Synthesis of isoquinolines and tetrahydroisoquinolines as potential antitumour agents

Article abstract of DOI:10.1016/S0040-4020(01)00826-2

The isoquinoline 17 and the tetrahydroisoquinoline 16 were synthesized from 2,3-dihydro-1,4-benzodioxin (1) by different synthetic strategies. Preparation of arylethylamines and their cyclization in Bischler-Napieralski conditions have been studied. Another approach to isoquinolines was based on the amination of the ketone 13 followed by cyclization in acidic media. The route via the amide 15 was found to be more successful with respect to both yield and ease of reaction.

Full text of DOI:10.1016/S0040-4020(01)00826-2

TETRAHEDRON
Pergamon
Tetrahedron 57 02001) 8297±8303
Synthesis of isoquinolines and tetrahydroisoquinolines as
potential antitumour agents
A. S. Capilla,a M. Romero,a M. D. Pujol,a,p D. H. Caignardb and P. Renardb
a
 Á Á
Laboratori de Quõmica Farmaceutica, Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
b
Â
Labor. ADIR, 1, rue Carle Hebert, 92415 Courbevoie, France
Received 7 May 2001;revised 26 June 2001;accepted 10 August 2001
AbstractÐThe isoquinoline 17 and the tetrahydroisoquinoline 16 were synthesized from 2,3-dihydro-1,4-benzodioxin 01) by different
synthetic strategies. Preparation of arylethylamines and their cyclization in Bischler±Napieralski conditions have been studied. Another
approach to isoquinolines was based on the amination of the ketone 13 followed by cyclization in acidic media. The route via the amide 15
was found to be more successful with respect to both yield and ease of reaction. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
the intermediate dihydroisoquinoline 8 from the corre-
sponding amide 7. Next an oxidative process was envisaged
for obtaining the isoquinoline, but although 8 was the
substrate for the projected oxidation step, the expected
isoquinoline 9 was only obtained when Pd/C in decahydro-
naphthalene at 2008C was used 0Scheme 1, pathway B).
Other oxidizing agents were tested 0DDQ, Ag2O, MnO2±
CrO3, K3Fe0CN)6, 3-nitrobenzenesulfonic acid) but all
attempts failed;starting material or degradation products
were obtained as 3,4,5-trimethoxybenzoic acid.
Quinolines and isoquinolines are important because of their
occurrence in nature and their physiological properties.1,2
Recently there has been a growing interest in developing
general and versatile synthetic methods3±5 for the synthesis
of these heterocyclic systems due to their value as synthetic
intermediates and their biological activity.
There are several methods for the synthesis of isoquinolines
of which the intramolecular cyclization of an appropriate
substituted amide is the most often employed. The cyclo-
dehydration of the corresponding amides formed from the
b-phenethylamine with POCl3 called Bischler±Napieralski,
is the most widely known.6,7
Therefore the reaction sequence was altered and the Pictet±
Gams8 modi®cation was applied. Thus the b-phenethyl-
amide 7 was substituted by an b-hydroxy-b-phenethyl-
amide 12 obtained from 11 by treatment with 3,4,5-
trimethoxybenzoyl chloride 0Scheme 1, pathway C). As
expected, this amide intermediate cyclized to the isoquino-
line 9 with low yield 012%). A number of attempts was
made to optimize this direct cyclization step. As classical
methods allow the preparation of the isoquinoline in lower
yields we decided to develop a new scheme involving
another cyclization process 0Scheme 1, pathway D). This
route began with selective bromination, using NBS9 in
methanol, at the C-6 position of the precursor 1,4-benzo-
dioxin ring, followed by condensation with 3,4,5-
trimethoxybenzaldehyde through the lithium derivative
formed by halogen/lithium exchange. The alcohol formed
in situ must be analysed by 1H NMR, but attemps to isolate
the intermediate compound was not successful due to fast
oxidation to ketone 13. The corresponding ketone 13 was
treated with aminoacetaldehyde dimethyl acetal in acidic
media in toluene, according to Pomeranz±Fritsch condi-
tions,10 followed by reduction of the imine formed in situ
using NaBH4 in methanol. Finally the cyclization of the
aminoacetal 14 with HCl 2N led to isoquinoline 17 in
quantitative yield. In an earlier attempt to synthesize 9,
The work presented here describes the preparation of new
1,4-dioxino[2,3-g]isoquinolines or their saturated analogues
from 2,3-dihydro-1,4-benzodioxin by four different routes
A, B, C and D in order to investigate further the antitumour
activity.
2. Results and discussion
Isoquinolines have interesting biological activities and are
also widely used as reactive intermediates in organic
synthesis.
Several methods are described for the preparation of iso-
quinolines. Among them, ®rst we selected the Bischler±
Napieralski6,7 reaction conditions for the construction of
Keywords: cyclization;1-substituted isoquinoline;1,4-benzodioxin.
Corresponding author. Fax: 1093)4035941;
e-mail: mdpujol@farmacia.far.ub.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020001)00826-2

8298
A. S. Capilla et al. / Tetrahedron 57 32001) 8297±8303
Scheme 1. i: 1. NBS/MeOH;2. n-BuLi/DMF/THF 2788C. ii: NaBH4/MeOH. iii: NBS/triphenylphosphine/DMF for compound 3;SOCl 2 for compound 4.
iv: NaCN/DMF/HMPT. v: H2/Pd/C MeOH. vi: Et3N/ethyl chloroformate/3,4,5-trimethoxybenzoic acid/CHCl3. vii: POCl3/toluene. viii: Pd/C decahydro-
naphthalene 2008C. ix: CH3NO2/n-BuLi/THF 2788C. x: P2O5/CH2Cl2. xi: 1. 3,4,5-trimethoxybenzoyl chloride/CHCl3/H2O/NaOH;2. POCl 3/toluene. xii: 1.
