(Z)-Ethyl 2-phenyl-1-(2-vinylphenyl)vinylcarbamates. Part 1: Synthesis and preliminary studies on their divergent transformation into benzo[c] phenanthridines and 2-phenyl-1,4-naphthoquinones

Article abstract of DOI:10.1016/j.tet.2010.10.035

Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-(2-vinylphenyl)-2-phenylethylenes, which can easily be transformed into N-carbethoxy-1-amino-2-phenylnaphthalenes. Bischler-Napieralski reaction of these latter

Full text of DOI:10.1016/j.tet.2010.10.035

Tetrahedron 66 (2010) 9986e9995
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
(Z)-Ethyl 2-phenyl-1-(2-vinylphenyl)vinylcarbamates. Part 1: Synthesis
and preliminary studies on their divergent transformation into
benzo[c]phenanthridines and 2-phenyl-1,4-naphthoquinones
a
,
b
c
a
,
b
a
,
,
*
Monica Treus , Cristian O. Salas , Marcos A. Gonazalez , Juan C. Estevez b, Ricardo A. Tapia c
,
ꢀ
ꢀ
ꢀ
a,b,
*
ꢀ
ꢀ
Ramon J. Estevez
a
ꢀ
ꢀ
Centro Singular de Investigacion en Química Biologica y Materiales Moleculares, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Organica (Facultad de Química), Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Departamento de Química Organica, Facultad de Química, Pontificia Universidad Catolica de Chile, 702843 Santiago de Chile, Chile
b
c
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 April 2010
Received in revised form 11 October 2010
Accepted 15 October 2010
Available online 22 November 2010
Treatment of N-carbethoxy-1-benzylideneisoquinolines with LDA gives N-ethoxycarbonyl-1-amino-1-(2-
vinylphenyl)-2-phenylethylenes, which can easily be transformed into N-carbethoxy-1-amino-2-phe-
nylnaphthalenes. BischlereNapieralski reaction of these latter compounds affords the corresponding
benzo[c]phenanthridines, while their hydrolysis and subsequent oxidation constitutes a novel route to
2-phenyl-1,4-naphthoquinones.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Stilbenes
Isoquinolines
Benzo[c]phenanthridines
Naphthoquinones
Nitro compounds
1. Introduction
triphenylene, do not show carcinogenic properties.5 The antineo-
plastic properties of benzo[c]phenanthridines have been attributed
1-Benzylisoquinolines have received considerable attention
both as synthetic and biogenetic precursors of a wide variety of
natural compounds of pharmacological interest, including mor-
phines, aporphines, protoberberines and benzo[c]phenanthridines
(1).1 These four families of isoquinoline alkaloids have a widespread
occurrence in nature and a broad range of biological activities,2,3
but only protoberberines and benzo[c]phenanthridines exhibit
antineoplastic activity. In fact, nitidine (1a) and benzo[c]phenan-
thridine analogues, such as fagaronine (1b), exhibit potent anti-
tumour activity by inhibition of DNA topoisomerase I,3a,4 a property
that has been related to their structural similarity with carcinogenic
polycyclic aromatic hydrocarbons, such as chrysene and dime-
thylbenzanthracene. This behaviour has been attributed to the
presence in their structures of a conformationally rigid embedded
2-phenylnaphthalene subunit, because other polycyclic aromatic
hydrocarbons where this subunit is not present, such as
to the fact that their tetracyclic framework includes the 2-phenyl-
naphthalene structural pattern present in chrysene, although in
this case it is formed not only by carbon atoms. The presence of
a nitrogen atom in these alkaloids modifies the electronic distri-
bution of the annular system and, furthermore, the presence of
alkoxy substituents at strategic positions of this annular system
interferes with the epoxidationehydroxylation processes involved
in the carcinogenesis mechanism.
The range of 2-phenylnaphthalene-based compounds that show
antineoplastic activity also includes several types of antibiotics with
antitumour activity, such as 5H-benzo[b]carbazole-6,11-diones
26 and ellipticine quinones 4,7 which retain a close structural
relationship with ellipticine 3,8 a naturally occurring 6H-pyrido[4,3-
b]carbazole alkaloid with powerful antitumour activity. The em-
bedded 2-phenylnaphthalene subunits present in 2 and 4 are a
2-phenyl-1,4-naphthoquinone and
dione, respectively (Fig. 1).
a 6-phenylisoquinoline-5,8-
As a result of these important pharmacological properties,
a variety of methods have been used for the synthesis of targets
1,9,10 211 and 4,12 and particularly attractive are those in which the
key step is the annelation of an appropriate 2-phenylnaphthalene
* Corresponding authors. Tel.: þ34 981 563 100; fax: þ34 981 591 014 (R.J.E.);
tel.: þ56 2 354 4429; fax: þ56 2 354 4744 (R.A.T.); e-mail addresses: rtapia@uc.cl
ꢀ
(R.A. Tapia), ramon.estevez@usc.es (R.J. Estevez).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.035

M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
9987
required carbon skeleton and a suitable functionality for the se-
quential construction of the central C and B rings of our targets 5.
Ring C should result from an electrocyclic cyclization, allowing the
transformation of stilbene compounds 8 into the corresponding
2-phenylnaphthalenes 7. In addition, ring B should result from
a previously described BischlereNapieralski cyclization of 2-phe-
nylnaphthalenes 7.
According to our synthetic plan, treatment of the known 1-
benzylideneisoquinoline 9a15 with LDA at 0 ꢀC provided the styr-
ylurethane 8a resulting from the expected cleavage of its C3eN
bond (Scheme 2).14
O
The structure of compound 8a was unambiguously established
from its analytical data and by 1D and 2D NMR studies, including
heteronuclear multiple-bond correlations (HMBC). A 1H NMR NOE
experiment on 8a established a Z configuration for its stilbenic
double bond. This conclusion was based on the observation that
0
irradiation of its H2, H6 and NeH protons results in a large increase
in the peak intensities of the protons indicated in Fig. 2.
Continuing with our plan, when a solution of compound 8a in o-
xylene containing 10% Pd/C was refluxed for 3 days, the desired 2-
phenylnaphthalene derivative 7a was obtained in only a 35%
yield,16 as a result of the generation of its C ring by a thermically
induced electrocyclic cyclization, as it was easily established from
analytical and spectroscopic data. In fact, its mass spectrum showed
the molecular weight expected for this compound (m/z¼351, Mþ,
100) and its 1H NMR spectrum includes signals for nine aromatic
protons (two less than 8a). After, compound 7a was easily con-
verted into its N-methyl derivative 11a by treatment with MeI in
a basic medium. Finally, following the designed plan for the se-
quential construction of rings B and C of our targets 5, the forma-
tion of the B ring of benzo[c]phenanthridine target 5a was easily
achieved in a 57% yield by subjecting its precursor 11a to the well
known BischlereNapieralski protocol for the synthesis of iso-
quinolines,17 by refluxing a solution of 11a and P2O5 in POCl3 during
1.5 h. The successful outcome of these reaction was easily stated
from analytic and spectroscopical data of 5a. Thus, its mass spec-
trum allowed to establish its molecular weight of 319 (46 mass
units fewer than those of 11a). In addition, its 1H NMR spectrum
includes signals for eight aromatic protons (a proton less than its
precursor 11a). A similar sequence led to the tetrasubstituted benzo
[c]phenanthridine 5b from the known 1-benzylideneisoquinoline
9b,15 via compounds 8b, 7b and 11b.
Fig. 1. Frameworks for benzo[c]phenanthridines, 5H-benzo[b]carbazole-6,11-diones,
ellipticines and ellipticine quinones.
precursor. Accordingly, different approaches for the synthesis of
2-phenylnaphthalenes have been developed. These include recent
approaches based on a key step consisting of the construction of
their biarylic bond, a process, that is, usually very sensitive to steric
hindrance.13 The search for new and efficient approaches to
2-phenylnaphthalenes is therefore of current interest.
2. Results and discussion
In a previous communication14 we reported preliminary results
on a novel access to 2-phenylnaphthalenes 7 (Scheme 1) from 1-
benzylideneisoquinolines 9 via the novel (Z)-alkyl 2-phenyl-1-(2-
vinylphenyl)vinylcarbamates 8, and their divergent transformation
into benzo[c]phenanthridin-1-ones
5 and 2-phenyl-1,4-naph-
thoquinones 6. The present article includes a full description of this
chemistry, together with the following unpublished related results:
(a) the novel photochemically induced transformation of com-
pound 8b into the complex compound 12 (Scheme 2); (b) a novel
formal synthesis of O-methyl fagaronine (1e) (Scheme 2) and (c)
the novel rearrangement of N-carbethoxy 1-(2-nitrobenzylide-ne)
isoquinoline 9c to 5-nitroisoquinolin-1(2H)-one 19, which, in turn,
rearranges to the novel 2-(2-methylamino-carbonyl)isoquinolin-1
(2H)-one 21 via its derivative 20 (Scheme 5).
Attempts to transform 2-phenylnaphthalene derivatives 7a and
7b into their respective N-unsubstituted benzo[c]phenanthridine-
1-ones 5d and 5e were partially satisfactory (Scheme 2). Thus
C
N
D
A
B
a
D
b
C
N
D
N
D
c
R
RO2C
A
5 R=H,Me
O
A
A
N
O
H
CO2Et
H
CO2Et
7
8
9
D
C
O
A
6
Scheme 1.
