Synthesis of Positional Isomeric Phenylphenalenones

Article abstract of DOI:10.1021/acs.joc.6b02985

A series of isomeric phenylphenalenones in which the phenyl ring is located at all possible peripheral positions of the phenalenone nuclei was synthesized. The structural characteristics of the series, in which topological variation is permitted with minimal electronic disturbance, could, in principle, allow for easy pharmacophore recognition when the compounds are aligned in steroidomimetic conformations.

Full text of DOI:10.1021/acs.joc.6b02985

Note
pubs.acs.org/joc
Synthesis of Positional Isomeric Phenylphenalenones
Felipe Ospina,† Adrian Ramirez,† Marisol Cano,† William Hidalgo,‡ Bernd Schneider,‡
and Felipe Otalvaro*,†
́
†Instituto de Química, Síntesis y Biosíntesis de Metabolitos Naturales, Universidad de Antioquia, AA 1226 Medellín, Colombia
‡
̈
Max Planck Institute fur Chemische Okologie, Beutenberg Campus, Hans-Knoll-Strasse 8, 07745 Jena, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A series of isomeric phenylphenalenones in
which the phenyl ring is located at all possible peripheral
positions of the phenalenone nuclei was synthesized. The
structural characteristics of the series, in which topological
variation is permitted with minimal electronic disturbance,
could, in principle, allow for easy pharmacophore recognition
when the compounds are aligned in steroidomimetic
conformations.
he determination of structure−activity relationships
T
(SAR) is crucial during the process of drug development.
This process requires a careful selection of structural analogs of
the lead compound in order to obtain valuable information
regarding binding phenomena.1 Unfortunately, synthetic
convenience rather than rational analysis often seems to be
the main driving force for analog synthesis.1 Using a convenient
chemical approach can be justified if it yields an optimized
molecule; however, these campaigns are often limited when
relied on exclusively. Addressing important structure−activity
relationship questions should be given the preference even at
the expense of tackling more challenging syntheses.2 In this
regard; positional isomers have proven valuable in examining
SAR preferences, especially because they facilitate the
interpretation of results.3
́
In 2013, Guitierrez and co-workers, using natural 9-
phenylphenalenones as a scaffold, disclosed 3-(4-methoxyphen-
yl)-1H-phenalen-1-one (compound 3 in Figure 1 is the parent
structure) as an antiplasmodial compound with an invariant
IC50 of ∼2 μM against two strains of P. falciparum (F-32 and
FCR-3) with different chloroquine susceptibility. 3-(4-Methox-
yphenyl)-1H-phenalen-1-one did not show cytotoxicity at
concentrations five times greater than its IC50.4 Interestingly,
an isomeric compound, namely 9-(4-methoxyphenyl)-1H-
phenalen-1-one (compound 9 in Figure 1 is the parent
structure), displayed an activity level 15-fold less than its 3-
(4-methoxyphenyl) isomer in the same assay.4 Previous work
has shown similar differential activity between 3-, 4-, and 9-(4-
methoxyphenyl)phenalenones (analogs of compounds 3, 4, and
9 in Figure 1) in antiprotozoal assays (Leishmania amazonensis
and Trypanosoma cruzi).5 Thus, the bioactivity of phenyl-
phenalenones seems to be a function of the spatial positioning
of the phenyl group, among other variables, in relation to the
carbonyl group.4,5 However, the systematic study of this
topological relationship requires the synthesis of isomers of the
parent phenylphenalenone for which unambiguous routes have
Figure 1. Phenalen-1-one (1) and isomeric phenylphenalenones (2−
9) synthesized in this work.
been reported only rarely.6,7 Such a series would have the
intrinsic advantage of allowing a “fair” comparison of
topological factors, which in principle should facilitate the
analysis of trends.
Received: December 13, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02985
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Here we report the synthesis of eight isomeric phenyl-
phenalenones (Figure 1) and discuss their potential as a toolkit
for inferring restrictions in the interaction of phenylphenale-
nones with biological targets.
Compounds 4 and 8 were prepared using our recently
described protocols (Scheme 3), and the reader is directed to
these publications for further details.7,19
Scheme 3. Synthesis of Compounds 47 and 819
Ideally, compounds 2−9 should be obtained from properly
substituted (i.e., halogenated) phenalenones via cross-coupling
reactions. However, phenalen-1-one (perinaphthenone, 1)
seems to be prone only to electrophilic substitution at position
C-2 and nucleophilic addition at C-9.8,9 Therefore, compounds
2 and 9 are, in principle, the only ones that do not require
elaborate phenalenone constructions. In fact, compound 9 was
prepared via the Michael addition of phenylmagnesium
bromide to phenalen-1-one as previously reported (Scheme
1).9,10
Scheme 1. Synthesis of Compounds 2 and 99,10
However, the strategy adopted in the synthesis of 8 proved
to be adequate for 5. In this sense, 2-bromo-6-methoxynaph-
thalene was coupled with phenylboronic acid via the Suzuki−
Miyaura reaction to give 2-methoxy-6-phenylnaphthalene (5a)
in 79% (Scheme 4). Compound 5a was submitted to a cascade
Scheme 4. Synthesis of Compound 5
Interestingly, compound 2 has been prepared via an
unexpected intramolecular Friedel−Crafts acylation of 3-
benzyl-1H,3-H-benzo[de]isochromen-1-one in 68% yield.11
Recently, compound 2 was reported as a natural product
from Macropidia fuliginosa and given the trivial name
“fuliginone”;12 however, the spectroscopic data of the natural
and synthetic compounds did not match. In our case, the direct
bromination of phenalenone (1, prepared rapidly via micro-
wave-enhanced synthesis), by means of alumina-supported N-
bromosuccinimide (NBS/Al2O3),13 provided 2-bromophena-
len-1-one8 (58%, 98% brsm) which was submitted to a Suzuki−
Miyaura coupling mediated by [1,3-bis(2,6-diisopropylphenyl)-
imidazole-2-ylidene](3-chloropyridyl)palladium(II)dichloride
(PEPPSI-IPr) under microwaves to provide 2-phenyl-1H-
phenalen-1-one (2) in 96% yield (Scheme 1). Analytical data
for compound 2 closely matches the data for 2-phenyl-1H-
phenalen-1-one reported by Asscher and Agranat11 and,
therefore, the structure of fuliginone had to be revised.12
The synthesis of compound 3 followed a similar strategy as
that for compound 2, starting from 3-hydroxy-1H-phenalen-1-
one (3a), which was prepared using a small-scale version of the
protocol reported by Eistert and co-workers.14 Thus,
compound 3a was triflated in the usual way and submitted to
Suzuki−Miyaura conditions to afford 3-phenyl-1H-phenalen-1-
one (3) in a 41% combined yield (Scheme 2). Compound 3, or
close analogs, was previously obtained either as a byproduct in
a synthesis of 4-phenylphenalenones15 or by following tedious
procedures9,16−18 and therefore, our protocol constitutes an
unambiguous and straightforward synthesis.
