The synthesis of 9-O-Methylpaepalantine and Dehydroxanthomegnin: Related Isocoumarin-Containing Natural Products

Article abstract of DOI:10.1002/ejoc.201801595

The first synthesis of two related isocoumarin-containing natural products, 9-O-methylpaepalantine and dehydroxanthomegnin is described. Commencing with 2,4-dimethoxybenzaldehyde and utilizing the Stobbe reaction as a key step resulted in the formation of the required naphthalene containing compound, ethyl 4-acetoxy-3-allyl-6,8-dimethoxynaphthalene-2-carboxylate. O-Allylation of 4-hydroxy-6,8-dimethoxynaphthalene-2-carboxylate followed by a Claisen rearrangement afforded the naphthol, ethyl 3-allyl-4-hydroxy-6,8-dimethoxynaphthalene-2-carboxylate. Introduction of a methoxy substituent onto the 1-position of the naphthalene nucleus utilizing a PIFA-mediated method afforded, after O-methylation, ethyl 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylate. Reduction of the ester was followed by oxidation to the aromatic acid, utilizing firstly a PCC oxidation and then a Pinnick oxidation to afford 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylic acid. Wacker oxidation of the aromatic acid resulted in the formation of 5,7,9,10-tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-one, which was then converted into 9-O-methylpaepalantine by treatment with boron trichloride. Utilizing similar synthetic methodology dehydroxanthomegnin was synthesized in thirteen steps commencing from 2,4,5-trimethoxybenzaldehyde in an overall yield of 1.3 %.

Full text of DOI:10.1002/ejoc.201801595

DOI: 10.1002/ejoc.201801595
Full Paper
Wacker Oxidation
The synthesis of 9-O-Methylpaepalantine and
Dehydroxanthomegnin: Related Isocoumarin-Containing Natural
Products
[a]
[a]
[a]
Jimmy E. Y. Sumani, Kennedy J. Ngwira, Andreas Lemmerer, and
Charles B. de Koning*[
a]
Abstract: The first synthesis of two related isocoumarin- ethyl
3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylate.
containing natural products, 9-O-methylpaepalantine and de- Reduction of the ester was followed by oxidation to the aro-
hydroxanthomegnin is described. Commencing with 2,4-di- matic acid, utilizing firstly a PCC oxidation and then a Pinnick
methoxybenzaldehyde and utilizing the Stobbe reaction as a oxidation to afford 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-
key step resulted in the formation of the required naphthalene carboxylicacid.Wackeroxidationofthearomaticacidresultedinthe
containing compound, ethyl 4-acetoxy-3-allyl-6,8-dimethoxy- formation of 5,7,9,10-tetramethoxy-3-methyl-1H-benzo[g]iso-
naphthalene-2-carboxylate. O-Allylation of 4-hydroxy-6,8-di- chromen-1-one, which was then converted into 9-O-methyl-
methoxynaphthalene-2-carboxylate followed by a Claisen re- paepalantine by treatment with boron trichloride. Utilizing simi-
arrangement afforded the naphthol, ethyl 3-allyl-4-hydroxy-6,8- lar synthetic methodology dehydroxanthomegnin was synthe-
dimethoxynaphthalene-2-carboxylate. Introduction of a meth- sized in thirteen steps commencing from 2,4,5-trimethoxy-
oxy substituent onto the 1-position of the naphthalene nucleus benzaldehyde in an overall yield of 1.3 %.
utilizing a PIFA-mediated method afforded, after O-methylation,
Introduction
Anhydrofusarubin lactone 1 and the related quinone containing
naphthopyranone 5-methoxy-3,4-dehydrosemixanthomegnin 2
(
also referred to as 5-methoxy-3,4-dehydroxanthomegnin or de-
hydroxanthomegnin) belong to a growing class of quinone con-
[
1]
[2]
taining compounds (Figure 1). Anhydrofusarubin lactone 1
is found in several fungi such as Nectria haematococca and Fu-
sarium solani, while 5-methoxy-3,4-dehydrosemixanthomegnin
[
3]
2
has been isolated from Paepalanthus latipes Silveira, Erio-
caulaceae, often found in Brazil. A related compound, paepalan-
tine 3 and its dimer 4 have been isolated from a related Erio-
[
4]
caulaceae species Paepalanthus bromelioides, as well as Pae-
[
5]
palanthus vellozioides.
This class of isocoumarin-containing compounds shows a
wide range of biological activities. For example, 5-methoxy-3,4-
Figure 1. Naturally occurring isocoumarins.
dehydrosemixanthomegnin
2
shows cytotoxicity against against the Helicobacter pylori bacterium, which is one of the
murine mammary tumor cells (LM2, CI50 74.6 μ
M
) and lung main causes of chronic gastritis, peptic ulcers and possibly
)[6] while paepalantine gastric cancer.
[8,9]
As a result of our interest in the synthesis of
we envisaged that the synthesis of the iso-
adenocarcinoma cells (LPO7, CI50 6.2 μ
M
[
10]
3
shows antimicrobial activity against bacteria including Bacillus isochromanes
–1
cereus (MIC 7.5 μg mL ), Staphylococcus aureus (MIC 7.5 μg coumarins, 5-methoxy-3,4-dehydrosemixanthomegnin 2 and
–
1
–1 [7]
mL ) and Staphylococcus epidermidis (MIC 15 mg mL ). In paepalantine 3 could be accomplished in our laboratories.
addition, both of these isocoumarins show promising activity
In this paper we describe the first synthesis of 5-methoxy-
3
,4-dehydrosemixanthomegnin 2 and 9-O-methylpaepalantine
[
a] Molecular Sciences Institute, School of Chemistry,
University of the Witwatersrand,
5, a methoxy derivative of paepalantine 3. A key step in the
synthesis of both of these isocoumarins is a Wacker-mediated
ring closure of the aromatic carboxylic acids 6 and 7 bearing an
allyl substituent to afford the isocoumarins 8 and 9 respectively
(Figure 2).
PO Wits 2050, Johannesburg, South Africa
E-mail: Charles.deKoning@wits.ac.za
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801595.
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We were now in a position to test one of the key steps of
the synthesis, the Wacker mediated ring closure. Exposure of
naphthalene 15 to catalytic palladium in the presence of a cop-
per(II) source afforded the desired isocoumarin 8 in 47 % yield
(Scheme 2). Disappointingly, a second product produced in a
significant yield was the five membered analogue 16 (21 %).
The structure of both compounds 8 and 16 was determined by
[
11]
Figure 2. Wacker-mediated oxidations for the synthesis of isocoumarins 8 and
X-ray crystallography (Figure 3). All other hydrolysis methods
for the conversion of 14 into the desired allyl-containing com-
pound 6 were unsuccessful.
9.
[
12]
Hence alternative methodology
had to be sought.
Results and Discussion
As a starting point for the synthesis of 9-O-methylpaepalantine
5
, the preparation of the naphthalene containing acid 6 was
[
10a]
needed. As described in the literature
commencing with
2,4-dimethoxybenzaldehyde, treatment with diethyl succinate
and potassium tert-butoxide in the Stobbe condensation reac-
tion, followed by an aromatic ring forming procedure afforded
naphthalene 10. As previously described, selective removal of
the acetate of 10, followed by O-allylation and a Claisen rear-
rangement afforded the naphthol 11 as shown in Scheme 1.
[
10c]
Following protocols developed in our laboratories
the extra
aromatic methoxy substituent was introduced onto the naphth-
alene nucleus by treatment of 11 with phenyliodine(III) bis(tri-
fluoroacetate (PIFA) in methanol to afford the intermediate 12.
In contrast to our previous work re-aromatization was best ac-
complished by treatment of 12 with potassium tert-butoxide in
ethanol to afford 13 in a 60 % yield. Protection of the naphthol
Scheme 2. Reagents and conditions: (i) cat. PdCl
atm, r.t., 24 h, 8 47 %, 16 21 %.
2 2 2 2 2
, CuCl ·2H O, DMF/H O, O (g)
1
3 as the methyl ether afforded 14. The stage was now set to
convert the ester of 14 into the corresponding aromatic acid
. Although a stubbornly slow reaction, treatment of 14 with
6
potassium hydroxide in an aqueous alcohol solution at reflux
was the best method for achieving this conversion (55 % yield).
Unfortunately, at the same time isomerization of the allyl sub-
stituent occurred resulting in the styrene 15 (Scheme 1).
Figure 3. ORTEP diagrams of compounds 16 and 8 (displacement ellipsoids
at 50 % probability).
Scheme 1. Reagents and conditions: (i) (a) 1 % KOH, EtOH/H
2 % aq. HCl, 88 %; (c) K CO , allyl bromide, Me CO, reflux, 24 h, 87 %; (d)
heat, 180 °C, N (g) atm, 24 h, 69 %; (ii) PIFA, MeOH, r.t., 15 min; (iii) tBuOK,
EtOH, r.t., 20 min, 60 %; (iv) K CO , Me SO , Me CO, reflux, 24 h, 89 %; (v) (a)
NaOH/KOH, MeOH/H O, reflux, 84 h; (b) 32 % aq. HCl, 55 %.
2
O, r.t., 3 h; (b)
Reduction of the ester group of 14 with lithium aluminium
hydride afforded the primary alcohol 17. Oxidation of 17 to the
intermediate aldehyde was followed by a Pinnick oxidation to
afford the desired aromatic acid 6 containing the required allyl
3
2
3
2
2
2
3
2
4
2
2
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substituent (Scheme 3). Subjecting 6 to Wacker oxidation con- methylpaepalantine 5 in a reasonable yield. However, none of
ditions gratifyingly only yielded the desired isocoumarin 8 in the methods[ we attempted resulted in the cleavage of the
good yield. Treatment of 8 with boron trichloride afforded 9-O- final O-methyl substituent to furnish paepalantine.