NBS/MeOH;2. n-BuLi/3,4,5-trimethoxybenzaldehyde/THF 2788C. xiii: H2NCH2CH0OCH3)2/PTSA/toluene. xiv: NaBH4/EtOH r.t. xv: HCl 2N. xvi: HCl/
EtOH. xvii: H2/Pd/C ethyl acetate. xviii: 3,4,5-Trimethoxybenzylaldehyde/CF3COOH. xix: NaOH 2N.

A. S. Capilla et al. / Tetrahedron 57 32001) 8297±8303
8299
compound 14 was treated with HCl at re¯ux. The product
mixture after a conventional work-up, showed that the
principal product present was the isoquinoline 17, resulting
from an unexpected cyclization of the function aldehyde at
the 20-position of the most activated aromatic ring and also
the most sterically hindered.
structures. The resultant tetrahydroisoquinoline 16 was
somewhat labile toward treatment with strong alkali or
acid at elevated temperature. The tetrahydroisoquinoline
16 was a convenient precursor of isoquinoline 9. Heating
a decaline solution of 16 in the presence of Pd/C to 2008C
gives 9 in acceptable yield.
Surprisingly, the reaction gave the isoquinoline 17 as the
sole product, and the dihydroisoquinoline was not detected.
The isoquinoline 17 was identi®ed by detailed NMR studies.
The successful deprotection, cyclization and oxidation in a
`one pot' procedure was the most remarkable of this
method. The cyclization of the corresponding ester instead
of the acetal did not allow the preparation of the desired
isoquinolone. The spontaneous aromatization in acidic
media with atmospheric oxygen is attributable to the
presence of the condensed 3,4,5-trimethoxy substructure.
In conclusion, the preparation of the isoquinoline 17 from
the 2,3-dihydro-1,4-benzodioxin has been achieved in a
short method using modi®ed Pomeranz±Fritzch conditions
0pathway D) with a global yield of 42%, whereas the treat-
ment and cyclization of the aminoalcohol 11 gave the
isoquinoline 9 in a 6% overall yield 0pathway C). The
more ef®cient synthesis of 16 and 9 was the treatment of
6 with 3,4,5-trimethoxybenzaldehyde using tri¯uoroacetic
acid 0pathway A).
We are working in this area preparing a series of isoquino-
lines and tetrahydroisoquinolines for systematic study of
their chemical and antitumour activity.
The aldehyde 2 obtained from the 2,3-dihydro-1,4-benzo-
dioxin by bromination followed by condensation with DMF
through Br/Li exchange was the intermediate for obtaining
the arylethylamine 6 and also the aminoalcohol 11. Treat-
ment of this aldehyde with NaBH4 in methanol yielded the
alcohol, which was converted to the bromide or chloride
derivates in 43% and 60%, respectively.11,12 Both
compounds 3 and 4 were successfully used in the synthesis
of nitrile 5.13 Though in both cases the reaction yields were
excellent, the direct replacement of bromine was preferable
0yield 98% versus 88%). In the next step, the nitrile 5 was
converted to the hydrogenated14 compound 6 in acceptable
yield. On the other hand, the aldehyde 2 was condensed with
nitromethane using n-butyl lithium in THF at 2788C and
thus afforded the nitroalcohol 10 expected in 79% yield. In
the same reaction a small amount of the corresponding
dehydrated compound was detected. This mixture was
reduced to the corresponding arylethylamine 6.
3. Experimental
3.1. General
Melting points were determined on an MFB 595010 M
Gallenkamp melting point apparatus and are uncorrected.
1
The H and 13C NMR spectra were recorded on a Varian
Gemini 200 or Varian Gemini 300 spectrometer or on a
Varian VXR-500 spectrometer with tetramethylsilane as
internal standard and using CDCl3 as solvent or CD3OD;
chemical shifts were expressed in ppm down®eld from
internal TMS or residual signal of deuterated solvent 0d).
IR spectra were recorded on an FTIR Perkin±Elmer 1600
spectrophotometer. Mass spectra were recorded on a
Hewlett±Packard spectrometer 5988-A 070 eV). The
chromatography was carried out on SiO2 0silica gel 60,
SDS, 60±200 mm). Microanalyses were determined on a
Subsequent treatment of 10 with P2O5 in dry dichloro-
methane15 gave the corresponding dehydrated compound,
which after simultaneous reduction of the ole®n and the
nitro group to amine, was converted to the amide 7 by
treatment of the primary amine with 3,4,5-trimethoxy-
benzoic acid in chloroform in the presence of ethyl
chloroformate. In the next step this amide was converted
to the corresponding dihydroisoquinoline 8 0pathway B).
Á
Carlo Erba 1106 Analyser by Serveis Cienti®co-Tecnics,
Universitat de Barcelona. All reagents were of commercial
quality or were puri®ed before use and the organic solvents
were of analytical grade or puri®ed by standard procedures.
3.1.1. 2-Bromomethyl-2,3-dihydro-1,4-benzodioxin ,3).