Our synthetic plan for benzo[c]phenanthridines 5 is based on
the three key steps depicted in Scheme 1. We reasoned that dis-
connection of the strategic bond a in isoquinolines 9 should allow
access to the novel stilbene-like compounds 8, which have the
2-phenylnaphthalene 7b remained unaltered when subjected to
the same BischlereNapieralski cyclization conditions as for 11a, but
satisfactory results were achieved when harsher reaction condi-
tions (triflic anhydride and DMAP) were used.18 Under these

9988
M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
Scheme 2.
H
MeO
MeO
OMe
H
Hb
H
OMe
4
MeO
Hc
NHCO2Et
12
CO2Et
NH
H6««
5
11
Ha
H
H6'
N
R
OMe
H2
10
9a
1
Hd
4.5%
H2
H2''
H
6
H
5.3%
8a
H
Fig. 2. Retrosynthetic plan for the divergent access to benzo[c]phenanthridines and
2-phenyl-1,4-napthoquinones.
OMe
MeO
(+)-12
conditions the expected compound 5e was obtained in 49% yield.
But the similar transformation of 7a into 5d did not occur under
these conditions, probably due to the absence of electron-donating
substituents on the A ring of 7a.
H6.67
Hb
2.42
OMe
3.85
H
Hc
In an attempt to improve the yield obtained in the trans-
formation of compounds 8 into compounds 7, we decided to ex-
plore the photoinduced electrocyclic cyclization of compound 8b.
Unexpectedly, irradiation of a solution of this compound in diethyl
ether with a medium pressure lamp (Hanovia, 450 W) for an hour,
using iodine and oxygen as oxidants,19 led to a reaction mixture
from which the desired phenylnaphthalene 7b was isolated in only
4% yield. The main reaction product was the complex bicyclic
compound 12, as established from its analytical and spectroscopical
data, including 1D and 2D NMR studies (COSY, HMQC, HMBC and
NOESY). The signals at 2.42 ppm (d, J¼9.5 Hz) and 2.72 ppm (dd,
J¼9.5 Hz and J¼4.5 Hz), corresponding to one of the methylene
groups, together with doublets at 2.98 ppm (J¼15.6 Hz) and
3.47 ppm (J¼15.6 Hz), both due to the second methylene group, are
consistent with its central bicyclic moiety.
Ha
H
2.72
5.29
N
R
OMe
Hd
H
H6.50
6.68
H
6.85
OMe
MeO
Fig. 3. Selected 13C HMBC and NOE correlations for compound 12.
A tentative mechanism was proposed to explain the formation of
this complex compound 12 (Scheme 3).20 It was envisaged that the
process begins with the formation of biradical 13 arising from an endo
cyclization involving the styrene and the stilbene moieties of the
starting material. Subsequent intramolecular biradical coupling af-
fordsthebicyclicintermediate14. Finally, anaromatizationprocessby
a [1,3] hydrogen sigmatropic rearrangement yields the bicycle 12.
The present strategy for the synthesis of benzo[c]phenan-
In addition, the COSY spectrum contains a signal at 3.85 ppm
(J¼4.5 Hz, H-5) coupled with a proton of the neighbouring meth-
ylene group at 2.72 ppm (Ha). Selected 2D, 1H-, 13C HMBC and NOE
correlations shown in Fig. 3 provide additional evidence supporting
the structure proposed for compound 12.
thridin-1-ones
5 was successfully applied to the efficient

M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
9989
MeO
MeO
MeO
OMe
OMe
MeO
H
EtO2CHN
H
MeO
MeO
hν, I2, O2
EtO2CHN
OMe
OMe
OMe
MeO
14
Et2O
rt, 2 h
50% yield
EtO2CHN
8b
MeO
MeO
MeO
OMe
OMe
H
MeO
EtO2CHN
EtO2CHN
13
OMe
12
MeO
Scheme 3.
preparation of benzo[c]phenanthridine 16 (Scheme 4),21 a syn-
thetic precursor of the known N-methyl fagaronine iodide (1c,
As an additional synthetic application of the novel N-styrylur-
ethanes 8, we report here the first example of the transformation of
these promising scaffolds into 2-phenyl-1,4-naphthoquinones. This
process was carried out as depicted in Scheme 4. Thus, 1-amino-2-
phenylnaphthalene 15 was easily converted into 2-phenyl-1,4-
naphthoquinone 6a by oxidation with Fremy’s salt.22 Finally, when
a solution of this quinone in aqueous/methanolic NaOH was heated
at 50 ꢀC, the known 2-hydroxy-1,4-naphthoquinone 6b was effi-
ciently obtained.14
This novel access to 2-phenyl-1,4-naphthoquinone 6b, com-
bined with the previous transformation of the known quinone 6c
into 5H-benzo[b]carbazole-6,11-dione 2a,23 prompted us to explore
the preparation of these targets by the novel synthetic approach to
quinones described herein. The preparation of the model com-
pound 2a should start from 1-(o-nitrobenzylidene)isoquinoline 9c,
with a nitro substituent conveniently placed for further trans-
X¼I).21 When
a solution of N-carbethoxy-1-amino-2-phenyl-
naphthalene 7b and aq KOH in ethanol was refluxed for 14 h, the
expected naphthylamine 15 was obtained quantitatively, as a result
of a basic hydrolysis of its N-carbethoxy subunit. Compound 15 was
directly solved in THF, formic-acetic anhydride was added and the
resulting solution was next heated at 65 ꢀC for 18 h. This provided
a 73% yield of formamide 7c, easily identified from analytical and
spectroscopic data. Its mass spectrum confirmed the molecular
weight expected for this compound (m/z¼367, Mþ, 100) and its IR
spectrum showed at 3297 and at 1684 cmꢁ1 two band dues to its
NeH and carbonyl groups, respectively. On the other hand, al-
though its 1H NMR and 13C NMR spectra denoted the presence of
a mixture of rotamers, a signal showed by its 1H NMR spectrum at
8.47 ppm, was unambiguously attributed to its formyl proton.
1
OMe
OMe
OMe
OMe
MeO
MeO
MeO
POCl3
4
MeCN
N
H
N
MeO
H
reflux, 3 h
82% yield
6
16
7c
O
HCO2COMe
THF
65 ºC, 18 h
73% yield
O
OMe
OMe
OMe
X
OMe
OMe
MeO
MeO
MeO
MeO
(KSO3)2NO
MeO
MeO
11 M aq KOH
OMe
acetone/H2O
rt, 2 h
65% yield
EtOH
N
NH2
O
H
CO2Et
reflux, 14 h
100% yield
6
Y
7b
15
NaOH, MeOH:H2O,
50 ºC, 4.5 h, 90% yield
a: X=Y=H,
b: X=OH, Y=H
c: X=OH, Y=NO2
Scheme 4.
Finally, when a solution of this amide 7c and POCl3 in acetoni-
trile was refluxed for 3 h, a 82% yield of the expected benzo[c]
phenanthridine 16 was obtained, as a result of the programmed
BischlereNapieralski cyclization. Its mass spectrum and micro-
analysis confirmed its molecular formula C21H19NO4 and its 1H
NMR showed signals for a total of seven aromatic protons, in-
cluding a signal at 9.26 ppm, corresponding to the highlight
deshielded proton at C-6. As compound 7c was previously
converted into O-methyl fagaronine iodide (1c),21 the present
approach to 7c formally constitutes a new, more efficient synthesis
of 1c.
formations. This isoquinoline was efficiently prepared according to
a protocol described for the preparation of its analogues 9a and 9b
(Scheme 2). Thus, treatment of the known dihydroisoquinoline 10a
with ethyl chloroformiate in a basic medium provided this key
compound 9c, as it was easily established from its analytical and
spectroscopical data. Its IR spectrum includes at 1695 cmꢁ1 a band
due to the carbamate carbonyl group, together with two bands at
1515 and 1340 cmꢁ1, dues to the nitro group. Its 1H NMR and 13C
NMR spectra are similar to those of 9a and 9b, and the former
spectrum includes signals for a total of six aromatic protons (one
less than 9a).

9990
M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
Proceeding as for 9a and 9b, reaction of compound 9c with LDA
in THF at 0 ꢀC for 1.5 h surprisingly gave a complex reaction mixture
that did not contain the desired stilbene 8c (Scheme 2). However,
new unexpected results were obtained when a solution of com-
pound 9c and NaH in DMF was heated at 130 ꢀC for 3 h. The main
reaction product was not the expected stilbene 8c but the iso-
quinoline 18 (Scheme 5), as deduced from its analytical and spec-
troscopic data. The 1H NMR spectrum includes at 5.27, 5.66 and
7.03e7.15 ppm signals dues to the vinyl substituent, and a broad
signal at 11.30 ppm was assigned to the amide proton. The IR
spectrum shows at 1664 cmꢁ1 a strong band due to the amide
carbonyl group and at 1515 and 1340 cmꢁ1 the typical bands of
nitro groups.
Fig. 4. ORTEP diagram of compound 21.
Scheme 5.
Formation of isoquinoline 18 may be regarded as being the re-
sult of a nitro facilitated thermally promoted electrocyclic cycliza-
tion of 9c involving its N-ethoxycarbonyl substituent, which should
lead to protoberberine derivative 17. Eventually, this compound
could spontaneously be converted into compound 18 by a Hof-
mann-like elimination by the action of hydride (Scheme 5).