As the synthesis of 9-O-methylpaepalantine 5 had been suc-
13]
cessful we wished to apply the same methodology to the syn-
thesis of 5-methoxy-3,4-dehydrosemixanthomegnin 2. Using
the same synthetic methodology naphthol 18 could easily be
prepared in 34 % yield over five steps from 2,4,5-trimethoxy-
[
14]
benzaldehyde.
Treatment of 18 with PIFA in methanol fol-
lowed by sodium ethoxide in ethanol resulted in the formation
of the desired product 21 (via 19 as shown in Scheme 4). How-
[
15]
ever, a small amount of a product identified as 20, (Figure 4a)
where methanol had added ortho to the naphthol substituent
of 18 was also isolated. The best way to accomplish this trans-
formation (18 → 21) was by subjecting 18 to PIFA in methanol
and then potassium tert-butoxide in ethanol which afforded 21
in a 60 % yield. The naphthol of 21 was easily converted into
[
16]
naphthalene ether 22 (Figure 4b).
Again, conversion of the
ester of 22 into the acid 7 was accomplished by reduction,
followed by oxidation with PCC and further Pinnick oxidation
to furnish 7. Wacker oxidation of 7 resulted in the formation
Scheme 3. Reagents and conditions: (i) LiAlH
CH Cl , N (g) atm, 4 h; (b) NaH PO , NaClO
h, 60 % over three steps (including the reduction step); (iii) (a) cat. PdCl
CuCl ·2H O, DMF/H O, O (g) atm, r.t., 24 h, 70 %; (iv) BCl , CH Cl , N (g) atm,
78 °C → r.t., 65 %.
4
, THF, 0 °C, 4 h; (ii) (a) PCC, silica,
2
2
2
2
4
2
, H O, tBuOH, 2-methyl-2-butene,
2
[
17]
6
2
,
of the desired isocoumarin 9 (Figure 4c) in a yield of 72 %.
2
2
2
2
3
2
2
2
Oxidation of 9 with silver(II) oxide resulted in the formation of
the quinone 23. Finally, treatment of 23 with boron trichloride
at low temperature gave the final product, 5-methoxy-3,4-de-
–
Scheme 4. Reagents and conditions: (i) PIFA, MeOH, r.t., 15 min; (ii) NaOEt,
EtOH, r.t., 20 min 10 % 20, 52 % 21; or (iii) tBuOK, EtOH, r.t., 20 min., 60 %
(
(
over two steps from 18); (iv) K
a) LiAlH , THF, 0 °C, 4 h; (b) PCC, silica gel, 4 h, N
, H O, tBuOH, 2-methyl-2-butene, 6 h, 66 % (over 3 steps); (vi) cat.
, CuCl ·2H O, DMF/H O, O (g) atm, r.t., 24 h, 72 %; (vii) AgO, 55 % aq.
, 1,4-dioxane, r.t., 75 %; (viii) 2 mol. equiv. BCl
r.t., 20 %.
2
CO
3
, Me
2
SO
4
, Me
2
CO, reflux, 24 h, 83 %; (v)
4
2
(g) atm; (c) NaH PO
2
4
,
NaClO
PdCl
HNO
2
2
2
2
2
2
2
3
3
, CH
2
Cl
2
, N
2
(g) atm, –78 °C
Figure 4. a-c: ORTEP diagrams of compounds 20, 22 and 9 (displacement
ellipsoids at 50 % probability).
→
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hydrosemixanthomegnin 2 in a poor yield of 20 %. We suspect 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.
this was as a result of our purification method by using silica
gel chromatography.
Ethyl
3-allyl-4-hydroxy-6,8-dimethoxynaphthalene-2-carboxylate
[
10a]
11
[
10a]
Conclusion
Ethyl 4-(allyloxy)-6,8-dimethoxynaphthalene-2-carboxylate
4.00 g, 12.6 mmol) was loaded neat in a 100 mL round-bottomed
(
In summary, the synthesis of two related isocoumarin contain-
ing natural products has been accomplished. 9-O-methyl-
flask equipped with a reflux condenser and a magnetic stirring bar.
The flask was then heated to 180 C in a silicone oil bath for 24 h
paepalantine 5 was synthesized in twelve steps from 2,4-di- under a N (g) atmosphere. After 24 h, the dark viscous residue was
°
2
methoxybenzaldehyde in an overall yield of 6.2 %. Commenc- cooled to r.t., dissolved in acetone and adsorbed on silica gel. Purifi-
ing with 2,4,5-trimethoxybenzaldehyde the synthesis of 5-meth- cation of the crude product on silica gel column chromatography
(
20 % EtOAc/hexane) yielded ethyl 3-allyl-4-hydroxy-6,8-dimethoxy-
oxy-3,4-dehydrosemixanthomegnin 2 was accomplished in thir-
teen steps in an overall yield of 1.3 %. In each of these synthe-
ses, one of the key steps was a Wacker-mediated oxidation to
convert the aromatic carboxylic acids 6 and 7, bearing an ortho-
allyl substituent, to afford in good yields the isocoumarins 8
and 9 respectively.
naphthalene-2-carboxylate 11 as a yellow amorphous solid (2.75 g,
6
Me Si) δ 8.37 (1H, s, H-1), 7.04 (1H, s, H-5), 6.50 (1H, s, H-7), 6.25–
6
1
9 %). R = 0.41 (20 % EtOAc/hexane); H NMR (500 MHz, CDCl3,
f
4
H
.04 (1H, m, ArCH CH=CH ), 5.65 (1H, s, ArOH), 5.23 (1H, dd, J = 3.8,
2 2
1
.6, one of ArCH CH=CH ), 5.18 (1H, dd, J = 3.5, 1.6, one of
2
2
ArCH CH=CH ), 4.38 (2H, q, J = 7.1, ArCO CH CH ), 3.97 (3H, s,
2
2
2
2
3
ArOCH ), 3.94 (3H, s, ArOCH ), 3.92 (2H, d, J = 6.0, ArCH CH=CH ),
3
3
2
2
13
1
.42 (3H, t, J = 7.1, ArCOOCH CH ); C NMR (126 MHz, CDCl , Me Si)
2 3 3 4
Experimental Section
δ 168.3 (ArCO CH CH ), 160.1 (C-6), 157.2 (C-8), 149.7 (C-4), 136.4
C 2 2 3
(
1
ArCH CH=CH ), 128.4 (C-4a), 125.6 (C-2), 120.3 (C-8a), 118.8 (C-3),
2 2
Solvents utilized for chromatographic techniques (ethyl acetate and
n-hexane) were distilled prior to use by means of conventional dis-
tillation processes. The solvents employed in reactions were first
dried with the suitable drying agent, followed by distillation under
an inert atmosphere (argon or nitrogen gas). Acetonitrile and di-
chloromethane were distilled from calcium hydride, whereas tetra-
hydrofuran was distilled from sodium with benzophenone as an
18.5 (ArCH CH=CH ), 116.2 (C-1), 98.8 (C-7), 92.3 (C-5), 60.8 (Ar-
2 2
CO CH CH ), 55.6 (ArOCH ), 55.4 (ArOCH ), 31.8 (ArCH CH=CH ),
2
2
3
3
3
2
2
1
4.4 (ArCO CH CH ).
2 2 3
Ethyl 3-allyl-4-hydroxy-1,6,8-trimethoxynaphthalene-2-carboxylate
[
18]
1
3
To a solution of ethyl 3-allyl-4-hydroxy-6,8-dimethoxynaphthalene-
indicator. Toluene was distilled from sodium. All the required chemi- 2-carboxylate 11 (3.50 g, 11.1 mmol) in absolute MeOH (80 mL),
cals or reagents were obtained from FLUKA, SIGMA ALDRICH or
MERCK and were used without further purification.
was added solid phenyliodine(III) bis(trifluoroacetate (PIFA) (5.12 g,
11.9 mmol) and the reaction mixture was stirred for 15 min at r.t.
After the 15 min had elapsed, saturated aqueous NaHCO3 was
added to the reaction mixture portion-wise until effervescence
stopped and MeOH was removed in vacuo. The aqueous layer was
then extracted with EtOAc (3 × 100 mL) and the combined organic
Normal chromatography was performed with silica gel 60 (Ma-
cherey-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 Ma-
cherey-Nagel Alugram Silica G/UV254 plates pre-coated with
layer was dried with anhydrous MgSO , filtered through a celite
4
pad and concentrated under reduced pressure. The residue was
dissolved in EtOH in a clean 250 mL round-bottomed flask to which
tBuOK (3.32 g, 29.6 mmol) was added and the resultant reaction
mixture was vigorously stirred for 20 min at r.t. The reaction was
0
.25 mm silica gel 60. The TLC plates were viewed under UV light
(254 nm and 366 nm).
Nuclear magnetic resonance (NMR) spectra were recorded on either
a Bruker AVANCE 300 MHz or a Bruker AVANCE III 500 MHz spec-
trometer. 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).
quenched with saturated aqueous NH Cl (50 mL) and the resultant
4
mixture was concentrated under reduced pressure. The aqueous
medium was extracted with EtOAc (3 × 100 mL). The combined
organic layers were dried with anhydrous MgSO , filtered through
4
a celite pad and the solvents evaporated in vacuo. Purification of
the residue by column chromatography (20 % EtOAc/hexane) on
silica gel afforded ethyl 3-allyl-4-hydroxy-1,6,8-trimethoxynaphth-
alene-2-carboxylate 13 as a pale-orange semi-solid (2.31 g, 60 %).
X-ray Crystallography: All five data sets were collected using
ω-scans on a Bruker D8 Venture diffractometer with a PHOTON de-
tector.
1
R = 0.37 (20 % EtOAc/hexane); H NMR (300 MHz, CDCl , Me Si) δ
f
3
4
H
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 re-
7
.08 (1H, s, H-5), 6.53 (1H, s, H-7), 6.19–5.89 (1H, m, ArCH CH=CH ),
2 2
5
.56 (1H, s, ArOH), 5.25 (2H, d, J = 16.9, ArCH CH=CH ), 4.40 (2H, q,
2
2
J = 7.1, ArCO CH CH ), 3.87 (9H, two br d, 3 overlapping ArOCH ),
2
2
3
3
–
1
ported on the wavenumber scale (cm ).
