New '2-phenylnaphthalene'-mediated synthesis of benzo[b]naphtho[2,3-d] furan-6,11-diones and 6-oxa-benzo[a]anthracene-5,7,12-triones: First total synthesis of 6-oxa-benzo[a]anthracen-5-ones

Article abstract of DOI:10.1016/j.tet.2004.10.044

We describe here a novel synthesis of benzo[b]naphtho[2,3-d]furan-6,11- diones based on the heteroannulation of 2-(2-bromophenyl)-3-hydroxy-1,4- naphthoquinones. The naphthoquinones were prepared from 3-(2-bromophenyl) naphthalen-2-ols, which were obtained by intramolecular aldol condensation of 2-[3-(2-bromophenyl)-2-oxo-propyl]benzaldehydes. Alternatively, benzo[b]naphtho[2,3-d]furan-6,11-diones were obtained more directly and efficiently by cyclization of 3-(2-bromophenyl)naphthalen-2-ols to benzo[b]naphtho[2,3-d]furans and oxidation of the resulting compounds. Furthermore, the first 6-oxabenzo[a]anthracen-5-one described was similarly obtained from 2-[3-(2-formylphenyl)-2-oxopropyl]benzoic acid and oxidized to 6-oxa-benzo[a]anthracene-5,7,12-trione.

Full text of DOI:10.1016/j.tet.2004.10.044

Tetrahedron 61 (2005) 1353–1362
New ‘2-phenylnaphthalene’-mediated synthesis of
benzo[b]naphtho[2,3-d]furan-6,11-diones and
6-oxa-benzo[a]anthracene-5,7,12-triones: first total synthesis of
6-oxa-benzo[a]anthracen-5-ones
*
Ana Martınez, Marcos Fernandez, Juan C. Estevez, Ramon J. Estevez and Luis Castedo
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Departamento de Quımica Organica and Unidade Asociada (C.S.I.C.), Universidade de Santiago, E-15782 Santiago de Compostela, Spain
Received 20 October 2003; revised 11 October 2004; accepted 14 October 2004
Available online 16 December 2004
Abstract—We describe here a novel synthesis of benzo[b]naphtho[2,3-d]furan-6,11-diones based on the heteroannulation of 2-(2-
bromophenyl)-3-hydroxy-1,4-naphthoquinones. The naphthoquinones were prepared from 3-(2-bromophenyl)naphthalen-2-ols, which were
obtained by intramolecular aldol condensation of 2-[3-(2-bromophenyl)-2-oxo-propyl]benzaldehydes. Alternatively, benzo[b]naphtho[2,3-
d]furan-6,11-diones were obtained more directly and efficiently by cyclization of 3-(2-bromophenyl)naphthalen-2-ols to benzo[b]-
naphtho[2,3-d]furans and oxidation of the resulting compounds. Furthermore, the first 6-oxabenzo[a]anthracen-5-one described was
similarly obtained from 2-[3-(2-formylphenyl)-2-oxopropyl]benzoic acid and oxidized to 6-oxa-benzo[a]anthracene-5,7,12-trione.
q 2004 Elsevier Ltd. All rights reserved.
A tricyclic structural pattern, consisting of a either a phenyl
ring attached to position 2 of a naphthalene nucleus or
composed of various heterocyclic ring units with similar
molecular structural arrangements, is present in a large
number of biologically and pharmacologically active
compounds.1 Examples include benzo[a]pyrene and 7,12-
dimethylbenz[a]anthracene (carcinogenic); coralyne and
nitidine (antileukemic); chartreusin and rabelomycin (anti-
bacterial, cytotoxic); camptothecin, streptonigrin, and
ellipticine (antineoplastic); WS-5995A (anticoccidial);
genistein (estrogenic); methaqualone (sedative, hypnotic,
anticonvulsive); and gossypol (antioxidant, male contra-
ceptive), among others.1 The structural pattern per se may
not be sufficient to provide biological activity. Nevertheless,
by attachment of the appropriate groups or substituents to
specific positions on both ring units, it is believed that
compounds with the desired biological actions can be
designed.
two ring units, as in streptonigrin, or through a condensed
structure, such as camptothecin or ellipticine.1
On the basis of the concept outlined above, a search for
suitable chemical structures to fulfil the requirements for
drug design has been undertaken in recent years. For
instance, it was found that 5H-benzo[d]naphtho[2,3-
b]pyran-5,7,12-triones (4) include compounds like the
antibiotic WS-5995 A,2 which is produced by a new strain
of Streptomyces designated S. auranticolor. In addition, two
recently described synthetic analogues, o-quinone J1 and
model p-quinone J7,3 were shown to be antitumour agents
that inhibit macromolecule synthesis, block nucleoside
transport, induce DNA fragmentation, and decrease the
growth and viability of L1210 leukemic cells more
effectively than ellagic acid and genistein in vitro.
Closely related benzo[b]naphtho[2,3-d]furan-6,11-dione 3
belongs to another family of compounds selected as suitable
starting structures for drug design. These compounds also
possess the characteristic ‘2-phenylnaphthalene-type’ struc-
tural pattern, with the presence of the ether linkage
connecting the rings making the structure planar. It was
found that although this compound did not exhibit anti-
cancer properties itself, compounds of type 3 bearing
substituents at specific positions proved to be promising
antitumoural agents.4
Among compounds possessing this structural pattern, it is
evident that many antineoplastic agents assume a coplanar
conformation. The coplanarity of the two ring systems can
be achieved either by hydrogen-bond formation between the
Keywords: Quinones; Heterocycles; Ketoacids; Ullman reaction.
* Corresponding author. Tel.: C34 981 563100; fax: C34 981 591014;
e-mail: qorjec@usc.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.044

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1354
Scheme 1. XZBr, CONEt2.
Previous syntheses of benzofuronaphthoquinones 3,5
benzopyronaphthoquinones46 andrelatedcompoundsinclude
a common 2-phenylnaphthalene-type strategy for the syn-
thesis of these targets. This method is based on the
heteroannulation of appropriate 2-phenyl-1,4-naphthoquin-
ones 2 (Scheme 1) obtained by mixed intramolecular Claisen
condensation of phenylacetylphenylacetic acids 1.5a,d,6h
However, this simple and efficient method is of limited
scope due to the lack of availability of starting materials 1.
benzopyronaphthoquinones 4 that does not suffer from the
limitations outlined above. This method also involves
heteroannulation of 2-hydroxy-3-phenyl-1,4-naphthoquin-
ones 2, which can be obtained by intramolecular aldol
cyclization of ketobenzaldehydes 5 followed by oxidation
of the resulting 3-phenyl-2-naphthols 6.7
This new route to naphthoquinones 2 was first applied to the
synthesis of unsubstituted benzofuronaphthoquinone 3a.
The starting bromophenylketopropylbenzaldehyde 5a was
obtained as follows (Scheme 2): condensation of 1-indanone
7a with o-bromobenzaldehyde (8) in basic conditions gave
We describe a novel, yet closely related, ‘2-phenylnaphtha-
lene’-based synthesis of benzofuronaphthoquinones 3 and
Scheme 2. 3, 5, 6, 7, 9, 11, 13, 14: (a) RZH; (b) RZOMe; 10: (a) RZH, XZBr, (b) RZXZH; (c) RZOMe, XZBr; (d) RZOMe, XZH. Conditions.
(i) NaMeO/MeOH, rt, 15–27 h. (ii) H2, Pd/C, AcOEt, 1 atm, 75–210 min. (iii) (a) NaBH4, MeOH, rt, 60–90 min; (b) H2SO4, reflux, 1–2 h. (iv) (a) O3, K78 8C,
3–6 min; (b) Me2S, K78 8C (4–7 h), rt (13 h). (v) NaOH aq, rt, 1.5–2 h. (vi) Fremy’s salt, K2HPO4, acetone, rt, 1–4 h. (vii) H2SO4, MeOH, reflux, 29 h.
(viii) CuO, K2CO3, pyr, reflux, 1.5–4 h. (ix) CrO3, AcOH, reflux, 10 min. (x) NaH, CO(OEt)2 , benzene, reflux, 0.5 h. (xi) NaH, 2-bromobenzyl bromide, DMF,
60 8C, 44.5 h. (xii) 48% HBr. 96% AcOH, 120 8C, 1.5 h.

