New approaches to 6-oxoisoaporphine and tetrahydroisoquinoline derivatives

Article abstract of DOI:10.1002/hlca.200900394

2,3-Dihydro-6-hydroxy-5-methoxy-7H-dibenzo[de,h]quinolin-7-one, 6-hydroxy-5-methoxy-7H-dibenzo[ de,h]quinolin-7-one, and 2-(6,7-dimethoxy-3,4- dihydroisoquinolin-1-yl)benzyl benzoate, easily available by a Bischler - Napieralski cyclization, were used as starting materials to afford 6-oxoisoaporphine and 2,3-dimethoxy-5,6,8,12b-tetrahydroisoindolo[1,2-a] isoquinoline as the main products. However, the catalytic hydrogenation of the benzyl benzoate derivative afforded, under mild conditions, 1,2,3,4-tetrahydro- 6,7-dimethoxy-1-(2-methylphenyl)isoquinoline.

Full text of DOI:10.1002/hlca.200900394

Helvetica Chimica Acta – Vol. 93 (2010)
1385
New Approaches to 6-Oxoisoaporphine and Tetrahydroisoquinoline
Derivatives
by Eduardo Sobarzo-Sa´nchez*a), Eugenio Uriarteb), Lourdes Santanab), Ricardo A. Tapiac), and
Paulo Pe´rez Louridod)
a) Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of
Santiago de Compostela, ES-15782 Santiago de Compostela
(phone: þ 34981563100-14936; e-mail: e.sobarzo@usc.es)
b) Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela,
ES-15782 Santiago de Compostela
c) Department of Organic Chemistry, Faculty of Chemistry, Pontifical Catholic University of Chile,
Santiago, Chile
d) Department of Inorganic Chemistry, Faculty of Chemistry, University of Vigo, ES-36210 Vigo,
Pontevedra
2,3-Dihydro-6-hydroxy-5-methoxy-7H-dibenzo[de,h]quinolin-7-one, 6-hydroxy-5-methoxy-7H-di-
benzo[de,h]quinolin-7-one, and 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)benzyl benzoate, easily
available by
a Bischler– Napieralski cyclization, were used as starting materials to afford 6-
oxoisoaporphine and 2,3-dimethoxy-5,6,8,12b-tetrahydroisoindolo[1,2-a]isoquinoline as the main prod-
ucts. However, the catalytic hydrogenation of the benzyl benzoate derivative afforded, under mild
conditions, 1,2,3,4-tetrahydro-6,7-dimethoxy-1-(2-methylphenyl)isoquinoline.
Introduction. – Oxoisoaporphines (¼ 7H-dibenzo[de,h]quinolin-7-ones) are a
family of oxoisoquinoline-derived alkaloids that have been isolated from Menisper-
mum dauricum DC. (Menispermaceae) as the sole known natural source [1]. In
traditional chinese medicine, these isoquinoline alkaloids, present in small quantities in
rhizomes of the plants, have been used as analgesic, antipyretic, and with some
cytotoxic activity [2 – 4], whilst the isolation and reactivity studies are difficult to be
carried out. However, compounds with the same skeleton, known as azabenzanthrones,
had been synthesized earlier due to their possible photo- and electrochemical
properties [5] and as dyes [6]. Later, the synthesis of 7H-dibenzo[de,h]quinolin-7-
one derivatives through the cyclization of N-(2-phenylethyl)phthalimides afforded a
new way to these compounds [7]. In addition, some authors reported the synthesis of
2,3-dihydro-oxoisoaporphine derivatives by cyclization of 3-{[(b-(dialkoxyaryl)ethyl]-
amino}phthalides with polyphosphoric acid (PPA) [8]. Later, study of the synthesis and
reactivity of these alkaloids with different substitution patterns on their isoquinoline
skeleton led to several derivatives by means of metals and catalytic hydrogenation [9].
In this sense, the reactivity of some oxoisoaporphine derivatives with PtO2 showed an
unexpected keto – enol tautomerism and a later formation of the C¼O group at C(6),
without evidence of a partial or complete hydrogenation of the aromatic system.
On the other hand, the major availability of this type of oxoisoaporphines allowed
studying its photoreduction, affording the unexpected formation of 1-(diethylamino)-
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

1386
Helvetica Chimica Acta – Vol. 93 (2010)
butadiene, when triethylamine Et3N was used as the electron donor under anaerobic
conditions [10].