The aldehyde 2 01.5 g, 9.13 mmol) was dissolved in metha-
nol 030 mL) and cooled to 08C. Then NaBH4 01.04 g,
27.41 mmol) was added slowly, and after stirring at 08C
for 30 min, a solution of HCl 2N 010 mL) was added, the
methanol removed under vacuo, and the residue was
extracted with CH2Cl2 03£15 mL). The combined organic
solution was dried 0Na2SO4), ®ltered and evaporated giving
the corresponding alcohol that was used without puri®cation
in the next reaction. This alcohol 01.48 g, 8.91 mmol) was
dissolved in DMF 010 mL). Triphenylphosphine 04.68 g,
17.81 mmol) and NBS 03.17 g, 17.81 mmol) were added.
The mixture was stirred at 608C for 2 h. Then water
020 mL) was added, and the mixture was extracted with
ether 03£15 mL). The organic layers were dried 0Na2SO4)
®ltered and evaporated to dryness. The crude product was
chromatographed 0silica gel hexane/ethyl acetate in a ratio
8:2) yielding 904 mg of 3 as an oil 043% yield). IR 0NaCl) n
0cm21) 2930, 1507, 1295, 1067. 1H NMR 0CDCl3,
Alternatively the nitroalcohol 10 was reduced with H2/Pd±
C to aminoalcohol 11 in good yield 085%) and immediately
treated with 3,4,5-trimethoxybenzoyl chloride according to
the Schotten±Baumann procedure obtaining the isoquino-
line 12 as indicated in Scheme 1. Finally 9 was converted to
the tetrahydroisoquinoline by catalytic hydrogenation.
Likewise the amine 6 could easily be converted to the
respective imine by condensation with the aldehyde,
which without puri®cation afforded the desired N-tri¯uoro-
acetyl tetrahydroisoquinoline 15 by treatment with a
mixture of tri¯uoroacetic acid and tri¯uoroacetic anhydride.
The stable amide 15 was hydrolyzed with NaOH 2N at room
temperature to the tetrahydroisoquinoline 16 in acceptable
yield 096%). The 13C NMR spectra of the new synthesized
tetrahydroisoquinoline showed signals that correspond to
the number of carbon atoms supporting the proposed

8300
A. S. Capilla et al. / Tetrahedron 57 32001) 8297±8303
200 MHz) d 0ppm) 4.22 0s, 4H, C2H2 and C3H2), 4.51 0s,
2H, ArZCH2ZBr), 6.81 0s, 2H, C5H and C8H), 6.85 0s, 1H,
C7H). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm) 33.8 0CH2,
ArZCH2ZBr), 64.2 and 64.3 0CH2, C2H2 and C3H2), 117.5
0CH, C5H), 117.9 0CH, C8H), 122.2 0CH, C7H), 130.8 0C,
C6), 143.3 and 143.7 0C, C4a and C8a).
hexane/ethyl acetate/methanol in a ratio 5:4:1) to give
158 mg of 6 as an oil 050% yield). IR 0NaCl) n 0cm21
)
1
3100, 1200. H NMR 0CDCl3, 200 MHz) d 0ppm) 1.72
0bs, 2H, NH2), 2.66 0m, 2H, CH2ZN), 2.81 0m, 2H,
CH2ZAr), 4.18 0m, 4H, C2H2 and C3H2), 6.62 0m, 3H,
C5H, C7H and C8H). 13C NMR 0CDCl3, 50.3 MHz) d
0ppm) 38.7 0CH2, CH2ZAr), 43.1 0CH2, CH2ZN), 63.8
and 63.9 0CH2, CH2ZO), 116.7 and 116.9 0CH, C5H and
C8H), 121.2 0CH, C7H), 132.5 0C, C6), 141.4 0C, C4a),
142.9 0C, C8a).
3.1.2. 2-Chloromethyl-2,3-dihydro-1,4-benzodioxin ,4).
NaBH4 0691 mg, 18.26 mmol) was added slowly to a solu-
tion of the aldehyde 2 01 g, 6.09 mmol) in methanol 030 mL)
under an inert atmosphere at 08C. The mixture was stirred at
08C for 30 min. Then a solution of HCl 2N 010 mL) was
added and the methanol removed under vacuo. The residue
was extracted with CH2Cl2 03£15 mL), the combined
organic solution was dried 0Na2SO4) ®ltered and evaporated
giving the corresponding alcohol. A mixture of alcohol
0988 mg, 5.94 mmol) and SOCl2 05 mL) was heated at
1108C for 15 min. A solution of NaOH 2N 010 mL) was
added slowly. The residue was extracted with CH2Cl2
03£15 mL). The combined organic phase was dried
0Na2SO4) ®ltered and evaporated. The crude product was
puri®ed by chromatography on silica gel 0hexane/ethyl
acetate in a ratio 8:2) to afford as an oil 682 mg of 4 060%
3.1.5. 2-,2,3-Dihydro-1,4-benzodioxin-6-yl)ethylamine ,6).
A mixture of alcohol 10 0173 mg, 0.76 mmol) and P2O5 in
dry CH2Cl2 010 mL) was stirred at room temperature for
45 min. Then water 015 mL) was added, and the aqueous
layer was extracted with CH2Cl2 03£15 mL). The combined
organic extract was dried and concentrated, and the result-
ing residue was puri®ed by column chromatography
0hexane/ethyl acetate in a ratio 6:4) giving 120 mg as a
yellow solid. A mixture of this yellow solid 0120 mg) and
Pd/C 012 mg, 10%) in methanol 020 mL) was stirred at room
temperature in an atmosphere of hydrogen for 6 h. The
catalyst was ®ltered off, the solvent was removed under
vacuo and the residue was puri®ed by column chromato-
graphy 0on silica gel hexane/ethyl acetate/methanol in a
ratio 5:4:1) to afford 96 mg of 6 051% yield).