Friedel−Crafts/Michael annulation19 using acryloyl chloride
and AlCl3 to afford 9-methoxy-5-phenyl-2,3-dihydro-1H-
phenalen-1-one (5b) in 22% (40% brsm). A reductive carbonyl
transposition process mediated by silica sulfuric acid (SSA)
19
after reduction of the keto group with NaBH4 afforded 5-
phenyl-1H-phenalen-1-one (5) in 31% combined yield after
preparative thin-layer chromatography (TLC), which seems to
accelerate the final dehydrogenation step (Scheme 4).
For the synthesis of compounds 6 and 7, a strategy adapted
from a previous synthesis of 4-methoxyphenalenone in which
the Heck reaction played a pivotal role was implemented.20
Hence, starting from the known symmetrical dibromonaph-
thalenes 6a and 7a (Scheme 5),21 a statistically controlled
Suzuki−Miyaura coupling afforded the corresponding bromo-
phenylnaphthalenes 6b and 7b in 60 and 55% yield,
respectively. Installation of the ethyl acrylate fragment by
means of a Heck coupling followed to provide 6c and 7c in
46% (85% brsm) and 71% for each compound. Compounds 6c
and 7c were hydrogenated, hydrolyzed and submitted to a one-
pot Friedel−Crafts/DDQ dehydrogenation20 to afford 6-
phenyl-1H-phenalen-1-one (6) and 7-phenyl-1H-phenalen-1-
one (7) in 41% and 29% combined yield, respectively (Scheme
5). Compound 7 was previously obtained from a mixture of
isomeric phenylaminophenalenones.18
Scheme 2. Synthesis of Compound 3
One interesting aspect of this series (compounds 2−9)
consists in the way they can be viewed as a phenalen-1-one with
a “walking” peripheral phenyl ring (Figure 1). However, fixing
the series in a steroidomimetic conformation22 (Figure 2A)
offers a unique perspective in which now the carbonyl group
B
DOI: 10.1021/acs.joc.6b02985
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The Journal of Organic Chemistry
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Scheme 5. Synthesis of Compounds 6 and 7
Figure 2. (A) Compounds 2−9 aligned in steroidomimetic conformation (in red) illustrating the “walking carbonyl” perspective. (B) Hypothetical
experiment illustrating the combined carbonyl approach for extrapolation.
Merck silica gel plates (60-F254) using UV light (254 nm) as a
visualizing agent and 98% sulfuric acid/methanol (9:1) solution and
heat as developing agents. Melting points were measured on a capillary
melting point apparatus and are uncorrected. 1H and 13C NMR
spectroscopic analyses were performed on a 500 MHz NMR
spectrometer operating at 500.13 MHz (1H) and 125.75 MHz
(13C). Chemical shifts are reported relative to residual solvent signals.
gives the impression to “walk”. Such scenario, analog to a clock
hand with an electron density excess at the tip, can provide, in
principle, valuable information about ion−dipole or dipole−
dipole interactions in the active site of an enzyme that
complexes with these compounds. To illustrate this point,
suppose that, out of the series, compounds 3, 4, and 7 are
evaluated as the most potent inhibitors of a suitable enzyme
(Figure 2B). One can extrapolate this hypothetical result to
postulate a compound like 6,9-dihydroxy-3-phenylphenalen-1-
one (if rapid tautomerism is assumed) as the substrate with
improved binding capabilities (Figure 2B). This “combined
carbonyl approach” to SAR suggests modifications of the core
nuclei that are hard to discover without the series evaluation.
In summary, we have prepared a series of positional isomeric
phenylphenalenones employing palladium mediated cross-
couplings as key steps. The strategies used are applicable to
the preparation of different analogues. The biological evaluation
of this small-homogeneous phenylphenalenone series in which
topological variation is allowed with minimum electronic
perturbation can provide useful insights for the further
optimization of properties.
1
1
Signals were assigned with the aid of HMQC, HMBC, and H, H−
COSY spectra measured on 600 or 500 MHz NMR spectrometers.
HRESIMS was recorded in positive ion mode on a UPLC−MS/MS
system (Orbitrap mass spectrometer). For microwave reactions, a
monomode microwave synthesizer equipped with infrared and optic
fiber temperature measurement was employed. Yields refer to weighed
chromatographically homogeneous samples.
Synthetic Procedures. Compounds 1a,8 4,7 6a,21 8,19 and 910
were prepared as described in the literature.
1H-Phenalen-1-one (1). In a 35 mL microwave vial were mixed
glycerol (664.5 mg, 7.2 mmol), 2-naphtol (469.8 mg, 3.2 mmol), boric
acid (283.1 mg, 4.6 mmol), sodium 3-nitrobenzenesulfonate (731.9
mg, 3.2 mmol), iron(II) sulfate heptahydrate (188.3 mg, 0.7 mmol),
and concentrated sulfuric acid (1.6 mL, 98% w/v) in that order. The
mixture was heated at 80 °C for 20 min under microwave radiation.
The crude was then slowly diluted with KOH (50 mL, 20% w/v) and
partitioned with AcOEt (3 × 100 mL) followed by flash
chromatography of the concentrated organic phase (n-hexane, bp
55−68 °C) to afford 1: 182.7 mg (31% yield); yellow solid; mp: 149−
151 °C; Rf (CH2Cl2) = 0.3. Compound 1 was identical in all respects
with a commercial material.
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were moni-
tored by thin-layer chromatography (TLC) carried out on 0.25 mm
C
DOI: 10.1021/acs.joc.6b02985
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2-Phenyl-1H-phenalen-1-one (2). In a 10 mL microwave vial were
mixed 2-bromo-1H-phenalen-1-one (50.2 mg, 0.2 mmol), PEPPSI-IPr
catalyst (4.2 mg, 0.006 mmol), K3PO4 (59.3 mg, 0.3 mmol),
phenylboronic acid (34.7 mg, 0.3 mmol), and dioxane (1.5 mL) in
that order. The mixture was then heated at 80 °C under microwave
radiation for 20 min. Partition of the crude reaction mixture between
CH2Cl2 (2 × 50 mL)/H2O (50 mL) followed by flash column
chromatography of the concentrated organic phase (n-hexane/CH2Cl2
1:1) produced the desired 2-phenylphenalenone (2).11 47.1 mg (96%
130.2 (C-2), 130.4 (C-3′-5′), 130.5 (C-4′), 130.9 (C-2′-6′), 131.2 (C-
9), 131.3 (C-9a), 133.2 (C-4), 134.1 (C-6), 134.6 (C-3a), 137.1 (C-7),
139.7 (C-1′), 155.3 (C-3), 185.416 (C-1); HRMS (ESI) [M+H]+
calcd for C19H13O m/z 257.09609, found m/z 257.09568.