Therefore, a further understanding of the reactivity of these compounds and the
possibility to obtain them by means of convenient synthetic routes will help us to study
their pharmacology and possible therapeutic use.
Here, we report the electrophilic behavior of 2,3-dihydro-6-hydroxy-5-methoxy-
and 6-hydroxy-5-methoxy-7H-dibenzo[de,h]quinolin-7-one (1 and 2, resp.) in the
presence of reducing agents, and the synthesis of 2-(3,4-dihydro-6,7-dimethoxyisoqui-
nolin-1-yl)benzyl benzoate (3) by a Bischler – Napieralski (BN) condensation between
homoveratrylamine (HV) and 2-(chlorocarbonyl)benzyl benzoate. The latter has been
used as a novel starting material for diverse studies of intramolecular cyclizations under
acidic conditions. Thus, 5-methoxy-6H-dibenzo[de,h]quinolin-6-one (4), 1,2,3,4-tetra-
hydro-6,7-dimethoxy-1-(2-methylphenyl)isoquinoline (6), and 5,6,8,12b-tetrahydro-
2,3-dimethoxyisoindolo[1,2-a]isoquinoline (7) were isolated in good yields as the main
products.
Results and Discussion. – In agreement with the catalytic hydrogenation of 2,3-
dihydro- and oxoisoaporphine derivatives [9], treatment of 6-hydroxy-5-methoxy-7H-
dibenzo[de,h]quinolin-7-one (2) with PtO2 in AcOH afforded 4 as the main product in a
poor yield. Despite the use of other catalysts and solvents, such as Pd/C and toluene,
respectively, the mentioned oxoisoaporphine was not generated, and the starting
material was recovered. It is possible that 2,3-dihydro-6-hydroxy-5-methoxyoxoisoa-
porphine (1) and its aromatic derivative 2, when treated with reducing reagents as
hydride donors, could form a major proportion of 4 using solvents of different polarity.
Thus, 1 and 2 were treated with LiAlH4 and NaBH4 in solvents such as MeOH,
EtOH, and THF from room temperature up to reflux. Nevertheless, there was no
reaction, leading to the formation of the secondary amine and/or alcohol, observed
(1H-NMR spectroscopy of the crude reaction mixture), and the starting material was
entirely recovered. Although the use of NaBH4 in AcOH at room temperature
afforded the same result, surprisingly 4 was generated in high yield without evidence of
a possible carbinolamine intermediate (INT) from 1, when the temperature of the
solution of 1 and 2 was raised to 808 (Scheme 1).
These experimental findings indicated that, prior to hydride uptake, obviously,
protonation of the C¼O group at C(7) has to take place, leading to an intermediate
with two OH groups at C(6) and C(7). The formation of a C¼O group at C(6) and the
concomitant generation of the aromatic system on ring C are rapid steps without
allowing demethylation of the MeO group.
On the other hand, the search for synthetic templates that generate the
oxoisoaporphine skeleton of 4, has led us to study the synthesis of 1-benzylisoquinoline
systems that, substituted with a (benzoyloxy)methyl moiety at C(2’), could generate 4
by an acid-catalyzed intramolecular cyclization easily and without the formation of side
products. The use of acidic conditions will allow us to study the reaction rate and
regioselectivity that, according to the influence of electron-donating substituents such
as MeO on ring B of the 1-benzylisoquinoline skeleton, would steer the formation of
2,3-dihydro-7H-dibenzo[de,h]quinoline (C), which, for a later oxidation of ring A,
would afford the oxoisoaporphine derivatives.

Helvetica Chimica Acta – Vol. 93 (2010)
1387
Scheme 1. Synthesis of 5-Methoxy-6H-dibenzo[de,h]quinolin-6-one (4) from Oxoisoaporphines 1 and 2
In this sense, the synthesis of 2-(3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl)benzyl
benzoate (3) was carried out by condensation of the commercially available 2-
(chlorocarbonyl)benzyl benzoate (A) and 2-(3,4-dimethoxyphenyl)ethylamine (ho-
moveratrylamine; HV). The isolated 2-({[2-(3,4-dimethoxyphenyl)ethyl]amino}carbo-
nyl)benzyl benzoate (B) was, without purification, treated under the conditions of the
Bischler – Napieralski reaction to give the desired product in excellent yield.
Thus, 3 was treated under acidic conditions to allow the cyclization at C(8) of the 1-
benzylisoquinoline skeleton to afford the required oxoisoaporphine (Scheme 2).
