Synthesis of 8-phenylphenalenones: 2-hydroxy-8-(4-hydroxyphenyl)-1h-phenalen-1-one from eichhornia crassipes

Article abstract of DOI:10.1021/acs.joc.5b02559

2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1), the first reported 8-phenylphenalenone from the roots of Eichhornia crassipes (water hyacinth), was synthesized starting from 2-methoxynaphthalene in 11 steps and with an overall yield of 2%. A cascade Friedel-Crafts/Michael annulation reaction between acryloyl chloride and 2-methoxynaphthalene afforded 9-methoxyperinaphthanone that, after transformation to 9-methoxy-2-(4-methoxyphenyl)-1H-phenalen-1-one by means of standard Suzuki-Miyaura methodology, was subjected to a reductive carbonyl transposition to afford 8-(4-methoxyphenyl)perinaphthanone. Dehydrogenation, epoxidation, and demethylation of the latter afforded 1.

Full text of DOI:10.1021/acs.joc.5b02559

Note
pubs.acs.org/joc
Synthesis of 8‑Phenylphenalenones: 2‑Hydroxy-8-(4-
hydroxyphenyl)‑1H‑phenalen-1-one from Eichhornia crassipes
†
‡
†
‡
,†
Felipe Ospina, William Hidalgo, Marisol Cano, Bernd Schneider, and Felipe Otal
†
́
varo*
Instituto de Química, Síntesis y Biosíntesis de Metabolitos Naturales, Universidad de Antioquia, AA 1226 Medellín, Colombia
‡
̈
̈
̈
r Chemische Okologie, Beutenberg Campus, Hans-Knoll-Strasse 8, 07745 Jena, Germany
Max Planck Institute fu
*
S Supporting Information
ABSTRACT: 2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1), the first reported
-phenylphenalenone from the roots of Eichhornia crassipes (water hyacinth), was
synthesized starting from 2-methoxynaphthalene in 11 steps and with an overall yield of
8
2
2
9
%. A cascade Friedel−Crafts/Michael annulation reaction between acryloyl chloride and
-methoxynaphthalene afforded 9-methoxyperinaphthanone that, after transformation to
-methoxy-2-(4-methoxyphenyl)-1H-phenalen-1-one by means of standard Suzuki−
Miyaura methodology, was subjected to a reductive carbonyl transposition to afford 8-
(
4-methoxyphenyl)perinaphthanone. Dehydrogenation, epoxidation, and demethylation
of the latter afforded 1.
n 2005, Ho
̈
lscher and Schneider reported the isolation of the
methoxyphenyl)phenalenones, with the 3-isomer being inactive
against Leishmania amazonensis and Trypanosoma cruzi, the 4-
isomer being active against the same protozoa, and the 9-isomer
active only against L. amazonensis. In addition, activity in the
submicrogram range was observed against Plasmodium
falciparum for the 3-isomer with a 15-fold difference with
I
first 8-phenylphenalenones from the roots of Eichhornia
crassipes (water hyacinth), a pantropical freshwater weed
characterized by its invasive nature. The biosynthesis of
these novel phenylphenalenones was suggested to involve an
unusual 1,2-aryl migration similar to that known to occur in the
biosynthesis of isoflavonoids. This work added another group
1
1
11
respect to its 9-phenylphenalenone counterpart. These
of phenylphenalenones, namely 8-phenylphenalenones, to the
well-known isomeric 4- and 9-phenylphenalenones (Figure 1)
findings indicate the importance of the spatial positioning of
the 4-methoxyphenyl group in relation to the carbonyl group,
1
1
as noticed by Gutier
́
rez and co-workers.
While the synthesis of several 4- and 9-phenylphenalenones
is well-established and the bioactivity of natural and synthetic
compounds of these types has been studied somewhat,
12
10,11,13
nothing is known about the biological activity or ecological role
of 8-phenylphenalenones and their structure−activity relation-
ship (SAR). Accordingly, the development of synthetic routes
to 8-phenylphenalenones seems desirable for conducting
systematic studies among phenylphenalenones.
Figure 1. Examples of natural isomeric phenylphenalenones: 2-
Ideal synthetic strategies toward 1 would exploit a late
functionalization of the commercially accessible perinaphthe-
none at position C-8. Unfortunately, perinaphthenone seems to
be prone only to electrophilic substitution at position C-2 or to
1
hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1), hydroxyani-
3
,4
2
gorufone, and irenolone.
14,12
1
−8
the addition of strong nucleophiles at C-9.
However,
occurring in the plant kingdom.
4-Phenylphenalenones
and 9-phenylphenale-
2
−4
position C-2 in perinaphthenone can be viewed as a latent C-8
position if somehow the carbonyl group can be transposed to
position C-9. Thus, a 1,2 reduction of 2-(4-methoxyphenyl)-9-
methoxyperinaphthenone (8) should in principle provide 8-(4-
methoxyphenyl)phenalenone (4) after an acidic workup
seem to be exclusive to Musaceae,
5
,6
2−4
nones are common in Hemodoraceae, Musaceae,
and
Pontederiaceae. Interestingly, 2-phenyl-1H-phenalen-1-one
fuliginone) has been reported for the first time as a natural
8
(
9
product from Macropidia fuliginosa (Hemodoraceae).
(
Scheme 1). Such a process closely resembles the 1,2 addition
A biological evaluation of isomeric phenylphenalenones
1
0,11
reveals a striking contrast in some activities.
For example,
10
Rosquete and co-workers reported a differential in vitro
Received: November 6, 2015
antiprotozoal activity among three isomeric 3-, 4-, and 9-(4-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 1. Retrosynthetic Analysis for 2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1)
Scheme 2. Synthesis of Key Substrate 8
Scheme 3. Model Studies toward Carbonyl Transposition
of nucleophiles to enol ethers of cyclohexane-1,3-diones that
methoxy-2,3-dihydro-1H-phenalen-1-one (11) after an acidic
15
was first reported by Frank and Hall and applied recently in a
workup. This reaction probably proceeds via sequential
1
6
18
similar context. Disconnection of the aryl moiety in 4 via
Suzuki−Miyaura coupling points to the use of 9-methoxyper-
inaphthenone (10) as the initial substrate.
Friedel−Crafts/Michael addition in that order. Direct treat-
ment of 11 with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) effected dehydrogenation to afford 9-methoxyper-
inaphthenone (10) in a 40% combined yield after column
chromatography (Scheme 2). Bromination of 10 with N-
bromosuccinimide (NBS) afforded 2-bromo-9-methoxy-1H-
phenalen-1-one (9) with suitable purity for synthetic purposes.
Attempts to transpose the carbonyl group in 9 by means of
Compound 10 was prepared by a reportedly difficult
17
methylation of 9-hydroxyperinaphthenone, which can be
obtained by condensation between 2-methoxynaphthalene and
cinnamoyl chloride followed by aromatization through
12,18
elimination of benzene.
