Electrocyclization-mediated approach to 2-methyltriclisine, an unnatural analog of the azafluoranthene alkaloid triclisine

Article abstract of DOI:10.1002/ejoc.200900673

The synthesis of 2-methyltriclisine, an unnatural analog of the azafluoranthene alkaloid, triclisine, is reported. The synthesis was achieved in 10 steps and 21% overall yield from 2-bromo-3,4-dimethoxybenzaldehyde, through the intermediacy of 3,4-dimetho

Full text of DOI:10.1002/ejoc.200900673

FULL PAPER
DOI: 10.1002/ejoc.200900673
Electrocyclization-Mediated Approach to 2-Methyltriclisine, an Unnatural
Analog of the Azafluoranthene Alkaloid Triclisine
Claudio C. Silveira,[a] Enrique L. Larghi,[b] Samuel R. Mendes,[a] Andrea B. J. Bracca,[b]
Francieli Rinaldi,[a] and Teodoro S. Kaufman*[b]
Keywords: Synthesis design / Nitrogen heterocycles / Natural products / Alkaloids / Azafluoranthenes / Electrocyclization
The synthesis of 2-methyltriclisine, an unnatural analog of
the azafluoranthene alkaloid triclisine, is reported. The syn-
thesis was achieved in 10 steps and 21% overall yield from
2-bromo-3,4-dimethoxybenzaldehyde, through the interme-
diacy of 3,4-dimethoxyfluoren-9-one. Construction of the
heterocyclic ring entailed the para-Claisen rearrangement of
an allyl-4-fluorenyl ether, followed by isomerization of the
resulting 2-allylfluoren-9-one and microwave-assisted
electrocyclization of the aza 6π-electron system formed by
oximation of its carbonyl function.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
a
Introduction
The azafluoranthenes are ubiquitous in nature; the par-
ent bases have been found in coal tar, cigarette smoke, river
and lake sediments and also as air pollutants in street
dust.[1] Being nitrogen-containing polycyclic aromatic com-
pounds, these heterocycles are also considered among the
environmental priority contaminants.[2]
The azafluoranthene alkaloids are a small and unique
class of naturally occurring compounds containing the in-
deno[1,2,3-ij]isoquinoline motif (1a, Figure 1);[3] it includes
the non-phenolic tetracycles rufescine (1b), imeluteine (1c)
and triclisine (1d),[3b] isolated from the Amazonian vines
Abuta rufescens, A. imene and Triclisia gilletii (Dewild)
Staner (Menispermaceae), respectively.
In addition, norrufescine (1e), found in A. rufescens, A.
imene and Telitoxicum peruvianum, together with telitoxine
(1f), isolated from T. peruvianum and T. glaziovii[3c] and nor-
imeluteine (1g) obtained from the tropical climbing shrub
Cissampelos pareira,[3d] constitute the phenolic members of
this family.
These compounds share some structural features with
the naturally occurring 2,7-diazafluoranthenes like eupo-
lauridine (2a) and its N-oxides 2b, 2c that can be found in including the eupolauridines 2a–c, stephaoxocanes 3a,b and
Figure 1. Chemical structures of indeno[1,2,3-ij]isoquinoline (1a),
the azafluoranthene alkaloids 1b–g and related natural products,
tropolo-isoquinolines 4a,b.
Annonaceae, as well as with the less widespread stephaox-
ocanes, such as stephaoxocanidine (3a) and eletefine (3b)
[a] Department of Chemistry, Universidade Federal de Santa Ma-
ria,
and the tropolo-isoquinolines, exemplified by grandirubrine
(4a) and imerubrine (4b).[4] Compounds carrying the latter
two skeletons have been isolated from Menispermaceous
plants, including species which are also sources of azafluor-
anthene alkaloids.[5a] Furthermore, azafluoranthene deriva-
tives have been prepared as part of some synthetic efforts
toward tropolo-isoquinolines.[5b,5c]
CEP 97105.900, Santa Maria, Brazil
[b] Institute of Chemistry of Rosario (IQUIR, CONICET-UNR)
and School of Biochemical and Pharmaceutical Sciences,
National University of Rosario,
Suipacha 531, S2002LRK Rosario, Argentina
Fax: +54-341-4370477
E-mail: kaufman@iquir-conicet.gov.ar
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900673.
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The azafluoranthene alkaloids display various properties
of biological and technological interest. They have been
patented as constituents of wound-healing agents[6a] and
have been reported to possess antidepressant activity.[6b] In
addition, compounds 1e and 1g were isolated with the aid
of a bioassay guided fractionation, monitoring the cytotoxi-
city against P-388 cells and demonstrated to be active at
5.8 µg/mL and 3.6 µg/mL, respectively,[3d] while related 4-
azafluoranthene derivatives have been shown to act as 5-
hydroxytryptamine subclass 3 receptor (5-HT3) agonists.[6c]
Furthermore, as part of their efforts aimed to develop
new approaches to discotic liquid crystals, which form tilted
columnar phases with ferroelectric properties, Scherowsky
et al. synthesized the azafluoranthene derivative 1h and de-
termined its crystal structure, confirming the suitability of
the tetracycle for the formation of discotic phases.[7]
The main synthetic approach used toward azafluoranth-
enes has been the Pschorr-type cyclization of 1-(2-ami-
nopheny1)-3,4-dihydro- and 1,2,3,4-tetrahydro-isoquinoline
derivatives.[8] Other strategies have included the use of 8-
phenylisoquinolin-1-one intermediates,[9a] the inverse elec-
tron demand Diels–Alder reaction of 3-methoxycarbonyl-
2-pyrones[9b] and an aza-Wittig reaction in tandem with an
intramolecular oxidative biaryl coupling under promotion
of vanadium reagents,[9e] as well as metallation cross-cou-
pling[9c] and photochemical[9d] reaction schemes. Interest-
ingly, some unsuccessful attempts have also been dis-
closed.[10]
Scheme 1. Retrosynthetic analysis of 2-methyltriclisine (5).