However, treatment of 3 by warming a sample with CF3COOH (TFA) and
polyphosphoric acid (PPA) between 80 – 1008 did not give the expected result, and
the starting material was recovered. Finally, by using a 5 :1 mixture of AcOH/H2SO4, it
was possible to obtain a compound that, purified by column chromatography on silica
gel, turned out to be 4. This result was confirmed by NMR spectroscopy [11] and now
also by an X-ray diffraction analysis (Scheme 2).
In agreement with these results, the formation of the oxoisoaporphine derivative 4
would be the result of a previous demethylation of MeOꢀC(7) of the 1-benzylisoqui-
noline skeleton of 3, probably due to steric hindrance with regard to MeOꢀC(6) and
concomitant oxidation of the ring A. Thereafter, the oxidation of HOꢀC(7) would
regenerate the C¼O group, which becomes the driving force for the cyclization and the
formation of ring C of the oxoisoaporphine. This type of mechanism has been described
for the synthesis of other oxoisoaporphine derivatives with a variable number of MeO
groups at the quinoline framework [12].
To confirm the reactivity of the intermediate 3 under acidic conditions, the
cyclization of the corresponding benzylic alcohol was studied. Thus, the benzyl
benzoate 3 was hydrolyzed in MeOH with K2CO3 to give [2-(3,4-dihydro-6,7-
dimethoxyisoquinolin-1-yl)phenyl]methanol (5) in good yield (Scheme 3). Its cycliza-

1388
Helvetica Chimica Acta – Vol. 93 (2010)
Scheme 2. Synthesis of 2-(3,4-Dihydro-6,7-dimethoxyisoquinolin-1-yl)benzyl Benzoate (3) and 5-
Methoxy-6H-dibenzo[de,h]quinolin-6-one (4)
Scheme 3. Reactivity of 5 under Acidic Conditions and with Halogen Reagents
a) CF3COOH (TFA) or polyphosphoric acid (PPA) AcOH/H2SO4, 1008, 1 h. b) MeSO3H/NaI/MeCN or
1H-imidazole/I2/PPh3 THF or CBr4/PPh3/CH2Cl2.
tion was tried in AcOH/H2SO4, TFA, and PPA under the same temperatures
mentioned previously. However, 5 was recovered without evidence (1H-NMR) of the
formation of 5,6-dimethoxy-2,3-dihydro-7H-dibenzo[de,h]quinoline (C) or of the
oxoisoaporphine 4.
The lack of the reactivity of the benzylic CH2OH group in 5, to afford by acid
cyclization the oxoisoaporphine 4, can be explained partly by the stability of the leaving
group. In case of 3, benzoic acid, in contrast to H2O, is a better leaving group for the
intramolecular cyclization between C(8) and the benzylic C-atom. Therefore, we tried
to replace the benzylic OH group of 5 by a better leaving group such as halogen for the
intramolecular cyclization. In the literature, there is a wide spectrum of synthetic
possibilities for the conversion of benzylic alcohols to the corresponding halogenides

Helvetica Chimica Acta – Vol. 93 (2010)
1389
[13]. Indeed, we studied three different routes using MeSO3H/NaI/MeCN [14], 1H-
imidazole/I2/PPh3/THF [15], and CBr4/PPh3/CH2Cl2 [16]. However, with none of them
we achieved a replacement of the OH group leading to the formation of the
halogenated derivative (D). Solely the starting material and various polar products,
which are difficult to separate were recovered.
In view of this dilemma of reactivity, a synthetic route was studied to obtain the
secondary amine from 3 without affecting the 2-[(benzoyloxy)methyl] group so that, as
soon as the quaternary salt is formed under acidic conditions, we could carry out the
same cyclization that afforded 4, but maintaining the tetrahydroisoquinoline system.
Thus, 3 was hydrogenated in EtOH with Pd/C. Unexpectedly, 1,2,3,4-tetrahydro-6,7-
dimethoxy-1-(2-methylphenyl)isoquinoline (6) was formed quantitatively under these
conditions (Scheme 4).
Scheme 4. Conversion of the Intermediate 3 and 5 into 1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(2-methyl-
phenyl)isoquinoline (6), and 5,6,8,12b-Tetrahydro-2,3-dimethoxyisoindolo[1,2-a]isoquinoline (7) under
Hydrogenation and Reducing Conditions
a) H2/Pd-C/EtOH. b) NaBH4/MeOH.
