Synthesis of a 2,3-dimethoxyrotenonoid

Article abstract of DOI:10.3987/com-00-9062

Photo-Fries rearrangement of the o- fluoro ester of 3-hydroxy-6, 7-dimethoxycoumarin yielded the corresponding 3-hydroxy-4-(2-fluorobenzoyl)-coumarin which, in the presence of potassium carbonate, cyclised to the 2,3-dimethoxyrotenonoid. (1)-Benzofuran-(2, 3-c)-(6H, 12H)-(1)-benzoxepin-6-ones underwent oxidation to the corresponding β -rotenonoids reluctantly.

Full text of DOI:10.3987/com-00-9062

HETEROCYCLES, Vol. 55, No. 1, 2001, pp. 91 - 98, Received, 13th September, 2000
SYNTHESIS OF A 2,3-DIMETHOXYROTENONOID
Karla-Sue C. Marriott, Mario Anderson, and Yvette A. Jackson*
Department of Chemistry, University of the West Indies, Mona,
Kingston 7, Jamaica, West Indies
Abstract - Photo-Fries rearrangement of the o- fluoro ester of 3-hydroxy-6, 7-
dimethoxycoumarin yielded the corresponding 3-hydroxy-4-(2-fluorobenzoyl)-
coumarin which, in the presence of potassium carbonate, cyclised to the 2,3-
dimethoxyrotenonoid. (1)-Benzofuran-(2, 3-c)–(6H, 12H)-(1)–benzoxepin-
6-ones underwent oxidation to the corresponding β -rotenonoids reluctantly.
INTRODUCTION
Rotenoids are well known and very potent naturally occurring insecticides, piscicides and antifeedants,1
showing a wide range of biological properties including antibacterial and antiviral activity.2 They occur
most frequently in members of the Leguminosae family. 6-Oxorotenoids, also referred to as rotenonoids,
have the general structure (1a), and have been found co-occurring with rotenoids in plants.3-6
R1
R2
1
O
11
4
5O
6
O
7
8
O
1a R1 = R2 = H
1b R1 = R2 = OMe
Oberholzer et al.4 suggested that the association of rotenoids with rotenonoids in the same plant, may be
indicative of a biogenetic pathway from rotenoids to rotenonoids. Their similarity in structure could also
indicate similar biological activity. Not a great deal is known about rotenonoids, however, as synthesis of
these compounds is quite difficult.
Synthesis of rotenonoids has primarily been by initial synthesis of rotenoids and subsequent oxidation
using either nitrosyl chloride, chromic acid or via Kornblum oxidation.7 This is a rather inefficient route
to rotenonoids, however, since rotenoids are themselves quite difficult to synthesize and most of the

pathways reported are long and low yielding.8 We set out to develop an efficient synthetic pathway to
rotenonoids (this would allow for detailed study of their biological activity), and approached the synthesis
from the following two standpoints.
i)
Rearrangement of β-rotenonoids (2) to rotenonoids under basic conditions is well known
(Scheme 1).9 The β-rotenonoids seemed amenable to synthesis, and with successful synthesis
of these, we could claim synthesis of rotenonoids.
O
O
O
O
MeO
aqueous
base
MeO
MeO
1b
O
HO
OH
O
HO
OH
O
MeO
MeO
MeO
O
HO
HO
O
2
Scheme 1
ii) Benzoates of 3-hydroxy-6, 7-dimethoxycoumarin (9)10 are known to undergo photo-Fries
rearrangement to the corresponding 3-hydroxy-4-benzoylcoumarins.11 Appropriately
substituted 3-hydroxy-4-benzoylcoumarins should cyclize readily to rotenonoids.
RESULTS AND DISCUSSION
In earlier work, we had developed a relatively efficient synthesis of (1)-benzofuran-(2,3-c)–(6H, 12H-
(1)–benzoxepin-6-ones e.g. 3, by the pathway outlined in Scheme 2.12 We synthesized compound (3)
with the hope of oxidizing it to the desired β-rotenonoid (2).
MeO
O
MeO
MeO
i)
iii)
MeO
O
MeO
MeO
HO
CO2R
O
CO2Et
O
O
O
4
5 R = Et
6 R = H
3
ii)
Reagents: i) TFA ii) NaOH, aq. EtOH iii) thionyl chloride, pyridine
Scheme 2
Since the only available position for oxidation in 2 is a methylene group which is both allylic and
benzylic, we anticipated success, though we approached it with some reserve since the difficulty with
which 3-benzylbenzofurans are oxidized to 3-aroylbenzofurans has been reported.13

