, 77%),
mp 165±1678C (EtOH). Anal. Calcd for C23H24F3NO7:
C, 57.14; H, 5.00; N, 2.90; F, 11.79. Found: C, 57.19;
H, 5.08; N, 3.09; F, 11.89. MS m/z: 483 (M1); IR n:
The reaction of 7 with Pb(OAc)4 in CH2Cl2 was carried out
in a manner reported previously3a (reaction time: 0.5 h) to
produce quantitatively o-quinol acetates (8), which were
used in the next reaction without further puri®cation.
1
1745, 1675, 1650, 1625 cm21; H NMR d: 2.01 (3H, s),
3.3.1. N-Tri¯uoroacetyl-1-(3,4-dimethoxy)benzyl-7-acet-
oxy-1,2,3,4,6,7-hexahydro-7-methoxy-6-oxoisoquinoline
3.26, 3.52 (3H, each s), 3.84 (6H, s), 5.58 (1H, s),
6.08±6.36 (4H, m).

270
O. Hoshino et al. / Tetrahedron 57 (2001) 265±271
3.4.2. N-Formyl-1-(3,4-dimethoxy)benzyl-8a-acetoxy-1,2,
3,4,6,8a-hexahydro-7-methoxy-6-oxoisoquinoline (9b). 8b
[prepared from 7b (100 mg)] and AcOH (5 mL) were used
(reaction time: 2.5 h): 9b (oil, 86 mg, 74%). MS m/z: 415
Acknowledgements
We are grateful to Sankyo Co. Ltd., for elementary analyses,
and also to Ms N. Sawabe and Mrs F. Hasegawa of this
Faculty for their 1H NMR and mass spectral measurements.
1
(M1); IR n: 1750, 1675, 1655, 1630 cm21; H NMR d:
2.02, 2.04, 2.32, 2.39 (3H, each s), 3.62, 3.82, 3.84 (9H,
each s), 7.80, 7.98, 8.07 (1H, each s).
References
3.4.3. N-[2-(3,4-dimethoxyphenyl)ethenyl]-N-[2-(2-acet-
oxy-5-hydroxy-4-methoxyphenyl)ethyl]acetamide (10c).
8c [prepared from 7c (100 mg)] and AcOH (5 mL) were
used (the reaction time; 2 h): 10c (oil, 66.3 mg, 57.4%).
MS m/z: 429 (M1); HRMS m/z Calcd for C23H27NO7
(M1): 429.1785. Found: 429.1789. IR n: 3550, 1760,
1. For a review: Umezawa, B.; Hoshino, O. Heterocycles, 1975,
3, 1005.
2. Cf. Monographs: (a) Hoshino, O; Umezawa, B. In The
Alkaloids; Chemistry and Pharmacology; Brossi, A., Ed.;
Academic: New York, 1989; Vol. 36, pp 69±134. (b) Hoshino,
O. In Studies in Natural Products Chemistry; Stereoselective
Synthesis (Part J); Atta-ur-Rahman, Ed.; Elsevier: Amsterdam,
1995; Vol. 16, pp 519±530.
1
1670, 1640 cm21; H NMR d: 2.08, 2.24, 2.29, 2.32 (6H,
each s), 3.84, 3.88, 3.91 (each 3H, s), 5.36±5.68 (1H, m),
5.90, 5.93 (1H, each d, Jˆ14.3 Hz), 6.55 (1H, s), 6.65±6.98
(4H, m), 7.00, 7.86 (1H, each d, Jˆ14.3 Hz).
3. (a) Hoshino, O.; Ogasawara, H.; Suzuki, M.; Umezawa, B.
Heterocycles, 1987, 25, 151. (b) Hoshino, O.; Ogasawara,
H.; Suzuki, M.; Arasawa, M.; Umezawa, B. Heterocycles,
1990, 30, 385. (c) Hoshino, O.; Ogasawara, H.; Arasawa,
M.; Suzuki, M.; Iizima, K. Heterocycles, 1993, 35, 1005.
(d) Ogasawara, H.; Suzuki, M.; Shiohara, T.; Hoshino, O.
Heterocycles, 1998, 47, 921.
3.4.4. Ethyl N-[2-(3,4-dimethoxyphenyl)ethenyl]-N-[2-
(2-acetoxy-5-hydroxy-4-methoxyphenyl)ethyl]carbamate
(10d). 8d [prepared from 7d (100 mg)] and AcOH (5 mL)
were used (reaction time; 2 h): 10d (oil, 40 mg, 35%). MS
m/z: 459 (M1); HRMS m/z Calcd for C24H29NO7 (M1):
459.1890. Found: 459.1873. IR n: 3550, 1760, 1700,
4. Hoshino, O.; Suzuki, M.; Ogasawara, H. Heterocycles, 2000,
52, 751.
