Total synthesis of the natural product benzo[j]fluoranthene-4,9-diol: An approach to the synthesis of oxygenated benzo[j]fluoranthenes

Article abstract of DOI:10.1021/jo401887t

A synthetic sequence to the benzo[j]fluoranthene nucleus is described. Crucial steps of the procedure include a Suzuki coupling between appropriately substituted 2-bromo-acenaphthylene-1-carbaldehydes and 2-formylbenzeneboronates followed by McMurry ring closure. The synthesis represents a new approach to the benzo[j]fluoranthene ring system and specifically provides a method for the rapid preparation of differently substituted derivatives. Following this strategy, the first total synthesis of the recently isolated natural product benzo[j]fluoranthene-4,9-diol was carried out.

Full text of DOI:10.1021/jo401887t

Article
pubs.acs.org/joc
Total Synthesis of the Natural Product Benzo[j]fluoranthene-4,9-diol:
An Approach to the Synthesis of Oxygenated Benzo[j]fluoranthenes
Santosh Lahore,† Umesh Narkhede,† Lucio Merlini, and Sabrina Dallavalle*
Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Universita
Via Celoria 2, 20133 Milano, Italy
̀
di Milano,
S
* Supporting Information
ABSTRACT: A synthetic sequence to the benzo[j]fluoranthene
nucleus is described. Crucial steps of the procedure include a Suzuki
coupling between appropriately substituted 2-bromo-acenaphthylene-1-
carbaldehydes and 2-formylbenzeneboronates followed by McMurry
ring closure. The synthesis represents a new approach to the
benzo[j]fluoranthene ring system and specifically provides a method
for the rapid preparation of differently substituted derivatives. Following
this strategy, the first total synthesis of the recently isolated natural
product benzo[j]fluoranthene-4,9-diol was carried out.
INTRODUCTION
■
Small molecules produced in biological contexts have been, and
still are, a large reservoir of new biologically active substances,
which can become scaffolds for the discovery of drugs,
agrochemicals, or can be utilized in other applications.1
The fluoranthene carbon skeleton with annelated rings is of
interest for different areas of chemistry, including medicinal
chemistry and material science for organic electronics as well as
sensing.2
A number of polyketide-derived fungal metabolites, mostly
from xylariaceous fungi,3 possess a differently oxygenated and/
or reduced benzo[j]fluoranthene nucleus. Examples are
bulgarein,4 bulgarhodin,4 hortein,5 daldinones A−D,6,7 trunca-
tone,8 hypoxylonols A,B,9 and xylarenol.10 There are also some
unnamed analogues,11 among which is benzo[j]fluoranthene-
4,9-diol, recently isolated by Tan and co-workers12 as one of
the metabolites of Mantis-associated Daldinia eschscholzii
fungus (Figure 1).
It is quite likely that these compounds derive from an
Figure 1. Polyketide-derived fungal metabolites with benzo[j]-
fluoranthene nucleus.
oxidative phenol coupling of two hydroxylated naphthalene
units, followed by further oxidative condensation.7 This
hypothesis is supported by the fact that in most of the
metabolites, the carbon atoms 3, 4, 9, 10 are oxygenated.
Some of them exhibit significant biological activity, e.g.,
topoisomerase I inhibition for bulgarein,13 cytotoxicity for
daldinone C and D,7 immunosuppressive activity for benzo[j]-
fluoranthene-4,9-diol12 and tyrosine kinase inhibition10 for
other compounds.
To the best of our knowledge, no attempt to synthesize any
of these compounds has been reported in literature so far.
The benzo[j]fluoranthene nucleus has been little studied
from a synthetic point of view. Apart from the parent
hydrocarbon, which can be obtained by gas phase high
temperature reactions,14 few syntheses of substituted benzo-
[j]fluoranthenes have been reported in the literature so far.
Ring closures with Friedel−Crafts reactions according to
disconnections a,15 b,16,17 and c15,16 (Scheme 1) or with a
Suzuki reaction (disconnection d18) have been reported to
prepare fluoro, methoxy, and methylthio derivatives by
Rice15,16,18 and Panda.17 The recent synthesis of 10,11-
dihydrobenzo[j]fluoranthen-12-one by Chang19 mimics the
last steps of the putative biosynthetic scheme.7
Continuing our interest in potential antitumor compounds,
we developed a convergent and efficient synthetic pathway to
prepare oxygenated natural metabolites, as well as their
Received: August 20, 2013
Published: September 30, 2013
© 2013 American Chemical Society
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Scheme 1. Retrosynthetic Disconnections of
Scheme 3. Synthesis of Acenaphthylen-1(2H)-ones
Benzo[j]fluoranthene Ring (1)
analogues. Following this procedure, the first total synthesis of
the recently isolated benzo[j]fluoranthene-4,9-diol12 was
carried out and is reported here.
RESULTS AND DISCUSSION
■
As we needed a rapid and versatile way for the construction of
the benzo[j]fluoranthene skeleton, in which the introduction of
substituents could be easily modulated, we developed a
retrosynthetic sequence following a different disconnection
(e) (Scheme 2).