2-Methoxy-6-phenylnaphthalene (5a). In a 10 mL flask were
mixed 2-bromo-6-methoxynaphthalene (224.7 mg, 0.9 mmol), phenyl-
boronic acid (140.5 mg, 1.1 mmol), K3PO4 (620.9 mg, 2.9 mmol),
bis(triphenylphosphine) palladium(II) dichloride (30.2 mg, 0.04
mmol), and dioxane (7 mL). The mixture was refluxed under argon
for 16 h. Partition of the crude reaction between CH2Cl2 (2 × 80
mL)/H2O (100 mL) followed by dryness of the organic phase
afforded 2-methoxy-6-phenylnaphthalene (5a)23 after column chro-
matography (n-hexane): 176.1 mg (79% yield); white solid; mp: 147−
1
yield); yellow solid; mp: 139−140 °C; Rf (CH2Cl2) = 0.6; H NMR
(C2D6CO) δ 7.40 (1H, tt, J = 7.5 and 1.5 Hz, H-4′), 7.46 (2H, m, H-
3′-5′), 7.74 (3H, m, H-5 and H-2′-6′), 7.91 (1H, dd, J = 7.3 and 8.1
Hz, H-8), 8.04 (1H, d, J = 6.9 Hz, H-4), 8.07 (1H, s, H-3), 8.21 (1H,
∼ d, J = 8.2 Hz, H-6), 8.41 (1H, dd, J = 1.1 and 8.1 Hz, H-7), 8.62
(1H, dd, J = 1.1 and 7.3 Hz, H-9); 13C NMR (C2D6CO) δ 128.7 (C-
9b), 129.0 (C-5), 129.2 (C-8), 129.71 (C-4′), 129.76 (C-3′-5′), 129.9
(C-3a), 130.9 (C-2′-6′), 131.6 (C-9a), 132.0 (C-9), 133.3 (C-6), 133.7
(C-4), 134.0 (C-6a), 136.6 (C-7), 138.6 (C-1′), 140.6 (C-2), 141.4
(C-3), 184.8 (C-1); HRMS (ESI) [M+H]+ calcd for C19H13O m/z
257.0961, found m/z 257.0961.
1
148 °C; Rf (n-hexane/AcOEt 6:1) = 0.5; H NMR (C2D6CO) δ 3.94
(3H, s, -OMe), 7.19 (1H, dd, J = 2.6 and 8.8 Hz, H-3), 7.33 (1H, d, J =
2.6 Hz, H-1), 7.37 (1H, tt, J = 1.3 and 7.3 Hz, H-4′), 7.49 (2H, t, J =
7.3 Hz, H-3′-5′), 7.78 (3H, m, H-7 and H-2′-6′), 7.89 (1H, d, J = 8.8
Hz, H-8), 8.10 (1H, d, J = 1.5 Hz, H-5); 13C NMR (C2D6CO) δ 56.6
(2-OMe), 107.4 (C-1), 120.9 (C-3), 127.2 (C-5), 127.5 (C-7), 128.7
(C-2′/6′), 128.9 (C-4′), 130.7 (C-3′/5′), 131.2 (C-4a), 131.5 (C-4),
136.0 (C-8a), 137.9 (C-6), 142.8 (C-1′), 159.9 (C-2); HRMS (ESI)
[M+H]+ calcd for C17H15O m/z 235.1122, found m/z 235.1117.
9-Methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-one (5b). In a
25 mL round bottomed flask, a solution of 2-methoxy-6-phenyl-
naphthalene (418.8 mg, 1.8 mmol) in CH2Cl2 (12 mL) was cooled to
−10 °C. AlCl3 (359.8 mg, 2.7 mmol) was then slowly added and the
mixture agitated for 10 min (solution turns brown). To this mixture,
acryloyl chloride (168.8 μL, 1.9 mmol) was added (solution turns dark
red), after 30 min the reaction mixture was allowed to warm to room
temperature with further stirring (5 h). The crude was passed through
a column of silica (previously packaged using n-hexane) employing an
isocratic system (n-hexane/CH2Cl2 2:1). Compound 5b was further
purified via preparative TLC (n-hexane/CH2Cl2 1:2 × 2): 112.7 mg
(22% yield, 40% brsm); brown oil; Rf (CH2Cl2) = 0.6; 1H-NMR
(C2D6CO) δ 2.89 (2H, t, J = 7.3 Hz, H-2), 3.37 (2H, t, J = 7.3 Hz, H-
3), 4.03 (3H, s, -OMe), 7.40 (1H, tt, J = 1.1 and 7.5 Hz, H-4′), 7.51
(2H, ∼ d, J = 7.5 Hz, H-3′-5′), 7.53 (1H, d, J = 8.9 Hz, H-8), 7.80
(2H, ∼ dd, J = 1.1 and 7.5 Hz, H-2′-6′), 8.01 (1H, d, J = 8.9 Hz, H-7),
8.34 (1H, d, J = 1.8 Hz, H-6), 8.38 (1H d, J = 1.8 Hz, H-4); 13C NMR
(C2D6CO) δ 23.1 (C-3), 39.2 (C-2), 57.6 (9-OMe), 115.9 (C-8),
119.2 (C-9a), 125.7 (C-4), 128.7 (C-2′/6′), 129.4 (C-4′), 130.0 (C-7),
130.9 (C-3′/5′), 131.2 (C-6a), 131.4 (C-3a), 132.9 (C-6), 133.8 (C-
9b), 137.2 (C-5), 141.9 (C-1′), 156.7 (C-9), 199.0 (C-1); HRMS
(ESI) [M+H]+ calcd for C20H17O2 m/z 289.1228, found m/z
289.1224.
3-Hydroxy-1H-phenalen-1-one (3a). A small-scale version of the
protocol reported by Eistert and co-workers was followed.9 In an open
test tube were mixed naphtalic anhydride (635.5 mg, 3.2 mmol),
ZnCl2 (861.5 mg, 6.3 mmol) and diethylmalonate (1 mL, 6.6 mmol).
The mixture was heated at 155 °C for 2 h, (color change from white to
brown). At that point the tube was heated to 175 °C for another hour.
The resulting sticky mixture was then cooled and adsorbed in silica.
Purification by column chromatography (n-hexane) afforded 3a: 545.5
mg (87% yield); yellow solid, mp: 255−256 °C (decompose); Rf (n-
hexane/AcOEt 1:1) = 0.4. Compound 3a was identical in all respects
with a commercial material.
1-Oxo-1H-phenalen-3-yl trifluoromethanesulfonate (3b). A sol-
ution of 3-hydroxy-1H-phenalen-1-one (1002.6 mg, 5.1 mmol),
dimethyl amino pyridine (DMAP, 20.8 mg, 0.2 mmol) in dry pyridine
(10 mL) was stirred at −10 °C in a 25 mL rounded bottomed flask.