1
1645 cm21; H NMR d: 1.30 (3H, t, Jˆ7.1 Hz), 2.28 (3H,
s), 3.84, 3.86, 3.90 (each 3H, s), 4.22 (2H, q, Jˆ7.1 Hz),
5.36±5.62 (1H, m), 5.80 (1H, d, Jˆ14.3 Hz), 6.55 (1H, s),
6.60±6.96 (4H, m), 7.24±7.68 (1H, m).
5. Kametani, T.; Takeshita, M.; Takano, S. J. Chem. Soc., Perkin
Trans. 1 1972, 2834.
6. Hoshino, O.; Ohtani, M.; Umezawa, B. Chem. Pharm. Bull.
1979, 27, 3101.
3.4.5. N-[2-(3,4-dimethoxyphenyl)ethenyl]-N-[2-(2-acet-
oxy-5-hydroxy-4-methoxyphenyl])ethyl]methanesulfona-
mide (10e). 8e [prepared from 7e (100 mg)] and AcOH
(20 mL) were used (reaction time; 2 h): 10e (32 mg, 27%),
mp 156±1588C (EtOH). MS m/z: 465 (M1). Anal.Calcd
for C22H27NO8S: C, 56.77; H, 5.85; N, 3.01; S, 6.87.
Found: C, 56.77; H, 5.75; N, 3.14; S, 6.62. IR n:
7. Hoshino, O.; Ohyama, K.; Taga, M.; Umezawa, B. Chem.
Pharm. Bull. 1974, 22, 3101.
8. The reaction of 8a in CHCl3 containing AcOH at room
temperature did not take place.
9. The reaction of 8a in CHCl3 containing silicic acid (40 times
for weight of 8a) at room temperature for 12 h produced 9a in
33% yield.
3530, 1750, 1640 cm21 1H NMR d: 2.18, 2.86 (each
;
10. Cf. In our laboratory, treatment of N-methyl-4a-acetoxy-1,
2,3,4,4a,7-hexahydro-6-methoxy-7-oxoisoquinoline (p-QA)
with NaBH4 in MeOH at room temperature is found to
give N-methyl-1,2,3,4-tetrahydro-6-methoxyisoquinolin-7-ol
(corypalline).
3H, s), 3.84, 3.87, 3.91 (each 3H, s), 5.49 (1H, s), 5.85
(1H, d, Jˆ14.9 Hz), 6.46±6.94 (5H, m), 7.06 (1H, d,
Jˆ14.9 Hz).
3.4.6. Reduction of 9a with NaBH4. A solution of 9a
(100 mg, 0.21 mmol) and NaBH4 (78 mg, 2.1 mmol) in
MeOH (10 mL) was stirred at 08C for 10 min. The reaction
mixture was acidi®ed with 10% HCl and the product
was taken up in CH2Cl2. Usual work-up of the organic
layer gave an oily residue (74.5 mg), which upon
trituration in EtOH produced 7a (71 mg, 81%), mp 148±
1498C (benzene). This compound was identical to an
authentic sample by each comparison (1H NMR, IR, and
mixed mp).
11. A chemical behavior different between N-methyl o-QA (12)
and N-acyl o-QA (8) would be ascribable to the stereo-
electronic effect of each N-substituent. The former (12), in
which the nitrogen atom is an sp3 hybrid orbital, generates
an aziridinium intermediate (A) by elimination of an acetoxyl
group followed by intramolecularly nucleophilic attack of the
nitrogen atom to the C8a position. Furthermore, A leads to
4-acetoxytetrahydroisoquinolinol (13) through B (Scheme
7).12 On the other hand, the N-tri¯uoroacetyl o-QA (8a)
generates a carbenium ion (C) by elimination of an acetoxyl
Scheme 7.

O. Hoshino et al. / Tetrahedron 57 (2001) 265±271
271
Scheme 8.
group followed by allylic rearrangement, because the nitrogen
(1)-2-phenylpropionic acid produces a mixture of diastereo-
isomers of optically active N-tri¯uoroacetyl p-quinol esters
[Hara, H.; Komoriya, S.; Miyashita, T.; Hoshino, O.
Tetrahedron: Asymmetry, 1995, 6, 1683]. These ®ndings
suggest the transformation of N-tri¯uoroacetyl o-QA (8a) in
AcOH to 9a to proceed in the intermolecular substitution.
atom, which is an sp2-like hybrid orbital, cannot attack to the
C8a position. Accordingly, 9a is formed by the intermolecular
substitution13 of C with AcOH (Scheme 8).
12. See Ref. 7.
13. LTA oxidation of (^)-N-tri¯uoroacetyl-1,2,3,4-tetrahydro-1-
(3,4-dimethoxy)benzyl-6-methoxyisoquinolin-7-ol in (S)-