1
yield). H NMR 0CDCl3, 200 MHz) d 0ppm) 4.26 0s, 4H,
C2H2 and C3H2), 4.51 0s, 2H, CH2Cl), 6.85 0s, 2H, C5H and
C8H), 6.91 0s, 1H, C7H).
3.1.3. 2-,2,3-Dihydro-1,4-benzodioxin-6-yl)acetonitrile ,5).
The compound 4 0312 mg, 1.68 mmol) was dissolved in
mixture of DMF/HMPT 3:1 05 mL). Then NaCN 0165 mg,
3.37 mmol) was added and the resulting mixture was stirred
at room temperature for 2 h 30 min. Then water 015 mL)
was added and the reaction mixture was extracted with
ether 03£20 mL). The combined organic layers were
washed with water several times and ®nally dried
0Na2SO4), ®ltered and the solvent removed under vacuo.
The crude was puri®ed by column chromatography 0on
silica gel hexane/ethyl acetate in a ratio 6:4) to give
3.1.6. N-,2,3-Dihydro-1,4-benzodioxin-2-yl)ethyl-3,4,5-
trimethoxybenzamide ,7). A solution of ethyl chloro-
formate 096 mg, 0.89 mmol) in dry CHCl3 01 mL) was
cooled to 08C and then a solution of 3,4,5-trimethoxy-
benzoic acid 0189 mg, 0.89 mmol) and Et3N 090 mg,
0.89 mmol) in dry CHCl3 03 mL) was added, then the
reaction mixture was stirred at 08C for 30 min. After a solu-
tion of 6 0160 mg, 0.89 mmol) in CHCl3 03 mL) was added
dropwise, the mixture was stirred at 808C for 22 h. A solu-
tion of NaOH 2N 015 mL) was added, the mixture extracted
with CH2Cl2 03£15 mL). The extracts were dried 0Na2SO4),
®ltered and after removal of the solvent, the residue was
puri®ed by column chromatography 0on silica gel hexane/
ethyl acetate in a ratio 7:3) to give 149 mg of 7 as a white
solid 047% yield). Melting point 116±1178C. IR 0NaCl) n
261 mg of 5 as an oil 088% yield). IR 0NaCl) n 0cm21
)
1
2249. H NMR 0CDCl3, 500 MHz) d 0ppm) 3.61 0s, 2H,
CH2CN), 4.23 0s, 4H, C2H2 and C3H2), 6.75 0dd,
J7±8ˆ8.5 Hz, J07±5ˆ2.5 Hz, 1H, C7H), 6.81 0d,
J5±7ˆ2.5 Hz, 1H, C5H), 6.83 0d, J8±7ˆ8.5 Hz, 1H, C8H).
13C NMR 0CDCl3, 50.3 MHz) d 0ppm) 22.6 0CH2, CH2CN),
64.0 and 64.1 0CH2, C2H2 and C3H2), 116.7 0CH, C5H),
117.6 0CH, C8H), 118.0 0C, CN), 120.6 0CH, C7H), 122.7
0C, C6), 143.1 0C, C8a), 143.7 0C, C4a).
1
0cm21) 3293, 2941, 1633. H NMR 0CDCl3, 200 MHz) d
0ppm) 2.82 0t, Jˆ6.5 Hz, 2H, ArZCH2), 3.66 0q, Jˆ6.5 Hz,
2H, CH2ZN), 3.85 0s, 3H, p-OCH3), 3.88 0s, 6H, m-OCH3),
4.25 0s, 4H, C2H2 and C3H2), 6.10 0bs, 1H, NH), 6.77
0m, 2H, C7H and C8H), 6.92 0s, 1H, C5H), 7.30 0s, 1H,
C20H and C60H). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm)
34.8 0CH2, CH2ZN), 41.2 0CH2, ArZCH2), 56.0 0CH3,
p-OCH3), 60.7 0CH3, m-OCH3), 64.2 0CH2, C2H2 and
C3H2), 104.1 0CH, C20H and C60H), 117.2 and 117.3
0CH, C7H and C8H), 121.6 0CH, C5H), 130.0 0C, C10),
132.0 0C, C6), 142.1 and 143.4 0C, C4a and C8a), 152.9
0C, C30, C40 and C50), 167.1 0C, CO).
Compound 5 was prepared also from 3 0428 mg,
1.86 mmol) as the starting reagent, and obtained in a yield
of 98% as an oil 0324 mg) following the same procedure.
3.1.4. 2-,2,3-Dihydro-1,4-benzodioxin-6-yl)ethylamine ,6).
To a solution of 5 0307 mg, 1.75 mmol) in methanol
020 mL), Pd/C 061 mg, 20%) and concentrated HCl
00.2 mL) were added, and the suspension stirred at room
temperature under an atmosphere of hydrogen for 18 h.
The catalyst was ®ltered off and the ®ltrate was evaporated
to dryness under vacuo and the resulting residue diluted
with solution of NaOH 2N 015 mL) and then extracted
with CH2Cl2 03£15 mL). The extracts were dried
0Na2SO4), ®ltered and after removal of the solvent the resi-
due was puri®ed by column chromatography 0on silica gel,
3.1.7.