In our case, it was postulated
16
that a cascade process mediated by Lewis acid and involving 2-
methoxynaphthalene and acryloyl chloride could provide 10 in
a straightforward way (Scheme 1).
Treatment of 2-methoxynaphthalene with acryloyl chloride
in the presence of AlCl3 in dichloromethane afforded 9-
NaBH according to Nishida and co-workers afforded 9-
4
methoxyperinaphthenone (10) as the major product. Interest-
ingly, those conditions are reported to effectively transform 2-
bromo-5,8-di-tert-butyl-4,9-dimethoxy-1H-phenalen-1-one into
1
6
8-bromo-2,5-di-tert-butyl-6-methoxy-1H-phenalen-1-one.
B
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Mechanistic Rationales for the 8a → 7a and 6b → 5b Conversions
Scheme 5. Completion of the Synthesis of 1
Therefore, installation of the aryl moiety prior to a reductive
carbonyl transposition seemed to be adequate. In this regard,
reaction of 9 and 4-methoxyphenylboronic acid mediated by
position C-9 in 8a followed by SSA-mediated conjugate
substitution of the methoxyl by water at position C-4. Scheme
4 provides a mechanistic rationale for this process. Refluxing 8a
[
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-
with excess LiAlH in THF allowed 9-methoxy-2-phenyl-2,3-
4
chloropyridyl)palladium(II) dichloride (PEPPSI-IPr) using a
standard protocol afforded 9-methoxy-2-(4-methoxyphenyl)-
dihydro-1H-phenalen-1-one (7b) in 25% yield [38% based on
recovered starting material (brsm)] to be isolated from a
reaction mixture that also contained the same product that was
obtained in the DIBAL-H reduction (Scheme 3). Although 7b
was not the expected product, molecular modeling of this
compound revealed a dihedral angle of 28.27° defined by the
1H-phenalen-1-one (8) in a gratifying yield of 66% from 10
after column chromatography.
Model studies with 9-methoxy-2-phenyl-1H-phenalen-1-one
(8a) (prepared in a manner similar to that of 8) demonstrated
the recalcitrant properties of this compound toward reduction.
19
O, C-1, C-9a, and C-9 atoms. This result shows that the
In fact, treatment of 8a with NaBH according to Nishida and
4
1
6
carbonyl group in 7b is not part of a conjugated system and
therefore should be accessible to reduction. Fortunately, this
proved to be the case, and reduction of 7b with NaBH4
afforded 9-methoxy-2-phenyl-2,3-dihydro-1H-phenalen-1-ol
co-workers did not provide any detectable product of
reduction or carbonyl transposition. The addition of cerium-
(
8
III) chloride did not improve the situation. Moreover, treating
a with diisobutylaluminum hydride (DIBAL-H) at room
(
6b) (98%); upon treatment with SSA, that was transformed
temperature generated an unidentified compound that rapidly
to 8-phenyl-2,3-dihydro-1H-phenalen-1-one (5b) (40%, 28%
from 8a without purification of intermediates) presumably
through tautomerization from 8-phenyl-7,8-dihydro-1H-phena-
len-1-ol (Scheme 4). Dehydrogenating 5b with DDQ afforded
8-phenylphenalenone (4b) in 78%.
reverted to the starting material in the open air. Treating the
DIBAL-H product with silica sulfuric acid (SSA) in wet CH Cl2
2
(
Scheme 3) allowed for the isolation of 7-hydroxy-8-phenyl-
,3-dihydro-1H-phenalen-1-one (7a) (33% yield), suggesting
that the DIBAL-H reduction introduced the hydride into
2
C
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
With the route established for 4b, we decided to conduct the
final steps toward the natural product 1 (Scheme 5). Thus, the
sequential reduction of 8 with LiAlH and NaBH followed by
SSA treatment (Scheme 5) afforded 8-(4-methoxyphenyl)-2,3-
dihydro-1H-phenalen-1-one (5) (15%, 23% brsm) together
with 2-(4-methoxyphenyl)-1H-phenalen-1-one (12%) after
preparative TLC. The formation of the latter compound,
presumably the product of a conjugate hydride addition at
160.9 (C-9), 185.7 (C-1); HRMS (ESI) [M + H] calcd for C14H O
11 2
m/z 211.0754, found m/z 211.0752.
For identification purposes, compound 11 was isolated by column
chromatography (CH Cl ) using the same procedure as described
above without treatment with DDQ.
-Methoxy-2,3-dihydro-1H-phenalen-1-one (11). 424 mg (21%
yield, rapidly decomposes); brown oil; H NMR (CDCl ) δ 2.91 (2H,
t, J = 7.4 Hz, H-2), 3.37 (2H, t, J = 7.4 Hz, H-3), 3.98 (3H, s, -OMe),
7.31 (1H, d, J = 9.0 Hz, H-8), 7.41 (1H, dd, J = 8.0 and 7.1 Hz, H-5),
7.80 (1H, d, J = 9.0 Hz, H-7), 7.99 (1H, d, J = 8.0 Hz, H-4), 8.15 (1H,
) δ 21.5 (C-3), 37.6 (C-2), 56.1
-OMe), 113.2 (C-8), 117.6 (C-9a), 123.1 (C-4), 125.6 (C-5), 127.6
4
4
2
2
9
1
3
position C-9, was detected after the addition of NaBH and
4
d, J = 7.1 Hz, H-6); 13C NMR (CDCl
could not be suppressed by the addition of CeCl ·7H O.
3
3
2
(
(
(
2
Moreover, this unexpected process was not detected during the
model study of the synthesis of 4b. Treating 5 with DDQ
effected dehydrogenation to produce 8-(4-methoxyphenyl)-1H-
phenalen-1-one (4, 77%). The installation of the hydroxyl
group in 4 was achieved through the epoxidation of the enone
followed by an acid-catalyzed oxirane opening to produce 2-
hydroxy-8-(4-methoxyphenyl)-1H-phenalen-1-one (2) in 85%
combined yield. Demethylating 2 with HBr (55%, 90% brsm)
afforded compound 1, which was identical in all respects with
the natural product.
In summary, we have developed an 11-step synthesis of 2-
hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1) starting
from 2-methoxynaphthalene in a 2% global yield using a
reductive carbonyl transposition as a key step. The use of a
Friedel−Crafts/Michael annulation reaction for the construc-
tion of 9-methoxyperinaphthanone is also noteworthy.
C-6), 128.6 (C-9b), 129.0 (C-6a), 132.9 (C-3a), 134.0 (C-7), 154.5
C-9), 198.9 (C-1); HRMS (ESI) [M + H] calcd for C H O m/z
+
1
4
13
2
13.0910, found m/z 213.0916.
-Bromo-9-methoxy-1H-phenalen-1-one (9). In a round-bottom
flask, covered with aluminum foil, were mixed compound 10 (252 mg,
.2 mmol), NBS (281 mg, 1.6 mmol), and N,N-dimethylformamide
(DMF, 4 mL) in that order. The mixture was stirred at room
temperature for 3 h, and the crude material was partitioned between
CH Cl (2 × 100 mL) and H O (200 mL). The organic phase was
dried to afford crude 2-bromo-9-methoxy-1H-phenalen-1-one (9) at a
suitable purity [R (9) = 0.4 (CH Cl )] for the next step. Compound 9
was further purified by column chromatography (petroleum ether/
CH Cl ) using a gradient elution scheme (10:1 to 9:2 to 8:3 to 7:4 to
:5) accounting for a total of 10 fractions (100 mL each): 233 mg
67% yield); yellow solid; mp 210−212 °C (uncorrected); H NMR
(C D CO) δ 4.21 (3H, s, -OMe), 7.63 (1H, d, J = 9.2 Hz, H-8), 7.77
(1H, dd, J = 7.9 and 7.5 Hz, H-5), 8.33 (1H, d, J = 9.2 Hz, H-7), 8.37
1H, dd, J = 7.9 and 1.3 Hz, H-6), 8.64 (1H, dd, J = 7.5 and 1.3 Hz, H-
), 8.67 (1H, s, H-3); 13C NMR (C D CO) δ 58.3 (-OMe), 114.8 (C-
9a), 116.0 (C-8), 125.2 (C-3a) 127.2 (C-5), 129.6 (C-6a), 129.7 (C-
9b), 130.0 (C-2), 134.2 (C-4), 137.6 (C-6), 138.0 (C-7), 138.4 (C-3),
161.3 (C-9), 179.0 (C-1); HRMS (ESI) [M + H]+ calcd for
C H BrO m/z 288.9859, found m/z 288.9841.
2
1
2
2
2
f
2
2
2
2
6
(
1
2
6
(
4
2
6
EXPERIMENTAL SECTION
■
General Experimental Procedures. All reactions were moni-
tored by thin-layer chromatography (TLC) conducted on 0.25 mm
Merck silica gel plates (60-F254) using UV light (254 nm) as a
visualizing agent and a 98% sulfuric acid/methanol (9:1) solution and
heat as developing agents. NMR spectroscopic analyses were
performed on a 500 MHz NMR spectrometer operating at 500.13
14
10
2
9-Methoxy-2-(4-methoxyphenyl)-1H-phenalen-1-one (8). Com-
pound 9 (all crude material from previous step), K CO (561 mg, 4.0
2
3
mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-
chloropyridyl)palladium(II) dichloride (PEPPSI-IPr, 17 mg, 0.025
mmol), (4-methoxyphenyl)boronic acid (216 mg, 1.4 mmol), and
dioxane (4 mL) were mixed in that order in a 25 mL round-bottom
flask. The mixture was stirred under argon at 60 °C for 18 h.
Partitioning the mixture between CH Cl (2 × 100 mL) and H O
1
13
MHz ( H) and 125.75 MHz ( C). Chemical shifts are reported
relative to residual solvent signals. Signals were assigned with the aid of
1
1
HMQC, HMBC, and H− H COSY spectra. HRESIMS was
conducted in positive ion mode on an UPLC−MS/MS system
consisting of an Ultimate 3000 series RSLC (Dionex, Idstein,
Germany) system and an Orbitrap mass spectrometer. Yields refer
to weighed chromatographically homogeneous samples.
2
2
2
(200 mL) followed by drying of the organic phase afforded 9-methoxy-
2-(4-methoxyphenyl)-1H-phenalen-1-one [8; R = 0.4 (CH Cl )] after
f
2
2
Synthetic Procedures. 9-Methoxyperinaphthenone (10). A
column chromatography (2:1 petroleum ether/CH Cl ): 250 mg
2 2
solution of 2-methoxynaphthalene (1.5 g, 9.5 mmol) in CH Cl (25
(66% yield from 10); orange solid; mp 134−136 °C (uncorrected);
2
2
1
mL, rotovaporated from MgSO ) was cooled to −10 °C (salt/ice
H NMR (C D CO) δ 3.86 (3H, s, 4′-OMe), 4.19 (3H, s, 9-OMe),
4
2
6
bath). AlCl (1.9 g, 14.5 mmol) was then added and the mixture
7.01 (2H, ∼d, J = 9.0 Hz, H-3′-5′), 7.62 (1H, d, J = 9.2 Hz, H-8), 7.69
(2H, ∼d, J = 9.0 Hz, H-2′-6′), 7.75 (1H, dd, J = 7.9 and 7.5 Hz, H-5),
8.24 (1H, d, J = 9.2 Hz, H-7), 8.31 (1H, dd, J = 7.9 and 1.3 Hz, H-6),
3
agitated for 15 min (solution turns green). To this mixture was slowly
added acryloyl chloride (850 μL, 9.9 mmol) (1 min addition, solution
turns red), and the reaction mixture was allowed to warm to room
temperature (25 °C in 30 min) with further stirring (3 h). Reaction
progress was checked by TLC [CH Cl , R (11) = 0.6]. The reaction
1
3
8.31 (1H, s, H-3), 8.63 (1H, dd, J = 7.5 and 1.3 Hz, H-4); C NMR
(C D CO) δ 56.5 (9-OMe), 58.1 (4′-OMe), 115.1 (C-3′-5′), 115.9
2
6
2
2
f
(C-8), 126.8 (C-5), 132.1 (C-2′-6′), 133.1 (C-4), 133.4 (C-6), 136.2
was quenched with a 18% HCl(aq) solution (20 mL, slow addition, gas
(C-7), 136.5 (C-3), 161.0 (C-9), 161.4 (C-4′), 184.5 (C-1); HRMS
+
evolution!) and the mixture partitioned between CH Cl (3 × 200
(ESI) [M + H] calcd for C H O m/z 317.1172, found m/z
2
2
21 17
3
mL) and H O (200 mL). The organic phase was evaporated, dissolved
317.1169.
2
in CH Cl (50 mL), and refluxed with DDQ (2.2 g, 9.5 mmol) for 1.5
8-(4-Methoxyphenyl)-2,3-dihydro-1H-phenalen-1-one (5). To a
2
2
h. Reaction progress was checked by TLC [CH Cl , R (10) = 0.3].
suspension of LiALH (101.4 mg, 2.7 mmol) in dry THF (9 mL) was
2
2
f
4
After cooling, the reaction mixture was adsorbed in silica gel, and
compound 10 was purified by isocratic column chromatography
added compound 8 (262 mg, 0.8 mmol), and the mixture was refluxed
for 2 h. After cooling, the crude reaction was quenched with ethyl
acetate (AcOEt, dropwise until gas evolution ceased) and then the
mixture partitioned between AcOEt (2 × 100 mL) and 5% HCl(aq)
(150 mL). The organic phase was dried and reconstituted with MeOH
(
CH Cl ) prior to stabilization of the stationary phase with petroleum
2 2
ether (bp 55−68 °C): 800 mg (40% yield); yellow solid; mp 79−81
1
°
C (uncorrected); H NMR (C D CO) δ 4.16 (3H, s, -OMe), 6.58
(
2 6
1H, d, J = 9.9 Hz, H-2), 7.58 (1H, d, J = 9.2 Hz, H-8), 7.71 (1H, dd, J
8.1 and 7.3 Hz, H-5), 8.23 (1H, d, J = 9.9 Hz, H-3), 8.24 (1H, d, J =
(5 mL). To this solution was added NaBH (263 mg, 7 mmol), and
4
=
the mixture was stirred for 45 min at room temperature. The mixture
9
7
9
9
.2 Hz, H-7), 8.28 (1H, dd, J = 8.1 and 1.3 Hz, H-4), 8.53 (1H, dd, J =
was dried and partitioned between CH Cl (3 × 100 mL) and H O
2
2
2
.3 and 1.3 Hz, H-6); 13C NMR (C D CO) δ 58.0 (-OMe), 114.7 (C-
(200 mL), and the organic phase was concentrated. The mixture was
2
6
2
0
a), 115.8 (C-8), 126.7 (C-5), 128.8 (C-2), 129.8 (C-6a), 130.5 (C-
b), 131.0 (C-3a), 132.3 (C-6), 136.5 (C-4), 136.6 (C-7), 136.9 (C-3),
treated with silica sulfuric acid (SSA, 1.0 g) in CH Cl (15 mL) for
2 2
24 h and adsorbed on silica gel for subsequent column
D
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
chromatography [2:1 petroleum ether/CH Cl ; R (5, CH Cl ) = 0.6]:
(C-8), 143.6 (C-3), 161.9 (C-4′), 186.4 (C-1); HRMS (ESI) [M +
2
2
f
2
2
1
+
3
5 mg (15% yield from 8); brown oil; H NMR (C D CO) δ 2.96
H] calcd for C H O m/z 287.1067, found m/z 287.1068.
2
6
20 15
2
(
2H, t, J = 7.2 Hz, H-2), 3.47 (2H, t, J = 7.2 Hz, H-3), 3.88 (3H, s,
2-Hydroxy-8-(4-methoxyphenyl)-1H-phenalen-1-one (2). A sol-
ution of compound 4 (50 mg, 0.2 mmol) in benzene (4 mL) was
treated with triton B (24 μL, 40% in MeOH) and t-BuOOH (24 μL,
-
1
OMe), 7.11 (2H, ∼d, J = 9.0 Hz, H-3′-5′), 7.51 (1H, ∼dd, J = 7.0 and
.3 Hz, H-4), 7.56 (1H, dd, J = 8.1 and 7.0 Hz, H-5), 7.80 (2H, ∼d, J =
.0 Hz, H-2′-6′), 7.95 (1H, ∼dd, J = 8.1 and 1.3 Hz, H-6), 8.36 (1H, d,
9
70% in H O) and stirred at 0 °C for 0.5 h. The ice bath was removed
2
13
J = 2.0 Hz, H-9), 8.43 (1H, d, J = 2.0 Hz, H-7); C NMR (C D CO)
and stirred continually for an additional 1 h followed by another
addition of triton B (24 μL, 40% in MeOH) and t-BuOOH (24 μL,
2
6
δ 29.9 (C-3), 40.1 (C-2), 56.7 (-OMe), 116.4 (C-3′-5′), 124.9 (C-9),
1
1
1
for C H O m/z 289.1223, found m/z 289.1224.
For identification purposes, compounds 6 and 7 were isolated by
preparative TLC (CH Cl ) using the same procedure without
treatment with NaBH and SSA or SSA (R values of 0.6 and 0.4,
respectively).
-Methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-phenalen-1-
one (7). H NMR (C D CO) δ 3.63 (2H, m, H-3), 3.74 (3H, s, 4′-
OMe), 4.03 (3H, s, 9-OMe), 4.13 (1H, dd, J = 8.8 and 6.6 Hz, H-2),
6
7
7
8
27.1 (C-4), 128.2 (C-6), 128.7 (C-5), 130.1 (C-2′-6′), 132.1 (C-7),
70% in H O). Agitation for an additional 1 h, followed by CH Cl (2
2 2 2
×
100 mL)/H O (200 mL) partitioning, afforded 50 mg of crude
32.2 (C-6a), 132.2 (C-9b), 134.0 (C-1′), 135.5 (C-3a), 136.1 (C-9a),
2
+
material after rotary evaporation of the organic phase. The crude
material was dissolved in CH Cl (4 mL) and treated with the soluble
39.6 (C-8), 161.8 (C-4′), 199.0 (C-1); HRMS (ESI) [M + H] calcd
2
2
20
17
2
fraction of p-toluenesulfonic acid (p-TSA, 10 mg) in diethyl ether (2
mL) for 2 h. The addition of another portion of p-TSA (10 mg) was
followed by stirring for an additional 13 h. Partitioning the crude
2
2
4
f
extract between CH Cl (2 × 100 mL) and H O (200 mL), followed
2
2
2
by rotary evaporation of the organic phase, afforded 2-hydroxy-8-(4-
methoxyphenyl)-1H-phenalen-1-one (2) in suitable purity for the next
9
1
2
6
step: R (2, CH Cl ) = 0.4; 51 mg (85% yield); red solid; mp 222−224
f
2
2
1
°
∼
7
C (uncorrected); H NMR (CDCl ) δ 3.90 (3H, s, -OMe), 7.07 (2H,
.83 (2H, ∼d, J = 8.8 Hz, H-3′-5′), 7.19 (2H, ∼d, J = 8.8 Hz, H-2′-6′),
.47 (1H, dd, J = 8.1 and 7.2 Hz, H-5), 7.54 (1H, d, J = 9.2 Hz, H-8),
.96 (1H, d, J = 9.2 Hz, H-7), 8.06 (1H, dd, J = 7.2 and 1.3 Hz, H-4),
3
d, J = 8.6 Hz, H-3′-5′), 7.17 (1H, s, H-3), 7.60 (1H, dd, J = 8.1 and
.0 Hz, H-5), 7.69 (1H, d, J = 7.0 Hz, H-4), 7.75 (2H, ∼d, J = 8.6 Hz,
.12 (1H, dd, J = 8.1 and 1.3 Hz, H-6); 1 C NMR (C D CO) δ 30.5
3
H-2′-6′), 7.97 (1H, d, J = 8.1 Hz, H-6), 8.41 (1H, s, H-7), 8.96 (1H, s,
2
6
H-9); 13C NMR (CDCl ) δ 55.4 (O-Me), 113.8 (C-3), 114.6 (C-3′-
(
C-3), 53.3 (C-2), 56.4 (4′-OMe), 57.6 (9-OMe), 115.5 (C-3′-5′),
3
5
2
6
′), 123.1 (C-9b), 127.5 (C-5), 127.7 (C-3a), 128.2 (C-9a), 128.6 (C-
′-6′), 129.9 (C-6), 130.0 (C-9), 130.2 (C-4), 131.8 (C-1′), 132.5 (C-
1
1
9
15.6 (C-8), 118.7 (C-9a), 125.0 (C-5), 127.7 (C-4), 129.7 (C-7),
30.6 (C-6a), 130.9 (C-3a), 131.1 (C-2′-6′), 133.2 (C-1′), 134.3 (C-
a), 133.4 (C-7), 139.5 (C-8), 149.5 (C-2), 159.8 (C-4′), 180.6 (C-1);
b), 135.6 (C-6), 156.7 (C-9), 160.6 (C-4′), 199.1 (C-1); HRMS
+
+
HRMS (ESI) [M + H] calcd for C H O m/z 303.1016, found m/z
20
15
3
(
3
ESI) [M + H] calcd for C H O m/z 319.1329, found m/z
21
19
3
3
03.1015.
For identification purposes, an aliquot of the crude material was
taken prior to treatment with p-TSA.
19.1326.
(
1S*,2S*)-9-Methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-phe-
1
nalen-1-ol (6). H NMR (C D CO) δ 3.06 (1H, m, H-2), 3.06 and
3
(
6
7
7
2
6
5
-(4-Methoxyphenyl)-7a,8a-dihydro-7H-phenaleno[1,2-b]oxiren-
.42 (2H, m, H-3), 3.78 (3H, s, 4′-OMe), 3.94 (3H, s, C-9-OMe), 4.20
1H, d, J = 6.2 Hz, -OH), 5.10 (1H, dd, J = 10.8 and 6.2 Hz, H-1),
1
7
-one (3). H NMR (C D CO) δ 3.88 (3H, s, -OMe), 4.13, (1H, d, J
2 6
=
3.9 Hz, H-8a), 4.78 (1H, d, J = 3.9 Hz, H-7a), 7.12 (2H, ∼d, J = 8.8
.88 (2H, ∼d, J = 8.8 Hz, H-3′-5′), 7.29 (2H, ∼d, J = 8.8 Hz, H-2′-6′),
.34 (1H, dd, J = 8.2 and 7.2 Hz, H-5), 7.39 (1H, d, J = 9.0 Hz, H-8),
.70 (1H, d, J = 7.2 Hz, H-4), 7.73 (1H, d, J = 8.2 Hz, H-6), 7.80 (1H,
Hz, H-3′-5′), 7.67 (1H, dd, J = 8.4 and 7.0 Hz, H-2), 7.82 (2H, ∼d, J =
.8 Hz, H-2′-6′), 8.02 (1H, dd, J = 7.0 and 1.1 Hz, H-1), 8.15 (1H, dd,
J = 8.4 and 1.1 Hz, H-3), 8.54 (1H, d, J = 2.0 Hz, H-4), 8.55 (1H, d, J
8
13
d, J = 9.0 Hz, H-7); C NMR (C D CO) δ 31.6 (C-3), 48.7 (C-2),
2
6
13
=
2.0 Hz, H-6); C NMR (C D CO) δ 56.7 (-OMe), 58.3 (C-8a),
2 6
5
5
1
3
6.4 (4′-OMe), 57.4 (9-OMe), 74.5 (C-1), 114.6 (C-8), 115.5 (C-3′-
′), 121.3 (C-9a), 124.5 (C-4), 125.5 (C-5), 128.4 (C-6), 128.8 (C-7),
30.5 (C-6a), 130.9 (C-2′-6′), 131.8 (C-9b), 137.5 (C-1′), 140.3 (C-
5
1
3
4
3
8.5 (C-7a), 116.4 (C-3′-5′), 128.1 (C-6), 128.5 (C-2), 129.2 (C-8c),
29.5 (C-8c), 130.1 (C-3a), 130.2 (C-2′-6′), 131.3 (C-1), 131.8 (C-
8
2
), 133.2 (C-4), 133.4 (C-1′), 135.8 (C-8b), 140.6 (C-5), 162.0 (C-
+
a), 154.8 (C-9), 160.3 (C-4′); HRMS (ESI) [M + Na] calcd for
+
′), 193.7 (C-7); HRMS (ESI) [M + H] calcd for C H O m/z
2
0
15
3
C H NaO m/z 343.1305, found m/z 343.1307.
21
20
3
03.1016, found m/z 303.1017.
2-(4-Methoxyphenyl)-1H-phenalen-1-one was also found at the end
2
-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1). Com-
pound 2 (34 mg, 0.1 mmol) was dissolved in glacial acetic acid
AcOH, 4 mL) followed by addition of HBr (47 μL, 48% in water).
of this sequence in a yield of 12% from 8 [R = 0.4 (CH Cl )]: mp:
1
f
2
2
1
36−137 °C (uncorrected); H NMR (C D CO) δ 3.86 (3H, s,
2
6
(
-
OMe), 7.02 (2H, ∼d, J = 8.8 Hz, H-3′-5′), 7.70 (2H, ∼d, J = 8.8 Hz,
The mixture was refluxed for 7 h and then partitioned between
CH Cl (2 × 100 mL) and H O (200 mL). The organic phase was
H-2′-6′), 7.72 (1H, dd, J = 8.1 and 7.0 Hz, H-5), 7.90 (1H, dd, J = 8.2
and 7.2 Hz, H-8), 8.01 (1H, d, J = 7.0 Hz, H-4), 8.03 (1H, s, H-3),
2
2
2
dried and subjected to preparative TLC (CH Cl , four runs) to give 2-
2
2
8
8
.18 (1H, d, J = 8.1 Hz, H-6), 8.40 (1H, dd, J = 8.1 and 1.3 Hz, H-7),
.62 (1H, dd, J = 7.3 and 1.3 Hz, H-9); 13C NMR (C D CO) δ 56.6
hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1) along with
2
6
recovered 2. Compound 1 displays an R of 0.1 in 3:1 petroleum
f
(
-OMe), 115.2 (C-3′-5′), 128.7 (C-9b), 129.0 (C-5), 129.2 (C-8),
ether/AcOEt.
1
6
1
30.1 (C-9a), 130.9 (C-1′), 131.7 (C-3a), 132.0 (C-9), 132.2 (C-2′-
The NMR data are in full agreement with those reported for the
′), 133.0 (C-6), 133.4 (C-4), 134.1 (C-6a), 136.6 (C-7), 140.1 (C-2),
1
1
1
1
natural product. H NMR (Figure S35) and H− H COSY spectra
Figure S37) exhibited the spin system of a 4-substituted aryl ring (δ
7.05 and 7.78, J = 8.8 Hz), a three-spin system of H-4−H-6 (d 7.81, dd
.67, d 8.11), a singlet of H-3 (δ 7.21), and doublets at δ 8.62 (H-7)
+
40.2 (C-3), 161.6 (C-4′), 185.2 (C-1); HRMS (ESI) [M + H] calcd
(
for C H O m/z 287.1067, found m/z 287.1068.
20
15
2
8
-(4-Methoxyphenyl)-1H-phenalen-1-one (4). To a solution of
7
compound 5 (35 mg, 0.1 mmol) in CH Cl (10 mL) was added DDQ
4
2
2
and 8.86 (H-9) with J = 2.0 Hz. This J coupling (2.0 Hz) indicates
that a substituent must be located at the position between these two
protonated carbon atoms. A complete set of HSQC (Figure S38) and
HMBC (Figure S39) correlations confirmed the structure of
compound 1. Correlations of H-3 and H-9 with δ 182.0 assigned
the carbonyl carbon atom to C-1. Most importantly, attachment of the
4-hydroxyphenyl substituent to the phenalenone nucleus was
confirmed by HMBC cross signals of the H-2′−H-6′ doublet with
(
62 mg, 0.3 mmol). The mixture was refluxed for 10 h. The adsorption
of the mixture in a silica gel was followed by column chromatography
2:1 petroleum ether/CH Cl , R (4, CH Cl ) = 0.4]: 22 mg (77%
[
2
2
f
2
2
1
yield); orange solid; mp 102−104 °C (uncorrected); H NMR
(
(
7
(
=
C D CO) δ 3.87 (3H, s, -OMe), 6.65 (1H, d, J = 9.9 Hz, H-2), 7.11
2 6
2H, ∼d, J = 8.8 Hz, H-3′-5′), 7.69 (1H, dd, J = 7.0 and 8.3 Hz, H-5),
.82 (2H, ∼d, J = 8.8 Hz, H-2′-6′), 7.90 (1H, d, J = 7.0 Hz, H-4), 7.93
1H, d, J = 9.9 Hz, H-3), 8.21 (1H, d, J = 8.3 Hz, H-6), 8.56 (1H, d, J
2.0 Hz, H-7), 8.72 (1H, d, J = 2.0 Hz, H-9); 13C NMR (C D CO) δ
1
C-8 (δ 141.5): 16 mg (55% yield); red solid; mp 160−161 °C dec; H
2
6
NMR (C D CO) δ 7.05 (2H, ∼d, J = 8.8 Hz, H-3′-5′), 7.21 (1H, s, H-
2
6
5
3
(
6.7 (-OMe), 116.4 (C-3′-5′), 128.0 (C-9b), 129.2 (C-5), 129.5 (C-
a), 129.8 (C-9), 130.3 (C-2′-6′), 130.6 (C-2), 131.6 (C-9a), 133.1
C-4), 133.3 (C-7), 133.6 (C-1′), 133.9 (C-6), 134.9 (C-6a), 141.2
3), 7.67 (1H, dd, J = 8.1 and 7.0 Hz, H-5), 7.78 (2H, ∼d, J = 8.8 Hz,
H-2′-6′), 7.81 (1H, d, J = 7.0 Hz, H-4), 8.11 (1H, d, J = 8.1 Hz, H-6),
1
3
8.62 (1H, d, J = 2.0 Hz, H-7), 8.86 (1H, d, J = 2.0 Hz, H-9); C NMR
E
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
C D CO) δ 115.5 (C-3), 117.9 (C-3′-5′), 124.8 (C-9b), 129.5 (C-5),
= 1.5 Hz, H-7); 13C NMR (CDCl ) δ 28.5 (C-3), 38.6 (C-2), 124.5
2
6
3
1
6
8
30.3 (C-9a), 130.3 (C-9), 130.4 (C-2′-6′), 130.5 (C-3a), 131.3 (C-
(C-9), 125.5 (C-4), 126.5 (C-6), 126.7 (C-5), 127.4 (C-3′-5′), 127.9
8
0
6
), 131.4 (C-4), 132.4 (C-1′), 134.5 (C-7), 134.8 (C-6a), 141.5 (C-
(C-4′), 129.0 (C-2′-6′), 130.2 (C-6a), 130.8 (C-9b), 131.5 (C-7),
1
+
), 152.3 (C-2), 159.8 (C-4′), 182.0 (C-1); HRMS (ESI) [M + H]
133.2 (C-1′), 133.9 (C-3a), 138.5 (C-9a), 140.0 (C-8), 198.6 (C-1);
+
calcd for C H O m/z 289.0859, found m/z 289.0857.
HRMS (ESI) [M + H] calcd for C H O m/z 259.1117, found m/z
19
13
3
19 15
9
-Methoxy-2-phenyl-1H-phenalen-1-one (8a). 2-Bromo-9-me-
259.1115.
thoxy-1H-phenalen-1-one (10, 150 mg, 0.5 mmol), phenylboronic
acid (74 mg, 0.6 mmol), and bis(triphenylphosphine)palladium(II)
dichloride (18 mg, 5 mol %) were dissolved in dioxane (7 mL) and
For identification purposes, compounds 7b and 6b were isolated
after parts 1 and 2, respectively.
9-Methoxy-2-phenyl-2,3-dihydro-1H-phenalen-1-one (7b). R =
f
1
treated with Na CO
(0.8 mL, 2 M). The mixture was refluxed for 4
0.8 (CH
Cl ); H NMR (C D CO) δ 3.67 (2H, ddd for each proton,
2 2 2 6
2
3(aq)
h. Partitioning between AcOEt and H O followed by column
Jset_a = 16.5, 9.2, and 0.7 Hz, Jset_b = 16.5, 6.2, and 0.6 Hz, H-3), 4.04
2
chromatography (1:1 petroleum ether/CH Cl ) afforded 110 mg of
(3H, s, -OMe), 4.21 (1H, dd, J = 9.2 and 6.2 Hz, H-2), 7.26 (5H, m,
-Ph), 7.49 (1H, dd, J = 8.1 and 7.2 Hz, H-5), 7.56 (1H, d, J = 9.0 Hz,
H-8), 7.98 (1H, d, J = 9.0 Hz, H-7), 8.08 (1H, dd, J = 7.2 and 1.3 Hz,
2
2
8
a: 110 mg (74% yield); orange solid; mp: 157−158 °C
1
(
uncorrected); R = 0.4 (CH Cl ); H NMR (C D CO) δ 4.20 (3H,
f 2 2 2 6
H-4), 8.15 (1H, dd, J = 8.1 and 1.3 Hz, H-6); 13C NMR (C
D CO) δ
s, -OMe), 7.34 (1H, tt, J = 7.5 and 1.3 Hz, H-4′), 7.45 (2H, m, -Ph),
2 6
7
.63 (1H, d, J = 9.2 Hz, H-8), 7.72 (2H, m, -Ph), 7.76 (1H, dd, J = 8.0
30.6 (C-3from HMQC), 54.2 (C-2), 57.6 (-OMe), 115.7 (C-8), 118.7 (C-
9a), 125.0 (C-5), 127.7 (C-4), 128.6 (C-4′), 129.8 (C-7), 130.1 (C-3′-
5′), 130.2 (C-2′-6′), 130.6 (C-6a), 134.4 (C-9bfrom HMBC), 135.7 (C-6),
and 7.4 Hz, H-5), 8.27 (1H, d, J = 9.2 Hz, H-7), 8.33 (1H, dd, J = 8.0
and 1.3 Hz, H-6), 8.36 (1H, s, H-3), 8.64 (1H, dd, J = 7.4 and 1.3 Hz,
H-4); 13C NMR (C D CO) δ 58.1 (-OMe), 114.9 (C-9a), 115.9 (C-
141.4 (C-1′from HMBC), 156.7 (C-9from HMBC), 198.9 (C-1from HMBC);
2
6
+
8
), 126.9 (C-5), 129.4 (C-4′), 129.6 (C-9b), 129.7 (C-3′-5′), 130.0
HRMS (ESI) [M + H] calcd for C20
289.1226.
H O m/z 289.1223, found m/z
17 2
(
C-6a), 130.9 (C-2′-6′), 131.5 (C-3a), 133.1 (C-4), 134.6 (C-3), 136.6
(
C-6 and C-7), 138.9 (C-2), 139.5 (C-1′), 161.3 (C-9), 184.2 (C-1);
9-Methoxy-2-phenyl-2,3-dihydro-1H-phenalen-1-ol (6b). R
f
= 0.4
Cl ); H NMR (CDCl ) δ 3.44 (3H, m, H-2 and H-3), 4.02 (3H,
2 2 3
+
1
HRMS (ESI) [M + H] calcd for C H O m/z 287.1067, found m/z
(CH
s, -OMe), 5.16 (1H, ∼s, H-1), 7.44 (8H, m), 7.84 (2H, m); C NMR
(CDCl ) δ 22.9 (C-3), 44.8 (C-2), 56.4 (-OMe), 73.0 (C-1), 113.2
20
15
2
1
3
2
87.1068.
7
-Hydroxy-8-phenyl-2,3-dihydro-1H-phenalen-1-one (7a). Com-
3
pound 8a (96.1 mg, 0.3 mmol) was dissolved in dry THF (5 mL) and
the solution cooled to −78 °C. To this solution was added DIBAL-H
(C-8), 119.9 (C-9a), 123.4 (C-4), 125.9 (C-5), 126.9 (C-6), 127.1 (C-
7), 128.3 (C-3′-5′), 128.6 (C-2′-6′), 129.0 (C-6a), 129.3 (C-9b), 135.6
(C-1′), 142.5 (C-3a), 153.5 (C-9).
(
1 M in THF) (0.75 mL, 2 equiv, color change from orange to red),
and the solution was stirred for 1 h. The cooling bath was removed,
and the solution was left to warm for an additional 2 h. The reaction
was quenched with 1 mL of AcOEt (slow addition) followed by
saturated NH Cl (2 mL). Partitioning between AcOEt and H O (150
8-Phenyl-1H-phenalen-1-one (4b). Compound 5b (18 mg, 0.07
mmol) in CH Cl (2 mL) was treated with DDQ (22 mg, 0.12 mmol).
2 2
The DDQ addition (7 mg, 0.03 mmol) was repeated after 3 h and the
mixture refluxed for 20 h. Column chromatography (1:1 petroleum
4
2
mL each) and evaporation of the organic phase afforded crude material
ether/CH
2
Cl
2
, two runs) of the reaction mixture afforded 14 mg of
= 0.3 (CH Cl ); yellow solid;
mp 96−97 °C (uncorrected); H NMR (C CO) δ 6.66 (1H, d, J =
9.7 Hz, H-2), 7.47 (1H, tt, J = 7.3 and 1.3 Hz, H-4′), 7.57 (2H, m,
Ph), 7.72 (1H, dd, J = 8.4 and 7.0 Hz, H-5), 7.88 (2H, m, -Ph), 7.93
1H, d, J = 7.0 Hz, H-4), 7.94 (1H, d, J = 9.7 Hz, H-3), 8.25 (1H, d, J
8.4 Hz, H-6), 8.63 (1H, d, J = 2.0 Hz, H-7), 8.76 (1H, d, J = 2.0 Hz,
that was picked in CH Cl (5 mL, not dry) and treated with SSA (201
compound 4b: 14 mg (78% yield); R
f
2
2
2
2
1
mg) for 1 h at room temperature. Preparative TLC of the reaction
D
2 6
mixture (1:1 petroleum ether/CH Cl , five rounds) afforded 22 mg of
2
2
1
-
(
7
a: 27 mg (33% yield); R = 0.5 (CH Cl ); H NMR (C D CO) δ
f 2 2 2 6
2.87 (2H, t, J = 7.3 Hz, H-2), 3.44 (2H, t, J = 7.3 Hz, H-3), 7.41 (1H,
=
tt, J = 7.3 and 1.3 Hz, H-4′), 7.51 (2H, m∼t, J = 7.3 Hz, H-3′-5′), 7.55
13
H-9); C NMR (C D CO) δ 128.4 (C-9b), 129.2 (C-3′-5′), 129.3
(
2H, ∼d, J = 5.5 Hz, H-4 and H-6), 7.60 (2H, m, H-2′-6′), 8.06 (1H, s,
2
6
13
(
(
(
(
C-5), 129.6 (C-3a), 130.0 (C-4′), 130.1 (C-9), 130.7 (C-2), 131.0
H-9), 8.29 (1H, m∼t, J = 5.5 Hz, H-5); C NMR (C D CO) δ 30.2
(
2
6
C-2′-6′), 131.7 (C-9a), 133.4 (C-4), 134.0 (C-6), 134.1 (C-7), 134.9
C-3), 39.7 (C-2), 122.5 (C-5), 124.5 (C-8), 124.8 (C-6a), 126.5 (C-
C-6a), 141.4 (C-1′), 141.5 (C-8), 143.6 (C-3), 186.2 (C-1); HRMS
9
a), 127.6 (C-4), 127.8 (C-6), 129.5 (C-4′), 130.1 (C-9), 130.7 (C-3′-
+
ESI) [M + H] calcd for C H O m/z 257.0961, found m/z
5′), 131.6 (C-2′-6′), 134.3 (C-9b), 135.4 (C-3a), 139.5 (C-1′), 156.3
19 13
+
2
57.0959.
(
C-7), 197.6 (C-1); HRMS (ESI) [M + H] calcd for C H O m/z
19
15
2
2
75.1067, found m/z 275.1065.
-Phenyl-2,3-dihydro-1H-phenalen-1-one (5b). Part 1. LiAlH4
111 mg, 3 mmol) was suspended in dry THF (6 mL) and treated
with compound 8a (73.1 mg, 0.3 mmol). After the change in color
green), the suspension was refluxed for 2 h. The reaction mixture was
8
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02559.
■
(
*
S
(
cooled to room temperature, treated with AcOEt (1 mL, slow
addition), and partitioned between AcOEt and H O (75 mL each).
The aqueous phase was washed with AcOEt (2 × 50 mL), and the
combined organic extracts were concentrated and picked with 6 mL of
MeOH.
1H and 13C NMR spectra for all products (PDF)
2
AUTHOR INFORMATION
Corresponding Author
*E-mail: leon.otalvaro@udea.edu.co.
Notes
■
Part 2. The methanolic solution was treated with CeCl ·7H O
3
2
(
145.2 mg, 0.4 mmol), followed by NaBH (172.7 mg, 4.6 mmol, slow
4
addition, gas evolution!, color change from orange to pale yellow).
The mixture was agitated for 15 h, concentrated, and partitioned
between CH Cl and H O (50 mL each). The aqueous phase was
The authors declare no competing financial interest.
2
2
2
further extracted with CH Cl (2 × 50 mL) and the organic phase
2
2
ACKNOWLEDGMENTS
concentrated and picked in CH Cl (5 mL).
■
2
2
Part 3. The dichloromethane solution mentioned above was treated
with SSA (201 mg). Addition of SSA was repeated after 1 h (550 mg)
and the mixture agitated for a further 24 h. The mixture is adsorbed in
silica gel and subjected to column chromatography (1:1 petroleum
ether/CH Cl ) to afford 19 mg of 5b (R = 0.5 in CH Cl ): 19 mg
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.
2
2
f
2
2
1
(
25% yield, 38% brsm); H NMR (CDCl ) δ 3.03 (2H, t, J = 7.1 Hz,
3
REFERENCES
H-2), 3.47 (2H, t, J = 7.1 Hz, H-3), 7.47 (5H, m), 7.77 (2H, m), 7.86
1H, d, J = 8.1 Hz, H-6), 8.29 (1H, d, J = 1.5 Hz, H-6), 8.49 (1H, d, J
■
̈
lscher, D.; Schneider, B. Phytochemistry 2005, 66, 59−64.
(
(1) Ho
F
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(
2) Luis, J. G.; Echeverri, F.; Quin
Torres, F.; Cardona, G.; Aguiar, Z.; Pelaez, C.; Rojas, M. J. Org. Chem.
993, 58, 4306−4308.
3) Kamo, T.; Kato, N.; Hirai, N.; Tsuda, M.; Fujioka, D.; Ohigashi,
H. Biosci., Biotechnol., Biochem. 1998, 62, 95−101.
4) Kamo, T.; Hirai, N.; Iwami, K.; Fujioka, D.; Ohigashi, H.
Tetrahedron 2001, 57, 7649−7656.
5) Cooke, R. G.; Edwards, J. M. Prog. Chem. Org. Nat. Prod. 1981,
0, 153−190.
6) Fang, J.; Paetz, C.; Ho
̃
́
ones, W.; Brito, I.; Lopez, M.;
1
(
(
(
4
(
̈
lscher, D.; Munde, T.; Schneider, B.
Phytochem. Lett. 2011, 4, 203−208.
(
(
̈
7) Holscher, D.; Schneider, B. J. Nat. Prod. 2000, 63, 1027−1028.
8) (a) Della Greca, M.; Molinaro, A.; Monaco, P.; Previtera, L.
Tetrahedron 1992, 48, 3971−3976. A special group of tetraoxygenated
-phenylphenalenones occurring in some Haemodoraceae plants seem
7
to have a tautomeric relationship with 9-phenylphenalenones.
Therefore, they are considered a subgroup of the latter: See:
(
b) Fang, J.; Kai, M.; Schneider, B. Phytochemistry 2012, 81, 144−
1
1
1
52. (c) Dias, D.; Goble, D.; Silva, C.; Urban, S. J. Nat. Prod. 2009, 72,
075−1080. (d) Bick, I.; Blackman, A. Aust. J. Chem. 1973, 26, 1377−
380.
(
9) Brkljaca
608.
10) Rosquete, L. I.; Cabrera-Serra, M. G.; Pin
Rodríguez, P.; Fernandez-Perez, L.; Luis, J. G.; McNaughton-Smith,
G.; Abad-Grillo, T. Bioorg. Med. Chem. 2010, 18, 4530−4534.
11) Gutierrez, D.; Flores, N.; Abad-Grillo, T.; McNaughton-Smith,
G. Exp. Parasitol. 2013, 135, 456−458.
12) (a) Koelsch, C.; Anthes, J. J. Org. Chem. 1941, 6, 558−565.
b) Cooke, R.; Dagley, I. Aust. J. Chem. 1978, 31, 193−197. (c) Cano,
M.; Rojas, C.; Hidalgo, W.; Saez, J.; Gil, J.; Schneider, B.; Otalvaro, F.
Tetrahedron Lett. 2013, 54, 351−354.
13) (a) Otalvaro, F.; Nanclares, J.; Vas
Echeverri, F.; Arango, R.; Schneider, B. J. Nat. Prod. 2007, 70, 887−
90. (b) Hidalgo, W.; Cano, M.; Arbelaez, M.; Zarrazola, E.; Gil, J.;
Schneider, B.; Otalvaro, F. Pest Manage. Sci. 2015, n/a. (c) Luque-
Ortega, J.; Martínez, S.; Saugar, J.; Izquierdo, L.; Abad, T.; Luis, J.;
Pinero, J.; Valladares, B.; Rivas, L. Antimicrob. Agents Chemother. 2004,
8, 1534−1540. (d) Holscher, D.; et al. Proc. Natl. Acad. Sci. U. S. A.
014, 111, 105−110.
14) Hidalgo, W.; Duque, L.; Saez, J.; Arango, R.; Gil, J.; Rojano, B.;
Schneider, B.; Otalvaro, F. J. Agric. Food Chem. 2009, 57, 7417−7421.
15) Frank, R. L.; Hall, H. K. J. Am. Chem. Soc. 1950, 72, 1645−1648.
16) Nishida, S.; Kariyazono, K.; Yamanaka, A.; Fukui, K.; Sato, K.;
̌
, R.; White, J.; Urban, S. J. Nat. Prod. 2015, 78, 1600−
1
(
̃
ero, J. E.; Martín-
́
́
(
́
(
(
́
́
(
́
́
̃
quez, L.; Quinones, W.;
8
́
̃
4
2
̈
(
́
(
(
Takui, T.; Nakasuji, K.; Morita, Y. Chem. - Asian J. 2011, 6, 1188−
1196.
(
(
(
17) Franz, K. D.; Martin, R. L. Tetrahedron 1978, 34, 2147−2151.
18) Jensen, D.; Caes, B. J. Chem. Educ. 2008, 85, 413−415.
19) Gas phase geometry optimization was conducted in Spartan ’10
using the following procedure: B3LYP/6-311+G**//AM1//MMFF:
Spartan ’10, version 1.1.0; Wavefunction, Inc.: Irvine, CA, 2011.
(
20) Zolfigol, M. A. Tetrahedron 2001, 57, 9509−9511.
G
DOI: 10.1021/acs.joc.5b02559
J. Org. Chem. XXXX, XXX, XXX−XXX