Reactions of [2-(2-Naphthyl)phenyl]acetylenes and 2-(2-Naphthyl)benzaldehyde O-Phenyloximes: Synthesis of the Angucycline Tetrangulol and 1,10,12-Trimethoxy-8-methylbenzo[c]phenanthridine

Article abstract of DOI:10.1002/ejoc.201601373

The Suzuki–Miyaura coupling reaction between (1,4,5-trimethoxynaphthalen-2-yl)boronic acid and 2-iodo-3-methoxy-5-methylbenzaldehyde gave the intermediate 3-methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde. Conversion of this benzaldehyde

Full text of DOI:10.1002/ejoc.201601373

A Journal of
Accepted Article
Title: Reactions of 2-naphthylphenylacetylenes and 2-
naphthylbenzaldehyde O-phenyl oximes. A synthesis of
the angucycline tetrangulol and 1,10,12-trimethoxy-8-
methylbenzo[c]phenanthridine
Authors: Charles de Koning, Amanda Rousseau, Myron Johnson, and
Kennedy Ngwira
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601373
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Reactions of 2-naphthylphenylacetylenes and 2-
naphthylbenzaldehyde O-phenyl oximes. A synthesis of the
angucycline tetrangulol and 1,10,12-trimethoxy-8-
methylbenzo[c]phenanthridine
Kennedy J. Ngwira,[a] Amanda L. Rousseau,[a] Myron M. Johnson[a] and Charles B. de Koning*[a]
Abstract: The Suzuki-Miyaura coupling reaction between 1,4,5-
(trimethoxynaphthalen-2-yl)boronic acid and 2-iodo-3-methoxy-5-
methylbenzaldehyde afforded intermediate, 3-methoxy-5-methyl-2-
(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde. Conversion of this
model studies towards their synthesis were conducted by
Valderrama. [20]
benzaldehyde
into
the
alkyne,
2-(2-ethynyl-6-methoxy-4-
was accomplished
methylphenyl)-1,4,5-trimethoxynaphthalene
utilizing the Corey-Fuchs reaction. Exposure of the derived
acetylene to a catalytic platinum(II)-mediated ring closure yielded the
required tetracyclic aromatic product, 1,7,8,12-tetramethoxy-3-
methyltetraphene which was converted into tetrangulol. Exposure of
the related 3-methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-
yl)benzaldehyde O-phenyl oxime to microwave irradiation in an ionic
liquid yielded 1,10,12-trimethoxy-8-methylbenzo[c]phenanthridine,
instead of the desired natural product phenanthroviridone.
Introduction
The angucyclines are a large group of naturally occurring
quinones that display a wide range of biological activities,
including anticancer and antibacterial activity.[1] Examples
include the aromatic quinone tetrangulol 1 or the more complex
quinone aquayamycin
2 (Figure 1). The biosynthetically
related[2] complex natural products jadomycin A 3 and jadomycin
Y 4 also exhibit interesting biological properties.[3-7] The simpler
benzo[b]phenanthridine skeleton is found in the natural product
phenanthroviridone 5, which displays anticancer activities.[8]
Figure 1. Naturally occurring angucyclines and benzo[b]phenanthridines
As a result of their biological activity and interesting structures,
many methods have been developed for the synthesis of
angucyclines. The first synthesis of tetrangulol was developed in
1976,[9] however since then, a variety of other methods have
been reported with a number of them involving the Diels-Alder
reaction as a key step.[10,11,12] Other methods involve carbonyl
condensation chemistry in key steps[13-15] while Kraus[16] has
taken advantage of an interesting base mediated ring closure in
a key step of his synthesis. Phenanthroviridone 5 has been
synthesized by Gould,[17] Echavarren[18] and Snieckus,[19] while
As part of our programme on the synthesis of aromatic and
heteroaromatic compounds,[21] we report here on our results
leading to the synthesis of tetrangulol 1. The key final aromatic
ring forming reaction takes place by exposure of 2-
naphthylphenylacetylenes to platinum(II) chloride or gold(III)
chloride. Secondly, we outline our attempts to use UV light and
microwave methodology to synthesize the natural product
phenanthroviridone 5, from the related 2-naphthylbenzaldehyde
O-phenyl oximes and how this resulted in the formation of the
undesired
benzo[c]phenanthridine,
1,10,12-trimethoxy-8-
methylbenzo[c]phenanthridine.
[a]
Molecular Sciences Institute, School of Chemistry
University of the Witwatersrand
PO Wits 2050, Johannesburg, South Africa
E-mail: Charles.deKoning@wits.ac.za
https://www.wits.ac.za/science/schools/chemistry/staff/prof-charles-de-
koning/
Supporting information for this article is given via a link at the end of
the document.
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Results and Discussion
aromatic bromination took place initially and only on the addition
of two mole equivalents was the dibrominated anisole 15
containing a benzylic bromine furnished (Scheme 2). Initially
carbon tetrachloride was utilized as a solvent in the reaction.
However, we were also able to replace this solvent with ethyl
acetate[29] and microwave irradiation to effect the same
transformation.
Previously in our laboratories, we have used the ring-closing
metathesis (RCM) reaction as a key step in the assembly of
carbazoles.[22] We thought that our first target compound,
tetrangulol 1, could be synthesized utilizing this approach
starting from a suitably substituted bis-styrene such as 6 (Figure
2). Further disconnection would lead to the naphthalene boronic
acid 7 (which could be prepared from bromonaphthalene 8) with
the Suzuki- Miyaura coupling partner being the benzaldehyde 9.
Scheme 2. Reagents and Conditions: (a) (i) NBS, benzoyl peroxide, CCl4, r.t.;
or (ii) NBS, benzoyl peroxide, EtOAc, microwave (300W), reflux; (b) CaCO3,
dioxane/H2O, reflux. For CCl4, method, 70% over 2 steps; for EtOAc method
72% over 2 steps; (c) n-BuLi, THF, -78 °C, 94%; (d) (i) n-BuLi, Et2O, -78 °C;
(ii) I2 in THF, 0 °C, 65%; (e) MnO2, CH2Cl2, 98%.
Figure 2. Retrosynthesis of Tetrangulol 1
Using this methodology we could make gram quantities of 15.
The benzyl bromide could easily be converted into the benzyl
alcohol 16 by using a mixture of dioxane and water in the
presence of calcium carbonate, rather than using the Hass
procedure to afford the related benzaldehyde as described in the
literature.[30] Lithiation of 16 followed by aqueous work-up
allowed for the removal of the aromatic bromine. This compound
was isolated and under the conditions developed by
Takahashi[27] was exposed to further n-BuLi in Et2O and then
treated with iodine, which allowed for the exclusive formation of
17. This was readily oxidized to the desired substituted
benzaldehyde 18.
2-Bromo-5-methoxy-1,4-naphthoquinone 10 was synthesized in
4 steps from 1,5-dihydroxynaphthalene 11 in an overall yield of
73% using previously reported methodology.[23] When 10 was
treated with vinyl acetic acid, in the presence of silver nitrate as
detailed by Asao,[24] this furnished the desired 3-allyl substituted
naphthoquinone 12 (Scheme 1). Reduction of the quinone of 12
followed by protection as the O-dimethyl ether[25] afforded the
desired compound 8.
The next step entailed the Suzuki-Miyaura cross-coupling
reaction between benzaldehyde 18 and the naphthalene boronic
acid 7, which was synthesized from the previously prepared
bromonaphthalene 8. Disappointingly, very low yields of the
desired biaryl compound 19 (Scheme 3) were obtained,
presumably as a tetra-substituted biaryl axis is being formed.
Scheme 1. Reagents and Conditions: (a) (i) vinyl acetic acid, AgNO3, MeCN,
65 °C, (ii) (NH4)2S2O8, H2O, 16 h, 65 °C, 72%; (b) Na2S2O4, TBAI, KOH,
Me2SO4, THF-H2O, r.t., 18 h, 75%.
Next we set about the synthesis of bromobenzaldehyde 9.
However, in our hands all attempts to convert 3,5-
dimethylanisole
13
to
1-(bromomethyl)-3-methoxy-5-
methylbenzene 14 as reported in the literature by Kamikawa[26]
and Takahashi[27] were unsuccessful. It appeared (as also
described by Bickelhaupt)[28] that under the radical conditions
utilized for bromination by Kamikawa and Takahashi that nuclear
Scheme 3. Reagents and Conditions: (a) cat. Pd(PPh3)4, aq. Na2CO3, DME,
reflux, 12%.