6-,3,4,5-Trimethoxyphenyl)-2,3,8,9-tetrahydro-
[1,4]dioxino[2,3-g]isoquinoline ,8). POCl3 00.5 mL) was
added to a solution of compound 7 075 mg, 0.02 mmol) in
dry toluene 05 mL), and the reaction mixture was stirred at
1108C for 5 h. The reaction was quenched by addition of
NaOH 2N solution 010 mL) and the mixture extracted with
ether 03£15 mL). The organic phase was dried 0Na2SO4),
®ltered and the solvent was removed. The crude product was

A. S. Capilla et al. / Tetrahedron 57 32001) 8297±8303
8301
puri®ed by column chromatography on silica gel 0hexane/
ethyl acetate in a ratio 6:4) giving 68 mg of 8 as an oil 095%
0Na2SO4), ®ltered and the solvent evaporated to dryness
under vacuo. The residue was subjected to column chroma-
tography on silica gel 0hexane/ethyl acetate in a ratio 7:3) to
afford 547 mg of 10 as a colorless solid 079% yield). Melt-
ing point 72±738C. IR 0KBr) n 0cm21) 3457, 2934, 1591. 1H
NMR 0CDCl3, 200 MHz) d 0ppm) 2.82 0bs, 1H, OH), 4.25
0s, 4H, C2H2 and C3H2), 4.45 0dd, J<13.2 Hz, J<3.6 Hz,
1H, CH2NO2), 4.54 0dd, J<13.2 Hz, J0<4 Hz, 1H,
CH2NO2), 5.34 0dd, J<4 Hz, J0<3.6 Hz, 1H, CHOH),
6.86 0s, 2H, C5H and C7H), 6.91 0s, 1H, C8H); 13C NMR
0CDCl3, 50.3 MHz) d 0ppm) 64.2 0CH2, C2H2 and C3H2),
70.3 0CH, CHOH), 81.1 0CH2, CH2NO2), 114.9 0CH, C5H),
117.5 0CH, C8H), 118.9 0CH, C7H), 131.5 0C, C6), 143.6
and 143.7 0C, C4a and C8a). MS 0EI) m/z 0relative
intensity) 225 0M1, 82), 178 061), 165 0100), 163 068),
137 066).
1
yield). IR 0NaCl) n 0cm21) 1612, 1130,1090. H NMR
0CDCl3, 200 MHz) d 0ppm) 2.61 0t, Jˆ6 Hz, 2H, C9H),
3.70 0m, 2H, C8H), 3.80 0s, 9H, m and o-OCH3), 4.19 0m,
4H, C2H2 and C3H2), 6.88 0s, 1H, C10H), 6.73 0s, 2H, C20H
and C60H), 6.76 0s, 1H, C5H).
3.1.8. 6-,3,4,5-Trimethoxyphenyl)-[1,4]dioxino[2,3-g]iso-
quinoline ,9). To a solution of the aminoalcohol 11 050 mg,
0.25 mmol) in CHCl3 010 mL) cooled to 08C, was added
another solution of NaOH 85% 0102 mg, 2.56 mmol) in
water 05 mL). The mixture was stirred for 5 min and a
solution of 3,4,5-trimethoxybenzoyl chloride 0147 mg,
6.40 mmol) in CHCl3 03 mL) was added dropwise, and the
stirring was continued at room temperature for 2 h 30 min.
The reaction mixture was extracted with CH2Cl2
03£15 mL), and the extracts were dried 0Na2SO4) and
®ltered. After removal of the solvent the residue was
dissolved in dry toluene 010 mL), POCl3 00.5 mL) was
added and the mixture was stirred at 1208C for 5 h. The
toluene was removed under vacuo, and the crude product
was washed with water and the aqueous phase was extracted
with ethyl acetate 03£10 mL). The combined organic
extracts were dried 0Na2SO4) and concentrated, and the
residue was chromatographed 0hexane/ethyl acetate in a
ratio 8:2) giving 10 mg of 9 as an oil 012% yield). IR
0NaCl) n 0cm21) 2936, 1612, 1125, 1067. 1H NMR
0CDCl3, 200 MHz) d 0ppm) 3.88 0s, 3H, p-OCH3), 4.03 0s,
3H, m-OCH3), 4.06 0s, 3H, m-OCH3), 4.33 0s, 4H, C2H2 and
C3H2), 6.99 0d, J<8 Hz, 1H, C20H), 7.23 0d, J<8 Hz, 1H,
C60H), 7.26 0s, 1H, C5H), 7.27 0s, 1H, C10H), 8.70 0d,
J<5 Hz, 1H, C9H), 8.46 0d, J<5 Hz, 1H, C8H). 13C NMR
0CDCl3, 50.3 MHz) d 0ppm) 55.9 0CH3, CH3ZO), 61.2
0CH3, CH3ZO), 61.5 0CH3, CH3ZO), 64.4 and 64.5 0CH2,
C2H2 and C3H2), 101.9 0CH, C20H), 113.6 0CH, C60H),
117.1 0CH, C5H), 118.7 0CH, C10H), 122.8 0CH, C9H),
123.7 0C, C5a), 128.9 0C, C10), 133.4 0C, C9a), 140.7
0CH, C8H), 143.6 0C, C4a), 143.9 0C, C10a), 153.2 0C,
C30, C40 and C50), 157.9 0C, C6). MS 0EI) m/z 0relative
intensity) 353 0M1, 100), 338 058), 322 026), 313 06). Calcu-
lated for C20H19O5N: C, 67.98;H, 5.42;N, 3.96. Found: C,
68.02;H, 5.72;N, 4.05.