3
.43 (2H, br s, ArCH CH=CH ), 1.38 (3H, t, J = 7.1, ArCO CH CH );
2
2
2
2
3
13
Melting points were determined on a Reichert hot-stage micro-
scope and remain uncorrected. All crystalline compounds were re-
crystallized from the appropriate solvents prior to melting point
determination. Microwave reactions were conducted in a CEM Dis-
cover microwave.
C NMR (75 MHz, CDCl
3
, Me
4
Si) δ
C
168.5 (ArCO
2
CH
2
CH
CH=CH
), 116.3 (C-8a), 115.2 (C-2),
CH ), 58.4 (ArOCH ), 56.0
CH=CH ), 14.3 (ArCO CH CH ).
Ethyl 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylate 14
3
), 158.8 (C-
6), 157.5 (C-8), 147.5 (C-1), 145.5 (C-4), 135.4 (ArCH
(C-4a), 124.7 (C-3), 117.2 (ArCH CH=CH
99.5 (C-7), 92.8 (C-5), 61.3 (ArCO CH
(ArOCH ), 55.3 (ArOCH ), 32.9 (ArCH
), 129.4
2
2
2
2
2
2
3
3
3
3
2
2
2
2
3
High-resolution mass spectra were obtained with a Waters-LCT-Pre-
mier mass spectrometer. The sample was dissolved in methanol to A mixture of ethyl 3-allyl-4-hydroxy-1,6,8-trimethoxynaphthalene-2-
a concentration of 2 ng/μL and introduced by direct infusion. The carboxylate 13 (2.30 g, 6.64 mmol), anhydrous K CO (1.17 g,
2
3
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8
.50 mmol) and Me SO (0.804 mL, 8.50 mmol) in acetone (100 mL)
were dissolved in DMF/H O mixture (2:1, v/v, 100 mL) in a 2-neck
2
4
2
was heated under reflux for 24 h under a N (g) atmosphere. The
round-bottomed flask to which PdCl (53.4 mg, 0.301 mmol) was
2
2
reaction mixture was then cooled to r.t., filtered through a celite
pad and the solvent removed in vacuo. The resultant residue was
added under the atmosphere of O (g). The reaction mixture was
vigorously stirred for 24 h at r.t. after which it was filtered through
2
dissolved in EtOAc (100 mL) and successively washed with 25 % a thick celite bed which was washed slowly with CH Cl (3 × 50
2
2
(
v/v) aqueous NH (2 × 50 mL). The EtOAc layer was then acidified
mL). The combined organic layers were washed with brine (3 × 50
3
to pH 4 with 32 % (v/v) aqueous HCl and the acidic solution was
mL) and dried with anhydrous MgSO , filtered through a pad of
4
washed with deionised H O until the aqueous layer was neutral.
celite and the solvent was removed in vacuo. Purification of the
crude residue by column chromatography (EtOAc/CH Cl /hexane,
2
The organic layer was dried with anhydrous MgSO , filtered through
4
2
2
a bed of celite and concentrated in vacuo. Purification of the residue
2:1:7) on silica gel afforded two compounds. The first compound
by silica gel column chromatography (10 % EtOAc/hexane) yielded was 5,7,9,10-tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-one
ethyl 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylate 14 as a
8,obtained as a light-yellow solid (0.467 g, 47 %). R = 0.38 (EtOAc/
f
–1
°
light-yellow solid (2.13 g, 89 %). R = 0.41 (20 % EtOAc/hexane); Mp
CH Cl /hexane, 3:1:6); Mp 154–156 C; IR v (cm ) 1689 (C=O),
2 2 max
f
°
1
1
7
8–80 C; H NMR (300 MHz, CDCl , Me Si) δ 6.98 (1H, d, J = 2.2,
1603 (C=C); H NMR (300 MHz, CDCl , Me Si) δ 6.98 (1H, d, J = 2.3,
3
4
H
3 4 H
H-5), 6.53 (1H, d, J = 2.2, H-7), 5.98 (1H, ddt, J = 16.4, 10.1, 6.2, H-6), 6.51 (1H, d, J = 2.3, H-8), 6.48 (1H, s, H-4), 3.99 (3H, s, ArOCH3),
ArCH CH=CH ), 5.07 (2H, dd, J = 3.7, 1.7, ArCH CH=CH ), 4.39 (2H, 3.97 (3H, s, ArOCH ), 3.96 (3H, s, ArOCH ), 3.90 (3H, s, ArOCH ), 2.27
2
2
2
2
3
3
3
q, J = 7.1, ArCO CH CH ), 3.94 (3H, s, ArOCH ), 3.90 (3H, s, ArOCH ),
(3H, s, CH3); 13C NMR (75 MHz, CDCl , Me Si) δ 161.4 (C-7), 160.0
2
2
3
3
3
3 4 C
3
.85 (6H, br s, two overlapping ArOCH ), 3.57 (2H, d, J = 6.2,
(C-1), 159.4 (C-9), 159.3 (C-10), 153.4 (C-3), 143.7 (C-5), 135.5 (C-5a),
126.6 (C-4a), 116.4 (C-9a), 108.6 (C-10a), 99.4 (C-8), 97.3 (C-6), 92.2
3
1
3
ArCH CH=CH ), 1.38 (3H, t, J = 7.1, ArCO CH CH ); C NMR (75 MHz,
2
2
2
2
3
CDCl , Me Si) δ 168.0 (ArCO CH CH ), 159.3 (C-6), 157.9 (C-8), 150.4 (C-4), 62.9 (ArOCH ), 61.6 (ArOCH ), 56.4 (ArOCH ), 55.5 (ArOCH ),
3
4
C
2
2
3
3
3
3
3
+
(
C-1 or C-4), 149.3 (C-1 or C-4), 136.3 (ArCH CH=CH ), 132.7 (C-4a),
26.6 (C-3), 125.1 (C-8a), 115.9 (ArCH CH=CH ), 115.3 (C-2), 99.2 (C- found [M + H] 331.1181. The second compound was (Z)-3-ethylid-
), 93.2 (C-5), 63.8 (ArCO CH CH ), 61.6 (ArOCH ), 61.1 (ArOCH ),
6.1 (ArOCH ), 55.3 (ArOCH ), 31.8 (ArCH CH=CH ), 14.3 (Ar- tained as a yellow crystalline solid (0.209 g, 21 %): R = 0.40 (EtOAc/
CO CH CH ); HRMS (m/z), calculated for [M + H] C H O 361.1646
found [M + H] 361.1649.
19.8 (CH ); HRMS (m/z), calculated for [M + H] C H O : 331.1176,
2
2
3 18 19 6
+
1
7
5
2 2
ene-4,6,8,9-tetramethoxynaphtho[2,3-c]furan-1(3H)-one 16,ob-
2
2
3
3
3
3
3
2
2
f
–1
+
°
CH Cl /hexane, 3:1:6); Mp 154–156 C); IR v (cm ) 1762 (C=O),
2
2
3
20 25
6
2 2 max
+
1
1679 (C=C); H NMR (300 MHz, CDCl , Me Si) δ 7.02 (1H, d, J = 2.3,
3 4 H
H-5), 6.56 (1H, d, J = 2.2, H-7), 5.92 (1H, q, J = 7.3, ArC=CHCH ), 4.06
3
1
,4,6,8-Tetramethoxy-3-((E)-prop-1-enyl)naphthalene-2-carboxylic
(
3H, s, ArOCH ), 3.98 (3H, s, ArOCH ), 3.97 (3H, s, ArOCH ), 3.91 (3H,
3 3 3
acid 15
13
s, ArOCH ), 2.04 (3H, d, J = 7.3, ArC=CHCH ); C NMR (75 MHz,
3
3
To a solution of ethyl 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-
carboxylate 14 (2.10 g, 5.83 mmol) in MeOH (100 mL) was added
an aqueous solution of NaOH (0.933 g, 23.32 mmol) in H O (50 mL)
and the resultant reaction mixture was heated under reflux for 36 h.
To this reaction mixture, an aqueous solution of KOH (1.59 g,
CDCl , Me Si) δ 164.8 (C-1), 161.3 (C-6), 160.1 (C-8), 155.4 (C-9),
3
4
C
144.5 (C-3), 143.8 (C-4), 137.0 (C-4a), 125.4 (C-3a), 117.5 (C-8a), 111.2
2
(C-9a), 106.8 (ArC=CHCH ), 99.9 (C-7), 93.1 (C-5), 63.4 (ArOCH ), 59.9
3
3
(
ArOCH ), 56.3 (ArOCH ), 55.5 (ArOCH ), 11.7 (ArC=CHCH ); HRMS
3 3 3 3
+
+
(m/z), calculated for [M + H] C H O : 331.1176, found [M + H]
18 19 6
2
8.3 mmol) in H O (50 mL) was added portion-wise and the result-
2
331.1174.
