Photochemically induced cyclization of N-[2-(o-styryl)phenylethyl]acetamides and 5-styryl-1-methyl-1,2,3,4-tetrahydroisoquinolines: New total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines

Article abstract of DOI:10.1016/S0040-4020(01)00041-2

Two new total syntheses of 1-methyl-1,2,3,4-dihydronaphtho[1,2-f]isoquinolines are based on photochemically induced cyclization of N-{2-[(E)-2-phenyl-1-etheynyl]phenylethyl]}acetamides or 1-methyl-5-[(E)-2-phenyl-1-ethenyl]-1,2,3,4-tetrahydroisoquinolines.

Full text of DOI:10.1016/S0040-4020(01)00041-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1981±1986
Photochemically induced cyclization of
N-[2-(o-styryl)phenylethyl]acetamides and
5-styryl-1-methyl-1,2,3,4-tetrahydroisoquinolines:
new total syntheses of 1-methyl-1,2,3,4-
tetrahydronaphtho[2,1-f]isoquinolines
p
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Elena Martõnez, Juan C. Estevez, Ramon J. Estevez and Luis Castedo
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Departamento de Quõmica Organica and Unidad Asociada al Instituto de Investigaciones Quõmicas (C.S.I.C.), Universidad de Santiago,
15706 Santiago de Compostela, Spain
Received 25 February 2000; revised 20 December 2000; accepted 11 January 2001
AbstractÐTwo new total syntheses of 1-methyl-1,2,3,4-dihydronaphtho[1,2-f]isoquinolines are based on the construction of their
phenanthrene ring system by photochemically induced cyclization of N-{2-[(E)-2-phenyl-1-ethenyl]phenylethyl}acetamides or 1-methyl-
5-[(E)-2-phenyl-1-ethenyl]-1,2,3,4-tetrahydroisoquinolines. q 2001 Elsevier Science Ltd. All rights reserved.
Our previous paper1 reported the ®rst total syntheses of
naphtho[2,1-f]isoquinolines (1), a class of isoquinolines
that received negligible attention until the recent isolation
of litebamine2 and annoretine,3 and two subsequent partial
syntheses of litebamine4,5 from its probable biogenetic
precusor,4 the aporphine boldine.
phenylethylacetamide 3a was obtained in 81% yield. Its
mass spectrum con®rmed the expected molecular weight
1
(m/zˆ265) and its H NMR spectrum the E con®guration
of the stilbene double bond showing two doublets at 7.03
(1H, Jˆ16.1 Hz) and 7.27 ppm (1H, Jˆ16.1 Hz).
We next studied the preparation of dimethoxystyrylphenyl-
ethylacetamide 3b by this route. Since Heck coupling
between 6b8 and styrene in the above conditions furnished
3b in only 25% yield, we explored a longer but, as it
turned out, more ef®cient route based on the opening of
benzylideneisoquinolines 10 to o-phenylacetylphenylethyl-
acetamides 119 (Scheme 2). Reaction between homo-
veratrylamine (6c) and phenylacetyl chloride (7a) gave
phenylacetylphenylethylamine 8a, which was cyclized to
benzyldihydroisoquinoline 9a under typical Bichler±
Napieralski conditions.10 Treatment of this isoquinoline
with Ac2O gave N-acetyl-1-benzylideneisoquinoline 10a,
which upon treatment with 10% aqueous HCl solution
opened to the desired phenylacetylphenylacetamide 11a.9
Reduction of this latter with NaBH4 gave its hydroxy
derivative 12a, which was directly dehydrated to styryl-
phenylethylacetamide 3b. The overall yield for this indirect
route to 3b was 70%.
Here, we describe two additional total syntheses of
naphthoisoquinolines 1. Like those described in Ref. 1,
they are both based on a sequential construction of rings
C and A, but start from styrylphenylethylacetamides 3,
these latter include a stilbene-like system allowing construc-
tion of the phenanthrene ring system of acetamides 2 trans-
formation of which into the target compounds 1 is described
in Ref. 1. Alternatively, ring A can be constructed ®rst,
giving 5-styrylisoquinolines 4,5 that can be transformed
into naphthoisoquinolines 1 by electrocyclic cyclization
(Scheme 1).
We ®rst studied the preparation of starting o-styrylphenyl-
ethylacetamide 3a by Heck6 coupling of an appropriate
halobenzene to styrene (Scheme 2). When a deoxygenated
solution of phenylethylacetamide 6a,7 styrene (5a), triethyl-
amine and palladium acetate was heated at 1358C in a sealed
tube for 3 days, the desired unsubstituted o-styryl-
Finally, tetramethoxystyrylphenylethylacetamide 3c was
prepared by the above both routes. Heck coupling of
o-bromohomoveratrylamine (6b) with dimethoxystyrene
5b11 afforded 3c in 47% yield. The indirect route from
previously prepared o-acetylphenylethylacetamide 11b1
via hydroxyacetamide 12b gave a yield of 75%.
Keywords: alkaloids; biaryls; isoquinolines; electrocyclic reactions; photo-
chemistry.