3.1.10. 1-,2,3-Dihydro-1,4-benzodioxin-6-yl)-2-amino-
ethanol ,11). A mixture of compound 10 0270 mg,
1.19 mmol) and Pd/C 027 mg, 10%) in methanol 020 mL)
was stirred at room temperature under an atmosphere of
hydrogen for 21 h. The catalyst was ®ltered, and the solvent
was removed under vacuo. The residue was puri®ed by
column chromatography 0on silica gel hexane/ethyl acetate
in a ratio 5:5) giving 198 mg of 11 as an oil 085% yield). IR
0NaCl) n 0cm21) 3449, 2879, 1228, 1065. 1H NMR 0CDCl3,
200 MHz) d 0ppm) 2.66 0d, Jˆ6.2 Hz, 2H, CH2ZNH2), 3.20
0bs, 2H, OH and NH), 4.21 0s, 4H, C2H2 and C3H2), 4.84
0t, Jˆ6.2 Hz, CHZOH), 6.81 0s, 2H, C5H and C7H), 6.85 0s,
1H, C8H). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm) 27.6
0CH2, CH2ZNH2), 64.2 0CH2, C2H2 and C3H2), 69.2 0CH,
CHZOH), 114.4 0CH, C5H), 117.4 0CH, C8H), 118.5 0CH,
C7H), 134.4 0C, C6), 143.4 and 143.6 0C, C4a and C8a). MS
0EI) m/z 0relative intensity) 195 0M1, 25), 177 062).
3.1.11.
6-,3,4,5-Trimethoxybenzoyl)-2,3-dihydro-1,4-
benzodioxin ,13). NBS 01.32 g, 7.41 mmol) was added to
a solution of 1 01 g, 7.34 mmol) in methanol 010 mL) under
an inert atmosphere at 08C. The resulting mixture was stir-
red at room temperature for 5 h. Then a solution of NaOH
2N 020 mL) was added dropwise, and the methanol was
removed under vacuo. The resulting mixture was extracted
with CH2Cl2 03£15 mL), the combined organic solution was
dried 0Na2SO4), ®ltered and evaporated giving the bromo
derivative. This residue 01.46 g, 6.77 mmol) was dissolved
in dry THF 08 mL) under argon and the solution cooled to
2788C. A solution of 1.6 M n-butyl lithium in hexane
04.7 mL, 12.9 mmol) was added slowly and the reaction
mixture was stirred for 1 h. Then a solution of 3,4,5-
trimethoxybenzaldehyde 010.1 g, 25.4 mmol) in dry THF
010 mL) was added. The stirring continued until the mixture
reached room temperature. A saturated solution of NH4Cl
010 mL) was added. The water layer was extracted with
ether 03£10 mL). The combined organic solution was
dried 0Na2SO4), ®ltered and evaporated. The crude product
was puri®ed by column chromatography 0silica gel, hexane/
ethyl acetate in a ratio 7:3) giving 1.73 g of 13 as a white
solid 071% yield). Melting point 129±1308C. IR 0KBr) n
0cm21) 1649. 1H NMR 0CDCl3, 300 MHz) d 0ppm) 3.78 0s,
3H, p-OCH3), 3.79 0s, 3H, m-OCH3), 3.83 0s, 3H, m-OCH3),
4.20 0s, 4H, C2H2 and C3H2), 6.81 0d, Jˆ8.1 Hz, C8H), 6.92
0s, 2H, C20H and C60H), 7.21 0d, Jˆ8 Hz, 1H, C7H), 7.31 0s,
1H, C5H). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm) 56.2
The isoquinoline 9 can also be obtanied by oxidation of
the tetrahydroisoquinoline 16 or the dihydroisoquinoline 8
with Pd/C 010% w/w) in decahydronaphthalene at 2008C
for 12 h. After being cooled to room temperature, the
mixture was ®ltered, the solvent was destilled and the
crude product was puri®ed by silica gel column cromato-
graphy to give the isoquinoline 9 in 55% or 78% yield,
respectively.
3.1.9. 2-Nitro-1-,2,3-dihydro-1,4-benzodioxin-6-yl)etha-
nol ,10). To a solution of CH3NO2 00.30 mL, 6.09 mmol)
in dry THF 05 mL) under argon was added a solution 1.6 M
n-butyl lithium in hexane 03.80 mL, 6.09 mmol) at 2788C
and the reaction was stirred at this temperature for 30 min.
A solution of 2 0500 mg, 3.04 mmol) in dry THF 05 mL) was
added and the stirring was continued until the mixture
reached room temperature. Then a saturated solution of
NH4Cl 015 mL) was added and the mixture was extracted
with ether 03£10 mL). The organic layers were dried

8302
A. S. Capilla et al. / Tetrahedron 57 32001) 8297±8303
0CH3, m-OCH3), 60.8 0CH3, p-OCH3), 64.0 and 64.6 0CH2,
C2H and C3H), 107.3 0CH, C20H and C60H), 116.8 0CH,
C8H), 119.5 0CH, C5H), 124.1 0CH, C7H), 130.9 0C, C10),
132.9 0C, C6), 143.1 0C, C4a), 147.5 0C, C8a), 152.6 0C,
C30, C40 and C50), 194.3 0C, CO). Calculated for
C18H18O6´CH3OH: C, 62.97;H, 6.12. Found: C, 62.95;H, 6.19.
0C, Jˆ36 Hz, CO). MS 0EI) m/z 0relative intensity): 543
0M1, 71), 438 0100), 286 031).
3.1.14.