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A. Martınez et al. / Tetrahedron 61 (2005) 1353–1362
1355
the bromobenzylideneindanone 9a (98% yield),8 which
when subjected to controlled catalytic hydrogenation
furnished the expected bromobenzylindanone 10a9 (98%
yield) without the formation of compound 10b through
simultaneous hydrogenolysis of the C–Br bond. Subsequent
reduction of indanone 10a with NaBH4 gave a mixture of
indanols,10 which was directly converted into bromobenzyl-
indene 11a11 by refluxing with concentrated sulfuric acid
for an hour. Finally, indene 11a was transformed into the
desired ketoaldehyde 5a by ozonolysis.12 This key inter-
mediate was easily identified from spectroscopic and
analytical data. The mass spectrum showed the molecular
ion peaks at m/z 318 and m/z 316, with the typical isotope
pattern expected for bromo compounds. The 1H NMR
spectrum contained a singlet at 10.01 ppm due to the
aldehyde proton. Several representative signals in the 13C
NMR include a signal at 125.2 ppm, due to the carbon
bearing the bromo- substituent, and two signals at 193.3 and
203.2 ppm, due to the ketone and aldehyde carbonyls,
respectively.
accompanied by the undesired hydrogenolysis of its C–Br
bond. Indeed, an oil consisting of a mixture of the
bromobenzylindanone 10c (major component) and benzyl-
indanone 10d (minor component) was obtained and only a
small portion the desired compound 10c could be isolated
from this. However, 10c was efficiently obtained as follows:
treatment of methoxyindanone 7b with NaH and diethyl
carbonate gave 2-ethoxycarbonyl-1-indanone 14b in 62%
yield. This compound was efficiently converted into
2-ethoxycarbonyl-1-indanone 15b by reaction with NaH
and o-bromobenzyl bromide.19 Finally, a solution of 15b
and concentrated HBr was heated under reflux in acetic acid
for 1.5 h. This reaction gave the desired o-bromobenzylin-
danone 10c in 72% yield as a result of the hydrolysis of the
ester functionality followed by decarboxylation of the
resulting ketoacid.20
We next proceeded to apply this novel 2-phenylnaphtha-
lene-based methodology for the synthesis of benzonaphtho-
furans 13 and benzofuronaphthoquinones 3 to the
preparation of related benzonaphthopyranone 17a and
benzopyronaphthoquinone 4.
Intramolecular aldol condensation of ketoaldehyde 5a
readily gave a quantitative yield of the expected bromo-
phenylnaphthol 6a.13 Treatment of this compound with
Fremy’s salt yielded bromophenylnaphthoquinone 12a in
94% yield14 and this was reacted with sodium hydroxide in
methanol at rt for 15 min to give bromophenylhydroxy-
naphthoquinone 2 in only 7% yield.15 However, the yield of
this reaction was improved to 93% when it was carried out
under acidic conditions (H2SO4, MeOH, reflux).16 Finally,
when compound 2 was subjected to previously described
Ullman reaction conditions,15 the expected benzo-
furonaphthoquinone 3a was obtained in 71% yield.
2-Ethoxycarbonyl-1-indanone 14a was quantitatively trans-
formed into the corresponding 2-ethoxycarbonyl-2-benzyl-
1-indanone 15a by reaction19 with 2-ethoxycarbonylbenzyl
bromide, which was obtained21 by reaction of o-ethoxy-
carbonyltoluene with NBS (Scheme 3). A solution of 15a
in acetic acid was reacted with HBr at 120 8C for 3.25 h in
order to hydrolyse the two ester functions and to transform
the resulting dicarboxylic acid 15c into benzylindanone 10e
by decarboxylation.20 Unexpectedly, the only compound
formed was the spiro diindanone 16a,22 as deduced from
spectroscopic and analytical data. The mass spectrum
indicated a molecular formula C17H12O2 for this compound.
Moreover, the IR spectrum showed bands at 1720 and
Alternatively, when 3-bromophenyl-2-naphthol 6a was
submitted to the Ullman reaction conditions,15 73% yield
of the benzonaphthofuran 13a was obtained. Oxidation of
13a with CrO3 in acetic acid17 gave the target 3a in
quantitative yield. The molecular formula of compound 13a
1
1694 cmK1 due to the two carbonyl groups. The H NMR
spectrum showed two signals at 3.73 and 3.20 ppm,
corresponding to the two methylene groups, together with
signals for a total of eight aromatic protons. Characteristic
signals in the 13C NMR spectrum were observed at
153.8 ppm, due to the spiranic quaternary carbon, and
202.07 ppm, due to the carbonyl groups. Formation of spiro
compound 16a can be explained by assuming that indanone
15a readily undergoes a highly regioselective hydrolysis of
the ethoxycarbonyl group in the position a to the ketone.
This is followed by decarboxylation and subsequent
intramolecular mixed Claisen condensation of the resulting
ethoxycarbonylbenzylindanone 15d under the acidic reac-
tion conditions.
1
(C16H10O) was confirmed by mass spectrometry. The H
NMR contained signals between 7.35 and 8.42 ppm due to
the ten aromatic protons. Two characteristic signals in the
13C NMR were observed at 154.8 and 157.6 ppm due to the
carbons of the ethereal bridge.
This alternative synthesis of 3a is clearly more convenient
than the route via hydroxyphenylnaphthoquinone 2a, not
only because it is both shorter and more efficient, but
because it avoids experimental problems encountered with
the former route due to the manipulation of quinone
compounds in earlier stages of the synthesis. Moreover,
this new route constitutes a novel synthetic approach to
benzonaphthofurans 13,18 as illustrated by the preparation
of benzonaphthofuran 13a (brazan), which was originally
isolated2 from coal tar distillate.
As expected, reaction of 16a with NaOH readily gave a
retro-aldol process and led to the desired indanone ketoacid
10e.23 This compound was subjected to a reaction sequence
similar to that used for the transformation of bromo
compounds 6 into benzofuronaphthoquinones 3. Thus,
reduction of ketoacid 10e with NaBH4 gave a quantitative
yield of a mixture of indanols, which were reacted with 10%
HCl in dioxane to provide the desired indene 11c.
Subsequent ozonolysis of 11c gave the key ketoaldehyde
5c, which was reacted with NaOH directly to furnish the
target compound 17a. This process probably involves the
initial formation of the expected 2-naphthol 6c resulting
The general interest of this novel route was immediately
demonstrated by the similar transformation of methoxyin-
danone 7b into benzonaphthofuran 13b and its benzofur-
onaphthoquinone derivative 3b via benzylideneindanone
9b, benzylindanone 10b, benzylindene 11b, ketoaldehyde
5b and bromophenylnaphthol 6b. In this case, catalytic
hydrogenation of benzylideneindanone 9b was

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1356
Scheme 3. 15: (a) RZH, R0ZEt, XZCO2Et; (c) RZH, R0ZOH, XZCO2H; (d) RZXZH, R0ZEt; (e) RZOMe, R0ZEt, XZCO2Et; (f) RZOMe, R0ZOH,
XZCO2H; (g) RZOMe, XZH, R0ZEt. 10: (e) R1ZR2ZH; (f) R1ZOMe, R2ZH; (g) R1ZH, R2ZOMe; 5, 6,11: (c) R1ZR2ZH; (d) R1ZOMe, R2ZH;
(e) R1ZH, R2ZOMe. 16, 17: (a) R1ZR2ZH; (b) R1ZOMe, R2ZH; (c) R1ZH, R2ZOMe. Conditions. (i) HBr, AcOH, reflux, 3.25 h. (ii) 1.25 M aq NaOH,
EtOH, reflux, 5 h. (iii) (a) NaBH4, MeOH, 0–O5 8C, 8.25 h; (b) HCl, dioxan, reflux, 10.5 h. (iv) (a) O3, K78 8C, 3–6 min; (b) Me2S, K78 8C (4–7 h), rt (13 h).
(v) NaOH aq, rt, 1.5–2 h. (vi) CrO3, AcOH, reflux, 10 min.
from the intramolecular aldol cyclization, followed by the
spontaneous lactonization of this compound under the
reaction conditions. Finally, as predicted, benzonaphtho-
pyranone 17a was easily oxidized to benzopyronaphtho-
quinone 4 when reacted with CrO3.
oxidation of these materials to benzofuronaphthoquinones
3. The extension of this novel synthetic methodology to
benzopyronaphthoquinones 4 resulted in the first total
synthesis of benzonaphthopyranone 17a. This target
compound was efficiently oxidized to unsubstituted benzo-
pyronaphthoquinone 4. This route does, however, seems to
be limited to the preparation of benzonaphthopyranones 17
with a substitution pattern compatible with the opening of
spiro compound 16 to a single indanone ketoacid 10.
The synthesis of 4 reported here is clearly more convenient
than previous routes6 via hydroxyphenylnaphthoquinones 2
and has the additional advantage that it allows the
generation of the quinone moiety to be left until the final
step of the synthesis. This aspect overcomes the problems
associated with the manipulation of quinone compounds.
Moreover, the new route constitutes the first total synthesis
of 6-oxa-benzo[a]anthracen-5-one, as illustrated by the
preparation of benzonaphthopyranone 17a.
