Improved synthesis of 4-phenylphenalenones: The case of isoanigorufone and structural analogs

Article abstract of DOI:10.1016/j.tetlet.2012.11.118

2-Hydroxy-4-phenyl-1H-phenalen-1-one (isoanigorufone, 1), a phytoalexin exclusive of Musaceae, was synthesized starting from 3-(2-hydroxynaphthalen-1- yl)propanenitrile in nine steps in an overall yield of 10%. Hydrolysis of ethyl 3-(2-phenylnaphthalen-1-

Full text of DOI:10.1016/j.tetlet.2012.11.118

Tetrahedron Letters 54 (2013) 351–354
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Improved synthesis of 4-phenylphenalenones: the case of isoanigorufone
and structural analogs
Marisol Cano a, Carlos Rojas a, William Hidalgo b, Jairo Sáez a, Jesús Gil c, Bernd Schneider b,
,
⇑
Felipe Otálvaro a,
⇑
a Instituto de Química-Universidad de Antioquia, Calle 67# 53-108, A.A. 1226 Medellín, Colombia
b Max-Planck Institut für Chemische Ökologie, Beutenberg Campus, Hans-Knöll-Strasse 8, 07745 Jena, Germany
c Universidad Nacional de Colombia sede Medellín, Autopista Norte, Calle 64 Cra 65, A.A. 1027 Medellín, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Hydroxy-4-phenyl-1H-phenalen-1-one (isoanigorufone, 1), a phytoalexin exclusive of Musaceae, was
synthesized starting from 3-(2-hydroxynaphthalen-1-yl)propanenitrile in nine steps in an overall yield
of 10%. Hydrolysis of ethyl 3-(2-phenylnaphthalen-1-yl)propanoate obtained from Suzuki–Miyaura cou-
pling between the parent triflate and phenylboronic acid afforded the corresponding propionic acid
which, after Friedel–Crafts acylation and bromine-mediated dehydrogenation, was subjected to Yang–
Finnegan epoxidation to furnish 1. The preparation of analogs using this procedure is also discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 October 2012
Revised 7 November 2012
Accepted 12 November 2012
Available online 1 December 2012
Keywords:
Friedel–Crafts acylation
4-Phenylphenalenones
Suzuki–Miyaura coupling
Musa acuminata plants (bananas) exposed to chemical or biotic
stress accumulate phenylphenalenones, which can be roughly
divided into three types: 9-phenylphenalenones, 4-phenylphenale-
nones, and phenylnaphthalic anhydrides.1 Similar or even identical
compounds have been isolated from Haemodoraceae and Ponteder-
iaceae plants as well; however, 4-phenylphenalenones remain
exclusive to Musa.2 Bioassay studies have suggested the involve-
ment of a photooxidation component in the mode of action of phe-
nalenones against Fusarium oxysporum and Mycosphaerella fijiensis.3
Interestingly, these and other in vitro experiments have shown that
the phenalenone isomer with a substitution at position C-4 is
generally more active than corresponding phenalenones without a
substitution in this position.3,4 This fact can be partially rationalized
in terms of the superior quantum yield of singlet oxygen production
displayed by 4-phenylphenalenones in comparison with their
9-phenyl counterparts.4a
In spite of these results, no systematic study has been reported
addressing structure–activity relationships among 4-phenylphe-
nalenones, in part because only minute amounts can be isolated
from natural sources with a minimum of structural variability.1
In addition, there is only one report on the synthesis of 4-phenyl-
phenalenones based on 9-phenylphenalenone carbonyl transposi-
tion via reduction–oxidation that leads to an isomeric mixture
that is difficult to purify.5 Moreover, the synthesis of 9-heterocyclic
phenalenones, which can serve as educts for carbonyl transposi-
tion, is of limited success.4c Therefore, the development of other
versatile and experimentally simpler synthetic routes for 4-
phenylphenalenones is desirable.
Previously, we stated the plausibility of synthesizing 4-phenyl-
phenalenones from 4-methoxyperinaphthenone via cross-coupling
reactions.6a This strategy, however, is not free from pitfalls, as it
implies the activation of 4-hydroxyperinaphthenone, a process
that can afford a mixture of isomers due to the presence of its 7-
hydroxyperinaphthenone tautomer.6b Here, we report the synthe-
sis of 2-hydroxy-4-phenyl-1H-phenalen-1-one (isoanigorufone, 1)7
using a tactical variant in which the phenyl substituent was intro-
duced prior to the formation of the perinaphthenone moiety in or-
der to avoid the problem of tautomerism.