Scheme 2. Retrosynthetic Analysis for Benzo[j]fluoranthene
Scheme 4. Synthesis of 2-Bromo-5,6-
dimethoxyacenaphthylene-1-carbaldehyde
The crucial step of our strategy was an intramolecular
McMurry coupling reaction of a dialdehyde 2, which would
allow the construction of the pentacyclic system.20 In turn,
compounds 2 could be obtained by Suzuki reaction of a
boronate (3) with a bromoacenaphthylenecarbaldehyde (4).
To test the feasibility of our approach, we first synthesized
the unsubstituted benzo[j]fluoranthene. The strategy was then
applied to the preparation of oxygenated compounds.
Initially, we concentrated on the synthesis of the building
blocks 4 (Schemes 3 and 4). Compound 4a was prepared
starting from acenaphthene 5, according to a reported
procedure.21
The synthesis of 2-bromo-6-methoxyacenaphthylene-1-car-
baldehyde 4b, required for the preparation of the natural
compound benzo[j]fluoranthene-4,9-diol, was accomplished
from ketone 9b. This was obtained in four steps from 6 by a
cleaner and shorter sequence than the one described in the
literature.22 Reaction of commercially available 4-hydroxy-1-
naphthaldehyde 6 with Ph3PCHOCH3 and subsequent
acidic hydrolysis gave the homologous aldehyde 7. Oxidation
to acid 8 followed by intramolecular Friedel−Crafts acylation
gave ketone 9b in good yield. Compounds 9a,b were converted
into the bromoaldehydes 4a,b by an Arnold-modified
Vilsmeier−Haack reaction.23 (Scheme 3).
As in most naturally occurring benzo[j]fluoranthenes,
carbons 3 and 4 are oxygenated, the synthesis of a compound
with two methoxy groups in those position was undertaken,
starting from 2-bromo-5,6-dimethoxyacenaphthylene-1-carbal-
dehyde 4c (Scheme 4).
Naphthosultone 10 was thermally hydrolyzed24 with KOH at
300 °C for 30 min to give 1,8-dihydroxynaphthalene in 80%
yield. Methylation by methyl iodide under phase transfer
conditions25 with Aliquat336, followed by Friedel−Crafts
acylation with oxalyl chloride and AlCl3 in dry dichloro-
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methane25 afforded cyclic diketone 12 in high yield.
Subsequently, reduction with sodium borohydride in etha-
nol−water medium, gave quantitatively 5,6-dimethoxyacenaph-
thene-1,2-diol 13, which was dehydrated smoothly by p-TSA in
dry toluene to give 5,6-dimethoxyacenaphthenone 14 in 75%
yield.26 Applying Arnold-modified Vilsmeier−Haack condi-
tions23 to 14, the requested intermediate β-bromovinylaldehyde
4c was obtained using PBr3-DMF in chloroform at 0 °C.
With aldehydes 4a−c in our hands, we turned to the second
building block required for the Miyaura−Suzuki coupling, e.g.,
compound 3.
Scheme 6. Synthesis of Benzo[j]fluoranthene
Boronate 3b was synthesized starting from 2-methoxyben-
zoic acid 15, which was converted in 95% yield into the N-
diisopropylamide 1627 via the acid chloride. The conversion to
the amide group allowed both directed ortho-metalation to
insert the boronic acid group, and the synthesis of the aldehyde
by reduction. Thus, generation of a carbanion ortho to the N,N-
diisopropyl amide group by tert-BuLi in THF at −78 °C for 2 h,
followed by quenching with trimethyl borate and acidic
workup, gave regiospecifically N,N′-diisopropylcarbamoyl-3-
methoxy-1-phenylboronic acid 17.28 This was protected by
reaction with pinacol in toluene under azeotropic distillation
conditions, to give pinacolate 18, which afforded aldehyde 3b in
73% yield by treatment with DIBAL-H at 0 °C (Scheme 5).
Scheme 5. Synthesis of 3b
spectra of 1b completely matched the spectra reported for the
natural compound.
CONCLUSION
■
In conclusion, a synthetic sequence to the benzo[j]fluoranthene
nucleus has been developed, which could be adopted for the
synthesis of variously substituted compounds with this skeleton.
Crucial steps for our strategy include a Suzuki coupling
followed by a McMurry ring closure. The approach is modular
and rapid and can be utilized to synthesize natural products,
biologically active analogues or building blocks for the
preparation of materials.
The two building blocks 3 and 4 were subjected to a Suzuki
condensation for the construction of the polycyclic system.
Several attempts were made to couple model intermediates 3a
and 4a by using various bases and solvents. Use of Pd(PPh3)4
as a palladium source and aq. Na2CO3, KOAc, or CsF as a base
in DMF, toluene, DMSO, or DME gave undesirable hydrolytic
deboronation products and the homocoupled product of β-
bromovinyl aldehyde. By using Pd(OAc)2 with K2CO3 as a base
under phase transfer catalysis, a small amount of the expected
dialdehyde occurred. A satisfactory conversion, though, was
finally obtained by Pd(PPh3)4 with K2CO3 in 1,4-dioxane:water
medium. Under these optimized conditions, 2a was synthesized
in 73% yield .
Boronate 3b was coupled under the same conditions with 4b
and 4c to give dialdehydes 2b and 2c, respectively, in high
yields (Scheme 6).
Finally, treatment of the dialdehydes 2a−c with Zn/TiCl4 in
THF29 under McMurry conditions, followed by deprotection of
hydroxy groups using pyridine hydrochloride at 140−150 °C
gave benzo[j]fluoranthenes 1a−c. The 1H and 13C NMR
Work is in progress to synthesize C-7 and/or C-8 oxygenated
compounds by coupling the dialdehydes under different
conditions.
EXPERIMENTAL SECTION
■
General Experimental Method. All reagents and solvents were
reagent grade or were purified by standard methods before use.
Melting points were determined in open capillaries and are
uncorrected. NMR spectra were recorded at 300 MHz. Chemical
shifts (δ values) and coupling constants (J values) are given in ppm
and Hz, respectively. Solvents were routinely distilled prior to use;
anhydrous tetrahydrofuran (THF) and ether (Et2O) were obtained by
distillation from sodium-benzophenone ketyl; dry methylene chloride
was obtained by distillation from phosphorus pentoxide. All reactions
requiring anhydrous conditions were performed under a positive
nitrogen flow, and all glassware were oven-dried and/or flame-dried.
Isolation and purification of the compounds were performed by flash
column chromatography on silica gel 60 (230−400 mesh). Analytical
thin-layer chromatography (TLC) was conducted on Fluka TLC
plates (silica gel 60 F254, aluminum foil).
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Compounds 9a,30 1,8-naphthalendiol,24 11,31 and 1627 were
synthesized according to literature procedures.
a solution of dry DMF (66 mg, 0.07 mL, 0.91 mmol) and dry
chloroform (3 mL), and the resulting white suspension was stirred at
room temperature for 30 min. A solution of 9b (60 mg, 0.30 mmol) in
anhydrous chloroform (1.5 mL) was added dropwise over 10 min at 0
°C. After stirring at room temperature for 12 h, the solution was
poured into ice cold water. Sodium bicarbonate was carefully added to
neutralize the acid, and the aqueous phase was extracted with CH2Cl2
(2 × 15 mL). The combined organic layers were washed with water (2
× 10 mL) and dried to give a residue, which was purified by flash
column chromatography to afford 4b (70 mg, 80% yield) as a orange
red solid: mp = 187−188 °C; 1H NMR (CDCl3) δ 10.28 (1H, s), 8.28
(1H, d, J = 8.2 Hz), 8.18 (1H, d, J = 7.9 Hz), 7.91 (1H, d, J = 7.2 Hz),
7.62 (1H, dd, J = 7.2, 8.2 Hz), 6.76 (1H, d, J = 7.9 Hz); 13C NMR
(CDCl3) δ 188.1, 158.1, 135.5, 133.3, 130.8, 128.5, 128.2, 127.1, 126.6,
126.5, 126.2, 121.4, 105.5, 55.6. Anal. Calcd for C14H9BrO2: C, 58.16;
H, 3.14. Found: C, 58.31, H, 3.12.
(4-Methoxy-naphthalen-1-yl)acetaldehyde (7).32 t-Butyl lith-
ium (1.7 M in hexane, 4 mL, 6.80 mmol) was added dropwise to a
suspension of methoxymethyltriphenylphosphonium chloride (2.20 g,
6.50 mmol) in dry THF (60 mL) at −78 °C in a round-bottom flask
under nitrogen. The color of solution turned to red. After stirring for
30 min, 4-methoxy-naphthalene-1-carbaldehyde (1 g, 5.35 mmol) was
added in a single lot. The solution was allowed to gradually warm to
room temperature, and the color changed to pale yellow. The reaction
was stirred at room temperature for 12 h, and then it was quenched by
adding diethyl ether (100 mL) and water (50 mL). The aqueous layer
was extracted with ether (2 × 25 mL). Evaporation of solvent and
purification by flash column chromatography provided a viscous oil.
NMR analysis showed it was a 1:1 mixture of (E)- and (Z)-1-methoxy-
4-(2-methoxyvinyl)naphthalene isomers (0.815 g, 70%), which were
not separated and were directly used for the next step.
5,6-Dimethoxy-acenaphthylene-1,2-dione (12). In an oven-
dried flask, 1,8-dimethoxynaphthalene 11 (2 g, 10.64 mmol) was
dissolved in dry dichloromethane (35 mL) under argon atmosphere.
The resulting solution was cooled to 0−5 °C. After 30 min anhydrous
AlCl3 (1.71 g, 12.80 mmol) was added in a single lot, followed by
dropwise addition of oxalyl chloride (0.68 g, 480 μL, 5.30 mmol). The
reaction mixture was allowed to reach room temperature overnight,
and then poured slowly into ice−water (200 mL) containing 40 mL of
conc. HCl under stirring. After addition of 50 mL of n-hexane, the
above mixture was stirred for further 35−40 min. The resultant
mixture was filtered through a sintered funnel, and the residue was
washed with water (100 mL) and 2% EtOAc/n-Hexane (30 mL).
Purification by flash column chromatography using acetone−DCM
(1:99) as an eluent afforded the diketone as an orange solid (2.06 g,
(E/Z)-1-methoxy-4-(2-methoxyvinyl)naphthalene (0.50 g, 2.30
mmol) was dissolved in 50 mL of THF. A 2.0 M HCl (2.3 mL,
4.60 mmol) solution was added, and the reaction was refluxed for 3 h.
The reaction was diluted with ethyl acetate (75 mL), washed with a
satd. solution of NaHCO3 (50 mL × 2) water (25 mL), and finally
with brine (25 mL). The organic layer was evaporated to give a crude
that was purified by flash column chromatography to provide 7 (0.320
1
g, 70% yield) as a white solid after refrigeration: mp = 55−56 °C; H
NMR (CDCl3) δ 9.76 (1H, s), 8.37 (1H, d, J = 7.9 Hz), 7.82 (1H, d, J
= 7.9 Hz), 7.64−7.50 (2H, m), 7.32 (1H, d, J = 7.9 Hz), 6.82 (1H, d, J
= 7.9 Hz), 4.03 (3H, s); 13C NMR (CDCl3) δ 200.4, 155.7, 133.2,
128.7, 127.3, 126.2, 125.5, 123.5, 123.0, 120.3, 103.6, 55.7, 48.1. Anal.
Calcd for C13H12O2: C, 77.98; H, 6.04. Found: C, 77.84; H, 6.06.
2-(4-Methoxynaphthalen-1-yl)acetic acid (8).33 Compound 7
(0.30 g, 1.50 mmol) was dissolved in a 1:1 solution of H2O:t-BuOH
(0.1 M). To this suspension 2-methyl-2-butene (2.10 g, 30 mmol),
KH2PO4 (0.41 g, 3.0 mmol) and sodium chlorite (0.34 g, 3.75 mmol)
were added in sequence, and the mixture was stirred for 40 min at
room temperature.34 The reaction mixture was diluted with ethyl
acetate (50 mL), the aqueous layer was re-extracted by ethyl acetate (2
× 15 mL), and the combined organic layers were then treated with
saturated aq. NaHCO3 (2 × 20 mL). The basic layer was then washed
with ethyl acetate (2 × 15 mL), and then cooled and carefully acidified
by dil. HCl. The precipitate formed was filtered, and then dissolved in
ethyl acetate and washed with water and with brine. The organic layer
was dried and concentrated to give compound 8 (0.30 g, 93% yield) as
a white solid: mp = 147−148 °C (lit.32 144 °C); 1H NMR (CDCl3) δ
8.32 (1H, d, J = 8.4 Hz), 7.88 (1H, d, J = 8.4 Hz), 7.59−7.46 (2H, m),
7.31 (1H, d, J = 7.8 Hz), 6.76 (1H, d, J = 7.8 Hz), 3.99 (5H, s);13C
NMR (CDCl3) δ 178.5, 155.6, 133.0, 128.4, 127.2, 126.1, 125.4, 123.7,
122.9, 121.9, 103.5, 55.7, 38.5. Anal. Calcd for C13H12O3: C, 72.21; H,
5.59. Found: C, 72.10; H, 5.61.
1
80% yield): mp = 262−265 °C (dec.); H NMR (CDCl3 + TFA) δ
8.06 (2H, d, J = 8.4 Hz), 7.03 (2H, d, J = 8.4 Hz); 4.12 (6H, s); 13C
NMR (CDCl3 + TFA) δ 188.3, 163.4, 152.9, 127.1, 120.3, 114.4,
107.6, 57.0. Anal. Calcd for C14H10O4: C, 69.42; H, 4.16. Found: C,
69.25; H, 4.18.
5,6-Dimethoxyacenaphthene-1,2-diol (13). To a suspension of
diketone 12 (2 g, 8.26 mmol) in ethanol (334 mL) and water (71
mL), NaBH4 (6.25 g, 165.30 mmol) was added in portions with
stirring at room temperature. The reaction was stirred for further 21 h
at room temperature, and then poured into ice-cold water (400 mL),
and treated with solid NH4Cl (16.70 g). DCM (400 mL) was added,
and the mixture stirred for 30 min. The organic layer was separated,
and the aqueous layer was extracted with DCM (3 × 100 mL). The
combined organic layers were dried and evaporated. The obtained
residue was washed with EtOAc:hexane (1:99) and filtered through a
sintered funnel to give diol 13 in quantitative yield: 1H NMR (DMSO-
d6) Mixture of diastereomers 2:1, Major δ 7.30 (2H, d, J = 7.9 Hz),
6.90 (2H, d, J = 7.9 Hz), 5.60 (2H, d, J = 5.8 Hz, exchanges with
D2O), 5.03 (2H, d, J = 5.8 Hz), 3.84 (6H, s), minor δ 7.46 (2H, d, J =
7.9 Hz), 6.95 (2H, d, J = 7.9 Hz), 5.89 (2H, s), 3.87 (6H, s); 13C NMR
(DMSO-d6) Major δ 155.0, 132.7, 121.2, 107.4, 82.1, 56.0, minor δ
156.1, 139.0, 135.3, 123.0, 80.0, 56.0. Anal. Calcd for C14H14O4: C,
68.28; H, 5.73. Found: C, 68.45; H, 5.76.
5-Methoxyacenaphthylen-1(2H)-one (9b).22 Oxalyl chloride
(38 mg, 0.30 mmol) was added dropwise to a solution of 8 (50 mg,
0.23 mmol) in dry CH2Cl2 (1.5 mL) at 0 °C under nitrogen. The
solution was stirred at 25 °C for 3 h. The solvent was evaporated to
give a colorless oil that was added with dry CH2Cl2 (1.5 mL) under
nitrogen. The solution was cooled to −78 °C, and then pulverized
AlCl3 (52 mg, 0.39 mmol) was added portionwise, and stirring was
continued for 12 h at room temperature. The reaction was quenched
at −78 °C by dropwise addition of 4 N HCl (0.24 mL), and then it
was diluted with CH2Cl2 (15 mL), and the aqueous layer was extracted
by CH2Cl2 (2 × 10 mL). The combined organic layers were dried to
give a crude that was purified by flash column chromatography to
provide 9b (30 mg, 65% yield) as a colorless off-white solid: mp =
163−164 °C ; 1H NMR (CDCl3) δ 8.32 (1H, d, J = 7.9 Hz), 7.96(1H,
d, J = 7.1 Hz), 7.66 (1H, dd, J = 7.1, 7.9 Hz), 7.33 (1H, d, J = 7.5 Hz),
6.85 (1H, d, J = 7.5 Hz), 4.02 (3H, s), 3.73 (2H, s);13C NMR (CDCl3)
δ 204.0, 154.2, 144.2, 134.5, 127.3, 127.2, 126.5, 123.9, 122.1, 121.5,
105.8, 55.8, 41.7. Anal. Calcd for C13H10O2: C, 78.77; H, 5.09. Found:
C, 78.96; H, 5.07.
5,6-Dimethoxy-2H-acenaphthylen-1-one (14). To a suspen-
sion of diol 19 (1.5 g, 6.10 mmol) in dry toluene (150 mL), p-
toluenesulfonic acid (0.25 g, 1.31 mmol) was added under N2
atmosphere. The reaction mixture was heated at 80 °C for 2 h. and
then cooled to room temperature and washed with aq. satd. NaHCO3
(100 mL). The separated organic layer was sequentially washed with
brine (2 × 100 mL) and water (2 × 100 mL). The separated organic
layer was dried, and the solvent evaporated to a crude product that was
purified by chromatography using acetone:DCM (1:99) as an eluent
to give ketone 14 (1.04 g, 75% yield) as an orange colored powder:
1
mp = 133 °C; Rf 0.23 (1% acetone in DCM); H NMR (CDCl3) δ
7.94 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 7.9 Hz), 7.01 (1H, d, J = 7.9
Hz), 6.87 (1H, d, J = 7.9 Hz), 4.10 (3H, s), 4.01 (3H, s), 3.71 (2H, s);
13C NMR (CDCl3) δ 201.8, 161.2, 154.8, 146.1, 129.3, 127.1, 125.9,
125.7, 123.7, 122.9, 121.8, 114.1, 107.0, 106.2, 56.2, 55.8, 41.5. Anal.
Calcd for C14H12O3: C, 73.67; H, 5.30. Found: C, 73.89; H, 5.27.
2-Bromo-6-methoxyacenaphthylene-1-carbaldehyde (4b).
PBr3 (0.22 g, 0.07 mL, 0.81 mmol) was added dropwise at 0 °C to
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2-Bromo-5.6-dimethoxyacenaphthylene-1-carbaldehyde
(4c). To a precooled solution of dry DMF (0.91 g, 957 μL, 12.30
mmol) in dry chloroform (13.75 mL) under argon atmosphere, PBr3
(3.03 g, 1.06 mL, 11.19 mmol) was added dropwise at 0 °C over 20
min. The reaction was stirred for 1 h at the same temperature, and
then the solution of ketone 14 (0.85 g, 3.73 mmol) in anhydrous
chloroform (12.2 mL) was added over 30 min maintaining the
temperature to 0 °C. The reaction mixture was allowed to reach room
temperature overnight, and then was poured slowly into ice−water
mixture (100 g to 100 mL) to avoid emulsion, and neutralized by solid
NaHCO3 to pH 7. The organic layer was separated, and the aqueous
layer was again extracted with EtOAc (2 × 100 mL). The combined
organic layers were dried on Na2SO4. Evaporation of solvent gave a
crude product that was purified by chromatography using EtOAc:n-
hexane (30:70) as an eluent to give 4c (0.22 g, 79% yield) as an orange
colored powder: mp = 132−136 °C; 1H NMR (CDCl3 + TFA) δ. 9.91
(1H, s), 8.29 (1H, d, J = 8.2 Hz), 8.05 (1H, d, J = 8.2 Hz), 7.11 (1H, d,
J = 8.2 Hz), 6.96 (1H, d, J = 8.2 Hz), 4.16 (3H, s), 4.09 (3H, s); 13C
NMR (CDCl3 + TFA) δ 190.6, 165.1, 159.2, 138.0, 132.1, 131.4,
130.6, 129.6, 129.0, 126.0, 112.8, 109.2, 108.2, 57.2, 56.9. Anal. Calcd
for C15H11BrO3: C, 56.45; H, 3.47. Found: C, 56.63; H, 3.45.
84.2, 55.8, 29.9, 25.0. Anal. Calcd for C14H19BO4: C, 64.15; H, 7.31.
Found: C, 64.32; H, 7.28.
2-(2-Formylphenyl)acenaphthylene-1-carbaldehyde (2a). A
solution of 2-formylboronic acid 3a (58 mg, 0.39 mmol),
bromoaldehyde 4a (100 mg, 0.386 mmol) and K2CO3 (319 mg,
2.31 mmol) in 1,4-dioxane/water (4/1) was degassed by purging N2
for 30 min. Pd(PPh3)4 (8.8 mg, 0.0076 mmol) was added, and the
resulting reaction mixture was refluxed at 80 °C for 4 h under N2
atmosphere, and then cooled to room temperature, diluted with
diethyl ether (10 mL) and filtered through a small silica gel bed. The
bed was washed with diethyl ether (3 × 10 mL). The resulting mixture
was dried and evaporated. Purification by chromatography using
EtOAc:n-hexane (4:96) as an eluent gave dialdehyde 2a as a bright
1
orange colored powder (73 mg, 73% yield): mp = 150−151 °C; H
NMR (CDCl3) δ 10.08 (1H, s), 10.05 (1H, s), 8.49 (1H, d, J = 7.1
Hz), 8.19 (1H, dd, J = 1,5, 8.2 Hz), 8.09 (1H, m), 7.96 (1H, d, J = 8.2
Hz), 7.81−7.57 (6H, m); 13C NMR (CDCl3) δ 190.9, 188.7, 151.4,
139.4, 136.1, 135.7, 135.6, 135.1, 134.0, 132.23, 132.17, 129.9, 129.1,
128.9, 128.74, 128.69, 128.51, 128.48, 128.0, 127.8. Anal. Calcd for
C20H12O2: C, 84.49; H, 4.25. Found: 84.62; H, 4.27.
2-(2-Formyl-3-methoxyphenyl)-6-methoxyacenaphthylene-
1-carbaldehyde (2b). The compound was prepared following the
procedure described for the synthesis of 2a from 3b (55 mg, 0.19
mmol) and 4c (55 mg, 0.19 mmol). Purification by flash column
chromatography using EtOAc:n-hexane (30:70) as an eluent gave
compound 2b as a bright orange colored solid (70 mg, 80% yield): mp
2-N,N-Biisopropylcarbamoyl-3-methoxyphenyl-1-boronic
acid (17).28 In an oven-dry flask, N,N-di-isopropyl-2-methoxybenza-
mide 1627 (2 g, 8.51 mmol) was dissolved in dry THF (50 mL) under
argon atmosphere, and the resulting solution was cooled to −78 °C.
t
To the solution BuLi (1.7 M solution in hexane, 8.34 mL, 14.13
1
mmol) was added dropwise over 30 min to avoid rise in temperature.
The reaction mixture was stirred at −78 °C for additional 2 h resulting
in a thick slurry that was quenched with trimethyl borate (3.42 g, 3.75
mL, 32.87 mmol). The solution was warmed to 25 °C, and THF
removed under reduced pressure. The residue was rinsed with DCM
(100 mL), and then washed with 10% HCl (3 × 30 mL). The aqueous
washings were back extracted with DCM (2 × 30 mL). The combined
organic layers were dried over Na2SO4, the solvent evaporated under
reduced pressure, and the resulting residue was purified by acid−base
extraction, to give 17 as a white solid (1.66 g, 70% yield): mp = 149−
150 °C; 1H NMR (CDCl3) δ 7.47 (1H, d, J = 7.3 Hz), 7.33 (1H, dd, J
= 7.3, 8.2 Hz), 6.96 (1H, d, J = 8.2 Hz), 6.40 (2H, brs), 3.81 (3H, s),
3.62 (1H, sept, J = 6.7 Hz), 3.52 (1H, sept, J = 6.7 Hz), 1.57 (6H, d, J
= 6.7 Hz), 1.08 (6H, d, J = 6.7 Hz); 13C NMR (CDCl3) δ 171.5, 154.6,
132.0, 129.3, 127.7, 127.2, 112.8, 55.5, 51.7, 46.4, 20.7, 20.5, 20.4. Anal.
Calcd for C14H22BNO4: C, 60.24; H, 7.94. Found: C, 60.11; H, 7.96.
N,N-Diisopropyl-2-methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolan-2-yl)-benzamide (18). In a flask fitted with
azeotropic distillation condenser under N2 atmosphere, a suspension
of boronic acid 17 (1 g, 3.58 mmol) and pinacol (466 mg, 3.94 mmol)
in dry toluene (50 mL) was heated to 120 °C for 5h. Toluene was
removed to give the boronate 18 as a white solid (1.23 g, 95% yield):
mp = 136−137 °C; Rf 0.35 (30% EtOAc:Hexane); 1H NMR (CDCl3)
δ 7.40 (1H, d, J = 7.3 Hz), 7.27 (1H, dd, J = 7.3 Hz), 6.96 (1H, d, J =
8.2 Hz), 3.79 (3H, s), 3.62 (1H, sept., J = 6.7 Hz), 3.49 (1H, sept., J =
6.7 Hz), 1.59 (6H, d, J = 6.7 Hz), 1.31 (12H, s), 1.11 (6H, d, J = 6.7
Hz); 13C NMR (CDCl3) δ 168.3, 155.0, 134.7, 128.4, 128.1, 113.8,
84.1, 55.7, 51.1, 45.8, 25.0, 20.6, 20.4. Anal. Calcd for C20H32BNO4: C,
66.49; H, 8.93. Found: C, 66.65; H, 8.90.
= 82−83 °C; H NMR (CDCl3) δ 10.41 (1H, s), 9.96 (1H, s), 8.30
(1H, d, J = 7.7 Hz), 8.25 (1H, m), 7.61 (1H, m), 7.58−7.49 (2H, m),
7.15 (1H, d, J = 8.6 Hz), 7.07 (1H, d, J = 7.7 Hz), 6.85 (1H, d, J = 7.7
Hz), 4.04 (3H, s), 4.01 (3H, s); 13C NMR (CDCl3) δ 190.0, 189.2,
162.1, 158.8, 152.5, 138.1, 135.8, 134.7, 134.3, 129.64, 129.58, 127.8,
127.14, 127.11, 126.5, 124.8, 124.6, 122.3, 112.6, 106.3, 56.3, 56.2.
Anal. Calcd for C22H16O4: C, 76.73; H, 4.68. Found: C, 76.89; H, 4.66.
2-(2-Formyl-3-methoxy-phenyl)-5,6-dimethoxy-acenaph-
thylene-1-carbaldehyde (2c). To a solution of boronate 3b (166
mg, 0.634 mmol), bromoaldehyde 4c (200 mg, 0.627 mmol) and
K2CO3 (518 mg, 3.746 mmol) in 1,4-dioxane/water (11 mL/2.6 mL),
previously degassed by purging N2 for 30 min, Pd(PPh3)4 (14.5 mg,
0.01 mmol) was added, and the resulting reaction mixture was refluxed
at 80 °C for 4 h under N2 atmosphere. The reaction was cooled to
room temperature, diluted with diethyl ether (10 mL), and filtered
through a short silica gel bed. The silica gel bed was washed with
diethyl ether (3 × 20 mL), and the resulting mixture was dried and
evaporated. Purification by flash column chromatography using
EtOAc:DCM (2:98) as an eluent, afforded dialdehyde 2c as a red
colored powder (210 mg, 89% yield): mp = 128.4−129 °C; 1H NMR
(CDCl3) δ 10.34 (1H, s), 9.92 (1H, s), 8.42 (1H, d, J = 7.9 Hz), 7.64
(1H, dd, J = 7.9, 8.2 Hz), 7.53 (1H, d, J = 7.9 Hz), 7.17 (1H, d, J = 8.2
Hz), 7.11 (1H, d, J = 7.9 Hz), 6.98 (1H, d, J = 7.9 Hz), 6.90 (1H, d, J
= 7.9 Hz), 4.10 (3H, s), 4.09 (3H, s), 4.04 (3H, s); 13C NMR (CDCl3)
δ 190.3, 188.7, 162.4, 161.6, 159.4, 151.0, 136.7, 134.5, 132.7, 131.3,
130.9, 129.8, 129.7, 127.4, 124.9, 124.8, 112.4, 107.7, 107.5, 107.1,
56.8, 56.7, 56.3. Anal. Calcd for C23H18O5: C, 73.79; H, 4.85. Found:
C, 73.92; H, 4.82.
Benzo[j]fluoranthene (1a).18 TiCl4 (55 mg, 316 μL, 2.87 mmol)
was carefully added under N2 atmosphere to dry THF (10 mL) at 0
°C, giving a bright-yellow mixture of TiCl4·2THF complex. The
solution was refluxed for 20 min and cooled to room temperature.
Zinc dust (406 mg, 6.21 mmol, not activated) was added, and the
mixture was refluxed for 2 h, during which the color changed from
yellow to dark greenish blue. The mixture was cooled, and pyridine
(227 mg, 231 μL, 2.88 mmol) was added. Refluxing continued for 30
min.
A solution of dialdehyde 2a (40 mg, 0.145 mmol) in dry THF (10
mL) was added, the reaction mixture was refluxed for a further 4 h,
and then it was cooled. Saturated aqueous K2CO3 solution was added
until the aqueous layer became almost colorless and transparent, and
then the aqueous layer was extracted with ethyl acetate (2 × 20 mL).
Evaporation of the solvent and purification by flash column
chromatography on silica gel column provided benzo[j]fluoranthene
2-Methoxy-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-
benzaldehyde (3b). Under argon atmosphere, to a precooled
solution of boronate 24 (430 mg, 1.19 mmol) in anhydrous THF (20
mL) at 0 °C, a solution of DIBAL-H (1 M in hexane, 170 mg, 1.2 mL,
1.19 mmol) was added slowly at 0 °C over 30 min to avoid rise in
temperature. The reaction was quenched with 1 M HCl (1.5 mL), pH
7 buffer (10 mL). The organic layer was separated, and the aqueous
layer was extracted with saturated brine:ether:DCM (2 × 100 mL).
The combined organic layer was dried on Na2SO4 and concentrated.
The obtained residue was dissolved in minimum amount of hot n-
hexane, filtered, and concentrated under reduced pressure to give 3b as
a white powder (230 mg, 73% yield): mp = 107−108 °C; Rf 0.30 (30%
1
EtOAc:Hexane); H NMR (CDCl3) δ 10.43 (1H, s), 7.52 (1, dd, J =
7.6, 8.8 Hz), 7.05 (1H, d, J = 7.6 Hz), 6.96 (1H, d, J = 8.8 Hz), 3.90
(3H, s); 13C NMR (CDCl3) δ191.0, 161.7, 135.6, 128.3, 124.6, 112.4,
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Article
1a (30 mg, 83% yield): mp = 164 °C (lit.18 165 °C). H, 13C NMR
1
Author Contributions
and analytical data as reported in the literature.18
†S. Lahore and U. Narkhede contributed equally.
4,9-Dimethoxybenzo[j]fluoranthene (19). Prepared from dia-
ldehyde 2b (50 mg, 145 mmol) following the procedure described for
1a. The residue was purified by flash column chromatography on silica
gel column to provide 3,10-dimethoxybenzo[j]fluoranthene as a
yellow solid (40 mg, 89% yield): mp = 164−165 °C; 1H NMR
(CDCl3) δ 8.44 (1H, d, J = 7.2 Hz), 8.32 (1H, d, J = 8.6 Hz), 8.28
(1H, d, J = 8.6 Hz), 8.13 (1H, d, J = 8.6 Hz), 7.98 (1H, d, J = 8.6 Hz),
7.90 (1H, d, J = 7.6 Hz), 7.67 (1H, m), 7.52 (1H, m), 6.88 (1H, d, J =
7.6 Hz), 6.81 (1H, d, J = 7.6 Hz), 4.07 (3H, s), 4.05 (3H, s); 13C NMR
(CDCl3) δ 158.0, 156.5, 138.3, 137.5, 133.4, 133.3, 131.8, 129.7, 127.4,
127.2, 125.4, 124.5, 122.7, 122.3, 122.2, 121.9, 118.8, 116.7, 105.7,
103.2, 56.0, 55.7. Anal. Calcd for C22H16O2: C, 84.59; H, 5.16. Found:
C, 84.73; H, 5.14.
3,4,9-Trimethoxybenzo[j]fluoranthene (20). Prepared from
dialdehyde 2c (140 mg, 0.374 mmol) following the procedure
described for 1a. The obtained residue was purified by column
chromatography using DCM:Hexane (50:50) as an eluent, to give
3,4,9-trimethoxy-benzo[j]fluoranthene as a yellow colored powder
(103 mg, 80% yield): mp = 168 °C; 1H NMR (CDCl3) δ 8.37 (1H, d,
J = 7.8 Hz), 8.31−8.20 (2H, m), 8.02−7.93 (2H, m), 7.50 (1H, dd, J =
7.8, 7.8 Hz), 7.03−6.92 (2H, m), 6.81 (2H, d, J = 7.3 Hz), 4.10 (3H,
s), 4.09 (3H, s), 4.04 (3H, s); 13C NMR (CDCl3) δ 158.7, 158.0,
156.5, 137.3, 135.2, 132.8, 131.3, 130.3, 129.3, 127.0, 125.8, 125.3,
122.6, 120.9, 118.7, 116.7, 114.4, 107.0, 106.8, 103.2, 56.7, 56.6, 55.7.
Anal. Calcd for C23H18O3: C, 80.68; H, 5.30. Found: C, 80.84; H, 5.32.
Benzo[j]fluoranthene-4,9-diol (1b). A mixture of 4,9-
dimethoxybenzo[j]fluoranthene (40 mg, 0.128 mmol) and pyridine
hydrochloride (537 mg, 4.65 mmol) was heated under N2 at 140−150
°C for 30 min, during which the solid mixture became homogeneous.
After complete conversion, the reaction was allowed to cool to room
temperature. The reaction was poured in ice cold water and was
extracted with ethyl acetate (2 × 20 mL). The combined organic layers
were washed with water (2 × 10 mL) and dried over sodium sulfate to
give a residue, which was purified by flash column chromatography to
afford 1b as a dark greenish yellow solid (24 mg, 65% yield): mp =
164−165 °C; 1H NMR (acetone-d6) δ 9.62 (1H, brs), 9.17 (1H, brs),
8.63 (1H, d, J = 7.0 Hz), 8.38 (1H, d, J = 8.6 Hz), 8.33 (1H, dd, J =
8.5, 0.8 Hz), 8.25 (1H, d, J = 8.0 Hz), 8.09 (1H, d, J = 8.6 Hz), 8.03
(1H, d, J = 7.5 Hz), 7.78 (1H, dd, J = 8.0, 7.0 Hz), 7.50 (1H, dd, J =
8.5, 7.5 Hz), 7.08 (1H, d, J = 7.5 Hz), 6.96 (1H, dd, J = 7.5, 0.8 Hz);
13C NMR (acetone-d6) δ 157.0, 155.1, 139.2, 138.2, 134.1, 133.3,
133.0, 129.3, 128.6, 127.8, 125.3, 123.9, 123.4, 122.9, 122.7, 119.0,
116.2, 111.2, 108.2. Anal. Calcd for C20H12O2: C, 84.49; H, 4.25.
Found: C, 84.65; H, 4.27.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are indebted to MIUR (PRIN 2009 project) for financial
support.
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yield): mp = 175 °C; Rf 0.33 (4% MeOH:DCM); 1H NMR (acetone-
d6) δ 9.97 (1H, brs), 9.06 (1H, brs), 8.43 (1H, d, J = 7.8 Hz), 8.25
(1H, d, J = 8.5 Hz), 8.21 (1H, d, J = 8.5 Hz), 8.07−8.02 (2H, m), 7.42
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ASSOCIATED CONTENT
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S
* Supporting Information
Copies of the 1H and 13C NMR spectra of the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: sabrina.dallavalle@unimi.it.
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