6-,3,4,5-Trimethoxyphenyl)-2,3,6,7,8,9-hexa-
hydro-[1,4]dioxino[2,3-g]isoquinoline ,16). The amide
15 was added to a solution of NaOH 2N/ethanol 05:1)
025 mL) and the mixture was stirred at room temperature
for 18 h. It was extracted with ethyl acetate, dried, ®ltered
and concentrated under vacuo. The residue was puri®ed by
column chromatography 0hexane/ethyl acetate/methanol,
5:4:1). The tetrahydroisoquinoline 16 was obtained as a
white solid 0yield: 96%). Melting point 131±1328C
3.1.12. 6-,1-,N-,2-Dimethoxyethyl)amino)-1-,3,4,5-tri-
methoxyphenyl)-2,3-dihydro-1,4-benzodioxin ,14). Amino-
acetaldehyde dimethyl acetal 01.59 g, 15.13 mmol) and PTSA
015 mg) were added to a toluene solution of 13 and the reac-
tion mixture was re¯uxed for 20 h. The water formed is
removed with a Dean±Stark system. The toluene was evapo-
rated to dryness under vacuo, and the resulting residue was
dissolved with ethanol 015 mL). Then NaBH4 0457 mg,
12.08 mmol) was added slowly and, after stirring for 1 h at
room temperature, a solution of HCl 2N 010 mL) was added
and the ethanol removed under vacuo. The residue was
extracted with CH2Cl2 03£15 mL), and the combined organic
solution was dried 0Na2SO4), ®ltered and evaporated to
dryness. The crude product was puri®ed by column chromato-
graphy 0silica gel, hexane/ethyl acetate in a ratio 5:5) giving
770 mg of 14 as an oil 060% yield). IR 0NaCl) n 0cm21) 3327,
2932, 1711, 1237, 1128. 1H NMR 0CDCl3, 200 MHz) d 0ppm)
1.98 0bs, 1H, NHZ), 2.68 0d, J<5 Hz, 2H, CH2ZN), 3.56 0s,
3H, OCH3), 3.80 0s, 3H, OCH3), 3.83 0s, 3H, OCH3), 4.23 0s,
4H, C2H2 and C3H2), 4.52 0t, J<5 Hz, 1H, CH0OCH3)2), 4.63
0s, 1H, ArZCHZAr), 6.64 0s, 2H, C20H and C60H), 6.86 0m,
3H, C5, C7 and C8). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm)
49.3 0CH2), 53.8 0CH3, OCH3), 53.9 0CH3, OCH3), 56.1 0CH3,
m-OCH3), 60.8 0CH3, p-OCH3), 64.3 0CH2, C2H and C3H),
66.9 0CH, CHZN), 103.5 and 103.8 0CH, C20H and C60H),
115.9 0H, C5H), 117.2 0CH, C8H), 120.1 0CH, C7H), 136.2
0C, C10), 139.1 0C, C6), 142.6 0C, C4a), 143.3 0C, C8a), 153.1
0C, C30, C40 and C50). MS 0EI) m/z 0relative intensity) 419
0M1);387 016);315 024);271 095).
1
0ether), IR 0KBr) n 0cm21) 3100, 1589, 1297, 1125. H
NMR 0CDCl3, 200 MHz) d 0ppm) 2.05 0bs, 1H, NH), 2.60
0m, 1H, C-9Heq), 2.91 0m, 1H, C-9Hax), 3.00 0m, 1H,
CHZNax), 3.79 0m, 1H, CHZNeq), 3.81 0s, 6H, OCH3),
3.83 0s, 3H, OCH3), 4.19 0m, 4H, OCH2), 4.88 0s, 1H,
C6H), 6.28 0s, 1H, C10H), 6.51 0s, 2H, C20, C60), 6.63 0s,
1H, C5H). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm) 28.9
0CH2, C9), 43.0 0CH2, CH2N), 56.0 0CH3, OCH3), 60.7
0CH3, OCH3), 62.4 0CH, C6), 64.2 and 64.3 0CH2, OCH2),
105.6 0CH, C20 and C60), 115.9 0CH, C5), 116.6 0CH, C10),
128.1 0C, C5a), 131.3 0C, C9a), 140.1 0C, C10), 141.3 0C,
C4a), 141.9 0C, C10a), 152.9 0C, C30 and C50). Calculated
for C20H23NO5: C, 67.21;H, 6.49;N, 3.92. Found: C, 67.40;
H, 6.22;N, 4.01.
3.1.15. 1-,2,3-Dihydro-1,4-benzodioxin-6-yl)-5,6,7-tri-
methoxyisoquinoline ,17). A mixture of 14 0770 mg,
1.86 mmol) and solution of HCl 2N 05 mL) was stirred at
1008C for 20 h. A solution of NaOH 50% was added until
basic pH and extracted with CH2Cl2 03£15 mL). The
combined organic phase was dried 0Na2SO4), ®ltered and
the solvent removed under vacuo. The residue was puri®ed
by column chromatography 0silica gel, hexane/ethyl acetate
in a ratio 8:2) giving 630 mg of 17 as an oil 097% yield). IR
0NaCl) n 0cm21) 2942, 1618, 1140, 1100. 1H NMR 0CDCl3,
200 MHz) d 0ppm) 3.76 0s, 9H, OCH3), 4.34 0s, 4H, OCH2),
6.81 0s, 1H, C8H), 7.03 0s, 1H, C50H), 7.05 0m, 1H, C70H),
7.18 0m, 1H, C80H), 7.65 0d, Jˆ5 Hz, 1H, C4H), 8.76 0d,
Jˆ5 Hz, 1H, C3H). 13C NMR 0CDCl3, 50.3 MHz) d 0ppm)
55.9 0CH3, OCH3), 64.3 0CH2, OCH2), 64.5 0CH2, OCH2),
112.3 0CH, C8H), 117.6 0CH, C70H), 118.4 0CH, C50H),
120.1 0CH, C8H), 122.5 0CH, C4H), 125.6 0C, C4a),
128.0 0C, C8a), 129.0 0C, C60), 143.9 0C, C4a0), 144.7 0C,
C8a0), 149.8 0CH, C3H), 151.3 0C, C5, C7), 152.0 0C, C6),
157.9 0C, C1). Calculated for C20H19NO5: C, 67.97%;
H, 5.42%;N, 3.96%. Found: C, 67.65%;H, 5.83%;N, 4.14%.
