Synthesis of 5-carbapterocarpens by α-arylation of tetralones followed by one-pot demethylation/cyclization with BBr3

Article abstract of DOI:10.1002/ejoc.201301505

5-Carbapterocarpens, one of them displaying estrogenic activity, were prepared from α-aryltetralones in high yields through a one-pot, BBr ₃-promoted O-demethylation and cyclization sequence. The key α-aryltetralone intermediates were obtained

Full text of DOI:10.1002/ejoc.201301505

FULL PAPER
DOI: 10.1002/ejoc.201301505
Synthesis of 5-Carbapterocarpens by α-Arylation of Tetralones Followed by
One-Pot Demethylation/Cyclization with BBr3
Talita de A. Fernandes,[a,b] Jorge L. O. Domingos,*[c,d] Luiza I. A. da Rocha,[a]
Sabrina de Medeiros,[a] Carmen Nájera,*[d] and Paulo R. R. Costa*[a]
Keywords: Medicinal chemistry / Oxygen heterocycles / C–C coupling / Arylation / Cyclization / Pterocarpens
5-Carbapterocarpens, one of them displaying estrogenic ac-
tivity, were prepared from α-aryltetralones in high yields
through a one-pot, BBr3-promoted O-demethylation and
cyclization sequence. The key α-aryltetralone intermediates
were obtained by direct α-arylation of tetralones with o-alk-
oxybromoarenes in the presence of Pd2(dba)3 (2.5 mol-%)
and tBu3PHBF4 (10 mol-%) as catalysts, together with
2.5 equiv. of KOH in dioxane/H2O (4:1), under microwave ir-
radiation conditions (80 W, 100 °C, 40 min), leading to α-
monoaryltetralones in good yields.
to ERα (IC50 3 nm) and to ERβ (IC50 4 nm) with similar
affinities, whereas 3 had the same affinity for ERβ but
showed a lower affinity for ERα, thus being more selective
(ERα, IC50 129 nm; ERβ, IC50 4 nm). Compound 4 also
showed essentially the same affinity as 1 and 3 for ERβ but
was less selective (ERα, IC50 18 nm; ERβ, IC50 3 nm). These
compounds were claimed to be useful for the treatment of
hormone-sensitive cancers.[3] The bioselectivity observed in
the case of the 5-carbapterocarpen showed its potential as
a scaffold for prospecting new estrogen receptors.
Introduction
Estrogen receptors (ERs) are a group of intracellular
proteins activated by the hormone estrogen [17β-estradiol
(1), Figure 1].[1] These receptors, divided into ERα and ERβ
subtypes, play a central role in toxicology and human dis-
ease, exerting pleiotropic effects on tissues such as ovary,
testis, prostate, breast, uterus, bone, and liver, as well as
the immune system and cardiovascular and central nervous
systems.[1] Estrogen receptor antagonists are potentially
useful in the chemotherapy of hormone-dependent cancers:
tamoxifen (2, Figure 1), for example, has being used in
breast cancer treatment.[2] In 2006, Miller et al. reported[3]
the synthesis of pterocarpens and analogues such as 3 and
4, respectively, and the affinities of these compounds for
estrogen receptors were studied. The natural ligand 1 binds
[a] Laboratório de Química Bioorgânica, Núcleo de Pesquisas de
Produtos Naturais, Universidade Federal do Rio de Janeiro,
Centro de Ciências da Saúde,
Bloco H, Ilha da Cidade Universitária, 21941-590 Rio de
Janeiro, RJ, Brazil
E-mail: prrcosta2011@gmail.com
http://www.nppn.ufrj.br/
[b] Instituto de Química, Universidade Federal do Rio de Janeiro,
Centro de Tecnologia,
Figure 1. Estrogen (1), tamoxifen (2), pterocarpen (3), and 5-
carbapterocarpen (4).
Bloco A, Ilha da Cidade Universitária, 21941-909 Rio de
Janeiro, RJ, Brazil
http://www.iq.ufrj.br/
5-Carbapterocarpens such as 4 and analogues 5 can be
prepared through multistep synthesis from α-aryl-α-
[c] Departamento de Química Orgânica, Centro de Tecnologia e
Ciências, Universidade do Estado do Rio de Janeiro,
Rua São Francisco Xavier 524, Pav. Haroldo Lisboa da tetralones 6 or substituted dihydronaphthalenes 7 as precur-
sors. Miller et al.[3] (Scheme 1) reported a five-step synthesis
Cunha – s 406 – Maracanã, 20550-900 Rio de Janeiro, RJ,
Brazil
of 5-carbapterocarpens such as 4 and analogues 5, the last
step being the phenol deprotection followed by the cycliza-
tion, but these reactions were accomplished only under
drastic conditions, leading to low yields of products. α-Aryl-
α-tetralones 6 were obtained through Suzuki or Stille cou-
pling between compounds 8 (prepared from the corre-
sponding halides) and α-bromoenol acetate derivatives of 9.
E-mail: jlo.domingos@uerj.br
http://www.ppgq-iq.uerj.br/
[d] Departamento de Química Orgánica, Facultad de Ciencias and
Instituto de Síntesis Orgánica (ISO), Alicante University,
Apdo. 99, 03080 Alicante, Spain
E-mail: cnajera@ua.es
http://iso.ua.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301505.
1314
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of 5-Carbapterocarpens
It is worth mentioning that was necessary to use anhydrous
We envisaged that a most straightforward and green ap-
conditions to prepare compounds 8 and that stoichiometric proach to the preparation of these compounds would be
amounts of tin or boron had to be used in the C–C bond- the direct α-arylation of α-tetralones 9 with O-protected o-
formation step.
halophenols 10 (Scheme 2),[5] followed by in situ deprotec-
tion and cyclization of the resulting α-tetralones 6. Here we
report the synthesis of 4 and of seven new analogues, with
different patterns of oxygenated substituents in the A- and
the D-rings, from commercially available starting materials
by this approach.