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We therefore adopted an alternative strategy. Further
retrosynthetic analysis of tetrangulol 1 led us to the biaryl
intermediate 20 (Figure 3). In order to complete the synthesis
from this intermediate an extra carbon atom would have to be
introduced in order to form the last aromatic ring of tetrangulol.
Further disconnection led us to the naphthalene boronic acid 21
lacking the 3-allyl substituent and the same benzaldehyde, 2-
iodo-3-methoxy-5-methylbromobenzaldehyde 18 that we had
previously synthesized.
chloride resulted in the formation of the desired tetracyclic
product 25 in a yield of 61%. Evidence was provided by the H
1
NMR spectrum where the aromatic protons for the newly formed
aromatic ring were found at  8.03 (d, J = 9.2 Hz) and  7.36 (d,
J = 9.2 Hz). In the reaction, surprisingly a second aromatic
product was also formed in 23% yield which was identified as
1,10,12-trimethoxy-8-methylchrysene 26. The two products were
easily separable by silica gel chromatography. When gold(III)
chloride was used as the catalyst the same two aromatic
products 25 and 26 were formed from 20 in yields of 56% and
31% respectively.
Figure 3. Retrosynthesis of Tetrangulol 1
The synthesis of 2-bromo-1,4,5-trimethoxynaphthalene 22 has
been reported in the literature. [23] Conversion of 10 to 22 was
accomplished utilizing a reductive methylation procedure[25] in
good yields (Scheme 4). When 22 was subjected to n-BuLi and
then triisopropylborate, followed by work up with dilute acid
yielded the desired boronic acid 21 needed for the Suzuki-
Miyaura
coupling
reaction.
Treatment
of
21
with
bromobenzaldehyde 18 under palladium catalysis conditions
afforded the desired naphthalene, 3-methoxy-5-methyl-2-(1,4,5-
trimethoxynaphthalen-2-yl)benzaldehyde 20, in good yields.
Scheme 5. Reagents and Conditions: (a) PPh3, CBr4, CH2Cl2, 0 °C, 90%; (b)
n-BuLi, THF, -78 °C, 88%; (c) cat. PtCl2, PhMe, 90 °C, 61% 25 and 23% 26 or
cat. AuCl3, PhMe, 90 °C, 56% 25 and 31% 26; (d) CAN, MeCN/H2O, 86% (e)
[11}BBr3, CH2Cl2, -78 °C.
Scheme 4. Reagents and Conditions: (a) Na2S2O4, TBAI, KOH, Me2SO4, THF-
H2O, r.t., 18 h, 79%; (b) n-BuLi, B(OiPr)3, THF, -78 °C; (c) 18, cat. Pd(PPh3)4,
aq. Na2CO3, DME, reflux, 80%.
Examination of the literature[31a][33] led us to speculate that the
2
Alkynes have been used extensively by Fürstner[31a] and
Echavarren[31b] for the construction of rings, including aromatic
rings either using gold(III) or platinum(II) catalysis. Significantly,
the application of the platinum-mediated methodology has been
used to assemble angularly fused polycyclic aromatic
hydrocarbons.[31a] [32] In our case, application of the Corey-Fuchs
reaction allowed for the facile transformation of benzaldehyde 20
to alkyne 24 via 23, in good yields (Scheme 5). Next was the
key step, the formation of the final aromatic ring of the
tetrangulol skeleton. Exposure of 24 to catalytic platinum(II)
desired product 25 would be formed by initial formation of the ᶯ
complex I (Figure 4). The complex could then undergo a
„Friedel-Crafts“-type reaction to yield II by means of a 6-endo dig
cyclization, which would ultimately lead to 25. In an analoguos
manner, 26 would be formed by the related „Friedel-Crafts“-type
reaction to furnish III. After explusion of a methoxy anion
intermediate IV would be formed, which would aromatize to
afford 26.
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Alternatively, the vinylidene complex V could be formed from I
which then undergoes a 6π–electrocyclization to form the new
aromatic ring VI, allowing for the formation of 25 (Figure 5). In a
similar manner, the 6π–electrocyclization on VII would result in
VIII, which after expulsion of a methoxy anion would yield 26.
hands this reaction proceeded to afford tetrangulol 1 in good
yield together with a minor unidentified impurity.
Using this methodology we believed it would be possible to
synthesize phenanthroviridone 5, the nitrogen analog of
tetrangulol, as long as the synthesis of the aromatic oxime 28
(Figure 6) could be accomplished. We anticipated that the
oxime 28 could be synthesized from benzaldehyde 20, which
had been used in our synthesis of tetrangulol.
Figure 6. Retrosynthesis of phenanthroviridone 5
In the literature there are examples of the use of oximes, either
as the oxime ether or as the oxime ester, leading to the
formation of nitrogen heterocycles by intramolecular reactions of
suitably substituted aromatic compounds, as shown in the two
examples in Scheme 6. The first[34] is a light-induced cyclisation
in which 29 leads to the formation of 30 as the major product
and significant amounts of 31. The second[35] uses microwave
irradiation to afford exclusively 30 in good yield (76%) from the
oxime ether 32. Alternatively, the use of catalytic iron
acetylacetonate in acetic acid can also be used to facilitate
similar transformations.[36] A third procedure we also decided to
investigate was the Pd2(dba)3 mediated method developed
utilizing oxime esters by Hartwig,[37] also for the formation of
carbon nitrogen bonds on an aromatic nucleus.
Figure 4. Plausible mechanism for the formation of 25 and 26
Scheme 6. Reagents and Conditions: (a) 29, h, 400W mercury lamp, Pyrex,
t-butanol, r.t., 58% 30, 28% 31; (b) 32, microwave irradiation, emimPF4, t-
butanol, 30 min, 160 °C, 76%; 30, 0% 31. [33], [34]
The conversion of 20 to the oxime ethers 28a and 28b
proceeded smoothly on exposure to either NH2OAc•HCl or
NH2OPh•HCl (Scheme 7). Disappointingly, exposure of 28a to
Pd2(dba)3 under conditions developed by Hartwig only allowed
for the formation of benzonitrile 33. UV irradiation of 28a in the
presence of t-butanol afforded a product in which there were
only three methoxy substituents in the 1H NMR spectrum instead
of the required four. It was clear from the 1H NMR spectrum that
two aromatic singlets at  9.15 and  8.87 were present, along
with two broad singlets for the two meta-substituted aromatic
singlets. Comparison of the 1H NMR spectrum of the product
Figure 5. Alternative plausible mechanism for the formation of 25 and 26
Compound 25 was subjected to CAN oxidation to afford the
quinone 27 (Scheme 5). The synthesis of quinone 27 represents
a formal synthesis of tetrangulol 1 as 27 has been treated with
boron tribromide to yield tetrangulol 1 in 97% yield.[11] In our
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with that reported on the naphthol equivalent 34,[19]
in an overall yield of 58%. Conversion of 20 into the desired
disappointingly
indicated
that
the
undesired
alkyne,
2-(2-ethynyl-6-methoxy-4-methylphenyl)-1,4,5-
benzo[c]phenanthridine 35 had been synthesized (Scheme 7).
Microwave irradiation of 28b in the presence of one mole
equivalent of the ionic liquid EmimPF6 also afforded the same
benzo[c]phenanthridine 35 together with small amounts of the
benzonitrile 33.
trimethoxynaphthalene 24 was accomplished utilizing the Corey-
Fuchs reaction. Exposure of 24 to a catalytic platinum(II)
mediated ring closure afforded the required tetracyclic aromatic
product 25 which was converted into tetrangulol 1.
Attempted conversion of the intermediate 3-methoxy-5-methyl-2-
(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde 20 to the
nitrogen derivative of tetrangulol, phenanthroviridone 5, by
treatment of the oxime ethers 28a or 28b with microwave
irradiation in the presence of the ionic liquid EmimPF6 furnished
the undesired benzo[c]phenanthridine, 1,10,12-trimethoxy-8-
methylbenzo[c]phenanthridine 35.
Experimental Section
Solvents utilized for chromatographic techniques (ethyl acetate and n-
hexane) were distilled prior to use by means of conventional distillation
processes. The solvents employed in reactions were first dried over the
suitable drying agent, followed by distillation under an inert atmosphere
(argon or nitrogen gas). Acetonitrile and dichloromethane were distilled
over calcium hydride, whereas tetrahydrofuran was distilled over sodium
with benzophenone as an indicator. Toluene was distilled over sodium.