The ether (4) was readily prepared in 91% yield from phenol and ethyl 3-bromomethylbenzofuran-2-
carboxylate,14 in the presence of potassium carbonate and dry acetone. Rearrangement of the ether in
trifluoroacetic acid (TFA) produced the ester (5), which was then hydrolysed to the acid (6). Subsequent
cyclization using thionyl chloride/pyridine yielded the lactone (3) in about 40% overall yield from the
ether (4).
OH
MeO
H
[O]
3
2
O
MeO
O
O
7
Scheme 3
The lactone (3), however, proved very resistant to oxidation. Many different reagents – SeO2, DDQ,
benzeneseleninic anhydride, tert-BuOOH and NBS/DMSO, were tried, all without success. When tert-
butyl hydroperoxide was used in conjunction with chromium trioxide or with pyridinium dichromate, we
saw evidence of a very small yield of the intermediate hydroxylated lactone (7) (Scheme 3), which
proved to be unstable.
Biotransformation reactions using Fusarium oxysporum, subculture of Curvularia protuberata,
Mortierella isabellina, Cunninghamella echinulata var. elegans, all fungi known to carry out allylic
oxidations15 were also attempted, but these proved unsuccessful.
Still in anticipation of the β-rotenonoid, we went on to pursue another route. Trimethylamine-N-oxide
(TMANO) is known to convert alkyl halides to the corresponding aldehyde or ketone.16 Compound (3)
was thus converted to the allyl bromide (8) by treatment with N-bromosuccinimide (NBS). Reaction of 8
with TMANO in DMSO produced, after work-up, not the β-rotenonoid as we had anticipated, but the
rotenonoid (1b) in 7% yield from lactone (3) (Scheme 4).
OMe
Br
MeO
H
MeO
O
O
NBS
TMANO/DMSO
3
O
MeO
O
O
O
8
O
Scheme 4
This observation suggested that we had achieved allylic oxidation of 8 to 2, and that rearrangement of the
β-rotenonoid had also occurred under these conditions. The reaction, however, went very poorly. It is

clear that compounds of type (3) undergo oxidation to the corresponding β-rotenonoids reluctantly, if at
all. 1H-NMR data of the reaction product showed the characteristic downfield singlet (δ 8.9) which
corresponds to the proton at C-1 in rotenonoids, and IR absorptions at 1741 and 1640 cm-1, which are also
markers for the rotenonoid system.4-6, 17
We next turned to synthesis of the title compound via photo-Fries rearrangement of the o-fluorobenzoate
of 3-hydroxycoumarin (9), and subsequent cyclization. This proved to be a much more facile pathway.
ii) then iv)
OMe
F
MeO
F
O
MeO
MeO
OH
O
MeO
MeO
O
O
iii)
i)
ii)
1b
O
O
O
O
OH
O
9
10
11
Reagents: i) o-fluorobenzoyl chloride, pyridine ii) benzene:ethanol, light iii) K2CO3, toluene
iv) K2CO3, MeI, acetone
Scheme 5
The fluoroester (10) was prepared in 80% yield by condensation of 9 with o-fluorobenzoyl chloride.
Irradiation of a 0.2% solution of 10 in benzene:ethanol (1:1), by sunlight, for 8 h, produced the compound
(11) which when treated with potassium carbonate in refluxing acetone, was quickly converted to 1b
(79%). The compound obtained from TMANO reaction of 8 is identical in all respects (MP, IR, NMR,
MS) to the product (1b) obtained from the pathway in Scheme 5. With our improved synthesis of
compound (9),10 this route signifies an efficient and general pathway to rotenonoids.
EXPERIMENTAL
General
All mp are uncorrected. IR spectra were obtained on a Perkin Elmer 735B model or a Perkin Elmer 1600
FT-IR spectrophotometer and are for KBr discs. NMR spectra (Bruker 200 MHz spectrometer) were
determined in CDCl3 solution and the resonances are reported in δ units downfield from TMS; J values
are given in Hz. Elemental analyses were carried out by MEDAC Ltd., Egham, Surrey, UK.
5,6-Dimethoxy-2-carboethoxy-3-phenoxymethylbenzofuran (4)
To a solution of phenol (0.285 g, 3.03 mmol) in acetone (38 mL) was added, with stirring, potassium
carbonate (1.630 g, 11.8 mmol) followed by 3-bromomethyl-2-carboethoxy-5,6-dimethoxybenzo-furan
(0.869 g, 2.87 mmol).14 The reaction mixture was then heated at reflux for 2 h, filtered and the filter cake