Results and Discussion
Palladium-catalyzed direct coupling between enolizable
ketones and aryl halides, described by Buchwald,[6a] Hart-
wig,[6b] and Miura,[6c] is a well-established methodology.[6]
In spite of intensive study of α-arylations of ketones,[6] how-
ever, only scattered examples of reactions between substi-
tuted tetralones and aryl halides bearing alkoxy groups at
their ortho-positions have been described.[5,7]
We starting by studying the α-arylation of 9a (Scheme 2)
with o-chloroanisole, but high reaction times and low con-
version were observed, so we then moved to bromoarenes
10a–f. Initially we used 2 equiv. of tetralone (9a) and
1 equiv. of o-bromoanisoles 10a–f in the presence of
Pd2(dba)3 and tBu3PHBF4 as catalysts and KOH as base,
in dioxane/H2O as solvent (Scheme 2 and Table 1). These
conditions, except for the use of KOH instead of KHCO3,
were described by Bellina et al., for the α-arylation of
chromanones.[8] In this work we also tested the robust
oxime-derived palladacycle 4[9] as a palladium source.
Scheme 1. Strategies for the synthesis of pterocarpens and 5-
carbapterocarpens.
In our lab, 5-carbapterocarpens 5 were prepared through
a seven-step synthesis, with intramolecular Heck coupling
of compounds 7 as the last (Scheme 1).[4a] In these cases,
higher yields were observed when iodo derivatives (7, R1 =
I) were employed. More direct methods for the synthesis of
5-carbapterocarpens have also been described, but in these
cases only products not oxygenated in the A- or the D-ring
were prepared. In one case the synthesis proceeded through
α-arylation of α-tetralones with ortho-bromophenol, fol-
lowed by acid-catalyzed cyclization to give benzo[b]furans
in good yields.[4b] In the other, dihalogenated arenes were
used for α-arylation of α-tetralones, followed by intramolec-
ular O-arylation of the resulting aryltetralones.[4c]
Table 1. Major conditions and yields for reactions shown in
Scheme 2.
Entry
ArBr 9a/10 Pd [a]
Conditions[b]
6
Yield [%][c]
1
2
10a
10a
10a
10b
10c
10d
10e
10f
2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
Pd2(dba)3
Pd2(dba)3
palladacycle
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
CH
6a
6a
6a
6b
6c
6d
6e
6f
80
78
70
58
81
71
81
64
77
62
MW
MW
MW
MW
MW
MW
MW
MW
MW
3[d]
4
5
6
7
8
9
10
10a
10d
1:1.2 Pd2(dba)3
1:1.2 Pd2(dba)3
6a
6d
[a] 2.5 mol-%. [b] CH: conventional heating (reflux, 16 h). MW: mi-
crowave heating (80 W, 120 °C, 1 h). Entries 9 and 10: 80 W, 100 °C,
40 min. [c] After purification by chromatography on silica gel. [d]
20 mol-% of TBAB was added.
When the arylation of 9a in the presence of Pd2(dba)3
was performed under reflux for 16 h, total conversion of
o-bromoanisole (10a) was observed, leading to 6a in 80%
isolated yield (Entry 1). The reaction was faster under mi-
crowave heating conditions (1 h), furnishing 6a in 78% yield
(Entry 2). The oxime-derived palladacycle was also tested
under these latter conditions, but in this case it was neces-
sary to use tetra-n-butylammonium bromide (TBAB,
20 mol-%) as additive. Total conversion of 10a was ob-
served, but 6a was obtained in lower yield (70%, Entry 3).
In the next experiments we decided to use Pd2(dba)3 and
Scheme 2. α-Arylation of α-tetralone (9a) with O-alkylated o-
bromophenols 10a–g.
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J. L. O. Domingos, C. Nájera, P. R. R. Costa, et al.
FULL PAPER
microwave heating, which had been selected as the best con- highly apolar, arylated products 6a and 6d could easily be
ditions. The use of benzyl as a protecting group for o- purified by flash chromatography on silica gel.
bromophenol (compound 10b) in the reaction with 9a led
Our next goal was to study palladium-catalyzed α-aryl-
to 6b in a moderate 58% yield (Entry 4), whereas the use ation of commercially available tetralones 9b–f (Scheme 3,
of MOM as protecting group (compound 10c) furnished 1 equiv.) with 10a and also with the less activated bromoar-
adduct 6c in 81% yield (Entry 5). The use of less activated ene 10d (1.2 equiv.), both substituted with MeO groups, un-
bromoarenes 10d and 10e gave rise to adducts 6d and 6e, der MW conditions. The resulting 5-carbapterocarpens
respectively, in good yields (Entries 6 and 7). Surprisingly, bearing methoxy or hydroxy groups have oxygenation pat-
activated bromoarene 10f led to 6f in only moderate yield terns in the A- and D-rings similar to those observed in the
(Entry 8).
naturally occurring pterocarpens and in natural isoflavono-
It is worth mentioning that no diarylated products could ids in general. Although the introduction of methoxy
be detected in the crude reaction mixtures in any of these groups onto the tetralone aromatic ring reduces the acidity
reactions. As 9a and the α-arylated adduct 6 have similar of the α-hydrogen and consequently makes the enolate for-
Rf values on silica gel, however, the use of an excess of mation required for α-arylation reaction more difficult,[10]
9a makes purification troublesome, requiring carefully the α-monoarylation products 11a and 11b to 15a and 15b
chromatographic separation in silica gel. In addition, some could be obtained in reasonable to excellent yields under
oxygenated derivatives of 9a are expensive, making these the conditions used, in spite of the oxygenation patterns on
conditions less attractive. Because bromoarenes 10 are steri- 9 and 10. In these experiments we observed only traces of
cally hindered, we suspected that in this case the diarylation diarylation side products by GC, and the desired α-aryl-α-
step might be disfavored relative to reactions between other tetralones could easily be purified just by filtration through
ketones and bromoarenes not substituted at their o-posi- a pad of silica gel.
tions, in which the ketones were used in excess to minimize
As mentioned above, 5-carbapterocarpens 4 and some
diarylation.[8] We therefore reinvestigated the α-arylation of analogues have been synthesized by a laborious route by
9a with 10a and 10d, and after some experimentation we Miller et al.[3] In our hands, 4 could be obtained in only
changed the ketone/bromoarene ratio to 1.0:1.2 and also two steps, by direct α-arylation of tetralone 9c with bro-
lowered the reaction temperature and time (Entries 9 and moarene 10d (78% yield) followed by one-pot demethyl-
10). Under these new MW conditions, α-aryltetralones 6a ation/cyclization of the resulting 12a (95% yield), in the
and 6d were obtained in similar yields (compare with En- presence of an excess of BBr3[11] in CH2Cl2 at 0 °C, followed
tries 2 and 6). In addition, although bromoarenes 10a–d are by allowing the reaction mixture to warm to room tempera-
Scheme 3. α-Arylation reactions of substituted tetralones 9.