The general features of the isoanigorufone synthesis are out-
lined retrosynthetically in Scheme 1.
The Hardman8 synthesis of 3-(2-hydroxynaphthalen-1-yl)pro-
panenitrile (9) by means of refluxing acrylonitrile with a basic
solution of 2-naphthol in benzene provided, after purification by
flash column chromatography, the starting point for the synthesis
of 1 in sufficient quantities (40 g) (Scheme 2).8 Aqueous alkaline
hydrolysis of 9,9 followed by Fisher esterification with ethanol
according to the method of Nudelman, afforded ethyl 3-(2-hydrox-
ynaphthalen-1-yl)propanoate (7) in 90% overall yield.10 The treat-
ment of 7 with trifluoromethanesulfonic anhydride in pyridine
generated the corresponding triflate (6) in 62% (70% brsm) as a so-
lid that can be chromatographed and set the stage for the cross-
coupling reaction.11 Coupling trimethyl(phenyl)tin and triflate 6
⇑
Corresponding authors. Tel.: +49 364 1571600; fax: +49 364 1571601 (B.S.);
tel.: +57 421 95653; fax: +57 423 30120 (F.O.).
E-mail addresses: schneider@ice.mpg.de (B. Schneider), pipelion@quimica.
udea.edu.co (F. Otálvaro).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.118

352
M. Cano et al. / Tetrahedron Letters 54 (2013) 351–354
Epoxidation
Friedel-Crafts
O
OH
CO2H
O
1
4
Suzuki-Miyaura
1
2
4
Michael
CN
OH
OH
9
Scheme 1. Retrosynthetic analysis of isoanigorufone (1).7
O
OEt
O
OEt
CN
OH
OH
OTf
a, b
c
90%
62%
9
7
6
O
OR
OH
O
O
g, h
40%
d
e, f
50%
95%
4:
5:
2
1
R = H
R = Et
a, 98%
Scheme 2. Reagents and conditions: (a) NaOH 30%, 5 h reflux, then HCl until pH ꢀ1; (b) EtOH, CH3COCl (25 mol %), 4 h reflux; (c) Tf2O (1.5 equiv), pyridine, 0 °C, 30 min, then
25 °C, 2.5 h; (d) (PPh3)2PdCl2 (5 mol %), PhB(OH)2 (1.5 equiv), Na2CO3(aq) (2 M), dioxane, 22 h reflux; (e) SOCl2, 30 °C until dryness, then CH2Cl2, AlCl3 (3 equiv) 10 min; (f) NBS
(1.2 equiv), CCl4, 3 h reflux under irradiation (170 W UHE lamp, 1800 lumens); (g) t-BuOOH (80%), triton B, benzene, 0 °C, 5 min, then 25 °C, 18 h; (h) p-TSA, CH2Cl2, 25 °C, 1 h.