washed with hot acetone. The filtrate was concentrated in vacuo and the crude product recrystallised
from methanol to produce 4 as fluffy white needles (0.934 g, 91%), mp 123 - 125°C; νmax /cm-1 1704,
1593; δH 1.42 (3H, t, J 7, -O-CH2-CH3), 3.80 (6H, s, 2 x OCH3), 4.42 (2H, q, J 7, -O-CH2-CH3), 5.60
(2H, s, -CH2-OPh), 7.00 (4H, m), 7.35 (3H, m); δc 14.3, 56.1, 61.3, 61.8, 94.8, 102.5, 114.5, 119.2, 121.2,
129.5, 139.8, 147.3, 150, 151.2, 158.2. Anal. Calcd for C20H20O5: C, 67.39; H, 5.66. Found: C, 67.00; H,
5.58.
5,6-Dimethoxy-2-carboethoxy-3-(2’-hydroxyphenylmethyl)benzofuran (5)
Compound (4) (3.0 g, 9.22 mmol) was dissolved in trifluoroacetic acid (TFA) (50 mL) with stirring. The
reaction mixture was then heated at reflux for 6 h. TFA was removed in vacuo and the crude product was
dissolved in chloroform and washed to neutral with water. The chloroform solution was then dried
(Na2SO4), concentrated in vacuo and chromatographed (SiO2, hexane-EtOAc 5:2) to yield 5 as a pale
yellow powder (1.4 g, 46%), mp 163-165°C (MeOH/hexane); νmax /cm-1 1699, 1657, 3373; δH 1.50 (3H,
t, J 7, -O-CH2-CH3), 3.90 (6H, s, 2 x OMe), 4.40 (2H, s, CH2-Ar), 4.50 (2H, q, J 7, -O-CH2-CH3), 6.80
(2H, m) 6.95 (1H, s, 6-H), 7.10 (2H, m), 7.40 (1H, d, J 8.5, 6´-H), 7.62 (1H, br s, OH); δc 14.2, 25.7,
56.13, 61.8, 94.9, 101.6, 116.7, 119.9, 120.1, 123.7, 128.3, 129.2, 130.6, 139.0, 147.2, 150.0, 151.4,
154.7, 162.0. Anal. Calcd for C20H20O6: C, 67.39; H, 5.66. Found: C, 67.38; H, 5.63.
5,6-Dimethoxy-3-(2’-hydroxyphenylmethyl)benzofuran-2-carboxylic acid (6)
3M NaOH (9.5 mL, 28.5 mmol) was added to a mixture of compound (5) (1.302 g, 4.0 mmol) in
methanol (40 mL) and the mixture was heated at reflux for 3 h. The mixture was then concentrated in
vacuo and the resulting solid was diluted with the minimum volume of water and acidified with
concentrated HCl. The mixture was cooled and the resultant white precipitate was collected by filtration
and washed to neutral with cold water. The product was dried in an oven at 80°C to give 6 as a white
powder (1.15 g, 96%), mp 223-225°C (EtOH); νmax /cm-1 1670, 1580, 3503, 3435; δH 3.80 (3H, s, OMe),
3.90 (3H, s, OMe), 4.42 (2H, s, CH2-Ar), 6.70 - 6.90 (2H, m), 7.00 - 7.28 (3H, m), 7.40 (1H, s, 4-H); δc
24.5, 55.9, 94.5, 101.9, 115.1, 115.5, 119.4, 120.1, 124.6, 127.4, 128.6, 130.1, 146.6, 149.6, 150.8, 154.8,
162.7.
2,3-Dimethoxy-(1)-benzofuran-(2, 3-c)-(6H, 12H)-(1)-benzoxepin-6-one (3)
To a solution of the carboxylic acid (6) (1.01 g, 3.41 mmol) in pyridine (30 mL) was added thionyl
chloride (0.5 mL, 6.85 mmol) and the reaction mixture left to stand for 2 h. The mixture was then poured
into crushed ice/water (200 mL). The brown precipitate formed was collected by filtration and