In pursuit of our interest in the elaboration of polycyclic
tetrahydroisoquinoline-type natural products, their deriva-
tives[11] and bioactive analogs,[12] herein we report the syn- removing activating and protecting groups. Threrefore, and
thesis of 2-methyltriclisine (5), an unnatural analog of tricli- taking into account the technological and biomedical im-
sine (1d), from the known 3,4-dimethoxyfluoren-9-one (8) portance of fluoren-9-ones, their usefulness as synthetic in-
and a new synthesis of this tricyclic ketone. The reaction termediates and their occurrence as natural products,[15] we
sequence toward 5 features the electrocyclization reaction also decided to devise a new strategy toward 8.
of an aza 6π-electron system as the final key transforma-
Despite that a number of different approaches to flu-
tion, which involves formation of the N–2C bond. Synthesis oren-9-ones have been reported, the most useful ones be-
of isoquinoline derivatives based on the formation of this long to either one of two groups. The first one (route a)
bond is still one of the less exploited strategic alternatives involves formation of the five-membered ring by closure of
toward constructing these heterocyles; however, it is cur- a properly functionalized biphenyl intermediate (9), usually
rently receiving considerable attention.[13]
through an intramolecular acylation, while the second and
comparatively less explored group consists of the intramo-
lecular arylation (route b) of a suitably activated benzophe-
none-type precursor (10).[16]
Results and Discussion
We conjectured that for our purpose, in either case
As shown in the retrosynthetic analysis of 5 depicted in known aldehydes 11a,b[17a,17b] readily available in gram
Scheme 1, we envisioned that our target could be obtained quantities from isovanillin (11c) through its selective ortho-
from oxime derivative 6; in turn, it was considered that this halogenation, followed by a Williamson etherification of
intermediate would be accessed from fluoren-9-one 7, the free phenol, would be appropriate starting materials.
through a sequence which should include the Claisen re- The high atom efficiency of transition metal-mediated “di-
arrangement of its allyl ether moiety, as well as O-methyl- rect” arylations inclined us toward exploring the intramo-
ation and oximation of the fluoren-9-one carbonyl. Finally, lecular arylation alternative.
7 could be reached from the known fluoren-9-one 8.[14]
Therefore, the synthesis (Scheme 2) began with the treat-
However, among the reported routes toward 8, the most ment of iodoaldehyde 11a[17a] with phenylmagnesium bro-
efficient one furnished the fluorenone in six steps and ap- mide. This furnished 85% of benzhydrol 12a, which once
proximately 60% overall yield, from 2,3,4-trimethoxyben- oxidized with PDC, gave 93% of benzophenone derivative
zoic acid.[14a] We concluded that this sequence was excess- 10a, setting the stage for the exploration of the direct palla-
ively long, partly because of the need of introducing and dium-catalyzed intramolecular biaryl coupling.[18]
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Unnatural Analog of the Azafluoranthene Alkaloid Triclisine
siderably reduced yields were observed, in the absence of
K2CO3, while use of Pd(OAc)2 as source of palladium re-
sulted in complete decomposition of the starting material
when triethanolamine was employed as solvent.
The cyclization reaction of aldehydes 10a,b to furnish 8
probably proceeds through the initial oxidative addition of
the palladium catalyst to the starting aryl halide to afford
an arylpalladium halide intermediate (A), the PdII center
of which would then undergo intramolecular nucleophilic
attack by the phenyl moiety, yielding complex B after
deprotonation, as first suggested by the group of
Miura.[20b–20d]
Then, reductive elimination of Pd0 from complex B
should result in formation of the required biaryl bond and
release of the catalyst. Being an electron-rich ligand, the
bulky Buchwald’s phosphane 13 may facilitate both, the
oxidative addition step and also dissociation of the halide,
yielding a more reactive cationic palladium(II) species (A).
Having secured a short and efficient access of fluoren-9-
one 8, we turned our attention to the task of dealkylating
its 4-OMe group. Sodium alkyl sulfides have gained general
acceptance as efficient and selective agents for dealkylation
of methyl ethers.[21] Not quite unexpectedly, when 8 was
submitted to reaction with sodium ethyl sulfide in DMF, a
60:40 inseparable mixture of both possible mono-methyl
ethers 14a and 14b, as assessed by 1H NMR integration
of the signals of their methyl ether moieties, was smoothly
obtained in 92% combined yield (Scheme 3).
Scheme 2. Reagents and conditions: a) PhMgBr, THF, 0 °CǞr.t.
(12a, 85%; 12b, 94%); b) PDC, CH2Cl2, room temp., 15 h (10a,
93%; 10b, 92%); c) Pd(PPh3)4, DavePhos (13), KOAc, K2CO3,
DMA, 110 °C, 22 h (10aǞ8, 34%; 10bǞ8, 88–96%).
However, when cyclization of 10a was attempted using
the Pd(OAc)2–triethanolamine reagent system,[19] the deha-
logenated starting material (10c)[17c] was obtained as the
sole product in 84% yield (Table 1). On the other hand,
submission of 10a to cyclization in dimethylacetamide
(DMA) under Pd(PPh3)4 catalysis, employing DavePhos
(13) as ligand in the presence of a mixture of KOAc and
Interestingly, however, despite that the stabilizing effect
K2CO3, gave only 34% yield of 8, along with 19% of the on the phenoxide intermediate resulting from dealkylation
dehalogenated benzophenone 10c, which hindered the puri- of a methyl ether ortho/para to an electron-withdrawing
fication of the cyclized product.
group has been invoked as a factor that may facilitate a
Taking into account that iodide salts have been found to second O-demethylation process,[22a] in this case the bis-de-
exert a poisoning effect in the direct arylation reaction,[20a] methylated product could not be detected.
the analogous bromoaldehyde 11b[17b] was employed as
The observed product ratio is also interesting, given the
starting material for a similar reaction sequence, furnishing apparent key role that electronic factors play in the selectiv-
benzophenone 10b in 87% overall yield. To our satisfaction, ity of this process, which is particularly prone to dealkyate
after several attempts it was observed that submission of methyl ethers located ortho or para to electron-withdrawing
10b to the Pd(PPh3)4-catalyzed cyclization in DMA, em- groups.[22b] The preferred demethylation of the ortho-disub-
ploying ligand 13 in the presence of a mixture of KOAc stituted methyl ether moiety[23a,23b] could arise from the
and K2CO3, smoothly and consistently afforded 8, in yields out-of-plane preferred conformation adopted by the methyl
ranging from 88 to 96% after heating 22 h at 110 °C. Con- group in these compounds, which may facilitate their reac-
Table 1. Optimization of the direct arylation reaction.
Starting material
Pd source
Reagents and conditions
Product (% yield)
10a
10a
10b
10b
10b
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
N(CH2CH2OH)3, microwave, 120 °C, 10 min
KOAc, K2CO3, 13, DMA, 110 °C,[a] 23 h
N(CH2CH2OH)3, microwave, 120 °C, 30 min
KOAc, 13, DMA, 135 °C,[a] 4 h
10c (84)
8 (34)
deccomposition
8 (56)
8 (88–96)
KOAc, K2CO3, 13, DMA, 110 °C,[a] 22 h
[a] Bath preheated at the designated temperature.
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T. S. Kaufman et al.
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Scheme 3. Reagents and conditions: a) NaH, EtSH, DMF, 50 °C,
17 h (14a/14b = 60:40); b) H2C=CHCH2Br, K2CO3, EtOH, reflux,
90 min (7, 52%; 15, 33%, from 8); c) 1,2-Cl2-C6H4, reflux, 12 h
(80%).