All the required chemicals or reagents were obtained from FLUKA,
SIGMA ALDRICH or MERCK and were used without further purification.
Normal chromatography was performed with silica gel 60 (Macherey-
Nagel, particle size 0.063-0.200 mm) adsorbent, with both isocratic and
gradient eluent systems being employed. Thin layer chromatography
(TLC) of the compounds was executed on Macherey-Nagel Alugram Sil
G/UV254 plates pre-coated with 0.25 mm silica gel 60. The TLC plates
were viewed under UV light (254 nm and 366 nm).
Scheme 7. Reagents and Conditions: (a) (i) NH2OAc•HCl, pyridine, r.t., 86%
28a; NH2OPh•HCl, pyridine, r.t., 93%, 28b; (b) 28a, cat. Pd2(dba)3 toluene,
CsCO3, 150 °C, 33, 62% (b) (i) 28a, EmimPF6, t-PhBu, microwave, 160 °C, 33
11%, 35 58%; Or (ii) 28b, UV reactor, t-BuOH, 33 18%, 35 46%.
Nuclear magnetic resonance (NMR) spectra were recorded on either a
Bruker AVANCE 300 MHz or
a Bruker AVANCE III 500 MHz
Presumably the benzo[c]phenanthridine 35 is formed via the
formation of the iminyl radical 36 which results in addition to the
naphthalene with the expulsion of a methoxy radical to regain
aromaticity and form 35. As opposed to the expulsion of a
hydrogen radical that we had anticipated based on the
cyclizations conducted using gold(III) or platinum(II) catalysis.
While the synthesis of the benzo[c]phenanthridine nucleus was
undesired this methodology may provide a novel route to access
this class of natural products.[38]
spectrometer. All spectra were recorded in chloroform-d. All chemical
shift values are reported in parts per million referenced against
tetramethylsilane which is given an assignment of zero parts per million.
Coupling constants (J-values) are given in Hertz (Hz).
The infrared spectra were recorded on a Bruker Tensor 27 standard
system spectrometer. Measurements were made by loading the sample
directly onto a diamond cell. The measurements are reported on the
wavenumber scale (/cm-1).
Melting points were determined on a Reichert hot-stage microscope, and
remain uncorrected. All crystalline compounds were recrystallized from
appropriate solvents prior to melting point determination. Microwave
reactions were conducted in a CEM Discover microwave.
Conclusions
Novel synthetic methodology has been developed for the
synthesis of tetrangulol 1. The synthesis of the key intermediate
3-methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-
yl)benzaldehyde 20 was accomplished utilizing the Suzuki-
Miyaura coupling reaction of 1,4,5-trimethoxynaphthalen-2-
yl)boronic acid 21 and 2-iodo-3-methoxy-5-methylbenzaldehyde
18. The benzaldehyde 18 was prepared in five steps from 3,5-
dimethylanisole in an overall yield of 43%, while the boronic acid
21 was prepared from 1,5-dihydroxynaphthalene in seven steps
High resolution mass spectra were obtained with a Waters-LCT-Premier
mass spectrometer. The sample was dissolved in methanol to a
concentration of 2 ng/μl and introduced by direct infusion. The ionization
mode was electrospray positive with a capillary voltage of 2500 V and a
desolvation temperature of 250 °C using nitrogen gas at 250 L/hr.
Photochemical reactions were done using a 450W UV power supply
source with
a Quartz Mercury vapor arc lamp. Reactions were
undertaken in a quartz photochemical reactor vessel.
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2-Bromo-5-methoxy-1,4-naphthoquinone 10
n-BuLi (1.2 M, 3.02 mL, 3.62 mmol, 2.0 eq.) was added dropwise to a
solution of 3-allyl-2-bromo-1,4,5-trimethoxynaphthalene 8 (610 mg, 1.81
mmol, 1.0 eq.) in THF (15 mL) at −78 °C. The reaction mixture was
stirred for 30 min at −78 °C, then B(OiPr)3 (1.67 mL, 7.24 mmol, 4.0 eq.)
was added. The resulting mixture was stirred at −78 °C for a further 30
min and then allowed to warm to r.t. The reaction mixture was made
acidic with 10% aq. HCl solution and extracted with Et2O (3 × 30 mL).
The organic layer was then dried with MgSO4 and concentrated under
reduced pressure to afford 3-allyl-1,4,5-trimethoxynaphthalen-2-yl-2-
boronic acid 7 as an off-white crystalline material (510 mg, 1.70 mmol,
94%), which was used without further purification or characterization.
In a 100 mL round bottom flask equipped with a magnetic stirring bar was
placed 2-bromo-5-hydroxy-1,4-naphthoquinone[23] (4.70 g, 18.60 mmol)
dissolved in CH2Cl2 (60 mL) followed by Ag2O (10.80 g, 46.63 mmol). To
this suspension, MeI (7.92 g, 3.6 mL, 55.81 mmol) was added and the
reaction mixture was stirred at r.t. for 24 h under argon. The suspension
was filtered through a pad of celite and the solvent removed in vacuo.
The crude product was purified by column chromatography (silica gel,
30% EtOAc/hexane) to give 2-bromo-5-methoxy-1,4-naphthoquinone 10
as a yellow solid (5.90 g, 17.9 mmol, 96 %). 1H NMR (300 MHz, CDCl3) δ
7.81 (1H, dd, J = 7.7, 1.2, H-8), 7.69 (1H, t, J = 8.4, H-7), 7.39 (1H, s, H-
3), 7.35 (1H, dd, J = 8.5, 1.2, H-6), 4.02 (3H, s, OMe); 13C NMR (75 MHz,
CDCl3) δ 181.4, 178.2, 160.0, 142.3, 136.8, 135.0, 133.0, 120.6, 119.3,
118.5, 56.6.[23]
2-Bromo-5-methoxy-3-methylbenzyl alcohol 16
Method 1: To a stirred solution of 3,5-dimethylanisole 13 (2.07 mL, 14.68
mmol, 1.00 eq.) in CCl4 (30.0 mL), NBS (2.62 g, 14.68 mmol, 1.00 eq.)
and benzoyl peroxide (356 mg, 1.47 mmol) were added at r.t. under
3-Allyl-2-bromo-5-methoxy-1,4-naphthoquinone 12
argon. The reaction mixture was refluxed for
4 h and after the
succinimide was filtered off the filtrate was successively washed with 100
mL each of 10% aq. HCl, sat. aq. NaHCO3, H2O and brine, before being
extracted with CH2Cl2 (2 x 100 mL). The organic layer was then dried
over MgSO4 and concentrated in vacuo. The residue was used in the
next reaction without further purification. To the residue in dioxane (30.0
mL) and H2O (30.0 mL), was added CaCO3 (2.94 g, 29.36 mmol, 2.00
eq.) at r.t. under argon. The reaction mixture was stirred at reflux for 12 h
and then cooled to r.t. and extracted with EtOAc (3 x 100 mL). The
combined organic layer was washed with brine (100 mL) and dried over
MgSO4 and concentrated in vacuo. The crude product was purified by
chromatography (silica gel, 30% EtOAc/hexane) to afford the benzyl
alcohol 16 as an off-white solid (2.37 g, 10.28 mmol, 70%). 1H NMR (500
MHz, CDCl3) δ 6.86 (1H, d, J = 3.2, ArH), 6.69 (1H, d, J = 3.1, ArH), 4.64
(2H, s, CH2OH), 3.75 (3H, s, OMe), 2.85 (1H, br-s, OH), 2.34 (3H, s,
ArMe); 13C NMR (126 MHz, CDCl3) δ 158.6, 141.0, 139.2, 115.5, 115.1,
111.3, 65.3, 55.4, 23.4. [39]
To a mixture of 2-bromo-5-methoxy-1,4-naphthoquinone 10 (2.20 g, 8.24
mmol) and silver nitrate (0.71 g, 4.18 mmol) in dry MeCN (140 mL) was
added vinyl acetic acid (1.42 g, 1.40 mL, 16.48 mmol). The reaction
mixture was heated to 65 °C and (NH4)2S2O8 (3. 76 g, 16.48 mmol) in
distilled water (120 mL) was added dropwise to the reaction mixture over
30 min. After stirring for 16 h at 65 °C under argon, the cooled reaction
mixture was extracted with EtOAc (3 x 100 mL), washed with aq.
NaHCO3 (2 x 100 mL) followed by brine (100 mL) and dried over MgSO4.