3.1.13.
N-Tri¯uoroacetyl-6-,3,4,5-trimethoxyphenyl)-
2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline
,15). To a solution of the amine 6 0250 mg, 1.39 mmol) in
30 mL of ethanol was added 0.75 mL of concentrated HCl,
Ê
molecular sieves 4 A and 3,4,5-trimethoxybenzaldehyde
0348 mg, 2.09 mmol). Dry K2CO3 was added until a
pH<6±6.5 was reached and the mixture stirred overnight
at re¯ux temperature. The reaction mixture was then treated
with NaOH 2N and extracted with ethyl acetate. The organic
layers were separated and dried with Na2SO4, ®ltered and
evaporated. The crude product obtained was dissolved in
TFA/TFAA 01:1), and the mixture stirred for 18 h at re¯ux.
It was then poured out in NaOH 2N/ethyl acetate. The
organic fractions were dried, ®ltered and evaporated.
Yield 300 mg of the amide 15 as an oil. IR 0NaCl) n
0cm21) 1686, 1504, 1299, 1127. 1H NMR 0CDCl3,
200 MHz) d 0ppm) 2.95 0m, 2H, CH2N), 3.50 0m, 2H,
CH2Ar), 3.76 0s, 3H, OCH3), 3.77 0s, 3H, OCH3), 3.83 0s,
3H, OCH3), 4.25 0m, 4H, OCH2), 5.30 0s, 1H, C1), 6.45 0s,
2H, C20 and C60), 6.57 0s, 1H, C5H), 6.70 0s, 1H, C10). 13C
NMR 0CDCl3, 50.3 MHz) d 0ppm) 28.4 0CH2, CH2N), 39.5
0CH2, CH2Ar), 56.2 0CH, C6), 60.8 0CH3, OCH3), 64.4
0CH3, OCH3), 106.2 0CH, C20 and C60), 116.5 0CH, C5),
116.2 0C, Jˆ288 Hz, CF3), 116.8 0CH, C10), 126.0 0C,
Jˆ17 Hz, C10), 136.5 0C, C5a), 137.8 0C, C9a), 142.3 and
142.9 0C, C4a and C10a), 153.0 0C, C30, C40 and C50), 156.4
Acknowledgements
We wish to thank the CIRIT 0Project QFN 95-4704) the
Comissionat per Universitats i Recerca de la Generalitat
de Catalunya 097SGR-140) and ADIR-Laboratories for
their support of this work.
References
1. van Muijlwijk-Koezen, J. E.;Timmerman, H.;Link, R.;van
der Goot, H.;IJzerman, A. P. J. Med. Chem. 1998, 41, 3987±
3993.

A. S. Capilla et al. / Tetrahedron 57 32001) 8297±8303
8303
2. Zeng, Q.;Kwok, Y.;Kerwin, S. M.;Mangold, V.;Hurley,
L. H. J. Med. Chem. 1998, 41, 4273±4278.
10. Birch, A. J.;Jackson, A. H.;Shannon, P. V. R. J. Chem. Soc.,
Perkin Trans. 1 1974, 2185±2190.
3. Larsen, R. D.;Reamer, R. A.;Corley, E. G.;Davis, P.;
Grabowski, E. J. J.;Reider, P. J.;Shinkai, I. J. Org. Chem.
1991, 56, 6034±6038.
11. Ponpipom, M. M.;Hanessian, S. Carbohydr. Res. 1971, 18,
342±344.
12. Caliendo, G.;Cirino, G.;Greco, G.;Novellino, E.;Perissutti,
E.;Pinto, A.;Santagada, V.;Silipo, C.;Sorrentino, L. Eur. J.
Med. Chem. 1994, 29, 381±388.
Â
13. Vazquez, M. T.;Rosell, G.;Pujol, M. D. Il Farmaco 1996, 51
03), 215±217.
4. Cushman, M.;Nagarathnam, D.;Gopal, D.;He, H.-M.;Lin,
C.-M.;Hamel, E. J. Med. Chem. 1992, 35, 2293±2306.
5. Clark, R. D.;Jahangir J. Org. Chem. 1989, 54, 1174±1178.
6. Fodor, G.;Nagubandi, S. Tetrahedron 1980, 36, 1279±1300.
7. Fodor, G.;Gal, J.;Phillips, B. A. Angew. Chem., Int. Ed. Engl.
1972, 11, 919±920.
14. Prabhakaran, P. C.;Woo, N.-T.;Yorgey, P. S.;Gould, S. J.
J. Am. Chem. Soc. 1988, 110, 5785±5791.
15. Rosini, G.;Ballini, R. Synthesis 1988, 833±847.
8. Pictet, A.;Gams, A. Chem. Ber. 1909, 42, 2943±2952.
9. Capilla, A. S.;Pujol, M. D. Synth. Commun. 1996, 26 09),
1729±1738.