Finally, based on these new and unexpected results, the reactivity of the
dihydroisoquinoline intermediates 3 and 5 was studied with regard to the reduction
with NaBH4/MeOH and thereby obtaining C and later the oxoisoaporphine. However,
in both cases, 5,6,8,12b-tetrahydro-2,3-dimethoxyisoindolo[1,2-a]isoquinoline (7) was
formed in high yield as the main product (Scheme 4; see also [17] for further
information).
Crystal Structure of 5-Methoxy-6H-dibenzo[de,h]quinolin-6-one (4). The com-
pound was recrystallized from MeOH to afford crystals suitable for X-ray diffraction
studies. Compound 4 crystallizes in the centro-symmetric space group P21/c with one
molecule per asymmetric unit. The ORTEP [18] view of the molecule, with the atomic
numbering scheme, is given in the Figure.
The molecule of 4 is largely planar with the MeO group almost coplanar with the
aromatic ring B. The bond length of the C¼O group at C(6) [C(1)ꢀO(1a)] of 1.224 ꢂ
is similar to that of the studied oxoisoaporphine derivatives [19].

1390
Helvetica Chimica Acta – Vol. 93 (2010)
Figure. ORTEP [18] drawing of the molecular structure of 4 indicating atom numbering. Thermal
ellipsoids represent 50% probabilities.
Conclusions. – It is noteworthy to emphasize that the reaction of the 2,3-dihydro-6-
hydroxy-5-methoxy- and 6-hydroxy-5-methoxy-7H-dibenzo[de,h]quinolin-7-one (1 and
2, resp.) with reducing agents such as NaBH4, as well as the use of 3 and 5 as
intermediates for the formation of 6-oxoisoaporphine 4 and some isoquinoline
derivatives, allowed us to determine the experimental conditions under which
oxoisoaporphine compounds, which are not accessible under reductive and acidic
intramolecular cyclization conditions, are generated. These findings could be used and
applied to other alkaloids as oxoaporphines or similar imino-quinones to obtain other
quinone derivatives as main products.
Experimental Part
General. The commercial reagents were used without purification. The utilized solvents were dried
by means of distillation under N2 or Ar, using the following reagents: Na/benzophenone, for Et2O,
toluene, and THF; and CaH2 for MeOH, EtOH, CH2Cl2, and MeCN. The catalytic hydrogenation was
carried out in a Parr shaker hydrogenator using 100-ml bottles. The purification and separation of the
products were carried out by means of low-pressure column chromatography (CC), using silica gel 60
(SiO2; 230 – 400 mesh; Merck). M.p.: Kofler Reichert – Jung Galen III apparatus; uncorrected. IR
Spectra: Perkin – Elmer Paragon 1000 FT-IR spectrometer at the University of Santiago de Compostela.
The 1H- and 13C-NMR spectra: at r.t., with a Bruker AMX 300 MHz spectrometer at 300 MHz (1H) and
75.5 MHz (13C); CDCl3, unless otherwise specified, as solvent containing TMS as an internal standard.
HR-MS: Micromass Autospec-Q spectrometer. Elemental analyses: Fisons EA 1108 analyzer with
sulfanilamide and coal for the calibration.

Helvetica Chimica Acta – Vol. 93 (2010)
1391
2-(3,4-Dihydro-6,7-dimethoxyisoquinolin-1-yl)benzyl benzoate (3). To a stirred soln. of 2-(3,4-
dimethoxyphenylethyl)amine (HV; 2.0 ml, 17 mmol) in cold Et2O (150 ml) was added dropwise a 10%
aq. soln. of KOH (250 ml) at 0 – 58. Then, 2-(chlorocarbonyl)benzyl benzoate (A; 4.6 g, 17 mmol) was
slowly added during 15 min. The formed precipitate was filtered off and dissolved in CH2Cl2. The CH2Cl2
layer was washed with 10% aq. HCl and H2O, and dried (Na2SO4). Evaporation of the solvent and
purification of the residue by CC (CHCl3/20% MeOH) gave 6.9 g (98%) of the respective 2-({[2-(3,4-
dimethoxyphenyl)ethyl]amino}carbonyl)benzyl benzoate (B), recrystallized from cyclohexane as white
needles.
Compound B (6.2 g, 14 mmol) was heated with POCl3 (30 ml) in dry toluene (30 ml) at 1208 for 3 h.