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Synthesis of 5-Carbapterocarpens
ture, as shown in Scheme 4. Under these reaction condi- ane/water allowed the corresponding α-aryl-α-tetralones to
tions compound 16 was obtained from 12b in excellent be obtained in good yields. By controlling the temperature,
yields. The demethylation reaction was site-selective, and 3- demethylation of α-aryltetralones 11a, 11b, 12a, 12b, 13a,
methoxy-5-carbapterocarpens 17a and 17b could be ob- and 13b in the presence of BBr3, followed by one-pot cycli-
tained from 12a and 12b respectively, just by keeping the zation, could be smoothly and selectively accomplished, af-
reaction temperature at 0 °C.
fording 5-carbapterocarpens in high yields. These com-
pounds are strong candidates for evaluation as ligands for
estrogenic receptors.
Experimental Section
General: 1H NMR and 13C NMR spectra were obtained with a
Bruker AC-300, a Varian 400-MR, or a Varian 500-NMR with
CDCl3 or MeOD as solvent and TMS as internal standard. Low-
resolution electron impact (GC-EI) mass spectra were obtained at
70 eV with a Shimadzu QP-5000, and HRMS (GC-EI) were re-
corded with a Finnigan MAT 95S instrument. Analytical TLC was
performed with Schleicher & Schuell F1400/LS silica gel plates, and
the spots were visualized under UV light (λ = 254 nm). Melting
points were determined with a Fisatom 430 apparatus and are un-
corrected. For flash chromatography we employed Merck silica gel
60 (0.040–0.063 mm). CEM Discover and Explorer-Coolmate ac-
cessory were employed in the microwave-assisted reactions for the
generation of α-aryltetralones.
General Procedure for the Microwave-Assisted Synthesis of α-Aryl-
α-tetralones: A suspension of Pd2(dba)3 (6.9 mg, 0.0075 mmol),
tBu3PHBF4 (8.7 mg, 0.03 mmol), KOH (42 mg, 0.75 mmol), aryl
bromide 9 (0.36 mmol), and tetralone 10 (0.3 mmol) in a mixture
of dioxane/water (4:1, v/v, 3 mL) was degassed and heated under
Ar by microwave irradiation (80 W initial power, 100 °C, 40 min,
infrared probe). The mixture was then allowed to cool to room
temp., diluted in AcOEt, washed with saturated NH4Cl solution,
dried with anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The crude material was purified by silica gel
chromatography.
Scheme 4. Synthesis of 5-carbapterocarpens from α-arylated-α-
tetralones.
The structures of these compounds were assigned by 2D
NMR experiments (COSY, HMBC and HSQC). In cases in
which the oxygen atoms of the methoxy groups in the A-
ring in 12a and 12b, as well in 17a and 17b, are less basic
(conjugation with the carbonyl group and the double bond,
respectively), they should have weaker affinities for coordi-
nating with BBr3, explaining the site selectivity observed.[11]
In contrast, in cases in which the methoxy group in the A-
ring was not conjugated with the carbonyl group, as in 11a,
11b, 13a, and 13b, completely deprotected products 18a,
18b, 19a, and 19b, respectively, were obtained even at 0 °C.
Because it was impossible to observe non-cyclized products,
even with use of short reaction times, the high reactivity of
an o-methoxy group in the α-aryl moiety can be explained
in terms of a favorable coordination of BBr3 with the carb-
onyl group in the tetralone moiety, through a complex-in-
duced proximity effect (CIPE).[12]
2-(2-Methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one (6a): The
crude product was purified by preparative TLC with a mixture of
hexane/AcOEt (95:5) as eluent, to give 6a as a brown solid; m.p.
78–80 °C. 1H NMR (400 MHz, CDCl3): δ = 8.10 (dd, J = 7.8,
1.2 Hz, 1 H), 7.49 (td, J = 7.5, 1.4 Hz, 1 H), 7.33 (t, J = 7.6 Hz, 1
H), 7.30–7.23 (m, 2 H), 7.11 (dd, J = 7.5, 1.7 Hz, 1 H), 6.96–6.89
(m, 2 H), 4.05 (dd, J = 12.2, 4.7 Hz, 1 H), 3.75 (s, 3 H), 3.13 (ddd,
J = 16.2, 11.7, 4.4 Hz, 1 H), 3.00 (dt, J = 16.5, 4.1 Hz, 1 H), 2.50
(dtd, J = 16.4, 12.0, 4.4 Hz, 1 H), 2.27 (ddd, J = 13.1, 8.7, 4.4 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 198.1, 157.1, 144.1,
133.2, 133.1, 129.4, 129.3, 128.7, 128.2, 127.6, 126.6, 120.8, 111.1,
55.5, 50.0, 30.0, 29.5 ppm. MS (EI): m/z (%) = 252 (33) [M]+, 234
(11), 90 (100), 63 (18). HRMS: calcd. for C17H16O2 252.1150; found
252.1142.
2-[2-(Benzyloxy)phenyl]-1-tetralone (6b): The crude product was
purified by preparative TLC with a mixture of hexane/AcOEt
(95:5) as eluent, to give 6b as a pale brown oil. 1H NMR: δ = 8.10–
6.90 (m, 13 H), 5.02 (s, 2 H), 4.04 (dd, J = 12.3, 4.7 Hz, 1 H), 3.20–
2.90 (m, 2 H), 2.60–2.45 (m, 1 H), 2.30–2.20 (m, 1 H) ppm. 13C
NMR: δ = 198.1, 156.3, 144.2, 137.1, 133.2, 133.1, 130.0, 129.8,
128.7, 128.5, 128.3, 127.8, 127.7, 127.2, 126.7, 121.2, 112.4, 70.3,
50.8, 30.1, 29.6 ppm. MS (EI): m/z (%) = 328 (7) [M]+, 237 (59),
91 (100). HRMS: calcd. for C23H20O2 328.1463; found 328.1483.