Scheme 4. Reagents and conditions: a) MeI, K2CO3, EtOH, reflux,
2 h (92%); b) PdCl2(MeCN)2, CH2Cl2, reflux, 60 h (90%); c)
H2NOMe·HCl, NaOAc, EtOH, 2 h (95%); d) 1,2-Cl2-C6H4, micro-
wave (115 W, 180 °C), 60 min (81%).
tion with the sulfur nucleophile. Unfortunately, use of the
more hindered sodium tert-butyl sulfide did not provide
better selectivity, furnishing at best a 1.07:1 ratio of mono-
methyl derivatives, in 68% combined yield after conducting
the reaction 10 h at 50 °C.
90% of the 1-propenyl-fluorenone derivative 18 as a single
isomer to which the E configuration was attributed, on the
basis of the observed coupling constants between its vinylic
protons (J = 15.9 Hz).
Without further purification, the mixture of phenols
14a,b was treated with allyl bromide and anhydrous potas-
sium carbonate in absolute EtOH, yielding 7 and 15 in 52%
and 33% overall yield, respectively, after chromatographic
separation. Unequivocal identification of both pair of com-
pounds, the phenols 14a,b and their corresponding allyl
ethers 7 and 15 was aided by the clearly evident 4–5 ppm
downfield shift of the methyl carbon atom in the fluoren-9-
ones 14b and 15, which bear an ortho disubstituted methyl
ether.[23b,23c]
Secondly, 18 was subjected to oximation with meth-
oxylamine hydrochloride, furnishing 89% of the corre-
sponding N-methoxy oxime 6a. Interestingly, again only
one isomer was detected, to which the anti stereochemistry
was assigned on the basis that this configuration avoids the
steric congestion between the vinylic protons of the pro-
penyl group and the methoxy moiety of the oxime.
Finally, submission of the 1-azatriene 6a to the proposed
microwave-assisted electrocyclization reaction, smoothly
furnished the expected final product 5. The best results were
obtained when the transformation was carried out in 1,2-
Cl2-C6H4, where 81% yield of product was obtained, after
heating at 180 °C during 1 h.
Next, the projected para-Claisen rearrangement of 7 was
performed. Despite that microwave heating of the allyl ether
in 1,2-Cl2-C6H4 (180 °C, 2 h) and in Ph2O (180 °C, 80 min
or 260 °C, 20 min) furnished rearranged products in accept-
able yields, the best results were achieved by submitting the
allyl ether to conventional reflux in 1,2-Cl2-C6H4. This gave
allylfluorenone derivative 16 in 80% yield. The product,
A detailed spectroscopic analysis of 5 was carried out,
based on evidences provided by HMQC, HMBC and selec-
tive NOE experiments, which allowed the unequivocal as-
1
signment of its H and 13C NMR resonances.
1
which displayed 2-H as a singlet in its H NMR spectrum
The observation of signal enhancement of 7-H upon irra-
diation of the 6-OMe group in the NOE experiment, unam-
biguously located the chemical shift of 7-H; this also al-
lowed to establish that 5-OMe (δH = 3.97 ppm) is more
shielded than 6-OMe (δH = 4.04 ppm), suggesting that the
previously reported assignments for these groups in triclis-
ine (1d)[27] could be reversed.
(δH = 6.46 ppm), was uneventfully alkylated under standard
conditions (Scheme 4), with MeI in refluxing EtOH to
which excess K2CO3 was added, giving 1-allylfluoren-9-one
17 in 92% yield.
In order to elaborate the heterocyclic ring, two alterna-
tives were considered. One of them included the established
thermal electrocyclization of an ortho-propenyl oxime,[24]
while the second possibility consisted in the palladium-cata-
lyzed cyclization of an oxime derived from the the 1-allyl-
fluorenone derivative 17, as described by Tsutsui and Nara-
saka.[25] The latter transformation does not seem to imply
isomerization of the allyl moiety and electrocyclization of
Conclusions
The synthesis of 2-methyltriclisine (5), an unnatural ana-
the resulting intermediate; however, since its reported yields log of the azafluoranthene alkaloid triclisine (1d) was
were only moderate, the first alternative was pursued. achieved, in ten steps and 21% overall yield from 2-bromo-
Therefore, the allyl moiety of 17 was first isomerized with 3,4-dimethoxy benzaldehyde (11a), through the intermedi-
PdCl2(MeCN)2 in refluxing CH2Cl2 during 60 h[26] to give acy of known 3,4-dimethoxyfluoren-9-one (8) and without
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Unnatural Analog of the Azafluoranthene Alkaloid Triclisine
mation of fluoren-9-one 8 was monitored employing a Shimadzu
model 14B gas chromatograph fitted with a J&W Scientific
30 mϫ0.25 mm polydimetylsiloxane capillary column and a flame
ionization detector. Hydrogen (1 mL/min) was employed as carrier
resorting to the use of protecting groups. The synthesis fea-
tures a para-Claisen rearrangement and a microwave as-
sisted 6π electrocyclization reaction of a properly substi-
tuted 1-propenylfluoren-9-one-oxime for construction of
the heterocyclic ring. In addition, it includes a new and ef-
ficient three-step synthesis of 8, in 78% overall yield from
2-bromo-3,4-dimethoxybenzaldehyde (11a), employing a
strategy consisting in Grignard addition to polysubstituted
benzaldehyde 11a, followed by oxidation of the so produced
benhydrol and a palladium-catalyzed direct arylation of the
resulting benzophenone, as key transformation.
gas. Chromatographic parameters were: Tdet = 270 °C; Tinj
=
250 °C. The temperature gradient program was 50–250 °C at 10 °C/
min. Microwave-assisted reactions were performed in a CEM Dis-
cover microwave oven.
3,4-Dimethoxyfluoren-9-one (8) from 2-Iodo-3,4-dimethoxybenzal-
dehyde (11a):
A stirred solution of aldehyde 11a (400 mg,
1.37 mmol) in THF (15 mL) was cooled to –40 °C and treated
dropwise (20 min) with a freshly prepared THF solution of phenyl-
magnesium bromide (0.30 , 6 mL). After 1 h, the reaction was
treated with saturated NH4Cl solution (5 mL), the system was al-
lowed to reach room temperature and the product was extracted
with EtOAc (3ϫ15 mL). The combined organic phases were
washed with brine (10 mL), dried with Na2SO4 and subjected to
chromatography, giving (2-iodo-3,4-dimethoxyphenyl)phenylmeth-
anol (12a) (594 mg, 85%), as a white solid; m.p. 123–125 °C (hex-
Experimental Section
General: The reactions were carried out under dry nitrogen or ar-
gon atmosphere, employing oven-dried glassware. Reagents were
used as received; anhydrous THF was prepared by distillation from
Na-benzophenone ketyl; anhydrous DMF was obtained by heating
the PA grade product over BaO for 4 h, followed by distillation
under reduced pressure; absolute EtOH was accessed by refluxing
the solvent over clean magnesium turnings and distilling from the
resulting magnesium ethoxide; anhydrous DMA and 1,2-dichloro-
benzene were prepared by distillation of the corresponding com-
mercial products; anhydrous CH2Cl2 was prepared by a 4 h reflux
of the solvent over P2O5 followed by distillation; anhydrous sol-
vents were stored in dry Young ampoules. All other reagents were
used as received.