After filtering through celite, the solvent was removed in vacuo and the
crude product was purified by column chromatography (silica gel, 20-
30%
EtOAc/hexane)
to
yield
3-allyl-2-bromo-5-methoxy-1,4-
1
naphthoquinone 12 as a yellow solid (1.82 g, 5.93 mmol, 72%). H NMR
(300 MHz, CDCl3) δ 7.80 (IH, dd, J = 7.7, 1.1, H-8), 7.66 (1H, t, J = 8.4,
H-7), 7.32 (1H, dd, J = 8.5, 0.9, H-6), 5.94 – 5.77 (1H, m, =CH-), 5.27
(1H, dd, J = 17.1, 1.5, =CH2), 5.12 (1H, dd, J = 10.0, 1.4, =CH2), 4.01 (3H,
s, OMe), 3.60 (2H, d, J = 6.6, -CH2-); 13C NMR (75 MHz, CDCl3) δ 180.2,
178.1, 160.1, 150.6, 136.6, 134.9, 133.3, 131.7, 120.3, 119.2, 118.2,
118.2, 56.6, 35.7. [24]
Method 2: To an ethyl acetate (15 mL) solution of 3,5-dimethylanisole 13
(900 mg, 6.61 mmol, 1.00 eq.), was added benzoyl peroxide (8 mg;
0.033 mmol, 0.5 mol%) and N-bromosuccinimide (2.47 g, 13.88 mmol,
2.1 eq.). The reaction mixture was refluxed for 60 min under microwave
heating (magnetron power of 300W). The crude product in EtOAc was
washed with 30 mL each of 10% HCl, sat. aq. NaHCO3, H2O and brine,
dried over MgSO4 and the solvent removed in vacuo. The residue was
used for the next reaction without further purification. To a stirred solution
of the residue in dioxane (30.0 mL) and H2O (30 mL), CaCO3 (1.32 g,
13.22 mmol, 2.00 eq.) was added at r.t. under argon. The reaction
mixture was stirred at reflux for 18 h and then cooled to r.t. and extracted
with EtOAc (3 x 50 mL). The combined organic layer was washed with
brine (50 mL), dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography (silica gel, 30%
EtOAc/hexane) to afford the benzyl alcohol 16 as an off-white solid (1.10
g, 4.76 mmol, 72%).
3-Allyl-2-bromo-1,4,5-trimethoxynaphthalene 8
To a clear solution of 3-allyl-2-bromo-5-methoxy-1,4-naphthoquinone 12
(1.40 g, 4.56 mmol) in THF (80 mL) was added Na2S2O4 (3.97 g, 22.80
mmol) in H2O (25 mL) and TBAI (0.17 g, 0.46 mmol). The reaction was
stirred at r.t. under argon for 30 min followed by the addition of KOH
(2.56 g, 45.60 mol) in H2O (140 mL). The reaction was stirred for 1 h and
Me2SO4 (5.75 g, 4.32 mL, 45.6 mol) was added. The reaction mixture
was then stirred for 18 h before being quenched with 25% aq. NH4OH
(100 mL) and the organic material extracted into EtOAc (3 x 100 mL).
The combined organic extracts were washed sequentially with distilled
water (100 mL), 10% aq. HCl (100 mL) and brine (100 mL). The organic
extract was dried over MgSO4, filtered through celite and concentrated
under reduced pressure. The crude product was purified by column
chromatography (silica gel, 10% EtOAc/hexane) to give 3-allyl-2-bromo-
1,4,5-trimethoxynaphthalene 8 as a yellowish-brown solid (1.12 g, 3.42
mmol, 75%). 1H NMR (500 MHz, CDCl3) δ 7.71 (1H, d, J = 8.4, H-8), 7.41
(1H, t, J = 8.1, H-7), 6.90 (1H, d, J = 7.7, H-6), 6.16 – 5.93 (1H, m, =CH-),
5.20 – 4.83 (1H, m, =CH2), 4.00 (3H, s, OMe), 3.94 (3H, s, OMe), 3.80
(5H, m, OMe and -CH2-); 13C NMR (75 MHz, CDCl3) δ 156.1, 151.2,
149.7, 136.1, 130.4, 129.7, 126.7, 120.0, 117.5, 115.7, 115.0, 106.6,
62.9, 61.1, 56.2, 34.4.[24]
2-Iodo-3-methoxy-5-methylbenzyl alcohol 17
In an oven-dried 250 mL two-neck round-bottom flask equipped with a
magnetic stirring bar was placed 16 (7.62 g, 33.00 mmol) in dry THF (150
mL) under an argon atmosphere. The mixture was cooled to −78 °C and
a 1.3 M solution of n-BuLi in hexanes (38.08 mL, 49.50 mmol) was added
dropwise. The mixture was stirred at −78 °C for 2 h and was then slowly
warmed to r.t. The reaction was quenched with water (50 mL) and then
extracted with EtOAc (3 × 100 mL). The combined organic extracts were
washed with brine, dried over MgSO4 and evaporated under reduced
pressure. The crude product was purified by column chromatography
(silica gel, 20-30% EtOAc/hexane) to afford the intermediate 3-methoxy-
3-Allyl-1,4,5-trimethoxynaphthalen-2-yl-2-boronic acid 7
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601373
European Journal of Organic Chemistry
FULL PAPER
1
5-methylbenzyl alcohol as a yellowish oil (4.72 g, 31.02 mmol, 94%). H
NMR (500 MHz, CDCl3) δ 6.74 (1H, d, J = 0.7, ArH), 6.69 (1H, d, J = 0.8,
ArH), 6.63 (1H, d, J = 0.6, ArH), 4.57 (2H, s, CH2OH), 3.76 (3H, s, OMe),
2.31 (3H, s, ArMe), 2.28 (1H, brs, OH); 13C NMR (126 MHz, CDCl3) δ
159.8, 142.4, 139.7, 120.0, 114.0, 109.3, 65.2, 55.2, 21.5. [19] In an oven-
dried 50 mL three-neck round-bottom flask equipped with a magnetic
stirring bar was placed some of the above 3-methoxy-5-methylbenzyl
alcohol (500 mg, 3.29 mmol) in dry Et2O (17 mL) under argon
atmosphere. The mixture was cooled to −78 °C and a 1.2 M solution of n-
BuLi in hexanes (6.05 mL, 7.26 mmol) was added dropwise. The mixture
was then slowly warmed to r.t. and stirred for 4 h. The solution was
cooled to 0 °C and THF (9 mL) was then added to the solution and the
mixture further stirred for 1 h followed by the slow addition of I2 (1.00 g,
3.95 mmol)) dissolved in THF (4.0 mL). After being stirred at 0 °C for 30
min, the reaction mixture was poured into aq. Na2S2O3 and extracted with
EtOAc (3 x 50 mL). The combined organic layer was washed with brine,
dried over MgSO4 and evaporated under reduced pressure. The crude
product was purified by chromatography (silica gel, 20% EtOAc/hexane)
62.7, 60.7, 56.2, 55.6, 32.1, 21.7; HRMS (ESI+): Found (M + Na)+
429.1657 and (M + H)+ 407.1838, C25H26O5 (M + Na)+ requires 429.1673
and (M + H)+ requires 407.1854, m/z 429.1657 [(M + Na)+, 100%],
407.1838 [(M + H)+, 60%].
2-Bromo-1,4,5-trimethoxynaphthalene 22
To a clear solution of 2-bromo-5-methoxy-1,4-naphthoquinone 10[23]
(6.10 g, 22.85 mmol) in THF (380 mL) was added Na2S2O4 (19.9 g,
114.30 mmol) in H2O (100 mL) and TBAI (0.84 g, 2.28 mmol). The
reaction was stirred at r.t. under argon for 30 min followed by the addition
of KOH (12.8 g, 0.23 mol) in H2O (300 mL). The reaction was stirred for 1
h and Me2SO4 (28.8 g, 21.6 mL, 0.23 mol) was added. The reaction
mixture was then stirred for 18 h before being quenched with 25% aq.