Conclusions
In conclusion, an efficient two-step route for the synthe-
sis of 5-carbapterocarpens has been achieved. Use of palla-
dium-catalyzed α-arylation of α-tetralones with alkoxylated
2-[2-(Methoxymethoxy)phenyl]-1-tetralone (6c): The crude product
bromoarenes under microwave heating conditions in diox- was purified by preparative TLC with a mixture of hexane/AcOEt
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J. L. O. Domingos, C. Nájera, P. R. R. Costa, et al.
FULL PAPER
(95:5) as eluent, to give 6c as a brown oil. 1H NMR: δ = 8.14–6.89
(m, 8 H), 5.11 (d, J = 6.6 Hz, 1 H), 5.07 (d, J = 6.7 Hz, 1 H), 4.03
(dd, J = 12.3, 4.7 Hz, 1 H), 3.38 (s, 3 H), 3.20–2.95 (m, 2 H), 2.60–
7-Methoxy-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one
(11b): The crude product was purified by column chromatography
with a mixture of hexane/AcOEt (97:3) as eluent, to give 11b as a
1
2.45 (m, 1 H), 2.35–2.25 (m, 1 H) ppm. 13C NMR: δ = 197.89, pale brown solid; m.p. 84–85 °C. H NMR (400 MHz, CDCl3): δ
154.92, 144.18, 133.22, 129.90, 129.72, 128.79, 128.31, 127.67,
126.75, 121.99, 114.40, 94.55, 56.14, 50.55, 30.11, 29.60 ppm. MS
= 7.59 (d, J = 2.8 Hz, 1 H), 7.29–7.23 (m, 1 H), 7.20 (d, J = 8.4 Hz,
1 H), 7.12–7.05 (m, 2 H), 6.96–6.89 (m, 2 H), 4.03 (dd, J = 12.1,
(EI): m/z (%) = 282 (19) [M]+, 250 (41), 237 (73), 218 (100), 189 4.7 Hz, 1 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 3.06 (ddd, J = 16.1, 11.6,
(57), 165 (28), 118 (25), 90 (36). HRMS: calcd. for C18H18O3
282.1256; found 282.1260.
4.3 Hz, 1 H), 2.95 (dt, J = 16.3, 4.2 Hz, 1 H), 2.47 (qd, J = 12.4,
4.3 Hz, 1 H), 2.25 (dq, J = 13.0, 4.3 Hz, 1 H) ppm. 13C NMR (by
HSQC and HMBC): δ = 197.9, 158.3, 156.9, 136.6, 133.6, 129.7,
129.2, 128.1, 121.3, 120.5, 111.0, 109.5, 55.4, 55.3, 49.7, 30.0,
28.5 ppm. MS (EI): m/z (%) = 282 (100) [M]+, 264 (31), 161 (46),
148 (29), 120 (53). HRMS: calcd. for C18H18O3 282.1256; found
282.1227.
2-(2,4-Dimethoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one
(6d):
The crude product was purified by column chromatography with a
mixture of hexane/AcOEt (95:5) as eluent, to give 6d as a pale
yellow solid; m.p. 114–116 °C. 1H NMR (400 MHz, CDCl3): δ =
8.09 (d, J = 7.8 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.33 (t, J =
7.6 Hz, 1 H), 7.26 (s, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 6.49 (s, 1 H), 2-(2,4-Dimethoxyphenyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-
6.47 (d, J = 8.3 Hz, 1 H), 3.98 (dd, J = 12.3, 4.5 Hz, 1 H), 3.80 (s,
3 H), 3.73 (s, 3 H), 3.13 (ddd, J = 16.0, 12.0, 4.0 Hz, 1 H), 3.01
(dt, J = 16.5, 3.5 Hz, 1 H), 2.47 (qd, J = 12.3, 4.0 Hz, 1 H), 2.25 12a as a pale brown solid; m.p. 110–111 °C. H NMR (400 MHz,
one (12a): The crude product was purified by column chromatog-
raphy with a mixture of hexane/AcOEt (90:10) as eluent, to give
1
(ddd, J = 12.6, 8.3, 4.1 Hz, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 198.4, 159.8, 158.1, 144.1, 133.2 133.1, 129.6, 128.6,
127.6, 126.5, 121.7, 104.4, 99.1, 55.4, 55.3, 49.4, 30.1, 29.5 ppm.
MS (EI): m/z (%) = 282 (100) [M]+, 264 (10), 151 (38), 131 (27),
118 (33). HRMS: calcd. for C18H18O3 282.1256; found 282.1244.
CDCl3): δ = 8.07 (d, J = 8.7 Hz, 1 H), 6.98 (d, J = 8.3 Hz, 1 H),
6.85 (dd, J = 8.7, 2.5 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 6.49 (d,
J = 2.4 Hz, 1 H), 6.45 (dd, J = 8.3, 2.4 Hz, 1 H), 3.95 (dd, J =
11.9, 4.6 Hz, 1 H), 3.87 (s, 3 H), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.08
(ddd, J = 16.0, 11.6, 4.3 Hz, 1 H), 2.95 (dt, J = 16.3, 4.1 Hz, 1 H),
2.43 (dtd, J = 12.9, 11.9, 4.2 Hz, 1 H), 2.27–2.17 (m, 1 H) ppm.
13C NMR (by HSQC and HMBC): δ = 197.5, 164.0, 160.4, 159.2,
148.1, 131.0, 130.3, 127.3, 122.8, 114.3, 114.1, 105.8, 99.9, 56.7,
56.6, 56.4, 49.9, 30.9, 30.2 ppm. MS (EI): m/z (%) = 312 (100)
[M]+, 161 (45), 148 (94). HRMS: calcd. for C19H20O4 312.1362;
found 312.1310.
2-[3,4-Methylenedioxy-6-(methoxymethoxy)phenyl]-1-tetralone (6e):
The crude product was purified by preparative TLC with a mixture
of hexane/AcOEt (95:5) as eluent, to give 6e as a brown solid; m.p.