recrystallised from chloroform/methanol, to produce 3 as fluffy brown crystals (0.873 g, 92%), mp 206-
208°C; νmax /cm-1 1733, 1624, 1572; δH 3.90 (3H, s, OMe), 3.95 (3H, s, OMe), 4.12 (2H, s, CH2-Ar), 6.95
(1H, s, 1- or 4-H), 7.00 (1H, s, 1- or 4-H), 7.05-7.35 (4H, m); δc 27.3, 56.3, 56.4, 95.2, 100.5, 122.4,
126.0, 128.5, 129.4, 147.9, 151.5, 152.0. Anal. Calcd for C18H14O5: C, 69.66; H, 4.49. Found: C, 69.18;
H, 4.49.
6,7-Dimethoxycoumarin-3-(2’-fluoro)benzoate (10).
3-Hydroxy-6, 7-dimethoxycoumarin (2.5 g, 11.3 mmol) was dissolved in pyridine (45 mL) and 2-
fluorobenzoyl chloride (1.35 mL, 11.3 mmol) was added with cooling. The reaction mixture was stirred
at rt for 24 h then poured onto crushed ice (~250 g) with stirring. The resultant brown precipitate was
collected by suction filtration and recrystallised to give 10 as light brown crystals (3.11 g, 80%), mp
(MeOH) 218-220°C; νmax /cm-1 1723, 1760; δH 3.92 and 3.97 (each 3H, s, OMe), 6.88 and 6.93 (each 1H,
s, 5- and 8-H), 7.20-7.35 (2H, m), 7.57 – 7.70 (2H, m), 8.10-8.20 (1H, m, 6´-H); δc 55.93, 56.1, 99.8,
108.6, 117.0, 117.5, 124.6, 132.4, 133.1, 136.2, 136.4, 146.4, 147.6, 152.2, 159.1, 164.3. Anal. Calcd. for
C18H13O6F. H2O : C, 59.67 ; H, 4.14. Found: C, 59.79; H, 3.78.
2,3-Dimethoxyrotenonoid (1b)
a) From (1)-Benzofuran-(2, 3-c)-(6H, 12H-1)-benzoxepin-6-one (3). To a mixture of compound (3)
(0.25 g, 0.89 mmol) in CCl4 (17 mL), N-bromosuccinimide (0.23 g, 1.29 mmol) was added with stirring.
The reaction was enclosed in a dark box and illuminated with a 100 watt bulb for 8 h. (This allowed
gentle reflux.) The reaction mixture was then filtered and the filtrate concentrated in vacuo to produce 8
as a brown solid (0.16 g) which was used in the next reaction without further purification.
Trimethylamine-N-oxide (0.18 g, 2.40 mmol) dissolved in DMSO (12 mL), was added to the above solid
with stirring. The reaction mixture was left to stir at rt for 4 h and then poured into a 50% saline solution
and left to stand for 24 h. The aqueous mixture was extracted with chloroform, the organic extract dried
(Na2SO4), and the solution concentrated in vacuo. The crude product was recrystallised from
chloroform/ethanol to yield 1b as bright yellow needles (20 mg, 7% from lactone (3)), mp 312-313°C;
νmax /cm-1 1741, 1640, 1612, 1516; δH 3.90 and 4.05 (each 3H, s, OCH3), 6.90 (1H, s, 4-H), 7.53 (1H, td,
J 7, 2, 9-H), 7.70-7.90 (2H, m, 8-H, 10-H), 8.33 (1H, dd, J 9, 2, 11-H), 8.97 (1H, s, 1-H); δc 56.3, 56.2,
99.3, 107.3, 107.5, 111.7, 118.5, 125.7, 125.8, 135.2, 145.2, 148.2, 154.3, 155.6, 165.7; m/z (relative
intensity) 324 (100), 309 (36). HRMS calcd for C18H12O6: 324.0634. Found: 324.0660. Anal. Calcd for
C18H12O6: C, 66.65; H, 3.73. Found: C, 66.92; H, 3.86.

b) From 6,7-dimethoxycoumarin-3-(2’-fluoro)benzoate (10). A solution of the ester (10) (600 mg,
1.74 mmol) in benzene:ethanol (1:1, 300 mL) was irradiated by sunlight for 8 h, in an atmosphere of
nitrogen. The solvent was evaporated in vacuo and the residue purified by chromatography (SiO2,
acetone: hexane-2:3). The major product was 11 - a bright yellow powder (240 mg) which proved
difficult to characterise. Treatment of 11 (160 mg, 0.47 mmol) in acetone (12 mL) with K2CO3(160 mg,
1.16 mmol), MeI (0.10 mL, 1.61 mmol) - in an effort to get a more stable and more readily characterised
product, yielded 1b. Compound (11) was therefore subjected to cyclization using potassium carbonate.
To a solution of the above solid (0.20 g) in toluene (8 mL) was added potassium carbonate (0.16 g, 1.16
mmol), and the mixture was heated at reflux for 45 min. The mixture was cooled, filtered and the filter
cake washed with ethyl acetate (15 mL). The combined organic solution was concentrated in vacuo and
the crude solid purified by chromatography (SiO2, CHCl3) to yield 1b as a bright yellow powder (148 mg,
79% (32% from ester 10)).
ACKNOWLEDGEMENTS
This work was supported in part by a UWI/IDB research grant, which is gratefully acknowledged.
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