ant mixture was again heated under reflux for 48 h (monitored
by TLC). The mixture was then cooled to r.t. and the solvent was
concentrated under reduced pressure. The remaining aqueous me-
dium was carefully acidified to pH 4.0 with 32 % (v/v) aqueous HCl
and extracted with EtOAc (3 × 150 mL). The combined organic layer
Allyl-1,4,6,8-tetramethoxynaphthalene-2-carboxylic acid 6
To a solution of ethyl 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-
carboxylate 14 (4.20 g, 10.76 mmol) in dry THF (200 mL), cooled to
0
°C in an ice bath, LiAlH (0.569 g, 15.0 mmol) was added portion-
4
wise over a period of 10 min. The reaction mixture was warmed to
was dried with anhydrous MgSO , filtered through a celite bed and
4
r.t. and stirred for a further 4 h under an N (g) atmosphere. The
concentrated in vacuo. The residue was purified by column chroma-
tography (20 % EtOAc/hexane). The isolated product was then dis-
solved in hot solution of 20 % EtOAc/hexane and allowed to slowly
crystallize yielding 1,4,6,8-tetramethoxy-3-((E)-prop-1-enyl)naphth-
2
°
mixture was again cooled to 0 C in an ice bath and cold H O was
2
added dropwise until effervescence stopped. A 32 % (v/v) aqueous
HCl (10 mL) was then added and the resultant mixture was filtered
through a thick celite bed and the THF was removed in vacuo. The
aqueous medium was extracted with EtOAc (3 × 100 mL) and the
combined organic layer was dried with anhydrous MgSO , filtered
through a celite bed and concentrated under reduced pressure. The
thick brown residue was carried forward without further purification
alene-2-carboxylic acid 15 as white crystals (1.07 g, 55 %). R = 0.26
f
°
–1
(
1
40 % EtOAc/hexane). Mp 138–140 C; IR v
(cm ) 3680 (O-H),
681 (C=O), 1545 (C=C); H NMR (300 MHz, MeOD) δ 7.05 (1H, d,
max
1
4
H
J = 2.3, H-5), 6.63 (1H, d, J = 2.2, H-7), 6.57 (1H, dq, J = 16.1, 1.5,
ArCH=CHCH ), 6.41 (1H, dq, J = 16.1, 6.3, ArCH=CHCH ), 3.96 (3H, s,
3
3
apart from noting the difference in R value compared to the start-
ArOCH ), 3.92 (3H, s, ArOCH ), 3.82 (3H, s, ArOCH ), 3.79 (3H, s,
f
3
3
3
1
3
ing material. The presumed alcohol intermediate 17 was dissolved
ArOCH ), 1.93 (3H, dd, J = 6.4, 1.4, ArCH=CHCH ); C NMR (75 MHz,
3
3
in CH Cl (200 mL) and silica gel (2.00 g) was added followed by
MeOD) δ 170.7 (ArCO H), 159.6 (C-6), 157.6 (C-8), 149.1 (C-1 or C-4),
2
2
C
2
PCC (4.31 g, 20.0 mmol) in two portions. The reaction mixture was
1
48.8 (C-1 or C-4), 132.4 (ArCH=CHCH ), 131.5 (C-4a), 124.5 (ArCH=
3
stirred under N (g) atmosphere for 4 h as monitored by TLC. After
CHCH ), 124.3 (C-2), 123.7 (C-3), 114.8 (C-8a), 99.2 (C-7), 92.9 (C-5),
2
3
the starting material was completely consumed, the reaction mix-
ture was filtered through a bed of celite and the filtrate was concen-
trated in vacuo. The resultant viscous brown oil was taken to the
next step without further purification. The crude intermediate was
6
2.7 (ArOCH ), 59.5 (ArOCH ), 55.1 (ArOCH ), 54.4 (ArOCH ), 18.2
3 3 3 3
+
(ArCH=CHCH ); HRMS (m/z), calculated for [M + H] C H O :
3 18 21 6
+
3
33.1333, found [M + H] 333.1336.
5
,7,9,10-Tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-one 8
dissolved in 2-methyl-2-butene (113 mL) to which H O (150 mL),
2
and (Z)-3-ethylidene-4,6,8,9-tetramethoxynaphtho[2,3-c]furan-
1
tBuOH (150 mL), NaClO (5.43 g, 60.0 mmol) and NaH PO (7.20 g,
2
2
4
(3H)-one 16
60.0 mmol) were added. The biphasic mixture was stirred rapidly
1
,4,6,8-Tetramethoxy-3-((E)-prop-1-enyl)naphthalene-2-carboxylic
for 6 h after which the layers were separated, and the aqueous
acid 15 (1.00 g, 3.01 mmol) and CuCl ·2H O (0.597 g, 3.50 mmol) layer was further extracted with CH Cl (3 × 100 mL). The combined
2
2
2
2
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5
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
organic layers were dried with anhydrous MgSO , filtered and con-
(ArOCH ), 56.4 (ArOCH ), 19.8 (C-3′); HRMS (m/z), calculated for
4
3
+
3
+
centrated in vacuo. The residue was purified by silica gel column
chromatography. The isolated product was recrystallized from a hot
solution (20 % EtOAc/hexane) to afford allyl-1,4,6,8-tetramethoxy-
[M + H] C H O : 317.1020 found [M + H] 317.1021.
17 17 6
Ethyl 4-(allyloxy)-5,6,8-trimethoxynaphthalene-2-carboxylate[14]
naphthalene-2-carboxylic acid 6 as white crystals (2.34 g, 60 %). R =
To a solution of ethyl 4-hydroxy-5,6,8-trimethoxynaphthalene-2-
f
°
–1
[17]
0
.26 (40 % EtOAc/hexane); Mp 138–140 C; IR v
(cm ) 3680 (O-
carboxylate (3.80 g, 12.4 mmol) in acetone (100 mL) was added
max
1
H), 1681 (C=O), 1545 (C=C); H NMR (300 MHz, CDCl , Me Si) δ
anhydrous K
(1.81 g, 15.0 mmol). The reaction mixture was heated under reflux
H-7), 6.01 (1H, ddt, J = 16.3, 10.1, 6.2, ArCH CH=CH ), 5.12 (2H, dd, for 24 h under a N (g) atmosphere. After this time had elapsed, the
J = 2.8, 1.7, ArCH CH=CH ), 3.97 (3H, s, ArOCH ), 3.94 (3H, s, reaction mixture was cooled to r.t., filtered through a celite pad and
CO (2.07 g, 15.0 mmol) followed by allyl bromide
2 3
3
4
H
1
0.82 (1H, s, ArCO H), 7.00 (1H, d, J = 2.3, H-5), 6.55 (1H, d, J = 2.3,
2
2
2
2
2
2
3
ArOCH ), 3.91 (3H, s, ArOCH ), 3.87 (3H, s, ArOCH ), 3.69 (2H, d, J =
the solvent evaporated in vacuo. The residue was purified by silica
3
3
3
13
6
.2, ArCH CH=CH ); C NMR (75 MHz, CDCl , Me Si) δ 172.3 (Ar- gel column chromatography (10 % EtOAc/hexane) yielding ethyl 4-
CO H), 159.7 (C-6), 158.0 (C-8), 150.9 (C-4), 149.5 (C-1), 136.3 (allyloxy)-5,6,8-trimethoxynaphthalene-2-carboxylate as a yellow
2 2 3 4 C
2
1
(
ArCH CH=CH ), 133.1 (C-2), 126.9 (C-4a), 123.5 (C-3), 116.1
amorphous solid (3.82 g, 89 %). R
NMR (300 MHz, CDCl , Me Si) δ
d, J = 1.4, H-3), 6.67 (1H, s, H-7), 6.20 (1H, ddt, J = 17.1, 10.4, 5.1,
CH=CH ), 5.60 (1H, dd, J = 17.2, 1.6, one of ArOCH CH=CH ),
5.33 (1H, dd, J = 10.5, 1.4, one of ArOCH CH=CH ), 4.71 (2H, d, J =
.1, ArOCH CH=CH ), 4.41 (2H, q, J = 7.1, ArCO CH CH ), 3.98 (3H,
f
= 0.56 (20 % EtOAc/hexane); H
2
2
(
ArCH CH=CH ), 115.2 (C-8a), 99.5 (C-7), 93.4 (C-5), 64.1 (ArOCH ),
3
4
H
8.56 (1H, d, J = 1.5, H-1), 7.43 (1H,
2
2
3
6
1.6 (ArOCH ), 56.1 (ArOCH ), 55.4 (ArOCH ), 31.6 (ArCH CH=CH );
3 3 3 2 2
HRMS (m/z), calculated for [M + H] C H O : 333.1333, found [M ArOCH
+
1
8 21 6
2
2
2
2
+
+
H] 333.1332.
2
2
5
2
2
2
2
3
5
,7,9,10-Tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-one 8
s, OCH ), 3.96 (3H, s, OCH ), 3.82 (3H, s, OCH ), 1.43 (3H, t, J = 7.1,
3
3
3
1
3
ArCO CH CH ); C NMR (75 MHz, CDCl , Me Si) δ 167.1 (Ar-
2
2
3
3
4
C
In a 2-neck round-bottomed flask equipped with a magnetic stirring
bar and charged with 3-allyl-1,4,6,8-tetramethoxynaphthalene-2-
carboxylic acid 6 (2.00 g, 6.02 mmol) and CuCl ·2H O (1.53 g,
CO CH CH ), 153.4 (C-8), 149.3 (C-4), 136.4 (C-6), 126.6 (ArOCH CH=
2
2
3
2
CH ), 124.4 (C-5), 121.9 (C-2), 120.5 (C-8a), 116.5 (C-4a), 110.4 (C-1),
2
2
2
1
07.3 (ArOCH CH=CH ), 105.0 (C-3), 99.6 (C-7), 63.9 (ArOCH CH=
2
2
2
9
.00 mmol) in DMF/H O mixture (2:1 v/v, 100 mL), was added PdCl2
2
CH ), 61.4 (ArCO CH CH ), 56.1 (ArOCH ), 55.3 (ArOCH ), 52.1
2
2
2
3
3
3
(
0.107 g, 0.602 mmol) under an atmosphere of O (g) and the mix-
2
(
ArOCH ), 14.3 (ArCO CH CH ).
