Heck-mediated synthesis and photochemically induced cyclization of [2-(2-styrylphenyl)ethyl]carbamic acid ethyl esters and 2-styryl-benzoic acid methyl esters: Total synthesis of naphtho[2,1f]isoquinolines (2-azachrysenes)

Article abstract of DOI:10.1016/S0040-4020(03)01073-1

We describe two new closely related total syntheses of naphtho[2,1-f]isoquinolines. The first synthesis consists of a Heck coupling reaction between trifluoromethanesulfonic acid 2-(2-ethoxycarbonylaminoethyl)phenyl esters and styrenes to give [2-(2-styrylphenyl)ethyl]carbamic acid ethyl esters. These compounds cyclize to give (2-phenanthren-1-yl-ethyl)carbamic acid ethyl esters, from which 2-azachrysenes can be obtained in a three-step sequence. The second synthesis includes a new total synthesis of 2-styrylbenzoic acid methyl esters by Heck coupling of methyl o-iodobenzoates to styrenes, followed by the transformation of the resulting benzoic acid derivatives into phenanthrene-1-carboxylic acid methyl esters and then into the target compounds by a six-step sequence including a Bischler-Napieralski cyclization.

Full text of DOI:10.1016/S0040-4020(03)01073-1

Tetrahedron 59 (2003) 7231–7243
Heck-mediated synthesis and photochemically induced cyclization
of [2-(2-styrylphenyl)ethyl]carbamic acid ethyl esters and
2-styryl-benzoic acid methyl esters: total synthesis of
naphtho[2,1f]isoquinolines (2-azachrysenes)q
a
M. Carme Pampın, Juan C. Estevez, Ramon J. Estevez, Miguel Maestro and Luis Castedo
a
a
b
a
,
*
´
´
´
´
a
´
´
Departamento de Quımica Organica, Universidade de Santiago, 15782 Santiago de Compostela, Spain
´ ´
Servicios Xerais de Apoio a Investigacion, Universidade de A Corun˜a, 15071 A Corun˜a, Spainqorjec@usc.es
b
Received 15 January 2003; revised 5 May 2003; accepted 16 May 2003
Abstract—We describe two new closely related total syntheses of naphtho[2,1-f]isoquinolines. The first synthesis consists of a Heck
coupling reaction between trifluoromethanesulfonic acid 2-(2-ethoxycarbonylaminoethyl)phenyl esters and styrenes to give [2-(2-
styrylphenyl)ethyl]carbamic acid ethyl esters. These compounds cyclize to give (2-phenanthren-1-yl-ethyl)carbamic acid ethyl esters, from
which 2-azachrysenes can be obtained in a three-step sequence. The second synthesis includes a new total synthesis of 2-styrylbenzoic acid
methyl esters by Heck coupling of methyl o-iodobenzoates to styrenes, followed by the transformation of the resulting benzoic acid
derivatives into phenanthrene-1-carboxylic acid methyl esters and then into the target compounds by a six-step sequence including a
Bischler–Napieralski cyclization.
q 2003 Elsevier Ltd. All rights reserved.
Polycyclic aromatic hydrocarbons (PAHs) have attracted
considerable attention because they are ubiquitous environ-
mental contaminants produced in the incomplete com-
bustion of fossil fuels and organic matter, as well as being
components of tobacco smoke.2 Some PAHs are potent
carcinogens and it is now generally accepted that carcino-
genic PAHs are activated by cytochrome P-450 enzymes to
form a reactive diol epoxide that binds covalently to DNA,
resulting in mutations that may lead to tumorigenesis.
Existing data indicate that PAHs such as pyrene and
benzo[e]pyrene possess very little or no carcinogenicity,
whereas other PAHs such as benz[a]anthracene, benzo[a]-
pyrene and chrysene (Fig. 1) are potent carcinogens.3
Studies on the relationship between the chemical structure
of PAHs and carcinogenicity have related this property with
the presence of a rigid planar embedded 2-phenylnaphthal-
ene subunit within the condensed ring systems, which may
facilitate the interaction of their diol epoxide derivatives
with DNA.4,5
The benzo[c]phenanthridine ring system resembles the
structure of the carcinogenic PAH chrysene and this led to
concern as to whether the former compounds could also be
carcinogenic. However, it was found that benzo[c]phenan-
thridines are not mutagenic.6 This finding led to suggestions
that structural modifications of PAHs may afford anti-
neoplastic compounds. This idea is supported, for example,
by the powerful anticancer activity of benzo[c]phenanthri-
dines such as nitidine and fagaronine (Fig. 1). These
properties indicate that the presence of a nitrogen atom in
Figure 1.
q See Ref. 1.
Keywords: Heck reactions; isoquinolines; photochemistry; polycyclic heterocyclic compounds.
*
Corresponding author. Tel.: þ34-981-563100x14242; fax: þ34-981-591014; e-mail: qorjec@usc.es
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01073-1

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7232
Scheme 1.
these alkaloids could modify the overall electronic distri-
bution of the tetracyclic ring system and the presence of
alkoxy groups at strategic positions may interfere with the in
vivo epoxidation-hydroxylation processes necessary for
mutagenic and oncogenic action.7 These facts clearly
imply that the antineoplastic action and mutagenicity (or
carcinogenicity) of a compound can be separated by
appropriate structural modifications. Such a possibility
provides a sound reason for an extensive search for
biologically, pharmacologically, and clinically antineo-
plastic active compounds of both natural and synthetic
origin.
These compounds contain an appropriate stilbene-like
system for construction of phenanthrene ring system of
the phenanthrenylethylurethanes 2 and a nitrogen substi-
tuent for final construction of the nitrogen ring by Bischler–
Napieralski cyclization of compounds 2 (Scheme 1).
We first prepared the starting o-triflylphenylethylurethane
6c, which was efficiently obtained as indicated in Scheme 2.
Treatment of 2-chromanone (4)10 with dimethylamine at
room temperature provided 96% yield of hydroxyamide 5a,
which was quantitatively converted into benzyloxy-
acetamide 5b by treatment with sodium hydride and benzyl
bromide at room temperature for 1 h. Acetamide 5b was
then converted into its o-triflyl derivative 6c in a four-step
sequence, starting with basic hydrolysis of 5b to give 93%
yield of phenylpropionic acid 5c. This compound was
tranformed into carbamate 6a through a Curtius sequence by
heating a solution of 5c, DPPA and Et3N under reflux for
1 h, followed by addition of CuCl and EtOH, and further
heating of this mixture under reflux for 1 h. Finally, when 6a
was subjected to catalytic hydrogenation, a quantitative
yield of carbamate 6b was obtained. Treatment of this
compound with phenyltriflylamide and Et3N for 6 days
provided the desired triflate 6c in 89% yield.
On the basis of the above considerations, benzo[c]phenan-
thridines may be regarded as azachrysenes because the
tetracyclic ring system can be constructed by replacement of
the CH group at position C(5) of chrysene by a nitrogen
atom. 2-Azachrysenes are structurally related to chrysene in
a similar way as benzo[c]phenanthridines and, therefore,
like the latter, should show antineoplastic activity. How-
ever, the chemistry of 2-azachrysenes has received much
less attention than benzo[c]phenanthridines. Indeed, the
synthesis of 2-azachrysenes has been almost completely
overlooked8 and investigation of their properties9 has been
limited to studies concerning pollution by 2-azachrysene
(Fig. 1).
We proceeded to study the viability of this route by
preparing 2-azachrysene (1a, Scheme 3) from o-styryl-
phenylethylurethane 3, which was easily obtained by
Heck11 coupling of triflate 6c to styrene (Scheme 2). A
deoxygenated solution of 6c, styrene, palladium acetate,
Ph3P and LiCl in dry, deoxygenated acetonitrile was heated
We describe here two new total syntheses of 2-aza-
chrysenes. Retrosynthetic consideration of structures 1
suggested a strategy based on formation of bonds b and a,
in that order, starting from styrylphenylethylurethanes 3.
Scheme 2. (i) Et3N, rt, 30 min. (ii) TBAF, NaH, BnBr, THF, argon, rt, 1 h. (iii) 11 M KOH, EtOH, rt, 22 h. (iv) (a) diphenylphophoryl azide, Et3N, dry PhMe,
reflux, 1 h; (b) CuCl2, dry EtOH, reflux, 1 h. (v) H2 (1 atm), Pd/C, AcOEt, rt, 2 h. (vi) N-triflimide, Et3N, CH2Cl2, rt, 2 days. (vii) Pd(OAc)2 (5% M), Ph3P, LiCl,
Et3N, MeCN, argon, 1008C, 3 days. (viii) UV light, I2, Et2O/CH2Cl2, rt 2 h.

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7233
Scheme 3. (i) POCl3, argon, reflux, 32 h. (ii) TPOCl3, 1558C, 28 h. (iii) Tf2O, DMPA, dry CH2Cl2, argon, 08C!rt, 21 h. (iv) Et3N, MeOH, Pd/C, rt, 24 h.
(v) LiAlH4, THF, argon, rt, 15 h. (vi) I2, AcONa, dry EtOH, argon, reflux, 15 h.
at 1008C in a sealed tube for 3 days. This reaction gave the
desired compound 3 in 77% yield together with a small
amount (3% yield) of the corresponding a-coupled alkene 7.
Although it was impossible to separate these two
compounds by chromatography because of their similar Rf
values, the mass spectrum of the mixture confirmed the
expected molecular weight (m/z¼295) for both isomers.
Furthermore, it was possible to assign the signals of the
major component from the 1H NMR spectrum of the
mixture, and hence to establish the E configuration of
the double bond of compound 3 on the basis of a doublet at
7.90 ppm (1H, J¼16.0 Hz); the doublet due to the other
alkene proton was masked by the signals corresponding to
the aromatic protons.
the desired naphthoisoquinolinone 11 (Scheme 3). In an
attempt to promote the desired cyclization, the reaction was
repeated in the presence of SnCl4, but 8a was once again
the only reaction product.14 In a third experiment, when the
reaction temperature was increased to 1608C and the
reaction time to 28 h, compound 8a gave a new compound,
which was identified as chloro-compound 10 on the basis of
its spectroscopic data; the mass spectrum contained peaks at
1
m/z 240 and 242 with relative intensities of 3:1 and the H
NMR spectrum contained signals for a total of nine aromatic
protons and two multiplets at 3.55–3.61 and 3.82–
3.87 ppm, corresponding to the two methylene groups.
Formation of compound 10 may be regarded in terms of a
von Braun reaction: nucleophilic attack of a chloride ion at
the a carbon of the nitrilium salt 9, with concomitant
formation of ethyl cyanide.15 This unexpected result seems
to be a consequence of the lack of reactivity of the
phenanthrene system of 2 to give the desired Bischler–
Napieralski cyclization to 11, probably due to the absence of
electron-donating substituents on the phenenthrene ring
system of intermediate 9, a factor that would facilitate this
cyclization.16
We next studied the photochemically induced electrocyclic
cyclization12 of styrylphenylethylurethane 3. Irradiation for
2 h of a solution of iodine and the above mixture of 3 and 7
in diethyl ether with a 450 W Hanovia medium-pressure
lamp equipped with a Pyrex filter, led to a product mixture
from which compound 7 was recovered and the cyclization
product 2 was isolated in 80% yield. The structure of
compound 2 was easily deduced from its spectroscopic and
analytical data. The 1H NMR spectrum of this product
showed signals for a total of nine aromatic protons (two
fewer than the starting material), including a multiplet at
8.65–8.75 ppm corresponding to the deshielded protons at
C(4) and C(5).
Taking into account the unsatisfactory results described
above, we decided to assess the desired cyclization 2 to 11
under the harsher conditions described by Banwell.17 Thus,
treatment of a solution of compound 2 in dichloromethane
with excess Tf2O/DMAP (5:3) at room temperature for 21 h
led to the expected isoquinolinone 11 via 8b and 9, together
with a compound identified as o-triflyldihydroisoquinoline
12. Formation of the latter compound under Banwell
conditions is probably due to the use of excess Tf2O,
which can promote N-triflation of the initially formed
Finally, construction of the nitrogen ring of 2-azachrysene
(1a) was attempted by treatment of phenanthrene 2 with
POCl3 under classical Bischler–Napieralski conditions.13
However, in this case compound 8a was obtained instead of