Addition of trifluoromethanesulfonic anhydride (1735 μL, 10.3 mmol)
followed, and the mixture was stirred under argon atmosphere for 6 h
(the solution turned dark red). Partition of the crude extract between
AcOEt (80 mL)/CuSO4 1 M aqueous solution (3 × 100 mL) and
extraction of the aqueous phase with AcOEt (200 mL) afforded
compound 3b as a brown sticky solid (1250.3 mg, 74% crude yield).
The crude product was employed directly for the synthesis of
compound 3. For identification purposes, an aliquot was purified via
preparative thin layer chromatography (n-hexane/CH2Cl2 1:1). yellow
1
solid mp: 127−128 °C; Rf (CH2Cl2) = 0.7; H NMR (CDCl3, 300
MHz) δ 6.77 (1H, s, H-2), 7.71 (1H, dd, J = 7.3 and 8.2 Hz), 7.82
(1H, dd, J = 7.3 and 8.0 Hz), 8.09 (1H, d, J = 7.3 Hz), 8.17 (1H, d, J =
8.2 Hz), 8.27 (1H, d, J = 8.0 Hz), 8.63 (1H, dd, J = 1.1 and 7.3 Hz);
13C NMR (CDCl3, 300 MHz) δ 118.5 (q, J = 320.3 Hz -CF3), 118.8
(C-2), 122.5, 126.5, 126.6, 127.2, 127.6, 128.4, 131.2, 132.1, 134.1,
136.0, 157.0 (C-3), 184.1 (C-1); HRMS (ESI) [M+H]+ calcd for
C14H8F3O4S m/z 329.0095, found m/z 329.0120
9-Methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-ol (5c). In a 15
mL flask, cerium(III) chloride heptahydrate (140.9 mg, 0.4 mmol) was
added to a dispersion of 9-methoxy-5-phenyl-2,3-dihydro-1H-
phenalen-1-one (72.1 mg, 0.2 mmol) in methanol (5 mL). Slow
addition of NaBH4 (164.6 mg, 4.3 mmol) followed, and the mixture
was stirred for 4 h. Partition with CH2Cl2 (50 mL x 2)/H2O (50 mL)
followed by column chromatography (n-hexane/AcOEt 5:1), afforded
9-methoxy-5-phenyl-2,3-dihydro-1H-phenalen-1-ol (5c): 47.8 mg
3-Phenyl-1H-phenalen-1-one (3). In a 50 mL flask were mixed 1-
oxo-1H-phenalen-3-yl trifluoromethanesulfonate (3b) (500.0 mg, 1.6
mmol), phenylboronic acid (192.4 mg, 1.6 mmol), bis-
(triphenylphosphine) palladium(II) dichloride (55.45 mg, 0.08
mmol), a solution of Na2CO3 2 M (2.4 mL), and dioxane (20 mL).
The solution was refluxed under argon atmosphere for 18 h, time at
which a second addition of phenylboronic acid (190.0 mg, 1.6 mmol)
was repeated. The reaction was kept under reflux for another 18 h.
Partition of the crude product between AcOEt/H2O and CH2Cl2/
H2O, evaporation of the organic phases and preparative TLC of the
organic extracts (n-hexane/ethoxyethane 8:1) afforded 3-phenyl-
phenalenone (3): 227 mg (56% yield); yellow solid; mp: 139−141
°C;17,18 Rf (CH2Cl2) = 0.4; 1H NMR (C2D6CO) δ 6.57 (1H, s, H-2),
7.57 (5H, m, -Ph), 7.67 (1H, dd, J = 7.3 and 8.2 Hz, H-5), 7.73 (1H,
dd, J = 0.9 and 7.3 Hz, H-4), 7.91 (1H, dd, J = 7.3 and 8.1 Hz, H-8),
8.23 (1H, dd, J = 0.9 and 8.2 Hz, H-6), 8.43 (1H, dd, J = 1.2 and 8.1
Hz, H-7), 8.59 (1H, dd, J = 1.2 and 7.3 Hz, H-9); 13C NMR
(C2D6CO) δ 128.5 (C-5), 128.9 (C-8), 129.6 (C-9b), 129.7 (C-6a),
1
(66% yield); pale brown oil; Rf (n-hexane/AcOEt 6:1) = 0.1; H-
NMR (C2D6CO) δ 2.05 (1H, m, H-2), 2.19 (1H, dddd, J = 3.8, 4.8,
7.5, and 12.5 Hz; H-2), 2.99 (1H, ddd, J = 4.8, 8.4, and 13.4 Hz; H-3),
3.21 (1H, ddd, J = 4.8, 7.5, and 12.5 Hz; H-3), 3.97 (3H, s, -OMe),
5.06 (1H, m, H-1), 7.36 (1H, tt, J = 1.3 and 7.3 Hz, H-4′), 7.40 (1H, d,
J = 9.0 Hz, H-8), 7.49 (2H, dd, J = 7.3 and 7.8 Hz, H-3′-5′), 7.78 (2H,
m, H-2′-6′), 7.86 (1H, d, J = 9.0 Hz, H-7), 7.90 (1H, d, J = 1.8, H-4),
8.00 (1H, d, J = 1.8 Hz, H-6); 13C NMR (C2D6CO) δ 20.8 (C-3), 31.8
(C-2), 56.5 (9-OMe), 69.2 (C-1), 114.0 (C-8), 120.7 (C-9a), 123.4
(C-4), 125.3 (C-6), 127.8 (C-2′-6′), 127.9 (C-4′), 128.1 (C-7), 129.8
(C-3′-5′), 130.1 (C-6a), 130.2 (C-9b), 136.3 (C-5), 139.6 (C-3a),
142.1 (C-1′), 154.2 (C-9); HRMS (ESI) [M−H2O]+ calcd for
C20H17O m/z 273.1273, found m/z 273.1274.
