Total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[2,1-f]isoquinolines involving free radical cyclizations induced by tributyltin(IV) hydride

Article abstract of DOI:10.1016/S0040-4020(01)00040-0

We describe two total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[1,2-f]isoquinolines based on free radical cyclization. One of them includes the cyclization of N-{2-[2-(2-bromophenyl)-1-methoxyethyl]phenylethyl}acetamides and subsequent transformation of the resulting N-[2-(10-methoxy-9,10-dihydro-1-phenanthryl)ethyl]acetamides. The second is based on the known cyclization of 1-(2-bromobenzyl)isochroman-3-ones to 4,5,6a,7-tetrahydrodibenzo[de,g]chroman-3-ones followed by transformation of the resulting 2-(1-phenanthryl)acetamides.

Full text of DOI:10.1016/S0040-4020(01)00040-0

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1973±1979
Total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[2,1-f]-
isoquinolines involving free radical cyclizations
induced by tributyltin(IV) hydride
p
Â
Â
Â
Â
Elena Martõnez, Juan C. Estevez, Ramon J. Estevez and Luis Castedo
  Â
Departamento de Quõmica Organica and Unidad Asociada al Instituto de Investigaciones Quõmicas (CSIC), University of Santiago,
15706 Santiago de Compostela, Spain
Received 25 February 2000; revised 20 December 2000; accepted 11 January 2001
AbstractÐWe describe two total syntheses of 1-methyl-1,2,3,4-tetrahydronaphtho[1,2-f]isoquinolines based on free radical cyclization.
One of them includes the cyclization of N-{2-[2-(2-bromophenyl)-1-methoxyethyl]phenylethyl}acetamides and subsequent transformation
of the resulting N-[2-(10-methoxy-9,10-dihydro-1-phenanthryl)ethyl]acetamides. The second is based on the known cyclization of
1-(2-bromobenzyl)isochroman-3-ones to 4,5,6a,7-tetrahydrodibenzo[de,g]chroman-3-ones followed by transformation of the resulting
2-(1-phenanthryl)acetamides. q 2001 Elsevier Science Ltd. All rights reserved.
It is thought that naphthoisoquinolines may have antineo-
plastic properties: their tetracyclic ring system is similar to
that of the carcinogenic hydrocarbon chrysene, but like the
ring system of antibacterial and antitumoral benzophenan-
thridine alkaloids, includes a nitrogen atom.1 Naphtho[1,2-f]-
isoquinolines nevertheless received very little chemical
attention2 prior to the recent isolation of two members of
this family, litebamine3 and annoretine4. Subsequent partial
synthesis of litebamine from the aporphine boldine led to the
hypothesis of biogenetic degradation of aporphines to
naphthoisoquinolines.5,6 With a view to eventual corrobo-
ration of the structures proposed for litebamine and anno-
retine, and to the synthesis of other naphthoisoquinolines of
possible chemical and biological interest, we have developed
the ®rst total synthesis of naphtho[1,2-f]isoquinolines 1
(Scheme 1).
Retrosynthetic considerations of structures 1 suggested a
strategy based on formation of bonds b and a, in that
order, starting from bromophenylacetylphenylethylaceta-
mides 3, which contain both a halogen atom conveniently
placed for generation of the phenanthrene ring system by
radical cyclization,7 and a nitrogen substituent for ®nal
construction of the nitrogen ring by Bichler±Napieralski
cyclization of compounds 2 (Scheme 1). We ®rst studied
the viability of this plan by applying it to 3a, which was
easily prepared by Friedel±Crafts acylation of N-acetyl-
phenylethylamine 5a with o-bromophenylacetyl chloride
(4b).8 Stirring a suspension of recently prepared 4b, 5a
and AlCl3 in nitromethane under argon for 3 h at room
temperature, afforded 3a in 65% yield (see Scheme 2);
compound 3a was reduced with NaBH4 in methanol at
room temperature to obtain methoxyphenylethylacetamide
Scheme 1.
Keywords: alkaloids; biaryls; cyclization; isoquinolines; radical reaction; chromanones.
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)00040-0

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1973±1979
1974
Scheme 2. 1, 2, 6, 7, 8: (a) RˆH, (b) RˆOMe, 3: (a) RˆH, XˆBr; (b) RˆOMe, XˆH; (c) RˆOMe, XˆBr. 4: (a) RˆH, YˆOH, XˆBr; (b) RˆH, YˆCl,
XˆBr; (c) RˆOMe, YˆOH, XˆH, (d) RˆOMe, YˆCl, XˆH, 5: (a) R0ˆAc, (b) R0ˆH.
6a, which when re¯uxed with n-Bu3SnH and AIBN in
benzene for 9 h under argon7d,9 afforded a 63% yield of
the expected phenanthreneacetamide 7a. Compound 7a
was easily identi®ed from spectroscopic and analytical
phenanthrene character was con®rmed by a multiplet at
9.63 ppm assigned to the deshielded proton at C(10).