The solvent and the excess reagent were removed by evaporation in vacuo, and the residue was
decomposed by adding MeOH and 10% aq. HCl. The acidic soln. was washed once with Et2O, made
alkaline with 10% aq. NH4OH, and extracted with CH2Cl2. The extract was washed with H2O, dried, and
the solvent was evaporated. The residue was purified by CC (CHCl3/20% MeOH). Recrystallization
from cyclohexane gave 4.6 g (78%) of 3 as light green needles.
Data of B. M.p. 99 – 1008. IR (KBr): 1719 (C¼O), 1636 (C¼O). 1H-NMR: 2.88 (t, J ¼ 7.1, CH2); 3.72
(t, J ¼ 6.6, CH2); 3.83 (s, MeO); 3.84 (s, MeO); 5.51 (s, CH2); 6.77 – 6.80 (m, 3 arom. H); 7.44 – 7.48 (m, 7
arom. H); 8.04 (d, J ¼ 7.2, 2 arom. H). 13C-NMR: 31.2 (CH2); 41.4 (CH2); 56.1 (MeO); 56.1 (MeO); 64.8
(CH2); 111.7 (CH); 112.2 (CH); 121.0 (CH); 127.7 (C); 127.8 (CH); 128.7 (CH); 128.8 (2 CH); 129.5
(CH); 130.0 (CH); 130.3 (C); 130.7 (CH); 131.1 (C); 131.6 (C); 133.5 (CH); 136.4 (CH); 149.4 (CꢀO);
151.4 (CꢀO); 166.6 (C¼O); 167.7 (C¼O). Anal. calc. for C25H25NO5: C 71.58, H 6.01, N 3.34; found: C
71.43, H 5.68, N 3.29.
Data of 3. M.p. 121 – 1238. IR (KBr): 1715 (C¼O). 1H-NMR: 2.73 (t, J ¼ 7.63, CH2); 3.56 (s, MeO);
3.84 (t, J ¼ 7.80, CH2); 3.90 (s, MeO); 5.39 (s, CH2); 6.47 (s, 1 arom. H); 6.68 (s, 1 arom. H); 7.32 – 7.35 (m,
3 arom. H); 7.46 – 7.49 (m, 3 arom. H); 7.58 – 7.60 (m, 1 arom. H); 7.86 – 7.89 (m, 2 arom. H). 13C-NMR:
25.5 (CH2); 47.6 (CH2); 55.9 (2 MeO); 64.7 (CH2); 110.2 (CH); 111.0 (CH); 122.3 (C); 128.1 (C); 128.1
(2 CH); 128.6 (C); 128.9 (CH); 129.4 (CH); 129.4 (2 CH); 129.8 (C); 131.3 (C); 132.8 (CH); 134.4 (CH);
139.0 (CH); 147.3 (CꢀO); 151.1 (CꢀO); 166.0 (C); 166.3 (C¼O). HR-EI-MS: 401.16168 (C25H23NO4;
calc. 401.4664). Anal. calc. for C25H23NO4: C 74.80, H 5.77, N 3.49; found: C 74.62, H 5.77, N 3.41.
5-Methoxy-6H-dibenzo[de,h]quinolin-6-one (4) [9]. To a soln. of 3 (1.0 g, 2.49 mmol) in AcOH
(30 ml) was added dropwise 97% H2SO4 soln. (10 ml), and the soln. was heated with stirring at 1008 for
1 h. Then, the org. residue was diluted with H2O, neutralized with NH4OH, and extracted with CH2Cl2.
The extracts were then dried (Na2SO4) and concentrated in vacuo. The residue was purified by CC
(hexane/AcOEt 1:4 (v/v)), and then recrystallized from MeOH to afford 4 (147 mg, 22%). Brownish-
yellow needles.
Synthesis of 4 from 1. To a soln. of 1 (152 mg, 0.57 mmol) in AcOH (20 ml) was added NaBH4
(110 mg, 2.90 mmol) with stirring at 808 for 1 h. After cooling, the mixture was poured into ice-water
(100 ml), the pH was adjusted with NH4OH, the mixture was extracted with CH2Cl2, dried (Na2SO4),
and the solvent was evaporated in vacuo. The residue was purified by CC (hexane/AcOEt (5%)) to give
83 mg (59%) of 4.