3 2 2 3
ture was stirred vigorously for 24 h at r.t. The reaction mixture was
then filtered through a thick celite pad and the pad was washed
Ethyl 3-allyl-4-hydroxy-5,6,8-trimethoxynaphthalene-2-carboxylate
[
14]
with CH Cl2 (3 × 100 mL). The combined organic layers were
18
Ethyl 4-(allyloxy)-5,6,8-trimethoxynaphthalene-2-carboxylate
4.00 g, 11.5 mmol) was loaded neat into a 100 mL round-bottomed
2
washed with brine (3 × 100 mL), dried with anhydrous MgSO , fil-
4
tered and the solvent was removed in vacuo. The residue was ad-
sorbed onto silica gel and purification was accomplished using flash
silica gel column chromatography (EtOAc/hexane/CH Cl , 2:1:7) to
(
flask equipped with a reflux condenser and a magnetic stirring bar.
The flask was heated to 180 °C in silicone oil bath for 24 h under a
2
2
afford 5,7,9,10-tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-
N (g) atmosphere. The dark viscous residue was cooled to 35 °C,
1
2
one 8 as a cream crystalline solid (1.39 g, 70 %). The H NMR and
dissolved in acetone (20 mL) and adsorbed on silica gel. Purification
by silica gel column chromatography (10 % EtOAc/hexane) yielded
ethyl 3-allyl-4-hydroxy-5,6,8-trimethoxynaphthalene-2-carboxylate
13
C NMR spectra were the same as those outlined previously.
9
5
-O-Methylpaepalantine 5
1
8 as a yellow amorphous solid (2.83 g, 71 %). R = 0.42 (20 %
f
1
,7,9,10-Tetramethoxy-3-methyl-1H-benzo[g]isochromen-1-one 8
EtOAc/hexane); H NMR (300 MHz, CDCl , Me Si) δ 10.09 (1H, s,
3
4
H
(
0.400 g, 1.21 mmol) was dissolved in a freshly distilled CH Cl (100
ArOH), 8.19 (1H, s, H-1), 6.48 (1H, s, H-7), 6.10 (1H, ddt, J = 16.1,
10.1, 6.0, ArCH CH=CH ), 5.04 (2H, dt, J = 15.9, 1.9, ArCH CH=CH ),
2
2
mL) in a 2-neck round-bottomed flask fitted with a rubber septum
and cooled to –78 °C under an N (g) atmosphere. BCl (2.40 mL,
2
2
2
2
2
3
4.37 (2H, q, J = 7.1, ArCO CH CH ), 3.98 (3H, s, OCH ), 3.92 (3H, s,
2
2
3
3
2
.40 mmol) was slowly added to the solution via a syringe and the
OCH ), 3.91–3.84 (5H, m, one of the OCH and ArCH CH=CH ), 1.41
3 3 2 2
°
C
13
reaction mixture was stirred for a further 40 min at –78 . The
mixture was then warmed to r.t. and stirred at this temperature for 168.1 (ArCO CH CH ), 153.7 (C-8), 151.0 (C-4), 149.1 (C-6), 137.4
(3H, t, J = 7.1, ArCO CH CH ); C NMR (75 MHz, CDCl , Me Si) δ
2 2 3 3 4 C
2
2
3
2
–
h. After the 2 h had elapsed, the mixture was again cooled to
78 °C and BCl3 (2.40 mL, 2.40 mmol) was slowly added to the
(ArCH CH=CH ), 135.7 (C-5), 127.7 (C-2), 120.9 (C-8a), 119.9 (C-4a),
2 2
119.4 (ArCH CH=CH ), 116.4 (C-3), 114.4 (C-1), 94.7 (C-7), 62.1 (Ar-
2
2
solution for the second time using a syringe. The reaction mixture
CO CH CH ), 60.8 (ArOCH ), 56.8 (ArOCH ), 55.7 (ArOCH ), 30.1
2 2 3 3 3 3
°
was stirred for a further 40 min at –78 C. Thereafter, it was warmed
(ArCH CH=CH ), 14.4 (ArCO CH CH ).
2 2 2 2 3
to r.t. and stirred at this temperature for 2 h. The reaction was then
Ethyl 3-allyl-4-hydroxy-1,5,6,8-tetramethoxynaphthalene-2-carb-
oxylate 21 and ethyl 3-allyl-3,4-dihydro-3,5,6,8-tetramethoxy-4-oxo-
naphthalene-2-carboxylate 20
carefully quenched with ice cold H O (50 mL) and extracted with
2
CH Cl (3 × 100 mL). The combined organic layers were dried with
2
2
anhydrous MgSO , filtered through a celite bed and concentrated
4
under reduced pressure. Purification of the residue by column chro-
To a solution of ethyl 3-allyl-4-hydroxy-5,6,8-trimethoxynaphth-
matography on silica gel (20 % EtOAc/hexane) afforded 9-O-methyl- alene-2-carboxylate 18 (3.00 g, 8.66 mmol) in absolute MeOH (80
paepalantine 5 as a yellow amorphous solid (0.249 g, 65 %). R = mL) in a 250 mL round-bottomed flask, PIFA (3.96 g, 9.20 mmol)
f
°
–1
0
3
.43 (3:2:5 EtOAc/hexane/CH Cl ); Mp 197–199 C; IR v
(cm ) was added in one portion and the reaction mixture was stirred for
580 (O-H), 1701 (C=O), 1620 (C=C); H NMR (300 MHz, CDCl ,
2
2
max
1
15 min at r.t. Saturated aqueous NaHCO (50 mL) was added por-
3
3
Me Si) δ 12.79 (1H, s, H-10), 6.86 (1H, d, J = 2.0, H-6), 6.44 (1H, s,
tion-wise until effervescence stopped and the MeOH was removed
in vacuo to leave an aqueous medium. The aqueous layer was ex-
tracted with EtOAc (3 × 100 mL) and the combined organic layers
4
H
H-4), 6.40 (1H, d, J = 2.0, H-8), 3.96 (3H, s, ArOCH ), 3.92 (3H, s,
3
1
3
ArOCH ), 3.81 (3H, s, ArOCH ), 2.24 (3H, s, H-3′); C NMR (75 MHz,
3
3
CDCl , Me Si) δ 160.0 (C-1), 161.4 (C-7), 159.4 (C-9), 159.3 (C-10),
were dried with anhydrous MgSO , filtered through a celite pad and
3
4
C
4
1
53.4 (C-3), 143.7 (C-5), 135.5 (C-5a), 126.6 (C-4a), 116.4 (C-9a), 108.6
concentrated under reduced pressure. The residue was then treated
with a 21 % (w/v) ethanolic solution of NaOEt (11.0 mL, 34.0 mmol)
(
C-10a), 99.4 (C-8), 97.3 (C-6), 92.2 (C-4), 62.9 (ArOCH ), 61.6
3
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6
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Full Paper
with vigorous stirring for 20 min at r.t. Saturated aqueous NH Cl
diate, ethyl 3-allyl-4-hydroxy-1,5,6,8-tetramethoxynaphthalene-2-
4
(50 mL) was added to the reaction and the resultant mixture was
carboxylate 21 (2.80 g, 7.44 mmol) and anhydrous K CO (1.55 g,
2
3
evaporated at reduced pressure to leave the aqueous medium
which was extracted with EtOAc (3 × 100 mL). The combined or-
11.2 mmol) in acetone (100 mL) in a 250 mL round-bottomed flask.
The mixture was then heated under reflux for 24 h after which it
was cooled to r.t., filtered through a bed of celite and the solvent
was removed in vacuo. The residue was dissolved in EtOAc (100
ganic layers were dried with anhydrous MgSO , filtered through a
4
celite pad and concentrated in vacuo. Purification of the residue by
silica gel column chromatography (20 % EtOAc/hexane) afforded mL) and successively washed with 25 % (v/v) aqueous NH (2 × 100
3
two compounds. The first compound was ethyl 3-allyl-4-hydroxy- mL) after which it was acidified to pH 4 using 32 % (v/v) aqueous
1
,5,6,8-tetramethoxynaphthalene-2-carboxylate 21 which was ob-
HCl. The organic layers were then washed with H O until the aque-
2
tained as an orange amorphous solid (1.70 g, 52 %). Compound 21
was characterised by H NMR and C NMR spectroscopy, as de- filtered through a bed of celite and concentrated in vacuo. Purifica-
ous layer was neutral. It was then dried with anhydrous MgSO4,
1
13
scribed in the next experimental procedure.