ane/EtOAc). IR (KBr): ν = 3469, 2961 1950, 1584, 1476, 1393,
˜
1278, 1134, 1026, 916, 814, 729 (and 661) cm–1. 1H NMR: δ = 2.51
(br. s, 1 H, w1/2 = 7.2 Hz, OH), 3.83 (s, 3 H, 3-OMe), 3.86 (s, 3 H,
4-OMe), 6.10 (s, 1 H, ArCH), 6.88 (d, J = 8.6 Hz, 1 H, 5-H), 7.15
(d, J = 8.6 Hz, 1 H, 6-H), 7.25–7.42 (m, 5 H, ArH) ppm. 13C NMR:
δ = 56.1 (4-OMe), 60.3 (3-OMe), 78.7 (C-OH), 98.2 (2-C), 112.5
(5-C), 124.1 (6-C), 127.1 (2 C, 2-CЈ and 6-CЈ), 127.6 (4-CЈ), 128.4
(2 C, 3-CЈ and 5-CЈ), 138.6 (1-C), 142.6 (1-CЈ), 148.5 (3-C), 152.0
(4-C) ppm. GC/MS: m/z (%) = 370 (88) [M+], 293 (21), 211 (30),
165 (39), 105 (100). Without further purification, a stirred solution
of 12a (406 mg, 1.10 mmol) in anhydrous CH2Cl2 (25 mL) was
treated with PDC (515 mg, 1.37 mmol) at room temperature. The
resulting suspension was stirred until complete consumption of the
starting material (15 h); then, the slurry was filtered through Celite
and concentrated under reduced pressure to give an oily residue,
which was chromatographed, affording (2-bromo-3,4-dimeth-
oxyphenyl)phenylmethanone 10a (375 mg, 93%), as a yellowish so-
In the conventional work-up procedure, the reaction mixture was
diluted with brine (5–10 mL) and the products were extracted with
EtOAc (4–5ϫ20 mL); the combined organic extracts were then
washed once with brine (5 mL), dried with Na2SO4 and concen-
trated under reduced pressure. The residue was subjected to flash
column chromatography with silica gel 60 H. Elution was carried
out with hexane/EtOAc mixtures, under positive pressure and em-
ploying gradient of solvent polarity techniques. All new com-
pounds gave single spots on TLC plates run in different hexane/
EtOAc and CH2Cl2/toluene solvent systems. Chromatographic
spots were detected by exposure to 254 nm UV light, followed by
spraying with ethanolic ninhydrin (nitrogen-containing com-
pounds) or with ethanolic p-anisaldehyde/sulfuric acid reagent and
careful heating of the plates for improving selectivity.
lid; m.p. 117–119 °C (hexane/EtOAc). IR (KBr): ν = 2938, 2840,
˜
1668, 1577, 1476, 1386, 1274, 1155, 1024, 959, 851, 717, 627 cm–1.
1H NMR: δ = 3.87 (s, 3 H, 3-OMe), 3.93 (s, 3 H, 4-OMe), 6.95 (d,
J = 8.4 Hz, 1 H, 5-H), 7.06 (d, J = 8.4 Hz, 1 H, 6-H), 7.44 (br. dd,
J = 7.4, 7.9 Hz, 2 H, 3Ј-H and 5Ј-H), 7.59 (dt, J = 1.2, 7.4 Hz, 1
H, 4Ј-H), 7.80 (dd, J = 1.2, 7.9 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. 13C
NMR: δ = 56.1 (4-OMe), 60.5 (3-OMe), 92.2 (2-C), 111.8 (5-C),
125.3 (6-C), 128.5 (2 C, 3-CЈ and 5-CЈ), 130.5 (2 C, 2-CЈ and 6-CЈ),
133.4 (4-CЈ), 136.3 (1-CЈ), 137.3 (1-C), 149.2 (3-C), 155.0 (4-C),
196.6 (C=O) ppm. Anhydrous KOAc (19 mg, 0.19 mmol), Da-
vePhos (3.7 mg, 0.0095 mmol) and K2CO3 (26 mg, 0.19 mmol)
were succesively added to a solution of Pd(PPh3)4 (6.5 mg,
0.0057 mmol) in DMA (1.5 mL) and the resulting suspension was
stirred at room temperature during 15 min, when a solution of
iodobenzophenone 10a (35 mg, 0.095 mmol) in DMA (0.5 mL) was
introduced via a cannula. The system was heated at 110 °C until
all the starting material was consumed (23 h). Then, the solvent
was removed in vacuo at 35 °C and the remaining solid was sus-
pended in EtOAc (4 mL), filtered through a short plug of cotton
and transferred to a separatory funnel. Water (4 mL) was added to
remove dissolved salts and the aqueous phase was back-extracted
with EtOAc (2ϫ5 mL). The combined organic extracts were
washed with brine (2.5 mL), dried with MgSO4 and chromato-
graphed, furnishing the benzophenone derivative 10c (4.3 mg, 19%)
as a white solid; m.p. 88–90 °C (hexane/EtOAc; ref.[17c] 86–90 °C).
Melting points were determined on an Leitz hot-stage microscope
(model 350) and are reported uncorrected. FTIR spectra were ac-
quired with a Shimadzu Prestige 21 spectrophotometer as thin
films held between NaCl cells or as solid dispersions in KBr disks.
The 1H and 13C NMR spectra were acquired in CDCl3 in a Bruker
Avance spectrometer (300.13 and 75.48 MHz for 1H and 13C,
respectively). The chemical shifts are reported in parts per million
downfield from tetramethylsilane used as internal standard, and
coupling constants (J) are expressed in Hertz. DEPT 135 and
DEPT 90 experiments aided the interpretation and assignment of
the fully decoupled 13C NMR spectra. In special cases, 2D-NMR
experiments (COSY, HMBC and HMQC) were also employed.