Synthesis of 4 from 2. To a soln. of 2 (200 mg, 0.70 mmol) in AcOH (30 ml) was added NaBH4
(200 mg, 5.30 mmol) with stirring at 808 for 1 h. After cooling, the mixture was poured into ice-water
(100 ml), the pH was adjusted with NH4OH, the mixture was extracted with CH2Cl2, dried (Na2SO4),
and the solvent was evaporated in vacuo. The residue was purified by CC (hexane/AcOEt 1:4 (v/v)) to
give 162 mg (86%) of 4.
X-Ray Crystal-Structure Analysis of Compound 41). Data were collected on an Enraf – Nonius
TURBOCAD4, using Cu radiation (l 1.54184) and were corrected for polarization effects. The structure
was solved by direct methods using SIR-97 [20] and refined using SHELXL-97 [21] within the WinGX
suite of programs [22]. Non-H-atoms were refined anisotropically, and H-atoms were identified from the
1
)
CCDC-643378 contains the supplementary crystallographic data of 4. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by e-mail: deposit@ccdc.cam.ac.uk, or by
contacting the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: þ 441223336033.

1392
Helvetica Chimica Acta – Vol. 93 (2010)
difference map and allowed to refine freely. The crystal data and refinement parameters are summarized
in the Table.
Table. Crystallographic Data of 4
Empirical formula
Formula weight
Crystal dimensions
Temp.
C17H11NO2
261.27
0.44 ꢁ 0.15 ꢁ 0.12 mm3
293(2) K
Crystal system
Space group
monoclinic
P21/c
Wavelength
1.54184 ꢂ
Unit cell parameters
a [ꢂ]
12.7085(6)
b [ꢂ]
13.0859(9)
c [ꢂ]
7.4080(5)
b [8]
V [ꢂ3]
92.174(4)
1231.08(13)
Z
4
F(000)
Dx
m(MoKa)
544
1.410 g cmꢀ3
0.753 mmꢀ1
q Range for data collection
Index ranges
3.48 to 74.878.
ꢀ 15 ꢂ h ꢂ 15, ꢀ 16 ꢂ k ꢂ 0, 0 ꢂ l ꢂ 9
2729
Reflections collected
Independent reflections
Completeness to q ¼ 74.878
Absorption correction
Max. and min. transmission
Refinement method
Data; restraints; parameters
Goodness-of-fit on F2
Final R indices [I > 2s(I)]
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
2526 [Rint ¼ 0.0170]
99.8%
Y-scan
0.9151 and 0.7330
Full-matrix least-squares on F2
2526; 0; 226
1.028
R1 ¼ 0.0391, wR2 ¼ 0.1076
R1 ¼ 0.0624, wR2 ¼ 0.1182
0.0022(4)
0.265 and ꢀ 0.141 e ꢂꢀ3
[2-(3,4-Dihydro-6,7-dimethoxyisoquinolin-1-yl)phenyl]methanol (5). To a stirred soln. of 3 (1.0 g,
2.51 mmol) in MeOH (30 ml) was added K2CO3 (550 mg, 3.97 mmol) at r.t., and stirring was continued
for 2 h. The mixture was poured into ice-water (100 ml), the pH was adjusted with glacial AcOH, and the
mixture was extracted with CH2Cl2, dried (Na2SO4), and the solvent was evaporated in vacuo. The
residue was purified by recrystallization from hexane to give 5 (560 mg, 75%). Yellow needles.
1
Data of 5. M.p. 129 – 1328. IR (KBr): 3154 (OH). H-NMR: 2.75 (t, J ¼ 7.4, CH2); 3.70 (s, MeO);
3.85 – 3.87 (m, CH2); 3.95 (s, MeO); 4.5 (s, CH2); 6.65 (s, 1 arom. H); 6.80 (s, 1 arom. H); 7.35 – 7.40 (m, 4
arom. H). 13C-NMR: 26.1 (CH2); 47.2 (CH2); 56.4 (MeO); 56.5 (MeO); 65.0 (CH2); 110.6 (CH); 112.3
(CH); 127.3 (2 CH); 129.9 (2 CH); 130.1 (C); 130.5 (C); 131.3 (C); 132.9 (C); 141.9 (CꢀO); 147.6
(CꢀO); 166.1 (C). HR-EI-MS: 297.13763 (C18H19NOþ3 ; calc. 297.3570). Anal. calc. for C18H19NO3: C
72.71, H 6.44, N 4.71; found: C 72.22, H 6.44, N 4.59.
1,2,3,4-Tetrahydro-6,7-dimethoxy-1-(2-methylphenyl)isoquinoline (6).