by means of the Stille reaction under a slight modification of
Papadopoulos conditions proved successful after 20 h reflux (50%
isolated yield).12 However, superior yields were achieved using
the Suzuki–Miyaura coupling under less demanding experimental
conditions and without the use of additives.12 Thus, the reaction of
triflate 6 and phenylboronic acid mediated by bis(triphenylphos-
phine)palladium(II)chloride and Na2CO3 in dioxane–water affor-
step.14 Similar dehydrogenation processes have been performed
by means of benzylic bromination–dehydrobromination se-
quences. Therefore, it was hoped that the combination of N-bromo-
succinimide (NBS) and white-light catalysis according to the
method of Mills could afford the desired 4-phenyl-1H-phenalen-
1-one (2) directly.15
Fortunately, this proved to be the case and compound 2 was ob-
tained in 62% yield after flash chromatography. The Yang–Finnegan
epoxidation of 2 (Scheme 2) went on to produce the epoxide which
was treated with p-toluenesulfonic acid to afford 2-hydroxy-4-
phenyl-1H-phenalen-1-one (isoanigorufone, 1) in 40% combined
yield.16 The spectroscopic data of 1 were identical with those of
the natural compound.7a
In order to check the diversification possibilities offered by the
synthetic route, steps d–f (Scheme 2) were repeated using five dif-
ferent boronic acid derivatives under the same conditions (Tables 1
and 2). Table 1 illustrates some generality in the Suzuki–Miyaura
coupling protocol developed for 1 independent of the electronic
nature of the aromatic partner (all yields Y1 between 88% and
97%). Execution of the Friedel–Crafts reaction on these propanoic
ded ethyl 3-(2-phenylnaphthalen-1-yl)propanoate (5) in
sufficiently pure, gratifying yield of 95% after 22 h reflux for the
next step (Scheme 2).12 Hydrolysis of
generated 3-(2-
a
5
phenylnaphthalen-1-yl)propanoic acid (4) (98% yield) of sufficient
purity for the anticipated regioselective Friedel–Crafts acylation.13
Unfortunately, the reaction of 4 with thionyl chloride, followed by
treatment with AlCl3 and 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) in dichloromethane according to our previously reported
one-pot procedure,6 afforded 4-phenyl-1H-phenalen-1-one (2) in
a disappointing 15% yield after many tedious purification steps.
Stepwise execution of this methodology allowed the preparation
of 4-phenyl-2,3-dihydro-1H-phenalen-1-one (3) in 80% yield and
identified the DDQ-mediated dehydrogenation as the problematic

M. Cano et al. / Tetrahedron Letters 54 (2013) 351–354
353
Table 1
Table 2
Synthesis of 3-(naphthalene-1-yl)propanoic acid analogs using conditions developed
for the synthesis of isoanigorufone
Synthesis of 4-phenylphenalenone analogs using conditions developed for the
synthesis of isoanigorufone
CO2Et
CO2H
CO2H
OR
B
O
1. SOCl2, then AlCl3/CH2Cl2
, (PPh3)2PdCl2, NaCO3
OR
1.
R1
OTf
R1
R1
R1
2. NBS/CCl4, hν
2. NaOH, reflux, then HCl
Product
Entry Educt
Product
Yield
Entry Boronic acid
derivative
Yield (%) Y1,
(%)
Y2
Y1, Y2
HO
HO
OH
CO2H
B
CO2H
CO2H
CO2H
CO2H
CO2H
O
OCH3
OCH3
OCH3
94,
43
1
2
97, 97
88, 96
1
2
3
4
5
58a
2a
2b
4a
OCH3
OH
4a
CO2H
CO2H
O
O
F
B
F
F
97,
56
4b
4b
F
N
NH
N
N
O
66,
O
B
NH
38a
NH
3
95, 97
2c
4c
4c
N
N
O
H
S
CO2H
CO2H
S
68b
S
O
O
B
4
5
94, 80
97, 98
4d
2d
O
4d
4e
S
O
O
72b
O
O
4e
2e
O
B
Y1 = yield for step 1.
Y2 = yield for step 2.
NBS = N-bromosuccinimide.
O
a
NBS/light replaced by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).
Step 2 omitted. Experimental details can be found in Supplementary data.
Y1 = yield for step 1.
Y2 = yield for step 2.
b
Experimental details can be found in Supplementary data.
substrates, probably due to the angular strain that would be
introduced.
acid substrates (Table 2) proved to be regioselective with prefer-
ence for the six-member cyclization mode (Table 2, entries 1–3).
However, electron rich five-member heterocycles displayed a ten-
dency for a seven-member ring formation to give the 1,2-dihydro-
3H-naphtho[20,10:3,4]cyclohepta[1,2-b]heterocyclic-3-one (Table
2, entries 4 and 5). This rather unexpected result represents the
first synthetic entry to this type of nuclei but renders the synthesis
unsuitable for the preparation of electron rich five-member hetero-
cyclic analogs. It also shows the important influence the electron-
density distribution of the lateral ring can exert on the ring size of
the final product. Interestingly, execution of the Friedel–Crafts and
In conclusion, we have developed an operationally simple nine-
step synthesis of 2-hydroxy-4-phenyl-1H-phenalen-1-one (isoani-
gorufone, 1) starting from 3-(2-hydroxynaphthalen-1-yl)propane-
nitrile in a 10% global yield using the Suzuki–Miyaura and
Friedel–Crafts reactions as key steps. The synthesis can be extrap-
olated to the preparation of 4-phenylphenalenone analogs with
confidence.