5-Phenyl-1H-phenalen-1-one (5). 9-Methoxy-5-phenyl-2,3-dihy-
dro-1H-phenalen-1-ol (5c) (45.5 mg, 0.2 mmol) was dissolved with
benzene (6 mL) in a 10 mL flask. The resulting pale yellow solution
was treated with silica sulfuric acid10 (SSA) (61.9 mg, solution turns
D
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orange) and then refluxed for 9 h. The benzene was then evaporated
and the crude submitted to two consecutive preparative TLC
(petroleum-ether/AcOEt 8:12) to afford 5-phenyl-1H-phenalen-1-
one (5): 19.1 mg (47% yield); yellow solid; mp: 151−152 °C; Rf
(CH2Cl2) = 0.3; 1H NMR (C2D6CO) δ 6.69 (1H, d, J = 9.7 Hz, H-2),
7.46 (1H, tt, J = 7.3 and 1.3 Hz, H-4′), 7.56 (2H, m, H-3′-5′), 7.89
(3H, m, H-8 and H-2′-6′), 8.03 (1H, d, J = 9.7 Hz, H-3), 8.29 (1H, d, J
= 1.6 Hz, H-4), 8.456 (1H, d, J = 1.6 Hz, H-6), 8.453 (1H, dd, J = 1.3
and 7.9 Hz, H-7), 8.50 (1H, dd, J = 1.3 and 7.3 Hz, H-9); 13C NMR
(C2D6CO) δ 128.4 (C-9b), 129.0 (C-2′-6′), 129.4 (C-8), 129.9 (C-
4′), 130.3 (C-9a), 130.91 (C-6), 130.97 (C-3′-5′), 131.04 (C-2),
131.09 (C-3a), 131.1 (C-9), 132.7 (C-4), 134.7 (C-6a), 137.0 (C-7),
141.3 (C-1′), 143.5 (C-3 and C-5), 186.3 (C-1); HRMS (ESI) [M
+H]+ calcd for C19H13O m/z 257.09609, found m/z 257.09596.
1-Bromo-4-phenylnaphthalene (6b). In a 50 mL round bottomed
flask were mixed 1,4-dibromonaphtalene (1151.0 mg, 4.0 mmol),
phenylboronic acid (260.0 mg, 2.0 mmol) and bis-
(triphenylphosphine)palladium(II) dichloride (71.8 mg, 0.1 mmol),
aqueous sodium carbonate (2M, 12 mL), and dioxane (20 mL). The
mixture was refluxed under argon for 2.5 h. Partition of the crude
reaction between AcOEt (2 × 50 mL)/H2O (100 mL) followed by
column chromatography (n-hexane) afforded 1-bromo-4-phenylnaph-
thalene (6b): 357 mg (62% yield); white solid; mp: 73−74 °C; Rf (n-
(C-4a′), 133.9 (C-8a′), 138.3 (C-1′), 141.0 (C-4′), 142.7 (C-1″),
174.0 (C-1); HRMS (ESI) [M+H]+ calcd for C21H21O2 m/z 305.1541,
found m/z 305.1560.
3-(4-Phenylnaphthalen-1-yl)propanoic Acid (6e). Compound 6d
(171.1 mg, 0.6 mmol) was dissolved in a mixture of MeOH/THF (3.5
mL, 1:2) and treated with a KOH solution (5 M, 0.6 mL) at room
temperature for 1 h. The crude was acidulated with HCl (12% w/v, 12
mL), diluted with H2O (20 mL), and partitioned with ethyl ether (50
mL). Evaporation of the organic phase afforded 3-(4-phenyl-
naphthalen-1-yl)propanoic acid (6e): 142.3 mg (91% yield); pale
brown solid; mp: 139−140 °C; Rf (AcOEt) = 0.8; 1H-NMR
(C2D6CO) δ 2.81 (2H, t, J = 7.7, H-2), 2.86 (1H, brs, −OH), 3.46
(2H, t, J = 7.7, H-3), 7.35 (1H, d, J = 7.1 Hz, H-3′), 7.49 (7H, m, H-
Ph, H-2′ and H-6′), 7.59 (1H, ddd, J = 1.3, 7.0, and 8.4 Hz, H-7′), 7.88
(1H, d, J = 8.4 Hz, H-5′), 8.21 (1H, d, J = 8.4 Hz, H-8′); 13C NMR
(C2D6CO) δ 29.7 (C-3), 36.1 (C-2), 125.7 (C-8′), 127.4 (C-6′), 127.5
(C-2′), 127.8 (C-7′), 128.4 (C-3′and C-6′), 129.1 (C-4″), 130.2 (C-
2″-6″), 131.8 (C-3″-5″), 133.8 (C-4a′), 133.9 (C-8a′), 138.5 (C-1′),
140.9 (C-4′), 142.7 (C-1″), 174.9 (C-1); HRMS (ESI) [M+H]+ calcd
for C19H17O2 m/z 277.1228, found m/z 277.1223.
6-Phenyl-1H-phenalen-1-one (6). Compound 6e (124.5 mg, 0.4
mmol) was treated with SOCl2 (0.5 mL) and the flask was air-dried
after gas evolution. This process was repeated twice. After dryness, the
resulting product was dissolved in CH2Cl2 (1.5 mL), treated with
AlCl3 (93.8 mg, 0.7 mmol) and then stirred at room temperature for 1
h. Addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ,
105.1 mg, 0.5 mmol) and CH2Cl2 (2.5 mL) followed, and the mixture
was refluxed for 2.5 h. The reaction crude was adsorbed on silica gel
and then purified by column chromatography (CH2Cl2) to give 6-
Phenyl-1H-phenalen-1-one (6): 52 mg (45% yield); orange solid; mp:
139−140 °C; Rf (CH2Cl2) = 0.4; 1H-NMR (C2D6CO) δ 6.68 (1H, d, J
= 9.9 Hz, H-2), 7.56 (5H, m, -Ph), 7.63 (1H, d, J = 7.3, Hz, H-5), 7.84
(1H, dd, J = 7.3 and 8.2 Hz, H-8), 7.99 (1H, d, J = 9.9 Hz, H-3), 8.01
(1H, d, J = 7.3 Hz, H-4), 8.28 (1H, dd, J = 1.1 and 8.2 Hz, H-7), 8.56
(1H, dd, J = 1.1 and 7.3 Hz, H-9); 13C NMR (C2D6CO) δ 128.9 (C-
3a), 129.0 (C-8), 129.5 (C-9b), 129.7 (C-5), 129.9 (C-4′), 130.1 (C-
9a), 130.2 (C-2), 130.4 (C-3′-5′), 131.4 (C-9), 131.9 (C-2′-6′), 132.4
(C-6a), 133.3 (C-4), 135.0 (C-7), 141.1 (C-1′), 143.8 (C-3), 146.3
(C-6), 186.5 (C-1); HRMS (ESI) [M+H]+ calcd for C19H13O m/z
257.09609, found m/z 257.09586.
1-Bromo-5-nitronaphthalene (7a‑2). In a 50 mL round bottomed
flask were mixed 1-nitronaphthalene (8.8331 g, 50.9 mmol) and FeCl3
(54.2 mg, 0.3 mmol). The mixture was stirred at 90 °C until the melt
(dark mixture) and bromine (3.9 mL) was added. After 1.5 h,
additional bromine (1.3 mL) was added and the reaction was let at 90
°C for another 2.5 h. The crude was then purified by recrystallization
with ethanol affording 1-bromo-5-nitronaphthalene (7a‑2): 3.9212 g
(30% yield); yellow solid; mp: 113−114 °C; Rf (n-hexane) = 0.5; 1H-
NMR (C2D6CO) δ 7.69 (1H, dd, J = 7.5 and 8.8 Hz, H-3), 7.87 (1H,
dd, J = 7.7 and 8.6 Hz, H-7), 8.07 (1H, dd, J = 0.9 and 7.5 Hz, H-2),
8.33 (1H, dd, J = 1.1 and 7.7 Hz, H-6), 8.37 (1H, dt, J =0.9 and 8.8 Hz,
H-4), 8.62 (1H, dt, J = 1.1 and 8.6 Hz, H-8); 13C NMR (C2D6CO) δ
124.5 (C-4), 124.7 (C-1), 126.1 (C-6), 127.8 (C-4a), 128.2 (C-7),
131.5 (C-3), 133.7 (C-2), 134.2 (C-8a), 134.5 (C-8), 149.3 (C-5);
HRMS (ESI) [M+H]+ calcd for C10H7BrNO2 m/z 251.9660, found
m/z 251.9658.