A soln. of 3 (2.6 g,
6.53 mmol) in EtOH (100 ml) was hydrogenated at r.t. in the presence of 10% Pd/C (400 mg) for 24 h
at 60 psi. The suspension was filtered, and the filtrate was diluted with H2O (100 ml), made alkaline with
10% aq. NH4OH, and extracted with CHCl3. The extracted materials were dried (Na2SO4), and the

Helvetica Chimica Acta – Vol. 93 (2010)
1393
solvent was evaporated. The residual crude product was purified by CC (CHCl3/10% MeOH) to give 6
(1.8 g, 100%). Brownish amorphous solid.
For further characterization, 6 was transformed into the HCl salt. Thus, 670 mg of 6 · HCl
(2.36 mmol) were dissolved in 50 ml of hot i-PrOH, and 37% HCl (0.2 ml) was added. The resulting
product was precipitated with EtO2 to give 6 · HCl (268 mg, 35%). White needles.
Data of 6. M.p. 2648 (dec.). 1H-NMR ((D6)DMSO): 2.55 (s, Me); 3.01 – 3.03 (m, 1 H of CH2); 3.33 –
3.36 (m, 3 H of 2 CH2); 3.47 (s, MeO); 3.77 (s, MeO); 5.78 (s, CH); 6.15 (s, 1 arom. H); 6.88 (s, 1 arom.
H); 7.05 (d, J ¼ 7.7, 1 arom. H); 7.22 – 7.24 (m, 1 arom. H); 7.32 – 7.35 (m, 2 arom. H). 13C-NMR
((D6)DMSO): 19.8 (Me); 24.9 (CH2); 39.1 (CH2); 54.6 (CH); 55.9 (2 MeO); 111.0 (CH); 111.9 (CH);
124.4 (C); 125.5 (C); 126.7 (CH); 129.5 (CH); 130.4 (CH); 131.2 (CH); 136.0 (C); 138.2 (C); 148.0
(CꢀO); 148.9 (CꢀO).
5,6,8,12b-Tetrahydro-2,3-dimethoxyisoindolo[1,2-a]isoquinoline (7). Treatment of a suspension of 5
(910 mg, 3.06 mmol) in MeOH (60 ml) with an excess of NaBH4 (5 g) in an ice-water bath resulted in
effervescence and dissolution of the material. The soln. was diluted with H2O (100 ml), and its pH was
adjusted to 8 – 9 with aq. AcOH. Finally, the mixture was extracted with CH2Cl2, the residue was dried
(Na2SO4), and the solvent was evaporated in vacuo. The residue was purified by CC (CH2Cl2/5%
MeOH) to give 7 (780 mg, 90%). Brownish amorphous solid.
Synthesis of 7 from 3. The addition of an excess of NaBH4 (5 g) to a suspension of 3 (752 mg,
1.87 mmol) in MeOH (60 ml), kept in an ice-water bath, resulted in effervescence and dissolution of the
material. The soln. was diluted with H2O (100 ml), and its pH was adjusted to 8 – 9 with aq. AcOH.
Finally, the mixture was extracted with CH2Cl2, the residue was dried (Na2SO4), and the solvent
evaporated in vacuo. The residue was purified by CC (CH2Cl2/5% MeOH) to give 7 (480 mg, 91%).
Brownish amorphous solid.
Data of 7. M.p. 138 – 1408. 1H-NMR: 2.76 – 2.79 (m, 1 H of CH2); 3.01 – 3.17 (m, 3 H of 2 CH2); 3.61
(s, MeO); 3.87 (s, MeO); 4.30 – 4.35 (m, CH2); 5.30 (s, CH); 6.22 (s, 1 arom. H); 6.65 (s, 1 arom. H); 7.10 –
7.13 (m, 1 arom. H); 7.28 – 7.33 (m, 3 arom. H). 13C-NMR: 28.1 (2 CH2); 55.82 (2 MeO); 64.4 (CH); 110.0
(CH); 111.4 (CH); 127.1 (CH); 127.6 (CH); 128.0 (CH); 128.3 (CH); 130.8 (C); 131.0 (C); 141.4 (C);
141.5 (C); 147.4 (CꢀO); 147.9 (CꢀO).
REFERENCES
[1] Y. Sugimoto, H. A. A. Babiker, S. Inanaga, M. Kato, A. Isogay, Phytochemistry 1999, 52,
1431.
[2] B.-W. Yu, L.-H. Meng, J.-Y. Chen, T.-X. Zhou, K.-F. Cheng, J. Ding, G.-W. Qin, J. Nat. Prod. 2001, 64,
968.