Corresponding author. Tel.: 134-981-563100, ext. 14242; fax: 134-981-
591014; e-mail: qorjec@usc.es
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00041-2

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E. Martõnez et al. / Tetrahedron 57 (2001) 1981±1986
1982
Scheme 1.
To sum up, the results of this part of the study suggest that
in¯uence of the substituents present on starting materials 5
and 6 is such that Heck coupling is ef®cient for the prepara-
tion of the unsubstituted styrylphenylethylacetamide 3a, but
the alternative sequence from 1-benzylisoquinolines 9 is
more ef®cient for methoxy-substituted compounds 3.
yield of naphthodihydroisoquinoline 13a, which was
reduced with NaBH4 to the desired naphthoisoquinoline
1a in 93% yield (Scheme 3).
Photolysis of dimethoxystyrylacetamide 3b under the above
conditions gave a 30% yield of phenanthreneacetamide 2b,
which in the previous work1 had been converted into tetra-
hydronaphthoisoquinoline 1b via dihydronaphthoisoquino-
line 13b by successive treatment with POCl3 and NaBH4.
Similar photolysis of tetramethoxystyrylacetamide 3c gave
the corresponding naphthoisoquinoline 2c in only 6% yield,
the main product being N-acetyltetrahydroisoquinoline 14,
which was probably formed by a radical process involving
photochemically induced attack13 on the stilbene double
bond by nitrogen. Following the same procedure as for the
preparation of 2a and 2b, 3c was easily converted into
naphthoisoquinoline 1c via its dihydroderivative 13c.
We next studied the photochemically induced electrocyclic
cyclization12 of styrylphenylethylacetamides 3. Irradiation
of 3a with a 450 W Hanovia medium-pressure lamp
equipped with a Pyrex ®lter gave a 70% yield of the
expected phenanthrylacetamide 2a, as deduced from spec-
1
troscopic and analytical data. H NMR spectrum of this
product showed signals for a total of nine aromatic protons,
including a multiplet at 8.58±8.67 ppm corresponding to the
deshielded protons on C(4) and C(5). Treatment of 2a with
POCl3 under Bichler±Napieralki conditions afforded a 73%
Scheme 2. 3: (a) RˆR0ˆH; (b) RˆH, R0ˆOMe; (c) RˆR0ˆOMe. 5: (a) RˆH; (b) RˆOMe. 6: (a) R0ˆH, R00ˆAc, XˆBr; (b) R0ˆOMe, R00ˆAc, XˆBr;
(c) R0ˆOMe, R00ˆXˆH. 7±12: (a) RˆH; (b) RˆOMe.

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E. Martõnez et al. / Tetrahedron 57 (2001) 1981±1986
1983
Scheme 3. 1,4: (a) RˆR0ˆZˆH; (b) RˆOMe, R0ˆZˆH; (c) RˆOMe, R0ˆH, ZˆCO2Et; (d) RˆR0ˆOMe, ZˆH; (e) RˆR0ˆOMe, ZˆCO2Et. 2,3,13,15:
(a) RˆR0ˆH; (b) RˆOMe, R0ˆH; (c) RˆR0ˆOMe.
The foregoing results suggest that the stilbene chromophore
of compounds 3 is altered by electron donating groups in a
way that disfavours the desired electrocyclization. This led
us to explore the alternative route from 3 to 1 via 5-styryl-
isoquinolines 4 (Scheme 1). Treatment of unsubstituted
styrylphenylethylamide 3a with POCl3 gave the correspond-
ing 5-styryldihydroisoquinoline 15a in a low yield (15%),
that we attribute to the absence of activating substituents on
the aromatic ring. We desisted from pursuing this route to
1a any further. However, the same conditions ef®ciently
transformed 3b and 3c into the substituted styrylisoquino-
lines 15b and 15c in 84% and 96% yield, respectively.
Compounds 15b and 15c were then ef®ciently reduced
with NaBH4 to the corresponding tetrahydroisoquinolines
4b and 4d, respectively.
5-styrylisoquinolines 4. In both routes, the yield of the
photocyclization step is highly in¯uenced by the presence
of electron-donating substituents on the aromatic rings; for
substituted naphthoisoquinolines, the route via 5-styryliso-
quinolines gives best results, because interaction between its
N atom and the stilbene-like system under irradiation is
prevented.
These photochemical approaches to naphthoisoquinolines 1
are simpler but not always as ef®cient as the free radical
route described in our previous work.1 On the whole, the
radical approach seems to be preferable for the preparation
of substituted naphthoisoquinolines.
Finally, we note the contribution of this study to the
chemistry of 5-styrylisoquinolines, which have hitherto
received virtually no attention.5
We next studied the photolysis of 5-styrylisoquinolines 4.
Irradiation of dimethoxystyrylisoquinoline 4b in the same
conditions as for 2b led to a complex reaction mixture. This
is attributed to the unshared electron pair on the nitrogen13
because protection of the nitrogen atom as the uretane
(ZˆCO2Et) by treatment with ethyl chloroformiate allowed
the resulting compound 4c to be cyclized to the expected
naphthoisoquinoline 1c in 60% yield (established from
1. Experimental
1.1. General
Melting points were determined in a Ko¯er Thermogerate
apparatus and are uncorrected. Infrared spectra were
recorded on a MIDAC FTIR spectrophotometer. Nuclear
magnetic resonance spectra were recorded on a Bruker
WM-250 apparatus, using deuteriochloroform solutions
containing tetramethylsilane as internal standard. Mass
spectra were obtained on a Kratos MS 50 TC mass spectro-
meter. Thin layer chromatography (TLC) was performed
using Merck GF-254 type 60 silica gel and dichloro-
methane/methanol mixtures as eluant; the TLC spots were
visualized with ultraviolet light or iodine vapour. Column
chromatography was carried out using Merck type 9385
silica gel. Compounds 9a and b were prepared as per Ref.
10. Solvents were puri®ed as per Ref. 14. Solutions of
extracts in organic solvents were dried with anhydrous
sodium sulphate.
1
analytical and spectroscopic data). H NMR spectrum of
1c is very complex in the aliphatic region and shows signals
for a total of six aromatic protons, the signal at 9.63 ppm
corresponding to the deshielded proton on C(10). Similarly,
tetramethoxystyrylisoquinoline 4d was reacted with ethyl
chloroformiate to give 4e, which upon irradiation with
UV light as above afforded a 20% yield of the desired
N-carbethoxyisoquinoline 1e. Final basic hydrolysis of 1c
and 1e gave products identical to the naphthoisoquinolines
1b and 1d that were obtained1 in our earlier work.
To sum up, we have developed two alternative photo-
chemical routes for the transformation of o-styryl-phenyl-
ethylacetamides 3 into naphthoisoquinolines 1 via the
corresponding phenanthrenylethylacetamides 2 or via the

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E. Martõnez et al. / Tetrahedron 57 (2001) 1981±1986
1984
1.1.1. N-{2-[(E)-2-Phenyl-1-ethenyl]phenylethyl}aceta-
mide (3a). deoxygenated mixture of 2-bromo-
(s, 2H, ±CH2±), 6.56 (bs, 1H, ±NH), 6.77 (s, 1H, Ar-H),
7.22±7.38 (m, 5H, 5£Ar-H), 7.27 (s, 1H, Ar-H). MS (m/z,
%): 341 (M1, 3), 323 (6), 281 (43), 280 (100), 250 (33), 208
(53), 191 (22), 167 (21), 149 (61), 91 (22), 58 (38). Anal.
calcd for C22H27NO6, C 65.82, H 6.78, N 3.49; found, C
65.97, H 6.92, N 3.61.
A
phenylethylacetamide (0.3 g, 1.2 mmol), styrene (0.16 mL,
1.37 mmol), palladium acetate (15 mg, 0.05 equiv.), tri-
phenylphosphine (32 mg, 0.1 equiv.) and triethylamine
(0.34 mL, 2.46 mmol) in dry acetonitrile (10 mL) was
heated in a sealed tube at 1308C for 3 days. The suspension
was then ®ltered through celite, the ®ltrate was concentrated
in vacuo and the residue was puri®ed by ¯ash column chro-
matography (eluant: 3:1 hexane/ethyl acetate), giving
compound 3a (0.26 mg, 81% yield). Mp 132±1348C
(methanol). IR (n, cm21, NaCl); 3280 (NH), 1645
1.1.4. N-[2-(1-Hydroxy-2-phenyl-1-hydroxyethyl)-4,5-di-
methoxyphenylethyl]acetamide (12a). Small portions of
sodium borohydride (250 mg) were added over 3 h to a
solution of acetamide 11a (1 g, 2.93 mmol) in THF
(40 mL) and after stirring at room temperature for 30 min,
the reaction mixture was poured into water (30 mL) and
acidi®ed to pH 3 with 20% aqueous hydrogen chloride solu-
tion. The methanol was evaporated in vacuo and the residue
was extracted with dichloromethane (3£40 mL), and the
pooled organic layers were washed with water (60 mL),
dried, ®ltered and concentrated in vacuo, giving compound
12a (1 g, 100% yield), which was used without further
puri®cation.
1
(CvO). H NMR (d, ppm): 1.88 (s, 3H, ±CH3), 2.97±
3.01 (m, 2H, ±CH2±), 3.35±3.58 (m, 2H, ±CH2±), 5.82
(bs, 1H, ±NH), 7.03 (d, Jˆ16.1 Hz, 1H, ±CvCH±),
7.16±7.68 (m, 9H, 9£Ar-H), 7.27 (d, Jˆ16.1 Hz, 1H,
±CHvC±). MS (m/z, %): 265 (M1, 18), 206 (100), 91
(83). Anal. calcd for C18H19NO3, C 81.47, H 7.22, N 5.28;
found, C 81.12, H 7.36, N 5.40.
1.1.2. N-{4,5-Dimethoxy-2-[(E)-2-phenyl-1-ethenyl]phe-
nylethyl}acetamide (3b). Procedure a. Compound 3b
was prepared in 25% yield from 2-bromo-4,5-dimethoxy-
phenylethylacetamide (0.15 g, 0.49 mmol) and styrene
(0.063 mL, 0.54 mmol) following the same procedure as
for compound 3a. Mp 154±1568C (methanol). IR (n,
cm21, KBr): 3239 (±NH), 1648 (CvO). 1H NMR (d,
ppm): 1.88 (s, 3H, ±CH3), 2.93±2.97 (m, 2H ±CH2±),
3.45±3.49 (m, 2H, ±CH2±), 3.90 (s, 3H, ±OCH3), 3.95 (s,
3H, ±OCH3), 5.53 (bs, 1H, ±NH), 6.68 (s, 1H, Ar-H), 6.92
(d, Jˆ16.0 Hz, 1H, ±CvCH±), 7.15 (s, 1H, Ar-H), 7.23±
7.56 (m, 6H, 5£Ar-H and ±CHvC±) MS (m/z, %): 326
[(M11)1, 19], 325 (M1, 82), 267 (21), 266 (100), 265
(9), 253 (27), 251 (18), 235 (38), 234 (68), 223 (10), 222
(35), 192 (66), 175 (45), 165 (18). Anal. calcd for
C20H23NO3, C 73.82, H 7.12, N 4.30; found, C 73.73, H
7.11, N 4.40.
1.1.5. N-{2-[(E)-2-(3,4-Dimethoxyphenyl)-1-ethenyl]-4,5-
dimethoxyphenylethyl}acetamide (3c). Procedure a.
Following the same procedure as for the preparation of
compound 3a, compound 3c was obtained in 47% yield
from 2-bromo-4,5-dimethoxyphenylethylacetamide (0.15 g,
0.49 mmol) and 3,4-dimethoxystyrene (0.17 g, 1.04 mmol).
Mp 168±1708C (ethyl acetate/ethyl ether). IR (n, cm21
,
KBr): 1654 (CvO). 1H NMR (d, ppm): 1.87 (s, 3H,
±CH3), 2.93±2.98 (m, 2H, ±CH2±), 3.40±3.48 (m, 2H,
±CH2±), 3.89 (s, 3H, ±OCH3), 3.90 (s, 3H, ±OCH3), 3.95
(s, 3H, ±OCH3), 4.00 (s, 3H, ±OCH3), 5.57 (bs, 1H, ±NH),
6.66 (s, 1H, Ar-H), 6.77 (d, Jˆ15.9 Hz, 1H, ±CvCH±),
6.84 (s, 1H, Ar-H), 7.04±7.23 (m, 3H, 3£Ar-H), 7.26 (d,
Jˆ15.9 Hz, 1H, ±CvCH±). MS (m/z, %): 386 [(M11)1,
26], 385 (M1, 100), 326 (22), 282 (21), 234 (17), 151 (79).
Anal. calcd for C22H27NO5, C 68.63, H 7.30, N 3.42; found,
C 68.55, H 7.06, N 3.63.
Procedure b. A solution of hydroxyamide 12a (1 g,
2.91 mmol) and 10% aqueous hydrogen chloride solution
(7 mL) in dioxan (20 mL) was re¯uxed for 45 min. The
dioxan was evaporated in vacuo and the aqueous residue
was diluted in water (20 mL) and extracted with chloroform
(3£15 mL). The pooled organic layers were dried, ®ltered
and concentrated in vacuo, and the residue was puri®ed by
¯ash column chromatography (eluant: 7:1 ethylacetate/
hexane), giving compound 3b as a white solid (0.89 g,
95% yield).
Procedure b. Compound 3c was prepared in 91% yield from
compound 12b (1.15 g, 2.85 mmol) following the same
procedure as for compound 3b (procedure b).
1.1.6. N-{2-[2-(3,4-Dimethoxyphenyl)-1-hydroxyethyl]-
4,5-dimethoxyphenyl}acetamide (12b). Compound 12b
was prepared in quantitative yield from compound 11b
(1.16 g, 2.90 mmol) following the same procedure as for
compound 12a and was used without further puri®cation.
1.1.3. N-[4,5-Dimethoxy-2-(2-phenylacetyl)phenylethyl]-
acetamide (11a). Ten percent aqueous hydrochloric acid
solution (25 mL) was added to a solution of acetamide
10a (1 g, 3.0 mmol) in methanol (12.5 mL) and the mixture
was re¯uxed for 5 h. The methanol was evaporated in vacuo
and the resulting suspension was basi®ed with saturated
aqueous potassium carbonate solution and extracted with
chloroform (3£25 mL). The pooled organic layers were
dried, ®ltered and concentrated in vacuo, giving amide
11a (1 g, 96% yield) as a white solid. Mp 118±1208C
(ethyl acetate). IR (n, cm21, NaCl): 3485 (±NH), 1667
1.1.7. N-[2-(1-Phenanthryl)ethyl]acetamide (2a). Air was
bubbled for 10 min through a stirred solution of compound
3a (88 mg, 0.33 mmol) in ethyl ether (180 mL) and
dichloromethane (5 mL). A catalytic amount of iodine
(12 mg, 0.03 mmoles) was added and the new mixture
was then irradiated for 2 h in a photochemical reactor
equipped with a Pyrex condenser and a Hanovia 450 W
medium pressure Hg vapour lamp. After addition of satu-
rated sodium thiosulphate (100 mL), and extraction of the
resulting mixture with dichloromethane (3£50 mL), the
pooled organic layers were dried, ®ltered and concentrated
in vacuo, giving a residue that upon puri®cation by prepara-
tive TLC (eluant: 3:1 ethyl acetate/hexane) afforded
phenanthrene 2a (57 mg, 65% yield). Mp 140±1428C
1
(CvO) 1640 (CvO). H NMR (d, ppm): 1.89 (s, 3H,
±CH3), 2.90±2.98 (m, 2H, ±CH2±), 3.41±3.52 (m, 2H,
±CH2±), 3.89 (s, 3H, ±OCH3), 3.91 (s, 3H, ±OCH3), 4.22

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E. Martõnez et al. / Tetrahedron 57 (2001) 1981±1986
1985
(methanol). IR (n, cm21, NaCl): 3277 (±NH), 1647 (CvO).
1H NMR (d, ppm): 1.92 (s, 3H, ±CH3), 3.30±3.35 (m, 2H,
±CH2±), 3.58±3.66 (n, 2H, ±CH2±), 5.70 (bs, 1H, ±NH),
7.43 (s, 1H, Ar-H), 7.55±7.67 (m, 3H, 3£Ar-H), 7.79 (d,
Jˆ9.2 Hz, 1H, 2£Ar-H), 7.89 (s, 1H, Ar-H), 8.03 (d,
Jˆ9.2 Hz, 1H, 2£Ar-H), 8.58±8.67 (m, 2H, 2£Ar-H). MS
(m/z, %): 264 [(M11)1, 2], 263 (M1, 13), 204 (100), 203
(27), 191 (34), 190 (12), 189 (21). Anal. calcd for
C18H17NO, C 82.10, H 6.51, N 5.32; found, C 81.75, H
4.96, N 5.60.
was identi®ed by direct comparison with an authentic
sample.
1.1.12. N-[2-(3,4,6,7-Tetramethoxy-1-phenanthryl)ethyl]-
acetamide (2c). Starting from 3c (125 mg, 0.33 mmol),
the photochemical procedure applied to cyclization of 3a
gave a 6% yield of compound 2c, identi®ed by comparison
with an authentic sample.
1.1.13. 8,9,11,12-Tetramethoxy-1-methyl-1,2,3,4-tetra-
hydronaphtho[2,1-f]isoquinoline (1d). Hydrolysis of
urethane 1e (100 mg, 0.26 mmol) under the conditions
described above for transformation of 1c afforded a 70%
yield of compound 1d, which was identi®ed by direct
comparison with an authentic sample.
1.1.8. 1-Methyl-3,4-dihydronaphtho[2,1-f]isoquinoline
(13a). POCl3 (0.089 mL, 0.95 mmol) was added dropwise
over 5 min to a solution of compound 2a (200 mg,
0.38 mmol) in dry acetonitrile (16 mL) and the mixture
was re¯uxed for 18 h under a calcium chloride tube and
then concentrated in vacuo. The residue was dissolved in
dichloromethane (40 mL), and this solution was washed
with 10% aqueous NaOH solution (2£30 mL) and water
(30 mL), dried, ®ltered and concentrated, giving dihydroi-
soquinoline 13a (68 mg, 73% yield). Mp 200±2048C
(methanol). IR (n, cm21, NaCl): 2351 (±CH), 1625
1.1.14. 1-Methyl-5[(E)-2-phenyl-1-ethenyl]3,4-dihydro-
isoquinoline (15a). Compound 3a (90 mg, 0.34 mmol)
was transformed into a yellow oil identi®ed as imine 15a
(14 mg, 19% yield) following the procedure used to obtain
13a. IR (n, cm21, NaCl): 1634 (CvO). 1H NMR (d, ppm):
2.42 (s, 3H, ±CH3), 2.79±2.89 (m, 2H, ±CH2±), 3.61±3.78
(m, 2H, ±CH2±), 7.01 (d, Jˆ16.1 Hz, 1H, ±CHvC±),
7.27±7.70 (m, 8H, 8£Ar-H), 7.34 (d, Jˆ16.1 Hz, 1H,
±CvCH±). MS (m/z, %): 248 [(M11)1, 19], 247 (M1,
100), 246 (85) High resolution MS calcd for C18H17N,
247.1361; found, 247.1357.
1
(CvN). H NMR (d, ppm): 2.52 (s, 3H, ±CH3), 3.07±
3.13 (m, 2H, ±CH2±), 3.78±3.86 (m, 2H, ±CH2±), 7.60±
7.69 (m, 6H, 6£Ar-H), 8.59±8.70 (m, 2H, 2£Ar-H). MS
(m/z, %): 246 [(M11)1, 13], 245 (M1, 74), 244 (100).
High resolution MS calcd for C19H15N, 245.1204; found,
245.1211.
1.1.15. 7,8-Dimethoxy-1-methyl-5-[(E)-2-phenyl-1-ethenyl]-
3,4-dihydroisoquinoline (15b). Compound 15b was
prepared in 54% yield as a yellow oil from compound 3b
(100 mg, 0.31 mmol) following the same procedure as for
the preparation of compound 13a. IR (n, cm21, NaCl): 1610
(CvN). 1H NMR (d, ppm): 2.52 (s, 3H, ±CH3), 2.64±2.69
(m, 2H, ±CH2±), 3.49±3.55 (m, 2H, ±CH2±), 3.88 (s, 3H,
±OCH3), 3.95 (s, 3H, ±OCH3), 6.91 (d, Jˆ16.1 Hz, 1H,
±CHvC±), 7.21±7.53 (m, 6H, 6£Ar-H), 7.37 (d,
Jˆ16.1 Hz, 1H, ±CvCH±). MS (m/z, %): 308 [(M11)1,
23], 307 (M1, 100), 306 (18), 293 (8), 292 (39), 276 (8), 248
(8), 216 (9), 202 (7). High resolution MS calcd for
C20H21NO2, 307.1572; found, 307.1569.
1.1.9. 1-Methyl-1,2,3,4-tetrahydronaphtho[2,1-f]isoquino-
line (1a). Following the same procedure as for reduction of
12a, treatment of compound 13a (60 mg, 0.24 mmol) with
NaBH4 (360 mg) gave naphthoisoquinoline 1a (56 mg, 93%
yield). Mp 143±1458C (methanol). IR (n, cm21, NaCl):
3261 (±NH). 1H NMR (d, ppm): 1.56±1.58 (m, 3H,
±CH3), 1.89 (bs, 1H, ±NH), 3.18±3.24 and 3.46 (2£m-
3H, 2£±CH2±), 4.33 (m, 1H, ±CH±), 7.47 (d, Jˆ8.7 Hz,
1H, Ar-H), 7.55±7.69 (m, 2H, 2£Ar-H), 7.79 (m, 1H, Ar-
H), 7.88 (m, 1H, Ar-H), 7.93 (d, Jˆ8.9 Hz, 1H, Ar-H), 8.54
(m, 1H, Ar-H), 8.69 (m, 1H, Ar-H). MS (m/z, %): 247 (M1,
7), 246 (8), 232 (100). Anal. calcd for C20H21NO5, C 67.61,
H 5.92, N 3.94; found, C 67.21, H 6.09, N 3.61.
1.1.16. 7,8-Dimethoxy-1-methyl-5-[(E)-2-phenyl-1-ethenyl]-
1,2,3,4-tetrahydroisoquinoline (4b). Compound 4b was
prepared in 99% yield from dihydroisoquinoline 15b
(185 mg, 0.6 mmol) following the same procedure as for
the reduction of compound 13a. Mp 112±1148C (methanol).
1H NMR (d, ppm): 1.48 (m, 3H, ±CH3), 2.73±2.78 (m, 2H,
±CH2±), 3.11±3.84 (m, 2H, ±CH2±), 3.89 (s, 3H, ±OCH3),
3.91 (s, 3H, ±OCH3), 4.36 (q, Jˆ6.7 Hz, 1H, ±CH±), 5.90
(bs, 1H, ±NH), 6.90 (d, Jˆ16.0 Hz, 1H, ±CHvC±), 7.07 (s,
1H, Ar-H), 7.27 (d, Jˆ16.0 Hz, H, ±CvCH±), 7.29±7.53
(m, 5H, 5£Ar-H). MS (m/z, %): 308 (M1, 0.7), 293 (35),
149 (100). Anal. calcd for C20H23NO2, C 77.64, H 7.49, N
4.53; found, C 77.89, H 7.18, N 4.26.
1.1.10. N-[2-(3-4-Dimethoxy-1-phenanthryl)ethyl]aceta-
mide (2b). Irradiation of o-styrylphenylethylacetamide 3b
(100 mg, 0.31 mmol) under the same conditions as for cycli-
zation of 3a afforded a 30% yield of the corresponding
phenanthrylethylacetamide 2b, which was identi®ed by
comparison with an authentic sample.
1.1.11. 11,12-Dimethoxy-1-methyl-1,2,3,4-tetrahydronaph-
tho[2,1-f]isoquinoline (1b). A mixture of potassium
hydroxide (2 g) and absolute ethanol (10 mL) was re¯uxed
under argon until total dissolution. This solution was added
under an argon atmosphere to 100 mg (0.323 mmol) of
N-ethoxycarbonylnaphthoisoquinoline 4c and the mixture
was re¯uxed for 15 h. Then a solution of citric acid (2 g)
in water (15 mL) was added dropwise and the mixture was
stirred at room temperature for 15 min. The ethanol was
evaporated and the residue was extracted with dichloro-
methane (3£25 mL). The pooled organic layers were
washed with water, dried and concentrated in vacuo, provid-
ing 75 mg (75% yield) of naphthoisoquinoline 1b, which
1.1.17. N-Carbethoxy-7,8-dimethoxy-1-methyl-5-[(E)-2-
phenyl-1-ethenyl]-1,2,3,4-tetrahydroisoquinoline (4c).
Ethyl chlorformate (0.24 mL, 2.44 mmol) was added to a
solution of crude amine 4b (150 mg, 0.28 mmol) and
triethylamine (0.32 mL) in chloroform (20 mL), and after
stirring at room temperature for 45 min, the reaction
mixture was concentrated in vacuo and the residue was

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1981±1986
1986
dissolved in dichloromethane (100 mL). The solution was
washed with 10% aqueous hydrochloric acid solution
(3£50 mL) and water (50 mL), dried, ®ltered and concen-
trated in vacuo, giving a residue that puri®ed by preparative
TLC (eluant: 1:4 ethyl acetate/hexane) afforded urethane 4c
(methanol). IR (n, cm21, NaCl): 2945 (±CH), 1690
(CvO). H NMR (d, ppm): 1.26 (m, 3H, ±CH3), 1.43 (m,
1
3H, ±CH3), 2.83 (m, 2H, ±CH2±), 3.32±3.38 (m, 1H,
±CH2±), 3.89±3.93 (m, 12H, 4£±OCH3), 4.00±4.21 (m,
3H, 2£±CH2±), 5.34±5.50 (8m, 1H, ±CH±), 6.83±7.10
(m, 6H, 4£Ar-H and 2£±CHvC±). MS (m/z, %): 443
[(M12)1, 4], 442 [(M11)1, 15], 441 (M1, 53), 429 (3),
428 (14), 427 (27), 426 (100). Anal. calcd for C25H31NO6,
C 68.01, H 7.08, N 3.17; found, C 67.73, H 6.87, N 3.43.
(150 mg, 81%). Mp 140±1428C (methanol). IR (n, cm21
,
NaCl): 1690 (CvO). 1H NMR (d, ppm): 1.30 (t, Jˆ7.0 Hz,
3H, ±CH3), 1.47±1.48 (m, 3H, ±CH3), 2.74±4.19 (m, 6H,
3£±CH2±), 3.93 (s, 6H, 2£±OCH3), 5.43 (m, 1H, ±CH±),
6.92 (d, Jˆ16.0 Hz, 1H, ±CHvC±), 7.08 (8s, 1H, Ar-H),
7.27 (d, Jˆ16.0 Hz, 1H, ±CvCH±), 7.16±7.54 (m, 5H,
5£Ar-H). MS (m/z, %): 381 (M1, 31), 368 (16), 367 (26),
366 (100), 338 (24). Anal. calcd for C23H27NO4, C 72.42, H
7.13, N 3.67; found, C 72.81, H 6.98, N 3.47.
1.1.22. N-Carbethoxy-8,9,11,12-tetramethoxy-1-methyl-
1,2,3,4-tetrahydronaphtho[2,1-f]isoquinoline (1e). Irradia-
tion of compound 4e (110 mg, 0.24 mmol) as for cyclization
of compound 3a gave a 15% yield of compound 1e. Mp
212±2148C (methanol). IR (n, cm21, NaCl): 1649 (CvO).
1H NMR (d, ppm): 1.26±1.46 (m, 3H, ±CH3), 1.54±1.61
(m, 3H, ±CH3), 3.20±4.20 (m, 6H, 3£±CH2±), 3.95 (s, 3H,
±OCH3), 4.06 (s, 3H, OCH3), 4.11 (s, 6H, 2£±OCH3), 5.56
(m, 1H, ±CH), 7.23 (s, 1H, Ar-H), 7.46±7.94 (m, 2H, 2£Ar-
H), 9.20 (s, 1H, Ar-H). MS (m/z, %): 440 [(M11)1, 13], 439
(M1, 47), 425 (27), 424 (100), 397 (4), 396 (18), 351 (5).
Anal. calcd for C25H29NO6, C 68.32, H 6.65, N 3.19; found,
C 68.73, H 6.49, N 3.01.
1.1.18. N-Carbethoxy-11,12-dimethoxy-1-methyl-1,2,3,4-
tetrahydronaphtho[2,1-f]isoquinoline (1c). Photolysis of
compound 4c (75 mg, 0.2 mmol) in the conditions used to
obtain 2a afforded phenanthrene 1c as yellow oil (37 mg,
50% yield). Mp 189±1918C (methanol). IR (n, cm21
,
NaCl): 1694 (CvO). 1H NMR (d, ppm): 1.33 (t,
Jˆ6.8 Hz, 3H, ±CH3), 1.55±1.59 (m, 3H, ±CH3), 3.19±
3.24 (m, 2H, ±CH2 ), 3.39±3.49 (m, 4H, 2£±CH2±), 3.94
(s, 3H, ±OCH3), 4.11 and 4.13 (2£s, 3H, ±OCH3), 5.57 (m,
1H, ±CH±), 7.57±7.71 (m, 3H, 3£Ar-H), 7.82±7.88 (m,
2H, 2£Ar-H), 9.63 (8m, 1H, Ar-H). MS (m/z, %): 380
[(M11)1, 10], 379 (M1, 35), 365 (27), 364 (100). Anal.
calcd for C23H25NO4, C 72.80, H 6.64, N 3.69; found, C
73.08, H 6.69, N 3.82.
Acknowledgements
We thank the Ministry of Education and Cultura (DGES)
and the Xunta de Galicia for ®nancial support.
1.1.19. 7,8-Dimethoxy-1-methyl-5-[(E)-2-(3,4-dimethoxy-
phenyl)-1-ethenyl]-3,4-dihydroisoquinoline (15c). Applied
to compound 3c (125 mg, 0.33 mmol), the procedure for the
preparation of 13a, gave a 96% yield of a yellow oil identi®ed
as compound 15c. IR (n, cm21, NaCl): 2940 (±CH), 1587
References
  Â
1. Martõnez, E.; Estevez, J. C.; Estevez, R. J.; Castedo, L.
Tetrahedron 2001, 57, 1973±1979.
1
(CvN). H NMR (d, ppm): 2.48 (s, 3H, ±CH3), 2.61±2.67
2. Wu, Y.-C.; Liou, J.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
Tetrahedron Lett. 1991, 32, 4169.
(m, 2H, ±CH2±), 3.47±3.52 (m, 2H, ±CH2±), 3.85 (s, 3H,
±OCH3), 3.88 (s, 3H, ±OCH3), 3.92 (6H, 2£OCH3), 6.84 (d,
Jˆ16.0 Hz, 1H, ±CHvC±), 6.81±7.17 (m, 4H, 4£Ar-H),
7.06 (d, Jˆ16.0 Hz, 1H, ±CvCH±). MS (m/z, %): 369
[(M12)1, 5], 368 [(M11)1, 26], 367 (M1, 100), 366 (15),
352 (24), 336 (7). High resolution MS clacd for C22H25NO4,
367.1784; found, 367.1778.
3. Wu, Y.-C.; Chang, G.-Y.; Duh, C.-Y.; Wang, S.-K.
Phytochemistry 1993, 33, 497.
4. Lee, S.-S.; Lin, Y.-J.; Chen, M.-Z.; Wu, Y.-C.; Chen, C.-H.
Tetrahedron Lett. 1992, 33, 6309.
5. Hara, H.; Kaneko, K.-I.; Endoh, M.; Uchida, H.; Hoshino, O.
Tetrahedron 1995, 51, 10189.
6. Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 43, 2941.
7. For the preparation of unsubstituted o-styrylphenylethylaceta-
mide 3a, o-bromophenylethylacetamide 6a was easily
obtained in 70% overall yield by reaction of o-bromobenzal-
dehyde with nitromethane, reduction of the resulting o-bromo-
nitrostyrene and ®nal protection of the amino group of
o-bromophenylethylamine as acetate.
1.1.20. 7,8-Dimethoxy-1-methyl-5-[(E)-2-(3,4-dimethoxy-
phenyl)-1-ethenyl]-1,2,3,4-tetrahydroisoquinoline (4d).
Compound 4d was prepared in quantitative yield from
dihydroisoquinoline 15c following the same procedure as
for the reduction of compound 13a. Mp 133±1358C
1
(methanol). H NMR (d, ppm): 1.48±1.59 (m, 3H, ±CH3),
3.07±3.55 (m, 4H, 2£±CH2±), 3.88 (s, 9H, 3£±OCH3),
3.91 (s, 3H, ±OCH3), 4.83±4.87 (m, 1H, ±CH±), 6.77±
6.96 (m, 2H, 2£Ar-H), 6.98±7.05 (m, 4H, 2£Ar-H and
2£±CHvC±), 9.94 (bs, 1H, ±NH). MS (m/z, %): 370
[(M12)1, 5], 368 (M1, 2), 356 (5), 355 (24), 354 (100),
339 (5), 338 (7), 177 (6). Anal. calcd for C22H27NO4, C
71.52, H 7.37, N 3.79; found, C 7.17, H 7.51, N 4.02.
8. o-Bromophenylethylacetamide 6b was prepared in a similar
way as used for 6a, starting now from o-bromoveratraldehyde.
9. Baxter, I.; Swan, G. A. J. Chem. Soc. B 1965, 4014.
10. Cava, M. P.; Mitchell, M. J.; Havlicek, S. C.; Lindert, A.;
Spangler, R. J. J. Org. Chem. 1970, 35, 175.
11. 1,2-Dimethoxystyrene 5b was prepared by reaction of
veratraldehyde with methytriphenylphosphine under typical
Witting reaction conditions.
1.1.21. N-Carbethoxy-7,8-dimethoxy-1-methyl-5-[(E)-2-
(3,4-dimethoxyphenyl)-1-ethenyl]-1,2,3,4-tetrahydroiso-
quinoline (4e). Compound 4e was prepared in 65% yield
from compound 4d (225 mg, 0.61 mmol) following the
procedure used to obtain compound 4c. Mp 165±1678C
12. Seijas, J. A.; De Lera, A. R.; Villaverde, M. C.; Castedo, L. J.
J. Chem. Soc., Chem. Commun. 1985, 893.
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