NH4OH (150 mL) and the organic material extracted into EtOAc (3 x 200
mL). The combined organic extracts were washed sequentially with
distilled water (200 mL), 10% HCl (200 mL) and brine (200 mL). The
organic extract was then dried over MgSO4, filtered through celite and
concentrated under reduced pressure. The crude product was purified by
column chromatography (silica gel, 10% EtOAc/hexane) to give 2-bromo-
1,4,5-trimethoxynaphthalene 22 as a yellowish-brown solid (5.43 g, 18.1
mmol, 79%). 1H NMR (500 MHz, CDCl3) δ 7.68 (1H, d, J = 8.4, H-8), 7.44
(1H, t, J = 8.0, H-7), 6.90 (1H, s, H-3), 6.88 (1H, dd, J = 7.8, 0.5, H-6),
3.95 (3H, s, OMe), 3.93 (3H, s, OMe), 3.92 (3H, s, OMe); 13C NMR (126
MHz, CDCl3) δ 157.5, 153.9, 146.7, 131.7, 127.5, 117.6 114.6, 112,6,
109.8, 106.9, 61.1, 56.8, 56.4. [23]
to afford 2-iodo-3-methoxy-5-methylbenzyl alcohol 17 as
a white
crystalline solid (641 mg, 2.31 mmol, 70%). 1H NMR (500 MHz, CDCl3) δ
6.90 (1H, d, J = 0.6, ArH), 6.58 (1H, d, J = 0.9, ArH), 4.65 (2H, s, CH2OH),
3.86 (3H, s, OMe), 2.34 (4H, s, ArMe and OH overlapping); 13C NMR
(126 MHz, CDCl3) δ 157.8, 144.0, 139.7, 121.8, 111.2, 85.4, 69.6, 56.5,
21.4.[40]
2-Iodo-3-methoxy-5-methylbenzaldehyde 18
In an oven-dried 10 mL round bottom flask equipped with a magnetic
stirring bar was placed 2-iodo-3-methoxy-5-methylphenyl)methanol 17
(360 mg, 1.29 mmol) in dry CH2Cl2 (5.0 mL). To this solution, MnO2 (450
mg, 5.2 mmol) was added and the reaction was stirred at r.t. for 24 h.
The solution was then filtered through a pad of celite and concentrated in
vacuo. The crude product was purified by chromatography (silica gel,
20 % EtOAc/hexane) to give 2-iodo-3-methoxy-5-methylbenzaldehyde 18
as an off-white solid (345 mg, 1.25 mmol, 97%). 1H NMR (500 MHz,
CDCl3) δ 10.16 (1H, s, ArCO), 7.31 (1H, s, ArH), 6.88 (1H, s, ArH), 3.93
(3H, s, OMe), 2.39 (3H, s, ArMe); 13C NMR (126 MHz, CDCl3) δ 196.6,
158.2, 140.0, 136.2, 122.9, 117.2, 90.1, 56.8, 21.1. [27]
(1,4,5-Trimethoxynaphthalen-2-yl)boronic acid 21
n-BuLi (1.5 M, 8.53 mL, 12.80 mmol, 2.0 eq.) was added dropwise to a
solution of 2-bromo-1,4,5-trimethoxynaphthalene 22 (1.90 g, 6.40 mmol,
1.0 eq.) in THF (50 mL) at −78 °C. The reaction mixture was stirred for 30
min at −78 °C, then B(OiPr)3 (3.61 g, 4.43 mL, 19.20 mmol, 4.0 eq.) was
added. The resulting mixture was stirred at −78 °C for a further 30 min
and then allowed to warm to r.t. The reaction mixture was acidified with
10% aq. HCl solution and extracted with Et2O (3 × 50 mL). The organic
layer was then dried (MgSO4) and concentrated under reduced pressure
to afford (1,4,5-trimethoxynaphthalen-2-yl)boronic acid 21 as an off-white
crystalline solid (1.61 g, 6.14 mmol, 96%), which was used without
further purification or characterization.
2-(2-Allyl-1,4,8-trimethoxynaphthalen-3-yl)-3-methoxy-5-
methylbenzaldehyde 19
3-Methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-
yl)benzaldehyde 20
A
deoxygenated solution of 3-allyl-1,4,5-trimethoxynaphthalen-2-yl-2-
boronic acid 7 (310 mg, 1.03 mmol, 1.5 eq.) and 2-iodo-3-methoxy-5-
methylbenzaldehyde 17 (185 mg, 0.67 mmol, 1.0 eq.) in DME (10 mL)
was added to Pd(PPh3)4 (77 mg, 0.067 mmol, 0.1 eq.) under an argon
atmosphere with stirring. To this was added a deoxygenated aq. Na2CO3
(2M, 1.34 mL, 2.68 mmol, 4.0 eq.) solution. The mixture was then heated
at reflux for 18 h. After this time, the mixture was cooled to r.t. and
reaction quenched with H2O (10 mL). The organic material was extracted
into EtOAc (3 x 30 mL), the combined extract dried with MgSO4, and the
solvent removed in vacuo. The crude product was purified by column
chromatography (silica gel, 10-20% EtOAc/hexane) to afford 2-(2-allyl-
A deoxygenated solution of (1,4,5-trimethoxynaphthalen-2-yl)boronic acid
21 (2.50 g, 9.51 mmol, 1.5 eq.) and 2-iodo-3-methoxy-5-
methylbenzaldehyde 18 (1.75 g, 6.34 mmol, 1.0 eq.) in DME (80 mL) was
added to Pd(PPh3)4 (10%, 0.73 g, 0.63 mmol) under argon atmosphere
with stirring. To this was added a deoxygenated aq. Na2CO3 solution (2M,
2.69 g, 12.68 mL, 25.36 mmol, 4.0 eq.). The mixture was then heated at
reflux for 18 h. After this time, the mixture was cooled to r.t. and reaction
quenched with H2O (100 mL). The organic material was extracted into
EtOAc (3 x 100 mL), the combined extracts dried with MgSO4, and the
solvent removed in vacuo. The crude product was purified by column
chromatography (silica gel, 10-20% EtOAc/hexane) to afford 3-methoxy-
5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde 20 as an off-
white solid (1.85 g, 5.07 mmol, 80%). Mp. 160-162 °C CH2Cl2; FTIR
(ν/cm-1): 2939 (C-H stretch), 1686.3 (C=O), 1597.6 (C=C), 1118.9 (C-O),
849.6; 1H NMR (300 MHz, CDCl3) δ 9.70 (1H, s, ArCHO), 7.75 (1H, dd, J
= 8.4, 1.0 Hz, H-8′), 7.50 (1H, d, J = 0.7 Hz, H-6), 7.44 (1H, t, J = 7.9 Hz,
H-7′), 7.08 (1H, d, J = 0.7 Hz, H-4), 6.93 (1H, dd, J = 7.8, 0.7 Hz, H-6′),
6.69 (1H, s, H-3′), 4.00 (3H, s, 5′-OMe), 3.92 (3H, s, 4′-OMe), 3.80 (3H, s,
3-OMe), 3.45 (3H, s, 1′-OMe), 2.49 (3H, s, ArMe); 13C NMR (126 MHz,
1,4,8-trimethoxynaphthalen-3-yl)-3-methoxy-5-methylbenzaldehyde
19
as an off-white solid (33 mg, 0.08 mmol, 12%). Mp. 54-56 °C CHCl3;
FTIR (ν/cm-1): 2944.0 (C-H stretch), 1690.6 (C=O), 1604.1 (C=C), 1568.6,
1446.0, 1054.8 (C-O); 1H NMR (300 MHz, CDCl3) δ 9.55 (1H, s, ArCHO),
7.71 (1H, dd, J = 8.4, 1.0, H-8´), 7.48 (1H, d, J = 0.8, H-6), 7.41 (1H, t, J
= 8.4, H-7´), 7.04 (1H, d, J = 0.9, H-4), 6.93 (1H, dd, J = 7.8, 1.0, H-6´),
5.65 (1H, m, =CH-), 4.72 (1H, dd, J = 10.1, 1.6, =CH2), 4.50 (1H, dd, J =
17.1, 1.8, =CH2), 4.04 (3H, s, OMe), 3.86 (5H, m, OMe and -CH2-), 3.74
(3H, s, OMe), 3.45 (3H, s, OMe), 2.49 (3H, s, ArMe). 13C NMR (75 MHz,
CDCl3) δ 192.7, 157.0, 156.1, 150.6, 150.1, 139.3, 136.6, 135.0, 130.1,
129.7, 126.7, 126.0, 125.0, 121.0, 119.2, 116.7, 115.3, 115.1, 106.6,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201601373
European Journal of Organic Chemistry
FULL PAPER
CDCl3) δ 192.8 (ArCHO), 157.4 (C-5′), 157.2 (C-3), 152.8 (C-4′), 147.8
(C-1′), 139.3 (C-5), 134.7 (C-1), 131.2 (C-8′a), 128.1 (C-2′), 126.9 (C-7′),
122.2 (C-2), 119.3 (C-6), 118.6 (C-4′a), 117.2 (C-4), 115.2 (C-8′), 109.7
(C-3′), 107.2 (C-6′), 60.8 (1′-OMe), 56.9 (4′-OMe), 56.6 (5′-OMe), 56.0 (3-
OMe), 21.7 (ArMe); HRMS (ESI+): Found [M + H]+ 367.1531, C22H23O5
[M + H]+ requires 367.1545, m/z 367.1531 (M + H+, 100%).