1
78–81 °C. H NMR: δ = 8.11–7.23 (m, 4 H), 6.79 (s, 1 H), 6.60 (s,
1 H), 5.91 (d, J = 1.4 Hz, 1 H), 5.90 (d, J = 1.4 Hz, 1 H), 5.01 (d,
J = 6.7 Hz, 1 H), 4.98 (d, J = 6.7 Hz, 1 H), 3.99 (dd, J = 12.6,
4.7 Hz, 1 H), 3.40 (s, 3 H), 3.22–2.97 (m, 2 H), 2.52–2.36 (m, 1 H),
6-Methoxy-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one
2.31–2.21 (m, 1 H) ppm. 13C NMR: δ = 198.12, 149.86, 147.04, (12b): The crude product was purified by column chromatography
144.14, 142.39, 133.31, 133.11, 128.81, 127.72, 126.77, 122.29,
108.82, 101.33, 98.69, 95.84, 56.08, 49.98, 30.42, 29.71 ppm. MS
with a mixture of hexane/AcOEt (95:5) as eluent, to give 12b as a
pale yellow solid; m.p. 78–80 °C. 1H NMR (400 MHz, CDCl3): δ
(EI): m/z (%) = 326 (13) [M]+, 308 (4), 281 (43), 262 (100), 233 (24), = 8.07 (d, J = 8.7 Hz, 1 H), 7.27–7.22 (m, 1 H), 7.09 (d, J = 7.3 Hz,
176 (36). HRMS: calcd. for C19H18O5 326.1154; found 326.1172. 1 H), 6.95–6.89 (m, 2 H), 6.85 (dd, J = 8.7, 2.2 Hz, 1 H), 6.73 (d,
J = 2.3 Hz, 1 H), 4.03 (dd, J = 11.8, 4.6 Hz, 1 H), 3.87 (s, 3 H),
2-[2-(Methoxymethoxy)-5-nitrophenyl]-1-tetralone (6f): The crude
3.76 (s, 3 H), 3.09 (ddd, J = 16.0, 11.7, 4.2 Hz, 1 H), 2.96 (dt, J =
product was purified by preparative TLC with a mixture of hexane/
16.5, 4.0 Hz, 1 H), 2.47 (qd, J = 12.2, 4.1 Hz, 1 H), 2.30–2.20 (m,
AcOEt (95:5) as eluent, to give 6f as a pale brown solid; m.p. 85–
1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 197.1, 163.4, 157.2,
89 °C. 1H NMR: δ = 8.20–7.19 (m, 7 H), 5.22 (d, J = 6.8 Hz, 1 H),
146.6, 130.1, 129.4, 129.4, 128.1, 126.8, 120.7, 113.0, 112.5, 111.1,
5.17 (d, J = 6.8 Hz, 1 H), 4.09 (dd, J = 13.2, 4.6 Hz, 1 H), 3.41 (s,
55.5, 55.4, 49.6, 30.0, 29.7 ppm. MS (EI): m/z (%) = 282 (94)
3 H), 3.30–3.03 (m, 2 H), 2.67–2.52 (m, 1 H), 2.38–2.27 (m, 1
[M]+, 264 (8), 161 (42), 148 (100). HRMS: calcd. for C18H18O3
H) ppm. 13C NMR: δ = 196.31, 160.04, 143.90, 142.15, 133.68,
282.1256; found 282.1259.
132.62, 130.72, 128.94, 127.73, 126.98, 125.53, 124.66, 113.70,
94.45, 56.64, 50.58, 29.74, 29.51 ppm. MS (EI): m/z (%) = 281 (18),
265 (100), 252 (15), 235 (15), 217 (47), 207 (32), 189 (69), 176 (11),
163 (16), 152 (11), 139 (9), 115 (15), 90 (31), 76 (10), 63 (13).
HRMS: calcd. for C18H17NO5 327.1107; found 327.1139.
2-(2,4-Dimethoxyphenyl)-5-methoxy-3,4-dihydronaphthalen-1(2H)-
one (13a): The crude product was purified by column chromatog-
raphy with a mixture of hexane/AcOEt (90:10) as eluent, to give
13a as a pale brown solid; m.p. 98–100 °C. 1H NMR (500 MHz,
CDCl3): δ = 7.70 (d, J = 7.8 Hz, 1 H), 7.29 (t, J = 8.0 Hz, 1 H),
7.03 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.3 Hz, 1 H), 6.50 (d, J =
1.9 Hz, 1 H), 6.47 (dd, J = 8.3, 2.1 Hz, 1 H), 3.99 (dd, J = 12.6,
4.5 Hz, 1 H), 3.88 (s, 3 H), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.18 (dt, J
= 17.4, 3.8 Hz, 1 H), 2.85–2.77 (m, 1 H), 2.41 (qd, J = 12.6, 4.3 Hz,
1 H), 2.25 (dq, J = 12.9, 4.3 Hz, 1 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 198.5, 159.8, 158.1, 156.7, 134.2, 133.1, 129.4, 126.7,
121.5, 119.3, 113.9, 104.3, 98.9, 55.7, 55.4, 55.3, 48.7, 29.3,
22.8 ppm. MS (EI): m/z (%) = 312 (100) [M]+, 294 (14), 161 (48),
151 (43), 148 (29). HRMS: calcd. for C19H20O4 312.1362; found
312.1364.
2-(2,4-Dimethoxyphenyl)-7-methoxy-3,4-dihydronaphthalen-1(2H)-
one (11a): The crude product was purified by column chromatog-
raphy with a mixture of hexane/AcOEt (95:5) as eluent, to give
1
11a as a pale yellow solid; m.p. 109–111 °C. H NMR (400 MHz,
CDCl3): δ = 7.58 (d, J = 2.8 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 1 H),
7.07 (dd, J = 8.4, 2.8 Hz, 1 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.50 (d,
J = 2.3 Hz, 1 H), 6.47 (dd, J = 8.2, 2.3 Hz, 1 H), 3.96 (dd, J =
12.2, 4.6 Hz, 1 H), 3.85 (s, 3 H), 3.81 (s, 3 H), 3.74 (s, 3 H), 3.05
(ddd, J = 16.0, 11.6, 4.3 Hz, 1 H), 2.94 (dt, J = 16.3, 4.1 Hz, 1 H),
2.43 (qd, J = 12.3, 4.3 Hz, 1 H), 2.23 (dq, J = 12.9, 4.3 Hz, 1
H) ppm. 13C NMR (by HSQC and HMBC): δ = 198.4, 159.8,
158.2, 158.0, 136.8, 133.9, 129.9, 129.6, 121.8, 121.4, 109.7, 104.3,
99.1, 55.5, 55.4, 55.3, 49.2, 30.3, 28.6 ppm. MS (EI): m/z (%) = 312
(100) [M]+, 294 (16), 174 (50), 161 (45), 151 (36), 120 (34). HRMS:
calcd. for C19H20O4 312.1362; found 312.1403.