Acknowledgments
DDQ mediated dehydrogenation as
a one-pot procedure on
We thank Marco Kai for mass spectrometric analyses, and Emily
Wheeler for editorial assistance. This research was financially sup-
ported by Universidad de Antioquia (Grant CODI EO1606) and the
Max-Planck-Institut für Chemische Ökologie.
substrate 4d allowed the isolation of 4-(4-methylthiophen-3-yl)-
1H-phenalen-1-one as a minor compound (4% yield, see Supple-
mentary data). No phenalenone could be detected in the case of
educt 4e. Dehydrogenation of the Friedel–Crafts products using
NBS/light (Table 2, entries 1–3) went as expected for the cases of
phenyl analogs. However, no dehydrogenation occurred when this
procedure was applied to the pyrazole derivative. This situation
was partially remediated by the use of DDQ (Table 2, entry 3) albeit
in low yield (38%, 44% brsm). Substrates 2d–2e proved recalcitrant
to the dehydrogenating conditions employed on the other
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.118.

354
M. Cano et al. / Tetrahedron Letters 54 (2013) 351–354
12. The Stille reaction was performed as described in Crisp, G.T.; Papadopoulus, S.
References and notes
Aust. J. Chem. 1988, 41, 1711–1715, using tris(dibenzylideneacetone)
dipalladium instead of bis(dibenzylideneacetone)palladium. Experimental
procedure for the Suzuki–Miyaura reaction: Compound 6 (3.08 g, 8.0 mmol),
phenylboronic acid (1.94 g, 16.0 mmol), and bis(triphenylphosphine)
palladium(II)chloride (281 mg, 5 mol %) were dissolved in dioxane (50 mL),
mixed with a Na2CO3 solution (12 mL, 2 M) and refluxed for 22 h. Liquid
partition with AcOEt/H2O, dryness (Na2SO4) and concentration of the organic
phase afforded 2.3 g (95%) of ethyl 3-(2-phenylnaphthalen-1-yl)propanoate
(5). 1H NMR (C3D6O, 500.13 MHz) d 8.16 (d, J = 8.5 Hz, H-80), 7.95 (d, J = 8.1 Hz,
H-50), 7.82 (d, J = 8.5 Hz, H-40), 7.61 (ddd, J = 8.5, 6.9, 1.2 Hz, H-70), 7.55 (ddd,
J = 8.1, 6.9, 1.2 Hz, H-60), 7.37–7.47 (m, H-200–H-600), 7.32 (d, J = 8.5 Hz, H-30),
4.03 (q, J = 7.1 Hz, –OCH2CH3), 3.33 (t, J = 7.7 Hz, H-3), 2.73 (t, J = 7.7 Hz, H-2),
1.15 (t, J = 7.1 Hz, –OCH2CH3); 13C NMR (C3D6O, 125.75 MHz) d 172.8 C-1),
143.4 (C-100), 140.6 (C-20), 134.5 (C-4a0), 134.4 (C-10), 132.7 (C-8a0), 130.1 (C-200/
600), 129.8 (C-50), 129.2 (C-300/500), 129.0 (C-30), 128.0 (C-400), 127.6 (C-70), 127.6
(C-40), 126.5 (C-60), 125.0 (C-80), 60.8 (–OCH2CH3), 37.0 (C-2), 28.7 (C-3), 14.5 (–
OCH2CH3). HREIMS: m/z 304.14510 (calcd for C21H20O2, 304.14633).
1. (a) Luis, J. G.; Fletcher, W. Q.; Echeverri, F.; Grillo, T. Tetrahedron 1994, 50,
10963–10970; (b) Luis, J. G.; Quiñones, W.; Echeverri, F.; Grillo, T. A.; Kishi, M.
P.; Garcia-Garcia, F.; Torres, F.; Cardona, G. Phytochemistry 1996, 41, 753–757;
(c) Kamo, T.; Kato, N.; Hirai, N.; Tsuda, M.; Fujioka, D.; Ohigashi, H. Biosci.