Work is now in progress to overcome this limitation and to
extend the 2-phenylnaphthalene-based synthetic method-
ology reported here to the preparation of tetracyclic
2-phenylnaphtahlene derivatives other than benzonaphtho-
furans 14, benzofuronaphthoquinones 3, benzonaphthopyr-
anones 17 and benzopyronaphthoquinones 4. It is envisaged
that the route will also include indolonaphthoquinones and
ellipticines, which are known to show antitumour
properties.
A predictable limitation of this route to benzonaphthopyr-
anones 17 was confirmed in the attempt to obtain
methoxybenzonaphthopyranone 17b from 2-ethoxycarbo-
nyl-2-benzyl-1-indanone 15e, prepared by reaction of
methoxyindanone 14b with 2-ethoxycarbonylbenzyl bro-
mide. As expected, treatment of 15e with HBr, as described
above, gave diindanone 16b but reaction of this compound
with NaOH gave a mixture of indanone ketoacids 10f and
10g. Since isolation of these compounds from the mixture
was not very efficient, they could not be transformed into the
corresponding benzonaphthopyranones 17b and 17c.
1. Experimental
1.1. General
Melting points were determined on a Kofler Thermogerate
apparatus and are uncorrected. Infrared spectra were
recorded on a MIDAC FTIR spectrophotometer. Nuclear
magnetic resonance spectra were recorded, unless otherwise
specified, on a Bruker WM-250 apparatus, using deutero-
chloroform solutions containing tetramethylsilane as
internal standard. Mass spectra were obtained on a Kratos
MS 50 TC mass spectrometer. Thin layer chromatography
(tlc) was performed using Merck GF-254 type 60 silica gel
and CH2Cl2/MeOH mixtures as eluants; the tlc spots were
In conclusion, we describe here a divergent synthesis of
benzofuronaphthoquinones 3 from phenylketopropylben-
zaldehydes 5. The route via 2-hydroxy-3-phenyl-1,4-
naphthoquinones 2 constitutes a more generally applicable
version of a previously described route. The alternative
shorter and more efficient route includes a novel total
synthesis of benzonaphthofurans 14 and the efficient

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A. Martınez et al. / Tetrahedron 61 (2005) 1353–1362
1357
visualized with ultraviolet light or iodine vapour. Column
chromatography was carried out using Merck type 9385
silica gel. Solvents were purified as per Ref. 24. Solutions of
extracts in organic solvents were dried with anhydrous
sodium sulfate.
stirred suspension was refluxed in a dry atmosphere for
30 min. 20% aq NaOH was added until a basic pH was
attained and the suspension was extracted with CH2Cl2 (3!
100 mL). The combined organic extracts were dried and
concentrated to dryness in vacuo. The remaining solid was
submitted to flash column chromatography (eluant: ethyl
acetate/hexane, 0.3:9.7) to give the title compound in 96%
yield (0.638 g) as a yellow oil. IR (nꢀ, cmK1, NaCl): 3071
(C]C). 1H NMR (d, ppm): 3.39 (s, 2H, –CH2), 4.01 (s, 2H,
–CH2), 6.52 (s, 1H, HC]C), 7.13–7.34 (m, 6H, 6!Ar–H),
7.42 (d, 1H, JZ7.2 Hz, Ar–H), 7.63 (d, 1H, JZ8.2 Hz,
Ar–H). 13C NMR (d, ppm): 37.9 (CH2), 41.1 (CH2), 120.4
(CH), 123.6 (CH), 124.1 (CH), 124.8 (CBr), 126.4 (CH),
127.7 (CH), 128.1 (CH), 128.5 (CH), 131.1 (CH), 139.6 (C),
143.4 (C), 145.4 (C), 147.6 (C). HRMS: C16H13Br (MC),
calcd 284.0201; found 284.0199.
1.1.1. 2-(2-Bromobenzylidene)indan-1-one (9a). A solution
of 1-indanone (1 g, 7.5 mmol) in dry MeOH (18 mL) was
added dropwise under argon to a solution of 2-benzaldehyde
(0.93 mL, 7.95 mmol) and sodium methoxide (120 mg,
2.35 mmol) in dry MeOH (22 mL). The mixture was stirred
at rt for 15 h and poured into water (50 mL). The resulting
suspension was acidified by the addition of 20% aq HCl and
extracted with CH2Cl2 (3!100 mL). The combined organic
extracts were dried and concentrated to dryness in vacuo.
Crystallisation of the solid residue from MeOH yielded the
title compound as white needless (2.2 g, 98%). Mp 134–
136 8C (MeOH). IR (nꢀ, cmK1, NaCl): 1695 (C]O), 1621
(C]C). 1H NMR (d, ppm): 3.94 (s, 2H, CH2), 7.23 (m, 1H,
Ar–H), 7.35–7.68 (m, 6H, 6!Ar–H), 7.91 (d, 1H, JZ
7.6 Hz, Ar–H), 7.97 (s, 1H, HC]C). 13C NMR (d, ppm):
31.7 (CH2), 124.6 (CH), 126.2 (CH), 126.6 (C), 127.5 (CH),
127.8 (CH), 130.0 (CH), 130.5 (CH), 132.5 (CH), 133.6
(CH), 134.8 (CH), 135.4 (C), 137.1 (C), 138.0 (C), 149.8
(C), 193.8 (C]O). MS (m/z, %): 300 [(MC2)C, 2], 298
(MC, 1.7), 219 [(MK79.9)C, 100], 189 (32). Anal. Calcd
for C16H11BrO, C: 64.24; H: 3.71; Br: 26.71. Found C:
64.41; H: 3.68; Br: 27.03.
1.1.4. 2-[3-(2-Bromophenyl)-2-oxopropyl]benzaldehyde
(5a). N2 and O2 were bubbled consecutively for 10 min
each through a solution of indene 11a (400 mg, 1.39 mmol)
in CH2Cl2 (60 mL) at K78 8C connected to an ozonizer. O3
was then bubbled through the solution for 2 min until a blue
colour appeared due to the presence of ozonide. O2 was then
bubbled through for 10 min to destroy the excess O3 and
finally N2 was bubbled through for 5 min. Dimethyl sulfide
(1.9 mL, 26.38 mmol) was added and the mixture was
stirred at K78 8C under argon for 7 h and at rt for 13 h. The
solvent was removed in vacuo and the solid residue was
submitted to column chromatography (eluant: ethyl acetate/
hexane, 0.5:9.5) to give the target compound (324 mg) in
73% yield as white crystals. Mp 68–69 8C (MeOH). IR
(nꢀ, cmK1, NaCl): 1719, 1693 (CHO, C]O). 1H NMR
(d, ppm): 4.11 (s, 2H, CH2), 4.20 (s, 2H, CH2), 7.24–7.53
(m, 7H, 7!Ar–H), 7.56 (t, 1H, JZ1.8 Hz, Ar–H), 10.01
(s, 1H, CHO). 13C NMR (d, ppm): 47.1 (CH2), 50.0 (CH2),
125.2 (C), 127.6 (CH), 127.8 (CH), 128.8 (CH), 132.2 (CH),
132.8 (2!CH), 133.7 (CH), 134.4 (C), 134.9 (C), 135.0
(CH), 135.8 (C), 193.3 (C]O), 203.2 (C]O). MS (m/z, %):
318 [(MC2)C, 0.37], 316 (MC, 0.34), 237 [(MK79.9)C,
2], 171 (36.4), 169 (37.6), 147 (100), 119 (88), 91 (65).
Anal. Calcd for C16H13BrO2, C: 60.59; H: 4.13; Br: 25.19.
Found C: 60.32; H: 4.19; Br: 24.96.
1.1.2. 2-(2-Bromobenzyl)indan-1-one (10a). 10% Pd–C
(50 mg) was added to a deoxygenated solution of bromo-
benzylideneindanone 9a (0.96 g, 3.21 mmol) in ethyl
acetate (80 mL) and the mixture was stirred under a
hydrogen atmosphere (1 atm) at rt for 1 h 15 min. After
removal of the excess of hydrogen in vacuo, the reaction
mixture was filtered though Celite, which was eluted with
ethyl acetate. The filtrate was concentrated to dryness in
vacuo to give the title compound as white crystals (0.947 g,
98% yield). Mp 67–69 8C (MeOH). IR (nꢀ, cmK1, NaCl):
1
1710 (C]O). H NMR (d, ppm): 2.86 (m, 2H, –CH2),
3.11–3.18 (m, 2H, CH2, CH), 3.53 (dd, 1H, JZ14.1 Hz,
J0Z4.0 Hz, CH2), 7.10 (m, 1H, Ar–H), 7.23–7.34 (m, 2H,
2!Ar–H), 7.37–7.43 (m, 2H, 2!Ar–H), 7.55–7.61 (d, 2H,
JZ7.5 Hz, 2!Ar–H), 7.79 (d, 1H, JZ7.5 Hz, Ar–H). 13C
NMR (d, ppm): 32.1 (CH2), 36.9 (CH2), 47.5 (CH), 124.1
(CH), 124.9 (C), 126.7 (CH), 127.5 (CH), 127.6 (CH), 128.2
(CH), 131.0 (CH), 133.1 (CH), 134.9 (CH), 136.6 (C), 139.2
(C), 153.5 (C), 207.4 (C]O). MS (m/z, %): 301 [(MC2)C,
0.15], 299 (MC, 0.09), 221 [(MK79.9)C, 100], 131 (26).
Anal. Calcd for C16H13BrO, C: 63.81; H: 4.35; Br: 26.53.
Found C: 64.09; H: 4.23; Br: 26.87.
1.1.5. 3-(2-Bromophenyl)naphthalen-2-ol (6a). A solution
of ketoaldehyde 5a (200 mg, 0.63 mmol) in 5% aq NaOH
(10 mL) was magnetically stirred in a dry atmosphere at rt
for 1 h. The reaction mixture was acidified by adding 10%
aq HCl and the resulting suspension was extracted with
CH2Cl2 (3!25 mL). The combined organic extracts were
washed with water (25 mL), dried and concentrated to
dryness in vacuo to give a quantitative yield of the title
compound (188 mg) as an oil. IR (nꢀ, cmK1, NaCl): 3535
(OH). 1H NMR (d, ppm): 7.18–7.42 (m, 6H, 6!Ar–H), 7.59
(s, 1H, Ar–H), 7.67–7.73 (m, 3H, 3!Ar–H). 13C NMR (d,
ppm): 110.3 (CH), 124.0 (CH), 124.4 (C), 125.9 (C), 126.4
(CH), 126.7 (CH), 127.8 (2!CH), 128.6 (C), 130.0 (2!
CH), 132.2 (CH), 133.2 (CH), 134.7 (C), 137.8 (C), 150.7
(C]O). MS (m/z, %): 300 [(MC2)C, 66], 298 (MC, 69),
219 (72), 218 (98), 191 880), 189 (100), 109 (42), 95 (63).
HRMS: C16H11BrO (MC), calcd 297.9993; found 297.9994.
1.1.3. 2-(2-Bromobenzyl)-1H-indene (11a). Small portions
of NaBH4 (540 mg, 1.43 mmol) were added every 15 min
during 1 h to a solution of benzylindanone 10a (700 mg,
0.23 mmol) in MeOH (60 mL) cooled to 0–5 8C using a
water/ice bath. The mixture was stirred at rt for 30 min and
poured into water (100 mL). The MeOH was evaporated in
vacuo and the remaining suspension was extracted with
CH2Cl2 (3!100 mL) and the combined organic extracts
were washed with water (3!100 mL), dried and concen-
trated to dryness in vacuo. The remaining solid was
immediately mixed with 9 M H2SO4 (75 mL) and the
1.1.6. 3-(2-Bromophenyl)-1,2-naphthoquinone (12a).
A solution of Fremy’s salt (1.187 g, 4.42 mmol) and

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1358
potassium biphosphate (215 mg, 1.58 mmol) in water
(30 mL) was added to a solution of naphthol 6a (137 mg,
0.46 mmol) in acetone (13 mL). The suspension was stirred
in a dry atmosphere at rt for 1 h and the acetone was
evaporated in vacuo. The pink suspension was extracted
with CH2Cl2 (3!25 mL) and the combined organic layers
were washed with water (25 mL), dried and concentrated to
dryness in vacuo. The solid residue was submitted to flash
column chromatography (eluant: ethyl acetate/hexane, 1:9)
and the title compound was isolated as red crystals (133 mg,
94% yield). Mp 164–166 8C (MeOH). IR (nꢀ, cmK1, NaCl):
(46), 163 (51). Anal. Calcd for C16H8O3, C: 77.42; H: 3.25.
Found C: 77.29; H: 3.33.
1.1.9. Benzo[b]naphtho[2,3-d]furan (13a). Reaction of a
suspension of bromonaphthol 6a (30 mg, 0.10 mmol), CuO
(0.31 mg, 3.1 mmol) and potassium carbonate (70 mg,
5.1 mmol) in dry deoxygenated pyridine was subjected to
the same conditions as for the preparation of benzofuro-
naphthoquinone 3a. The title compound was obtained as
white crystals (16 mg, 73% yield). Mp 210–212 8C
(MeOH). 1H NMR (d, ppm): 7.35–7.58 (m, 5H, 5!
Ar–H), 7.93 (s, 1H, Ar–H), 7.96–8.07 (m, 3H, 3!Ar–H),
8.42 (s, 1H, Ar–H). 13C NMR (d, ppm): 106.9 (CH), 111.6
(CH), 119.1 (CH), 121.3 (CH), 122.7 (CH), 123.9 (C), 124.3
(CH), 125.4 (C), 125.9 (CH), 127.8 (CH), 128.3 (2!CH),
130.2 (C), 133.0 (C), 154.8 (CO), 157.6 (CO). MS (m/z, %):
218 (MC, 100), 189 (24). Anal. Calcd for C16H10O, C:
88.05; H: 4.62. Anal. Calcd for C16H16O, C: 88.05; H: 4.62.
Found C: 87.72; H: 4.67.
1
1675 (C]O). H NMR (d, ppm): 7.15–7.64 (m, 8H, 7!
Ar–H, CH]C), 8.08 (d, 1H, JZ7.6 Hz, Ar–H). 13C NMR
(d, ppm): 123.4 (CBr), 127.4 (CH), 130.2 (2!CH), 130.3
(CH), 130.8 (CH), 131.1 (CH), 131.4 (C), 133.0 (CH), 134.7
(C), 135.5 (C), 135.9 (CH), 139.6 (C), 144.1 (CH), 178.8
(C]O), 178.9 (C]O). MS (m/z, %): 286 {[(MK28)C2]C,
15.2}, 284 [(MK28)C, 15.2}, 205 (100), 176 (43). Anal.
Calcd for C16H9BrO2, C: 61.37; H: 2.90; Br: 25.52. Found
C: 61.72; H: 2.93; Br: 25.11.
1.1.10. Benzo[b]naphtho[2,3-d]furan-6,11-dione (3a).
A solution of CrO3 (75 mg, 0.76 mmol) in glacial acetic
acid (6 mL) and water (1 mL) was added to a solution of
benzonnaphthofuran 13a (30 mg, 0.14 mmol) in glacial
acetic acid and the mixture was refluxed during 10 min. The
suspension was poured into CH2Cl2 (25 mL) and the
organic phase was washed with water (3!25 mL), dried
and concentrated in vacuo. The title compound was
obtained as a yellow solid (34 mg, 100% yield).
1.1.7. 2-(2-Bromophenyl)-3-hydroxy-1,4-naphthoqui-
none (2a). 20% aq sulfuric acid (2 mL) was added to a
suspension of quinone 12a (31 mg, 0.09 mmol) in MeOH
(2 mL) and the mixture was refluxed for 94 h. The MeOH
was removed in vacuo and the resulting suspension was
poured into water (25 mL) and extracted with CH2Cl2 (3!
25 mL). The combined organic extracts were washed with
water (25 mL), dried and concentrated to dryness in vacuo.
The solid residue was submitted to flash column chroma-
tography (eluant: ethyl acetate/hexane, 1:1) and the title
compound was obtained (30 mg, 93% yield) as red crystals.
Mp 172–174 8C (MeOH). IR (nꢀ, cmK1, NaCl): 3425 (OH),
1.1.11. 2-(2-Bromobenzylidene)-5-methoxyindan-1-one
(9b). 1-Methoxyindanone 7b (2 g, 12.33 mmol) and
o-bromobenzaldehyde (1.526 mL, 13.07 mmol) were
reacted under the same conditions as for the preparation
of benzylideneindanone 9a to give the title compound as
white crystals (3.31 g, 85% yield). Mp 158–160 8C
(MeOH). IR (nꢀ, cmK1, NaCl): 1685 (C]O), 1628
(C]C). 1H NMR (d, ppm): 3.81 (s, 2H, CH2), 3.86
(s, 3H, OCH3), 6.88–6.91 (m, 2H, 2!Ar–H), 7.17 (m, 1H,
Ar–H), 7.34 (t, JZ7.5 Hz, 1H, Ar–H), 7.58–7.63 (m, 2H,
2!Ar–H), 7.77–7.85 (m, 2H, 2!Ar–H). 13C NMR
(d, ppm): 31.7 (CH2), 55.6 (CH3), 109.5 (CH), 115.3
(CH), 126.1 (CH), 126.2 (C), 127.3 (CH), 129.7 (CH), 130.1
(CH), 131.0 (CH), 131.2 (C), 133.3 (CH), 135.3 (C), 137.5
(C), 152.5 (C), 165.2 (C]O), 191.9 (C]O). MS (m/z, %):
330 [(MC2)C, 42], 328 (MC, 43), 249 [(MK79.9)C, 100],
243 (23). Anal. Calcd for C17H13BrO2, C: 62.03; H: 3.98;
Br: 24.27. Found C: 62.31; H: 4.05; Br: 23.96.
1
1635 (C]O). H NMR (d, ppm): 6.99–7.14 (m, 3H, 3!
Ar–H), 7.46–7.55 (m, 2H, 2!Ar–H), 7.66 (t, 1H, JZ
7.5 Hz, Ar–H), 7.94 (d, 2H, JZ7.6 Hz, 2!Ar–H). 13C
NMR (d, ppm, CDCl3/MeOD): 119.9 (C), 124.9 (C), 125.1
(2!CH), 125.7 (CH), 127.2 (CH), 129.9 (C), 130.4 (CH),
131.1 (CH), 132.2 (CH), 134.1 (CH), 134.4 (C), 136.0 (C),
167.5 (C), 181.1 (C]O), 189.1 (C]O). MS (m/z, %): 249
[(MK79.9)C, 100], 165 (32). Anal. Calcd for C16H9BrO3,
C: 58.38; H: 2.76; Br: 24.28. Found C: 50.82; H: 2.83; Br:
24.62.
1.1.8. Benzo[b]naphtho[2,3-d]furan-6,11-dione (3a).
A mixture of naphthoquinone 2a (30 mg, 0.09 mmol),
CuO (23 mg, 0.28 mmol) and K2CO3 (64 mg, 5.1 mmol) in
dry deoxygenated pyridine (3 mL) was refluxed under argon
for 4 h. The mixture was then added to 20% aq HCl solution
(40 mL) and the resulting suspension was extracted with
CH2Cl2 (3!25 mL). The combined organic layers were
washed with 10% aq NaOH (3!25 mL), dried, filtered and
concentrated in vacuo. The solid residue was submitted to
flash column chromatography (eluant: ethyl acetate/hexane,
1:9) to give the title compound (16 mg, 71% yield) as
1.1.12. 2-(2-Bromobenzyl)-5-methoxyindan-1-one (10c).
Catalytic hydrogenation of bromobenzylideneindanone 9b
(1 g, 2.94 mmol), under the same conditions as for analogue
10a, resulted in a mixture of the title compound and
benzylindanone 10d. The mixture was purified by flash
column chromatography (eluant: ethyl acetate/hexane, 1:9)
to give the title compound (0.099 g, 9.8% yield) as a
colourless oil. IR (nꢀ, cmK1, NaCl): 1701 (C]O). 1H NMR
(d, ppm, CDCl3): 2.81 (m, 2H, CH2), 3.09 (m, 2H, CH2),
3.50 (m, 1H, CH), 3.85 (s, 3H, OMe), 6.81–6.91 (m, 2H,
ArH), 7.08 (m, 1H, ArH), 7.21–7.29 (m, 2H, ArH), 7.55 (m,
1H, ArH), 7.70 (dd, JZ8.5 Hz, J0Z2.8 Hz, 1H, ArH). 13C
NMR (d, ppm, CDCl3): 32.1 (CH2), 36.9 (CH2), 47.5 (CH),
55.5 (OMe), 109.6 (CH), 115.4 (CH), 124.7 (C), 125.6
yellow crystals. Mp 245–247 8C (MeOH). IR (nꢀ, cmK1
,
NaCl): 1674 (C]O). 1H NMR (d, ppm): 7.48–7.81 (m, 5H,
5!Ar–H), 8.22–8.34 (m, 3H, 3!Ar–H). 13C NMR (d,
ppm): 112.9 (CH), 122.7 (C), 124.0 (CH), 124.3 (C), 126.1
(CH), 126.8 (CH), 126.9 (CH), 129.6 (CH), 132.4 (C), 133.3
(C), 133.9 (CH), 134.2 (CH), 153.5 (C), 156.5 (C), 175.5
(C]O), 181.4 (C]O). MS (m/z, %): 248 (MC, 100), 220

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A. Martınez et al. / Tetrahedron 61 (2005) 1353–1362
1359
(CH), 127.4 (CH), 128.0 (CH), 129.6 (C), 130.8 (CH), 132.9
(CH), 139.1 (C), 156.4 (C), 165.3 (C), 205.5 (C]O).
HRMS: C17H15BrO2 (MC), calcd 330.0255; found
330.0258.
1.1.15. 2-(2-Bromobenzyl)-5-methoxyindan-1-one (10c).
A suspension of indanone 15a (128 mg, 0.317 mmol), 48%
HBr (0.7 mL) and 96% AcOH (0.6 mL) was stirred at
120 8C for 1.5 h. The mixture was cooled and diluted with
water (5 mL). The organic material was extracted with
diethyl ether (3!10 mL) and the combined organic extracts
were dried and concentrated in vacuo. The solid residue was
submitted to flash column chromatography (eluant: CH2Cl2/
hexane, 5.5:4.5) and the title compound (76 mg, 72% yield)
was isolated as an oil (76 mg, 72% yield). IR (NaCl, nꢀ, cmK1):
1.1.13. 5-Methoxy-1-oxoindan-2-carboxylic acid ethyl
ester (14b). A solution of methoxyindanone 7b (5.1 g,
32 mmol) in benzene (75 mL) was added dropwise under
argon during 4.5 h to a mixture of 80% sodium hydride
(1.66 g, 69 mmol), diethyl carbonate (7.5 mL, 62 mmol)
and benzene (40 mL) under reflux. A further quantity of
benzene (4.5 mL) was added and the mixture was heated for
a further 0.5 h. Water (35 mL) and acetic acid (6 mL) were
added to the reaction mixture and the organic layer was
separated and the aqueous layer extracted with benzene (2!
75 mL) and diethyl ether (2!75 mL). The combined
organic extracts were dried and concentrated in vacuo.
The solid residue was submitted to flash column chroma-
tography (eluant: CH2Cl2/hexane, 9:1) and the resulting
solid was refluxed in hexane (500 mL) for 30 min and
filtered immediately. The filtrate was concentrated to
dryness in vacuo to give the title compound as white
crystals (6.35 g, 62% yield). Mp 63–65 8C (ethyl acetate/
hexane). IR (nꢀ, cmK1, KBr): 1262 (C–OMe), 1707 (CO2Et),
1
1701 (C]O). H NMR (d, ppm, CDCl3): 2.81 (m, 2H,
CH2), 3.09 (m, 2H, CH2), 3.50 (m, 1H, CH), 3.85 (s, 3H,
–OMe), 6.81–6.91 (m, 2H, ArH), 7.08 (m, 1H, ArH), 7.21–
7.29 (m, 2H, ArH), 7.55 (m, 1H, ArH), 7.70 (dd, JZ8.5 Hz,
J0Z2.8 Hz, 1H, ArH). 13C NMR (d, ppm, CDCl3): 32.1
(CH2), 36.9 (CH2), 47.5 (CH), 55.5 (CH3), 109.6 (CH),
115.4 (CH), 124.7 (C), 125.6 (CH), 127.4 (CH), 128.0 (CH),
129.6 (C), 130.8 (CH), 132.9 (CH), 139.1 (C), 156.4 (C),
165.3 (C), 205.5 (C]O). HRMS: C17H15BrO2 (MC), calcd
330.0255; found 330.0251.
1.1.16. 2-(2-Bromobenzyl)-6-methoxy-1H-indene (11b).
Following the procedure for the preparation of benzylindene
11a, benzylindanone 10c (780 mg, 2.35 mmol) was trans-
formed into the title compound (3.71 mmol, 88% yield). Mp
1
1738 (C]O). H NMR (d, ppm): 1.25 (t, JZ7.2 Hz, 3H,
1
62–64 8C (MeOH). H NMR (d, ppm): 3.29 (s, 2H, CH2),
–CH3), 3.21–3.29 (m, 1H, –CH2), 3.41–3.48 (m, 1H, –CH2),
3.62–3.66 (m, 1H, –CH), 3.83 (s, 3H, –OCH3), 4.19 (q, JZ
7.2 Hz, 2H, –CH2O), 6.84–6.87 (m, 2H, ArH), 7.61–7.64
(m, 1H, ArH). 13C NMR (d, ppm): 13.9 (CH3), 30.0 (CH2),
53.2 (CH), 55.4 (CH3), 61.2 (CH2), 109.2 (CH), 115.6 (CH),
125.8 (CH), 128.1 (C), 156.5 (C), 165.6 (C), 169.1 C]O),
197.3 (C]O). MS (m/z, %): 234 (MC, 50), 188 (29),
160 (100).
3.78 (s, 3H, –OCH3), 3.90 (s, 2H, CH2), 6.38 (s, 1H,
HC]C), 6.76 (dd, 1H, JZ8.2 Hz, J0Z2.4 Hz, Ar–H), 6.96
(m, 1H, Ar–H), 7.13 (d, 1H, JZ8.3 Hz, Ar–H), 7.25–7.23
(m, 3H, 3!Ar–H), 7.55 (d, 1H, JZ7.7 Hz, Ar–H). 13C
NMR (d, ppm): 37.9 (CH2), 41.1 (CH2), 55.5 (CH3), 110.4
(CH), 111.7 (CH), 120.4 (CH). 124.7 (C), 126.1 (C), 127.5
(CH), 127.7 (CH), 127.9 (CH), 130.9 (CH), 132.9 (CH),
138.4 (C), 139.7 (C), 145.1 (C), 157.4 (CO). MS (m/z, %):
316 [(MC2)C, 14.8], 316 (MC, 15.0), 237 [(MK79.9)C,
9], 145 (100). Anal. Calcd for C17H15BrO, C: 64.78; H:
4.80; Br: 25.25. Found C: 64.92; H: 4.79; Br: 24.87.
1.1.14. 2-(2-Bromobenzyl)-5-methoxy-1-oxo-indan-2-
carboxylic acid ethyl ester (15a). A mixture of 80%
sodium hydroxide (24 mg, 1.13 mmol), indanone 14a
(237 mg, 1.10 mmol) and N,N-dimethylformamide
(0.5 mL) was heated at 60 8C for 1 h. A solution of 98%
2-bromobenzyl bromide (290 mg, 1.16 mmol) in N,N-
dimethylformamide (0.8 mL) was added and the mixture
was heated at 60 8C for 44.5 h. A few drops of water were
added and the suspension was extracted with diethyl ether
(3!10 mL). The combined organic extracts were washed
with saturated aq sodium chloride, dried and concentrated to
dryness in vacuo. The solid residue was submitted to flash
column chromatography (eluant: CH2Cl2/hexane, 3:1) and
the title compound was isolated as a transparent oil (319 mg,
78% yield). IR (nꢀ, cmK1, KBr): 1263 (C–OMe), 1706
1.1.17. 2-[3-(2-Bromophenyl)-2-oxopropyl]-4-methoxy-
benzaldehyde (5b). Ozonolysis of benzylindene 11b
(195 mg, 0.62 mmol) under the same conditions as for
analogue 11a gave the title compound as a white solid
(131 mg, 61% yield). Mp 87–88 8C (MeOH). IR (nꢀ, cmK1
,
1
NaCl): 1723, 1684 (CHO, C]O). H NMR (d, ppm): 3.75
(s, 3H, OCH3), 4.00 (s, 2H, CH2), 4. 01 (s, 2H, CH2), 6.62
(d, 1H, JZ2.3 Hz, Ar–H), 6.83 (dd, 1H, JZ8.5 Hz, J0Z
2.3 Hz, Ar–H), 7.16–7.24 (m, 3H, 3!Ar–H), 7.47 (d, 1H,
JZ7.9 Hz, Ar–H), 7.61 (d, 1H, JZ8.5 Hz, Ar–H), 9.76
(s, 1H, CHO). 13C NMR (d, ppm): 47.3 (CH2), 49.9 (CH2),
55.4 (CH3), 112.2 (CH), 118.8 (CH), 125.0 (C), 127.5 (CH),
128.6 (C), 128.7 (CH), 132.1 (CH), 132.6 (CH), 134.8 (C),
137.8 (CH), 138.2 (C), 163.5 (C]O), 191.7 (C]O), 203.2
(C]O). MS (m/z, %): 348 [(MC2)C, 0.52], 316 (MC,
0.60), 267 [(MK79.9)C, 2], 177 (92), 149 (100), 91 (33).
Anal. Calcd for C17H15BrO3, C: 58.81; H: 4.35; Br: 23.01.
Found C: 59.12; H: 4.31; Br: 22.79.
1
(CO2Et), 1738 (C]O). H NMR (d, ppm, CDCl3): 1.15
(t, JZ7.1 Hz, 3H, –CH3), 3.05 (d, JZ17.5 Hz, 1H, CHH),
3.43 (d, JZ14.7 Hz, 1H, CHH), 3.58 (d, JZ17.5 Hz, 1H,
CHH), 3.71 (s, 1H, CHH), 3.76 (s, 3H, OMe), 4.13 (q, JZ
7.2 Hz, 2H, –OCH2), 6.74 (d, JZ1.9 Hz, 1H, ArH), 6.81 (m,
1H, ArH), 6.90–6.96 (m, 1H, ArH), 7.00–7.06 (m, 1H,
ArH), 7.16 (m, 1H, ArH), m (m, 1H, ArH), 7.67 (m, 1H,
ArH). 13C NMR (d, ppm, CDCl3): 13.8 (CH3), 34.9 (CH2),
37.8 (CH2), 55.4 (CH3), 61.6 (CH2), 109.0 (CH), 115.7
(CH), 125.9 (CH), 126.1 (CH), 127.2 (CH), 128.1 (CH),
130.9 (CH), 132.7 (CH), 136.4 (C), 156.6 (C), 165.6 (C),
170.6 (C]O), 199.9 (C]O). HRMS: C20H19BrO4 (MC),
calcd 402.0467; found 402.0463.
1.1.18. 3-(2-Bromophenyl)-7-methoxynaphthalen-2-ol
(6b). Reaction of ketoaldehyde 5b with NaOH under the
same conditions as for analogue 5a provided the title
compound as a colourless solid (344 mg, 95% yield). Mp
145–147 8C (EtOH/H2O). IR (nꢀ, cmK1, NaCl): 3425 (OH).
1H NMR (d, ppm): 3.77 (s, 3H, –OCH3), 6.87–6.92 (m, 2H,

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1360
2!Ar–H), 7.10–7.17 (m, 2H, 2!Ar–H), 7.26 (s, 1H,
Ar–H), 7.27 (s, 1H, Ar–H), 7.44 (s, 1H, Ar–H), 7.51–7.60
(m, 2H, 2!Ar–H). 13C NMR (d, ppm): 55.2 (CH3), 104.4
(CH), 109.4 (CH), 116.7 (CH), 124.0 (C), 124.5 (C), 127.6
(C), 127.7 (CH), 129.3 (CH), 127.3 (CH), 129.7 (CH), 132.2
(CH), 133.0 (CH), 136.0 (C), 138.0 (C), 151.3 (C), 158.3
(C). MS (m/z, %): 330 [(MC2)C, 99.96], 316 (MC, 100),
250 (37), 234 (60), 206 (59), 178 (46), 175 (36). Anal. Calcd
for C17H13BrO2, C: 62.03; H: 3.98; Br: 24.27. Found C:
59.69; H: 3.91; Br: 24.62.
1.1.22. 2,20-Spirobiindanone (16a). A mixture of indanone
15b (2.67 g, 7.58 mmol), 96% AcOH (5.5 mL) and 48%
HBr (5 mL) was refluxed for 3.25 h. The cooled reaction
mixture was diluted with water (40 mL) and the resulting
suspension was extracted with diethyl ether (3!30 mL).
The combined organic extracts were dried and concentrated
in vacuo. Crystallisation of the solid residue from MeOH
yielded the title compound as white crystals (1.731 g, 92%
yield). Mp 171–173 8C (MeOH). IR (nꢀ, cmK1, KBr): 1694
1
(C]O), 1720 (C]O). H NMR (d, ppm, CDCl3): 3.20 (d,
JZ17 Hz, 2H, –CH2), 3.73 (d, JZ17 Hz, 2H, –CH2), 7.39–
7.45 (m, 2H, ArH), 7.55–7.78 (m, 6H, ArH). 13C NMR (d,
ppm, CDCl3): 38.0 (CH2), 65.3 (C), 124.9 (CH), 126.3 (CH),
127.8 (CH), 135.2 (CH), 135.4 (C), 153.8 (C), 202.7 (C]O).
MS (m/z, %): 248 (MC, 100), 220 (47), 191 (33). Anal. Calcd
for C17H12O2, C: 82.24; H: 4.87. Found C: 81.93; H: 4.79.
1.1.19. 8-Methoxybenzo[b]naphtho[2,3-d]furan (13b).
Reaction of naphthol 6b (55 mg, 0.17 mmol) under the
conditions used for analogue 6a gave the title compound as
a white solid (32 mg, 77% yield). Mp 208–210 8C (MeOH).
IR (nꢀ, cmK1, NaCl): 1222 (C–O–C). 1H NMR (d, ppm): 3.96
(s, 3H, –OCH3), 7.14 (dd, 1H, JZ9.0 Hz, J0Z2.4 Hz,
Ar–H), 7.24 (d, 1H, JZ5.5 Hz, Ar–H), 7.34 (t, 1H, JZ
7.3 Hz, Ar–H), 7.43–7.56 (m, 2H, 2!Ar–H), 7.79 (s, 1H,
Ar–H), 7.90 (d, 1H, JZ9.0 Hz, Ar–H), 8.01 (d, 1H, JZ
7.6 Hz, Ar–H), 8.30 (s, 1H, Ar–H). 13C NMR (d, ppm): 55.3
(CH3), 105.4 (CH), 105.8 (CH), 111.4 (CH), 117.7 (CH),
119.1 (CH), 120.9 (CH), 122.7 (CH), 123.0 (C), 124.2 (C),
125.8 (C), 127.7 (CH), 129.8 (CH), 134.5 (C), 155.6 (C),
157.3 (C), 157.8 (C). MS (m/z, %): 248 (MC, 93), 233 (18),
205 (100), 176 (22), 149 (29). Anal. Calcd for C17H12O2, C:
82.24; H: 4.87. Found C: 81.89; H: 4.96.
1.1.23. 2-(1-Oxoindan-2-ylmethyl)benzoic acid (10e).
A stirred suspension of diindanone 16a (1.731 mg,
6.97 mmol) and 1 M NaOH (1.25 mL) in EtOH (40 mL)
was refluxed during 5 h. The ethanol was removed in vacuo
and the remaining suspension was acidified by addition of
0.625 M HCl. The mixture was extracted with CHCl3 (3!
75 mL) and the combined organic extracts were dried and
concentrated in vacuo. Crystallisation of the solid residue
from benzene provided the title compound as a white solid
(1.632 mg, 88% yield). Mp 141–143 8C (benzene). IR (nꢀ,
cmK1, KBr): 1688 (C]O), 1706 (C]O), 2906 (C–OH). 1H
NMR (d, ppm, CDCl3): 2.89 (d, JZ13.6 Hz, 1H, CHH),
3.10–3.24 (m, 3H, CHH and CH2), 3.77–3.87 (m, 1H, CH),
7.30–7.58 (m, 6H, Ar–H), 7.77 (d, 1H, Ar–H), 8.07–8.10
(m, 1H, ArH), 10.70 (br s, 1H, –OH). 13C NMR (d, ppm,
CDCl3): 32.3 (CH2), 34.9 (CH2), 48.6 (CH), 123.9 (CH),
126.4 (CH), 126.5 (CH), 127.3 (CH), 128.7 (C), 131.6 (CH),
131.8 (CH), 132.8 (CH), 134.7 (CH), 136.4 (C), 142.5 (C),
153.5 (C), 172.6 (C]O), 208.1 (C]O). MS (m/z, %): 266
(MC, 46), 248 (100), 220 (49), 131 (63). Anal. Calcd for
C17H14O3, C: 76.68; H: 5.30. Found C: 77.03; H: 5.19.
1.1.20. 8-Methoxybenzo[b]naphtho[2,3-d]furan-6,11-
dione (3b). Oxidation of benzonaphthofuran 13b (15 mg,
0.06 mmol) under the same conditions as for analogue 13a
yielded the title compound as a yellow solid (4 mg, 24%
yield). Mp 254–256 8C (MeOH). IR (nꢀ, cmK1, NaCl): 1679
1
(C]O). H NMR (d, ppm): 4.00 (s, 3H, OCH3), 7.23 (m,
1H, Ar–H), 7.50–7.61 (m, 2H, 2!Ar–H), 7.68–7.71 (m, 2H,
2!Ar–H), 8.18 (d, 1H, JZ8.6 Hz, Ar–H), 8.32 (d, 1H, JZ
7.5 Hz, Ar–H). 13C NMR (d, ppm): 56.0 (OCH3), 111.0
(CH), 112.8 (CH), 119.9 (CH), 122.9 (C), 124.1 (CH), 124.4
(C), 126.0 (CH), 126.6 (C), 129.2 (CH), 129.6 (CH), 134.5
(C), 153.4 (C), 156.5 (C), 164.2 (C), 175.5 (C]O), 180.0
(C]O). MS (m/z, %): 278 (MC, 13), 149 (56), 85 (37), 83
(38), 71 (50), 69 (37), 58 (100), 57 (70). Anal. Calcd for
C17H10O4, C: 73.38; H: 3.62. Found C: 73.51; H: 3.54.
1.1.24. 2-(1H-Inden-2-ylmethyl)benzoic acid (11c).
Reaction of indanone 10e (1.601 g, 6.01 mmol) under the
same conditions as for analogue 10a provided the title
compound as a white solid (1.281 g, 85% yield). Mp 143–
145 8C (ethyl acetate/hexane). IR (nꢀ, cmK1, KBr): 1687
(C]O), 2881 (C–OH). 1H NMR (d, ppm, CDCl3): 3.34 (s,
2H, CH2), 4.28 (s, 2H, CH2), 6.37 (s, 1H, CH), 7.07–7.54
(m, 7H, ArH), 8.07–8.10 (m, 1H, ArH). 13C NMR (d, ppm,
CDCl3): 35.8 (CH2), 41.2 (CH2), 120.2 (CH), 123.4 (CH),
123.8 (CH), 126.2 (CH), 126.5 (CH), 127.7 (CH), 128.3 (C),
131.7 (CH), 131.8 (CH), 133.0 (CH), 142.6 (C), 143.3 (C),
145.3 (C), 149.4 (C), 172.7 (C]O). MS (m/z, %): 250 (MC,
60), 232 (100), 202 (63), 115 (66). Anal. Calcd for
C17H14O2, C: 81.58; H: 5.64. Found C: 81.72; H: 5.57.
1.1.21. 2-(2-Methoxycarbonylbenzyl)-1-oxoindan-2-car-
boxylic acid ethyl ester (15b). Treatment of indanone 14a
(4.602 g, 22.5 mmol) with o-methoxycarbonylbenzyl bro-
mide under the same conditions as for analogue 14b
furnished the title compound as a white solid (650 mg, 52%
yield). Mp 88–90 8C (MeOH). IR (,cmK1, KBr): 1716 (3!
1
C]O). H NMR (d, ppm, CDCl3): 1.18 (t, JZ7 Hz, 3H,
CH3), 3.05 (d, JZ17.5 Hz, 1H, CHH), 3.58–3.70 (m, 2H,
CH2), 3.82 (s, 3H, OMe), 4.05 (d, JZ14 Hz, 1H, CHH),
4.16 (q, JZ7 Hz, 2H, CH2O), 7.16–7.34 (m, 5H, ArH),
7.48–7.53 (m, 1H, ArH), 7.72–7.81 (m, 2H, ArH). 13C NMR
(d, ppm, CDCl3): 13.9 (CH3), 35.6 (CH2), 35.8 (CH2), 52.0
(Me), 61.8 (C), 124.5 (CH), 126.1 (CH), 126.7 (CH), 127.4
(CH), 130.5 (CH), 131.1 (C), 131.4 (CH), 131.7 (CH), 135.1
(CH), 138.1 (C), 153.7 (C), 168.1 (C]O), 170.9 (C]O),
202.6 (C]O). MS (m/z, %, CI): 353 (MC C1, 48), 321
(100), 307 (58), 275 (69), 205 (68). Anal. Calcd for
C21H20O5, C: 71.58; H: 5.72. Found C: 71.96; H: 5.59.
1.1.25. 2-[3-(2-Formylphenyl)-2-oxopropyl]benzoic acid
(5c). Indene 10e (100 mg, 0.40 mmol) was subjected to the
ozonolysis conditions used for the transformation of
analogue 10a and the title compound was obtained as a
white solid (50 mg, 44% yield). Mp 143–145 8C (ethyl
acetate/hexane). IR (nꢀ, cmK1, KBr): 1H NMR (d, ppm,
DMSO): 3.40 (s, 2H, CH2), 3.47 (s, 2H, –CH2), 6.27–6.78
(m, 7H, ArH), 6.94–7.05 (m, 1H, ArH), 9.13 (s, 1H, –CHO),
12.06 (br s, 1H, –CO2H). 13C NMR (d, ppm, CDCl3): 37.9

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A. Martınez et al. / Tetrahedron 61 (2005) 1353–1362
1361
(CH2), 38.5 (CH2), 127.5 (CH), 127.8 (CH), 128.1 (CH),
128.7 (CH), 128.8 (CH), 129.2 (C), 129.4 (CH), 134.2 (CH),
134.8 (CH), 136.6 (C), 136.9 (C), 137.7 (C), 165.0 (C]O),
CH2), 3.63–3.75 (m, 2H, CH2), 3.91 (s, 3H, OMe), 6.93–
6.98 (m, 2H, ArH), 7.40 (t, JZ7.5 Hz, 1H, ArH), 7.54–7.77
(m, 4H, ArH). 13C NMR (d, ppm, CDCl3): 38.0 (CH2), 38.1
(CH2), 55.7 (CH3), 65.4 (C), 109.4 (CH), 115.9 (CH), 124.7
(CH), 126.2 (CH), 126.4 (CH), 127.6 (CH), 128.4 (C), 135.1
(CH), 135.4 (C), 153.7 (C), 156.7 (C), 165.6 (C), 200.4
(C]O), 202.9 (C]O). MS (m/z, %): 278 (MC, 100), 250
(52), 178 (28). Anal. Calcd for C18H14O3, C: 77.68; H: 5.07.
Found C: 77.84; H: 5.02.
194.0 (C]O), 205.0 (C]O). HRMS: C17H14O4, (MC)
,
calcd 282.0892; found 282.0888.
1.1.26. 6-Oxabenzo[a]anthracen-5-one (17a). Ketoalde-
hyde 5c (88 mg, 0.31 mmol) was reacted with NaOH in the
same way as analogue 5a to give the title compound as a
white solid (43 mg, 56% yield). Mp 190–192 8C (MeOH).
IR (nꢀ, cmK1, KBr): 1725 (C]O). 1H NMR (d, ppm,
CDCl3): 7.42–7.89 (m, 7H, ArH), 8.20 (d, JZ8 Hz, 1H,
ArH), 8.33–8.42 (m, 2H, ArH). 13C NMR (d, ppm, CDCl3):
113.5 (CH), 118.0 (C), 121.4 (C), 121.9 (CH), 122.4 (CH),
125.7 (CH), 127.2 (CH), 127.5 (CH), 128.2 (CH), 128.9
(CH), 130.1 (C), 130.6 (CH), 133.9 (C), 134.5 (C), 134.7
(CH), 148.7 (C), 160.9 (C]O). MS (m/z, %): 246 (MC,
100), 218 (32), 189 (48). Anal. Calcd for C17H10O2, C:
82.91; H: 4.09. Found C: 83.24; H: 3.97.
1.1.30. 2-(5-Methoxy-1-oxoindan-2-ylmethyl)benzoic
acid and 4-methoxy-2-(1-oxoindan-2-ylmethyl)benzoic
acid (10f–10g). Reaction of spiroindanone 16b (451 mg,
1.72 mmol) under the same conditions as for analogue 16a
provided a solid reaction mixture. Purification by flash
column chromatography (eluant: CH2Cl2/MeOH, 98.5/1.5)
led to the isolation of small fractions of ketoacid 10f (71 mg,
30% yield) and ketoacid 10g (29 mg, 12% yield) as white
solids.
1.1.27. 6-Oxabenzo[a]anthracene-5,7,12-trione (4).
Oxidation of dibenzochromanone 17a (35 mg, 0.13 mmol)
under the same conditions as for benzonaphthofuran 13a
gave the title compound as a yellow solid (16 mg, 41%
yield). Mp 251–253 8C (MeOH/acetone/CH2Cl2). IR
1.1.31. Ketoacid a. Mp 150–152 8C (benzene/CH2Cl2). IR
(nꢀ, cmK1, KBr): 3434 (OH), 1709 (C]O), 1679 (C]O). 1H
NMR (d, ppm, CDCl3): 2.90 (d, JZ13.5 Hz, 1H, CHH),
3.16–3.23 (m, 3H, CHH and CH2), 3.77–3.85 (m, 4H, CH
and OMe), 6.80–6.87 (m, 2H, ArH), 7.32–7.41 (m, 2H,
ArH), 7.52–7.57 (m, 1H, ArH), 7.77 (d, JZ7.5 Hz, 1H,
ArH), 8.11 (d, JZ9.0 Hz, 1H, ArH) 13C NMR (d, ppm,
CDCl3): 32.3 (CH2), 35.1 (CH2), 48.6 (CH), 55.4 (CH3),
111.7 (CH), 117.1 (CH), 120.6 (C), 123.9 (CH), 126.5 (CH),
127, (CH), 134.5 (CH), 134.7 (CH), 136.6 (C), 139.3 (C),
145.7 (C), 153.6 (C), 163.1 (C]O), 207.9 (C]O). MS
(m/z, %): 296 (MC, 25), 278 (100), 250 (46). Anal. Calcd
for C18H16O, C: 72.96; H: 5.44. Found C: 73.15; H: 5.37.
1
(nꢀ, cmK1, KBr): 1755 (C]O), 1679 (C]O). H NMR (d,
ppm, TFA): 7.78–8.05 (m, 4H, ArH), 8.23 (t, JZ7.5 Hz,
2H, ArH), 8.47 (d, JZ8 Hz, 1H, ArH), 9.27 (d, JZ8.5 Hz,
1H, ArH). 13C NMR (d, ppm, TFA): 118.0 (C), 121.3 (C),
126.7 (CH), 126.9 (CH), 128.3 (CH), 128.3 (C), 129.1 (C),
129.9 (CH), 131.1 (C), 131.8 (CH), 134.4 (CH), 135.8 (CH),
136.7 (CH), 149.5 (C), 161.7 (C]O), 178.8 (C]O), 184.1
(C]O). MS (m/z, %): 276 (MC, 13), 248 (100), 220 (20),
163 (43). Anal. Calcd for C17H8O4, C: 73.91; H: 2.82.
Found C: 74.36; H: 2.77.
1.1.32. Ketoacid b. Mp 143–145 8C (benzene/CH2Cl2). IR
(nꢀ, cmK1, KBr): 1257 (C–OMe), 1703 (C]O ketone and
C]O acid); 3430 (C–OH). 1H NMR (d, ppm, CDCl3): 2.84
(d, JZ14.5 Hz, 1H, –CHH), 3.06–3.17 (m, 3H, CHH and
CH2), 3.77–3.84 (m, 4H, CH and OMe), 6.83–6.90 (m, 2H,
ArH), 7.29–7.38 (m, 2H, ArH), 7.46–7.52 (m, 1H, ArH),
7.71 (d, JZ8.5 Hz, 1H, ArH), 8.05–8.08 (m, 1H, ArH). 13C
NMR (d, ppm, CDCl3): 32.3 (CH2), 35.0 (CH2), 48.8 (CH),
55.6 (CH3), 109.6 (CH), 115.4 (CH), 125.7 (CH), 126.5
(CH), 129.7 (C), 131.6 (CH), 131.8 (CH), 132.8 (CH), 140.5
(C), 142.5 (C), 148.0 (C), 156.5 (C), 165.4 (C]O), 206.3
(C]O). MS (m/z, %): 296 (MC, 74), 278 (57), 250 (29),
161 (100). Anal. Calcd for C18H16O, C: 72.96; H: 5.44.
Found C: 72.69; H: 5.48.
1.1.28. 5-Methoxy-2-(2-methoxycarbonylbenzyl)-1-
oxoindan-2-carboxylic acid ethyl ester (15e). Reaction
of 2-ethoxycarbonylindanone 14b (1.159 g, 3.16 mmol)
with o-methoxycarbonylbenzyl bromide under the same
conditions as for analogue 14a furnished the title compound
as an oil (1.323 g, 73% yield). IR (nꢀ, cmK1, KBr): 1735
1
(C]O), 1717 (C]O). H NMR (d, ppm, CDCl3): 1.19 (t,
JZ7.0 Hz, 3H, –CH3), 3.56 (d, JZ17.5 Hz, 1H, –CHH),
3.65 (d, JZ14.0 Hz, 1H, –CHH), –), 3.81 (s, 3H, OMe),
3.83 (s, 3H, OMe), 3.87 (s, 1H, –CHH), 4.03 (d, JZ14.0 Hz,
1H, –CHH), 4.16 (q, JZ7.0 Hz, 2H, –CH2O), 6.73 (d, JZ
2.0 Hz, 1H, ArH), 6.84 (m, 1H, ArH), 7.16–7.27 (m, 3H,
ArH), 7.66 (d, JZ8.5 Hz, 1H, ArH), 7.79 (m, 1H, ArH). 13C
NMR (d, ppm, CDCl3): 35.4 (CH2), 35.7 (CH2), 52.0 (CH3),
55.5 (CH3), 61.7 (CH2), 61.9 (C), 109.0 (CH), 115.5 (CH),
126.0 (CH), 126.4 (CH), 128.1 (C), 130.3 (CH), 130.9 (CH),
131.2 (CH), 131.5 (C), 138.1 (C), 156.7 (C), 165.4 (C),
167.9 (C), 170.9 (C), 200.3 (C]O). HRMS: C22H22O6 (MC
C1), calcd 383.1416; found 383.1419.
Acknowledgements
We thank the Spanish Ministry of Science and Technology
and the Xunta de Galicia for financial support and the latter
for grants to A.M. and M.F.
1.1.29. 5-Methoxy-2,20-spirobiindanone (16b). A mixture
of benzylindanone 15d (1.393 g, 3.80 mmol) in 96% AcOH
(5.5 mL) and 48% HBr (2.9 mL) was subjected to the same
reaction conditions as for analogue 15b. The title compound
was obtained as a white solid (531 mg, 53% yield). Mp 176–
78 8C (MeOH). IR (nꢀ, cmK1, KBr): 1709 (C]O), 1690
(C]O). 1H NMR (d, ppm, CDCl3): 3.10–3.20 (m, 2H,
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