5-Methoxy-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-one
(13b): The crude product was purified by column chromatography
with a mixture of hexane/AcOEt (95:5) as eluent, to give 13b as a
brown solid; m.p. 109–110 °C. 1H NMR (400 MHz, CDCl3): δ =
1318
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1314–1320

Synthesis of 5-Carbapterocarpens
7.71 (d, J = 7.8 Hz, 1 H), 7.33–7.22 (m, 2 H), 7.10 (dd, J = 7.5,
1.6 Hz, 1 H), 7.04 (d, J = 8.1 Hz, 1 H), 6.96–6.89 (m, 2 H), 4.06
(dd, J = 12.5, 4.6 Hz, 1 H), 3.88 (s, 3 H), 3.76 (s, 3 H), 3.19 (dt, J
= 17.5, 4.1 Hz, 1 H), 2.88–2.76 (m, 1 H), 2.45 (qd, J = 12.6, 4.4 Hz,
1 H), 2.28 (dq, J = 13.1, 4.6 Hz, 1 H) ppm. 13C NMR (by HSQC
and HMBC): δ = 198.1, 157.1, 156.7, 134.0, 133.0, 129.3, 128.9,
128.1, 126.7, 120.7, 119.2, 113.9, 110.9, 55.6, 55.4, 49.1, 28.9,
22.6 ppm. MS (EI): m/z (%) = 282 (100) [M]+, 264 (29), 161 (55),
148 (38). HRMS: calcd. for C18H18O3 282.1256; found 282.1244.
m/z (%) = 312 (100) [M]+, 294 (20), 191 (63), 178 (84), 163 (29).
HRMS: calcd. for C19H20O4 312.1362; found 312.1373.
General Procedure for the Synthesis of 5-Carbapterocarpens: The
aryltetralone 12a (50 mg, 0.16 mmol) was dissolved in anhydrous
CH2Cl2 (3 mL) and stirred in the dark under Ar at 0 °C for 15 min.
BBr3 (226 μL, 2.4 mmol) was then added dropwise with vigorous
stirring. The mixture was stirred at 0 °C for 90 min to prepare com-
pound 17. The reaction mixture was allowed to warm to room
temperature and stirred for more 2 h to prepare dihydroxylated
2-(2,4-Dimethoxyphenyl)-6,7-dimethoxy-3,4-dihydronaphthalen- product 4. After that, the reaction mixture was carefully added to
1(2H)-one (14a): The crude product was purified by column
chromatography with a mixture of hexane/AcOEt (85:15) as eluent,
to give 14a as a pale brown solid; m.p. 134–135 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.58 (s, 1 H), 6.98 (d, J = 8.3 Hz, 1 H),
6.70 (s, 1 H), 6.50 (d, J = 2.4 Hz, 1 H), 6.45 (dd, J = 8.3, 2.4 Hz,
1 H), 3.99–3.91 (m, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 3.80 (s, 3 H),
3.76 (s, 3 H), 3.05 (ddd, J = 15.9, 11.3, 4.4 Hz, 1 H), 2.91 (dt, J =
16.3, 4.3 Hz, 1 H), 2.43 (dtd, J = 12.8, 11.7, 4.3 Hz, 1 H), 2.23 (dq,
J = 13.2, 4.4 Hz, 1 H) ppm. 13C NMR (by HSQC and HMBC): δ
= 197.5, 159.7, 158.0, 153.0, 147.7, 138.8, 129.5, 126.3, 121.6, 110.1,
109.0, 104.2, 98.9, 56.4, 55.8, 55.3, 55.1, 48.5, 30.3, 28.9 ppm. MS
(EI): m/z (%) = 342 (100) [M]+, 324 (9), 204 (26), 191 (67), 178 (51),
151 (35), 150 (47). HRMS: calcd. for C20H22O5 342.1467; found
342.1455.
water (20 mL) at 0 °C with continuous stirring over 20 min. The
resulting suspension was extracted with EtOAc (4ϫ 15 mL). The
combined organic extracts were washed with brine and then dried
with anhydrous Na2SO4 and filtered. The solvent was removed un-
der reduced pressure to afford a pure product as a solid.
5,6-Dihydronaphtho[1,2-b]benzofuran-3,9-diol (4): The reaction
1
yielded a pure product as a pale purple solid; m.p. 207–208 °C. H
NMR (500 MHz, CD3OD): δ = 7.35 (d, J = 8.2 Hz, 1 H), 7.24 (d,
J = 8.3 Hz, 1 H), 6.88 (d, J = 2.1 Hz, 1 H), 6.72 (dd, J = 8.3,
2.0 Hz, 2 H), 6.67 (dd, J = 8.2, 2.3 Hz, 1 H), 2.98 (t, J = 7.9 Hz, 2
H), 2.83 (t, J = 7.9 Hz, 2 H) ppm. 13C NMR (101 MHz, CD3OD):
δ = 156.6, 156.0, 154.7, 150.7, 137.2, 121.1, 120.6, 119.9, 118.3,
115.1, 112.7, 111.2, 110.9, 97.5, 28.6, 18.8 ppm. MS (EI): m/z (%)
= 252 (100) [M]+, 251 (64), 234 (5), 223 (14). HRMS: calcd. for
C16H12O3: 252.0786; found 252.0765.
6,7-Dimethoxy-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-
one (14b): The crude product was purified by column chromatog-
raphy with a mixture of hexane/AcOEt (90:10) as eluent, to give
5,6-Dihydrobenzo[d]naphtho[1,2-b]furan-3-ol (16): The reaction
1
yielded a pure product as a pale brown solid; m.p. 129–130 °C. H
1
14b as a pale brown solid; m.p. 141–143 °C. H NMR (400 MHz,
NMR (500 MHz, CD3OD): δ = 7.48–7.40 (m, 3 H), 7.23–7.16 (m,
2 H), 6.74 (s, 1 H), 6.70 (dd, J = 8.2, 2.0 Hz, 1 H), 3.01 (t, J =
7.8 Hz, 2 H), 2.88 (t, J = 7.8 Hz, 2 H) ppm. 13C NMR (101 MHz,
CD3OD): δ = 157.2, 154.9, 152.0, 138.1, 128.3, 122.9, 122.3, 121.3,
119.4, 118.2, 115.1, 112.8, 110.8, 110.4, 28.6, 18.7 ppm. HRMS:
calcd. for C16H11O2 235.0765 [M – H]; found 235.0770.
CDCl3): δ = 7.59 (s, 1 H), 7.25 (td, J = 8.0, 1.7 Hz, 2 H), 7.08 (dd,
J = 7.8, 1.6 Hz, 1 H), 6.95–6.89 (m, 2 H), 6.70 (s, 1 H), 4.03 (dd,
J = 11.6, 4.7 Hz, 1 H), 3.96 (s, 3 H), 3.92 (s, 3 H), 3.78 (s, 3 H),
3.05 (ddd, J = 15.9, 11.2, 4.3 Hz, 1 H), 2.92 (dt, J = 16.4, 4.3 Hz,
1 H), 2.47 (dtd, J = 13.0, 11.5, 4.3 Hz, 1 H), 2.26 (dq, J = 13.2,
4.5 Hz, 1 H) ppm. 13C NMR (by HSQC and HMBC): δ = 197.2,
157.1, 153.2, 147.8, 138.8, 129.3, 127.9, 126.2, 120.9, 120.5, 110.2,
110.0, 109.0, 56.1, 55.8, 55.1, 51.1, 30.0, 28.4 ppm. MS (EI): m/z
(%) = 312 (100) [M]+, 294 (16), 191 (43), 178 (37), 150 (52). HRMS:
calcd. for C19H20O4 312.1362; found 312.1341.
3-Methoxy-5,6-dihydronaphtho[1,2-b]benzofuran-9-ol (17a): The re-
action yielded a pure product as a pale brown solid; m.p. 82–83 °C.
1H NMR (500 MHz, CD3OD): δ = 7.41 (d, J = 8.3 Hz, 1 H), 7.24
(d, J = 8.3 Hz, 1 H), 6.89 (s, 1 H), 6.82 (s, 1 H), 6.79 (d, J = 8.3 Hz,
1 H), 6.73 (d, J = 8.2 Hz, 1 H), 3.79 (s, 3 H), 3.00 (t, J = 7.8 Hz,
2 H), 2.82 (t, J = 7.7 Hz, 2 H) ppm. 13C NMR (by HSQC and
HMBC): δ = 158.9, 156.2, 154.9, 150.4, 137.1, 121.0, 120.9, 120.4,
118.3, 114.0, 111.6, 111.3, 111.0, 97.4, 54.1, 28.6, 18.8 ppm. MS
(EI): m/z (%) = 266 (100) [M]+, 265 (23), 251 (58), 221 (11). HRMS:
calcd. for C17H14O3 266.0943; found 266.0959.
2-(2,4-Dimethoxyphenyl)-5,8-dimethoxy-3,4-dihydronaphthalen-
1(2H)-one (15a): The crude product was purified by column
chromatography with a mixture of hexane/AcOEt (70:30) as eluent,
to give 15a as a pale brown solid; m.p. 134–135 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.04–6.96 (m, 2 H), 6.82 (d, J = 8.9 Hz, 1
H), 6.48–6.43 (m, 2 H), 3.98 (dd, J = 12.3, 4.8 Hz, 1 H), 3.83 (s, 6
H), 3.79 (s, 3 H), 3.72 (s, 3 H), 3.17 (dt, J = 17.5, 3.6 Hz, 1 H),
2.83–2.71 (m, 1 H), 2.38–2.17 (m, 2 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 198.0, 159.6, 158.0, 154.1, 150.2, 134.7, 129.6, 124.2,
121.9, 115.0, 110.6, 104.2, 98.8, 56.6, 56.0, 55.4, 55.3, 49.9, 29.0,
23.4 ppm. MS (EI): m/z (%) = 342 (100) [M]+, 324 (13), 191 (69),
178 (81), 151 (41). HRMS: calcd. for C20H22O5 342.1467; found
342.1498.
3-Methoxy-5,6-dihydrobenzo[d]naphtho[1,2-b]furan (17b): The reac-
tion yielded a pure product as a pale brown solid; m.p. 74–75 °C.
1H NMR (500 MHz, CD3OD): δ = 7.51 (d, J = 8.4 Hz, 1 H), 7.46
(t, J = 8.3 Hz, 2 H), 7.24–7.17 (m, 2 H), 6.87 (s, 1 H), 6.83 (d, J =
8.4 Hz, 1 H), 3.81 (s, 3 H), 3.06 (t, J = 7.8 Hz, 2 H), 2.90 (t, J =
7.9 Hz, 2 H) ppm. 13C NMR (by HSQC and HMBC): δ = 159.6,
155.0, 151.7, 137.9, 128.3, 123.2, 122.3, 121.1, 120.5, 118.4, 114.1,
111.4, 111.1, 110.5, 54.3, 28.4, 18.5 ppm. HRMS: calcd. for
C17H15O2 [M + H] 251.1072; found 251.1070.
5,8-Dimethoxy-2-(2-methoxyphenyl)-3,4-dihydronaphthalen-1(2H)-
one (15b): The crude product was purified by column chromatog-
raphy with a mixture of hexane/AcOEt (85:15) as eluent, to give
15b as a brown solid; m.p. 100–101 °C. 1H NMR (400 MHz,
5,6-Dihydrobenzo[d]naphtho[1,2-b]furan-4,9-diol (18a): The reaction
yielded a pure product as a brown solid; m.p. 186–187 °C. 1H
CDCl3): δ = 7.25–7.19 (m, 1 H), 7.12 (d, J = 7.4 Hz, 1 H), 6.99 (d, NMR (400 MHz, CD3OD): δ = 7.29 (d, J = 8.4 Hz, 1 H), 7.07 (s,
J = 9.0 Hz, 1 H), 6.91 (t, J = 7.4 Hz, 1 H), 6.87 (d, J = 8.2 Hz, 1
H), 6.82 (d, J = 9.0 Hz, 1 H), 4.05 (dd, J = 12.2, 4.9 Hz, 1 H), 3.84
1 H), 7.05 (d, J = 2.0 Hz, 1 H), 6.91 (d, J = 1.9 Hz, 1 H), 6.75 (dd,
J = 8.4, 2.0 Hz, 1 H), 6.72–6.67 (m, 1 H), 3.02 (t, J = 8.1 Hz, 2 H),
(s, 6 H), 3.74 (s, 3 H), 3.18 (dt, J = 17.4, 3.9 Hz, 1 H), 2.83–2.71 2.85 (t, J = 8.2 Hz, 2 H) ppm. 13C NMR (by HSQC and HMBC):
(m, 1 H), 2.41–2.2 (m, 2 H) ppm. 13C NMR (126 MHz, CDCl3): δ δ = 155.7, 154.0, 150.3, 128.8, 126.6, 121.5, 120.7, 120.4, 118.7,
= 197.7, 157.0, 154.1, 150.2, 134.7, 129.5, 129.4, 127.8, 124.1, 120.5,
115.1, 110.8, 110.5, 56.6, 56.1, 55.4, 50.5, 28.9, 23.3 ppm. MS (EI):
114.1, 113.5, 111.3, 111.2, 97.4, 20.4, 18.2 ppm. HRMS: calcd. for
C16H11O3 [M – H] 251.0714; found 251.0717.