Method 1: In an oven-dried 25 mL round bottom flask equipped with a
magnetic
stirring
bar
was
placed
2-(2-ethynyl-6-methoxy-4-
methylphenyl)-1,4,5-trimethoxynaphthalene 24 (810 mg, 2.24 mmol, 1.0
eq.) in dry PhMe (10 mL). PtCl2 (0.089 mg. 0.34 mmol) was then added
and the mixture was then stirred at 90 ºC for 24 h under an argon
atmosphere. The mixture was filtered through celite and the residue was
washed with CH2Cl2. Chromatographic purification (silica gel, 15-20%
EtOAc/hexane) afforded 1,7,8,12-tetramethoxy-3-methyltetraphene 25 as
a yellow solid (495 mg, 1.37 mmol, 61 %) and 1,10,12-trimethoxy-8-
methylchrysene 26 as yellowish brown solid (171 mg, 0.515 mmol, 23 %).
25: Mp. 80-82 °C CH2Cl2; FTIR (ν/cm-1): 2919.9 (C-H stretch), 1606.0
(C=C), 1121 (C-O), 1060.3, 832.3; 1H NMR (300 MHz, CDCl3) δ 8.11 (1H,
dd, J = 8.6, 1.0, H-11), 8.03 (1H, d, J = 9.2, H-6), 7.44 (1H, t, J = 8.8, H-
10), 7.36 (1H, d, J = 9.5, H-5), 7.17 (1H, d, J = 0.8, H-4), 6.92 (1H, d, J =
0.9, H-2), 6.89 (1H, d, J = 7.1, H-9), 4.07 (3H, s, 8-OMe), 3.97 (6H, s, 1-
OMe and 7-OMe overlapping), 3.51 (3H, s, 12-OMe), 2.54 (3H, s, ArMe);
13C NMR (75 MHz, CDCl3) δ 158.0 (C1-OMe), 156.2 (C8-OMe), 150.9
(C12-OMe), 147.1 (C7-OMe), 138.1 (C-3), 134.6 (C-4a), 129.7 (C-8a),
126.2 (C-5), 125.4 (C-10), 125.1 (C-6a), 122.1 (C-6), 119.6 (C-4), 118.6
(C-7a), 117.4 (C-12a), 116.6 (C-12b), 115.8 (C-11), 110.9 (C-2), 105.2
(C-9), 63.3 (1-OMe), 60.4 (12-OMe), 56.3 (8-OMe), 56.2 (7-OMe), 21.7
(ArMe); HRMS (ESI+): Found [M + H]+ 363.1593, C23H23O4 [M + H]+
requires 363.1596, m/z 363.1593 (M + H+, 100%), 362.1521 (55). 26: Mp.
176-178 °C CH2Cl2; FTIR (ν/cm-1): 2904.3 (C-H stretch), 1588.5 (C=C),
1077.4 (C-O); 742.3; 1H NMR (300 MHz, CDCl3) δ 9.20 (1H, s, H-11),
8.55 (1H, d, J = 9.1, H-5), 8.37 (1H, d, J = 8.5, H-4), 7.69 (1H, d, J = 9.1,
H-6), 7.56 (1H, t, J = 8.2, H-3), 7.34 (1H, d, J = 0.9, H-7), 7.05 (1H, d, J =
7.8, H-2), 6.92 (1H, d, J = 0.9, H-9), 4.15 (3H, s, 12-OMe), 4.11 (3H, s,
10-OMe), 4.03 (3H, s, 1-OMe), 2.54 (3H, s, ArMe); 13C NMR (75 MHz,
CDCl3) δ 158.6 (C-10), 157.4 (C-1), 154.9 (C-12), 136.5 (C-8), 135.3 (C-
6a), 134.0 (C-4a), 130.0 (C-10b), 126.6 (C-3), 124.8 (C-6), 123.5 (C-4b),
122.4 (C-5), 121.2 (C-7), 118.9 (C-10a), 116.7 (C-12a), 116.2 (C-4),
110.0 (C-9), 107.8 (C-2), 106.1 (C-11), 56.8 (1-OMe), 56.2 (10-OMe),
56.1 (12-OMe), 21.7 (ArMe); HRMS (ESI+): Found [M + H]+ 333.1387,
C22H21O3 [M + H]+ requires 333.1391.
2-(2-(2,2-Dibromovinyl)-6-methoxy-4-methylphenyl)-1,4,5-
trimethoxynaphthalene 23
In an oven-dried 25 mL round-bottom flask equipped with a magnetic
stirring bar was placed PPh3 (4.98 g, 19.0 mmol, 5.0 eq.) in dry CH2Cl2 (6
mL). The mixture was cooled to 0 °C and CBr4 (3.15 g, 9.50 mmol) was
added, and the mixture was stirred for 10 min at 0 °C. Aldehyde 20 (1.40
g, 3.81 mmol, 1.0 eq.) dissolved in dry CH2Cl2 (10 mL) was slowly added.
The mixture was flushed with argon and allowed to stir at 0 °C for 4 h.
The mixture was diluted with CH2Cl2 and washed with brine (2 x 30 mL)
followed by H2O (2 x 30 mL). The aqueous layer was extracted twice with
CH2Cl2 and the combined organic layer was dried over MgSO4. The
solvent was evaporated under reduced pressure and the crude product
purified by column chromatography (silica gel, 15-20% EtOAc/hexane) to
afford the vinyl dibromide 23 as a foamy yellow solid (1.77 g, 3.40 mmol,
89%). Mp. 133-135 °C (C2H5)2O; FTIR (ν/cm-1): 2912 (C-H stretch),
1598.9 (C=C), 1173.2 (C-O); 630.0; 1H NMR (300 MHz, CDCl3) δ 7.78
(1H, dd, J = 8.4, 1,0, H-8), 7.43 (1H, t, J = 8.1, H-7), 7.14 (1H, d, J = 0.8,
H-3´), 7.09 (1H, s, =CH-), 6.91 (1H, dd, J = 7.8, 1.1, H-6), 6.84 (1H, d, J =
0.9, H-5´), 6.55 (1H, s, H-3), 4.00 (3H, s, OMe), 3.92 (3H, s, OMe), 3.75
(3H, s, OMe), 3.52 (3H, s, OMe), 2.46 (3H, s, ArMe); 13C NMR (75 MHz,
CDCl3) δ 157.4, 157.0, 152.8, 147.3, 138.6, 137.1, 136.2, 131.6, 126.5,
124.7, 124.2, 121.7, 118.3, 115.3, 112.1, 109.6, 106.9, 90.6, 61.2, 56.9,
56.6, 55.9, 21.8; HRMS (ESI+): Found [M + H]+ 520.9960, C23H23O4Br2
[M + H]+ requires 520.9963, m/z 520.9960 (M + H+, 50%), 522.9937 (100).
2-(2-Ethynyl-6-methoxy-4-methylphenyl)-1,4,5-
trimethoxynaphthalene 24
Method 2: In an oven-dried 25 mL round-bottom flask equipped with a
In an oven-dried 25 mL two-necked round bottom flask equipped with a
magnetic stirring bar was placed the vinyl dibromide 23 (1.35 g, 2.59
mmol, 1.0 eq.) in dry THF (6 mL) under argon atmosphere. The mixture
was cooled to −78 ºC and a 1.2 M solution of n-BuLi in hexanes (5.40 mL,
6.48 mmol, 2.5 eq.) was added dropwise. The mixture was allowed to stir
at −78 C for 6 h and then for 1 h at r.t., at which time TLC showed the
reaction to be complete. The mixture was quenched with and extracted
with Et2O (3 × 30 mL). The combined organic layer was dried over
magnetic
stirring
bar
was
placed
2-(2-ethynyl-6-methoxy-4-
methylphenyl)-1,4,5-trimethoxynaphthalene 24 (820 mg, 2.27 mmol, 1.0
eq.) in dry PhMe (10 mL). AuCl3 (0.103 mg. 0.34 mmol) was then added
º
and the mixture was stirred at 90 C for 24 h under argon atmosphere.