5-Bromonaphthalen-1-amine (7a‑1). In a 100 mL round bottomed
flask were mixed 1-bromo-5-nitronaphthalene (3.7817 g, 15.0 mmol),
iron wire (cut in small pieces 8.3810 g, 150.1 mmol), ethanol (15 mL),
dioxane (15 mL), acetic acid (15 mL), H2O (7.5 mL), and HCl (2M,
187.5 μL). The mixture was refluxed for 1.6 h, the iron removed with a
magnet and the resulting crude washed with CH2Cl2 and AcOEt.
Purification by column chromatography (n-hexane) afforded 5-
bromonaphthalen-1-amine (7a‑1): 3.019 g (90% yield); gray solid;
mp: 63−65 °C; Rf (n-hexane/CH2Cl2 1:1) = 0.3; 1H-NMR (CDCl3) δ
4.14 (2H, bs, -NH2), 6.79 (1H, d, J = 7.5 Hz, H-2), 7.22 (1H, dd ∼ t, J
= 7.7 and 8.1 Hz, H-7), 7.36 (1H, dd, J = 7.5 and 8.4 Hz, H-3), 7.69
(1H, d, J =8.4 Hz, H-4), 7.74 (2H, d overlapped, J = 7.8 Hz, H-6 and
H-8); 13C NMR (CDCl3) δ 110.6 (C-2), 118.0 (C-7), 120.6 (C-8),
123.5 (C-5), 124.6 (C-8a), 124.8 (C-4), 127.7 (C-3), 130.0 (C-6),
1
hexane) = 0.6; H-NMR (C2D6CO) δ 7.34 (1H, d, J = 7.7 Hz, H-3),
7.52 (6H, m, H-6 and -Ph), 7.69 (1H, ddd, J = 1.3, 7.0, and 8.4 Hz, H-
7), 7.87 (1H, d, J = 8.4 Hz, H-5), 7.92 (1H, d, J = 7.7 Hz, H-2), 8.30
(1H, d, J = 8.4, H-8); 13C NMR (C2D6CO) δ 123.4 (C-1), 128.3 (C-
5), 128.9 (C-6 and C-8), 129.2 (C-3), 129.4 (C-7), 129.5 (C-4′),
130.3 (C-2′-6′), 131.5 (C-2), 131.7 (C-3′-5′), 133.8 (C-8a′), 134.7
(C-4a′), 141.6 (C-1′), 142.4 (C-4); HRMS (GC-EI) [M]+ Calc. for
C16H11Br m/z 282.0044, found m/z 282.0031.
Ethyl (E)-3-(4-Phenylnaphthalen-1-yl)acrylate (6c). Compound
6b (451.6 mg, 1.6 mmol) was mixed with bis(triphenylphosphine)-
palladium(II) dichloride (56.9 mg, 0.08 mmol), dioxane (25 mL) and
a solution of sodium carbonate (2M, 2.4 mL). Then an excess of ethyl
acrylate was added (1.2 mL, 10.9 mmol) and the mixture was refluxed
under argon. After 16 h, a second addition of ethyl acrylate (0.5 mL,
4.5 mmol) was made and the reaction was further refluxed for another
28 h. The mixture was partitioned with AcOEt (2 × 50 mL)/H2O
(100 mL). Adsorption on silica gel, followed by column chromatog-
raphy (n-hexane until the starting material was separated then n-
hexane/CH2Cl2 2:1) furnished ethyl (E)-3-(4-phenylnaphthalen-1-
yl)acrylate (6c): 223.2 mg (46% yield; 85% brsm); white solid; mp:
107−108 °C; Rf (n-hexane/CH2Cl2 2:1) = 0.6; 1H-NMR (C2D6CO) δ
1.34 (3H, t, J = 7.1 Hz, H-2 Et), 4.28 (2H, q, J = 7.1 Hz, H-1 Et), 6.65
(1H, d, J = 15.8 Hz, H-2), 7.52 (7H, m, -Ph, H-3′ and H-6′), 7.67 (1H,
ddd, J = 1.2, 7.0, and 8.3 Hz, H-7′), 7.92 (1H, d, J = 8.4 Hz, H-5′),
7.99 (1H, d, J = 7.5 Hz, H-2′), 8.32 (1H, d, J = 8.3 Hz, H-8′), 8.57
(1H, d, J = 15.8 Hz, H-3); 13C NMR (C2D6CO) δ 15.6 (2-OEt), 61.9
(1-OEt), 122.9 (C-2), 125.4 (C-8′), 126.6 (C-2′), 128.3 (C-6′), 128.4
(C-5′), 128.5 (C-3′), 128.7 (C-7′), 129.5 (C-4″), 130.3 (C-2″-6″),
131.6 (C-3″-5″), 133.0 (C-1′), 133.65 (C-4a′), 133.67 (C-8a′) 142.1
(C-1″), 142.7 (C-3), 144.4 (C-4′), 167.9 (C-1); HRMS (ESI) [M
+H]+ calcd for C21H19O2 m/z 303.1385, found m/z 303.1379.
Ethyl 3-(4-Phenylnaphthalen-1-yl)propanoate (6d). A solution of
6c (196.1 mg, 0.6 mmol) in acetone (7 mL) was treated with 19.5 mg
of palladium on activated charcoal catalyst (10% Pd basis). The
mixture was stirred under an atmosphere of hydrogen (balloon with a
needle in contact with the solution) at room temperature for 4 h. The
crude was filtered through a pad of silica-gel (1 g) employing CH2Cl2.