We next applied the same strategy to the preparation of
tetramethoxynaphthoisoquinoline 1b. Attempts to prepare
the required 2-bromophenyl-1-methoxyethylphenylethyl-
acetamide 3c in the same way as for 3a (but introducing
the bromine on 3b to obtain 3c) were unsuccessful; reacting
dimethoxyphenylacetyl chloride 4d with homoveratryl-
acetamide (5a) under the above Friedel±Crafts conditions
afforded a complex reaction mixture, as in previous acyl-
ations with homoveratroyl chloride (4d)11. However, 3c was
successfully prepared by opening the nitrogen ring of
N-acetyl-1-benzylideneisoquinoline 11 (Scheme 3).12 To
obtain 11, phenylacetylphenylethylamide 9 was easily
prepared from homoveratrylamine (5b) and phenylacetyl
chloride (4d) and was then subjected to standard Bichler±
Napieralski conditions to give benzyldihydroisoquinoline
10,10 which upon treatment with Ac2O gave 11. Re¯uxing
11 with 10% aq. HCl in methanol for 5 h then gave a 96%
yield of the tetramethoxyphenylacetylphenylethylacetamide
3b which was easily brominated in 86% yield by treatment
with bromine in a mixture of glacial acetic acid and water at
room temperature for 1 h. The presence of bromine at the
1
data: its H NMR spectrum shows singlets at 3.28, 3.67
and 3.90 ppm corresponding to the three methoxy sub-
stituents (the 3.28 ppm signal belonging to the shielded
methoxy at position C(4)), and signals for ®ve aromatic
protons (one less than the starting material), including a
multiplet at 8.44 ppm for H(5), which is deshielded due to
interaction with the methoxy substituent at C(4).
Treatment of methoxydihydrophenanthrene 7a with 10%
aq. HCl in dioxan at room temperature easily eliminated
methanol to give phenanthrylethylacetamide 2a, which
was cyclized10 to dihydronaphthoisoquinoline 8a by
re¯uxing with phosphoryl chloride in dry acetonitrile.
Finally, compound 8a was quantitatively reduced to
naphthoisoquinoline 1a when treated with NaBH4 in metha-
nol at room temperature. The structure of 1a was deduced
from microanalytic and spectroscopic data. Its tetrahydro-
isoquinoline character was established by the presence in its
1H NMR spectrum of a doublet at 1.62 (3H) due to the
methyl substituent and multiplets at 2.79±3.08 (2H),
3.22±3.39 (2H) and 4.61 (1H) ppm corresponding to the
aliphatic protons on carbons on the nitrogen ring, while its
1
required position of 3c was easily established from its H
NMR spectrum, which exhibits singlets corresponding to
Scheme 3.

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1973±1979
1975
Scheme 4. 2: (a) RˆH, R0ˆAc; (b) RˆOMe, R0ˆAc; (c) RˆR0ˆH; (d) RˆOme, R0ˆH, 12, 13, 14, 15, 16: (a) RˆH, (b) RˆOMe.
four aromatic protons at 6.76, 6.77, 7.05 and 7.31 ppm. Note
that preparation of 3b involves the regiospeci®c intramo-
lecular transfer of a phenylacetyl group from the nitrogen
atom of phenylethylamide 9 to the desired ortho position
in 3b by a three-step sequence that includes a Bichler±
Napieralski cyclization; this constitutes a way for acylating
aromatic rings that is less dependent on the electronic
properties of substituents than is Friedel±Crafts acylation.
The above two syntheses constitute the ®rst total syntheses
of members of the new compounds 1a and 1b of the
naphthoisoquinolines family. They con®rm the usefulness
of free radical cyclization for ef®cient construction of the
bi-arylic bonds of phenanthrene systems.7 It is envisaged
that they may be used for preparation of the alkaloids
litebamine and anoretine, and of other naphthoisoquinolines
of potential pharmacological interest.
Reduction of 3c with NaBH4 gave methoxyphenylethyl-
phenylacetamide 6b (Scheme 2), which was cyclized in
59% yield to phenanthreneacetamide 7b when reacted
with n-Bu3SnH and AIBN as for 7a. Subsequent treatment
of 7b with HCl led to phenanthrylethylacetamide 2b, which
was treated with POCl3 to obtain dihydronaphthoisoquino-
line 8b, which was easily converted to tetramethoxy-
naphthoisoquinoline 1b by reduction with NaBH4. The
spectra of 1b are very similar to those of 1a.
1. Experimental
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 vapor. Column
chromatography was carried out using Merck type 9385
silica gel. Compounds 9 and 10 were prepared as per Ref.
9. Solvents were puri®ed as per Ref. 13. Solutions of
extracts in organic solvents were dried with anhydrous
sodium sulphate.
The moderate yields achieved in the radical cyclizations
steps of the above syntheses led us to consider the
alternative route of naphthoisoquinolines 1 starting from
dibenzochromanones 14, which we had previously obtained
by n-Bu3SnH-mediated radical cyclizations of benzyliso-
chromanones 13 to dibenzochromanones 14.7c In this
work, the yields of cyclization of 13 to 14 are improved.
Re¯uxing a solution of dimethoxybromobenzylisochroma-
none 13a, n-Bu3SnH and AIBN in benzene under argon for
9 h afforded 14a in 76% yield (previous yield 45%). Subse-
quent opening of the lactone ring of 14a by treatment with
aq. ammonia furnished phenanthrylacetamide 16a presu-
mably by spontaneous dehydration of initially formed
hydroxyphenanthrylacetamide 15a, a process probably
favoured by the gain in aromaticity. Compound 16a was
then reduced to the corresponding amine 2c, which upon
reaction with acetyl chloride gave 2a. A similar sequence
was used to cyclize tetramethoxybromobenzylisochroma-
none 13b to the corresponding dibenzochromanone 14b
in 83% yield (previous yield 55%) and to transform
this latter compound into phenanthrylacetamide 16b,
phenanthrylethylamine 2d and phenanthrylethylacetamide
2b (Scheme 4).