The mixture was filtered through celite and the residue was washed with
CH2Cl2. Chromatographic purification on silica gel (15-20%
EtOAc/hexane) afforded 1,7,8,12-tetramethoxy-3-methyltetraphene 25 as
a yellow solid (0.460 mg, 1.27 mmol, 56 %) and 1,10,12-trimethoxy-8-
methylchrysene 26 as yellowish brown solid (234 mg, 0.704 mmol, 31 %).
º
MgSO4
and solvent evaporated
under reduced pressure.
Chromatographic purification (silica gel, 20% EtOAc/hexane) afforded the
alkyne 24 as a yellowish brown solid (0.83 g, 2.29 mmol, 88 %). Mp. 135-
137 °C CHCl3; FTIR (ν/cm-1): 3272.6 (≡C-H stretch), 2946.5 (C-H stretch),
2370.8 (C≡C), 1598.3 (C=C), 1078.3 (C-O); 1H NMR (300 MHz, CDCl3) δ
7.78 (1H, dd, J = 8.5, 1.0, H-8), 7.41 (1H, t, J = 8.2, H-7), 7.09 (1H, d, J =
0.9, H-3´), 6.89 (1H, dd, J = 8.5, 1,0, H-6), 6.84 (1H, d, J = 0.8, H-5´),
6.67 (1H, s, H-3), 3.98 (3H, s, OMe), 3.92 (3H, s, OMe), 3.73 (3H, s,
OMe), 3.57 (3H, s, OMe), 2.81 (1H, s, ≡CH), 2.41 (3H, s, ArMe); 13C
NMR (75 MHz, CDCl3) δ 157.4, 157.1, 152.6, 147.7, 138.6, 131.4, 128.3,
126.2, 125.8, 125.6, 123.2, 118.3, 115.4, 113.0, 109.9, 106.7, 82.6, 79.9,
61.4, 56.9, 56.6, 56.0, 21.5; HRMS (ESI+): Found [M + H]+ 363.1601,
C23H23O4 [M + H]+ requires 363.1596, m/z 363.1601 (M + H+, 100%),
348.1370 (30).
1,8-Dimethoxy-3-methyltetraphene-7,12-dione 27
In a 25 mL round bottom flask equipped with a magnetic stirring bar was
placed 1,7,8,12-tetramethoxy-3-methyltetraphene 25 (150 mg, 0.41 mmol,
1.0 eq.) in MeCN (5 mL). CAN (0.66 mg, 1.20 mmol, 3.0 eq.) in H2O (5
mL) was then added and the mixture stirred for 30 min. NaHCO3 was
then added and organic material was extracted with EtOAc (3 x 10 mL).
The combined organic layer was dried over MgSO4 and the solvent
removed in vacuo. The crude product was purified by column
chromatography (silica gel, 50% EtOAc/hexane) to give 1,8,-dimethoxy-
3-methyltetraphene-7,12-dione 27 as a yellow solid (117 mg, 0.353 mmol,
86%). 1H NMR (300 MHz, CDCl3) δ 8.22 (1H, d, J = 8.6, H-5), 7.91 (1H, d,
J = 8.6, H-6), 7.67 (2H, dd, J = 4.8, 0.7, ArH), 7.27-7.22 (2H, m, ArH),
6.89 (1H, d, J = 1.4, H-2), 4.03 (3H, s, OMe), 3.97 (3H, s, OMe), 2.52 (3H,
s, ArMe); 13C NMR (75 MHz, CDCl3) δ 186.6, 182.3, 159.4, 156.9, 140.3,
139.3, 137.8, 135.2, 135.0, 133.9, 132.5, 122.7, 120.7, 120.1, 119.1,
118.5, 116.2, 111.2, 56.5, 56.0, 22.1.[11]
1,7,8,12-Tetramethoxy-3-methyltetraphene
trimethoxy-8-methylchrysene 26
25
and
1,10,12-
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Tetrangulol: 1,8-Dihydroxy-3-methyltetraphene-7,12-dione 1
combined organic extracts were washed three times with CuSO4 to
remove traces of pyridine followed by brine and then dried over MgSO4
and the solvent removed in vacuo. The crude product was purified by
column chromatography (slica gel, 20% EtOAc/hexane) to give the O-
phenyl oxime 28b as a yellowish brown solid (0.70 g, 1.53 mmol, 93%).
Mp. 134-136 °C CH2Cl2; FTIR (ν/cm-1): 2939.5 (C-H stretch), 1578.4
(C=C), 1455.2, 1374.2 (N-O stretch), 1074.6 (C-O); 748.9; 1H NMR (300
MHz, CDCl3) δ 8.12 (1H, s, -N=CH-), 7.78 (1H, dd, J = 8.4, 0.9, H-8´),
7.63 (1H, d, J = 0.8, H-6), 7.43 (1H, t, J = 8.1, H-7´), 7.28 – 7.11 (4H, m,
ArH), 7.00 – 6.86 (3H, m, ArH), 6.59 (1H, s, H-3´), 3.97 (3H, s, OMe),
3.89 (3H, s, OMe), 3.74 (3H, s, OMe), 3.52 (3H, s, OMe), 2.47 (3H, s,
ArMe); 13C NMR (75 MHz, CDCl3) δ 159.40, 157.47, 157.20, 152.91,
150.84, 147.52, 139.04, 131.51, 130.92, 129.18, 126.76, 125.86, 123.90,
122.05, 118.45, 115.27, 114.41, 113.70, 109.67, 107.11, 60.97, 56.84,
56.58, 55.82, 21.76; HRMS (ESI+): Found [M + H]+ 458.1969, C28H28NO5
[M + H]+ requires 458.1967, m/z 458.1969 (M + H+, 60%), 364.1548 (100),
334.1434 (30).
In an oven-dried 25 mL two-necked round bottom flask equipped with a
magnetic stirring bar was placed 1,8,-dimethoxy-3-methyltetraphene-
7,12-dione 27 (40 mg, 0.120 mmol. 1.0 eq.) in CH2Cl2 (5 mL) under
argon atmosphere. The mixture was cooled to –78 ºC and BBr3 (1.20 mL,
1.20 mmol, 10.0 eq.) was added dropwise. The reaction was then slowly
º
warmed to r.t. and stirred for a further 18 h before being cooled to 0 C
and quenched with water. The organic material was extracted with
CH2Cl2 (3 × 10 mL) and the combined organic layers were dried over
MgSO4 and the solvent removed under reduced pressure. The crude
product was purified by column chromatography on silica gel (5%
EtOAc/hexane) to afford a brown solid (34.0 mg) consisting mainly
(~85%) of the desired compound, 1,8-dihydroxy-3-methyltetraphene-
7,12-dione (tetrangulol) 1 in a similar yield to that published by Hsu.11
However, 1 co-eluted with small amounts of an unidentified product. (see
NMR spectra in supplementary information). The spectroscopic data of
the major product 1 agreed with that published previously by Hsu.11 1H
NMR (300 MHz, CDCl3) δ 12.24 (1H, s, ArOH), 11.26 (1H, s, ArOH), 8.31
(1H, d, J = 8.6, H-5), 8.13 (1H, d, J = 8.6, H-6), 7.85 (1H, d, J = 7.6, H-
11), 7.73 – 7.63 (2H, m, ArH), 7.36 – 7.30 (2H, m, ArH), 7.14 (1H, d, J =
1.4, H-2), 2.49 (3H, s, ArMe); 13C NMR (75 MHz, CDCl3) δ 189.7, 187.9,
161.7, 155.3, 142.0, 139.1, 137.7, 136.9, 134.8, 132.4, 124.8, 123.2,
121.9, 121.3, 121.2, 120.2, 120.0, 114.7, 21.3.[11]
3-Methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzonitrile
33
To a solution of the acetyl oxime 28a (0.32 g, 0.76 mmol, 1.0 eq.) in
toluene (10 mL) was added Pd(dba)3 (44 mg, 0.076 mmol, 10 mol%) and
Cs2CO3 (0.248 g, 0.76 mmol, 1.0 eq.). The reaction was stirred at 150 °C
for 24 h. On completion, the reaction mixture was cooled to r.t. followed
by the addition of EtOAc (15 mL) and water (15 mL). The organic layer
was separated and subsequently washed with a saturated NH4Cl solution
(10 mL), water (10 mL) and brine (10 mL) and dried over MgSO4. The
crude product was purified using column chromatography on silica gel
(30% EtOAc/hexane) to afford the benzonitrile 33 as a yellow solid (0.17
g, 0.471 mmol, 62%). Mp. 184-186 °C CHCl3; FTIR (ν/cm-1): 2991.3 (C-H
3-Methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-
yl)benzaldehyde O-acetyl oxime 28a
To a solution of 3-methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-
yl)benzaldehyde 20 (0.505 g, 1.38 mmol, 1.00 eq.) in MeOH (5 mL) was
added hydroxylamine hydrochloride (0.19 g, 2.75 mmol, 2.0 eq.) and
NaOAc (0.170 g, 2.07 mmol, 1.5 eq.). The reaction mixture was heated
at reflux for 2 h and the solvent was removed in vacuo. To the residue,
dry CH2Cl2 (3 mL) and triethylamine (0.38 mL, 0.28 g, 2.75 mmol, 2.0
eq.) were added at 0 °C. To this cooled solution was slowly added a
solution of acetyl chloride (0.2 mL, 0.22 g, 2.75 mmol, 2.0 eq.) in dry
CH2Cl2 (1 mL). The reaction mixture was stirred at r.t. for 18 h. Upon
completion, the reaction was quenched with water (5 mL) and the mixture
extracted with CH2Cl2 (3 × 10 mL) and the combined organic extracts
were washed with aq. NaHCO3 (10 mL) and brine (10 mL) and dried over
MgSO4 and the solvent removed under reduced pressure. The crude
product was purified by column chromatography on silica gel (30 %
EtOAc/hexane) to afford the acetyl oxime 28a as a yellow solid (0.5 g,
1.18 mmol, 86%). Mp. 136-138 °C CH2Cl2; FTIR (ν/cm-1): 2946.8 (C-H
stretch), 1763.8 (C=O), 1581.1 (C=C), 1449.0, 1374.3 (N-O stretch),
1
stretch), 2364.7 (C≡N), 1597.0 (C=C), 1454.9, 1076.4 (C-O); 846.9.3; H
NMR (300 MHz, CDCl3) δ 7.78 (1H, dd, J = 8.4, 1.0, H-8´), 7.43 (1H, t, J
= 8.2, H-7´), 7.19 (1H, s, H-6), 7.03 (1H, s, H-4), 6.92 (1H, d, J = 7.8, H-
6´), 6.63 (1H, s, H-3´), 3.98 (3H, s, OMe), 3.93 (3H, s, OMe), 3.77 (3H, s,
OMe), 3.55 (3H, s, OMe), 2.44 (3H, s, ArMe); 13C NMR (75 MHz, CDCl3)
δ 157.5, 157.3, 153.2, 147.9, 139.9, 131.5, 128.9, 126.8, 125.0, 123.6,
118.9, 118.1, 116.5, 115.4, 114.5, 108.7, 107.4, 61.6, 57.0, 56.7, 56.1,
21.5. HRMS (ESI+): Found [M + H]+ 364.1552, C22H22 NO4 [M + H]+
requires 364.1549, m/z 364.1552 (M + H+, 100%).
1,10,12-Trimethoxy-8-methylbenzo[c]phenanthridine 35
Method 1: O- acetyl oxime 28a (80 mg, 0.17 mmol, 1.0 eq) was
introduced into a UV reactor and t-butanol (5 ml) was added and the
reaction mixture was degassed with argon. The solution was then
subjected to UV radiation (450W) for 20 min. After cooling, the crude
product was purified by column chromatography (silica gel, 20%
EtOAc/hexane) to afford the phenanthridine 35 (26 mg, 0.078 mmol,
46%) and the benzonitrile 33 (11 mg, 0.031 mmol, 18%). Mp. 211-213 °C
CHCl3); FTIR (ν/cm-1): 2914.4 (C-H stretch), 1589.4 (C=C), 1446.7,
1363.7, 1075.9 (C-O); 752.2; 1H NMR (500 MHz, CDCl3) δ 9.15 (1H, s,
H-6), 9.13 (1H, dd, J = 8.4, 0.7, H-4), 8.87 (1H, s, H-11), 7.64 (1H, t, J =
8.1, H-3), 7.45 (1H, s, H-7), 7.12 (1H, d, J = 7.7, H-2), 7.03 (1H, s, H-9),
4.15 (3H, s, 12-OMe), 4.11 (3H, s, 10-OMe), 4.04 (3H, s, 1-OMe), 2.56
(3H, s, ArMe); 13C NMR (126 MHz, CDCl3) δ 157.8 (C-10), 156.8 (C-1),
155.4 (C-12), 149.0 (C-6), 137.7 (C-8), 137.2 (C-4b), 135.4 (C-4a), 129.6
(C-6a), 127.0 (C-3), 122.6 (C-10b), 121.0 (C-10a), 120.6 (C-7), 117.9 (C-
4), 117.4 (C-12a), 112.7 (C-9), 108.7 (C-2), 103.7 (C-11), 56.8 (1-OMe),
56.1 (10-OMe), 56.0 (12-OMe), 21.8 (ArMe); HRMS (ESI+): Found [M +
H]+ 334.1447, C21H20NO3 [M + H]+ requires 334.1445, m/z 334.1447 (M +
H+, 100%), 335.1479 (25), 240.9883 (60).
1
1200.8 (C-O); 751.9; H NMR (300 MHz, CDCl3) δ 8.03 (1H, s, -N=CH-),
7.77 (1H, dd, J = 8.4, 0.8, H-8´), 7.67 (1H, s, H-6), 7.46 (1H, t, J = 8.1, H-
7´), 6.97 – 6.92 (2H, m, ArH), 6.57 (1H, s, H-3´), 4.00 (3H, s, OMe), 3.90
(3H, s, OMe), 3.77 (3H, s, OMe), 3.48 (3H, s, OMe), 2.46 (3H, s, ArMe),
2.08 (3H, s, CO2Me); 13C NMR (75 MHz, CDCl3) δ 168.6, 157.5, 157.1,
155.3, 155.3, 152.9, 147.4, 139.4, 131.5, 129.6, 126.8, 126.4, 123.5,
119.1, 115.3, 114.7, 109.6, 107.2, 61.0, 56.9, 56.6, 55.9, 21.6, 19.5;
HRMS (ESI+): Found [M + H]+ 424.1757, C24H26NO6 [M + H]+ requires
424.1760, m/z 424.1757 (M + H+, 7%), 364.1542 (100), 333.1357 (30).
3-Methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-
yl)benzaldehyde O-phenyl oxime 28b
O-Phenylhydroxyamine hydrochloride (0.240 g, 1.63 mmol, 1.0 eq.) was
dissolved in anhydrous pyridine (10 mL) under argon at r.t. and 3-
methoxy-5-methyl-2-(1,4,5-trimethoxynaphthalen-2-yl)benzaldehyde 20
(0.60 g, 1.63 mmol, 1.0 eq.) was added in one portion. The reaction was
stirred at room temperature for 18 hrs. On completion, the reaction was
quenched with water and extracted with EtOAc (3 × 20 mL). The
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10.1002/ejoc.201601373
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Method 2: O-phenyl oxime 28b (110 mg, 0.24 mmol, 1.0eq.) and
EmimPF6 (60 mg, 0.24 mmol) were dissolved in t-butylbenzene (3 mL) in
a microwave reactor tube. The reaction mixture was subjected to
microwave irradiation (300W, 160 °C) for 20 min. After cooling, the ionic
liquid was filtered off and the crude product was purified by column
chromatography (silica gel, 20% EtOAc/hexane) to afford the
phenanthridine 35 as a yellow solid (46 mg, 0.14 mmol, 58%) and the
benzonitrile 33 (9.60 mg, 0.026 mmol, 11%).
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Acknowledgements
This work was supported by SABINA (Southern African
Biochemistry and Informatics for Natural Products Network), the
National Research Foundation Pretoria, South Africa, and the
University of the Witwatersrand (Science Faculty Research
Council). The University of Stellenbosch is thanked for providing
the HRMS spectroscopy service.
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Kennedy J. Ngwira, Amanda L.
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Title Reactions of 2-
naphthylphenylacetylenes and 2-
naphthylbenzaldehyde O-phenyl
oximes. A synthesis of the
angucycline, tetrangulol and 1,10,12-
*angucyclines; Suzuki- Miyaura coupling; PtCl2
Cycloisomerization of the biaryl alkyne in the presence of catalytic PtCl2 allowed
for the formation of 1,7,8,12-tetramethoxy-3-methyltetraphene, which was easily
converted into the natural product tetrangulol.
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