This route constitutes a novel access to 3-(2-vinylphenyl)-iso-
quinolin-1(2H)-ones (18), which have previously been converted
into the corresponding benzo[c]phenanthridin-1-ones (5) by
a protocol,24 that when applied to isoquinolinone 18 produced
unexpected results. Thus, once compound 18 was converted into its
N-methyl derivative 19 by reaction with NaH and MeI, treatment of
19 with thallium trinitrate allowed us to obtain the slightly un-
stable acetal derivative 20, as deduced from its 1H NMR spectrum,
which showed at 2.70 ppm and at 3.10 ppm signals dues to its
methylene protons and at 4.50 ppm the signal corresponding to the
proton at the acetalic carbon.
allowed the development of the first divergent synthesis of benzo
[c]phenanthridines 5 and 3-phenyl-1,4-naphthoquinone 6a. This
new approach to benzo[c]phenanthridines involves the sequential
construction of their central rings. Firstly, ring B results from
a novel thermally induced electrocyclic cyclization of the key stil-
bene-like derivatives 8 and this is followed by a spontaneous oxi-
dation. This provided a novel access to 2-phenylnaphthalenes 7,
from which the C ring of benzo[c]phenanthridines is formed by the
known BischlereNapieralski cyclization. Unfortunately, however,
this first route for the preparation of (Z)-ethyl 2-phenyl-1-(2-
vinylphenyl)vinylcarbamates 8 showed to be limited to benzyliso-
quinolines 9 without nitro substituents at their A ring. In fact, the 2-
hydroxy-3-(o-nitrophenyl)-1,4-naphthoquinone 6c could not be
obtained from compound 9c via compound 8c, due to the unsta-
bility of 9c under the standard basic reaction conditions involved in
the transformation of compounds 9a and 9b into compounds 8a
and 8b, respectively.
This compound 20 was directly solved in a MeOH/H2O mixture,
p-toluensulfonic acid was added and the solution was heated at
70 ꢀC for two days. But, unfortunately, the expected benzo[c]phe-
nanthridin-1-one 5c was not obtained. Surprisingly, the resulting
compound was the isoquinolin-1-one 21, as it was established from
its analytical and spectroscopical data. Its mass spectrum con-
firmed its molecular formula C19H19N2O4 and its IR spectrum in-
cludes bands at 3331 and 1651 cmꢁ1, due to its amide moiety, and
no typical bands of nitro groups were present. Its 1H NMR includes
a key signal at 2.71 ppm (d, J¼5.2 Hz), corresponding to its NHeCH3
moiety. In addition, structure of compound 21 was firmly estab-
lished by means of an X-ray experiment (Fig. 4).25
Ongoing work in this field includes the search for experimental
conditions for the transformation of nitrobenzylydeneisoquinoline
9c into the corresponding stilbene 8c and for the transformation of
isoquinolinone 19 into the corresponding benzo[c]phenan-
thridinone 5c. Additional work is in progress, which is aimed at an
alternative transformation of N-styrylurethanes 8 into benzo[c]
phenanthridines 5, involving the sequential construction of their B
and C central rings in an opposite order to that here reported.
3. Experimental section
3.1. General
We assumed that the nitro group prevents the cyclization re-
quired for the transformation of compound 19 into the corre-
sponding benzo[c]phenanthridine 5c in favour of the novel,
complex rearrangement leading isoquinolinone 21.
To sum up, we report here the novel base-promoted Hoffman-
like opening of N-carbethoxy-1-benzylisoquinolines 9 to the novel
(Z)-ethyl 2-phenyl-1-(2-vinylphenyl)vinylcarbamates 8, which
Melting points were determined on a Kofler Thermogerate ap-
paratus and are uncorrected. Infrared spectra were recorded on
a JASCO FT/IR-400 spectrophotometer. Nuclear magnetic resonance
spectra were recorded, unless otherwise specified, on a Bruker
WM-250 apparatus using deuterochloroform solutions containing
tetramethylsilane as an internal standard. 1H NMR splitting

M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
9991
patterns are designated as singlet (s), doublet (d), triplet (t), quartet
(q) or quintuplet (p). All first-order splitting patterns were assigned
on the basis of the appearance of the multiplet. Splitting patterns
that could not be easily interpreted are designated as multiplet (m)
or broad (br). Mass spectra were obtained on an HP 5988A mass
spectrometer, using the electron impact (EI) or the chemical ioni-
zation (CI) techniques. Elemental analyses were performed on EA
1108 CHNS Fisons. Thin layer chromatography (TLC) was performed
using Merck GF-254 type 60 silica gel and dichloromethane/
methanol or ethyl acetate/hexane mixtures as eluents; the TLC
spots were visualized with ultraviolet light or iodine vapour. Col-
umn 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.
J¼7.1 Hz, OCH2), 6.37 (s, 1H, NH), 6.92e6.96 (m, 3H, 3ꢂAreH), 7.13
(s, 1H, AreH), 7.24 (s, 1H, AreH), 7.33 (d, 1H, J¼8.4 Hz, AreH), 7.70
(d, 1H, J¼8.4 Hz, AreH); 13C NMR (
d, ppm, CDCl3): 14.6 (CH3), 55.7
(2ꢂOCH3), 55.8 (OCH3), 55.9 (OCH3), 61.3 (OCH2), 102.4 (CH), 106.4
(CH), 111.1 (CH), 112.5 (CH), 121.4 (CH), 125.9 (CH), 126.2 (CH), 126.9
(C), 128.1 (C), 129.4 (C), 132.5 (C), 134.9 (C), 148.3 (CeOMe), 148.7
(CeOMe), 149.6 (CeOMe), 150.2 (CeOMe), 155.7 (C]O); MS (m/z,
%): 411 (Mþ, 100). Anal. Calcd for C23H25NO6: C, 67.14; H, 6.13; N,
3.40. Found: C, 67.25; H, 6.27; N, 3.23.
3.4. Ethyl 2-phenylnaphthalen-1-ylcarbamates 11: general
procedure
A suspension of NaH(4.64 mmol, 8.7 equiv)in dry THF (5 mL) was
stirred at 0 ꢀC for 30 min under an argon atmosphere. A solution of 7
(0.53 mmol) in dry THF (5 mL) was added dropwise and the mixture
was stirred at rt for 30 min CH3I (1.11 mL, 33.5 equiv) was added
dropwise and stirring was continued at rt for 45 min. The excess NaH
was destroyed by adding water (10 mL) and the THF was evaporated
off. The aqueous layer was extracted with CH2Cl2 (3ꢂ20 mL), the
combined extracts were dried, filtered and evaporated to dryness in
vacuo to give a residue that was purified bycolumn chromatography
(AcOEt/hexane 3:7 for 11a and AcOEt/hexane 1:1 for 11b).
3.2. (Z)-Ethyl 1-(2-vinylphenyl)-2-phenylvinylcarbamates 8:
general procedure
A solution of diisopropylamine (9.29 mmol, 4.8 equiv) in dry THF
(38 mL) was cooled to 0 ꢀC and n-BuLi (1.20 M, 9.29 mmol) was
added. The mixture was stirredat rt for 20 min and then cooledagain
to0 ꢀC. The freshlyprepared LDAwas added dropwise toa solution of
9 (1.93 mmol) in THF (23 mL) under an argon atmosphere. The
mixture was stirred at 0 ꢀC for 30 min for 9a and 1 h for 9b. Water
(7 mL) was added dropwise, the mixture was concentrated to dry-
ness in vacuo and water (30 mL) was added. The resulting suspen-
sion was extracted with CH2Cl2 (3ꢂ25 mL). The organic layer was
dried and concentratedtodryness, toprovidea chromatographically
pure white solid of 8a (100% yield) or 8b (100 yield).
3.4.1. Ethyl 6,7-dimethoxy-2-phenylnaphthalen-1-yl(methyl)carba-
mate (11a). White solid (74% yield); Rf¼0.53 (40% AcOEt/hexane);
mp 245 ꢀC (MeOH); IR ( , cmꢁ1, NaCl): 1695 (C]O); 1H NMR (
n
d, ppm,
CDCl3): as a mixture 4.5:1 of rotamers,1.05 (t, 3H, J¼7.1 Hz, CH3), 1.29
(t, 3H, J¼7.1 Hz, CH3), 2.91 (s, 3H, NCH3), 3.00 (s, 3H, NCH3), 3.94e4.26
(m, 8H, 2ꢂOCH3þOCH2), 7.02 (s,1H, AreH), 7.05 (s,1H, AreH), 7.17 (s,
1H, AreH), 7.19 (s, 1H, AreH), 7.26e7.47 (m, 6H, AreH), 7.69 (d, 1H,
3.2.1. (Z)-Ethyl 1-(4,5-dimethoxy-2-vinylphenyl)-2-phenylvinylcarba-
mate (8a). White solid (100% yield); Rf¼0.51 (40% AcOEt/hexane);
mp 106e109 ꢀC (Et2O).27
J¼8.4 Hz, AreH); 13C NMR (
d, ppm, CDCl3) as a mixture 4.5:1 of
rotamers, 14.8 (CH3), 15.0 (CH3), 36.9 (NCH3), 37.0 (NCH3), 55.8
(OCH3), 55.9 (OCH3), 56.0 (OCH3), 61.5 (OCH2), 61.6 (OCH2), 101.5
(CH), 101.6 (CH), 106.7 (CH), 106.8 (CH), 126.2 (CH), 126.3 (CHþC),
126.4 (C),126.7 (2ꢂCHþC),127.1 (CH),127.3 (CH),128.2 (2ꢂCH),128.4
(2ꢂCH), 128.6 (2ꢂCH), 128.8 (2ꢂCH), 130.0 (C), 130.7 (C), 134.9 (C),
135.5 (C), 136.1 (C), 140.0 (C), 140.1 (C), 149.7 (CeOMe), 150.6
(CeOMe), 156.3 (C]O), 156.6 (C]O); MS (m/z, %): 365 (Mþ, 100).