[3] S. Hu, S. Xu, X. Yao, C. Cui, Y. Tezuka, T. Kikuchi, Chem. Pharm. Bull. 1993, 41, 1866.
[4] C. Hou, H. Xue, Acta Pharm. Sin. 1985, 20, 112.
[5] S. Iwashima, T. Ueda, H. Honda, T. Tsujioka, M. Ohno, J. Aoki, T. Kan, J. Chem. Soc., Perkin Trans.
1 1984, 2177.
[6] G. Pieri, F. M. Carlini, C. Paffoni, G. Boffa, U.S. Patent 4,031,096, 1977; G. Boffa, A. Crotti, G. Pieri,
A. Mangini, A. Tundo, U.S. Patent 3,678,053, 1972; G. Ribaldone, G. Borsotti, F. Gonzati, U.S. Patent
3,960,866, 1976; G. Ribaldone, U.S. Patent 3,943,136, 1976; J. King, G. R. Ramage, J. Chem. Soc.
1954, 936; A. K. Wick, Helv. Chim. Acta 1966, 49, 1748; A. K. Wick, Helv. Chim. Acta 1966, 49, 1755.
[7] J.-L. Fabre, D. Farge, C. James, U.S. Patent 4,128,650, 1978.
[8] G. N. Walker, R. J. Kempton, J. Org. Chem. 1971, 36, 1413.
´
[9] E. Sobarzo-Sanchez, B. K. Cassels, L. Castedo, Synlett 2003, 1647.
´
[10] J. R. De la Fuente, C. Jullian, C. Saitz, V. Neira, O. Poblete, E. Sobarzo-Sanchez, J. Org. Chem. 2005,
70, 8712.
´
[11] E. Sobarzo-Sanchez, J. De la Fuente, L. Castedo, Magn. Reson. Chem. 2005, 43, 1080.
[12] J. Kunitomo, S. Kaede, M. Satoh, Chem. Pharm. Bull. 1985, 33, 2778.
[13] X. Wang, R. B. Silverman, J. Org. Chem. 1998, 63, 7357; G. A. Olah, B. G. Balaram Gupta, R.
Malhotra, S. C. Narang, J. Org. Chem. 1980, 45, 1638; Y. D. Vankar, C. Trinadha Rao, Tetrahedron

1394
Helvetica Chimica Acta – Vol. 93 (2010)
Lett. 1985, 26, 2717; A. K. Mandal, S. W. Mahajan, Tetrahedron Lett. 1985, 26, 3863; G. Dai-Ho, P. S.
´
˜
Mariano, J. Org. Chem. 1987, 52, 704; I. Fernandez, B. Garcꢃa, S. Munoz, J. R. Pedro, R. de la Salud,
Synlett 1993, 7, 489; M. Di Deo, E. Marcantoni, E. Torregiani, G. Bartoli, M. C. Bellucci, M. Bosco,
L. Sambri, J. Org. Chem. 2000, 65, 2830.
[14] A. Kamal, G. Ramesh, N. Laxman, Synth. Commun. 2001, 31, 827.
[15] C. A. Merlic, C. C. Aldrich, J. Albaneze-Walker, A. Saghatelian, J. Am. Chem. Soc. 2000, 122, 3224.
[16] G. Dai-Ho, P. S. Mariano, J. Org. Chem. 1988, 53, 5113.
[17] W. J. Houlihan, R. E. Manning, U.S. Patents 3,686,207, 3,644,370, 3,644,369, 3,642,777, 1972.
[18] L. J. Farrugia, ORTEP-3 for Windows – a version of ORTEP-III with Graphical User Interface
(GUI), J. Appl. Crystallogr. 1997, 30, 568.
´
[19] E. Sobarzo-Sanchez, L. Castedo, J. R. De la Fuente, Struct. Chem. 2006, 17, 483.
[20] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, A. G. G.
Moliterni, G. Polidori, R. Spagna, SIR-97: A new tool for crystal structure determination and
refinement. J. Appl. Crystallogr. 1999, 32, 115.
[21] G. M. Sheldrick, SHELXL-97, Program for the Refinement of Crystal Structures, University of
Gçttingen, Germany, 1997.
[22] L. J. Farrugia, WinGX suite for small-molecule single-crystal crystallography, J. Appl. Crystallogr.
1999, 32, 837.
Received November 9, 2009