Pairs of signals marked with asterisks (*) or hashes (#) indicate
that their assignments may be exchanged. GC-MS analyses were
performed with a Perkin–Elmer Q-700 spectrometer equipped with
an apolar fused silica capillary column (30 m ϫ0.25 mm), coated
with 5% phenyl- and 95% dimethyl-polysiloxane (DB-5, coating
thickness 0.25 µm). High-resolution mass spectroscopic data were
obtained from the University of California, Riverside (USA). For-
IR (KBr): ν = 3000, 2940, 2840, 1660, 1580, 1480, 1320, 1250, 1180,
˜
1
1030, 964, 814, 770, 690 cm–1. H NMR: δ = 3.94 (s, 3 H, OMe),
Eur. J. Org. Chem. 2009, 4637–4645
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4641

T. S. Kaufman et al.
FULL PAPER
3.96 (s, 3 H, OMe), 6.89 (d, J = 8.4 Hz, 1 H, 5-H), 7.38 (dd, J = (350 mg, 1.09 mmol) in DMA (0.5 mL) was introduced via a can-
1.8, 8.4 Hz, 1 H, 6-H), 7.44–7.52 (m, 2 H, 3Ј-H and 5Ј-H), 7.50 (d, nula. The system was heated at 110–120 °C during 22 h, until all
J = 1.8 Hz, 1 H, 2-H), 7.57 (ddt, J = 1.4, 6.6, 8.3 Hz, 1 H, 4ЈH), the starting material was consumed. Then, the solvent was removed
7.76 (dd, J = 1.4, 8.3 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. 13C NMR: δ
in vacuo at 35 °C and the remaining solid was suspended in EtOAc
= 56.0 (OMe), 56.1 (OMe), 109.7 (5-C), 112.1 (2-C), 125.5 (6-C),
(40 mL), filtered through a short plug of cotton and transferred to
128.2 (2 C, 3Ј-C and 5Ј-C), 129.7 (2 C, 2Ј-C and 6Ј-C), 130.2 (1- a separatory funnel. Water (40 mL) was added to remove dissolved
C), 131.9 (4Ј-C), 138.3 (1Ј-C), 149.0 (3-C), 153.0 (4-C), 195.6
(C=O) ppm. Increasing solvent polarity provided fluoren-9-one 8
(11.3 mg, 34%), as a bright yellow solid; m.p. 143.5–145 °C (hex-
salts and the aqueous phase was back-extracted with EtOAc
(2ϫ25 mL). The combined organic phases were washed with brine
(25 mL), dried with MgSO4 and chromatographed to furnish the
fluoren-9-one derivative 8 (262 mg, 90%), the melting point and
spectroscopic data of which were in agreement with those obtained
ane/EtOAc, ref.[14] 143–144.5 °C). IR (KBr): ν = 2924, 2831, 1702,
˜
1610, 1599, 1494, 1256, 1104, 1021, 959, 818, 756, 606 cm–1. 1H
NMR: δ = 3.93 (s, 3 H, 3-OMe), 3.96 (s, 3 H, 4-OMe), 6.73 (d, J for 8 when synthesized from iodooaldehyde 12a through the inter-
= 8.0 Hz, 1 H, 2-H), 7.26 (t, J = 7.4 Hz, 1 H, 7-H), 7.41 (d, J =
8.0 Hz, 1 H, 1-H), 7.46 (t, J = 7.4 Hz, 1 H, 6-H), 7.62 (d, J =
7.4 Hz, 1 H, 8-H), 7.83 (d, J = 7.4 Hz, 1 H, 5-H) ppm. 13C NMR:
δ = 56.2 (3-OMe), 60.4 (4-OMe), 111.2 (2-C), 121.4 (1-C), 123.8
(8-C), 124.0 (5-C), 128.0 (9a-C), 128.8 (7-C), 134.5 (6-C), 135.2 (8a-
C), 136.3 (4a-C), 142.5 (4b-C), 144.8 (4-C), 159.1 (3-C), 192.4
(C=O) ppm. GC/MS: m/z (%) = 368 (100) [M+], 291 (98), 226 (34),
105 (68).
mediacy of 2-iodobenzophenone derivative 10a.
4-Allyloxy-3-methoxyfluoren-9-one (7), and 3-Allyloxy-4-methoxy-
fluoren-9-one (15): A stirred solution of EtSH (0.27 mL, 3.6 mmol)
in DMF (5.0 mL) was treated with a 50% dispersion of NaH in
mineral oil (156.4 mg, 3.26 mmol) and heated at 50 °C during
20 min, when a solution of fluoren-9-one 8 (263 mg, 1.09 mmol) in
DMF (1.5 mL) was added via cannula to the thus formed sodium
ethanothiolate. The resulting reddish solution was stirred at 50 °C
during 17 h, until complete consumption of starting ketone was
verified by TLC. Then, the reaction was cautiously treated with
1.0  HCl (15 mL), rendering a yellow solution, which was ex-
tracted with Et2O (3ϫ10 mL). The combined organic phases were
washed with brine (2ϫ10 mL), dried with Na2SO4, concentrated
under reduced pressure and chromatographed, yielding 14a and
(2-Bromo-3,4-dimethoxyphenyl)phenylmethanol (12b):
A stirred
solution of 2-bromo-3,4-dimethoxybenzaldehyde (11b, 500 mg,
2.04 mmol) in THF (8 mL) was cooled to 0 °C and treated drop-
wise (20 min) with a freshly prepared THF solution of phenylmag-
nesium bromide (0.34 , 7.3 mL). After 1.5 h, the reaction was
warmed to room temperature, saturated NH4Cl solution (10 mL)
was added and the product was extracted with EtOAc (3ϫ15 mL).
The combined organic phases were washed with brine (2ϫ10 mL),
dried with MgSO4 and subjected to chromatography, furnishing
12b (617 mg, 94%), as a white solid; m.p. 102–103 °C (hexane/
1
14b, as an approximately 60:40 (by H NMR:) inseparable mixture
1
of regioisomers. Spectral data of 14a H NMR: δ = 3.92 (s, 3 H,
3-OMe), 6.15 (br. s, 1 H, w1/2 = 6 Hz, OH), 6.64 (d, J = 8.0 Hz, 1
H, 3-H), 7.23 (t, J = 7.4 Hz, 1 H, 7-H), 7.39 (d, J = 8.0 Hz, 1 H,
2-H), 7.45 (t, J = 7.4 Hz, 1 H, 6-H), 7.61 (d, J = 7.4 Hz, 1 H, 8-
H), 7.80 (d, J = 7.4 Hz, 1 H, 5-H) ppm. 13C NMR: δ = 56.4 (3-
OMe), 109.3 (2-C), 117.7 (1-C), 123.8 (5-C), 124.2 (8-C), 127.9 (9a-
C), 128.1 (7-C), 129.0 (4a-C), 134.6 (6-C), 134.7 (8a-C), 136.7 (4b-
C), 141.4 (4-C), 152.8 (3-C), 193.3 (C=O) ppm. Spectral data of
EtOAc). IR (KBr): ν = 3500, 2936, 2836, 1593, 1485, 1280, 1142,
˜
1
1031, 921, 812, 728, 649 cm–1. H NMR: δ = 2.80 (br. s, 1 H, w1/2
= 15 Hz, OH), 3.84 (s, 3 H, 3-OMe), 3.85 (s, 3 H, 4-OMe), 6.16 (s,
1 H, ArCH), 6.87 (d, J = 8.8 Hz, 1 H, 5-H), 7.20 (d, J = 8.8 Hz, 1
H, 6-H), 7.26–7.38 (m, 5 H, ArH) ppm. 13C NMR: δ = 56.1 (4-
OMe), 60.5 (3-OMe), 74.6 (C-OH), 111.4 (5-C), 118.9 (2-C), 123.6
(6-C), 126.9 (2 C, 2-CЈ and 6-CЈ), 127.6 (4-CЈ), 128.3 (2 C, 3-CЈ
and 5-CЈ), 135.7 (1-C), 142.5 (1-CЈ), 146.2 (3-C), 152.9 (4-C) ppm.