3.2.2. (Z)-Ethyl 1-(4,5-dimethoxy-2-vinylphenyl)-2-(3,4-dimethox-
yphenyl)vinylcarbamate (8b). White solid (100% yield); Rf¼0.67
(10% MeOH/CH2Cl2); mp 137e139 ꢀC (MeOH).27
3.3. Ethyl 2-phenylnaphthalen-1-ylcarbamates 7: general
procedure
3.4.2. Ethyl 2-(3,4-dimethoxyphenyl)-6,7-dimethoxynaphthalen-1-yl
Pd/C (560 mg, 10% in weight Pd) was added to a degassed so-
lution of carbamates 8 (1.59 mmol) in dry o-xylene (40 mL) and the
resulting suspension was heated under reflux under argon for 4
days. The solids were filtered off through a Celite pad, which was
washed with o-xylene, and the solvent was removed in vacuo.
Compounds 7a and 7b were isolated by flash column chromatog-
raphy (AcOEt/hexane 6:4).
(methyl)carbamate (11b). White solid (75% yield); Rf¼0.61 (40%
AcOEt/hexane); mp 152e155 ꢀC (MeOH); IR ( , cmꢁ1, NaCl): 1693
n
(C]O); 1H NMR (
d, ppm, CDCl3): as a mixture 4.5:1 of rotamers,1.08
(t, 3H, J¼7.1 Hz, CH3), 1.33 (t, 3H, J¼7.1 Hz, CH3), 2.92 (s, 3H, NCH3),
2.98 (s, 3H, NCH3), 3.88e4.03 (m, 12H, 4ꢂOCH3), 4.06e4.34 (m, 2H,
OCH2), 6.92e6.98 (m, 3H, AreH), 7.02e7.06 (m, 1H, AreH),
7.17e7.19 (m,1H, AreH), 7.34 (d, 1H, J¼8.4 Hz, AreH), 7.37 (d, 1H,
J¼8.4 Hz, AreH), 7.68 (d, 1H, J¼8.4 Hz, AreH), 7.70 (d, 1H, J¼8.4 Hz,
3.3.1. Ethyl 6,7-dimethoxy-2-phenylnaphthalen-1-ylcarbamate (7a).
White solid (26% yield); Rf¼0.64 (50% AcOEt/hexane); mp 157e160 ꢀC
AreH); 13C NMR (
d, ppm, CDCl3): as a mixture of rotamers, 15.0
(2ꢂCH3), 36.7 (NCH3), 36.8 (NCH3), 55.8 (3ꢂOCH3), 55.9 (3ꢂOCH3),
56.0 (OCH3), 56.1 (OCH3), 61.6 (OCH2), 61.7 (OCH2), 101.5 (CH), 101.6
(CH), 106.7 (CH), 106.8 (CH), 110.9 (CH), 111.1 (CH), 111.8 (CH), 112.1
(CH), 120.9 (CH), 121.0 (CH), 126.2 (CH), 126.4 (CH), 126.5 (CþCH),
126.7 (CH), 129.5 (C), 129.8 (C), 132.5 (C), 132.8 (C), 134.8 (C), 135.0
(C), 135.4 (C), 135.7 (C), 147.7 (CeOMe), 148.2 (CeOMe), 148.5
(CeOMe), 148.7 (CeOMe), 149.6 (CeOMe), 150.6 (CeOMe), 156.3
(C]O), 156.6 (C]O); MS (m/z, %): 425 (Mþ, 100).
(Et2O); IR ( d, ppm, CDCl3):
n
, cmꢁ1, NaCl): 1707 (C]O); 1H NMR (
0.99e1.30 (m, 3H, CH3), 3.98e4.13 (m, 8H, 2ꢂOCH3þCH2), 6.24 (s, 1H,
NH), 7.15 (s, 1H, AreH), 7.22e7.63 (m, 7H, 7ꢂAreH), 7.69 (d, 1H,
J¼8.4 Hz, AreH); 13C NMR (
d, ppm, CDCl3): 14.6 (CH3), 55.8 (OCH3),
55.9 (OCH3), 61.3 (OCH2),102.3 (CH),106.4 (CH),126.0 (CH),126.2 (CH),
126.9 (C), 127.1 (CH), 128.1 (C), 128.3 (2ꢂCH), 129.1 (2ꢂCH), 129.5 (C),
135.3 (C), 139.9 (C), 149.7 (CeOMe), 150.2 (CeOMe), 155.6 (C]O); MS
(m/z, %): 351 (Mþ, 100). Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N,
3.99. Found: C, 72.01; H, 5.97; N, 3.91.
3.5. 5-Methylbenzo[c]phenanthridin-6-(5H)-ones 5a and 5b:
general procedure
3.3.2. Ethyl 6,7-dimethoxy-2-phenylnaphthalen-1-ylcarbamate (7b).
White solid (26% yield); Rf¼0.52 (60% AcOEt/hexane); mp
P2O5 (374 mg, 2.63 mmol, 13.5 equiv) was added to a solution of
11a or 11b (0.195 mmol) in POCl3 (8 mL, 8.9 mmol) under an argon
atmosphere and the suspension was stirred and heated for 1.5 h for
11a and 1 h for 11b. The reaction mixture was evaporated to
164e167 ꢀC (AcOEt); IR ( , cmꢁ1, NaCl): 1721 (C]O); 1H NMR (
n
d,
ppm, CDCl3): 1.24 (t, 3H, J¼7.1 Hz, CH3), 3.84 (s, 3H, OCH3), 3.90 (s,
3H, OCH3), 3.95 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.10 (q, 2H,

9992
M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
dryness and the residue was taken up in water/ice (5 mL). The
suspension was neutralized with saturated aqueous NaHCO3 and
extracted with CH2Cl2 (3ꢂ20 mL). The organic layer was dried and
evaporated in vacuo to dryness to afford compounds 5a or 5b,
which were purified by column chromatography (AcOEt/hexane
1:1 for 5a and AcOEt/hexane 9:1 for 5b).
DMAP (71.3 mg, 0.583 mmol) in CH2Cl2 (5 mL) at 0 ꢀC under an
argon atmosphere. The reaction mixture was stirred at rt for 24 h
and diluted with CH2Cl2 (5 mL). The solution was washed with 20%
aqueous acetic acid (10 mL) and saturated aqueous Na2CO3 (10 mL),
dried (Na2SO4) and concentrated to dryness in vacuo. Purification
by column chromatography (MeOH/CH2Cl2 2:98) provided benzo
[c]phenanthridine 5e (35 mg, 49% yield) as a white solid. Rf¼0.23
3.5.1. 2,3-Dimethoxy-5-methylbenzo[c]phenan-thridin-6-(5H)-one
(50% AcOEt/hexane); mp 208e210 ꢀC (acetone/Et2O); IR (
n
, cmꢁ1
,
(5a). White solid (57% yield); Rf¼0.46 (5% MeOH/CH2Cl2); mp
NaCl): 1641 (C]O); 1H NMR (
d, ppm, DMSO-d6): 3.92 (s, 3H, CH3),
193e195 ꢀC (MeOH); IR (
n
, cmꢁ1, NaCl): 1641 (C]O); 1H NMR (
d
,
3.93 (s, 3H, CH3), 4.00 (s, 3H, CH3), 4.04 (s, 3H, CH3), 7.41 (s, 1H,
AreH), 7.62 (d, 1H, J¼9 Hz, AreH), 7.76 (s, 1H, AreH), 7.90 (s, 1H,
AreH), 8.20 (s, 1H, AreH), 8.29 (d, 1H, J¼9 Hz, AreH), 11.76 (s, 1H,
ppm, CDCl3): 4.00 (s, 3H, CH3), 4.01 (s, 3H, CH3), 4.02 (s, 3H, CH3),
7.13 (s, 1H, AreH), 7.51e7.57 (m, 3H, 3ꢂAreH), 7.69e7.76 (m, 1H,
AreH), 8.04 (d, 1H, J¼8.8 Hz, AreH), 8.20 (d, 1H, J¼8.2 Hz, AreH),
NH); 13C NMR (
d, ppm, DMSO-d6): 55.7 (OCH3), 55.8 (OCH3), 56.4
8.52 (dd, 1H, J¼7.9 Hz, J¼1.4 Hz, AreH); 13C NMR (
d
, ppm, CDCl3):
(OCH3), 56.5 (OCH3), 102.5 (CH), 104.3 (CH), 107.8 (CH), 107.9 (CH),
112.5 (C), 117.4 (C), 118.9 (C), 119.3 (CH), 121.4 (CH), 129.3 (C), 130.4
(C), 131.1 (C), 149.3 (CeOMe), 149.9 (2ꢂCeOMe), 153.8 (CeOMe),
161.5 (C]O); MS (m/z, %): 365 (Mþ, 100); HRMS calcd for
C21H19NO5 [M]þ 365.1258; found 365.1261.
41.0 (NCH3), 56.0 (2ꢂOCH3), 105.3 (CH), 107.1 (CH), 116.4 (C), 118.4
(CH), 119.6 (C), 121.8 (CH), 122.8 (CH), 125.0 (C), 127.5 (CH), 128.5
(CH), 131.1 (C), 132.6 (CH), 134.2 (C), 135.7 (C), 148.1 (CeOMe), 149.6
(CeOMe), 164.9 (C]O); MS (m/z, %): 319 (Mþ, 100). HRMS calcd for
C20H17NO3 [M]þ 319.1203; found 319.1204.
3.8. 2-(3,4-Dimethoxyphenyl)-6,7-dimethoxynaphthalen-1-
amine (15)
3.5.2. 2,3,8,9-Tetramethoxy-5-methylbenzo[c]phe-nanthridin-6(5H)-
one (5b). White solid (66% yield); Rf¼0.42 (5% MeOH/CH2Cl2); mp
220e250 ꢀC decomp. (MeCN); IR ( , cmꢁ1, NaCl): 1616 (C]O); 1H
n
To a solution of carbamate 7b (390 mg, 1.11 mmol, 1.00 equiv) in
ethanol (2.5 mL) was added 11 M KOH (2 mL, 21.93 mmol,
30.58 equiv) and the resulting mixture was heated under reflux for
14 h. The solution was neutralized with HCl (20%) and the aqueous
layer was extracted with CH2Cl2 (3ꢂ15 mL). The combined organic
layers were washed with H2O and brine, dried (Na2SO4) and con-
centrated to dryness in vacuo. The residue was purified by re-
crystallization and brown crystals corresponding to the amine 15
(290 mg, 100% yield) were isolated. Rf¼0.73 (50% AcOEt/hexane);
NMR (
d
, ppm, CDCl3): 4.04 (s, 9H, 3ꢂCH3), 4.05 (s, 3H, CH3), 4.10 (s,
3H, CH3), 7.17 (s, 1H, AreH), 7.56e7.59 (m, 3H, 3ꢂAreH), 7.90 (s, 1H,
AreH), 7.98 (d, 1H, J¼9 Hz, AreH); 13C NMR (
d, ppm, CDCl3): 41.0
(NCH3), 55.9 (2ꢂOCH3), 56.1 (OCH3), 56.2 (OCH3), 102.7 (CH), 105.4
(CH), 107.1 (CH), 108.5 (CH), 116.2 (C), 118.2 (CH), 119.0 (C), 119.7 (C),
122.6 (CH), 129.1 (C), 130.6 (C), 135.1 (C), 148.1 (CeOMe), 149.3
(CeOMe), 149.5 (CeOMe), 153.4 (CeOMe), 164.4 (C]O); MS (m/z,
%): 379 (Mþ, 100); HRMS calcd for C22H21NO5 [M]þ 379.1414; found
379.1417.
mp 149e151 ꢀC (EtOH); IR ( , cmꢁ1, NaCl): 3377 (NH); 1H NMR (
n
d,
ppm, CDCl3): 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 3.94 (s, 3H,
3.6. ( )-N-Ethoxycarbonyl-2,3,7,8-tetramethoxy-5,10-
methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-yl-
amine (12)
OCH3), 3.95 (s, 3H, OCH3), 6.89e7.19 (m, 7H, 7ꢂAreH); 13C NMR (
d,
ppm, CDCl3): 55.8 (2ꢂOCH3), 55.9 (2ꢂOCH3), 100.4 (CH), 107.0 (CH),
111.4 (CH), 112.7 (CH), 117.4 (CH), 119.0 (C), 121.6 (C), 121.7 (CH),
126.8 (CH), 129.3 (C), 132.7 (C), 137.3 (C), 148.0 (CeOMe), 149.0
(CeOMe), 149.1 (CeOMe), 149.2 (CeOMe); MS (m/z, %): 339 (Mþ,
100).
In
a photochemical reactor was dissolved 8b (150 mg,
0.368 mmol) and I2 (101 mg, 0.399 mmol,1.1 equiv) in Et2O (200 mL).
Oxygenwasbubbled through this solution for 15 min and the mixture
was then irradiated with a medium pressure lamp (Hanovia 450 W)
for 2 h. The reaction mixture was washed with saturated aqueous
Na2S2O3 (2ꢂ200 mL) and the organic layer was dried and evaporated
in vacuo to dryness. The residue was purified by column chroma-
tography (AcOEt/cyclohexane 4:6) to afford compounds 12 (75 mg,
0.182 mmol, 50%) and 7b (6 mg, 0.146 mmol, 4%), which were purified
by column chromatography (AcOEt/hexane 4:6). Compound 12,
3.9. N-Formyl-2-(3,4-dimethoxyphenyl)-6,7-dimethoxynaph-
thalen-1-amine (7c)
86 mL (2.28 mmol, 3.2 equiv) of formic acid were added drop-
wise under argon over 175 mL (1.85 mmol, 2.6 equiv) of acetic an-
hydride externally cooled at 0 ꢀC. The mixture was heated at
white solid (amorphous). Rf¼0.51 (50% AcOEt/hexane); IR (
n
, cmꢁ1
, ppm, CDCl3): 1.27 (t, 3H, J¼7.6 Hz,
,
50e60 ꢀC for 2 h, diluted with dry THF (0.3 mL) and added drop-
NaCl): 1708 (C]O); 1H NMR (
d
wise to a solution of phenylnaphthylamine 15 (242 mg,
CH3), 2.42 (d, 1H, J¼9.5 Hz, CHH), 2.72 (dd, 1H, J¼9.5, 4.5 Hz, CHH),
2.98 (d, 1H, J¼15.6 Hz, CHH), 3.47 (d, 1H, J¼15.6 Hz, CHH), 3.75 (s, 3H,
OCH3), 3.80(s, 3H, OCH3), 3.82(s, 3H, OCH3), 3.85(d,1H, J¼4.5 Hz, H5),
3.87 (s, 3H, OCH3), 4.15 (c, 2H, J¼7.6 Hz, OCH2), 5.29 (s, 1H, NH), 6.50
(s, 1H, AreH), 6.67 (s, 1H, AreH), 6.68 (s, 1H, AreH), 6.85 (s, 1H,
0.713 mmol) in dry THF (2 mL). This solution was heated at 65 ꢀC for
18 h and then concentrated in vacuo to dryness. The solid residue
was submitted to flash column chromatography (eluent: AcOEt/
hexane, 7:3/MeOH/CH2Cl2 1:9) and compound 7c was isolated
(191 mg, 73% yield) as a light brown solid. Rf¼0.16 (60% AcOEt/
AreH); 13C NMR (
d
, ppm, CDCl3): 14.6 (CH3), 38.8 (CH2), 45.6 (CH),
hexane); mp 222e223 ꢀC (EtOH); IR ( , cmꢁ1, NaCl): 3297 (NH),
n
47.5 (CH2), 55.8 (OCH3), 56.0 (OCH3), 56.1 (OCH3), 56.2 (OCH3), 60.7
(OCH2), 62.6 (C), 105.2 (CH), 105.6 (CH), 109.2 (CH), 113.3 (CH), 125.6
(C), 134.5 (C), 135.6 (C), 140.7 (C), 146.9 (CeOMe), 147.6 (CeOMe),
148.5 (CeOMe), 148.6 (CeOMe), 155.6 (C]O); MS (m/z, %): 413 (Mþ,
100); HRMS calcd for C23H27NO6 [M]þ 413.1833; found 413.1842.
1684 (C]O); 1H NMR (
d, ppm, CDCl3): as a mixture 4.5:1 of
rotamers, 3.86e3.92 (m, 15H, 2ꢂOCH3), 3.99e4.04 (m, 15H,
2ꢂOCH3), 6.92e6.95 (m, 7.5H, AreH), 7.12e7.19 (m, 4.5H, AreH),
7.31e7.48 (m, 4.25H, AreHþNH), 7.70e7.73 (m, 2.75H, AreH),
8.07e8.12 (m, 1.75H), 8.47 (s, 1H, CHO); 13C NMR (
d, ppm, CDCl3): as
a mixture 4.5:1 of rotamers, 55.8 (2ꢂOCH3), 55.9 (2ꢂOCH3), 101.4
(CH), 102.6 (CH), 106.5 (2ꢂCH), 111.0 (CH), 111.3 (CH), 112.4 (CH),
113.0 (CH), 121.2 (CH), 122.1 (CH), 125.9 (CH), 126.0 (CH), 126.1 (C),
126.4 (CH), 126.6 (CH), 126.9 (C), 127.2 (C), 129.3 (2ꢂC), 131.5 (C),
132.2 (C), 133.8 (C), 135.1 (C), 148.3 (C), 148.5 (C), 149.0 (C), 149.6 (C),
149.8 (C), 150.3 (C),150.6 (C), 160.8 (CHO),165.7 (CHO); MS (m/z, %):
3.7. 2,3,8,9-Tetramethoxybenzo[c]phenanthridin-
6(5H)-one (5e)
A 1.10 M solution of triflic anhydride in dry CH2Cl2 (0.972 mmol)
was added dropwise to a solution of 7b (80 mg, 0.194 mmol) and

M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
9993
367 (Mþ, 100). Anal. Calcd for C21H21NO4: C, 71.78; H, 6.02; N, 3.99.
Found: C, 72.01; H, 5.97; N, 3.91.
J¼8 Hz, AreH), 7.08 (s, 1H, OH), 7.18 (d, 1H, J¼8 Hz, AreH), 7.51 (s,
1H, AreH), 7.60 (s, 2H, 2ꢂAreH); 13C NMR (
d, ppm, CDCl3): 55.8
(OCH3), 55.9 (OCH3), 56.5 (OCH3), 56.6 (OCH3), 107.5 (CH), 109.0
(CH), 110.6 (CH), 114.1 (CH), 120.8 (C), 122.6 (C), 123.4 (C), 123.9
(CH), 128.1 (C), 148.3 (CeO), 149.3 (CeO), 151.8 (CeO), 152.8 (CeO),
154.6 (CeO), 180.9 (C]O), 183.7 (C]O); MS (m/z, %): 370 (Mþ, 100).
3.10. 2,3,8,9-Tetramethoxybenzo[c]phenanthridine (16)
To a solution of amide 7c (150 mg, 0.408 mmol) in dry MeCN
(7 mL) POCl3 (79.9 mL, 0.856 mmol, 2.1 equiv) was added dropwise
and the reaction mixture was refluxed for 3 h. The excess of POCl3
was removed under vacuum and the remaining suspension was
filtered. The solid was washed with 10% NaOH (10 mL) and later
with water (15 mL). The filtered solution was extracted with CH2Cl2
(3ꢂ20 mL), the pooled organic extracts were washed with water
(30 mL), dried (Na2SO4) and concentrated in vacuo to dryness. The
combined solid residues were crystallized from CHCl3 to give
compound 16 (117 mg, 82% yield) as white crystals. Rf¼0.70 (5%
3.13. (Z)-6,7-Dimethoxy-2-carbethoxy-1-(2-
nitrobenzylidene)-1,2,3,4-tetrahydroisoquinoline (9c)
A solution of ethyl chloroformiate (1.609 mL, 16.83 mmol) in
CH2Cl2 (10 mL) was added to a cooled (ice-water bath) solution of
dihydroisoquinoline 10a (1.34 g, 4.11 mmol) in CH2Cl2 (40 mL) and
10% aqueous sodium carbonate (40 mL). The reaction mixture was
then stirred at rt for 2.5 h and the two layers were separated. The
organic layer was washed with water (2ꢂ50 mL) and 5% aqueous
hydrochloric acid (2ꢂ50 mL), dried and concentrated to dryness.
The resulting residue was purified by column chromatography
(AcOEt/hexane 1:1), and compound 9c (722 mg, 44% yield) was
isolated as a yellow solid. Rf¼0.68 (50% AcOEt/hexane); mp
MeOH/CH2Cl2); mp 80e90 ꢀC (decomp.); IR ( , cmꢁ1, NaCl): 1615
n
(C]N), 1268 (AreOeR), 1202 (AreOeR), 1153 (AreOeR); 1H NMR
, ppm, CDCl3): 4.08 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 4.16 (s, 3H,
(d
OCH3), 4.20 (s, 3H, OCH3), 7.30 (s, 1H, AreH), 7.40 (s, 1H, AreH), 7.87
(d, 1H, J¼8.9 Hz, AreH), 7.90 (s, 1H, AreH), 8.30 (d, 1H, J¼8.9 Hz,
AreH), 8.74 (s, 1H, AreH), 9.26 (s, 1H, AreH); 13C NMR (
d
, ppm,
153e155 ꢀC (CH2Cl2/MeOH); IR (
n
, cmꢁ1, NaCl): 1695 (C]O), 1516
d, ppm, CDCl3): 0.64e0.88 (m, 3H,
CDCl3): 56.0 (OCH3), 56.1 (2ꢂOCH3), 56.2 (OCH3), 101.6 (CH), 104.1
(CH), 107.0 (CH), 107.3 (CH), 118.0 (CH), 119.8 (C), 122.1 (C), 126.1
(CH), 127.5 (C), 128.2 (C), 129.0 (C), 140.2 (C), 149.6 (CH), 149.7
(CeOMe), 150.0 (2ꢂCeOMe), 153.0 (CeOMe); MS (m/z, %): 349 (Mþ,
100). Anal. Calcd for C21H19NO4: C, 72.20; H, 5.48; N, 4.01. Found: C,
72.05; H, 5.41; N, 3.83.
(NO2), 1258 (NO2); 1H NMR (
CH3), 2.85e2.97 (m, 2H, CH2), 3.61e3.80 (m, 2H, CH2), 3.88e3.99
(m, 8H, 2ꢂOCH3þCH2), 6.62 (s, 1H, AreH), 7.25e7.27 (m, 2H,
2ꢂAreH), 7.34e7.39 (m, 1H, AreH), 7.48e7.58 (m, 2H, 2ꢂAreH),
8.06 (d, 1H, J¼7.9 Hz, AreH); 13C NMR (
d, ppm, CDCl3): 13.8 (CH3),
28.3 (CH2), 43.7 (CH2), 56.0 (OCH3), 56.1 (OCH3), 61.7 (OCH2), 106.7
(CH), 111.4 (CH), 113.6 (CH), 124.1 (C), 124.6 (CH), 127.3 (CH), 128.1
(C), 130.1 (CH), 133.0 (CH), 133.1 (C), 135.8 (C), 147.6 (C), 147.9 (2ꢂC),
149.9 (C); MS (m/z, %): 398 (Mþ, 15), 164 (100).
3.11. 2-(3,4-Dimethoxyphenyl)-6,7-dimethoxynaphthalene-
1,4-dione (6a)
A solution of Fremy’s salt (961 mg, 3.65 mmol, 5 equiv) and
potassium biphosphate (107 mg, 0.79 mmol, 1.1 equiv) in water
(23 mL) were added to a solution of naphthylamine 15 (243 mg,
0.72 mmol) in acetone (13 mL). The suspension was stirred at rt for
1 h and the acetone was evaporated in vacuo. The residue was
extracted with dichloromethane (3ꢂ15 mL) and the combined or-
ganic layers were washed with water (25 mL), dried and concen-
trated to dryness in vacuo. The solid residue was submitted to flash
column chromatography (eluent: AcOEt/hexane, 4:6) and com-
pound 6a was isolated (164 mg, 65% yield) as a red solid. Rf¼0.61
3.14. 3-(4,5-Dimethoxy-2-vinylphenyl)-5-nitro-2H-
isoquinolin-1-one (18)
A mixture of compound 9c (100 mg, 0.251 mmol) and sodium
hydride (42 mg, 1.757 mmol) in dry DMF (4 mL) was heated at
130 ꢀC under argon for 3 h. The mixture was cooled and the excess
sodium hydride was destroyed by adding a few drops of MeOH. The
DMF was removed in vacuo. The resulting residue was neutralized
with 20% aqueous acetic acid solution and extracted with CH2Cl2
(3ꢂ15 mL). The organic extracts were washed with water (30 mL),
dried and evaporated to dryness. The resulting solid was purified by
column chromatography (1:1 AcOEt/hexane) to afford compound
18 (43 mg, 55% yield) as an amorphous pale yellow solid. Rf¼0.28
(50% AcOEt/hexane); mp 192e194 ꢀC (MeOH); IR (
n
, cmꢁ1, NaCl):
, ppm, CDCl3): 3.87 (s, 6H, 2ꢂOCH3), 3.97 (s,
1649 (C]O); 1H NMR (
d
6H, 2ꢂOCH3), 6.87e6.90 (m, 2H, 2ꢂAreH), 7.07e7.19 (m, 2H,
2ꢂAreH), 7.44 (s, 1H, AreH), 7.51 (s, 1H, AreH); 13C NMR (
d
, ppm,
(50% AcOEt/hexane); IR (
n
, cmꢁ1, NaCl): 1664 (C]O), 1600 (C]C),
, ppm, CDCl3): 3.98 (s, 3H, OCH3),
CDCl3): 55.9 (2ꢂOCH3), 56.3 (OCH3), 56.4 (OCH3), 107.1 (CH), 108.3
(CH),110.8 (CH),112.3 (CH),122.7 (CH),126.0 (C),126.7 (C), 127.1 (C),
133.4 (CH), 146.8 (C), 148.6 (C), 150.7 (C), 153.2 (C), 153.3 (C), 184.0
(C]O), 184.5 (C]O); MS (m/z, %): 354 (Mþ, 21), 58 (100); HRMS
calcd for C20H18O6 [M]þ 354.1103; found 354.1099.
1515 (NO2), 1340 (NO2); 1H NMR (
d
4.00 (s, 3H, OCH3), 5.27 (m, 1H, HC]CHH), 5.66 (m, 1H, HC]CHH),
7.03e7.15 (m, 2H, AreHþHC]CH2), 7.25 (s, 1H, AreH), 7.47e7.56
(m, 1H, AreH), 7.79e7.82 (m, 2H, 2ꢂAreH), 8.25 (d, 1H, J¼7.7 Hz,
AreH), 11.30 (s, broad 1H, NH); 13C NMR (
d, ppm, CDCl3): 56.0
(OCH3), 56.1 (OCH3), 109.0 (CH), 111.9 (CH), 115.4 (CH2), 120.4 (C),
124.6 (C), 126.2 (CH), 126.9 (CH), 127.8 (CH), 130.4 (2ꢂC), 134.1 (CH),
134.9 (CH), 148.7 (C), 149.1 (C), 150.8 (C), 152.7 (C), 163.6 (C]O); MS
(m/z, %): 353 [(MþH)þ, 2.5], 309 (100); HRMS calcd for C19H17N2O5
[MþH]þ 353.1132; found 353.1134.
3.12. 2-(3,4-Dimethoxyphenyl)-3-hydroxy-6,7-dimethoxy-
naphthalene-1,4-dione (6b)
A suspension of quinone 6a (40 mg, 0.113 mmol), NaOH (23 mg,
0.619 mmol, 5.5 equiv) and a MeOH/H2O mixture (20 mL) was
stirred under a dry atmosphere at 50 ꢀC for 4.5 h. The mixture was
acidified with 10% HCl. The resulting red solid was filtered off and
washed with water. The aqueous layer was extracted with CH2Cl2
(3ꢂ10 mL). The combined organic layers were washed with H2O,
brine and dried (Na2SO4) and concentrated to dryness, to yield the
same red solid. These solids were combined and purified by re-
crystallization to give quinone 6b (37 mg, 90% yield). Rf¼0.53 (50%
3.15. 3-(4,5-Dimethoxy-2-vinylphenyl)-2-methyl-5-nitroiso-
quinolin-1(2H)-one (19)
To a suspension of NaH (52 mg, 1.73 mmol) in dry THF (2 mL) at
0
ꢀC compound 18 (70 mg, 0.199 mmol) in dry THF (2 mL) was
slowly added under argon and the resulting mixture was stirred at
rt for 30 min. MeI (0.414 mL, 6.66 mmol) was then added dropwise,
and the reaction mixture was stirred at rt for 2 h. The NaH was
destroyed adding water (1 mL) and the THF was evaporated off. The
aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL). The combined
AcOEt/hexane); mp 234e236 ꢀC (MeOH); IR (
(C]O), 3327 (OH); 1H NMR (
(s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.02 (s, 3H, OCH3), 7.00 (d, 1H,
n
, cmꢁ1, NaCl): 1645
, ppm, CDCl3): 3.98 (s, 3H, OCH3), 3.99
d

9994
M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
extracts were dried, filtered and evaporated to dryness in vacuo, to
give a residue that was purified by column chromatography (2:3
AcOEt/hexane) to afford compound 19 (50 mg, 69% yield) as a white
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.10.035. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
solid. Rf¼0.45 (60% AcOEt/hexane); IR (
n
, cmꢁ1, NaCl): 1677 (C]O),
1513 (NO2),1268 (NO2); 1H NMR (
d
, ppm, CDCl3): 3.33 (s, 3H, NCH3),
3.90 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 5.18 (d,1H, HC]CHH), 5.61 (d,
1H, HC]CHH), 6.45 (dd, 1H, Jcis]11 Hz, Jtrans¼17.3 Hz, HC]CH2),
6.86 (s, 1H, AreH), 7.13 (s, 1H, AreH), 7.48e7.55 (m, 1H, AreH),
7.72e7.77 (m, 2H, 2ꢂAreH), 8.33 (d, 1H, J¼7.9 Hz, AreH); 13C NMR
References and notes
(
d
, ppm, CDCl3): 33.2 (NCH3), 56.5 (2ꢂOCH3), 108.4 (CH), 110.9 (CH),
1. (a) Shamma, M. The Isoquinoline Alkaloids: Chemistry and Pharmacology, In.
Blomquist, A. T., Wasserman, H., Eds.; Academic Press: New York, London,
Verlag Chemie, Weinheim, 1972; (b) Shamma, M.; Moniot, J. L. Isoquinoline
Alkaloids Research 1972-1977, Plenum Press: New York, London, 1978; (c) Gui-
116.0 (CH2), 121.1 (C), 126.9 (C), 127.1 (CH), 127.5 (CH), 127.9 (CH),
129.1 (2ꢂC), 133.1 (CH), 134.8 (CH), 147.6 (C), 149.7 (C), 150.7 (C),
155.8 (C), 162.8 (C]O); MS (m/z, %): 321 (Mþꢁ44, 58), 58 (100).
Anal. Calcd for C20H19N2O5: C, 65.57; H, 4.95; N, 7.65. Found: C,
67.74; H, 5.22; N, 7.39.
ꢀ
naudeau, H.; Leboeuf, M.; Cave, A. J. Nat. Prod. 1990, 53, 235.
ꢀ
2. (a) Simanek, V. Benzophenanthridine Alkaloids In. The Alkaloids. Chemistry and
Pharmaology; Brossi, A., Ed.; Academic.: Orlando, 1985; Vol. 26; p 229; (b)
Bhakuni, D. S.; Jain, S. Protoberberine Alkaloids In. The Alkaloids. Chemistry and
Pharmacology; Brossi, A., Ed.; Academic.: Orlando, 1986; Vol. 28; p 169.
3. (a) Fang, S.-D.; Wang, L.-K.; Hetch, S. M. J. Org. Chem. 1993, 58, 5025; (b) Rashid,
M. A.; Gustafson, K. R.; Kashman, Y.; Cardellina, J. H., II; McMahon, J. B.; Boyd,
M. R. Nat. Prod. Lett. 1995, 6, 153; (c) Huang, F.-C.; Kutchan, T. M. Phytochemistry
2000, 53, 555; (d) Ishikawa, T. Med. Res. Rev. 2001, 21, 61; (e) Chang, Y.-C.; Hsieh,
P.-W.; Chang, F.-R.; Wu, R.-R.; Liaw, C.-C.; Lee, K.-H.; Wu, Y.-C. Planta Med. 2003,
69, 148.
4. (a) Cheng, C. C. Structural Aspects of Antineoplastic Agents-A New Approach In.
Progress in Medicinal Chemistry; Ellis, G. P., West, G. B., Eds.; Elsevier Science, B.
V. (Biomedical Division): Amsterdam, 1988; Vol. 25, pp 35e83; Vavreckova, C.;
Gawlik, I.; Muller, K. Planta Med. 1996, 62, 397; (b) Nakanishi, T.; Suzuki, M. J.
Nat. Prod. 1998, 61, 1263; (c) Fleury, F.; Sukhanova, A.; Ianoul, A.; Devy, J.; Ku-
delina, I.; Duval, O.; Alix, A. J. P.; Jardillier, J. C.; Nabiev, I. J. Biol. Chem. 2000, 275,
3501; (d) Gonzaga, W. A.; Weber, A. D.; Giacomelli, S. R.; Dalcol, I. I.; Hoelzel, S.
C. S.; Morel, A. F. Planta Med. 2003, 69, 371.
5. (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogene-
sis; Cambridge University: Cambridge, 1991; (b) Harvey, R. G. The Handbook of
Environmental Chemistry In. Part I: PAHs and Related Compounds; Hutzinger, O.,
Neilson, A., Eds.; Springer: Heidelberg, 1997; Vol. 3, pp 1e54 Chapter 1; (c) Wu
Harvey, R. G. Polycyclic Aromatic Hydrocarbons: Chemistry and Carcinogenesis;
Wiley-VCH: New York, NY, 1997.
6. (a) Bernardo, P. H.; Chai, C. L. L.; Le Guen, M.; Smith, G. D.; Waring, P. Bioorg.
Med. Chem. Lett. 2007, 17, 82; (b) Marco-Contelles, J.; Molina, M. Curr. Org. Chem.
2003, 7, 1433; (c) Gould, S. J. Chem. Rev. 1997, 97, 2499; (d) Luo, Y.-L.; Chou, T.-C.;
Cheng, C. C. J. Heterocycl. Chem. 1996, 33, 113; (e) Mocellin, S. Microarray Tech-
nology and Cancer Gene Profiling; Springer: Heidelberg, 2007, Chapter 8, p 98.
7. (a) Bennasar, M.-L. l.; Roca, T.; Ferrando, F. J. Org. Chem. 2005, 70, 9077; (b)
Bernardo, P. H.; Chai, C. L. L.; Heath, G. A.; Mahon, P. J.; Smith, G. D.; Waring, P.;
Wilkes, B. A. J. Med. Chem. 2004, 47, 4958; (c) Mal, D.; Senapati, B. K.; Pahari, P.
Tetrahedron 2007, 63, 3768; (d) Ashcroft, W. R.; Dalton, L.; Beal, M. G.; Hum-
phrey, G. L.; Joule, J. A. J. Chem. Soc., Perkin Trans. 1 1983, 2409.
3.16. 3-(2-(2,2-Dimethoxyethyl)-4,5-dimethoxyphenyl)-5-
nitroisoquinolin-1(2H)-one (20)
A solution of thallium trinitratetrihydrate(68 mg, 0.154 mmol) in
dry MeOH (2 mL) was added to a solution of compound 19 (50 mg,
0.137 mmol) in dry MeOH (2 mL) and the reaction mixture was
stirred at rt for 5 min. It was then filtered and the MeOH of the filtrate
was evaporated off. The residue was taken up in CH2Cl2 and the
solution was washed with saturated aqueous NaHCO3 solution
(2ꢂ5 mL) and water (5 mL), dried and evaporated to dryness. The
resulting unstable derivative 20 was used as a crude for the next step
without further purification. Rf¼0.27 (60% AcOEt/hexane); 1H NMR
(
d
, ppm, CDCl3): 2.70 (dd,1H, J¼14, 4.5 Hz, ArCHH), 3.10 (dd,1H, J¼14,
6 Hz, ArCHH), 3.18 (s, 3H, CH3), 3.25 (s, 3H, CH3), 3.40 (s, 3H, CH3),
3.88 (s, 3H, CH3), 3.95 (s, 3H, CH3), 4.50 [dd, 1H, J¼6, 4.5 Hz, CH
(OMe)2], 6.79 (s, 1H, AreH), 6.96 (s, 1H, AreH), 7.53 (t, 1H, J¼6.6 Hz,
AreH), 7.74e7.77 (m, 2H, 2ꢂAreH), 8.35 (d, 1H, J¼8.1 Hz, AreH).
3.17. 6,7-Dimethoxy-2-(2-methylaminocarbonyl)isoquinolin-
1(2H)-one (21)
To a solution of recently obtained 20 in a 1:1 mixture of MeOH/
H2O (4 mL) p-toluensulfonic acid (52 mg, 0.273 mmol) was added
and the resulting solution was heated at 70 ꢀC for 2 days. The MeOH
was removed in vacuo and more water was added (2 mL). The
resulting suspension was extracted with CH2Cl2 (3ꢂ5 mL). The or-
ganic extracts were washed with 10% aqueous sodium hydroxide
solution (5 mL) and water (5 mL), dried and evaporated to dryness.
Column chromatography (CH2Cl2/MeOH 95:5) of the resulting solid
residue provided compound 21 (43 mg, 86% yield), as a yellow solid.
8. (a) Gribble, G. W. In The Alkaloids; Brossi, A., Ed.; Academic: New York, NY, 1990;
Vol. 39; p 239; (b) Suffness, M.; Cordell, G. A. In The Alkaloids; Brossi, A., Ed.;
Academic: New York, NY, 1985; Vol. 25, p 89; p 304; (c) Kansal, V. K.; Potier, P.
Tetrahedron 1986, 42, 2389; (d) Gribble, G. W.; Saulnier, M. G.; Obaza-Nutaitis,
J. A.; Ketcha, D. M. J. Org. Chem. 1992, 57, 5891; (e) Ishikura, M.; Yaginuma, T.;
Agata, I.; Miwa, Y.; Yanada, R.; Taga, T. Synlett 1997, 214; (f) Díaz, M. T.; Cobas,
ꢀ
€
A.; Guitian, E.; Castedo, L. Synlett 1998, 157; (g) Ergun, Y.; Patir, S.; Okay, G. J.
Heterocycl. Chem. 1998, 35, 1445; (h) Ishikura, M.; Hino, A.; Yaginuma, T.; Agata,
I.; Katagiri, N. Tetrahedron 2000, 56, 193; (i) Anderson, W. K.; Gopalsamy, A.;
Reddy, P. S. J. Med. Chem. 1994, 37, 1955.
Rf¼0.15 (80% AcOEt/hexane); IR (
n
, cmꢁ1, NaCl): 3313 (NH), 1651
9. Mackay, S. P.; Meth-Cohn, O.; Waich, R. D. Advances in Heterocyclic Chemistry;
Academic: New York, NY, 1997; Vol. 67,pp 345e389.
(C]O); 1H NMR (
d
, ppm, CDCl3): 2.71 (d, 3H, J¼5.2 Hz, NCH3), 4.02
10. For
a review covering benzo[c]phenanthridine synthesis until 1998, see:
(s, 3H, OCH3), 4.03 (s, 3H, OCH3), 6.53 (d, 1H, J¼7.3 Hz, AreH),
6.95e7.00 (m, 3H, NHþ2ꢂAreH), 7.25e7.28 (m, 1H, AreH),
7.51e7.56 (m, 2H, 2ꢂAreH), 7.67e7.71 (m, 1H, AreH), 7.80 (s, 1H,
Ishikawa, T.; Ishii, H. Heterocycles 1999, 50, 627 For more recent articles on this
topic, see: (a) Nakanishi, T.; Suzuki, M. Org. Lett. 1999, 1, 985; (b) Geen, G. R.;
Mann, I. S.; Mullane, M. V.; McKillop, A. Tetrahedron 1998, 54, 9875; (c)
Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.; Abe, H.;
Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 523; (d) Treus, M.; Estevez, J. C.;
Castedo, L.; Estevez, R. J. Tetrahedron Lett. 2002, 43, 5323; (e) Le, T. N.; Gang,
S. G.; Cho, W.-J. J. Org. Chem. 2004, 69, 2768; (f) Harayama, T. Heterocycles
2005, 65, 697; (g) Styskala, J.; Cankar, P.; Soural, M.; Hlavac, J.; Hradil, P.;
Vicar, J.; Simanek, V. Heterocycles 2007, 73, 769; (h) Kohno, K.; Azuma, S.;
Choshi, T.; Nobuhiro, J.; Hibino, S. Tetrahedron Lett. 2009, 50, 590; (i)
Mandadapu, A. K.; Saifuddin, M.; Agarwal, P. K.; Kundu, B. Org. Biomol.
Chem. 2009, 7, 2796.
AreH); 13C NMR (
d
, ppm, CDCl3): 26.4 (CH3), 56.1 (2ꢂOCH3), 106.2
(2ꢂCH), 107.5 (CH), 119.5 (C), 128.2 (CH), 129.1 (2ꢂCH), 130.9
(2ꢂCH), 132.9 (C), 135.9 (C), 138.0 (C), 149.5 (C), 153.9 (C), 162.5 (C]
O), 167.7 (C]O); MS (m/z, %): 339 [(MþH)þ, 56], 308 (100). Anal.
Calcd for C19H18N2O4: C, 67.44; H, 5.36; N, 8.28. Found: C, 67.19; H,
5.53; N, 7.97.
11. See: Salas, C. O.; Reboredo, F. J.; Estevez, J. C.; Tapia, R.; Estevez, R. J. Synlett
2009, 3107 and references therein.
12. See: Mal, D.; Senapati, B. K.; Pahari, P. Tetrahedron 2007, 63, 3768 and references
therein.
Acknowledgements
We thank the Xunta de Galicia for financial support and for
providing a grant to M.T. The University of Santiago de Compostela
is also acknowledged for financial support for a visiting Professor-
ship for C.S. Additional thanks are given to FONDECYT (Research
Grants 11085027 and 1060592) for financial support.
13. (a) Du, C.; Chen, J.; Guo, Y.; Lu, K.; Ye, S.; Zheng, J.; Liu, Y.; Shuai, Z.; Yu, G. J. Org.
Chem. 2009, 74, 7322; (b) Brath, H.; Meskova, M.; Putala, M. Eur. J. Org. Chem.
2009, 3315; (c) Zhou, W.-J.; Wang, K.-H.; Wang, J.-X. J. Org. Chem. 2009, 74,
5599.
ꢀ
ꢀ
14. Treus, M.; Estevez, J. C.; Castedo, L.; Estevez, R. J. Tetrahedron Lett. 2000, 41,
6351.

M. Treus et al. / Tetrahedron 66 (2010) 9986e9995
15. Cava, M. P.; Mitchell, M. J.; Havlicek, S. C.; Lindert, A.; Spangler, R. J. J. Org. Chem. 22. Teuber, H.-J.; Hasselbach, M. Chem. Ber. 1959, 674.
9995
ꢀ ꢀ
23. (a) Estevez, J. C.; Estevez, R. J.; Castedo, L. Tetrahedron Lett. 1993, 34, 6479; (b)
1970, 35, 175.
ꢀ
ꢀ
16. Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem. 1995, 60, 1939.
17. Whaley, W. M.; Hartung, W. H. J. Org. Chem. 1949, 14, 650.
18. (a) Banwell, M. G.; Bissett, 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, 2551;
(b) Banwell, M. G.; Cowden, C. J.; Gable, R. W. J. Chem. Soc., Perkin Trans. 1 1994,
3515.
Cruces, J.; Martínez, E.; Treus, M.; Martínez, L. A.; Estevez, J. C.; Estevez, R. J.;
Castedo, L. Tetrahedron 2002, 58, 3015.
24. (a) Hanaoka, M.; Motonishi, T.; Mukai, C. J. Chem. Soc., Chem. Commun. 1984,
718; (b) Hanaoka, M.; Motonishi, T.; Mukai, C. J. Chem. Soc., Perkin Trans. 1 1986,
2253.
25. Crystallographic data for the structure of compound 21 have been deposited
with the Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC-800247. Copies of the data can be obtained free of charge on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44 1223 336 033;
e-mail deposit@ccdc.cam.ac.uk/).
19. Pampin, M. C.; Estevez, J. C.; Estevez, R. J.; Maestro, M.; Castedo, L. Tetrehedron
2003, 59, 7231.
ꢁ
ꢁ
ꢁ
ꢀ
ꢁ
ꢁ
20. Sindler-Kulyk, M.; Skoric, I.; Tomsic, S.; Marinic, Z; Mrvos-Sermek, D. Hetero-
cycles 1999, 51, 1355.
21. (a) Michael Quante, J.; Stermitz, F. R.; Miller, L. L. J. Org. Chem. 1979, 44, 293; (b)
Beugelmans, R.; Chastanet, J.; Ginsburg, H.; Quintero-Cortes, L.; Roussi, G. J. Org.
Chem. 1985, 50, 4933.
26. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals; Pergamon:
New York, NY, 1988.
27. For spectroscopic properties of compounds 8a and 8b, see Ref. 14.