The solvent was evaporated to furnish ethyl 3-(4-phenylnaphthalen-1-
yl)propanoate (6d): 197.2 mg (99% yield); pale yellow oil; Rf (n-
hexane) = 0.6; 1H-NMR (C2D6CO) δ 1.21 (3H, t, J = 7.1 Hz, H-2 Et),
2.79 (2H, t, J = 7.7 Hz, H-2), 3.46 (2H t, J = 7.7 Hz, H-3), 4.12 (2H, t,
J = 7.1 Hz, H-1 Et), 7.35 (1H, d, J = 7.5 Hz, H-3′), 7.49 (7H, m, -Ph,
H-2′ and H-7′), 7.59 (1H, dd ∼ t, J = 7.5 and 8.4 Hz, H-6′), 7.88 (1H,
d, J = 8.4 Hz, H-5′), 8.19 (1H, d, J = 8.4 Hz, H-8′); 13C NMR
(C2D6CO) δ 15.5 (2-OEt), 29.7 (C-3), 36.6 (C-2), 61.7 (1-OEt),
125.7 (C-8′), 127.5 (C-2′), 127.6 (C-6′), 127.8 (C-7′), 128.4 (C-
3′and C-5′), 129.1 (C-4″), 130.2 (C-2″-6″), 131.8 (C-3″-5″), 133.8
E
DOI: 10.1021/acs.joc.6b02985
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
132.8 (C-4a), 142.3 (C-1); HRMS (ESI) [M+H]+ calcd for C10H9BrN
m/z 221.9918, found m/z 221.9920.
hexane/CH2Cl2 2:1) = 0.4; 1H-NMR (C2D6CO) δ 1.20 (3H, t, J = 7.1
Hz, H-2-Et), 2.79 (2H, t, J = 7.7 Hz, H-2), 3.46 (2H, t, J = 7.7 Hz, H-
3), 4.11 (2H, q, J = 7.1 Hz, H-1-Et), 7.39 (1H, dd, J = 7.1 and 8.2 Hz,
H-3′), 7.47 (7H, m, H-2′, H-6′ and -Ph), 7.62 (1H, dd, J = 7.1 and 8.4
Hz, H-7′), 7.73 (1H, d, J = 8.2 Hz, H-4′), 8.16 (1H, d, J = 8.4 Hz, H-
8′); 13C NMR (C2D6CO) δ 15.5 (2-OEt), 30.0 (C-3), 36.7 (C-2),
61.7 (1-OEt), 125.0 (C-8′), 126.6 (C-4′), 127.4 (C-7′), 127.5 (C-3′),
127.9 (C-2′), 128.5 (C-6′), 129.1 (C-4″), 130.1 (C-2″-6″), 131.8 (C-
3″-5″), 133.95 (C-4a′), 133.98 (C-8a′), 139.0 (C-1′), 142.94 (C-5′),
142.96 (C-1″), 174.0 (C-1); HRMS (ESI) [M+H]+ calcd for
C21H21O2 m/z 305.15415, found m/z 305.15375.
3-(5-Phenylnaphthalen-1-yl)propanoic Acid (7e). Compound 7d
(219.8 mg, 0.7 mmol) was dissolved in a mixture of MeOH/THF (4
mL, 1:2) and treated with a KOH solution (5 M, 0.7 mL) at room
temperature for 1 h. The crude was acidulated with HCl (12% w/v, 12
mL), diluted with H2O (25 mL), and partitioned with ethyl ether (2 ×
25 mL). Evaporation of the organic phase afforded 3-(5-phenyl-
naphthalen-1-yl)propanoic acid (7e): 190.5 mg (95% yield); pale
yellow solid; mp: 180−181 °C; Rf (AcOEt) = 0.7; 1H-NMR
(C2D6CO) δ 2.79 (2H, d, J = 7.8 Hz, H-2), 2.89 (2H, d, J = 7.8
Hz, H-3), 7.38 (1H, dd, J = 6.9 and 8.4 Hz, H-3′), 7.43 (1H, dd, J =
1.1 and 6.9 Hz, H-6′), 7.49 (6H, m, -Ph and H-2′), 7.63 (1H, dd, J =
6.9 and 8.6 Hz, H-7′), 7.73 (1H, d, J = 8.4 Hz, H-4′), 8.18 (1H, d, J =
8.6 Hz, H-8′); 13C NMR (C2D6CO) δ 30.0 (C-3), 36.2 (C-2), 125.0
(C-8′), 126.5 (C-4′), 127.4 (C-7′), 127.5 (C-3′), 127.8 (C-2′), 128.5
(C-6′), 129.1 (C-4″), 130.1 (C-2″-6″), 131.7 (C-3″-5″), 133.94 (C-
4a′), 133.99 (C-8a′), 139.2 (C-1′), 142.91 (C-5′), 142.96 (C-1″),
174.9 (C-1); HRMS (ESI) [M+H]+ calcd for C19H17O2 m/z 277.1228,
found m/z 277.1226.
1,5-Dibromonaphthalene (7a). In a 100 mL plastic beaker were
stirred at 45 °C 5-bromonaphthalen-1-amine (2.0013 g, 9.0 mmol)
and HBF4 [30% w/w, 35 mL, prepared by slow addition (1 h) of
H3BO3 (37.2 g) to a cooled (0 °C) HF solution (136.1 g, 40% w/v)]
until a fine dispersion formed. The suspension was then cooled at −10
°C for 25 min and a slow addition of NaNO2 (940.7 mg, 13.2 mmol,
20 min) followed. The diazotization reaction was led for another 40
min under stirring at −10 °C after which a CuBr/HBr solution
(2.0023 g of CuBr in 20 mL HBr 40% w/v) was slowly incorporated
(reaction turns dark) and further stirred for 40 min. The reaction was
then left at r.t. for 85 min and finally heated at 45 °C for 40 min. The
crude was partitioned between AcOEt (175 mL) and H2O (350 mL)
and purified by column chromatography (n-hexane) to furnish 1,5-
dibromonaphthalene (7a):21 1.1025 g (42% yield); white solid; mp:
1
128−129 °C; Rf (n-hexane) = 0.7; H-NMR (C2D6CO) δ 7.59 (2H,
dd, J = 7.5 and 8.4 Hz, H-3−7), 7.98 (2H, d, J = 7.5 Hz, H-2−6), 8.28
(2H, d, J = 8.4 Hz, H-4−8); 13C NMR (C2D6CO) δ 124.3 (C-1−5),
128.9 (C-4−8), 129.9 (C-3−7), 133.1 (C-2−6), 134.7 (C-4a-8a);
HRMS (GC-EI) [M]+ calcd for C10H6Br2 m/z 283.8836, found m/z
283.8847.