tion of the crude product by silica gel column chromatography
10 % EtOAc/hexane) yielded ethyl 3-allyl-1,4,5,6,8-pentamethoxy-
(
The second product was ethyl 3-allyl-3,4-dihydro-3,5,6,8-tetra-
methoxy-4-oxonaphthalene-2-carboxylate 20 which was obtained
naphthalene-2-carboxylate 22 as a yellow oil (2.41 g, 83 %). R =
f
1
0
.53 (20 % EtOAc/hexane); H NMR (300 MHz, CDCl , Me Si) δ 6.73
3
4
H
as yellow crystals (0.326 g, 10 %). R = 0.40 (20 % EtOAc/hexane); IR
f
(
1H, s, H-7), 5.98 (1H, ddt, J = 16.4, 10.1, 6.2, ArCH CH=CH ), 5.13–
–1
°
1
2 2
vmax(cm ) 1708 (C=O), 1698 (C=C), 1625 (C=C); Mp 63–65 C; H
NMR (300 MHz, CDCl , Me Si) δ 8.09 (1H, s, H-1), 6.70 (1H, s, H-7),
4
.98 (2H, m, ArCH CH=CH ), 4.39 (2H, q, J = 7.1, ArCO CH CH ), 4.01
2 2 2 2 3
3
4
H
(
3H, s, ArOCH ), 3.98 (3H, s, ArOCH ), 3.82 (3H, s, ArOCH ), 3.78 (3H,
3 3 3
5
.59 (1H, ddt, J = 17.4, 10.1, 7.4, ArCH CH=CH ), 5.06–4.85 (2H, m,
2 2
s, ArOCH ), 3.77 (3H, s, ArOCH ), 3.57 (2H, dt, J = 6.2, 1.5, ArCH CH=
3
3
2
ArCH CH=CH ), 4.46–4.24 (2H, m, ArCO CH CH ), 3.94 (3H, s,
2
2
2
2
3
13
CH ), 1.39 (3H, t, J = 7.1, ArCO CH CH ); C NMR (75 MHz, CDCl3,
2
2
2
3
ArOCH ), 3.93 (3H, s, ArOCH ), 3.84 (3H, s, ArOCH ), 3.15 (3H, s, OCH
3
3
3
3
Me Si) δ 168.0 (ArCO CH CH ), 153.7 (C-8), 150.9 (C-1), 145.0 (C-6),
4
C
2
2
3
attached to C-3), 3.00–2.79 (2H, m, ArCH CH=CH ), 1.37 (3H, t, J =
2
2
1
49.2 (C-4), 136.7 (ArCH CH=CH ), 136.6 (Ar-C), 127.6 (Ar-C), 126.4
13
2 2
7
1
1
.1, ArCO CH CH ); C NMR (75 MHz, CDCl , Me Si) δ 198.3 (C-4),
2 2 3 3 4 C
(Ar-C), 125.7 (Ar-C), 116.0 (Ar-C), 115.7 (Ar-C), 97.1 (C-7), 63.8 (Ar-
65.5 (ArCO CH CH ), 156.2 (C-6), 153.3 (C-8), 143.1 (C-5), 132.4 (C-
2
2
3
CO CH CH ), 62.7 (ArOCH ), 62.1 (ArOCH ), 61.2 (ArOCH ), 56.9
2
2
3
3
3
3
), 131.3 (ArCH CH=CH ), 129.1 (C-2), 125.5 (C-4a), 118.9 (ArCH CH=
2
2
2
(
ArOCH ), 56.8 (ArOCH ), 31.6 (ArCH CH=CH ), 14.2 (ArCO CH CH );
3 3 2 2 2 2 3
CH ), 116.0 (C-8a), 101.4 (C-7), 84.9 (C-3), 61.6 (ArOCH , attached to
2
3
+
HRMS (m/z), calculated for [M + H] C H O : 391.1751, found [M
+
21 27 7
C-5), 60.8 (ArCO CH CH ), 56.4 (ArOCH ), 56.3 (ArOCH ), 53.7 (OCH
2
2
3
3
3
3
+
H] 391.1750.
attached to C-3), 43.3 (ArCH CH=CH ), 14.4 (ArCO CH CH ); HRMS
2
2
2
2
3
+
+
3-Allyl-1,4,5,6,8-pentamethoxynaphthalene-2-carboxylic acid 7
(
m/z), calculated for [M + H] C H O : 377.1595, found [M + H]
2
0 25 7
3
77.1591.
To a solution of ethyl 3-allyl-1,4,5,6,8-pentamethoxynaphthalene-2-
carboxylate 22 (2.10 g, 5.38 mmol) in dry THF (100 mL) cooled to
Ethyl 3-allyl-1,4,5,6,8-pentamethoxynaphthalene-2-carboxylate 22
°
0
C in an ice bath, LiAlH (0.486 g, 12.8 mmol) was added portion-
4
To a solution of ethyl 3-allyl-4-hydroxy-5,6,8-trimethoxynaphth- wise over a period of 5 min. The reaction mixture was warmed to
alene-2-carboxylate 18 (4.50 g, 13.0 mmol) in absolute MeOH (100
mL) in a 250 mL round-bottomed flask, PIFA (5.81 g, 13.5 mmol)
was added and the reaction was stirred for 15 min at r.t. A saturated
r.t. and stirred for a further 4 h under a N (g) atmosphere. After this
time had elapsed, the mixture was cooled to 0 °C for a second
2
time and cold H O was added portion-wise until the effervescence
2
aqueous NaHCO solution was added to the mixture until efferves- stopped. The resultant mixture was filtered through a thick celite
3
cence stopped and MeOH was removed in vacuo to leave an aque-
ous medium. This medium was then extracted with EtOAc (3 × 100
mL). The combined organic layers were dried with anhydrous
bed and the THF was removed in vacuo. The aqueous medium was
extracted with EtOAc (3 × 100 mL) and the combined organic layers
were dried with anhydrous MgSO , filtered through a bed of celite
4
MgSO , filtered through a celite pad and concentrated under re-
duced pressure. The residue was then dissolved in ethanol (200 mL)
and concentrated under reduced pressure. Purification of the resi-
due on silica gel column chromatography yielded 3-allyl-1,4,5,6,8-
4
and tBuOK (3.41 g, 30.4 mmol) was added with vigorous stirring for pentamethoxynaphthalen-2-yl)methanol (3.09 g, 80 %). R = 0.42
f
°
–1
20 min at r.t. The reaction was quenched by saturated aqueous
(30 % EtOAc/hexane); Mp 122–123 C; IR vmax(cm ) 3481 (O-H),
1580 (C=C); H NMR (300 MHz, CDCl , Me Si) δ 6.73 (1H, s, H-7),
1
solution NH Cl (50 mL) and the resultant mixture was evaporated
4
3
4
H
under reduced pressure to leave an aqueous medium. This medium
was extracted with EtOAc (3 × 100 mL) and the combined organic
6.14 (1H, ddt, J = 17.1, 10.5, 5.4, ArCH CH=CH ), 5.06 (1H, ddd, J =
2 2
17.1, 10.2, 1.7, one of ArCH CH=CH ), 4.95 (1H, ddd, J = 15.4, 3.4,
2
2
layers were dried with anhydrous MgSO , filtered through a celite
1.6, one of ArCH CH=CH ), 4.81 (2H, s, ArCH OH), 4.01 (3H, s,
4
2 2 2
pad and concentrated in vacuo. Purification of the crude product
ArOCH ), 4.00 (3H, s, ArOCH ), 3.84 (3H, s, ArOCH ), 3.79 (3H, s,
3 3 3
by silica gel column chromatography (15 % EtOAc/hexane) deliv- ArOCH ), 3.78–3.72 (5H, m, ArOCH , and ArCH CH=CH ), 2.46 (1H,
3
3
2
2
13
ered ethyl 3-allyl-4-hydroxy-1,5,6,8-tetramethoxynaphthalene-2- br s, ArCH OH); C NMR (75 MHz, CDCl , Me Si) δ 153.3 (C-8),
2
3
4
C
carboxylate 21 as an orange amorphous solid (2.94 g, 60 %). R =
151.9 (C-10), 150.3 (C-4), 149.3 (C-6), 138.3 (Ar-C), 136.7 (ArCH CH=
f
2
1
0
1
6
.46 (25 % EtOAc/hexane). H NMR (300 MHz, CDCl , Me Si) δ
0.20 (1H, s, ArOH), 6.64 (1H, s, H-7), 6.01 (1H, ddt, J = 16.4, 10.0, 115.3 (Ar-C), 97.1 (C-7), 63.2 (ArOCH ), 62.6 (ArOCH ), 62.0 (ArOCH ),
CH ), 130.3 (Ar-C), 128.6 (Ar-C), 125.8 (Ar-C), 116.4 (ArCH CH=CH ),
3
4
H
2
2
2
3
3
3
.3, ArCH CH=CH ), 5.16–4.96 (2H, m, ArCH CH=CH ), 4.40 (2H, q, 57.4 (ArCH OH), 56.9 (ArOCH ), 56.8 (ArOCH ), 30.4 (ArCH CH=CH ).
2
2
2
2
2
3
3
2
2
J = 7.1, ArCO CH CH ), 3.98 (3H, s, ArOCH ), 3.96 (3H, s, ArOCH ),
To a solution of majority of the 3-allyl-1,4,5,6,8-pentamethoxynaph-
thalen-2-yl)methanol (3.00 g, 8.61 mmol) in CH Cl (150 mL), flash
silica gel (1.50 g) and PCC (3.64 g, 16.9 mmol) were added portion-
2
2
3
3
3
3
.96 (3H, s, ArOCH ), 3.79 (3H, s, ArOCH ), 3.46 (2H, dt, J = 6.3, 1.4,
3
3
2
2
1
3
ArCH CH=CH ), 1.39 (3H, t, J = 7.1, ArCO CH CH ); C NMR (75 MHz,
2
2
2
2
3
CDCl , Me Si) δ 168.07 (ArCO CH CH ), 154.0 (C-8), 148.2 (C-1),
wise and the reaction mixture was stirred under N (g) atmosphere
3
4
C
2
2
3
2
1
47.1 (C-6), 145.5 (C-4), 136.5 (ArCH CH=CH ), 135.9 (Ar-C), 126.7
for 4 h. After the starting material was completely consumed (moni-
tored by TLC), the reaction mixture was filtered through a bed of
celite and the filtrate was concentrated in vacuo. The resultant vis-
2
2
(Ar-C), 120.1 (Ar-C), 118.0 (Ar-C), 115.2 (Ar-C), 115.2 (Ar-C), 96.8 (C-
7
5
), 63.8 (ArCO CH CH ), 62.3 (ArOCH ), 61.1 (ArOCH ), 56.9 (ArOCH ),
2 2 3 3 3 3
6.7 (ArOCH ), 31.5 (ArCH CH=CH ), 14.3 (ArCO CH CH ). Dimethyl- cous oil was taken to the next step without further purification
3
2
2
2
2
3
sulfate (1.06 mL, 11.2 mmol) was added to a solution of the interme-
apart from noting the difference in R value to the starting material.