HRMS calcd. C15H14BrO3: 321.0121 [M+ – H]; found 321.0121.
1
14b H NMR: δ = 3.96 (s, 3 H, 4-OMe), 6.83 (d, J = 8.0 Hz, 1 H,
3-H), 6.96 (br. s, 1 H, w1/2 = 12 Hz, OH), 7.27 (d, J = 8.0 Hz, 1 H,
2-H), 7.25 (t, J = 7.4 Hz, 1 H, 7-H), 7.47 (t, J = 7.4 Hz, 1 H, 6-H),
7.63 (d, J = 7.4 Hz, 1 H, 8-H), 7.69 (d, J = 7.4 Hz, 1 H, 5-H) ppm.
13C NMR: δ = 61.1 (4-OMe), 115.7 (2-C), 122.4 (3-C), 123.5 (5-
C), 124.0 (8-C), 128.1 (9a-C), 128.3 (7-C), 134.6 (4a-C), 134.5 (6-
C), 135.1 (8a-C), 141.7 (4b-C), 142.8 (4-C), 156.1 (3-C), 192.4
(C=O) ppm. The mixture of phenols (194.0 mg, 0.857 mmol) was
dissolved in absolute EtOH (1.5 mL); allyl bromide (0.096 mL,
1.12 mmol) and K2CO3 (165.5 mg, 1.2 mmol) were added under
gently stirring, and the resulting reddish suspension was heated un-
der reflux for 1.5 h. Then, the suspension was filtered, the solids
were washed with EtOAc (1 mL) and the filtrate was concentrated
under reduced pressure, leaving a solid residue, which was chro-
matographed to afford allyl ether 15 (75 mg, 33% overall yield), as
(2-Bromo-3,4-dimethoxyphenyl)phenylmethanone (10b): A solution
of 11b (420 mg, 1.30 mmol) in anhydrous CH2Cl2 (13.4 mL) was
treated with PDC (1.285 g) at room temperature. The resulting sus-
pension was stirred until full consumption of the starting material
(20 h); then, it was filtered through Celite and concentrated to give
an oily residue, which was chromatographed to afford benzophe-
none 10b (382 mg, 92%) as a white solid; m.p. 121–122 °C (hexane/
EtOAc). IR (KBr): ν = 3002, 2937, 2839, 1658, 1587, 1486, 1321,
˜
1299, 1180, 1034, 964, 813, 720, 699 cm–1. 1H NMR: δ = 3.89 (s, 3
H, 3-OMe), 3.93 (s, 3 H, 4-OMe), 6.87 (d, J = 8.8 Hz, 1 H, 5-H),
7.21 (d, J = 8.8 Hz, 1 H, 6-H) 7.45 (br. dd, J = 7.9, 7.4 Hz, 2 H,
3Ј-H and 5Ј-H), 7.58 (dt, J = 1.2, 7.4 Hz, 1 H, 4Ј-H), 7.80 (dd, J
= 1.2, 7.9 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. 13C NMR: δ = 56.2 (4-
OMe), 60.7 (3-OMe), 110.9 (5-C), 116.2 (2-C), 125.1 (6-C), 128.5
(2 C, 3-CЈ and 5-CЈ), 130.2 (2 C, 2-CЈ and 6-CЈ), 133.4 (4-CЈ), 133.7
(1-C), 136.7 (1-CЈ), 146.8 (3-C), 155.0 (4-C), 195.3 (C=O) ppm.
HRMS calcd. C15H14BrO3: 321.0121 [MH+]; found 321.0131.
an oil. IR (KBr): ν = 3020, 2950, 2848, 1699, 1557, 1498, 1360,
˜
1254, 1107, 1013, 926, 825, 758, 695 cm–1. 1H NMR: δ = 3.99 (s, 3
H, 4-OMe), 4.66 (dd, J = 1.4, 3.8 Hz, 2 H, ArOCH2), 5.35 (dd, J
= 1.4, 10.5 Hz, 1 H, CH=CH2cis), 5.47 (dd, J = 1.4, 17.2 Hz, 1 H,
CH=CH2trans), 6.08 (dddd, J = 3.8, 3.8, 10.5, 17.2 Hz, 1 H,
CH=CH2), 6.73 (d, J = 8.2 Hz, 1 H, 2-H), 7.26 (dt, J = 1.0, 7.5 Hz,
1 H, 7-H), 7.40 (d, J = 8.2 Hz, 1 H, 1-H), 7.47 (dt, J = 1.0, 7.5 Hz,
1 H, 6-H), 7.63 (dd, J = 1.0, 7.5 Hz, 1 H, 8-H), 7.85 (dd, J = 1.0,
7.5 Hz, 1 H, 5-H) ppm. 13C NMR: δ = 60.4 (4-OMe), 69.7 (Ar-
OCH2), 112.6 (2-C), 118.3 (CH=CH2), 121.2 (1-C), 123.8 (8-C),
3,4-Dimethoxyfluoren-9-one (8) from 2-Bromobenzophenone (10b):
A solution of Pd(PPh3)4 (78 mg, 0.0675 mmol), in DMA (5 mL)
was successivelly treated with anhydrous KOAc (219 mg,
2.23 mmol), DavePhos (44 mg, 0.111 mmol) and K2CO3 (309 mg, 124.0 (5-C), 128.2 (9a-C), 128.7 (6-C), 132.3 (CH=CH2), 134.6 (7-
2.24 mmol) and the resulting suspension was stirred at room tem-
perature during 15 min, when a solution of benzophenone 10b
C), 135.1 (8a-C), 136.5 (4a-C), 142.6 (4b-C), 145.0 (4-C), 158.0 (3-
C), 192.5 (C=O) ppm. HRMS calcd. C17H15O3: 267.1016 [MH+];
4642
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4637–4645

Unnatural Analog of the Azafluoranthene Alkaloid Triclisine
found 267.1017. Increasing solvent polarity allowed the isolation
pad of Celite, and the filtrate was concentrated and chromato-
of desired regioisomer 7 (119 mg, 52% overall yield), as a yellowish graphed, furnishing the isomerized olefin 18 (53 mg, 90%), as a
solid; m.p. 78–79 °C (hexane/EtOAc). IR (KBr): ν = 3022, 2951,
yellow solid; m.p. 174.5–175 °C (hexane/EtOAc). IR (KBr): ν =
˜
˜
2847, 1699, 1560, 1497, 1365, 1253, 1105, 1009, 926, 822, 757, 692
2972, 2850, 1697, 1584, 1426, 1371, 1257, 1172, 1023, 924, 837,
1
1
cm–1. H NMR: δ = 3.93 (s, 3 H, 3-OMe), 4.65 (br. d, J = 5.9 Hz, 750, 687 cm–1. H NMR: δ = 1.96 (dd, J = 1.7 and 6.8 Hz, 3 H,
2 H, ArOCH2), 5.28 (dd, J = 1.4, 10.4 Hz, 1 H, CH=CH2cis), 5.42
(dd, J = 1.4, 17.2 Hz, 1 H, CH=CH2trans), 6.14 (dddd, J = 5.9, 5.9,
10.4, 17.2 Hz, 1 H, CH=CH2), 6.74 (d, J = 8.0 Hz, 1 H, 2-H), 7.27
CH2-Me), 3.93 (s, 3 H, OMe), 3.94 (s, 3 H, OMe), 6.37 (dq, J =
6.8, 15.9 Hz, 1 H, CH-Me), 6.83 (s, 1 H, 2-H), 7.26 (dt, J = 1.4,
7.5 Hz, 1 H, 7-H), 7.45 (dt, J = 1.4, 7.5 Hz, 1 H, 6-H), 7.61 (dd, J
(t, J = 7.5 Hz, 1 H, 7-H), 7.43 (d, J = 8.0 Hz, 1 H, 1-H), 7.45 (t, J = 1.4, 7.5 Hz, 1 H, 8-H), 7.63 (dd, J = 1.7, 15.9 Hz, 1 H,
= 7.5 Hz, 1 H, 6-H), 7.63 (d, J = 7.5 Hz, 1 H, 8-H), 7.88 (d, J =
ArCH=CH), 7.85 (dd, J = 1.4, 7.5 Hz, 1 H, 5-H) ppm. 13C NMR:
δ = 18.8 (CH-Me), 56.0 (3-OMe), 60.4 (4-OMe), 107.0 (2-C), 122.5
7.5 Hz, 1 H, 5-H) ppm. 13C NMR: δ = 56.2 (3-OMe), 73.7 (Ar-
OCH2), 111.2 (2-C), 118.3 (CH=CH2), 121.4 (1-C), 123.8 (8-C), (1-C), 123.4 (8-C), 123.7 (5-C), 126.1 (ArCH=CH), 128.6 (7-C),
124.2 (5-C), 128.1 (9a-C), 128.7 (6-C), 133.8 (CH=CH2), 134.5 (7- 129.9 (ArCH=CH), 134.1 (6-C), 135.6 (9a-C),* 135.8 (8a-C),*
C), 135.2 (8a-C), 136.7 (4a-C), 142.6 (4b-C), 143.3 (4-C), 159.1 (3-
C), 192.5 (C=O) ppm. HRMS calcd. C17H15O3: 267.1016 [MH+];
found 267.1018.
136.0 (4a-C),# 141.8 (4b-C),# 143.9 (4-C),# 158.4 (3-C), 193.2
(C=O) ppm. HRMS calcd. C18H17O3: 281.1172 [MH+]; found
281.1171.
1-Allyl-4-hydroxy-3-methoxyfluoren-9-one (16): A solution of allyl
ether 7 (93.0 mg, 0.349 mmol) in 1,2-Cl2-C6H4 (3.0 mL) was heated
at reflux, until complete consumption of the starting material was
observed by TLC (12 h). Then, the solution was chromatographed
yielding 16 (74 mg, 80%), as a bright yellow solid; m.p. 185–
(E)-1-Propenyl-3,4-dimethoxyfluoren-9-one (Z)-O-Methyl Oxime
(6a): O-Methyl hydroxylamine hydrochloride (177.4 mg,
2.12 mmol) and anhydrous NaAcO (174.2 mg, 2.12 mmol) were
successively added to
a stirred solution of 18 (25.3 mg,
0.0903 mmol) in absolute EtOH (3.0 mL), and the reaction was
refluxed overnight, when an additional amount of methoxyamine
hydrochloride (50 mg) was added in order to drive the process to
completion. Then, the greenish suspension was evaporated to dry-
ness and the residue was subjected to column chromatography, fur-
nishing N-methoxy oxime 6a (22 mg, 89%), as a pale yellow solid;
185.5 °C (hexane/EtOAc). IR (KBr): ν = 3411, 3069, 2937, 2850,
˜
1625, 1599, 1466, 1385, 1249, 1129, 1004, 906, 851, 740, 666 cm–1.
1H NMR: δ = 3.80 (dd, J = 1.3, 5.3 Hz, 2 H, ArCH2), 3.94 (s, 3
H, 3-OMe), 5.06 (ddd, J = 1.4, 3.0, 10.0 Hz, 1 H, CH=CH2cis),
5.13 (ddd, J = 1.4, 3.0, 17.1 Hz, 1 H, CH=CH2trans), 5.92 (s, 1 H,
OH), 5.98 (dddd, J = 5.3, 5.3, 10.0, 17.1 Hz, 1 H, CH=CH2), 6.46
(s, 1 H, 2-H), 7.23 (dt, J = 0.8, 7.5 Hz, 1 H, 7-H), 7.45 (dt, J = 1.1,
7.5 Hz, 1 H, 6-H), 7.60 (br. d, J = 7.5 Hz, 1 H, 8-H), 7.83 (br. d,
J = 7.5 Hz, 1 H, 5-H) ppm. 13C NMR: δ = 34.9 (ArCH2), 56.4 (3-
OMe), 110.9 (2-C), 116.0 (CH=CH2), 123.4 (8-C), 124.0 (5-C),
124.4 (1-C), 128.0 (7-C), 128.5 (9a-C), 134.2 (6-C), 134.9 (8a-C),#
135.1 (4a-C),# 136.5 (CH=CH2), 140.0 (4b-C),# 142.2 (4-C),# 152.3
(3-C), 193.6 (C=O) ppm. HRMS calcd. C17H15O3: 267.1016
[MH+]; found 267.1017.
m.p. 87–88 °C (hexane/EtOAc). IR (KBr): ν = 3048, 2931, 2828,
˜
1
1603, 1567, 1428, 1372, 1293, 1198, 1057, 843, 740, 697 cm–1. H
NMR: δ = 1.97 (dd, J = 1.8, 6.6 Hz, 3 H, CH-Me), 3.94 (s, 3 H,
3-OMe), 3.96 (s, 3 H, 4-OMe), 4.22 (s, 3 H, N-OMe), 6.28 (dq, J
= 6.6, 15.8 Hz, CH=Me), 6.94 (s, 1 H, 2-H), 7.29 (dt, J = 1.0,
7.6 Hz, 1 H, 6-H), 7.41 (dt, J = 1.0, 7.6 Hz, 1 H, 7-H), 7.56 (br.
dd, J = 1.8, 15.8 Hz, 1 H, ArCH=CH), 8.05 (br. d, J = 7.6 Hz, 1
H, 5-H), 8.34 (br. d, J = 7.6 Hz, 1 H, 8-H) ppm. 13C NMR: δ =
18.8 (CH-Me), 56.0 (3-OMe), 60.3 (4-OMe), 63.4 (N-OMe), 108.1
(2-C), 123.4 (5-C), 124.1 (1-C), 127.2 (ArCH=CH), 127.8 (6-C),
129.1 (8-C), 129.2 (ArCH=CH), 130.8 (7-C), 131.5 (9a-C),* 131.8
(2 C, 4a-C and 8a-C),# 132.9 (4b-C),# 139.4 (4-C),# 143.9
(C=NOMe), 154.0 (3-C) ppm. HRMS calcd. C19H20NO3: 310.1438
[M+]; found 310.1442.
1-Allyl-3,4-dimethoxyfluoren-9-one
1.45 mmol) and K2CO3 (34.8 mg, 0.362 mmol) were successively
added to stirred solution of allylphenol 16a (64.3 mg,
(17):
MeI
(0.090 mL,
a
0.242 mmol) in absolute EtOH (4.0 mL) and the resulting suspen-
sion was heated under reflux until complete consumption of the
starting material was observed (2 h). The solvent was removed un-
der reduced pressure, the remaining solid was diluted with brine
(5 mL) and extracted with CHCl3 (5ϫ3 mL); filtration through a
short pad of silica gave 17 (62 mg, 92%), as a yellow solid; m.p.
5,6-Dimethoxy-2-methylindeno[1,2,3-ij]isoquinoline (2-methyltriclis-
ine, 5): A solution of oxime 6a (21 mg, 0.067 mmol) in 1,2-Cl2-
C6H4 (2.5 mL) was transferred to a microwave reactor tube; the
tube was purged with argon, sealed and heated at 180 °C during
60 min, when absence of starting material was ascertained by TLC.
The solution was submitted to column chromatography, giving 5
(15 mg, 81%) as a white solid; m.p. 126–128 °C (hexane/EtOAc).
112.5–113.5 °C (hexane/EtOAc). IR (KBr): ν = 3066, 2972, 2829,
˜
1697, 1505, 1425, 1371, 1257, 1172, 1023, 923, 836, 750, 665 cm–1.
1H NMR: δ = 3.83 (dt, J = 1.4, 6.9 Hz, 2 H, ArCH2), 3.93 (s, 3 H,
3-OMe), 3.94 (s, 3 H, 4-OMe), 5.09 (ddd, J = 1.4, 3.0, 7.1 Hz, 1 H,
CH=CH2trans), 5.15 (ddd, J = 1.4, 3.0, 17.1 Hz, 1 H, CH=CH2cis),
5.99 (dddd, J = 6.9, 6.9, 7.1, 17.1 Hz, 1 H, CH=CH2), 6.53 (s, 1
H, 2-H), 7.26 (dt, J = 1.1, 7.5 Hz, 1 H, 7-H), 7.46 (dt, J = 1.1,
7.5 Hz, 1 H, 6-H), 7.60 (br. d, J = 7.5 Hz, 1 H, 8-H), 7.85 (br. d,
J = 7.5 Hz, 1 H, 5-H) ppm. 13C NMR: δ = 35.1 (ArCH2), 56.1 (3-
OMe), 60.4 (4-OMe), 112.7 (2-C), 116.3 (CH=CH2), 123.5 (8-C),
123.8 (5-C), 124.1 (1-C), 128.7 (7-C), 134.3 (9a-C), 135.5 (8a-C),
136.2 (6-C), 136.7 (4a-C),# 138.9 (CH=CH2), 141.9 (4b-C),# 143.4
(4-C),# 158.6 (3-C), 193.1 (C=O) ppm. HRMS calcd. C18H16O3:
281.1172 [MH+]; found 281.1173.
IR (KBr): ν = 2943, 2853, 1592, 1488, 1354, 1251, 1038, 999, 843,
˜
1
744, 622 cm–1. H NMR: δ = 2.79 (s, 3 H, 2-Me), 3.97 (s, 3 H, 5-
OMe), 4.04 (s, 3 H, 6-OMe), 6.86 (s, 1 H, 4-H), 7.23 (s, 1 H, 3-H),
7.38 (ddd, J = 1.5, 7.4, 7.5 Hz, 1 H, 9-H), 7.43 (ddd, J = 1.5, 7.4,
7.5 Hz, 1 H, 8-H), 7.94 (br. dd, J = 1.5, 7.4 Hz, 1 H, 7-H), 8.15
(dd, J = 1.5, 7.4 Hz, 1 H, 10-H) ppm. 13C NMR: δ = 24.9 (Me-2),
56.3 (5-OMe), 61.4 (6-OMe), 104.2 (4-C), 115.4 (3-C), 121.6 (3a-
C), 121.9 (10-C), 124.7 (7-C), 126.3 (10c-C), 128.2 (8-C), 129.6 (9-
C), 131.2 (6a-C), 138.4 (10a-C), 139.2 (6b-C), 147.0 (6-C), 154.5
(2-C), 158.5 (10b-C), 159.1 (5-C) ppm. HRMS calcd. C18H16NO2:
278.1176 [MH+]; found 278.1179.
(E)-1-Propenyl-3,4-dimethoxyfluoren-9-one (18): A stirred solution
of 17 (58.4 mg, 0.208 mmol) in CH2Cl2 (5.0 mL) was treated with
PdCl2(MeCN)2 (4.7 mg, 0.018 mmol) and the reaction was refluxed
during 60 h. The resulting black slurry was filtered through a short
Supporting Information (see also the footnote on the first page of
this article): Copies of the 13C NMR spectra of the target com-
pounds and synthetic intermediates are provided.
Eur. J. Org. Chem. 2009, 4637–4645
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4643

T. S. Kaufman et al.
FULL PAPER
[12]
[13]
D. A. Bianchi, A. B. J. Bracca, G. Schmeda Hirschmann, C.
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Acknowledgments
Support for an international cooperation provided by Ministerio
de Ciencia, Tecnología e Innovación Productiva – Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (MINCyT-CAPES)
(Project BR-06/019), is greatly acknowledged. E. L. L. and T. S. K.
thank Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET) (PIP number 3294), and Agencia Nacional de Promo-
ción Científica y Tecnológica (ANPCyT) (PICT number 06-38165).
A. B. J. B. thanks CONICET for her fellowship.
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