1.1. General
1.1.1. N-{2-[2-(2-Bromophenyl)acetyl]-4,5-dimethoxy-
phenylethyl}acetamide (3a). A mixture of commercial
o-bromophenylacetic acid (4.45 g, 20.7 mmol) and thionyl
chloride (15 mL) was re¯uxed for 1 h under a dry atmos-
phere (calcium chloride tube). The excess thionyl chloride
was evaporated in vacuo and the residue was dissolved in
dry nitrobenzene (5 mL). This solution was added dropwise
to a stirred suspension of aluminium trichloride (1.84 g,
13.8 mmol) in dry nitrobenzene (8 mL) cooled at 08C in
an ice/water bath, and to this mixture, maintained at 08C,
a
solution of N-acetyl-3,4-dimethoxyphenylethylamine

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1973±1979
1976
(1.74 g, 7.8 mmol) in dry nitrobenzene (10 mL) was added
dropwise over 15 min. The resulting mixture was stirred for
2.5 h at 358C and then added to an ice/water mixture
(100 mL). The nitrobenzene was evaporated by steam distil-
lation and the mixture left was extracted with dichloro-
methane (3£50 mL). The pooled organic layers were
washed with saturated sodium bicarbonate solution
followed by water, dried and concentrated in vacuo to
give an oil which when washed with a small volume of
ethyl ether/ethyl acetate gave 3a as a white solid that was
separated by ®ltration (2.72 g, 83% yield). Mp 139±1408C
(ethyl acetate). IR (n, cm21, KBr): 3322 (±NH), 1666
±CH2±), 3.28 (s, 3H, ±OCH3), 3.33±3.52 (m, 4H, 2£
±CH2±), 3.67 (s, 3H, ±OCH3), 3.90 (s, 3H, ±OCH3), 4.63
(t, Jˆ2.6 Hz, 1H, ±CH±), 6.73 (bs, 1H, ±NH), 7.13±7.34
(m, 4H, 4£±Ar±H), 8.44 (m, 1H, Ar±H). MS (m/z, %): 355
(M1, 3), 323 (23), 264 (18), 207 (27), 164 (100), 151 (51).
Anal. calcd for C21H25NO4, C 70.96, H 7.09, N 3.94; found,
C 70.72, H 6.95, N 3.82.
1.1.4. N[2-(3,4-Dimethoxy-1-phenanthryl)ethyl]aceta-
mide (2a). Procedure a. A solution of phenanthrylaceta-
mide 7a (100 mg, 0.28 mmol), THF (3 mL) and 10%
aqueous hydrochloric acid solution (2 mL) was stirred at
room temperature for 5 min. After evaporation of the THF
in vacuo, the residue was suspended in water (40 mL) and
the suspension was extracted with dichloromethane
(3£20 mL). The pooled organic layers were dried, ®ltered
and concentrated in vacuo, giving a residue which when
subjected to preparative thin layer chromatography (eluant:
7:1 ethyl acetate/hexane) gave compound 2a (90 mg, 98%
yield). Mp 110±1128C (ethyl acetate/diethyl ether). IR (n,
1
(CvO), 1640 (CvO). H NMR (d, ppm): 1.87 (s, 3H,
±CH3), 2.95±3.02 (m, 2H, ±CH2±), 2.42±3.48 (m, 2H,
±CH2±), 3.92 (s, 3H, ±OCH3), 3.93 (s, 3H, ±OCH3), 4.39
(s, 2H, ±CH2±), 6.56 (bs, 1H, ±NH), 6.78 (s, 1H, Ar±H),
7.12±7.38 (m, 4H, 4£Ar±H), 7.60 (m, 1H, Ar±H). MS (m/z,
%): 421 (M1, 1), 419 (M1, 1), 361 (6), 208 (100), 191 847),
179 (20). Anal. calcd for C20H22BrNO4, C 57.15, H 5.27, N
3.33; found, C 56.83, H 4.94, N 3.41.
1
cm21, NaCl): 3284 (±NH), 1650 (CvO). H NMR (d,
1.1.2.
N-{2-[2-(2-Bromophenyl)-1-methoxyethyl]-4,5-
ppm): 1.95 (s, 3H, ±CH3), 3.24±3.38 (m, 2H, ±CH2±),
3.56±3.62 (m, 2H, ±CH2±), 3.93 (s, 3H, ±OCH3), 4.03 (s,
3H±OCH3), 5.60 (s, 1H, ±NH), 7.20 (s, 1H, Ar±H), 7.57±
7.72 (m, 3H, 3£Ar±H), 7.82±7.98 (m, 2H, 2£Ar±H), 9.66
(m, 1H, Ar±H). MS (m/z, %): 324 [(M11)1, 13], 323 (M1,
58), 264 (79), 251 (100), 249 (16), 217 (24), 165 (34). Anal.
calcd for C20H21NO3, C 74.28, H 6.54, N 4.33; found, C
74.41, H 6.69, N 4.29.
dimethoxyphenylethyl}acetamide (6a). Small portions of
sodium borohydride (500 mg) were added over a period of
3 h to a stirred solution of phenylethylacetamide 3a (2 g,
4.75 mmol) in methanol (40 mL), and the stirring was
continued for 30 min at room temperature. The reaction
mixture was then added to water (30 mL) and acidi®ed to
pH 3 with 20% aqueous hydrochloric acid solution. The
methanol was removed in vacuo, and the residue was
extracted with dichloromethane (4£40 mL). The pooled
organic layers were washed with water (60 mL), dried and
concentrated in vacuo to give compound 6a (2.03 g, 98%
yield) as a white solid. Mp 140±1428C (ethyl acetate/ethyl
ether). IR (n, cm21, KBr): 3284 (NH), 1647 (CvO). 1H
NMR (d, ppm): 1.92 (s, 3H, ±CH3), 2.54 (m, 1H, ±CH2±
), 2.72 (m, 1H, ±CH2±), 2.99 (dd, Jˆ13.4 and Jˆ6.7 Hz,
1H, ±CH2±), 3.21 (s, 3H, ±OCH3), 3.24±3.33 (m, 2H,
±CH2±), 3.32 (dd, Jˆ13.4 and Jˆ6.7 Hz, 1H, ±CH2±),
3.86 (s, 3H, ±OCH3), 3.89 (s, 3H, ±OCH3), 4.69 (t, Jˆ
6.7 Hz, 1H, ±CH±), 5.35 (bs, 1H, ±NH), 6.57 (s, 1H, Ar±
H), 6.95 (s, 1H, Ar±H), 6.97±7.16 (s, 3H, 3£Ar±H), 7.52 (s,
1H, Ar±H). MS (m/z, %): 267 (13), 266 (77), 192 (100), 191
(9), 177 (13), 170 (9), 161 (16). Anal. calcd for
C21H22BrNO4, C 57.81, H 6.00, N 3.21; found, C 57.97, H
6.11, N 3.33.
Procedure b. Acetyl chloride (1 mL) was added dropwise to
a solution of phenanthrylethylamine 2c (200 mg, 1.5 mmol)
and triethylamine (1 mL) in dry dichloromethane (10 mL) at
08C, and the mixture was then stirred at room temperature
for 3 h. Water (15 mL) was added and the organic layer was
isolated and washed with water (2£20 mL), dried, ®ltered
and concentrated in vacuo, giving a residue which upon
puri®cation by ¯ash column chromatography (eluant: 99:1
dichloromethane/methanol) gave acetamide 2a (181 mg,
90% yield).
1.1.5. 11,12-Dimethoxy-1-methyl-3,4-dihydronaphtho-
[2,1-f]isoquinoline (8a). POCl3 (0.36 mL, 2.4 mmol) was
added dropwise over 5 min to a solution of compound 6a
(180 mg, 0.48 mmol) in dry acetonitrile (15 mL) and the
mixture was re¯uxed for 6 h under a calcium chloride
tube. The reaction mixture was then concentrated in
vacuo, the solid residue was dissolved in dichloromethane
(20 mL), and this solution was washed with 10% aqueous
sodium hydroxide solution 2£15 mL) and water (15 mL),
dried, ®ltered and concentrated in vacuo giving a yellow
oil identi®ed as dihydronaphthoisoquinoline 8a (120 mg,
1.1.3. N-[2-(3,4,10-Trimethoxy-9,10-dihydro-1-phenan-
thryl)ethyl]acetamide (7a). A solution of tributyltin
hydride (1.5 mmol) and AIBN (0.1 mmol) in deoxygenated
dry benzene (10 mL) was added under argon over 6 h by
means of a syringe pump to a re¯uxing solution of acet-
amide 6a (300 mg, 0.69 mmol) in the same solvent
(100 mL). Following completion of the addition, the
reaction mixture was heated for an additional 3 h, the
benzene was evaporated in vacuo and the residue was
dissolved in acetonitrile (250 mL). This solution was
washed with hexane (3£50 mL), dried and concentrated in
vacuo, and the solid residue was subjected to ¯ash column
chromatography (eluant: 7:1 ethyl acetate/hexane), giving
phenanthrylethylacetamide 7a (124 mg, 63% yield). Mp
196±1988C (methanol). IR (n, cm21, KBr): 1665 (CvO).
1H NMR (d, ppm): 1.84 (s, 3H, ±CH3), 2.86±3.23 (m, 2H,
1
70% yield). IR (n, cm21, NaCl): 1665 (CvO). H NMR
(d, ppm): 2.60 (s, 3H, ±CH3), 3.03±3.10 (m, 2H, ±CH2±),
3.65±3.70 (m, 2H, ±CH2±), 3.96 (s, 3H, ±OCH3), 4.08
(s, 3H, ±OCH3), 7.62±7.69 (m, 3H, 3£Ar±H), 7.73±7.95
(m, 2H, 2£Ar±H), 9.65 (m, 1H, Ar±H). MS (m/z, %):
306 [(M11)1, 22], 305 (M1, 100), 304 (25). High
resolution MS calcd for C20H19NO2, 305.1416; found,
305.1414.
1.1.6. 11,12-Dimethoxy-1-methyl-1,2,3,4-tetrahydro-
naphtho[2,1-f]isoquinoline (1a). NaBH4 (50 mg) was

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1973±1979
1977
added over 3 h, in small portions, to a solution of dihydro-
isoquinoline 8a (100 mg, 0.33 mmol) in methanol (10 mL),
after which stirring was continued for 30 min. The reaction
mixture was then poured into water (20 mL) and acidi®ed
with 20% aqueous hydrochloric acid solution, the methanol
was evaporated in vacuo, and the resulting mixture was
extracted with chloroform (3£10 mL). The pooled organic
layers were dried, ®ltered and concentrated in vacuo, giving
a residue that when subjected to ¯ash column chroma-
tography (eluant: 7:1 eluant ethyl acetate/hexane) gave
naphthoisoquinoline 1a (95 mg, 94% yield). Mp 197±
mixture of acetic acid/water (20 mL) cooled at 108C with
an ice/water bath. The mixture was then stirred at room
temperature for 1 h, and the resulting precipitate was ®ltered
out and washed with water, giving bromophenylacetyl-
phenylethylacetamide 3c (0.52 g, 86%) as a white solid.
Mp 212±2148C (acetone). IR (n, cm21, NaCl): 1659
1
(CvO). H NMR (d, ppm): 1.87 (s, 3H, ±CH3), 2.92±
3.03 (m, 2H, ±CH2±), 3.41±3.58 (m, 2H, ±CH2±), 3.85
(s, 3H, ±OCH3), 3.86 (s, 3H, ±OCH3), 3.92 (s, 3H,
±OCH3), 3.93 (s, 3H, ±OCH3), 4.31 (s, 2H, ±CH2±), 6.57
(bs, 1H, ±NH), 6.76 (s, 1H, Ar±H), 6.77 (s, 1H, Ar±H), 7.05
(s, 1H, Ar±H), 7.31 (s, 1H, Ar±H). MS (m/z, %): 481 (M1,
2) 479 (M1, 2), 209 (14), 208 (100). Anal. calcd for
C22H26BrNO6, C 55.01, H 5.46, N 2.92; found, C 55.19, H
5.44, N 32.83
1
1988C (methanol). IR (n, cm21, NaCl): 3223 (±NH). H
NMR (d, ppm): 1.62 (d, Jˆ6.2 Hz, 3H, ±CH3), 2.79±3.08
(m, 2H, ±CH2±), 3.22±3.39 (m, 2H, ±CH2±), 3.95 (s, 3H,
±OCH3), 3.98 (s, 3H, ±OCH3), 4.61 (m, 1H, ±CH±), 7.58±
7.78 (m, 3H, 3£Ar±H), 7.82±7.98 (m, 2H, 2£Ar±H), 9.63
(m, 1H, Ar±H). MS (m/z, %): 307 (M1, 15), 293 (22), 292
(100). Anal. calcd. for C20H21NO2, C 78.15, H 6.89, N 4.56;
found, C 78.03, H 7.11, N 4.39.
1.1.10. N-{2-[2-(2-Bromo-4,5-dimethoxyphenyl)-1-meth-
(6b).
oxyethyl]-4,5-dimethoxyphenylethyl}-acetamide
Compound 6b was obtained in 72% yield from compound
3c (0.46 g, 0.96 mmol) following the same procedure as for
compound 6a. Mp 198±2008C (ethyl acetate/ethyl ether). IR
(n, cm21, NaCl): 1653 (CvO). 1H NMR (d, ppm), 1.86 (s,
3H, ±CH3), 2.38±2.84 (m, 4H, 2£±CH2±), 3.15 (s, 3H,
±OCH3), 3.16±3.26 (m, 2H, ±CH2±), 3.60 (s, 3H,
±OCH3), 3.75 (s, 3H, ±OCH3), 3.77 (s, 3H, ±OCH3), 3.81
(s, 3H, ±OCH3), 4.57 (t, Jˆ6.7 Hz, 1H, ±CH±), 5.72 (bs,
1H, ±NH), 6.37 (s, 1H, Ar±H), 6.50 (s, 1H, Ar±H), 6.88 (s,
1H, Ar±H), 6.90 (s, 1H, Ar±H). MS (m/z, %): 267 (15), 266
(86), 234 (14), 193 (14), 192 (100), 191 (7). Anal. calcd for
C23H30BrNO6, C 55.65, H 6.09, N 2.82; found, C 55.51, H
5.95, N 3.02.
1.1.7.
N-Acetyl-1-(3,4-dimethoxybenzylidene)-3,4-di-
hydro-6,7-dimethoxyisoquinoline (11). A solution of
isoquinoline 10 (2 g, 5.8 mmol) in 1:1 pyridine/acetic
anhydride (16 mL) was heated at 908C for 30 min and
then stirred at room temperature for 18 h. The liquids
were coevaporated in vacuo with ethyl acetate, giving
benzylideneisoquinoline 11 (2.16 g, 97% yield) as a
brown solid. Mp 194±1958C (ethyl acetate/ethyl ether). IR
(n, cm21, NaCl): 1638 (CvO). 1H NMR (d, ppm): 1.79 (s,
3H, ±CH3), 2.63±2.76 (m, 1H, ±CH2±), 3.11±3.21 (m, 2H,
±CH2±), 3.87 (s, 6H, 2£±OCH3), 3.88 (s, 3H,±OCH3), 3.96
(s, 3H,±OCH3), 4.98±5.09 (m, 1H, ±CH2±), 6.61 (s, 1H,
Ar±H), 6.70 (s, 1H, Ar±H), 6.84 (m, 1H, Ar±H), 7.01±7.04
(m, 2H, 2£Ar±H), 7.11 (s, 1H, Ar±H). MS (m/z, %): 384
[(M11)1, 25], 383 (M1, 100), 369 (5), 368 (22), 326 (98).
Anal. calcd for C22H25NO5, C 68.91, H 6.57, N 3.65; found,
C 68.83, H 6.41, N 3.84.
1.1.11. N-[2-(3,4,6,7,10-Pentamethoxy-9,10-dihydro-1-
phenanthryl)ethyl]acetamide (7b). Compound 7b was
obtained in 59% yield from compound 6b (283 mg,
0.57 mmol) by the same procedure as for compound 7a.
Mp 191±1938C (methanol). IR (n, cm21, KBr): 1655
1
(CvO). H NMR (d, ppm): 1.85 (s, 3H, ±CH3), 2.77±296
1.1.8. N-{2-[2-(3,4-Dimethoxyphenyl)acetyl]-4,5-dimethoxy-
phenylethyl}acetamide (3b). 10% Aqueous hydrochloric
acid solution (5 mL) was added to a solution of benzyl-
ideneisoquinoline 11 (1.0 g, 2.60 mmol) in methanol
(12.5 mL), and the mixture was re¯uxed for 5 h. The metha-
nol was evaporated in vacuo and the resulting suspension
was basi®ed with saturated aqueous potassium carbonate
solution and extracted with chloroform (3£75 mL). The
pooled organic layers were dried, ®ltered and concentrated
in vacuo, giving phenylethylacetamide 3b (1.0 g, 96%
yield) as a white solid. Mp 198±2008C (methanol). IR (n,
cm21, NaCl): 1657 (CvO). 1H NMR (d, ppm): 1.87 (s, 3H,
±CH3), 2.81±2.98 (m, 2H, ±CH2±), 3.41±3.52 (m, 2H,
±CH2±), 3.85 (s, 3H, ±OCH3), 3.86 (s, 3H, ±OCH3), 3.90
(s, 3H, ±OCH3), 3.92 (s, 3H, ±OCH3), 4.15 (s, 2H, ±CH2±),
6,56 (bs, 1H, ±NH), 6.72±6.96 (m, 4H, 4£Ar±H), 7.25 (s,
1H, Ar±H). MS (m/z, %): 402 [(M11)1, 1], 401 (M1, 5),
209 (13), 208 (100). Anal. calcd for C22H27NO6, C 65.82, H
6.78, N 3.49; found, C 65.97, H 6.92, N 3.61.
(m, 2H, ±CH2±), 3.30 (s, 3H, ±OCH3), 3.39±3.57 (m, 4H,
2£±CH2±), 3.65 (s, 3H, ±OCH3), 3.89 (s, 6H, 2£±OCH3),
3.92 (s, 3H, ±OCH3), 4.61 (m, 1H, ±CH±), 6.35 (bs,
1H, ±NH), 6.68 (s, 1H, Ar±H), 6.78 (s, 1H, Ar±H),
8.17 (s, 1H, Ar±H). MS (m/z, %): 417 [(M12)1, 2],
416 [(M11)1, 12], 415 (M1, 45), 384 (18), 383 (58),
326 (11), 325 (39), 324 (89), 311 (100). Anal. calcd for
C23H29NO6, C 66.49, H 7.03, N 3.37; found, C 66.71, H
6.95, N 3.39.
1.1.12. N-[2-(3,4,6,7-Tetramethoxy-1-phenanthryl)ethyl]-
acetamide (2b). Procedure a. When compound 7b
(100 mg, 0.24 mmol) was subjected to the conditions for
the transformation of 7a (Procedure a), compound 2b was
obtained in 98% yield. Mp 135±1388C (ethyl acetate/ethyl
1
ether). IR (n, cm21, NaCl): 1649 (CvO). H NMR (d,
ppm): 1.93 (s, 3H, ±CH3), 3.21±3.34 (m, 2H, ±CH2±),
3.57±3.63 (m, 2H, ±CH2±), 3.90 (s, 3H, ±OCH3), 3.99 (s,
3H, ±OCH3), 4.01 (s, 3H, ±OCH3), 4.05 (s, 3H, ±OCH3),
5.84 (s, 1H, ±NH), 7.13 (s, 1H, Ar±H),), 7.17 (s, 1H, Ar±H),
7.51 (d, Jˆ9.1 Hz, 1H, Ar±H), 7.78 (d, Jˆ9.1 Hz, 1H, Ar±
H). 9.24 (s, 1H, Ar±H). MS (m/z, %): 383 (M1, 100) 325
(20), 324 (83), 312 821), 311 (97), 309 (24), 297 (13), 293
(26). Anal. calcd for C22H25NO5, C 68.91, H 6.57, N 3.65;
found, C 68.94, H 6.78, N 3.56.
1.1.9. N-{2-[2-(2-Bromo-4,5-dimethoxyphenyl)acetyl]-
4,5-dimethoxyphenylethyl}acetamide (3c). A solution of
bromine (2.2 mL, 138 mmol) in glacial acetic acid (20 mL)
was added dropwise over 30 min to a solution of styryl-
phenylethylacetamide 3b (0.5 g, 1.25 mmol) in a 1:1

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1973±1979
1978
Procedure b. Alternatively, compound 2b was prepared
in 90% yield from compound 2d (180 mg 0.53 mmol)
following the same procedure as for preparation of com-
pound 2a (Procedure b).
(m, 2H, 2£Ar±H), 7.64 (d, Jˆ9.1 Hz, 1H, Ar±H), 7.74 (d,
Jˆ9.1 Hz, 1H, Ar±H), 7.85 (s, 1H, Ar±H), 9.65 (s, 1H, Ar±
H). MS (m/z, %): 295 (M1, 74), 252 (19), 251 (100), 237
(19), 165 (20). Anal. calcd for C19H17NO3, C 73.20, H 5.80,
N 4.74; found, C 73.02, H 5.83, N 4.32.
1.1.13. 8,9,11,12-Tetramethoxy-1-methyl-3,4-dihydro-
naphtho [2,1-f]isoquinoline (8b). Compound 8b was
prepared as a yellow oil in 70% yield from compound 2b
(135 mg, 0.36 mmol) using the same procedure as for
1.1.17. 2-(3,4-Dimethoxy-1-phenanthryl)-1-ethylamine
(2c). A solution of amide 16a (200 mg, 0.68 mmol) in dry
THF (10 mL) was added dropwise over 12 min to a vigor-
ously stirred suspension of LAH (70 mg) in dry THF
(20 mL). The mixture was re¯uxed for 5 h under a calcium
chloride tube and was then stirred at room temperature over-
night. After addition of a saturated solution of sodium
sulphate (4 drops), the suspension was ®ltered and the
®ltrate was concentrated in vacuo, giving an oil identi®ed
as the phenanthrylethylamine 2c (133 mg, 70% yield),
1
compound 8a. H NMR (d, ppm): 2.60 (s, 3H, ±CH3),
3.02±3.13 (m, 2H, ±CH2±), 3.62±3.79 (m, 2H, ±CH2±),
3.96 (s, 3H, ±OCH3), 4.07 (s, 3H, ±OCH3), 4.08 (s, 3H,
±OCH3), 4.11 (s, 3H, ±OCH3), 7.28 (s, 1H, Ar±H),
7.64 (d, Jˆ9.0 Hz, 1H, Ar±H), 7.86 (d, Jˆ9.0 Hz, 1H,
Ar±H), 9.22 (s, 1H, Ar±H). MS (m/z, %): 365 (M1, 100),
364 (7), 351 (13), 350 (39), 311 (8), 310 (33). High
resolution MS calcd for C22H23NO4, 365.1627; found,
365.1628.
1
which was used without further puri®cation. H NMR (d,
ppm): 3.15 (t, Jˆ6.3 Hz, 2H, ±CH2±), 3.30 (t, Jˆ6.3 Hz,
2H, ±CH2±), 3.92 (s, 3H, ±OCH3), 4.03 (s, 3H, ±OCH3),
7.24 (s, 1H, Ar±H), 7.50±7.70 (m, 3H, 3£Ar±H), 7.82 (m,
1H, Ar±H), 7.86 (d, Jˆ9.2 Hz, 1H, Ar±H), 9.65 (d, Jˆ
8.3 Hz, 1H, Ar±H). MS (m/z, %): 281 (M1, 36), 252 (90),
251 (100), 237 (23).
1.1.14. 8,9,11,12-Tetramethoxy-1-methyl-1,2,3,4-tetra-
hydronaphtho[2,1-f]isoquinoline (1b). Compound 1b
was prepared in 84% yield from compound 8b (50 mg,
0.14 mmol) following the same procedure as for compound
1a. Mp 231±2338C (methanol). IR (n, cm21, KBr): 3200
1
(±NH). H NMR (d, ppm): 1.75 (d, Jˆ6.1 Hz, 3H, ±CH3),
1.1.18. 1,2,9,10-Tetramethoxy-4,5,6a,7-tetrahydrodibenzo-
[de,g]chroman-5-one (14b). Compound 14b was prepared
in 83% yield from compound 13b (200 mg, 0.46 mmol)
following the same procedure as for compound 14a and
was identi®ed by comparison with an authentic sample.
2.98±3.71 (m, 4H, 2£±CH2±), 3.97 (s, 9H, 3£±OCH3),
4.03 (s, 3H, ±OCH3), 4.88 (m, 1H, ±CH±), 7.25 (s, 1H,
Ar±H), 7.29 (s, 1H, Ar±H) 7.80 (d, Jˆ9.1 Hz, 1H, Ar±
H), 8.09 (d, Jˆ9.1 Hz, 1H, Ar±H), 9.65 (s, 1H, Ar±H),
995 (bs, 1H, ±NH). MS (m/z, %): 367 (M1, 1), 352 (24),
351 (100). Anal. calcd for C22N25NO4, C 71.91, H 6.86, N
3.81; found, C 71.69, H 6.75, N 4.02.
1.1.19.
2-(3,4,6,7-Tetramethoxy-1-phenanthryl)aceta-
mide (16b). Compound 16b was prepared in 70% yield
from compound 14b (250 mg, 0.7 mmol) following the
same procedure as for compound 16a. Mp 162±1638C
(methanol). IR (n, cm21, KBr): 3430 (±NH), 1670
1.1.15. 1,2-Dimethoxy-4,5,6a,7-tetrahydrodibenzo[de,g]-
chroman-5-one (14a). A solution of tributylin hydride
(1.5 mmol) and AIBN (0.1 mmol) in deoxygenated dry
benzene (15 mL) was added under argon over 6 h by
means of a syringe pump to a re¯uxing solution of aceta-
mide 6a (800 mg, 2.12 mmol) in the same solvent (100 mL).
Following completion of the addition, the reaction mixture
was heated for an additional 3 h. The benzene was evapo-
rated in vacuo, the residue was dissolved in acetonitrile
(400 mL) and the resulting solution was washed with
hexane (3£50 mL), dried and concentrated in vacuo. After
thin layer chromatography of the solid residue (eluant: 95:5
dichloromethane/methanol), compound 14a was isolated as
a white solid (483 mg, 76% yield) and compared with an
authentic sample.
1
(CvO). H NMR (d, ppm): 3.96 (s, 3H, ±OCH3), 4.05
(s, 8H, ±CH2± and 2£±OCH3), 4.08 (s, 3H, ±OCH3), 5.34
(bs, 1H, ±NH2), 7.23 (s, 1H, Ar±H), 7.25 (s, 1H, Ar±H),
7.59 (d, Jˆ9.1 Hz, 1H, Ar±H). 7.67 (d, Jˆ9.1 Hz, 1H, Ar±
H), 9.27 (s, 1H, Ar±H). MS (m/z, %): 370 (M1, 100), 355
(42), 311 (39). Anal. calcd for C20H21NO5, C 67.61, H 5.92,
N 3.94; found, C 67.21, H 6.09, N 3.61. Anal. calcd for
C20H21NO5, C 67.59, H 5.96, N 3.94; found, C 67.86, H
5.61, N 3.69.
1.1.20. 2-(3,4,6,7-Tetramethoxy-1-phenanthryl)-1-ethyl-
amine (2d). Compound 2d was prepared in 75% yield
from compound 16b (0.5 g, 1.4 mmol) following the same
procedure as for compound 2c. 1H NMR (d, ppm): 1.89 (bs,
2H, ±NH2), 3.12 (t, Jˆ6.0 Hz, 2H, ±CH2±), 3.24 (t, Jˆ
6.0 Hz, 2H, ±CH2±), 3.92 (s, 3H, ±OCH3), 4.03 (s, 3H,
±OCH3), 4.04 (s, 3H, ±OCH3), 4.07 (s, 3H, ±OCH3), 7.19
(s, 1H, Ar±H), 7.20 (s, 1H, Ar±H), 7.53 (d, Jˆ9.1 Hz, 1H,
Ar±H), 7.77 (d, Jˆ9.1 Hz, 1H, Ar±H), 9.28 (s, 1H, Ar±H).
MS (m/z, %): 343 [(M12)1, 23], 342 [(M11)1, 100], 311
(54), 265 (12).
1.1.16. 2-(3,4-Dimethoxy-1-phenanthryl)acetamide (16a).
A mixture of lactone 14a (250 mg, 0.84 mmol), methanol
(5 mL) and concentrated aqueous ammonia solution (2 mL)
was stirred at room temperature for 18 h, and then added to
water (25 mL) acidi®ed with 10% aqueous hydrochloric
acid solution and extracted with chloroform (3£25 mL).
The pooled organic layers were dried, ®ltered and concen-
trated in vacuo, giving a residue which after puri®cation
by thin layer chromatography (95:5 dichloromethane/
methanol) gave 16a (200 mg, 80% yield) as a white solid.
Mp 147±1488C (methanol). IR (n, cm21, KBr): 3360
Acknowledgements
1
(±NH), 1660 (CvO). H NMR (d, ppm): 3.95 (s, 3H,
±OCH3), 4.04 (s, 5H, ±CH2± and ±OCH3), 5.34 (bs, 1H,
±NH2), 5.56 (bs, 1H, ±NH2), 7.25 (s, 1H, Ar±H), 7.57±7.68
We thank the Ministry of Education and Culture (DGES)
and the Xunta de Galicia for ®nancial support.

Â
E. Martõnez et al. / Tetrahedron 57 (2001) 1973±1979
1979
 Â
tion see: (a) Estevez, J. C.; Villaverde, M. C.; Estevez, R. J.;
Â
Castedo, L. Tetrahedron Lett. 1991, 32, 529. (b) Estevez, J. C.;
References
Â
Villaverde, M. C.; Estevez, R. J.; Castedo, L. Tetrahedron
1. Cheng, C. C. Structural Aspects of Antineoplastic AgentsÐA
New Approach. In Progress in Medicinal Chemistry; Ellis,
G. P., West, G. B., Eds.; Elsevier: Amsterdam, 1988; Vol.
25, pp 35±83.
Â
1992, 33, 5145. (c) Estevez, J. C.; Villaverde, M. C.; Estevez,
Â
R. J.; Castedo, L. Tetrahedron 1993, 49, 2783. (d) Estevez,
Â
J. C.; Villaverde, M. C.; Estevez, R. J.; Castedo, L.
Tetrahedron 1994, 50, 2107.
2. Whaley, W. M.; Meadow, M. J. Org. Chem. 1954, 19, 661.
3. Wu, Y.-C.; Liou, Y.-Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S.-T.
Tetrahedron Lett. 1991, 32, 4169.
8. Kazuhiko, O.; Tsutomu, M.; Hiroshi, S. Heterocycles 1998,
27, 2403.
9. Leit, S. M.; Paquette, L. A. J. Org. Chem. 1999, 27, 2403.
10. Cava, M. P.; Mitchell, M. J.; Havlicek, S. C.; Lindert, A.;
Spangler, R. J. J. Org. Chem. 1970, 35, 175.
11. Bentley, H. R.; Dawson, W.; Spring, F. C. J. Chem. Soc. 1952,
17631.
4. Wu, Y.-C.; Chang, G.-Y.; Duh, C.-Y.; Wang, S.-K. Phyto-
chemistry 1993, 33, 497.
5. Lee, S.-S.; Lin, Y.-J.; Chen, M.-Z.; Wu, Y.-C.; Chen, C.-H.
Tetrahedron Lett. 1992, 33, 6309.
6. Hara, H.; Kaneko, K.-I.; Endoh, M.; Uchida, H.; Hoshino, O.
Tetrahedron 1995, 51, 10189.
12. Baxter, I.; Swan, G. A. J. Chem. Soc. B. 1965, 4014.
13. Perrin, D. D.; Armarego, W. L. F. Puri®cation of Laboratory
Chemicals; Pergamon: Oxford, 1988.
7. For a review on bi-aryl bonds see: Bringmann, G.; Walter, R.;
Weirich, R. Angew Chem., Int. Ed. Engl. 1990, 29, 977. For
our previous work on radical-mediated bi-aryl bond construc-