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7234
isoquinolinone 11. This situation was confirmed when a
smaller amount of Tf2O was used, a change that gave only
compound 11 in the reaction. The 1H NMR spectrum of 11
showed signals for eight aromatic protons and two multi-
plets at 3.38–3.43 and 3.45–3.57 ppm, each corresponding
to two protons, due to the two methylene groups. The IR
spectrum includes a band at 3437 cm21 due to the NH group
and another at 1658 cm21 due to the carbonyl group of the
lactam. On the other hand, the mass spectrum of compound
12 confirmed its molecular mass (m/z¼379, Mþ) and the 1H
NMR spectrum also contained signals for eight aromatic
protons together with two triplets at 3.69 ppm (2H,
J¼5.9 Hz) and 4.37 ppm (2H, J¼5.9 Hz), corresponding
to the two methylene groups.
Taking into account this unsatisfactory result in terms of
yield, we decided to introduce a slight modification to this
low yielding route to 2-azachrysene (1a), a change that
resulted in the development of a general and more efficient
total synthesis of 2-azachrysenes. The new approach also
involves a sequential construction of rings C and A of
2-azachrysenes, but in this case starting from o-styryl-
benzoic acid esters 16; these latter compounds contain a
stilbene-like system that allows construction of the
phenanthrene ring system of phenanthrenoic acid esters
17, which were then efficiently transformed into the target
compounds 1 (Scheme 4).
We first studied the preparation of starting methyl
o-styrylbenzoates 16 by Heck coupling of methyl o-iodo-
benzoates 18 to styrene (Scheme 5).
Surprisingly, when we attempted to remove the triflate
substituent of imidate 12 by catalytic hydrogenation,
subjecting a solution of 12 in methanol containing a Pd/C
catalyst to hydrogenation under a hydrogen pressure of
50 psi for 24 h, an unknown compound of molecular
formula C19H16F3NO4S was obtained. Identification of
this compound proved impossible on the basis of its
spectroscopic data, but the structure of 13 was established
by X-ray18 analysis. This is the first time that compounds
like 13 have been described and they may result from the
opening of the N-triflyl lactam ring of compound 12 by
attack of MeOH on the highly reactive carbonyl (Fig. 2).
A methanolic solution of commercial o-iodobenzoic acid
containing a few drops of concentrated sulfuric acid was
heated under reflux and readily gave methyl o-iodobenzoate
18a. Coupling of this compound to styrene was carried out
under the Heck11 conditions described above for the
preparation of stilbene 3, by heating at 1008C for 24 h a
mixture of 18a, catalytic amounts of palladium acetate and
triphenylphosphine and a stoichometric amount of triethyl-
amine in acetonitrile. This reaction gave the desired
o-styrylbenzoate 16a (75% yield) together with 4% of
alkene 19a resulting from the a-coupling of iodobenzoate
18a to styrene.20 The structures of both compounds were
easily established from analytical and spectroscopic data. In
particular, the 1H NMR spectrum of compound 16a
contained signals for a total of seven aromatic protons,
together with a singlet at 3.78 ppm, corresponding to the
methoxy group, and two doublets at 6.92 ppm (1H,
J¼16.3 Hz) and 8.02 ppm (1H, J¼16.3 Hz), corresponding
to the protons of a double bond having an E configuration.
The initial total yield of this coupling reaction (79% yield)
was improved when the reaction was carried out at 808C.
Under these conditions, compound 16a was obtained in 84%
yield and compound 19a in 5% yield. This result is probably
due to the fact that the competitive dehalogenation reaction
of 18a now occurs to a lesser extent. However, this
hypothesis could not be proved because the volatility of
the resulting methyl benzoate precluded its isolation.
Finally, transformation of isoquinolinone 11 into
2-azachrysene (1a) was accomplished as follows: com-
pound 11 was reacted with LiAlH4 at room temperature for
15 h and the resulting tetrahydroisoquinoline 14 was
subjected to conditions for aromatization19 of its nitrogen
ring (by refluxing a solution of compound 14, I2 and NaOAc
in EtOH for 15 h) to give compound 1a in 10% yield along
with 23% of isoquinoline N-oxide 15. Both of these
compounds were easily identified from analytical and
spectroscopic data. The mass spectrum confirmed the
mass expected for compound 1a (m/z¼229) and elemental
1
analysis supported the molecular formula C17H11N. Its H
NMR spectrum showed signals for a total of eleven
aromatic protons, including a singlet at 9.37 ppm, corre-
sponding to the deshielded proton at C(1).
In accordance with our plan, a solution of methyl
o-styrylbenzoate 16a and iodine in methanol was
irradiated21 for 30 h with a 450 W Hanovia medium-
pressure lamp equipped with a Pyrex filter. This process
gave 80% yield of the expected phenanthrylbenzoate 17a,
the structure of which was deduced from its spectroscopic
and analytical data. The 1H NMR spectrum of this
compound showed signals for a total of nine aromatic
protons, including two doublets at 8.78 ppm (J¼9.4 Hz) and
8.92 ppm (J¼8.4 Hz), corresponding to the deshielded
protons at C(4) and C(5).
Finally, construction of the nitrogen ring of 2-azachrysene
(1a) was efficiently accomplished through a six-step
sequence,22 which included initial transformation of the
methoxycarbonyl group of phenanthrene 17a into a formyl
group. Treatment of a solution of 17a in THF with LiAlH4 at
room temperature gave quantitatively the corresponding
Figure 2. X-Ray structure of compound 13.

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7235
Scheme 4.
alcohol 17b, which was efficiently oxidized to aldehyde 17c
upon treatment with MnO2 at 408C for 24 h. Elongation of
the lateral chain of this aldehyde was then carried out in
order to achieve the necessary functionality for the
construction of the nitrogen ring of 2-azachrysene (1a).
Condensation of aldehyde 17c with malonic acid provided a
94% yield of (E)-3-phenanthren-1-yl-acrylic acid (20a),
which was identified from its analytical and spectroscopic
data. The mass spectrum confirmed the molecular mass
expected for the compound (m/z¼248) and the E configur-
ation of the double bond was easily established from the 1H
NMR spectrum, which showed two doublets at 6.64 ppm
(1H, J¼15.7 Hz) and 8.49 ppm (1H, J¼15.7 Hz). A cooled
solution of acid 20a, ClCO2Et and Et3N was stirred for
45 min and then NaN3 and water were added. The resulting
mixture was stirred for a further 30 min to furnish acyl azide
20b in 97% yield. This compound was dissolved in Ph2O
and the solution was heated under reflux for 1 h in the
presence of Bu3N to give compound 22a through a process
involving isomerization of the double bond and transform-
ation of the azyl azide group of 21a into the isocyanate
intermediate 21b. This intermediate spontaneously cyclized
to give lactam 22a. The mass spectrum of this compound
contained a peak at m/z 245 corresponding to its molecular
ion and the IR spectrum showed a band at 1650 cm21
1
corresponding to the amide carbonyl group. The H NMR
spectrum showed a complex group of signals due to the
presence of 10 aromatic protons. Finally, a solution of
compound 22a was heated under reflux in POCl3 for 3 h to
provide 85% yield of 1-chloro-2-azachrysene (1b), which
was immediately reacted with Zn and AcOH at room
temperature for 2 h to remove the chloro substituent.
2-Azachrysene (1a) was thus obtained in 90% yield.
We proceeded to apply the same strategy to the preparation
of dimethoxyazachrysene 1c.
Scheme 5. (i) Pd(OAc)2 (5% M), Ph3P, Et3N, MeCN, argon, 808C, 24 h. (ii) UV light, I2, Et2O, rt, 3 h. (iii) LiAlH4, THF, rt, 1.5 h. (iv) MnO2, CHCl3, 408C,
24 h. (v) CH2(CO2H)2, piperidine, pyr, 808C, 2 h, then reflux, 1 h. (vi) (a) ClCO2Et, Et3N, acetone, 08C, 45 min; (b) NaN3, H2O, 08C, 30 min. (vii) Bu3N, Ph2O,
reflux, 1 h. (viii) (a) POCl3, reflux, 3 h; (b) Zn, AcOH, reflux, 2 h.

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The required o-iodobenzoic acid ester 18c was easily
obtained in 74% yield by esterification of commercial 3,4-
dimethoxybenzoic acid with methanol followed by reaction
of the resulting ester 18b with Ipy2BF4 and
trifluoromethanesulfonic acid.23 Heck coupling of the
resulting o-iodobenzoate 18c to styrene under the same
conditions as for its analogue 18a gave a slightly
unsatisfactory result. The expected dimethoxylated o-styryl-
benzoate 16b was isolated in 68% yield, together with 13%
yield of the a-coupled alkene 19b and 19% yield of the
reduced starting material 18b.
magnetic resonance spectra were recorded, unless otherwise
specified, on a Bruker WM-250 apparatus, using deutero-
chloroform solutions containing tetramethylsilane as
internal standard. Mass spectra were obtained on a Kratos
MS 50 TC mass spectrometer. Thin layer chromatography
(TLC) was performed using Merck GF-254 type 60 silica
gel and dichloromethane/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. Solvents were purified as per
Ref. 26. Solutions of extracts in organic solvents were dried
with anhydrous sodium sulfate.
Stilbenic compound 16b was then converted into
dimethoxylated 2-azachrysene 1c in a similar manner to
the transformation of stilbene 16a into 2-azachrysene (1a).
Photocyclization of 16b under the same conditions as for
16a gave a 85% yield of the expected phenanthrene-
carboxilic acid ester 17d, which was converted into the
corresponding phenanthrene aldehyde 17f by treatment with
LiAlH4 and oxidation of the resulting alcohol 17e with
MnO2. Construction of the nitrogen ring of 1c was carried
out by treatment of 17f with malonic acid followed by the
transformation of the resulting derivative 20c into iso-
quinolinone 22b via acyl azide 20d. Finally, treatment of
22b with POCl3 provided the desired 1-chloro isoquinoline
1d, from which the target compound 1c was readily
obtained by removal of the chlorine atom by reduction of
1d with zinc and acetic acid. This new 2-azachrysene 1c was
easily identified from analytical and spectroscopical data.
The microanalysis and the mass spectrum confirmed the
molecular formula C19H15NO2 expected for the product.
1.1.1. N,N-Dimethyl-3-(2-hydroxyphenyl)propionamide
(5a). 33% Aq. dimethylamine (6 mL) was added to a
solution of chroman-2-one (4) (500 mg, 3.375 mmol) in
THF (6 mL) and the mixture was stirred at rt for 30 min. The
solvent was removed in vacuo, the residue was poured into
aq. hydrochloric acid (25 mL) and the resulting suspension
was extracted with dichloromethane (3£20 mL). The
combined organic extracts were washed with water
(50 mL), dried, filtered and concentrated to drynes to give
N,N-dimethyl-3-(2-hydroxyphenyl)propionamide
(5a)
(625 mg, 96% yield) as a white solid. Mp 102–1048C
(methanol). IR (n, cm21, NaCl): 3306 (–OH), 1632 (CO).
1H NMR (d, ppm): 9.80 (s, 1H, –OH), 7.15–7.00 (m, 2H,
2£ArH), 6.90–6.78 (m, 2H, 2£ArH), 2.91–2.86 (m, 8H,
–CH2- and 2£-NCH3), 2.67–2.62 (m, 2H, –CH2–). 13C
NMR (d, ppm): 173.64 (CO), 155.15 (C), 130.42 (ArH),
128.15 (C), 127.59 (ArH), 119.81 (ArH), 117.43 (ArH),
36.81 (–NCH3), 35.54 (–NCH3), 34.95 (–CH2–), 24.50
(–CH2–). MS (m/z, %): 193 (Mþ, 32), 149 (100).
1
The H NMR showed two singlets at 4.04 and 4.25 ppm,
corresponding to the methoxy substituents, and signals for a
total of nine aromatic protons (one more than its precursor
1d), including two singlets at 9.77 and 9.69 ppm, corre-
sponding to the protons at C(1) and C(10), respectively, both
of which are deshieldied due to steric interaction with
methoxy substituents at C(12) and C(11), respectively.
2-Azachrysene 1c was obtained more efficiently than its
analogue 1a, mainly due to the fact that photocyclization of
stilbene 16b was more efficient than that of 16a and the
yield corresponding to the cyclization of acyl azide 20d was
higher than the similar cyclization of 20b. This is probably
due to a favorable electronic effect of substituents in both
key steps.
1.1.2. 3-(2-Benzyloxyphenyl)-N,N-dimethylpropiona-
mide (5b). Tetrabutylammonium bromide (67 mg,
0.207 mmol), 80% sodium hydride (75 mg, 2.484 mmol)
and benzyl bromide (0.27 mL, 2.484 mmol) were added to a
solution of hydroxyphenylpropionamide 5a (400 mg,
2.069 mmol) in dry THF (10 mL) and the mixture was
stirred at rt under argon for 1 h. The solvent was removed
under vacuum using a rotary evaporator and the solid
residue was suspended in water (30 mL) and acidified with
10% hydrochloric acid. The resulting suspension was
extracted with dichloromethane (2£25 mL) and the com-
bined organic extracts were washed with water (30 mL),
dried, filtered and concentrated in vacuo to provide 3-(2-
benzyloxyphenyl)-N,N-dimethylpropionamide (5b) (586 mg,
100%) as a white solid. Mp 97–998C (methanol). IR (n,
cm21, NaCl): 1633 (CO). 1H NMR (d, ppm): 7.44–7.32 (m,
5H, 5£ArH), 7.25–7.15 (m, 2H, 2£ArH), 6.93–6.87 (m,
2H, 2£ArH), 5.07 (s, 2H, –CH2–), 3.01–2.95 (m, 2H,
–CH2–), 2.98 (s, 3H, –CH3), 2.77 (s, 3H, –CH3), 2.62–
2.56 (m, 2H, –CH2–). 13C NMR (d, ppm): 173.64 (CO),
155.15 (C), 130.42 (ArH), 128.15 (C), 127.59 (ArH), 119.81
(ArH), 117.43 (ArH), 36.81 (–NCH3), 35.54 (–NCH3),
34.95 (–CH2–), 24.50 (–CH2–). MS (m/z, %): 283 (Mþ, 1),
192 (22), 91 (100).
In conclusion, we describe here the first two total syntheses
of 2-azachrysenes. One route includes new general
syntheses of 2-styrylbenzoic acids and phenanthrenyl-
benzoic acids that are simpler and more efficient than
previously described routes.24,25 Work is now in progress to
obtain a range of 2-azachrysenes for a systematic study of
their chemical and biological properties, including their
antineoplastic activity.
1. Experimental
1.1. General
1.1.3. 3-(2-Benzyloxyphenyl)propionic acid (5c). 11 M
Potassium hydroxide (20 mL) was added to a solution of
propionamide 5b (1.070 g, 3.776 mmol) in ethanol (25 mL)
and the mixture was heated under reflux with the exclusion
of moisture (calcium chloride tube) for 22 h. The solvent
Melting points were determined on a Kofler Thermogerate
apparatus and are uncorrected. Infrared spectra were
recorded on a MIDAC FTIR spectrophotometer. Nuclear

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was removed in vacuo, the aqueous residue was acidified
with 20% hydrochloric acid and the suspension was
extracted with dichloromethane (3£30 mL). The combined
organic extracts were dried, filtered and concentrated in
vacuo to give 3-(2-benzyloxyphenyl)propionic acid (5c)
(968 mg, 93%) as a yellow oil. IR (n, cm21, NaCl): 2916
(COOH), 1711 (CO). 1H NMR (d, ppm): 7.37–7.20 (m, 5H,
5£ArH), 7.15–7.06 (m, 2H, 2£ArH), 6.84–6.78 (m, 2H,
2£ArH), 5.01 (s, 2H, –CH2–), 2.96–2.89 (m, 2H, –CH2–),
2.64–2.58 (m, 2H, –CH2–). 13C NMR (d, ppm): 179.62
(CO), 156.50 (C), 137.15 (C), 130.07 (ArH), 128.78 (C),
128.55 (2£ArH), 127.77 (ArH), 127.66 (ArH), 126.99
(2£ArH), 120.74 (ArH), 111.54 (ArH), 69.70 (–CH2–),
33.95 (–CH2–), 25.87 (–CH2–). MS (m/z, %): 256 (Mþ, 1),
91 (100).
14.50 (–OCH2CH3), 14.08 (–OCH2CH3). MS (m/z, %):
209 (Mþ, 23), 120 (100).
1.1.6. Trifluoromethanesulfonic acid 2-(2-ethoxycar-
bonylamino-ethyl)phenyl ester (6c). To a stirred deoxy-
genated solution of carbamic acid ethyl ester 6b (2.041 g,
9.754 mmol) in dry dichloromethane (30 mL) was added
N-triflimide (3.48 g, 9.754 mmol) and triethyl amine
(1.5 mL, 10.729 mmol). The reaction mixture was stirred
at rt for 2 days, poured into 10% sodium hydroxide (30 mL)
and the resulting suspension was extracted with dichloro-
methane (3£20 mL). The combined organic extracts were
washed with saturated sodium carbonate, dried and
concentrated in vacuo. The residue was purified by column
chromatography (eluant: 1:3 ethyl acetate/hexane) to yield
triflate 6c (2.963 g, 89% yield) as a yellow oil. IR (n, cm21
,
1.1.4. [2-(2-Benzyloxyphenyl)ethyl]carbamic acid ethyl
ester (6a). Diphenylphosphoryl azide (2.40 mL,
11.159 mmol) and triethylamine (1.55 mL, 11.159 mmol)
were added to a solution of phenylpropionic acid 5c (2.6 g,
10.114 mmol) in dry toluene (50 mL) and the mixture was
heated under reflux for 1 h under argon. Copper(II) chloride
(105 mg, 1.014 mmol) and anhydrous ethanol (25 mL) were
added and the mixture was heated under reflux for a further
1 h. The reaction mixture was concentrated in vacuo, the
solid residue was dissolved in diethyl ether and the solution
was successively washed with saturated sodium bicarbonate
(100 mL) and water. The organic extract was dried, filtered
and concentrated in vacuo to give [2-(2-benzyloxyphenyl)-
ethyl]carbamic acid ethyl ester (6a) (2.846 mg, 94% yield)
as colourless oil. IR (n, cm21, NaCl): 3336 (–NH), 1717
(CO). 1H NMR (d, ppm): 7.52–7.37 (m, 5H, 5£ArH), 7.31–
7.21 (m, 2H, 2£ArH), 7.01–6.95 (m, 2H, 2£ArH), 5.14 (s,
2H, –CH2–), 4.9 (bs, 1H, –NH), 4.39 (q, J¼7.1 Hz, 1H,
–OCH2CH3), 4.12 (q, J¼7.1 Hz, 2H, –OCH2CH3), 3.54–
3.46 (m, 2H, –CH2–), 2.96–2.91 (m, 2H, –CH2), 1.45 (t,
J¼7.1 Hz, 1.5H, –OCH2CH3), 1.26 (t, J¼7.1 Hz, 3H,
–OCH2CH3). 13C NMR (d, ppm): 156.60 (CO), 150.55
(C), 136.98 (C), 136.68 (C), 130.68 (ArH), 129.69 (ArH),
128.52 (2£ArH), 127.84 (ArH), 127.73 (ArH), 127.58 (C),
127.18 (2£ArH), 125.21 (ArH), 120.85 (ArH), 120.01
(ArH), 119.94 (ArH), 111.60 (ArH), 69.87 (–CH2–), 65.47
(–OCH2CH3), 60.46 (–OCH2CH3), 41.02 (–CH2–), 30.65
(–CH2–), 29.65 (–CH2–), 16.04 (–OCH2CH3), 14.58
(–OCH2CH3). MS (m/z, %): 299 (Mþ, 1), 91 (100).
NaCl): 3332 (–NH), 1701 (CO). 1H NMR (d, ppm): 7.40–
7.27 (m, 4H, 4£ArH), 4.89 (bs, 1H, –NH), 4.13 (q,
J¼7.1 Hz, 2H, –OCH2CH3), 3.53–3.45 (m, 2H, –CH2–),
2.99–2.94 (m, 2H, –CH2–), 1.25 (t, J¼7.1 Hz, 3H,
–OCH2CH3). MS (m/z, %, FAB): 342 ([Mþ1]þ, 100).
1.1.7. [2-(2-Styrylphenyl)ethyl]carbamic acid ethyl ester
(3). A deoxygenated solution of triflate 6c (1.5 g,
4.395 mmol), styrene (1.01 mL, 8.789 mmol), palladium
acetate (97 mg, 0.439 mmol), triphenylphosphine (23 mg,
0.878 mmol), lithium chloride (560 mg, 13.185 mmol) and
triethylamine (0.674 mL, 4.834 mmol) in dry acetonitrile
was heated under argon in a sealed tube at 1008C for 3 days.
The suspension was then filtered through celite, the filtrate
was washed with water and the organic extracts were dried
with anhydrous sodium sulfate and concentrated in vacuo.
The oily residue, consisting of a 1:23 mixture of compounds
3 and 7 (718 mg, 80% global yield), was used directly in the
next step without further purification. IR (n, cm21, NaCl):
3335 (–NH), 1695 (CO). MS (m/z, %): 295 (Mþ, 6), 206
(100).
Data for compound 3. 1H NMR (d, ppm): 7.90 (d,
J¼16.0 Hz, 1H, –CHvCH–), 7.73–7.53 (m, 3H,
3£ArH), 7.47–7.21 (m, 7H, 7£ArH), 4.88 (bs, 1H, –NH),
4.12 (q, J¼7.0 Hz, 2H, –OCH2CH3), 3.52–3.44 (m, 2H, –
CH2–), 3.08–3.03 (m, 2H, –CH2–), 1.24 (t, J¼7.0 Hz, 3H,
–OCH2CH3). 13C NMR (d, ppm): 156.58 (CO), 137.38 (C),
136.59 (C), 136.47 (C), 130.73 (ArH), 130.12 (ArH), 128.63
(2£ArH), 127.71 (ArH), 127.65 (ArH), 126.96 (ArH),
126.58 (2£ArH), 125.87 (ArH), 125.66 (ArH), 60.66
(–OCH2CH3), 41.80 (–CH2–), 33.53 (–CH2–), 14.52
(–OCH2CH3).
1.1.5. [2-(2-Hydroxyphenyl)ethyl]carbamic acid ethyl
ester (6b). Pd/C (3 g) was added to a deoxygenated solution
of carbamate 6a (2.92 g, 9.754 mmol) in ethyl acetate
(100 mL) and the suspension was stirred at rt under a
hydrogen atmosphere for 2 h. This suspension was filtered
through celite, which was washed with ethyl acetate, and the
filtrate was concentrated in vacuo to give [2-(2-hydroxy-
phenyl)ethyl]carbamic acid ethyl ester (6b) (2.041 g, 100%
yield) as an oil. IR (n, cm21, NaCl): 3334 (–NH, –OH),
1.1.8. (2-Phenanthren-1-yl-ethyl)carbamic acid ethyl
ester (2). Air was bubbled for 10 min through a stirred
solution of the mixture of compounds 3 and 7 (100 mg,
0.338 mmol) in diethyl ether (180 mL) and dichloro-
methane (5 mL). A catalytic amount of iodine (12 mg,
0.03 mmol) was added and the mixture was irradiated for
2 h in a photochemical reactor equipped with a Pyrex
condenser and a Hanovia 450 W medium pressure Hg
vapour lamp. Saturated sodium thiosulfate (100 mL)
was added, the organic layer was dried, filtered and
concentrated in vacuo. The residue was purified by column
chromatography (eluant 3:7 ethyl acetate/hexane) to afford
phenanthrene 2 (77 mg, 80% yield). Mp 86–898C (ethyl
1
1691 (CO). H NMR (d, ppm): 7.50 (bs, 1H, –OH), 7.16–
6.95 (m, 2H, 2£ArH), 6.78–6.70 (m, 2H, 2£ArH), 5.13 (bs,
1H, –NH), 4.03 (q, J¼7.0 Hz, 2H, –OCH2CH3), 3.35–3.28
(m, 2H, –CH2–), 2.78–2.72 (m, 2H, –CH2–), 1.14 (t,
J¼7.0 Hz, 3H, –OCH2CH3). 13C NMR (d, ppm): 157.48
(CO), 154.71 (ArOH), 130.61 (ArH), 127.83 (ArH), 124.93
(C), 120.16 (ArH), 115.58 (ArH), 61.07 (–OCH2CH3),
60.54 (–OCH2CH3), 41.20 (–CH2–), 30.88 (–CH2–),

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M. Carme Pampın et al. / Tetrahedron 59 (2003) 7231–7243
7238
acetate). IR (n, cm21, NaCl): 3342 (–NH), 1701 (CO). H
NMR (d, ppm): 8.75–8.65 (m, 2H, 2£ArH), 8.10
(d, J¼9.1 Hz, 1H, ArH), 7.96–7.93 (m, 1H, ArH), 7.84
(d, J¼9.1 Hz, 1H, ArH), 7.73–7.59 (m, 3H, 3£ArH), 7.48
(d, J¼7.0 Hz, 1H, ArH), 4.96 (bs, 1H, –NH), 4.21
(q, J¼7.0 Hz, 2H, –OCH2CH3), 3.62–3.56 (m, 2H,
–CH2–), 3.41–3.35 (m, 2H, –CH2–), 1.31 (t, J¼7.0 Hz,
3H, –OCH2CH3). 13C NMR (d, ppm): 156.64 (CO), 135.94
(C), 131.41 (C), 130.54 (C), 130.49 (C), 130.16 (C), 128.31
(ArH), 127.68 (ArH), 127.03 (ArH), 126.51 (ArH), 126.44
(ArH), 126.00 (ArH), 122.72 (ArH), 122.08 (ArH), 121.53
(ArH), 60.60 (–OCH2CH3), 41.75 (–CH2–), 33.62
(–CH2–), 14.52 (–OCH2CH3). MS (m/z, %): 293 (Mþ,
25), 204 (100). Anal. calcd for C19H19NO2, C 77.79, H 6.53,
N 4.77; found, C 78.02, H 6.31, N 4.95.
temperature. Dichloromethane (10 mL) was added and the
solution was washed with water (20 mL), saturated
potassium carbonate (20 mL) and water (25 mL). The
organic layer was dried and concentrated in vacuo to give
a residue that was purified by column chromatography
(eluant: dichloromethane/hexane 4:1) to afford compound
11 (123 mg, 45% yield) and compound 12 (146 mg, 35%).
1
Data for compound 11. Mp 233–2358C (methanol). IR (n,
cm21, NaCl): 3437 (–NH), 1658 (CO). 1H NMR (d, ppm):
8.90–8.82 (m, 2H, 2£ArH), 8.18–7.95 (m, 4H, 4£ArH),
7.76–7.67 (m, 2H, 2£ArH), 3.57–3.45 (m, 2H, –CH2–),
3.43–3.38 (m, 2H, –CH2–). 13C NMR (d, ppm): 165.28
(CO), 137.70 (C), 132.40 (C), 132.33 (C), 130.17 (C),
129.00 (ArH), 128.94 (C), 128.14 (ArH), 128.09 (ArH),
127.85 (C), 127.75 (ArH), 125.12 (ArH), 124.08 (ArH),
123.07 (ArH), 121.89 (ArH), 39.37 (–CH2 –), 24.59
(–CH2–). MS (m/z, %): 247 (Mþ, 100). Anal. calcd for
C17H13NO, C 82.57, H 5.30, N 5.66; found, C 82.29, H 5.67,
N 5.39.
1.1.9. (2-Phenanthren-1-yl-ethyl)-carbamic acid ethyl
ester derivative (8a). A solution of compound 2 (48 mg,
0.164 mmol) in POCl3 (3 mL) was refluxed under argon for
2 h and then concentrated in vacuo. The residue was
suspended in saturated sodium bicarbonate (5 mL), the
suspension was extracted with dichloromethane (3£10 mL)
and the combined organic extracts were washed with water
(15 mL), dried and concentrated to dryness to give
Data for compound 12. Mp 189–1908C (methanol). IR (n,
cm21, NaCl): 1703 (CO). 1H NMR (d, ppm, DMSO): 8.94–
8.92 (m, 2H, 2£ArH), 8.21 (d, J¼8.8 Hz, 1H, ArH), 8.10–
8.06 (m, 3H, 3£ArH), 7.79–7.76 (m, 2H, 2£ArH), 4.37 (t,
J¼5.9 Hz, 2H, –CH2–), 3.69 (t, J¼5.9 Hz, 2H, –CH2–).
13C NMR (d, ppm, DMSO): 163.24 (CO), 139.95 (C),
133.92 (C), 132.79 (C), 129.57 (C), 128.99 (ArH), 128.90
(ArH), 128.85 (ArH), 128.66 (C), 127.99 (ArH), 125.42
(ArH), 124.63 (C), 124.37 (ArH), 122.92 (ArH), 122.68
(ArH), 47.12 (–CH2–), 25.49 (–CH2–). MS (m/z, %): 379
(Mþ, 100), 246 (Mþ2Tf, 42).
1
compound 8a (55 mg, 82% yield) as a yellow solid. H
NMR (d, ppm): 8.61–8.53 (m, 2H, 2£ArH), 8.04 (d,
J¼9.2 Hz, 1H, ArH), 7.82–7.72 (m, 2H, 2£Ar-H), 7.56–
7.40 (m, 4H, 4£ArH), 4.23 (q, J¼7.1 Hz, 2H, –OCH2–),
4.11–4.00 (m, 2H, –CH2–), 3.98–3.37 (m, 2H, –CH2–),
1.24 (t, J¼7.1 Hz, 3H, –CH3). 13C NMR (d, ppm): 152.49
(d, J¼6.3 Hz, C–P), 134.00 (C), 131.48 (C), 130.68 (C),
130.52 (C), 130.41 (C), 128.42 (ArH), 127.41 (ArH), 126.68
(ArH), 126.60 (ArH), 126.20 (ArH), 122.83 (ArH), 122.12
(ArH), 64.21 (–OCH2–), 48.39 (–CH2–), 34.13 (–CH2–),
13.89 (–CH3). MS (m/z, %): 411 [(Mþ2)þ, 0.03)]; 409
(Mþ, 0.12), 204 (100).
1.1.12. 1-(2-Trifluoromethanesulfonylaminoethyl)phe-
nanthrene-2-carboxylic acid methyl ester (13). A solution
of compound 12 (100 mg, 0.243 mmol) and dry triethyl-
amine (0.92 mL) in methanol (15 mL) and isopropanol
(2 mL) was stirred in the presence of Pd/C (100 mg) at rt for
24 h and then concentrated in vacuo. The solid residue was
purified by column chromatography (eluant: 15% ethyl
acetate/hexane) and added to give 1-(2-trifluoromethane-
sulfonylaminoethyl)phenanthrene-2-carboxylic acid methyl
1.1.10. 1-(2-Chloroethyl)phenanthrene (10). A dry, oxy-
gen-free mixture of compound 2 (65 mg, 0.222 mmol) and
POCl3 (5 mL) was heated in a sealed tube at 1558C for 28 h
and the mixture was concentrated to dryness. The residue
was dissolved in dichloromethane (10 mL) and the solution
was washed with saturated potassium carbonate, dried and
concentrated in vacuo. The solid residue was subjected to
preparative TLC (eluant: 5% ethyl acetate/hexane) and
compound 10 (14 mg, 27% yield) was isolated as a white
solid. 1H NMR (d, ppm): 8.70–8.63 (m, 2H, 2£ArH),
7.94–7.87 (m, 2H, 2£ArH), 7.79 (d, J¼9.2 Hz, 1H, Ar-H),
7.66–7.47 (m, 4H, 4£ArH), 3.87–3.82 (m, 2H, –CH2–),
3.61–3.55 (m, 2H, –CH2–). 13C NMR (d, ppm): 134.61
(C), 131.52 (C), 130.84 (C), 130.63 (C), 130.00 (C), 128.51
(ArH), 128.11 (ArH), 127.43 (ArH), 126.82 (ArH), 126.70
(ArH), 126.24 (ArH), 122.92 (ArH), 122.23 (ArH), 121.69
(ArH), 44.29 (–CH2–), 36.87 (–CH2–). MS (m/z, %): 242
[(Mþ2)þ, 10]; 240 (Mþ, 32), 191 (100).
ester (13) (85 mg, 81% yield) as a white solid. IR (n, cm21
,
NaCl): 1634 (CvO). 1H NMR (d, ppm): 8.74–8.68 (m, 2H,
2£ArH), 8.06–7.87 (m, 4H, 4£ArH), 7.72–7.67 (m, 2H,
2£Ar-H), 7.03 (bs, 1H, ArH), 4.02 (s, 3H, –CO2CH3),
3.82–3.78 (m, 2H, –CH2–), 3.73–3.67 (m, 2H, –CH2–).
13C NMR (d, ppm): 170.29 (CO), 136.04 (C), 133.24 (C),
132.11 (C), 130.47 (C), 130.03 (C), 128.76 (ArHþC),
128.58 (ArH), 127.93 (ArH), 127.30 (ArH), 126.80 (ArH),
123.45 (ArH), 122.29 (ArH), 121.69 (ArH), 53.12
(–CO2CH3), 44.97 (–CH2–), 28.87 (–CH2–). MS (m/z,
%): 411 (Mþ, 29), 249 (100). High resolution MS calcd for
C19H16F3NO4S, 411.0752; found, 411.0755.
1.1.13. 1,2,3,4-Tetrahydronaphtho[2,1-f]isoquinoline
(14). A mixture of isoquinolinone 11 (70 mg, 0.283 mmol)
and lithium aluminium hydride (54 mg, 0.849 mmol) in
THF (10 mL) was stirred for 15 h at room temperature under
argon. Water (0.054 mL), 10% aq. sodium hydroxide
(0.054 mL) and water (0.016 mL) were successively added
to the reaction mixture and the resulting mixture was
filtered. The solid residue was washed with a mixture of
1.1.11. 3,4-Dihydro-2H-naphtho[2.1-f]isoquinolin-1-one
(11) and 2-trifluoromethanesulfonyl-3,4-dihydro-2H-
naphtho[2.1-f]isoquinolin-1-one (12). Triflic anhydride
(0.0930 mL, 5.529 mmol) was added dropwise over 5 min
to a solution of compound 2 (325 mg, 1.1 mmol) and DMAP
(406 mg, 3.320 mmol) in dry dichloromethane (12 mL) at
08C and the mixture was stirred for 21 h under argon at room

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M. Carme Pampın et al. / Tetrahedron 59 (2003) 7231–7243
7239
95:5 dichloromethane/methanol and the filtrate was con-
centrated in vacuo to give tetrahydroisoquinoline 14
(56 mg, 85% yield) as a yellow solid. Mp 164–1658C
(methanol, sublimation). IR (n, cm21, NaCl): 3429 (–NH).
1H NMR (d, ppm): 8.68 (d, J¼8.0 Hz, 1H, ArH), 8.54 (d,
J¼8.5 Hz, 1H, ArH), 7.92–7.82 (m, 3H, 3£ArH), 7.66–
7.59 (m, 2H, 2£ArH), 7.32 (d, J¼8.5 Hz, 1H, ArH), 4.20 (s,
2H, –CH2–), 3.36–3.31 (m, 2H, –CH2–), 3.26–3.24 (m,
2H, –CH2–). 13C NMR (d, ppm): 131.74 (C), 131.22 (C),
130.23 (C), 130.14 (C), 129.41 (C), 128.72 (C), 128.21
(ArH), 127.06 (ArH), 126.46 (ArH), 126.14 (ArH), 124.82
(ArH), 122.48 (ArH), 120.99 (ArH), 120.65 (ArH), 47.53
(–CH2–), 42.93 (–CH2–), 25.01 (–CH2–). MS (m/z, %):
233 (Mþ, 52), 204 (100). Anal. calcd for C17H15N, C 87.52,
H 6.48, N 6.00; found, C 87.73, H 6.27, N 5.79.
concentrated in vacuo. The resulting oil was purified by
column chromatography (eluant: 3:7 dichloromethane/
hexane) to give compound 16a (762 mg, 84% yield) as a
colourless oil, together with a small amount of compound
19a (45 mg, 5% yield).
Data for compound 16a. IR (n, cm21, NaCl): 1719 (CO). 1H
NMR (d, ppm): 8.02 (d, J¼16.3 Hz, 1H, –CHvCH–), 7.86
(dd, J¼7.8, 1.3 Hz, 1H, ArH), 7.58 (d, J¼7.7 Hz, 1H, ArH),
7.51–7.47 (m, 2H, 2£ArH), 7.35–7.17 (m, 5H, 5£ArH),
6.92 (d, J¼16.3 Hz, 1H, –CHvCH–), 3.78 (s, 3H,
–CO2CH3). 13C NMR (d, ppm): 167.28 (CO), 138.86 (C),
137.05 (C), 131.79 (ArH), 130.99 (ArH), 130.35 (ArH),
128.32 (2£ArH), 128.02 (C), 127.49 (ArH), 127.04 (ArH),
126.73 (ArH), 126.54 (3£ArH), 51.62 (–CO2CH3). MS
(m/z, %): 238 (Mþ, 79), 178 (100). High resolution MS
calcd for C16H14O2, 238.0994; found, 238.0991.
1.1.14. Naphtho[2.1-f]isoquinoline (1a) and 3.4-dihydro-
naphtho[2,1-f]isoquinoline-2-oxide (15). A solution of
tetrahydroisoquinoline 14 (61 mg, 0.261 mmol), iodine
(134 mg, 0.523 mmol) and sodium acetate (28 mg,
0.339 mmol) in anhydrous ethanol (8 mL) was refluxed
for 15 h under argon. Saturated sodium thiosulfate was
added dropwise to the reaction mixture until the iodine
colour had disappeared. The product was extracted with
dichloromethane (3£20 mL) and the combined organic
extracts were washed with saturated sodium chloride, dried,
filtered and concentrated in vacuo. The oily residue was
subjected to preparative TLC (eluant 98:2 dichloromethane/
methanol) and naphthoisoquinoline 1a (6 mg, 10% yield)
and N-oxide 15 (15 mg, 23% yield) were isolated.
1.1.16. Phenanthrene-1-carboxylic acid methyl ester
(17a). Irradiation of stilbene 16a (350 mg, 1.291 mmol)
under the same conditions as for the cyclization of 2
afforded phenanthrene 17a (242 mg, 80% yield) as a yellow
oil. IR (n, cm21, NaCl): 1714 (CO). 1H NMR (d, ppm): 8.92
(d, J¼8.4 Hz, 1H, ArH), 8.78 (d, J¼9.4 Hz, 1H, ArH), 8.70
(d, J¼7.9 Hz, 1H, ArH), 8.22 (d, J¼7.4 Hz, 1H, ArH), 7.93
(d, J¼7.4 Hz, 1H, ArH), 7.87 (d, J¼9.4 Hz, 1H, ArH),
7.70–7.64 (m, 3H, 3£ArH), 4.04 (s, 3H, –CO2CH3). 13C
NMR (d, ppm): 168.25 (CO), 131.42 (C), 130.73 (C),
130.46 (C), 129.83 (C), 129.69 (ArH), 128.62 (ArH), 128.37
(ArH), 127.95 (C), 126.97 (ArH), 126.92 (ArH), 126.75
(ArH), 125.12 (ArH), 123.57 (ArH), 122.26 (ArH), 52.17
(–CO2CH3). MS (m/z, %): 236 (Mþ, 100). High resolution
MS calcd for C16H12O2, 236.0837; found, 236.0832.
Data for compound 1a. Mp 224–2268C (methanol). IR (n,
1
cm21, NaCl): 2925 (ArH), 1728 (–CvN–). H NMR (d,
ppm): 9.37 (bs, 1H, ArH), 8.85–8.78 (m, 3H, 3£ArH), 8.65
(d, J¼9.0 Hz, 1H, ArH), 8.50 (d, J¼5.5 Hz, 1H, ArH),
8.11–8.01 (m, 3H, 3£ArH), 7.80–7.67 (m, 2H, 2£ArH).
13C NMR (d, ppm): 152.09 (ArH), 144.59 (ArH), 134.53
(C), 133.04 (C), 130.62 (C), 130.13 (C), 128.75 (ArH),
128.16 (ArH), 127.39 (ArH), 127.14 (ArH), 126.53 (C),
125.56 (ArH), 123.45 (ArH), 122.77 (ArH), 120.76 (ArH).
MS (m/z, %): 229 (Mþ, 100).
1.1.17. Phenanthren-1-yl-methanol (17b). Lithium
aluminium hydride (273 mg, 7.195 mmol) was added over
3 h to a stirred solution of phenathrene 17a (340 mg,
1.439 mmol) in dry THF (10 mL) at 08C under argon. The
reaction mixture was stirred for 1.5 h at rt. Water (273 mL),
15% sodium hydroxide (273 mL) and water (820 mL) were
consecutively added to the cooled (08C) reaction mixture to
destroy the excess lithium aluminiun hydride. The resulting
precipitate was filtered off and the filtrate was dried, filtered
and concentrated in vacuo to give phenanthrenylmethanol
17b (300 mg, 100% yield) as a white solid. Mp 162–1638C
(methanol/diethyl ether). IR (n, cm21, NaCl): 3296 (–OH).
1H NMR (d, ppm): 8.72–8.66 (m, 2H, 2£ArH), 8.05 (d,
J¼9.2 Hz, 1H, ArH), 7.92–7.88 (m, 1H, ArH), 7.80 (d,
J¼9.2 Hz, 1H, ArH), 7.69–7.59 (m, 4H, 4£ArH), 5.15 (s,
2H, –CH2OH). 13C NMR (d, ppm): 136.77 (C), 131.33 (C),
130.20 (C), 129.48 (2£C), 128.14 (ArH), 126.81 (ArH),
126.31 (ArH), 126.23 (ArH), 125.77 (ArH), 125.74 (ArH),
122.49 (ArH), 122.24 (ArH), 121.86 (ArH), 63.07
(–CH2OH). MS (m/z, %): 208 (Mþ, 69), 179 (100). Anal.
calcd for C15H12O, C 86.51, H 5.81; found, C 86.93, H 6.08.
Data for compound 15. Mp 268–2708C (methanol). IR (n,
1
cm21, NaCl): 1657 (–CvN–). H NMR (d, ppm): 8.71–
8.63 (m, 2H, 2£ArH), 8.52 (bs, 1H, –CHvN–), 7.96
(d, J¼9.2 Hz, 1H, ArH), 7.92–7.89 (m, 1H, ArH), 7.82
(d, J¼9.2 Hz, 1H, ArH), 7.72–7.60 (m, 2H, 2£ArH), 7.57
(d, J¼8.4 Hz, 1H, ArH), 3.95 (t, J¼7.4 Hz, 2H, –CH2–),
3.19 (t, J¼7.4 Hz, 2H, –CH2–). 13C NMR (d, ppm): 160.81
(–CHvN–), 133.69 (C), 132.32 (C), 132.21 (C), 130.38
(C), 128.93 (C), 128.64 (ArH), 127.75 (ArH), 127.31 (ArH),
127.01 (ArH), 125.20 (ArH), 123.18 (ArH), 121.57 (ArH),
121.54 (ArH), 47.44 (–CH2–), 21.36 (–CH2–). MS (m/z,
%): 247 (Mþ, 63), 189 (100).
1.1.15. 2-Styrylbenzoic acid methyl ester (16a). A
deoxygenated mixture of methyl 2-iodobenzoate (18a)
(1 g, 3.816 mmol), styrene (0.525 mL, 4.579 mmol),
palladium acetate (65 mg, 0.286 mmol), triphenylphosphine
(150 mg, 0.572) and triethylamine (0.640 mL, 4.579 mmol)
in dry acetonitrile (20 mL) was heated in a sealed tube at
808C for 21 h. The suspension was filtered through celite,
the filtrate was washed with water (5 mL), dried and
1.1.18. Phenanthrene-1-carbaldehyde (17c). Mangane-
se(IV) oxide (1.064 g, 12.140 mmol) was added to a
solution of alcohol 17b (255 mg, 12.240 mmol) in chloro-
form (30 mL) and the stirred mixture was heated at 358C for
24 h. The suspension was filtered through celite, which was
washed with chloroform, and the filtrate was washed with
water (5 mL), dried and concentrated in vacuo to give

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M. Carme Pampın et al. / Tetrahedron 59 (2003) 7231–7243
7240
aldehyde 17c (230 mg, 91% yield) as a white solid. Mp 97–
998C (methanol). IR (n, cm21, NaCl): 1682 (CO). 1H NMR
(d, ppm): 10.36 (s, –CHO), 8.99 (d, J¼9.3 Hz, 1H, ArH),
8.72 (d, J¼8.3 Hz, 1H, ArH), 8.50–8.46 (m, 1H, ArH), 7.88
(dd, J¼7.2, 1.1 Hz, 1H, ArH), 7.82–7.77 (m, 2H, 2£ArH),
7.61–7.54 (m, 3H, 3£ArH). 13C NMR (d, ppm): 193.32
(–CHO), 134.87 (ArH), 131.52 (C), 131.30 (C), 130.54 (C),
130.08 (C), 129.96 (ArH), 129.49 (C), 128.71 (ArH), 128.42
(ArH), 127.07 (ArH), 126.96 (ArH), 125.39 (ArH), 122.60
(ArH), 121.94 (ArH). MS (m/z, %): 206 (Mþ, 92), 178
(100). Anal. calcd for C15H10O, C 87.36, H 4.89; found, C
86.97, H 5.08.
solid. Mp 254–2558C (hexane). IR (n, cm21, NaCl): 3014
(–NH), 1650 (CO). H NMR (d,ppm): 8.90–8.83 (m, 2H,
1
2£ArH), 8.53 (d, J¼9.2 Hz, 1H, ArH), 8.36 (d, J¼8.9 Hz,
1H, ArH), 8.06–7.99 (m, 2H, 2£ArH), 7.71–7.68 (m, 2H,
2£ArH), 7.46–7.41 (m, 2H, 2£ArH). 13C NMR (d, ppm):
162.35 (CO), 136.76 (C), 132.81 (C), 132.34 (C), 130.82
(ArH), 130.05 (C), 129.03 (ArH), 128.29 (ArH), 128.19
(ArH), 127.81 (ArH), 126.95 (C), 124.67 (ArH), 124.58 (C),
124.29 (ArH), 122.64 (ArH), 121.82 (ArH), 101.19 (ArH).
MS (m/z, %): 245 (Mþ, 100). Anal. calcd for C17H11NO, C
83.25, H 4.52, N 5.71; found, C 83.53, H 4.77.
1.1.22. 1-Chloronaphtho[2,1-f]isoquinoline (1b). A stirred
22a
1.1.19. 3-Phenanthren-1-yl-acrylic acid (20a). A solution
of aldehyde 17c (220 mg, 1.066 mmol), dry pyridine
(7 mL), malonic acid (255 mg, 2.45 mmol) and two drops
of piperidine was heated for 2 h at 808C under argon. The
reaction mixture was poured into a 1:1 mixture of 10%
hydrochloric acid and ice. The resulting precipitate was
filtered off and washed with water (3£25 mL) to give acid
20a (1.007 mg, 94% yield) as a white solid. Mp 225–2288C
(methanol). IR (n, cm21, NaCl): 3430 (–COOH), 1723
solution
of
naphthoisoquinolinone
(45 mg,
0.183 mmol) and POCl3 (2 mL) was heated under reflux
for 3 h, allowed to cool and poured into ice/water (10 mL).
The mixture was neutralized with saturated potassium
carbonate solution and the product was extracted with
dichloromethane (3£10 mL). The combined organic
extracts were washed with water, dried, filtered and
concentrated in vacuo to give chloroisoquinoline 1b
(41 mg, 85% yield) as a yellow solid. Mp 165–1678C
(MeOH, sublimation). IR (n, cm21, NaCl): 1568 (–CvN–).
1H NMR (d, ppm): 8.83 (d, J¼9.4 Hz, 1H, ArH), 8.75 (d,
J¼7.9 Hz, 1H, ArH), 8.53 (d, J¼9.1 Hz, 1H, ArH), 8.47–
8.38 (m, 3H, 3£ArH), 8.06–8.00 (m, 2H, 2£ArH), 7.77–
7.72 (m, 2H, 2£ArH). 13C NMR (d, ppm): 151.66 (C-Cl),
142.55 (ArH), 136.69 (C), 132.93 (C), 130.71 (C), 129.69
(C), 128.61 (2£ArH), 127.72 (ArH), 127.28 (ArH), 126.32
(C), 125.15 (C), 123.92 (ArH), 123.52 (ArH), 123.35 (ArH),
120.64 (ArH), 116.43 (ArH). MS (m/z, %): 265 (Mþþ2, 35),
263 (Mþ, 100). Anal. calcd for C17H10ClN, C 77.42, H 3.82,
Cl 13.44, N 5.31; found, C 77.12, H 4.11, Cl 13.78, N 5.13.
1
(CO). H NMR (d, ppm): 12.65 (bs, –OH), 8.97–8.85 (m,
2H, 2£ArH), 8.49 (d, J¼15.7 Hz, 1H, –CHvCH–), 8.16
(d, J¼9.2 Hz, 1H, ArH), 8.06–8.02 (m, 2H, 2£ArH), 7.97
(d, J¼9.2 Hz, 1H, ArH), 7.77–7.66 (m, 3H, 3£ArH), 6.64
(d, J¼15.7 Hz, 1H, –CHvCH–). 13C NMR (d, ppm):
167.99 (CO), 141.20 (–CHvCH–), 132.24 (C), 131.73 (C),
130.74 (C), 130.32 (C), 129.95 (C), 129.04 (ArH), 128.58
(ArH), 127.87 (ArH), 127.77 (ArH), 127.17 (ArH), 126.39
(ArH), 125.62 (ArH), 123.78 (ArH), 122.87 (ArH), 122.04
(ArH). MS (m/z, %): 248 (Mþ, 24), 203 (100). Anal. calcd
for C17H12O2, C 82.24, H 4.87; found, C 81.89, H 5.11.
1.1.20. 3-Phenanthren-1-yl-acrylic acid acyl azide (20b).
Triethylamine (190 mL, 1.360 mmol) and a solution of ethyl
chloroformate (62 mL, 0.679 mmol) in dry acetone (10 mL)
were added to a suspension of acid 20a (150 mg,
0.604 mmol) in dry acetone (10 mL) and the mixture was
stirred for 45 min. A solution of sodium azide (74 mg,
1.133 mmol) in water (4 mL) was added dropwise and the
mixture was stirred at 08C for 30 min and then poured into
ice/water. The resulting precipitate was filtered off to give
acylazide 20b (160 mg, 97% yield) as a yellow solid, which
was used without purification. IR (n, cm21, NaCl): 2138
1.1.23. Naphtho[2,1-f]isoquinoline (1a). A stirred suspen-
sion of 1-chloroisoquinoline 1b (35 mg, 0.133 mmol) and
zinc (113 mg, 1.725 mmol) in acetic acid (3 mL) was
refluxed for 2 h under argon and then allowed to cool down.
10% Sodium hydroxide was added to neutralize the mixture
and the product was extracted with chloroform (3£10 mL).
The combined organic extracts were washed with water,
dried, filtered and concentrated in vacuo to give naphthoi-
soquinoline 1a (27 mg, 90% yield) as a yellow solid. Mp
224–2268C (methanol). IR (n, cm21, NaCl): 2925 (ArH),
1
1728 (–CvN–). H NMR (d, ppm): 9.37 (bs, 1H, ArH),
1
(N3), 1679 (CO). H NMR (d, ppm): 8.76–8.60 (m, 3H,
8.85–8.78 (m, 3H, 3£ArH), 8.65 (d, J¼9.0 Hz, 1H, ArH),
8.50 (d, J¼5.5 Hz, 1H, ArH), 8.11–8.01 (m, 3H, 3£ArH),
7.80–7.67 (m, 2H, 2£ArH). 13C NMR (d, ppm): 152.09
(ArH), 144.59 (ArH), 134.53 (C), 133.04 (C), 130.62 (C),
130.13 (C), 128.75 (ArH), 128.16 (ArH), 127.39 (ArH),
127.14 (ArH), 126.53 (C), 125.56 (ArH), 123.45 (ArH),
122.77 (ArH), 120.76 (ArH). MS (m/z, %): 229 (Mþ, 100).
Anal. calcd for C17H11N, C 89.06, H 4.84, N 6.11; found, C
88.83, H 4.61, N 5.99.
3£ArH), 8.04 (d, J¼9.2 Hz, 1H, ArH), 7.90–7.57 (m, 6H,
6£ArH), 6.49 (d, J¼15.6 Hz, 1H, –CHvCH–). 13C NMR
(d, ppm): 171.93 (CO), 143.93 (–CHvCH–), 131.62 (C),
131.46 (C), 130.79 (C), 130.27 (C), 130.17 (C), 128.62
(ArH), 128.36 (ArH), 127.12 (ArH), 127.09 (ArH), 126.10
(ArH), 125.78 (ArH), 125.60 (ArH), 122.84 (ArH), 121.65
(ArH), 121.37 (ArH). MS (m/z, %): 273 (Mþ, 20), 203
(100).
1.1.21. 2H-Naphtho[2,1-f]isoquinolin-1-one (22a). A sol-
ution of acylazide 20b (155 mg, 0.567 mmol) in diphenyl
ether (10 mL) was added slowly under argon to a solution of
tributylamine (1.62 mL) in diphenyl ether (10 mL) and the
mixture was heated under reflux for 1 h, allowed to cool and
then diluted with hexane (20 mL). The resulting yellow
precipitate was filtered off and washed with hexane (5 mL)
to give isoquinolinone 22a (108 mg, 78% yield) as a white
1.1.24. 2-Iodo-4,5-dimethoxybenzoic acid methyl ester
(18c). Trifluoromethanesulfonic acid (2.364 mL) was added
over 5 min to a stirred solution of methyl benzoate 18b
(2.18 g, 11.131 mmol) and IPy2BF4 (4.97 g, 13.357 mmol)
in dichloromethane (15 mL) and the stirring was continued
for 30 min. The reaction mixture was then poured into
saturated sodium thiosulfate (30 mL), the resulting suspen-
sion was extracted with dichloromethane (3£15 mL), the

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M. Carme Pampın et al. / Tetrahedron 59 (2003) 7231–7243
7241
combined organic extracts were washed with water (5 mL),
dried, filtered and concentrated in vacuo. The solid residue
was purified by column chromatogaphy (eluant: 3:2
dichloromethane/hexane) to give methyl iodobenzoate 18c
(2.653 g, 74% yield) as a white solid. Mp 105–1078C
1.1.28. 3,4-Dimethoxyphenanthrene-1-carbaldehyde
(17f). Compound 17f was prepared in 85% yield from
phenanthrenylmethanol 17e (186 mg, 0.559 mmol) and
activated manganese dioxide (486 mg, 5.50 mmol) follow-
ing the same procedure as for the oxidation of compound
17b. Mp 85–878C (ethyl acetate). IR (n, cm21, NaCl): 1680
(CO). 1H NMR (d, ppm): 10.53 (s, 1H, –CHO), 9.60–9.56
(m, 1H, ArH), 8.80 (d, J¼9.3 Hz, 1H, ArH), 7.84–7.81 (m,
1H, ArH), 7.75 (s, 1H, ArH), 7.69 (d, J¼9.3 Hz, 1H, ArH),
7.65–7.56 (m, 2H, 2£ArH), 4.02 (s, 3H, –OCH3), 3.98 (s,
3H, –OCH3). 13C NMR (d, ppm): 191.05 (CO), 152.47 (C),
150.62 (C), 132.49 (C), 129.13 (C), 128.71 (ArH), 128.32
(C), 128.27 (ArH), 127.76 (ArH), 127.07 (ArH), 127.02
(ArH þ C), 125.00 (C), 120.51 (ArH), 117.68 (ArH), 59.94
(–OCH3), 56.34 (–OCH3). MS (m/z, %): 266 (Mþ, 100).
Anal. calcd for C17H14O3, C 76.68, H 5.30; found, C 76.39,
H 5.53.
1
(methanol). IR (n, cm21, NaCl): 1708 (CO). H NMR (d,
ppm): 7.39 (s, 1H, ArH), 7.34 (s, 1H, ArH), 3.89 (s, 3H,
–OCH3), 3.88 (s, 3H, –OCH3). 13C NMR (d, ppm): 165.05
(CO), 151.23 (ArOMe), 147.92 (ArOMe), 125.15 (C),
123.02 (ArH), 113.15 (ArH), 84.21 (C–I), 55.72 (–OCH3),
55.44 (–OCH3), 51.73 (–CO2CH3). MS (m/z, %): 322 (Mþ,
100).
1.1.25. 4,5-Dimethoxy-2-styrylbenzoic acid methyl ester
(16b). Compound 16b was prepared in 68% yield from
compound 18c (1 g, 3.104 mmol) and styrene (0.392 mL,
3.415 mmol) following the same procedure as for com-
pound 16a. Mp 86–888C (methanol). IR (n, cm21, NaCl):
1
1708 (CO). H NMR (d, ppm): 8.07 (d, J¼16.2 Hz, 1H,
1.1.29. 3-(3,4-Dimethoxyphenanthren-1-yl)acrylic acid
(20c). Compound 17f (255 mg, 0.957 mmol) was reacted
with malonic acid (460 mg, 4.404 mmol) following the
same conditions as for compound 17c to give compound 20c
–CHvCH–), 7.54–7.51 (m, 2H, 2£ArH), 7.44 (s, 1H,
ArH), 7.36–7.22 (m, 3H, 3£ArH), 7.10 (s, 1H, ArH), 6.89
(d, J¼16.2 Hz, 1H, –CHvCH–), 3.94 (s, 3H, –OCH3),
3.89 (s, 3H, –OCH3), 3.87 (s, 3H, –CO2CH3). 13C NMR (d,
ppm): 166.94 (CO), 151.76 (C), 147.63 (C), 137.27 (C),
133.69 (C), 129.69 (ArH), 128.39 (2£ArH), 127.41 (ArH),
127.38 (ArH), 126.45 (2£ArH), 120.14 (C), 112.75 (ArH),
108.67 (ArH), 55.71 (–OCH3), 55.68 (–OCH3), 51.69
(–CO2CH3). MS (m/z, %): 298 (Mþ, 100). Anal. calcd for
C18H18O4, C 72.47, H 6.08; found, C 72.13, H 5.97.
in 93% yield. Mp 220–2238C (methanol). IR (n, cm21
,
NaCl): 3436 (–COOH), 1693 (CO). 1H NMR (d, ppm): 9.62
(d, J¼7.8 Hz, 1H, ArH), 8.58 (d, J¼15.7 Hz, 1H,
–CHvCH–), 7.99 (d, J¼9.1 Hz, 1H, ArH), 7.87–7.83
(m, 1H, ArH), 7.68–7.60 (m, 3H, 3£ArH), 7.57 (s, 1H,
ArH), 6.48 (d, J¼15.7 Hz, 1H, –CHvCH–), 4.06 (s, 3H,
–OCH3), 3.96 (s, 3H, –OCH3). 13C NMR (d, ppm): 168.93
(CO), 150.78 (C), 148.91 (C), 142.68 (ArH), 132.57 (C),
129.34 (C), 128.12 (ArH), 128.07 (C), 127.75 (ArH), 126.74
(2£ArH), 126.59 (ArH), 124.87 (C), 121.46 (ArH), 120.44
(ArH), 111.58 (ArH), 59.73 (–OCH3), 56.27 (–OCH3). MS
(m/z, %): 308 (Mþ, 100). Anal. calcd for C19H16O4, C 74.01,
H 5.23; found, C 73.76, H 5.47.
1.1.26. 3,4-Dimethoxyphenanthrene-1-carboxylic acid
methyl ester (17d). Irradiation of stilbene 16b (320 mg,
0.993 mmol) under the same conditions as for the cycliza-
tion of 16a afforded the corresponding phenanthrene-
carboxylic acid 17d in 80% yield. Mp 108–1118C (ethyl
acetate). IR (n, cm21, NaCl): 1712 (CO). 1H NMR (d, ppm):
9.66–9.62 (m, 1H, ArH), 8.65 (d, J¼9.3 Hz, 1H, ArH), 7.92
(s, 1H, ArH), 7.88–7.84 (m, 1H, ArH), 7.69 (d, J¼9.3 Hz,
1H, ArH), 7.65–7.60 (m, 2H, 2£ArH), 4.06 (s, 3H,
–OCH3), 4.02 (s, 3H, –OCH3), 3.97 (s, 3H, –CO2CH3).
13C NMR (d, ppm): 168.10 (CO), 150.69 (C), 150.07 (C),
132.59 (C), 129.33 (C), 128.18 (ArH), 127.96 (ArH), 127.67
(C), 127.53 (ArH), 126.97 (ArH), 126.78 (ArH), 125.34 (C),
123.94 (C), 123.42 (ArH), 116.01 (ArH), 59.93 (–OCH3),
56.54 (–OCH3), 52.38 (–CO2CH3). MS (m/z, %): 296 (Mþ,
100). Anal. calcd for C18H16O4, C 72.96, H 5.44; found, C
73.24, H 5.29.
1.1.30. 3-(3,4-Dimethoxyphenanthren-1-yl)acrylic acid
acyl azide (20d). Compound 20c (150 mg, 0486 mmol)
was transformed into acyl azide 20d (145 mg, 90%), a
yellow solid, following the procedure used to obtain 20b.
Mp 130–1318C (water). IR (n, cm21, NaCl): 2251 (N3),
1636 (CO). 1H NMR (d, ppm): 9.62 (d, J¼7.8 Hz, 1H, ArH),
8.59 (d, J¼15.5 Hz, 1H, –CHvCH–), 7.93 (d, J¼9.2 Hz,
1H, ArH), 7.86–7.82 (m, 1H, ArH), 7.67–7.60 (m, 3H,
3£ArH), 7.49 (s, 1H, ArH), 6.43 (d, J¼15.5 Hz, 1H,
–CHvCH–), 4.03 (s, 3H, –OCH3), 3.96 (s, 3H, –OCH3).
13C NMR (d, ppm): 171.83 (CO), 150.97 (C), 150.06 (C),
143.85 (ArH), 132.66 (C), 129.51 (C), 128.32 (ArH), 128.00
(ArH), 127.16 (ArHþC), 127.02 (2£ArH), 125.20 (C),
121.23 (ArH), 120.77 (ArH), 111.71 (ArH), 59.96
(–OCH3), 56.47 (–OCH3). MS (m/z, %): 333 (Mþ, 10),
305 (100).
1.1.27. (3,4-Dimethoxyphenanthren-1-yl)methanol (17e).
Reduction of phenanthrenecarboxylic acid ester 17d (180 mg,
0.607 mmol) with lithium aluminiun hydride (115 mg,
3.037 mmol) under the same conditions as for 17a provided
the expected phenanthrenylmethanol 17e as an oil in 95%
yield. IR (n, cm21, NaCl): 3392 (–OH). 1H NMR (d, ppm):
9.57 (d, J¼8.5 Hz, 1H, ArH), 7.72–7.46 (m, 4H, 4£ArH),
7.39 (d, J¼9.1 Hz, 1H, ArH), 7.14 (s, 1H, ArH), 4.87 (s,
2H, –CH2OH), 3.78 (s, 3H, –OCH3), 3.66 (s, 3H, –OCH3).
13CNMR(d, ppm):150.27(C),146.03(C),132.99(C),132.48
(C), 129.49 (C), 128.02 (ArH), 127.55 (ArH), 126.31
(2£ArH), 125.56 (ArH), 125.16 (C), 124.54 (C), 121.62
(ArH), 112.53 (ArH), 62.98 (–CH2–), 59.46 (–OCH3), 55.85
(–OCH3). MS (m/z, %): 268 (Mþ, 100). High resolution
MS calcd for C17H16O3, 268.1099; found, 268.1094.
1.1.31. 11,12-Dimethoxy-2H-naphtho[2,1-f]isoquinolin-
1-one (22b). Compound 22b was prepared in 84% yield
from acyl azide 20d (100 mg, 0.300 mmol) following the
same procedure as for 22a. Mp 263–2658C (methanol). IR
1
(n, cm21, NaCl): 3157 (–NH), 1645 (CO). H NMR (d,
ppm): 11.37 (bs, 1H, –NH), 9.63–9.61 (m, 1H, ArH), 8.53
(d, J¼9.3 Hz, 1H, ArH), 8.08–8.06 (m, 1H, ArH), 7.97 (d,
J¼9.3 Hz, 1H, ArH), 7.75–7.72 (m, 2H, 2£ArH), 7.41 (d,
J¼7.5 Hz, 1H, ArH), 7.34–7.33 (m, 1H, ArH), 3.95 (s, 3H,
–OCH3), 3.92 (s, 3H, –OCH3). 13C NMR (d, ppm): 159.54

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M. Carme Pampın et al. / Tetrahedron 59 (2003) 7231–7243
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Compounds; Hutzinger, O., Neilson, A., Eds.; Springer:
Heidelberg, 1997; Vol. 3, pp 1–54 Chapter 1.
(CO), 151.11 (C), 149.56 (C), 134.59 (C), 133.15 (C),
129.49 (ArH), 128.45 (C), 128.34 (ArH), 127.69 (ArH),
127.59 (ArH), 127.25 (ArH), 127.04 (ArH), 126.93 (C),
124.76 (C), 122.15 (ArH), 119.58 (C), 100.02 (ArH), 61.53
(–OCH3), 60.21 (–OCH3). MS (m/z, %): 305 (Mþ, 100).
Anal. calcd for C19H15NO3, C 74.74, H 4.95, N 4.59; found,
C 75.01, H 5.14, N 4.32.
3. Wu Harvey, R. G. Polycyclic Aromatic Hydrocarbons:
Chemistry and Carcinogenesis; Wiley-VCH: New York,
1997.
4. (a) Denisenko, M. F.; Pao, A.; Tang, M.; Pfeifer, G. P. Science
1996, 274, 430. (b) Pfeifer, G. P.; Denissenko, M. F. Environ.
Mol. Carcin. 1998, 31, 197. (c) Denissenko, M. F.; Cheng,
J. X.; Tang, M.; Pfeifer, G. P. Proc. Natl Acad. Sci. USA 1997,
94, 3893. (d) Cheng, J. X.; Zheng, Y.; West, M.; Tang, M.
Cancer Res. 1998, 58, 2170.
1.1.32. 1-Chloro-11,12-dimethoxynaphtho[2,1-f]iso-
quinoline (1d). Treatment of naphthoisoquinolinone 22b
(10 mg, 0.0327 mmol) with POCl3 (2 mL) under the same
conditions as for preparation of 1b gave chloronaphthoiso-
quinoline 1d (10 mg, 95% yield) as a yellow solid. Mp 177–
1798C (methanol). IR (n, cm21, NaCl): 1552 (–CvN–). 1H
NMR (d, ppm): 9.75–9.72 (m, 1H, ArH), 8.59–8.45 (m,
3H, 3£ArH), 8.03–7.98 (m, 2H, 2£ArH), 7.75–7.72 (m,
2H, 2£ArH), 4.19 (s, 3H, –OCH3), 4.03 (s, 3H, –OCH3).
13C NMR (d, ppm): 151.94 (C), 147.54 (C), 146.75 (C),
142.14 (ArH), 135.30 (C), 133.78 (C), 129.14 (C), 128.44
(2£ArH), 128.22 (ArH), 127.69 (ArH), 127.54 (C), 127.26
(ArH), 125.69 (C), 121.68 (C), 120.81 (ArH), 116.14
(ArH), 61.78 (–OCH3), 60.18 (–OCH3). MS (m/z, %):
323 (Mþ, 100). Anal. calcd for C19H14ClNO2, C 70.48, H
4.36, Cl 10.95, N 4.33; found, C 72.81, H 4.09, Cl 11.17, N
4.28.
5. Cheng, C. C. Structural Aspects of Antineoplastic Agents—A
New Approach. Progress in Medicinal Chemistry; Ellis, G. P.,
West, G. B., Eds.; Elsevier (Biomedical Division):
Amsterdam, 1988; Vol. 25, pp 35–83.
6. Cheng, C. C.; Engle, R. R.; Hudson, J. R.; Ing, R. B.; Wood,
H. B.; Yan, S. J.; Zee-Cheng, R. K. Y. J. Pharm. Sci. 1977, 66,
1781.
7. (a) Zee-Cheng, K. Y.; Cheng, C. C. J. Heterocycl. Chem.
1973, 10, 867. (b) Zee-Cheng, K. Y.; Cheng, C. C. J. Med.
Chem. 1975, 18, 66. (c) Stermitz, F. R.; Gillespie, L. G.;
Amoros, L. G.; Romero, R.; Stermitz, T. A.; Larson, K. A.;
Earl, S.; Ogg, J. E. J. Med. Chem. 1975, 18, 708. (d) Huang,
A.-X.; Li, Z.-H. Acta Chim. Sin. 1980, 38, 535. (e) Fang, S.-D.;
Wang, L.-K.; Hetch, S. M. J. Org. Chem. 1993, 58, 5025.
(f) Taira, Z.; Matsumoto, M.; Ishida, S.; Icikawa, T.; Sakiya,
Y. Chem. Pharm. Bull. 1994, 42, 1556.
1.1.33. 11,12-Dimethoxynaphtho[2,1-f]isoquinoline (1c).
Following the same procedure as for reduction of 1b,
reaction of chloronaphthoquinone 1d (9 mg, 0.028 mmol)
with zinc (24 mg, 0.361 mmol) provided naphthoisoquino-
line 1c (7.6 mg, 94%) as a yellow solid. Mp 152–1548C
(methanol). IR (n, cm21, NaCl): 2927 (ArH), 1446
(–CvN–). 1H NMR (d, ppm): 9.77 (d, J¼8.3 Hz, 1H,
ArH), 9.69 (bs, 1H, ArH), 8.77 (bs, 1H, ArH), 8.63 (d,
J¼9.0 Hz, 1H, ArH), 8.46–8.45 (m, 1H, ArH), 8.01–7.98
(m, 2H, 2£ArH), 7.74–7.68 (m, 2H, 2£ArH), 4.25 (s, 3H,
–OCH3), 4.04 (s, 3H, –OCH3). 13C NMR (d, ppm): 149.19
(C), 147.02 (C), 146.87 (ArH), 144.04 (ArH), 133.89 (C),
132.12 (C), 129.85 (C), 128.57 (ArH), 128.17 (ArH), 127.91
(ArH), 127.52 (C), 127.29 (ArH), 127.03 (ArH), 125.78 (C),
120.61 (ArH), 116.17 (ArH), 61.80 (–OCH3), 60.31
(–OCH3). MS (m/z, %): 289 (Mþ, 2), 58 (100). Anal.
calcd for C19H15NO2, C 78.87, H 5.23, N 4.84; found, C
78.53, H 5.41, N 4.96.
8. (a) Whaley, W. M.; Meadow, M. J. Org. Chem. 1954, 19, 661.
(b) Galiazzo, G.; Bortolus, P.; Masetti, F. J. Chem. Soc.,
Perkin Trans. 2 1975, 1712. (c) Masetti, F.; Bartocci, G.;
Mazzucato, U. Gazz. Chim. Ital. 1982, 112, 255. (d) Tanga,
M. J.; Almquist, R. G.; Smith, T. H. J. Heterocycl. Chem.
1985, 22, 1597.
9. Chen, H.-Y.; Preston, M. R. Environ. Sci. Technol. 1998, 32,
577.
10. Sthephan, E.; Aubouet, R.; Pourcelot, G.; Gresson, P.
Tetrahedron: Asymmetry 1994, 5, 41.
11. (a) Ziegler, C. B.; Heck, R. F. J. Org. Chem. 1978, 46, 4416.
(b) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
12. (a) Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76,
509. (b) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30,
1. (c) Liu, L.; Yang, B.; Katz, T. J.; Poindexter, M. K. J. Org.
Chem. 1991, 56, 3769.
13. (a) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6,
74. (b) Nagubandi, S.; Fodor, G. Heterocycles 1981, 15, 165.
14. Tsuda, Y.; Isobe, K.; Taba, J. Heterocycles 1976, 5, 157.
15. Nabugandi, S.; Fodor, G. Tetrahedron 1980, 36, 1279.
16. Nabugandi, S.; Fodor, G. Heterocycles 1981, 15, 165.
17. Banwell, M. G.; Bisset, B. D.; Busato, S.; Cowden, C. J.;
Hockless, D. C. R.; Holman, J. W.; Read, R. W.; Wu, A. W.
J. Chem Soc., Chem. Commun. 1995, 24, 2551.
Acknowledgements
We thank the Spanish Ministry of Science and Technology
and the Xunta de Galicia for financial support.
18. Crystal structure determination of 13. A suitable crystal of
compound
13
(prism,
colourless,
dimensions
0.45£0.30£0.20 mm3) was used for the structure determi-
nation. X-Ray data were collected using a Bruker SMART
CCD area detector single-crystal diffractometer with graphite
References
1. A preliminary communication concerning the work described
´ ´
here has recently been published. See: Pampın, C.; Estevez,
˚
monochromatized Mo Ka radiation (l¼0.71073 A) by the
´
J. C.; Castedo, L.; Estevez, R. J. Tetrahedron Lett. 2001, 42,
2307.
phi–omega scan method at 298(2) K. A total of 1271 frames
of intensity data were collected for each compound. The first
50 frames were recollected at the end of data collection to
monitor for decay. The crystal used for the diffraction study
showed slight decomposition during data collection (0.1%).
The integration process yield a total of 10600 reflections, of
2. (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons:
Chemistry and Carcinogenesis; Cambridge University:
Cambridge, 1991. (b) Harvey, R. G. In The Handbook of
Environmental Chemistry. Part I: PAHs and Related

´
M. Carme Pampın et al. / Tetrahedron 59 (2003) 7231–7243
7243
which 36756 [R(int)¼0.0200] were independent. Absorption
corrections were applied using the SADABS (a) program
(maximum and minimum transmission coefficients, 0.9542
and 0.9009). The structure was solved using the Bruker
SHELXTL-PC (b) software by direct methods and refined by
full-matrix least-squares methods on F 2. Hydrogen atoms
were located on residual density maps and refined in the riding
mode. For 13 convergence was reached at a final R1¼0.0370
[for I.2s(I)], wR2¼0.01066 [for all data], 337 parameters,
with allowance for the thermal anisotropy for all non-
hydrogen atoms. The weighting scheme employed was
iodobenzene to o-vinylbenzoic acid has recently been carried
out by Kim, B. M.; Park, J. K. Bull. Kor. Chem. Soc. 1999, 20,
744. As far as we know, other o-styrylbenzoic acids have not
been obtained by similar procedures: see Refs. 23,24.
21. Karmakar, A. C.; Kar, G. K.; Ray, J. K. J. Chem. Soc., Perkin
Trans. 1 1991, 1997.
22. (a) Rubin, M. B.; Welner, S. J. Org. Chem. 1980, 45, 1847.
(b) Koszyk, F. J.; Lenz, G. R. J. Chem. Soc., Perkin Trans. 1
1984, 1273.
´
23. Ezquerra, J.; Pechegal, C.; Lamas, C.; Barluenga, J.; Perez,
´ ´ ´
M.; Garcıa-Martın, M. A.; Gonzalez, J. M. J. Org. Chem.
w¼[s 2(Fo2þ(0.0812P)2þ(0.4066P)] and P¼(lFol þ2lFcl )
and the goodness-of-fit on F 2 was 1.031 for all observed
reflections. Crystallographic data (excluding structure factors)
for the structure reported in this paper have been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication no. CCDC- 196493. Copies of the data
can be obtained free of charge on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44-1223-336-
033; e-mail: deposit@ccdc.cam.ac.uk). Crystallographic data
for 13: C19H16NO4F3S, M¼411.39. Monoclinic, space group
2
2 /3
1996, 61, 5804.
24. For previous syntheses of o-styrylbenzoic acids, see Ref. 1.
See also: (a) Noda, M. Chem. Pharm. Bull. 1998, 46, 1157.
(b) Zehnter, R.; Gerlach, H. Tetrahedron: Asymmetry 1995, 6,
2779. (c) Yoshikawa, M.; Harada, E.; Yagi, N.; Okuno, Y.;
Muraoka, O.; Aoyama, H.; Murakami, N. Chem. Pharm. Bull.
1994, 42, 721. (d) Mal, D.; Majumdar, G.; Pal, R. J. Chem.
Soc., Perkin Trans. 1 1994, 1115. (e) Bowden, K.; Ghadir, K.
J. Chem. Soc., Perkin Trans. 2 1990, 1333. (f) Lazer, E. S.;
Wong, H. C.; Wegner, C. D.; Graham, A. G.; Farina, P. R.
J. Med. Chem. 1990, 33, 1892. (g) Eicher, T.; Tiefensee, K.;
Pick, R. Synthesis 1988, 525. (h) Bellinger, G. C. A.;
Campbell, W. E.; Giles, R. G. F.; Tobias, J. D. J. Chem.
Soc., Perkin Trans. 1 1982, 2819. (i) Meyers, A. I.; Gabel, R.;
Mihelich, E. D. J. Org. Chem. 1978, 43, 1372.
˚
˚
P2(1)/c with a¼10.2567(6) A, b¼6.6768(4) A, c¼
˚
26.2812(16) A, a¼908, b¼93.3560(1)8, g¼908, V¼
3
1797.75(19) A , Dc (Z¼4)¼1.524 g cm23. F(000)¼848.
˚
Absorption coefficient¼0.0097(11) cm21(a) Sheldrick, G. M.
SADABS: Program for absorption corrections using Bruker
¨
CCD data; University of Gottingen: Germany, 1996.
(b) Sheldrick, G.M. SHELXTL-PC: Program for Crystal
25. (a) Citterio, A.; Pesce, L.; Sebastiano, R.; Santi, R. Synthesis
1990, 142. (b) Caluwe, P.; Pepper, T. J. Org. Chem. 1988, 53,
1786. (c) Rubin, M. B.; Welner, S. J. Org. Chem. 1980, 45,
1847.
¨ ¨
Structure Solution; University of Gottingen: Gottingen,
Germany, 1997.
19. Sotomayor, N.; Domınguez, E.; Lete, E. Tetrahedron 1995,
´
26. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon: New York, 1988.
51, 12721.
20. Preparation of an o-styrylbenzoic acid by Heck coupling of