Eur. J. Org. Chem. 2014, 1314–1320
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1319

J. L. O. Domingos, C. Nájera, P. R. R. Costa, et al.
FULL PAPER
atsu, M. G. Parker, J. A. Gustafsson, Pharmacol. Rev. 2006, 58,
773–81; b) K. Dahlman-Wright, V. Cavailles, S. A. Fuqua, V. C.
Jordan, J. A. Katzenellenbogen, K. S. Korach, A. Maggi, M.
Muramatsu, M. G. Parker, J. A. Gustafsson, J. Clin. Invest.
2006, 116, 561–567.
V. C. Jordan, Br. J. Pharmacol. 2006, 147 (Suppl. 1), S269–
S276.
5,6-Dihydrobenzo[d]naphtho[1,2-b]furan-4-ol (18b): The reaction
yielded a pure product as a beige solid; m.p. 140–141 °C. 1H NMR
(500 MHz, CD3OD): δ = 7.51–7.44 (m, 1 H), 7.26–7.22 (m, 1 H),
7.20 (t, J = 7.2 Hz, 1 H), 7.14 (d, J = 7.4 Hz, 1 H), 7.09 (t, J =
7.8 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 3.06 (t, J = 8.1 Hz, 1 H),
2.89 (t, J = 8.2 Hz, 1 H) ppm. 13C NMR (126 MHz, CD3OD): δ =
155.2, 154.2, 151.7, 128.4, 128.2, 126.7, 123.7, 122.4, 121.4, 118.7,
114.8, 113.4, 111.8, 110.6, 20.5, 18.2 ppm. HRMS: calcd. for
C16H11O2 [M – H] 235.0765; found 235.0762.
[2]
[3]
[4]
C. P. Miller, M. D. Collini, R. L. Morris, R. R. Singhaus, U.S.
Pat. Appl. Publ., US 20060004087, 2006.
a) D. P. Santanna, V. D. Pinho, M. C. L. S. Maior, P. R. R. Co-
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J. D. Burch, Org. Lett. 2008, 10, 4211–14; c) M. C. Willis, D.
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5,6-Dihydrobenzo[d]naphtho[1,2-b]furan-2,9-diol (19a): The crude
product was diluted in CH2Cl2 and filtered through diatomaceous
earth to yield a pure product as a brown solid; m.p. 160–161 °C.
1H NMR (400 MHz, CD3OD): δ = 7.24 (d, J = 8.4 Hz, 1 H), 7.00
(d, J = 8.1 Hz, 1 H), 6.97 (d, J = 2.5 Hz, 1 H), 6.90 (d, J = 2.1 Hz,
1 H), 6.73 (dd, J = 8.4, 2.1 Hz, 1 H), 6.57 (dd, J = 8.1, 2.5 Hz, 1
H), 2.89 (t, J = 7.8 Hz, 2 H), 2.80–2.74 (t, J = 8.0 Hz, 2 H) ppm.
13C NMR (101 MHz, CD3OD): δ = 156.3, 155.8, 155.3, 150.3,
128.6, 128.5, 126.0, 120.8, 118.9, 114.3, 113.2, 111.5, 106.5, 97.6,
27.4, 19.2 ppm. HRMS: calcd. for C16H11O3 [M – H] 251.0714;
found 251.0709.
[5]
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a) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
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5,6-Dihydrobenzo[d]naphtho[1,2-b]furan-2-ol (19b): The crude prod-
uct was diluted in CH2Cl2 and filtered through diatomaceous earth
to yield a pure product as a beige solid; m.p. 115–117 °C. 1H NMR
(400 MHz, CD3OD): δ = 7.49–7.44 (m, 2 H), 7.27–7.16 (m, 2 H),
7.09–7.04 (m, 2 H), 6.65 (dd, J = 8.2, 2.5 Hz, 1 H), 2.98–2.90 (m,
1 H), 2.88–2.81 (m, 1 H) ppm. 13C NMR (101 MHz, CD3OD): δ
= 156.0, 155.1, 151.6, 128.6, 28.2, 128.1, 126.7, 123.8, 122.5, 118.8,
114.1, 114.0, 110.7, 107.0, 27.3, 19.0 ppm. HRMS: calcd. for
C16H11O2 [M – H] 235.0765; found 235.0760.
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Received: October 4, 2013
Acknowledgments
Financial support from the Brazilian agencies Coordenação de Ap-
erfeiçoamento de Pessoal de Nível Superior (CAPES-DGU Project
number 200/09), Conselho Nacional de Desenvolvimento Ci-
entífico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa
do Estado do Rio de Janeiro (FAPERJ) is gratefully acknowledged.
The Spanish Ministerio de Ciencia e Innovación (MICINN) (pro-
ject
numbers
PHB2008-0037-PC,
CTQ2007-62771/BQU,
CTQ2010-20387, Consolider INGENIO 2010 grant number
CSD2007-00006), (FEDER), Generalitat Valenciana (project PRO-
METEO/2009/038), and the University of Alicante are also grate-
fully acknowledged. The authors thank Prof. Diego A. Alonso for
helpful discussions and Dr. Rosa Ortiz for MS measurements.
[1] a) K. Dahlman-Wright, V. Cavailles, S. A. Fuqua, V. C. Jordan,
J. A. Katzenellenbogen, K. S. Korach, A. Maggi, M. Muram-
Published Online: December 13, 2013
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