f
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
7
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
The crude intermediate was dissolved in 2-methyl-2-butene (113 anhydrous MgSO , filtered through a celite bed and concentrated
4
mL) in a 500 mL round-bottomed flask to which H O (187 mL), under reduced pressure. Purification of the residue on silica gel col-
2
tBuOH (169 mL), NaClO (2.71 g, 30.0 mmol) and NaH PO (3.60 g,
umn chromatography (EtOAc/hexane/CH Cl ) afforded 5,7,10-tri-
2
2
4
2 2
3
0.0 mmol) were added. The biphasic mixture was stirred rapidly
methoxy-3-methyl-1H-benzo[g]isochromene-1,6,9-trione 23 as an
for 6 h after which the layers were separated, and the aqueous
layer was further extracted with CH Cl (3 × 100 mL). The combined
orange amorphous solid (1.10 g, 75 %). R = 0.40 (EtOAc/CH Cl /
f
–1
2
2
°
hexane, 4:2:4); Mp 220–222 C; IR v (cm ) 1788 (C=O), 1762 (C=
2
2
max
1
organic layers were dried with MgSO , filtered through a celite bed
O), 1712 (C=C), 1693 (C=C), 1606 (C=C); H NMR (300 MHz, CDCl ,
4
3
and concentrated in vacuo. The residue was purified by silica gel
column chromatography (30 % EtOAc/hexane) and the isolated
Me Si) δ 6.66 (1H, s, H-8), 6.12 (1H, s, H-4), 4.02 (3H, s, ArOCH ),
4
H
3
1
3
3.93 (3H, s, ArOCH ), 3.88 (3H, s, ArOCH ), 2.34 (3H, s, H-3′); C NMR
3
3
product was re-crystallized from a hot 20 % EtOAc/hexane solution (126 MHz, CDCl , Me Si) δ 182.4 (C=O), 178.9 (C=O), 159.3 (Ar-C),
3
4
C
affording 3-allyl-1,4,5,6,8-pentamethoxynaphthalene-2-carboxylic
159.1 (Ar-C), 159.0 (Ar-C), 157.4 (Ar-C), 151.0 (Ar-C), 141.2 (Ar-C),
127.7 (Ar-C), 123.4 (Ar-C), 119.4 (Ar-C), 111.6 (C-4), 97.8 (C-8), 63.0
(ArOCH ), 62.8 (ArOCH ), 56.5 (ArOCH ), 20.2 (CH ); HRMS (m/z), cal-
acid 7 as white crystals (2.06 g, 66 %). R = 0.21 (50 % EtOAc/hex-
f
°
–1
ane); Mp 140–142 C; IR v
(
(cm ) 3680 (O-H), 1692 (C=O), 1637
C=C); H NMR (300 MHz, CDCl , Me Si) δ 10.80 (1H, s, ArCO H),
max
3
3
3
3
1
+
+
culated for [M + H] C H O : 331.0812, found [M + H] 331.0814.
3
4
H
2
17 15 7
6
5
1
.76 (1H, s, H-7), 6.04 (1H, ddt, J = 16.3, 10.1, 6.2, ArCH CH=CH ),
2 2
-Methoxy-3,4-dehydrosemixanthomegnin 2[19]
5
.14 (1H, dd, J = 13.8, 1.7, one of ArCH CH=CH ), 5.10 (1H, dd, J =
2
2
3.8, 1.6, one of ArCH CH=CH ), 4.02 (3H, s, ArOCH ), 4.00 (3H, s,
5,7,10-Trimethoxy-3-methyl-1H-benzo[g]isochromene-1,6,9-trione
23 (0.334 g, 1.01 mmol) was dissolved in a freshly distilled CH Cl
(50 mL) in a 150 mL 2-neck round-bottomed flask fitted with a
2
2
3
ArOCH ), 3.90 (3H, s, ArOCH ), 3.81 (3H, s, ArOCH ), 3.80 (3H, s,
ArOCH ), 3.70 (2H, d, J = 6.2, ArCH CH=CH ); C NMR (75 MHz,
CDCl , Me Si) δ 172.4 (ArCO H), 153.8 (C-8), 151.3 (C-10), 150.3 (Ar- rubber septum. The reaction flask was cooled to –78 C under a
2
2
3
3
3
1
3
3
2
2
°
3
4
C
2
C), 149.3 (Ar-C), 136.6 (ArCH CH=CH ), 127.6 (Ar-C), 126.6 (Ar-C),
blanket of N (g) atmosphere and BCl (2.02 mL, 2.02 mmol) was
2 3
2
2
1
24.3 (Ar-C), 116.0 (ArCH CH=CH ), 115.8 (Ar-C), 97.3 (H-7), 63.9
slowly added to the solution using a syringe. The reaction mixture
was stirred for a further 40 min at –78 C and was then warmed to
r.t. The mixture was stirred at this temperature for 2 h after which
2
2
°
(
(
ArOCH ), 62.7 (ArOCH ), 62.0 (ArOCH ), 56.9 (ArOCH ), 56.8
ArOCH ), 31.4 (ArCH CH=CH ); HRMS (m/z), calculated for [M + H]
3
3
3
3
+
3
2
2
+
C H O : 363.1438, found [M + H] 363.1434.
it was carefully quenched with cold H O (100 mL) and the lower
2
19 23 7
layer was separated. The aqueous medium was further extracted
5
,6,7,9,10-Pentamethoxy-3-methyl-1H-benzo[g]isochromen-1-one 9
with CH Cl2 (2 × 50 mL) and the combined organic layers were
2
To a 250 mL 2-neck round-bottomed flask equipped with a mag-
netic stirring bar and charged with 3-allyl-1,4,5,6,8-pentamethoxyn-
aphthalene-2-carboxylic acid 7 (2.00 g, 5.52 mmol) in DMF/H O (150
mL, v/v, 2:1) was added CuCl ·2H O (1.77 g, 10.4 mmol). The reac-
tion mixture was vigorously stirred under a blanket of O (g). After
dried with anhydrous MgSO , filtered through a celite bed and con-
4
centrated under reduced pressure. The residue was purified on de-
activated silica gel column chromatography (20 % EtOAc/hexane)
affording 10-hydroxy-5,7,9-trimethoxy-3-methyl-1H-benzo[g]iso-
2
2
2
2
chromen-1-one 2 as a dirty-red solid (51.1 mg, 20 %). R = 0.49
f
10 min of stirring, PdCl (97.9 mg, 0.552 mmol) was added to the
°
°
[19] 1
2
(EtOAc/CH Cl /hexane, 3:2:5); Mp 139–140 C (140–142 C);
H
2
2
reaction mixture and it was further stirred vigorously for 24 h at r.t.
The reaction mixture was then filtered through a thick celite bed
and the pad was washed with CH Cl (3 × 50 mL). The combined
organic layers were washed with brine (3 × 50 mL), dried with anhy-
drous MgSO , filtered and the solvent was removed in vacuo. The
residue was adsorbed on silica and purification by silica gel column
chromatography (EtOAc/CH Cl /hexane, 3:1:6) afforded 5,6,7,9,10-
pentamethoxy-3-methyl-1H-benzo[g]isochromen-1-one 9 as a
cream crystalline solid (1.43 g, 72 %). R = 0.43 (EtOAc/CH Cl /hex-
NMR (500 MHz, CDCl ) δ 14.57 (1H, s, OH attached to C-10), 6.67
3
H
(
1H, s, H-8), 6.16 (1H, s, H-4), 3.94 (3H, s, ArOCH ), 3.88 (3H, s,
3
13
2
2
ArOCH ), 2.37 (3H, s, C-3′); C NMR (126 MHz, CDCl , Me Si) δ
3
3
4
C
1
89.3 (C-9), 177.9 (C-6), 161.4 (C-1), 161.0 (C-10), 160.7 (C-7), 157.7
(C-3), 148.0 (C-5), 143.5 (C-5a), 125.1 (C-4a), 113.0 (C-10a), 111.2 (C-
a), 109.3 (C-8), 98.3 (C-4), 62.3 (ArOCH ), 56.9 (ArOCH ), 20.4 (CH ).
4
9
3
3
3
2
2
The spectroscopic data are in general agreement with that reported
[19]
by Raddi and co-workers (see supplementary information).
f
2
2
°
–1
CCDC 1867674 (for 8), 1867675 (for 16), 1867676 (for 20), 1867677
(for 22) and 1867678 (for 9) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
ane, 4:2:4). Mp 160–162 C; IR v
(cm ) 1741 (C=O), 1605 (C=C);
max
1
H NMR (300 MHz, CDCl , Me Si) δ 6.73 (1H, s, H-8), 6.57 (1H, s, H-
3
4
H
4
), 4.04 (3H, s, ArOCH ), 4.02 (3H, s, ArOCH ), 3.95 (3H, s, ArOCH ),
3 3 3
13
3
.83 (3H, s, ArOCH ), 3.82 (3H, s, ArOCH ), 2.26 (3H, s, H-3′); C NMR
3
3
(
75 MHz, CDCl , Me Si) δ 159.4 (C-1), 156.3 (C-3), 156.2 (Ar-C), 153.2
3 4 C
(
Ar-C), 152.9 (Ar-C), 143.6 (Ar-C), 135.8 (Ar-C), 129.0 (C-6a), 127.5 (C-
0a), 116.7 (C-4a), 108.9 (C-9a), 97.4 (C-4), 96.9 (C-8), 63.0 (ArOCH3),
Acknowledgments
1
6
3
2.8 (ArOCH ), 62.0 (ArOCH ), 57.3 (ArOCH ), 56.5 (ArOCH ), 19.8 (C- This work was supported by SABINA (Southern African Bio-
3
3
3
3
+
′); HRMS (m/z), calculated for [M + H] C H O : 361.1282, found chemistry and Informatics for Natural Products Network), the
1
9 21 7
+
[
M + H] 361.1287.
National Research Foundation Pretoria, South Africa, and the
,7,10-Trimethoxy-3-methyl-1H-benzo[g]isochromene-1,6,9-trione University of the Witwatersrand (Science Faculty Research
5
23
Council).