1-Bromo-5-phenylnaphthalene (7b). In a round bottomed flask
were mixed 1,5-dibromonaphtalene (875.5 mg, 3.1 mmol), phenyl-
boronic acid (199 mg, 1.6 mmol) and bis(triphenylphosphine)-
palladium(II) dichloride (54.9 mg, 0.08 mmol), aqueous sodium
carbonate (2M, 9 mL), and dioxane (22 mL). The mixture was
refluxed under argon for 2.5 h. Partition of the crude reaction between
AcOEt (2 × 50 mL)/H2O (100 mL) followed by column
chromatography (n-hexane) afforded 1-bromo-5-phenylnaphthalene
1
7-Phenyl-1H-phenalen-1-one (7). Compound 7e (160.8 mg, 0.6
mmol) was treated with SOCl2 (1.0 mL) and the flask was air-dried
after gas evolution. This process was repeated twice (0.2 mL of SOCl2
per addition). After dryness, the resulting product was dissolved in
CH2Cl2 (2 mL), slowly treated with AlCl3 (120.9 mg, 0.9 mmol), and
then stirred at room temperature for 1 h. Addition of 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ, 136.0 mg, 0.6 mmol) and CH2Cl2
(2.5 mL) followed, and the mixture was refluxed for 2.5 h. The crude
was adsorbed on silica gel and then purified by column
chromatography (CH2Cl2) to give 7-Phenyl-1H-phenalen-1-one (7):
46 mg (31% yield); yellow solid; mp: 107−108 °C;18 Rf (CH2Cl2) =
(7b): 253 mg (55% yield); pale yellow oil; Rf (n-hexane) = 0.5; H-
NMR (C2D6CO) δ 7.39 (1H, dd, J = 7.3 and 8.6, H-3), 7.48 (3H, m,
H-4′ and H-2′-6′), 7.54 (3H, m, H-6 and H-3′-5′), 7.73 (1H, dd, J =
7.1 and 8.6 Hz, H-7), 7.86 (1H, dt, J =1.1 and 8.6 Hz, H-4), 7.89 (1H,
dd, J = 1.1 and 7.3 Hz, H-1), 8.28 (1H, dt, J = 1.1 and 8.6 Hz, H-8);
13C NMR (C2D6CO) δ 124.4 (C-1), 127.9 (C-4), 128.2 (C-8), 128.4
(C-3), 128.9 (C-7), 129.4 (C-2′-6′), 129.8 (C-6), 130.3 (C-3′-5′),
131.7 (C-4′), 132.0 (C-2), 133.9 (C-8a′), 134.7 (C-4a′), 141.9 (C-1′),
142.7 (C-5); HRMS (ESI) [M+H]+ calcd for C16H12Br m/z 283.0122,
found m/z 283.0121.
Ethyl (E)-3-(5-Phenylnaphthalen-1-yl)acrylate (7c). Compound
7b (397.9 mg, 1.6 mmol) was mixed with bis(triphenylphosphine)-
palladium(II) dichloride (51.8 mg, 0.07 mmol), dioxane (17 mL), and
a solution of sodium carbonate (2M, 2 mL). Then an excess of ethyl
acrylate was added (1.0 mL, 9.1 mmol) and the mixture was refluxed
under argon for 24 h. The mixture was partitioned with AcOEt (2 ×
50 mL)/H2O (100 mL) followed by dryness of the organic phase.
Adsorption of the crude on silica gel followed by column
chromatography (n-hexane until the starting material was separated
then n-hexane/CH2Cl2 3:1) afforded ethyl (E)-3-(5-phenylnaphtha-
len-1-yl)acrylate (7c): 300.0 mg (71% yield); pale yellow oil; Rf (n-
hexane/CH2Cl2 2:1) = 0.4; 1H-NMR (C2D6CO) δ 1.34 (3H, t, J = 7.1
Hz, H-2-Et), 4.28 (2H, q, J = 7.1 Hz, H-1-Et), 6.62 (1H, d, J = 15.7
Hz, H-2), 7.51 (7H, m, -Ph, H-3′ and H-8′), 7.69 (1H, dd, J = 7.1 and
8.4 Hz, H-7′), 7.92 (2H, d, J = 7.9 Hz, H-2′ and H-4′), 8.26 (1H, d, J =
8.4 Hz, H-6′), 8.57 (1H, d, J = 15.7 Hz, H-3); 13C NMR (C2D6CO) δ
15.6 (2-OEt), 61.9 (1-OEt), 123.2 (C-2), 124.6 (C-6′), 127.0 (C-2′),
127.6 (C-4″), 128.3 (C-7′), 129.1 (C-8′), 129.3 (C-3′), 130.0 (C-4′),
130.2 (C-2″-6″), 131.8 (C-3″-5″), 133.6 (C-8a′), 133.7 (C-4a′), 133.9
(C-5′), 142.4 (C-1′), 142.9 (C-1″), 143.1 (C-3), 167.8 (C-1); HRMS
(ESI) [M+H]+ calcd for C21H19O2 m/z 303.13850, found m/z
303.13855.
1
0.4; H-NMR (C2D6CO) δ 6.67 (1H, d, J = 9.9 Hz, H-2), 7.58 (5H,
m, -Ph), 7.67 (1H, dd, J = 6.9 and 8.6 Hz, H-5), 7.81 (1H, d, J = 7.7
Hz, H-8), 7.97 (1H, d, J = 6.9 Hz, H-4), 7.98 (1H, d, J = 9.9 Hz, H-3),
8.08 (1H, dd, J = 1.1 and 8.6 Hz, H-6), 8.57 (1H, d, J = 7.7 Hz, H-9);
13C NMR (C2D6CO) δ 128.8 (C-5), 129.6 (C-9b), 129.9 (C-3a),
130.1 (C-8 and C-4′), 130.4 (C-3′-5′), 130.52 (C-9a), 130.54 (C-2),
131.0 (C-9), 131.95 (C-6), 131.97 (C-2′-6′), 132.2 (C-6a), 133.4 (C-
4), 141.2 (C-1′), 143.8 (C-3), 149.2 (C-7), 186.0 (C-1); HRMS (ESI)
[M+H]+ calcd for C19H13O m/z 257.0961, found m/z 257.0965.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02985.
1H and 13C NMR spectra for all products (PDF)
AUTHOR INFORMATION
■
Ethyl 3-(5-Phenylnaphthalen-1-yl)propanoate (7d). A solution of
7c (237.4 mg, 0.8 mmol) in acetone (7 mL) was treated with 23.8 mg
of palladium on activated charcoal catalyst (10% Pd basis). The
mixture was stirred under hydrogen atmosphere (balloon with a
needle in contact with the solution) at room temperature for 4 h. The
crude was filtered through a pad of silica-gel (1 g) employing CH2Cl2.
The solvent was evaporated to furnish ethyl 3-(5-phenylnaphthalen-1-
yl)propanoate (7d): 236.3 mg (99% yield); pale yellow oil; Rf (n-
Corresponding Author
*E-mail: leon.otalvaro@udea.edu.co.
ORCID
Felipe Otalvaro: 0000-0002-3905-4650
́
Notes
The authors declare no competing financial interest.
F
DOI: 10.1021/acs.joc.6b02985
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
ACKNOWLEDGMENTS
■
We thank Emily Wheeler for editorial assistance. This research
was financially supported by Universidad de Antioquia,
COLCIENCIAS (grant 111565842551) and the Max-Planck-
̈
Institut fur Chemische Okologie.
̈
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DOI: 10.1021/acs.joc.6b02985
J. Org. Chem. XXXX, XXX, XXX−XXX