Biotechnol. Biochem. 1998, 62, 95–101; (d) Kamo, T.; Hirai, N.; Iwami, K.;
Fujioka, D.; Ohigashi, H. Tetrahedron 2001, 57, 7649–7656; (e) Jitsaeng, K.;
Schneider, B. Phytochem. Lett. 2010, 3, 84–87.
2. (a) Cooke, R. G.; Edwards, J. M. Prog. Chem. Org. Nat. Prod. 1981, 40, 153–190; (b)
Greca, M. D.; Previtera, L.; Zarelli, A. Tetrahedron Lett. 2008, 49, 3268–3272; (c)
Opitz, S.; Hölscher, D.; Oldham, N. J.; Bartram, S.; Schneider, B. J. Nat. Prod.
2002, 65, 1122–1130; (d) Fang, J.; Paetz, C.; Hölscher, D.; Munde, T.; Schneider,
B. Phytochem. Lett. 2011, 4, 203–204.
3. (a) Lazzaro, A.; Corominas, M.; Martí, C.; Flors, C.; Izquierdo, L. R.; Grillo, T. A.;
Luis, J. G.; Nonell, S. Photochem. Photobiol. Sci. 2004, 3, 706–710; (b) Hidalgo,
W.; Duque, L.; Saez, J.; Arango, R.; Gil, J.; Rojano, B.; Schneider, B.; Otálvaro, F. J.
Agric. Food Chem. 2009, 57, 7417–7421.
13. Hydrolysis of 5 (2.3 g, 7.6 mmol) was performed using aqueous NaOH (30%,
50 mL, 5 h reflux) to obtain 2.0 g (98%) of crude 3-(2-phenylnaphthalen-1-
yl)propanoic acid (4) as a white solid after acidic workup. 1H NMR (C3D6O,
500.13 MHz) d 8.24 (d, J = 8.5 Hz, H-80), 7.87 (d, J = 8.1 Hz, H-50), 7.73 (d,
J = 8.5 Hz, H-40), 7.56 (ddd, J = 8.5, 6.9, 1.2 Hz, H-70), 7.48 (ddd, J = 8.1, 6.9,
1.2 Hz, H-60), 7.36-7.44 (m, H-200–H-600), 7.28 (d, J = 8.5 Hz, H-30), 3.29 (t,
J = 7.7 Hz, H-3), 2.46 (t, J = 7.7 Hz, H-2); 13C NMR (C3D6O, 125.75 MHz) d 181.7
(C-1), 144.2 (C-100), 140.5 (C-20), 136.4 (C-10), 134.8 (C-4a0), 133.2 (C-8a0), 130.4
(C-200/600), 129.7 (C-50), 129.3 (C-30), 129.3 (C-300/500), 127.9 (C-400), 127.4 (C-40),
127.1 (C-70), 126.5 (C-60), 125.6 (C-80), 40.4 (C-2), 27.4 (C-3). HREIMS: m/z
276.11528 (calcd for C19H16O2, 276.11503).
14. Experimental procedure: Compound 4 (1.4 g, 5.0 mmol) was treated with 1 mL
of SOCl2 and the flask was air-dried after gas evolution. This process was
repeated four times. The product was dissolved in CH2Cl2 (15 mL) and AlCl3
(2.0 g, 15.0 mmol) was added in one portion (the solution turns red). After
10 min, the reaction mixture was dried and immediately submitted to column
chromatography using CH2Cl2 as eluent to give 1.0 g (80%) of 4-phenyl-2,3-
dihydro-1H-phenalen-1-one (3) as a pale yellow oil. Compound 3 decomposes
rapidly upon exposure to open air. 1H NMR (C3D6O, 500.13 MHz) d 8.19 (dd,
J = 8.1, 1.1 Hz, H-9), 8.14 (dd, J = 7.2, 1.1 Hz, H-7), 7.92 (d, J = 8.4 Hz, H-6), 7.65
(dd, J = 8.1, 7.2 Hz, H-8), 7.48 (d, J = 8.4 Hz, H-5), 7.42–7.50 (m, H-200–H-600),
3.34 (t, J = 6.8 Hz, H-3), 2.81 (t, J = 6.8 Hz, H-2); 13C NMR (C3D6O, 125.75 MHz) d
198.8 C-1), 142.9 (C-10), 140.8 (C-4), 135.7 (C-9), 134.8 (C-6a), 133.6 (C-9b),
132.1 (C-9a), 132.0 (C-3a), 131.1 (C-20/60), 130.6 (C-5), 130.2 (C-30/50), 129.1 (C-
40), 128.1 (C-6), 127.4 (C-8), 126.8 (C-7), 39.8 (C-2), 28.3 (C-3). HREIMS: m/z
258.10515 (calcd for C19H14O, 258.10447).
15. Mills, F.D. J. Org. Chem. 1981, 46, 2389–2393. Experimental procedure: To a
refluxing solution (PYREXÒ glassware) of compound 3 (450 mg, 1.7 mmol) in
CCl4 (15 mL) irradiated with an EPSON Powerlite S4 video beam (170 W UHE
lamp, 1800 lumens) were added 3 mg of benzoyl peroxide and 100 mg of N-
bromosuccinimide (NBS). NBS addition was repeated twice over 30 min
intervals (1.7 mmol total). The mixture was refluxed for another hour (a
change in color to intense yellow was noticed). Evaporation of the solvent and
purification by column chromatography (CH2Cl2–n-hexane (1:1)) afforded
270 mg (62%) of 4-phenyl-1H-phenalen-1-one (2) as a yellow solid. 1H NMR
(C3D6O, 500.13 MHz) d 8.57 (dd, J = 7.5, 1.3 Hz, H-9), 8.39 (dd, J = 8.0, 1.3 Hz, H-
7), 8.23 (d, J = 8.5 Hz, H-6), 7.87 (dd, J = 7.9, 7.5 Hz, H-8), 7.83 (d, J = 10.1 Hz, H-
3), 7.66 (d, J = 8.5 Hz, H-5), 7.53–7.58 (m, H-200–H-600), 6.60 (d, J = 10.1 Hz, H-2);
13C NMR (C3D6O, 125.75 MHz) d 184.9 C-1), 145.7 (C-4), 140.2 (C-3), 140.1 (C-
10), 135.9 (C-7), 132.8 (C-6), 132.8 (C-6a), 131.3 (C-20/60), 131.0 (C-9), 130.6 (C-
9a), 130.3 (C-5), 129.6 (C-2), 129.5 (C-30/50), 129.2 (C-40), 128.8 (C-9b), 128.0
(C-8), 125.1 (C-3a). HREIMS: m/z 256.08960 (calcd for C19H12O, 256.08882).
16. Experimental procedure: A solution of compound 2 (68 mg, 0.3 mmol) in benzene
4. (a) Flors, C.; Ogilby, P. R.; Luis, J. G.; Grillo, T. A.; Izquierdo, L. R.; Gentili, P.;
Bussotti, L.; Nonell, S. Photochem. Photobiol. 2006, 82, 95–103; (b) Quiñones,
W.; Escobar, G.; Echeverri, F.; Torres, F.; Rosero, Y.; Arango, V.; Cardona, G.;
Gallego, A. Molecules 2000, 5, 974–980; (c) Rosquete, L. I.; Cabrera-Serra, M. G.;
Piñero, J. E.; Martín, P. R.; Fernández, L. P.; Luis, J. G.; McNaughton, G. S.; Grillo,
T. A. Bioorg. Med. Chem. 2010, 18, 4530–4534.
5. Luis, J. G.; Fletcher, W. Q.; Echeverri, F.; Grillo, T. A. Tetrahedron 1994, 50,
10963–10970.
6. (a) Nanclares, J.; Gil, J.; Rojano, B.; Saez, J.; Schneider, B.; Otálvaro, F.
Tetrahedron Lett. 2008, 49, 3844–3847; (b) In fact, triflation of 4-
hydroxyperinaphthenone (prepared as described in Ref. 3b) afforded
60:22:18 mixture of
a
1,1-dioxo-1H,10H-[2,20-biphenalene]-4,40-diyl
bis(trifluoromethanesulfonate), 1-oxo-1H-phenalen-7-yl trifluoromethanesul
fonate, and 1-oxo-1H-phenalen-4-yl trifluoromethanesulfonate, respectively
(for experimental details see Supplementary data).
7. (a) Luis, J. G.; Lahlou, E. H.; Andrés, L. S. Nat. Prod. Lett. 1999, 13, 299–304; (b)
Otálvaro, F.; Nanclares, J.; Vásquez, L. E.; Quiñones, W.; Echeverri, F.; Arango,
R.; Schneider, B. J. Nat. Prod. 2007, 70, 887–890.
8. (a) Hardman, A. F. J. Am. Chem. Soc. 1948, 70, 2119–2120; (b) Duque, L.;
Restrepo, C.; Sáez, J.; Gil, J.; Schneider, B.; Otálvaro, F. Tetrahedron Lett. 2010, 51,
4640–4643.
9. Hydrolysis of 9 (32 g) was performed according to Ref. 8a using aqueous NaOH
(30%, 100 mL, 5 h reflux) to obtain 38 g of crude 3-(2-hydroxynaphthalen-1-
yl)propanoic acid (8) as a white solid after acidic workup. 1H NMR (C3D6O,
500.13 MHz) d 7.95 (d, J = 8.1 Hz, H-50), 7.92 (d, J = 8.5 Hz, H-80), 7.67 (d,
J = 8.9 Hz, H-40), 7.44 (ddd, J = 8.5, 6.9, 1.2 Hz, H-70), 7.26 (ddd, J = 8.1, 6.9,
1.2 Hz, H-60), 7.18 (d, J = 8.9 Hz, H-30), 3.31 (t, J = 7.5 Hz, H-3), 2.66 (t, J = 7.5 Hz,
13
H-2); C NMR (C3D6O, 125.75 MHz) d 177.4 C-1), 153.6 (C-20), 131.7 (C-8a0),
130.0 (C-4a0), 129.3 (C-50), 128.7 (C-40), 127.1 (C-70), 123.3 (C-60), 123.2 (C-80),
119.9 (C-10), 119.7 (C-30), 35.2 (C-2), 21.3 (C-3). HREIMS: m/z 216.07904 (calcd
for C13H12O3, 216.07864).
10. Nudelman, A.; Bechor, Y.; Falb, E.; Fischer, B.; Wexler, B.A.; Nudelman, A. Synth.
Commun.
1998,
28,
471–474.
Experimental
procedure:
3-(2-
Hydroxynaphthalen-1-yl)propanoic acid (8) (38.0 g, 0.2 mol), dissolved in
200 mL of distilled EtOH (not anhydrous), was treated with 3 mL of acetyl
chloride and refluxed. Addition of acetyl chloride (1 mL) was repeated after 2 h
and the mixture was kept under reflux for another 2 h. Evaporation of the
reaction mixture and purification by column chromatography (CH2Cl2)
afforded 35 g (90% from 9) of ethyl 3-(2-hydroxynaphthalen-1-yl)propanoate
(7) as a yellow oil. 1H NMR (C3D6O, 500.13 MHz) d 7.95 (d, J = 8.1 Hz, H-50), 7.78
(d, J = 8.5 Hz, H-80), 7.67 (d, J = 8.9 Hz, H-40), 7.47 (ddd, J = 8.5, 6.9, 1.2 Hz, H-70),
7.29 (ddd, J = 8.1, 6.9, 1.2 Hz, H-60), 7.20 (d, J = 8.9 Hz, H-30), 4.10 (q, J = 7.1 Hz, –
OCH2CH3), 3.36 (t, J = 7.7 Hz, H-3), 2.63 (t, J = 7.7 Hz, H-2), 1.19 (t, J = 7.1 Hz, –
(4 mL) was treated with benzyltrimethylammonium hydroxide (40
lL of a 40%
13
OCH2CH3); C NMR (C3D6O, 125.75 MHz) d 174.1 C-1), 153.1 (C-20), 134.2
triton B solution in MeOH) and t-BuOOH (40 L of an 80% solution in water) at
l
(C-8a0), 130.2 (C-4a0), 129.5 (C-50), 128.9 (C-40), 127.3 (C-70), 123.5 (C-60), 123.3
(C-80), 119.2 (C-10), 119.0 (C-30), 60.9 (–OCH2CH3), 34.7 (C-2), 21.2 (C-3), 14.5
(–OCH2CH3). HREIMS: m/z 244.10888 (calcd for C15H16O3, 244.10994).
0 °C. The mixture was allowed to warm to room temperature, after which the
same addition of triton B and t-BuOOH was repeated twice at intervals of 50 min
and the reaction was stirred for additional 2 h. The crude mixture was submitted
to flash column chromatography (CH2Cl2–n-hexane (1:4)). This last step was
found to ameliorate complications in the purification of isoanigorufone (1) if the
epoxide was treated in the same flask with p-toluenesulfonic acid (p-TSA). 1-
Phenyl-7a,8a-dihydro-7H-phenaleno[1,2-b]oxiren-7-one: 1H NMR (C3D6O,
500.13 MHz) d 8.40 (dd, J = 7.3, 1.2 Hz, H-6), 8.37 (dd, J = 8.2, 1.2 Hz, H-4), 8.17
(d, J = 8.5 Hz, H-3), 7.79 (dd, J = 8.2, 7.3 Hz, H-5), 7.66 (d, J = 8.5 Hz, H-2), 7.53–
7.64 (m, H-200–H-600), 4.61 (d, J = 3.9 Hz, H-7a), 4.05 (d, J = 3.9 Hz, H-8a); 13C NMR
(C3D6O, 125.75 MHz) d 193.4 C-7), 145.7 (C-1), 141.1 (C-10), 137.0 (C-4), 134.5
(C-3a), 131.8 (C-20/60), 131.4 (C-3), 131.3 (C-8c), 130.7 (C-2), 130.5 (C-30/50),
130.1 (C-6), 129.9 (C-40), 129.0 (C-6a), 128.3 (C-5), 126.2 (C-8b), 58.6 (C-8a), 56.7
(C-7a). HREIMS: m/z 272.08198 (calcd for C19H12O2, 272.08373). The purified
product (epoxide) was dissolved in CH2Cl2 (10 mL) and treated with p-TSA
(5 mg) under stirring (30 min) at room temperature to give 33 mg (40% from 2)
of 2-hydroxy-4-phenyl-1H-phenalen-1-one (isoanigorufone, 1). HREIMS: m/z
272.08308 (calcd for C19H12O2, 272.08373). Other spectroscopic data were
identical with those of the natural compound.7a
11. Experimental procedure:
A solution of 7 (12.87 g, 56.4 mmol) in pyridine
(10 mL) was cooled to ꢁ10 °C and treated with triflic anhydride (18.8 mL,
112.8 mmol, 20 min addition). The reaction mixture was allowed to warm
(room temperature) and stirred for an additional 2.5 h. The crude mixture was
partitioned between saturated aqueous CuSO4 and ethyl acetate, and the
organic fraction was dried (Na2SO4), concentrated and submitted to column
chromatography (AcOEt–n-hexane (1:9)) to give 13.2 g (62%) of ethyl 3-(2-
(((trifluoromethyl)sulfonyl)oxy)naphthalene-1-yl)propanoate (6) as
a
white
solid. 1H NMR (C3D6O, 500.13 MHz)
d
8.25 (d, J = 8.5 Hz, H-80), 8.05 (d,
J = 8.1 Hz, H-50), 8.02 (d, J = 9.1 Hz, H-40), 7.72 (ddd, J = 8.3, 6.9, 1.4 Hz, H-70),
7.65 (ddd, J = 8.1, 6.9, 1.2 Hz, H-60), 7.50 (d, J = 9.1 Hz, H-30), 4.11 (q, J = 7.1 Hz, –
OCH2CH3), 3.53 (t, J = 7.7 Hz, H-3), 2.71 (t, J = 7.7 Hz, H-2), 1.20 (t, J = 7.1 Hz, –
13
OCH2CH3); C NMR (C3D6O, 125.75 MHz) d 172.3 C-1), 146.0 (C-20), 134.0 (C-
4a0), 133.2 (C-8a0), 130.1 (C-10), 130.7 (C-40), 130.0 (C-50), 128.9 (C-70), 128.1 (C-
60), 125.4 (C-80), 120.9 (q, JC–F = 319.3 Hz, –SO3CF3), 120.3 (C-30), 61.1 (–
OCH2CH3), 34.8 (C-2), 22.3 (C-3), 14.5 (–OCH2CH3). HREIMS: m/z 376.06340
(calcd for C16H15F3O6S, 376.05923).