AgO (1.18 g, 9.50 mmol) was added to the stirred solution of
,6,7,9,10-pentamethoxy-3-methyl-1H-benzo[g]isochromen-1-one 9
1.60 g, 4.44 mmol) in 1,4-dioxane (40 mL). The reaction mixture
was stirred for 10 min at r.t. after which 55 % (v/v) aqueous HNO3
was added dropwise until all the AgO dissolved. The resultant solu-
tion was stirred for a further 5 min which was followed by addition
5
(
Keywords: Synthetic methods · Oxidation · Aromatic
compounds · Oxygen heterocycles · Isocoumarins
[
1] C. D. Donner, Nat. Prod. Rep. 2015, 32, 578–604.
of CH Cl (50 mL) and H O (50 mL). The lower organic layer was
2
2
2
[2] a) D. Parisot, M. Devys, J.-P. Férézou, M. Barbier, Phytochemistry 1983, 22,
1301–1303; b) J. H. Tatum, R. A. Baker, R. E. Berry, Phytochemistry 1989,
28, 283–284.
separated, and the aqueous solution was further extracted with
CH Cl (2 × 100 mL). The combined organic layers were dried with
2
2
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
[
[
3] R. R. Kitagawa, M. S. Raddi, L. C. dos Santos, W. Vilegas, Chem. Pharm.
Bull. 2004, 52, 1487–1488.
4] K. F. Devienne, M. S. Raddi, E. A. Varanda, W. Vilegas, Z. Naturforsch. C
catalytic Pd(OAc)
2
, PPh
3
and morpholine yielded the same isomerized
carboxylic acid, 1,4,6,8-tetramethoxy-3-((E)-prop-1-enyl)naphthalene-2-
carboxylic acid 15 in 56 % yield.
[
3
13] The use of a number of Lewis acids including BBr did not facilitate the
2002, 57, 85–88.
removal of the methyl of 9 OMe substituent of compound 5 to afford
paepalantine.
14] C. B. de Koning, S. S. Manzini, J. P. Michael, E. M. Mmutlane, T. R. Tshabidi,
W. A. L. van Otterlo, Tetrahedron 2005, 61, 555–564.
5] E. A. Varanda, M. S. G. Raddi, F. de Luz Dias, M. C. P. Araújo, S. C. Gibran,
C. S. Takahashi, W. Vilegas, Teratogenesis, Carcinogenesis, and Mutagenesis
[
1
997, 17, 85–95.
6] R. R. Kitagawa, W. Vilegas, I. Z. Carlos, M. S. Raddi, Rev. Bras. Farmacogn.
011, 21, 1084–1088.
[
[
15] Crystal data for 20, CCDC 1867676 C20
H
24
O
7
: M
dimensions (mm ) 0.540 × 0.370 × 0.220; crystal system, Monoclinic;
space group, P2 /n; unit cell dimensions and volume, a = 7.4837(7) Å,
b = 9.9832(8) Å, c = 25.142(2) Å, α= 90°, ꢀ= 98.200(2)°, γ = 90°, V =
376.39 g mol–1; crystal
r
2
3
[
[
[
7] W. Vilegas, N. F. Roque, A. Salatino, A. M. Giesbrecht, S. Davino, Phyto-
chemistry 1990, 29, 2299–2301.
1
8] R. R. Kitagawa, C. Bonacorsi, L. M. da Fonseca, W. Vilegas, M. S. Raddi,
Rev. Bras, Farmacogn. Bras. Farmacogn. 2012, 22, 53–59.
9] J. P. Damasceno, R. P. Rodrigues, R. de C. R. Gonçalves, R. R. Kitagawa,
Molecules 2017, 22, 786.
3
1
859.2(3) Å , no. of formula units in the unit cell Z = 4; calculated density
3
–1
r
calcd 1.345 Mg/m ; linear absorption coefficient, m 0.102 mm ; radiation
and wavelength, MoK = 0.71073 Å; temperature of measurement,
73(2) K, 2 Qmax 28.00°; no of measured and independent reflections,
0025 and 3493; Rint = 0.0239; R [I > 2.0σ(I)] = R = 0.0352, wR = 0.1032,
α
1
2
[
[
10] a) E. M. Mmutlane, I. R. Green, J. P. Michael, C. B. de Koning, Org. Biomol.
Chem. 2004, 2, 2461–2470; b) S. Govender, E. M. Mmutlane, W. A. L.
van Otterlo, C. B. de Koning, Org. Biomol. Chem. 2007, 5, 2433–2440; c)
A. Pillay, A. L. Rousseau, M. A. Fernandes, C. B. de Koning, Org. Biomol.
Chem. 2012, 10, 7809–7819.
1
2
GoF = 1.199, refined on F; residual electron density, 0.402 and –0.526
–3
e Å
16] Crystal data for 22, CCDC 1867677 C21
dimensions (mm ) 0.570 × 0.300 × 0.180; crystal system, Triclinic; space
.
390.42 g mol–1; crystal
26 7 r
H O : M
[
3
11] Crystal data for 8, CCDC 1867674 C18
H
18
O
6
: M
r
330.32 g mol–1; crystal
group, P1; unit cell dimensions and volume, a = 7.9910(4) Å, b =
¯
3
dimensions (mm ) 0.700 × 0.600 × 0.500; crystal system, Triclinic; space
9.4841(4) Å, c = 13.7738(6) Å, α= 88.342(2)°, ꢀ= 75.427(2)°, γ = 76.988(2)°,
group, P1¯; unit cell dimensions and volume, a=7.3600(3) Å, b=9.3270(4)
V = 76.988(2) Å
3
, no. of formula units in the unit cell Z = 2; calculated
3
–1
Å, c=12.3290(5) Å, α= 106.474(2)°, ꢀ= 106.037(2)°, γ=94.670(2)°, V=
density rcalcd 1.318 Mg/m ; linear absorption coefficient, m 0.099 mm
radiation and wavelength, MoKα = 0.71073 Å; temperature of measure-
ment, 173(2) K, 2 Qmax 28.00°; no of measured and independent reflec-
tions, 18604 and 4756; Rint = 0.0229; R [I > 2.0σ(I)] = R1 = 0.0399, wR2
;
3
7
r
68.21(6) Å , no. of formula units in the unit cell Z=2; calculated density
3
–1
calcd 1.428 Mg/m ; linear absorption coefficient, m 0.108 mm ; radiation
and wavelength, MoK =0.71073 Å; temperature of measurement, 173(2)
K, 2 Qmax 28.00°; no of measured and independent reflections, 15256
and 3709; Rint=0.0266; R [I > 2.0σ(I)] = R =0.0418, wR =0.1111, GoF=
.041, refined on F; residual electron density, 0.271 and –0.343 e Å
α
=
0.1107, GoF = 1.053, refined on F; residual electron density, 0.333 and
–
3
1
2
–0.273 e Å
.
–
3
[17] Crystal data for 9, CCDC 1867678 C19H20O : M 360.35 g mol–1; crystal
1
;
7
r
–
1
3
Crystal data for 16, CCDC 1867675 C18
dimensions (mm ) 0.470 × 0.160 × 0.050; crystal system, Monoclinic;
H
18
O
6
: M
r
330.32 g mol ; crystal
dimensions (mm ) 0.640 × 0.340 × 0.170; crystal system, triclinic; space
group, P1¯; unit cell dimensions and volume, a = 7.2651(3) Å, b =
9.5241(3) Å, c = 13.0014(5) Å, α= 79.4850(10)°, ꢀ= 91.4520(10)°, γ =
3
space group, P2
1
/n; unit cell dimensions and volume, a=7.0616(2) Å, b=
3
1
1
8.1308(6) Å, c=11.9516(4) Å, α= 90°, ꢀ= 91.4520(10)°, γ=90°, V=
79.6200(10)°, V = 844.28(6) Å , no. of formula units in the unit cell Z =
3
3
529.70(8) Å , no. of formula units in the unit cell Z=4; calculated density
2; calculated density rcalcd 1.417 Mg/m ; linear absorption coefficient, m
3
–1
0.109 mm–1; radiation and wavelength, MoK
r
calcd 1.434 Mg/m ; linear absorption coefficient, m 0.108 mm ; radiation
and wavelength, MoK =0.71073 Å; temperature of measurement, 173(2)
K, 2 Qmax 28.00°; no of measured and independent reflections, 40839
and 3687; Rint=0.0360; R [I > 2.0σ(I)] = R =0.0533, wR =0.1369, GoF=
.054, refined on F; residual electron density, 0.713 and –0.297 e Å
α
= 0.71073 Å; temperature
of measurement, 173(2) K, 2 Qmax 28.00°; no of measured and independ-
ent reflections, 22542 and 4075; Rint = 0.0227; R [I > 2.0σ(I)] = R
0.0394, wR = 0.1087, GoF = 1.034, refined on F; residual electron density,
0.334 and –0.254 e Å
[18] G. A. Kraus, H. Ogutu, Tetrahedron 2002, 58, 7391–7395.
α
1
=
1
2
2
–
3
–3
1
.
.
[
12] Numerous acid and base mediated methods were attempted. This in-
cluded the use of sodium, lithium and potassium hydroxide, as well as
[19] see ref.[
3]
.
concentrated hydrochloric and sulfuric acid. In addition, exposure of the
related allyl ester, allyl-3-allyl-1,4,6,8-teratmethoxy2-naphthoate[
10c]
to
Received: October 26, 2018
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Wacker Oxidation
A key step in the total synthesis of two
aromatic isocoumarin-containing
products, 9-O-methylpaepalantine and
J. E. Y. Sumani, K. J. Ngwira,
A. Lemmerer, C. B. de Koning* .... 1–10
5
-methoxy-3,4-dehydrosemixantho-
The synthesis of 9-O-Methylpaepa-
lantine and Dehydroxanthomegnin:
megnin is a Wacker-mediated ring clo-
sure. For example, expoure of 3-allyl-
Related
Isocoumarin-Containing
1
,4,5,6,8-pentamethoxynaphthalene-2-
Natural Products
carboxylic acid to catalytic PdCl , CuCl2
2
and O afforded 5,7,9,10-tetrameth-
2
oxy-3-methyl-1H-benzo[g]isochromen-
1
-one in 72 % yield.
DOI: 10.1002/ejoc.201801595
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
10
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim