Synthesis of O-methyl epi-heliannuol E

Article abstract of DOI:10.1016/j.tet.2003.08.059

A synthesis of the methyl ether of an epimer of the alleochemical heliannuol E is described. The route involves indium mediated allylation of a benzopyranone carboxylate and subsequent one carbon degradation to a vinyl group.

Full text of DOI:10.1016/j.tet.2003.08.059

Tetrahedron 59 (2003) 8375–8381
Synthesis of O-methyl epi-heliannuol E
*
Subir Kumar Sabui and Ramanathapuram V. Venkateswaran
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
Received 4 June 2003; revised 30 July 2003; accepted 29 August 2003
Abstract—A synthesis of the methyl ether of an epimer of the alleochemical heliannuol E is described. The route involves indium mediated
allylation of a benzopyranone carboxylate and subsequent one carbon degradation to a vinyl group.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Heliannuol E 1,1 isolated recently from the extracts of
Helianthus annus, represents a new structural type among
the family of heliannuol sesquiterpenes obtained from
cultiver sun flowers. These compounds have been found to
display significant allelopathic activity,2 a new branch of
applied science involving biochemical plant–plant and
plant–microorganism interactions. Increasing awareness
into the need to restore the natural ecological balance and
efforts to reduce the use of artificial weed control agents in
agriculture have provided a new impetus to find natural
herbicide models. In this, allelochemicals, isolated from
plants and microbes, have assumed prime importance
during the last two decades as biocommunicators3 and as
a potential source of new structural types of herbicides with
new modes of action without harmful effects of synthetic
pesticides. The cultiver sun flowers are a rich source of
useful allelochemicals and continued investigations have
led to the isolation of a new group of sesquiterpenes termed
heliannuols. Heliannuol E 1, along with the other reported
heliannuols A–D 2–5,4 comprise an interesting comple-
ment of benzofused 6, 7 and 8 membered cyclic ether
skeleta. The gross structure and relative stereochemistry of
1 was established by Macias1 and the absolute stereo-
chemistry was assigned as 8R,10S by Shishido following a
synthesis.5
The irregular terpenoid structure of 1 and the associated
significant biological activity are expected to prompt further
reports on its synthesis.6 We have initiated a comprehensive
programme into the synthesis of these structurally intriguing
new terpenoid compounds and have recently reported a
synthesis of heliannuol A and D.7 We now report a synthesis
of the methyl ether of an epimer of heliannuol E.
2. Results and discussion
We envisaged that a properly substituted benzopyranone
Keywords: allelochemical; heliannuol E; methyl ether of epimer; transfer
hydrogenation of chromone; indium mediated allylation.
carboxylate 10,8 embodying the central benzoxacyclic core
of 1, could serve as a suitable intermediate for transform-
ation into the natural compound. The presence of the ester
*
Corresponding author. Tel.: þ9103324734971; fax: þ91-33-24732805;
e-mail: ocrvv@mahendra.iacs.res.in
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.08.059

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S. K. Sabui, R. V. Venkateswaran / Tetrahedron 59 (2003) 8375–8381
Scheme 1. Reagents and conditions: (i) anhyd. AlCl3, 160–1658C; (ii) MeI, K2CO3, acetone, reflux; (iii) diethyl oxalate, NaH, THF, then PTSA, benzene,
reflux; (iv) HCOONH4, C2H5OH, Pd–C (10%), reflux, or H2, Pd–C (10%), C2H5OH, then Jones oxidation.
function may facilitate a preferred nucleophilic attack on the
carbonyl group from the opposite face to provide the
required trans geometry of the resulting 1,3 substitutions.
The ester function is also amenable for conversion into the
isopropanol moiety. With this in mind, synthesis of the
benzopyranone carboxylate 10 was undertaken.
The C-8 carbonyl group in 10 proved impervious to a
variety of conditions to introduce an aldehyde or a
methylene group through a Wittig reaction for further
transformation into a vinyl side chain as in 1. The sulfonium
or sulfoxonium methylide procedure also did not yield any
useful results. Attempted direct introduction of a vinyl
residue through reaction of 10 with vinyl magnesium
bromide resulted in a primary attack on the ester function.
Hence, it was decided to transform the ester function first
into the desired isopropanol moiety and then direct efforts
for incorporation of the vinyl group at the site of the
carbonyl function. This required the initial protection of the
carbonyl group. Attempted ketalisation through conden-
sation with ethylene glycol catalysed by toluene-p-sulfonic
acid in refluxing benzene did not afford any reasonable yield
of the corresponding ketal even after long hours of reaction.
However, condensation with ethane dithiol in the presence
of boron trifluoride etherate proceeded smoothly to furnish
the thioketal 11 in excellent yield. Reaction of this thioketal
with excess methyl magnesium iodide afforded the
isopropanol 12, also in high yield. The hydroxy group in
12 was protected as the benzyl ether through reaction with
benzyl bromide in the presence of sodium hydride and
furnished the benzylated thioketal 13 as a crystalline solid
which on treatment with mercuric chloride and calcium
carbonate in aqueous acetonitrile resulted in the deprotec-
tion of the thioketal moiety to reveal benzylated benzo-
pyranone 14. The keto group in this benzopyranone also
failed to respond to various attempts at a one carbon
homologation to incorporate an aldehyde function.
2-Methylhydroquinone diacetate 6, on Fries rearrangement
followed by monomethylation afforded the acetophenone 8
in an overall yield of 56%. We have found this procedure to
be more convenient with better overall yield compared to a
reported method.9 Base induced condensation of this
acetophenone with diethyl oxalate10 followed by treatment
of the resulting product with toluene-p-sulfonic acid in
boiling benzene afforded the chromone carboxylate 9 in
85% yield. Reduction of the double bond in 9 was fraught
with problems. However, application of a transfer hydro-
genation procedure11 involving refluxing an ethanolic
solution of 9 with ammonium formate in presence of
Pd–C led to facile reduction to furnish the desired
benzopyranone carboxylate 10 in good yield (Scheme 1).
We have recently generalised this as a useful protocol for
the reduction of chromones to chromanones.12 Sub-
sequently it was also found that carefully controlled
(monitored by TLC) catalytic hydrogenation of 9 in the
presence of Pd–C (10%) results in smooth reduction of the
double bond and also the ketone to produce the correspond-
ing chromanol, which could be efficiently oxidised by Jones
reagent to the benzopyranone carboxylate 10 in good overall
yield.
Scheme 2. Reagents and conditions: (i) HSCH2CH2SH, BF3.(C2H5)2O, (C2H5)2O, rt, 8 h; (ii) MeMgI, (C2H5)2O, reflux; (iii) BnBr, NaH, THF, rt, 10 h;
(iv) HgCl2, CaCO3, CH3CN, H2O, rt, 14 h; (v) [(C2H5)O]2P(O)CH2CO2C2H5, NaH, THF, 20 h, rt; (vi) Pd–C (10%), C2H5OH,6 h.

S. K. Sabui, R. V. Venkateswaran / Tetrahedron 59 (2003) 8375–8381
8377
However, a Wittig–Horner condensation with triethyl
phosphonoacetate in the presence of sodium hydride gave
the unsaturated ester 15, as a single unknown isomer in
reasonable yield. The stereochemical outcome was not
deemed relevant since the next step involved hydrogenation.
Thus, catalytic hydrogenation of the unsaturated ester 15 in
the presence of Pd–C resulted in the reduction of the double
bond and concomitant cleavage of the benzyl protecting
group to afford the saturated ester 16 (Scheme 2). However,
this proved to be the undesired cis isomer. The stereo-
chemistry was arrived at from the NOE effect observed
between the hydrogens at C-8 and C-10.
selenocyanate in the presence of tri n-butyl phosphine.
Treatment of this selenide with hydrogen peroxide resulted
in oxidative elimination to afford the vinylated carboxylate
22. Efforts at base catalysed epimerisation of this vinylated
carboxylate for even minor conversion to the trans isomer
were infructuous. Interaction of 22 with excess methyl
magnesium iodide furnished the methyl ether 23 of epi-
heliannuol E (Scheme 3). This showed no NOE effects
between H-7 and H-10 as reported for the natural compound
further attesting to the stereochemical assignment.
In summary we have described a short approach to the
development of the basic structural features as found in the
allelochemical heliannuol E, resulting in a synthesis of
the methyl ether of its epimer. Further studies are under way
and are expected to provide useful analogs for exploration
of structure activity relationships.
In view of the failure to achieve the desired trans orientation
of the substituents for a subsequent transformation into
heliannuol E, it was decided to once again explore the
possibility of addition of appropriate nucleophiles to the
carbonyl group in the benzopyranone carboxylate 10.
The ester group may be usefully utilised for any required
epimerisation. Success was finally achieved in allylation
through indium metal13 promoted reaction of 10 with allyl
bromide and afforded the allylated carboxylates 17 in 74%
yield as a 2:1 mixture of diasteromers. Separation of the
isomers proved difficult at this stage and hence the mixture
was taken to the next sequence of steps for conversion of the
allyl side chain into a vinyl residue. Treatment of 17 with
osmium tetroxide followed by cleavage of the resulting diol
furnished the aldehydes 18. Borohydride reduction to the
diols 19 followed by hydrogenolysis of the benzylic
hydroxy group produced the 1,3-disubstituted carboxylate
20, encouragingly as a single isomer. This also proved to be
the undesired cis isomer as evidenced from the NOE effect
observed between the C-8 and C-10 hydrogens. It was,
however, decided to proceed further and transform the
ethanolic side chain at C-8 into a vinyl group as in the
natural product and explore the possibility of any
epimerisation to the desired trans isomer.
3. Experimental
3.1. General
Melting points are uncorrected. Purity of the products was
routinely monitored by TLC. Preparative TLC was
performed with silica gel 60 HF254 plates of 1-mm
thickness. The petroleum ether that was used is that fraction
of bp 60–808C. Na2SO4 was used to dry organic extracts.
The IR spectra are of CHCl3 solutions. 1H NMR spectra of
CDCl3 solutions were recorded at 300 MHz and 13C NMR
spectra at 75 MHz.
3.1.1. 2,5-Dihydroxy-4-methyl acetophenone (7). A finely
powdered mixture of 2-methyl hydroquinone diacetate 6
(20 g, 96 mmol) and anhydrous aluminium chloride (43 g,
321 mmol) was heated slowly in an oil bath to 110–1208C
and kept at this temperature for 30 min. Then it was raised to
160–1658C and kept at this temperature for 3 h. The
reaction mixture was cooled and decomposed with crushed
ice (150 g) and conc.hydrochloric acid (15 mL). The
resulting solid was filtered and washed with cold water
(3£30 mL). It was crystallised from ethanol to furnish the
Dehydration of the primary hydroxy group to the vinyl side
chain was smoothly achieved through application of
Grieco’s protocol.14 Thus, the alcohol was converted into
the o-nitrophenyl selenide 21 by reaction with o-nitrophenyl
Scheme 3. Reagents and conditions: (i) In, BrCH2CH:CH2,THF, rt; (ii) OsO4, NaIO4, (C2H5)2O, H2O; (iii) NaBH4, C2H5OH, 08C; (iv) H2, Pd–C (10%),
C2H5OH, AcOH, HClO4, 60% overall for three steps; (v) o-NO2C6H4SeCN, nBu3P, THF, rt; (vi) 30% H2O2, THF, rt; (vii) MeMgI, (C2H5)2O, reflux.

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S. K. Sabui, R. V. Venkateswaran / Tetrahedron 59 (2003) 8375–8381
dihydroxy acetophenone 7 (8.3 g, 52%), mp 139–1418C; IR
1665 cm21; dH (300 MHz, CDCl3) 2.26 (s,3H),2.54 (s, 3H),
4.95 (bs, OH),6.76 (s,1H), 7.09 (s,1H), 11.86 (s, OH); dC
(75 MHz, CDCl3) 15.6, 25.5, 113.8, 116.5, 118.9, 134.9,
145.1, 155.6, 202.5. Anal. calcd for C9H10O3: C,65.06;
H,6.02. Found: C, 64.66; H, 5.70.
chromatography of the residue and elution with ethyl
acetate–petroleum ether (1:4) furnished benzopyranone
carboxylate 10 as a colourless solid (200 mg, 75%),
crystallised from ether–petroleum ether, mp 99–1018C;
IR 1678, 1759 cm21; dH (300 MHz, CDCl3) 1.29 (t,
J¼7.2 Hz, 3H), 2.23 (s, 3H), 3.0 (d, J¼6.5 Hz, 2H), 3.81
(s, 3H), 4.26 (J¼7.2 Hz, 2H), 5.01 (t, J¼6.5 Hz, 1H), 6.90
(s, 1H), 7.19 (s, 1H); dC (75 MHz, CDCl3) 14.1, 17.0, 39.3,
55.7, 62.0, 75.2, 105.0, 118.7, 119.9, 138.1, 153.1, 154.6,
168.9, 189.5. Anal. calcd for C14H16O5: C, 63.64; H, 6.06.
Found: C, 63.62; H, 6.01.
3.1.2. 2-Hydroxy-5-methoxy-4-methyl acetophenone (8).
A solution of dihydroxy acetophenone 7 (5 g, 30 mmol),
anydrous potassium carbonate (4.5 g, 32.6 mmol) and
methyl iodide (6.4 g, 45 mmol) in acetone (60 mL) was
refluxed for 6 h. The reaction mixture was cooled and most
of the acetone was distilled off. The residue was poured into
water (40 mL) and extracted with dichloromethane
(20 mL£3). The organic extract was washed with water
(10 mL£3), dried and concentrated to afford a yellow solid
which was subjected to chromatography over silica gel.
Elution with ethyl acetate–petroleum ether (1:5) furnished
the monomethylated acetophenone 8 as a pale yellow solid,
(4.9 g, 90%); crystallised from ether–petroleum ether, mp
107–1088C (lit.,9 mp 108–1098C); IR 1660 cm21; dH
(300 MHz, CDCl3) 2.19 (s, 3H), 2.55 (s, 3H), 3.78 (s,
3H), 6.72 (s, 1H), 6.94 (s,1H), 11.99 (s, OH); dC (75 MHz,
CDCl3) 17.2, 26.9, 56.1, 109.9, 117.3, 120.4, 138.7, 150.6,
157.3, 203.7. Anal. calcd for C10H12O3: C, 66.67; H, 6.67.
Found: C, 66.36; H,6.43.
A solution of the chromone 9 (260 mg, 1 mmol) in ethanol
(5 mL) containing Pd–C (10%, 40 mg) was subjected to
hydrogenation. Immediately after the disapperance of the
starting material (TLC) the catalyst was filtered off and
ethanol was removed. The colourless solid residue (240 mg)
obtained corresponded to the 4-chromanol (IR 3410,
1760 cm21). The above crude chromanol was taken in
acetone and oxidised with Jones reagent. Usual work-up
followed by chromatographic purification [ethyl acetate–
petroleum ether (1:4)] afforded the benzopyranone
carboxylate 10 as a colourless solid (180 mg, 70%). The
mp and spectra (IR and 1H NMR) were identical with
material obtained from transfer hydrogenation.
3.1.5. Ethyl-6-methoxy-7-methyl-4,4-dithioethane-2H-1-
benzopyran-2-carboxylate (11). To a mixture of the
benzopyranone carboxylate 10 (530 mg, 2 mmol) and
ethane dithiol (750 mg, 8 mmol) in ether (5 mL) boron
trifluoride etherate (0.4 mL) was added in ice-cold con-
dition. The mixture was left at rt for 10 h, then diluted with
water (30 mL) and extracted with ether (25 mL£3). The
ethereal extract was washed with water (15 mL£3), dried,
and concentrated. The viscous residue was chromato-
graphed over neutral alumina. Fraction eluted by ethyl
acetate–petroleum ether (1:9) furnished the thioketal 11 as a
solid (610 mg, 90%); Crystallised from ether–petroleum
ether, mp 52–548C; IR 1755 cm21; dH (300 MHz, CDCl3)
1.26 (t, J¼7.2 Hz, 3H), 2.07 (s, 3H), 2.51–2.77 (m, 2H),
3.31–3.65 (m, 4H), 3.73 (s, 3H), 4.23 (q, J¼7.2 Hz, 2H),
4.73 (dd, J¼2.7, 10.5 Hz, 1H), 6.63 (s, 1H), 7.14 (s, 1H). dC
(75 MHz, CDCl3) 14.6, 16.4, 40.6, 41.3, 45.0, 56.1, 62.0,
64.5, 74.0, 110.6, 119.5, 119.9, 129.8, 147.3, 152.8, 170.2.
Anal. calcd for C16H20O4S2: C, 56.47; H, 5.88. Found: C,
56.32; H, 5.72.
3.1.3. Ethyl-6-methoxy-7-methyl chromone-2-carboxyl-
ate (9). To a cooled (ice-bath), stirred slurry of sodium
hydride, freed from oil (3 g, 62.5 mmol, 50% dispersion in
oil) in anhydrous ether (15 mL) under nitrogen, a mixture of
2-hydroxy-4-methyl-5-methoxy acetophenone 8 (5.8 g,
32.2 mmol) and diethyloxalate (9.4 g, 64.4 mmol) in THF
(20 mL) was added slowly and the reaction mixture was left
overnight at rt. It was then poured into ice-water (70 mL)
and acidified with cold dilute hydrochloric acid (6N, 25 mL)
and extracted with ether (40 mL£3). The ether extract was
washed with water (20 mL£2), dried and concentrated. The
solid residue was dissolved in benzene (120 mL) and
toluene-p-sulfonic acid (80 mg) was added and refluxed
for 8 h, using a Dean–Stark water separator. It was then
cooled, washed with saturated aqueous sodium bicarbonate
solution, water, dried and solvent removed to get a
yellowish solid. This was subject to chromatography over
silica gel. Elution with ethyl acetate–petroleum ether (1:3)
furnished the chromone carboxylate 9 as a colourless solid,
(7 g, 85%); crystallised from ether–petroleum ether, mp
132–1348C; IR 1643, 1739 cm21; dH (300 MHz, CDCl3)
1.43 (t, J¼7.2 Hz, 3H), 2.34 (s, 3H), 3.92 (s, 3H), 4.45 (q,
J¼7.2 Hz, 2H), 7.08 (s, 1H), 7.40 (s, 1H), 7.43 (s, 1H); dC
(75 MHz, CDCl3) 13.9, 16.9, 55.8, 62.7, 102.5, 113.7,
120.0, 123.1, 136.8, 150.5, 151.5, 156.0, 160.5, 178.0. Anal.
calcd for C14H14O5: C, 64.12; H, 5.34. Found: C, 64.09; H,
5.32.
3.1.6. 2-(1-Hydroxy-1-methyl)-ethyl-4,4-dithioethane-6-
methoxy-7-methyl-2H-1-benzopyran (12). To a magneti-
cally stirred solution of MeMgI [prepared from Mg
(120 mg, 5 mmol), MeI (850 mg, 6 mmol)] in ether
(5 mL) at 08C was added a solution of the thioketal 11
(680 mg, 2 mmol) in ether (4 mL). The mixture was brought
to rt and stirred for 30 min. Then it was refluxed for 4 h. The
reaction mixture was cooled to 08C and was decomposed by
adding saturated aqueous NH4Cl solution (2 mL). The
organic layer was separated. The aqueous layer was
extracted with ether (10 mL£2). The combined organic
layer was washed with water (5 mL£2), dried and
concentrated. The residue after column chromatography
over neutral alumina using ethyl acetate–petroleum ether
(1:6) afforded the alcohol 12 (610 mg, 94%), as a highly
viscous oil. IR 3445 cm21; dH (300 MHz, CDCl3) 1.21 (s,
3.1.4. Ethyl-6-methoxy-7-methyl-2H-1-benzopyran-4-
one-2-carboxylate (10). A solution of the chromone 9
(260 mg, 1 mmol) and ammonium formate (190 mg,
3 mmol) in ethanol (5 mL) containing palladium charcoal
(10%, 80 mg) was refluxed for 6 h. The catalyst was filtered
and the residue after removal of ethanol was extracted with
ether (20 mL£3). The ether extract was washed with brine
solution and dried. Removal of solvent followed by column

S. K. Sabui, R. V. Venkateswaran / Tetrahedron 59 (2003) 8375–8381
8379
3H), 1.26 (s, 3H), 2.07 (s, 3H), 2.29–2.43 (m, 2H), 3.26–
3.63 (m, 4H), 3.73 (s, 3H), 3.92 (dd, J¼2.49, 10.5 Hz, 1H),
6.52 (s, 1H), 7.15 (s, 1H); dC (75 MHz, CDCl3) 16.3, 25.3,
25.9, 40.4, 41.2, 43.0, 56.1, 65.4, 71.8, 81.6, 110.9, 119.0,
120.8, 129.3, 148.3, 152.2. Anal. calcd for C16H22O3S2: C,
58.89; H, 6.74. Found: C, 58.78; H, 6.63.
ethereal extract was dried, concentrated and the residue
subjected to column chromatography over silica gel. Elution
with ethyl acetate–petroleum ether (3:17) furnished the
product 15 as a gummy oil (120 mg, 58%). IR 1708 cm21
;
dH (300 MHz, CDCl3) 1.22 (t, J¼7.1 Hz, 3H), 1.33 (s, 3H),
1.34 (s, 3H), 2.12 (s, 3H), 2.50–2.60 (m, 2H), 3.74 (s, 3H),
3.86 (dd, J¼2.2, 13.1 Hz, 1H), 4.14 (q, J¼7.1 Hz, 2H), 4.49
(d, J¼11.5 Hz, 1H), 4.54 (d, J¼11.5 Hz, 1H), 6.18 (bs 1H),
6.67 (s, 1H), 6.86 (s, 1H), 7.15–7.31 (m, 5H); dC (75 MHz,
CDCl3) 12.3, 14.4, 19.2, 21.2, 24.9, 53.7, 57.8, 62.3, 74.4,
79.0, 102.1, 106.9, 118.1, 125.15, 125.2, 126.2, 126.3,
130.6, 137.6, 147.2, 149.1, 150.3, 164.9. Anal. calcd for
C25H30O5: C, 73.17; H, 7.31. Found: C, 72.90; H, 7.12.
3.1.7. 2-(1-Benzyloxy-1-methyl)-ethyl-4,4-dithioethane-
6-methoxy-7-methyl-2H-1-benzopyran (13). To a mag-
netically stirred suspension of NaH [(70 mg, 1.5 mmol, 50%
dispersion in oil)] in THF (2 mL) was added dropwise a
solution of the tertiary alcohol 12 (330 mg, 1 mmol) in THF
(3 mL). The mixture was stirred at rt for 2 h and then cooled
in a ice-bath. HMPA (0.3 mL) was added followed by
benzyl bromide (340 mg, 2 mmol). After stirring for 30 min.
at rt it was refluxed for 6 h, cooled to rt and quenched by
adding cold water (3 mL). It was extracted with ether
(15 mL£2). Concentration of the ether extract followed by
column chromatography of the residue using ethyl acetate–
petroleum ether (1:19) as eluent furnished the benzyl ether
13 (290 mg, 70%) as a colourless solid, crystallised from
ether–petroleum ether; mp 103–1058C; dH (300 MHz,
CDCl3) 1.27 (s, 3H), 1.35 (s, 3H), 2.07 (s, 3H), 2.30–2.60
(m, 2H), 3.22–3.63 (m, 4H), 3.73 (s, 3H), 4.13 (dd, J¼1.4,
11.4 Hz, 1H), 4.51 (s, 2H), 6.53 (s, 1H), 7.17 (s, 1H), 7.22–
7.27 (m, 5H); dC (75 MHz, CDCl3) 16.1, 21.5, 23.3, 40.0,
40.9, 42.5, 55.9, 64.3, 65.6, 76.1, 80.0, 110.7, 119.0, 120.5,
127.2, 127.3, 128.3, 129.0, 139.6, 148.6, 152.0. Anal. calcd
for C23H28O3S2: C, 66.34; H, 6.73. Found: C, 65.94; H,
6.32.
3.1.10. 2-(1-Hydroxy-1-methyl)-ethyl-4-carbethoxy-
methyl-6-methoxy-7-methyl-2H-1-benzopyran (16). An
ethanolic solution of 15 (50 mg, 0.121 mmol) containing
Pd–C (10%, 20 mg) was stirred over a hydrogen atmos-
phere till hydrogen uptake was complete. The catalyst was
filtered, the solvent removed and the residue was purified by
preparative TLC ((ethyl acetate–petroleum ether (1:4)( to
furnish the saturated hydroxy ester 16 as a colourless liquid
(35 mg, 91%). IR 1732, 3446 cm21; dH (300 MHz, CDCl3)
1.18 (s, 3H), 1.20 (t, J¼7.2 Hz, 3H), 1.23 (s, 3H), 1.41–1.53
(m, 1H), 1.61 (–OH), 2.08 (s, 3H), 2.29–2.37 (m, 2H), 2.86
(dd, J¼4.7, 15.6 Hz, 1H), 3.28–3.38 (m, 1H), 3.60–3.75
(m, 1H), 3.68 (s, 3H), 4.12 (q, J¼7.2 Hz, 2H), 6.51 (s, 1H),
6.59 (s, 1H). dC (75 MHz, CDCl3) 13.2, 14.7, 23.3, 24.8,
28.5, 30.6, 39.4, 54.9, 59.6, 70.7, 80.6, 107.2, 118.0, 120.6,
125.6, 147.2, 150.9, 171.4. Anal. calcd for C18H25O5: C,
67.28; H 7.78. Found: C, 66.89; H, 7.62.
3.1.8. 2-(1-Benzyloxy-1-methyl)-ethyl-6-methoxy-7-
methyl-2H-1-benzopyran-4-one (14). To a solution of
the thioketal 13 (420 mg, 1 mmol) in CH3CN:H2O (4:1)
(15 mL) was added HgCl2 (600 mg, 2.2 mmol) followed by
CaCO3 (230 mg, 2.3 mmol) at rt and stirred for 10 h. Then
the reaction mixture was filtered and the filtrate extracted
with ether (15 mL£2). The ethereal extract was washed with
brine, dried and concentrated to afford a yellow mass.
Purification was carried out by column chromatography
over silica gel using ethyl acetate–petroleum ether (1:4) to
furnish 14 as a colourless solid (240 mg, 70%); crystallised
3.1.11. Ethyl-4-hydroxy-4-(prop-2-enyl)-6-methoxy-7-
methyl-2H-1-benzopyran-2-carboxylate(s) (17). To a
stirred mixture of indium metal (170 mg, 1.5 mmol, small
pieces) in THF (2 mL), allyl bromide (300 mg, 2 mmol) was
added dropwise and stirring was continued at rt untill all the
metal dissolved. To this solution the benzopyran carbox-
ylate 10 (260 mg, 1 mmol) in THF (3 mL) was added
slowly. The reaction was carried out at rt over a period of
another 2 h. and then quenched by aqueous NH4Cl solution
(0.5 mL), extracted with ether (10 mL£3) and concentrated.
The residue was subjected to column chromatography using
silica gel. Elution with ethyl acetate–petroleum ether (1:4)
afforded the allylated product 17 as a viscous liquid
(220 mg, 71%); IR 1739 cm21; For two isomers dH
(300 MHz, CDCl3) 1.20 (t, J¼7.1 Hz, 3H), 2.09 (s, 3H),
2.11 (s, 3H), 2.36 (dd, J¼4.3, 14.0 Hz, 1H), 2.42–2.76 (m,
2H), 2.84–3.09 (m, 2H), 3.71 (s, 3H), 3.74 (s, 3H), 4.15 (m,
2H), 4.62 (dd, J¼4.2, 7.0 Hz, 1H), 4.68 (dd, J¼4.2, 7.0 Hz,
1H), 5.06–5.10 (m, 3H), 5.31 (dd, J¼1.7, 16.4 Hz), 5.52–
5.90 (m, 1H). dC (75 MHz, CDCl3) (13.0, 13.1), (15.0,
15.1), (27.2, 31.1), (34.6, 35.8), (44.8, 45.4), (54.7, 54.8),
(60.3, 60.4), (72.3, 72.6), (104.8, 105.8), (116.3, 117.1),
(118.3, 118.5), (127.6, 128.3), (132.0, 132.1), (133.8),
(144.9, 146.2), (151.4, 151.5), (169.3, 170.4). Anal. calcd
for C17H22O5: C, 66.66; H, 7.18. Found: C, 66.24; H, 7.02.
from ether–petroleum ether, mp 88–898C; IR 1682 cm21
;
dH (300 MHz, CDCl3) 1.34 (s, 6H), 2.16 (s, 3H), 2.73–2.77
(m, 2H), 3.74 (s, 3H), 4.23 (m, 1H), 4.47 (d, J¼11.4 Hz,
1H), 4.52 (d, J¼11.4 Hz, 1H), 6.75 (s, 1H), 7.14 (s, 1H),
7.16–7.25 (m, 5H). dC (75 MHz, CDCl3) 15.9, 19.6,
22.0, 36.8, 54.6, 63.2, 74.9, 82.2, 104.0, 117.7, 118.7,
126.0, 126.2, 127.2, 136.3, 138.1, 151.5, 155.0, 192.0. Anal.
calcd for C21H24O4: C, 74.11; H, 7.05. Found: C, 73.75; H,
6.75.
3.1.9. 2-(1-Benzyloxy-1-methyl)-ethyl-4-carbethoxy-
methylene-6-methoxy-7-methyl-2H-1-benzopyran (15).
To a magnetically stirred suspension of NaH (50 mg,
1 mmol, 50% dispersion in oil) in dry THF (1 mL),
triethylphosphonoacetate (280 mg, 1.25 mmol) was added
at rt and stirring was continued untill a clear solution was
obtained. This clear solution was stirred at rt for another
40 min. Then the benzyl ether 14 (170 mg, 0.5 mmol) in
THF (2 mL) was added dropwise and allowed to stir for
additional 20 h. The reaction mixture was poured into cold
water (7 mL) and extracted with ether (10 mL£3). The
3.1.12. Ethyl-4-(2-hydroxyethyl)-6-methoxy-7-methyl-
2H-1-benzopyran-2-carboxylate (20). To a stirred suspen-
sion of NaIO4 (1.28 g, 6 mmol) in water (5 mL), the
alkenol(s) 17 (310 mg, 1 mmol) in diethyl ether (10 mL)
was added. After stirring for 15 min, a catalytic amount of

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S. K. Sabui, R. V. Venkateswaran / Tetrahedron 59 (2003) 8375–8381
OsO4 was added and stirred at rt till the starting alkenol
disappeared completely (TLC). The organic layer was
separated, washed with aqueous saturated NaHCO3 solution
(3 mL£2), water (5 mL£2), dried and concentrated to
furnish a coloured viscous material (210 mg). IR 1734,
petroleum ether (1:9)] furnished the alkene 22 (20 mg, 86%)
as a colourless liquid. IR 1750 cm21; dH (300 MHz, CDCl3)
1.24 (t, J¼7.1 Hz, 2H), 1.84–1.95 (m, 1H), 2.08 (s, 3H),
2.29 (ddd, J¼2.4, 6.1, 7.2 Hz, 1H), 3.48–3.59 (m, 1H), 3.67
(s, 3H), 4.19 (q, J¼7.1 Hz, 3H), 4.52 (dd, J¼2.4, 10.7 Hz,
1H), 5.11–5.20 (m, 2H), 5.57–5.69 (m, 1H), 6.46 (s, 1H),
6.69 (s, 1H). dC (75 MHz, CDCl3) 14.5, 16.2, 32.7, 40.7,
56.2, 61.7, 73.9, 110.5, 117.5, 119.6, 120.8, 127.4, 140.6,
147.0, 152.6, 171.0. Anal. calcd for C16H20O4: C, 69.56; H,
7.24. Found: C, 69.31; H, 7.02.
1754 cm21
.
NaBH4 (30 mg, 0.789 mmol) was added with stirring in
small portions to a solution of the above crude aldehyde
(210 mg) in ethanol (2 mL) at ice-cold temperature. Stirring
was continued at that temperature for additional 2 h.
Ethanol was removed and the residue diluted with water
(2 mL) and extracted with ether (10 mL£2). The ethereal
extract was washed with water (3 mL£2) and concentrated
to furnish the corresponding crude diol which without
further purification was subject to hydrogenolysis. An
ethanolic solution of the dihydroxy compound containing
Pd–C (10%), (20 mg), HClO4 (2 drops), AcOH (3 drops)
was hydrogenated as for 16. The crude material was purified
by preparative TLC to furnish the hydroxy ester 20 (180 mg,
60% overall for three steps) as a crystalline colourless solid,
mp 42–448C; IR 1754, 3400 cm21. dH (300 MHz, CDCl3)
1.24 (t, J¼7.1 Hz, 3H), 1.51–1.63 (m, 1H), 1.71–1.83 (m,
1H), 1.86 (bs, OH), 2.06 (s, 3H), 2.12–2.23 (m, 1H), 2.36
(ddd, J¼2.6, 6.3, 13.4 Hz, 1H), 3.06–3.10 (m, 1H), 3.68 (s,
3H), 3.70–3.76 (m, 2H), 4.17 (q, J¼7.1 Hz, 2H), 4.44 (dd,
J¼2.6, 10.3 Hz, 1H), 6.56 (s, 1H), 6.68 (s, 1H). dC (75 MHz,
CDCl3) 14.5, 16.2, 31.4, 31.6, 38.1, 56.2, 60.5, 61.8, 74.1,
109.1, 119.7, 122.9, 126.8, 147.8, 152.7, 171.5. Anal. calcd
for C16H22O5: C, 65.30; H, 7.48. Found: C, 64.96; H, 7.42.
3.1.15. 4-Ethenyl-2-(1-hydroxy-1-methyl)-ethyl-6-meth-
oxy-7-methyl-2H-1-benzopyran (23). To a magnetically
stirred solution of MeMgI [prepared from Mg (5 mg,
0.208 mmol), MeI (200 mg, 0.140 mmol)] in ether (2 mL),
at 08C was added a solution of the ester 22 (15 mg,
0.54 mmol) in ether (2 mL). The mixture was brought to rt
and stirred for 30 min. Then it was refluxed for 2 h. The
reaction mixture was cooled to 08C and was decomposed by
adding saturated aqueous NH4Cl solution (0.5 mL) and was
extracted with ether (5 mL£3). The ether solvent was dried
and concentrated. The residue was purified by preparative
TLC, ethyl acetate–petroleum ether (1:9) to afford the
alcohol 23 (13.5 mg, 95%) as a colourless liquid. IR 3438,
1637 cm21; dH (300 MHz, CDCl3) 1.19 (s, 3H), 1.24 (s,
3H), 1.52–1.65 (m, 1H), 1.96 (ddd, J¼1.5, 5.7, 13.2 Hz,
1H), 2.03 (s, 3H), 3.39–3.44 (m, 1H), 3.67 (s, 3H), 3.72 (dd,
J¼1.5, 11.4 Hz, 1H), 5.13 (dd, J¼1.5, 9.9 Hz, 1H), 5.19 (dd,
J¼1.5, 7.1 Hz, 1H), 5.58–5.70 (m, 1H), 6.5 (s, 1H), 6.59 (s,
1H). dC (75 MHz, CDCl3) 14.9, 23.3, 24.8, 28.7, 40.3, 54.9,
70.8, 80.5, 109.3, 115.6, 117.7, 120.2, 125.7, 140.0, 146.8,
150.8. Anal. calcd for C16H22O3: C, 73.28; H, 8.39. Found:
C, 73.19; H, 8.32.
3.1.13. Ethyl-4-(2-nitrophenylselenoethyl)-6-methoxy-7-
methyl-2H-1-benzopyran-2-carboxylate (21). To a sol-
ution of the alcohol 20 (30 mg, 0.102 mmol) in THF
(0.5 mL) containing o-nitrophenyl selenocyanate (50 mg,
0.22 mmol) was added tri-n-butylphosphine (40 mg,
0.198 mmol) dropwise, resulting in a brick red solution
that slowly turned bright yellow over 4 h stirring at rt. The
solvent was removed in vacuum and the residue purified by
column chromatography. Elution with ethyl acetate–
petroleum ether (1:6) afforded the seleno derivative as a
solid product (40 mg, 82%), crystallised from ether
petroleum ether, mp 122–1248C; IR 1752 cm21; dH
(300 MHz, CDCl3) 1.33 (t, J¼7.1 Hz, 3H), 1.92–2.08 (m,
2H), 2.15 (s, 3H), 2.27–2.34 (m, 1H), 2.42–2.50 (ddd,
J¼2.64, 6.48, 10.77 Hz, 1H), 2.84–3.03 (m, 2H), 3.21–3.24
(m, 1H), 3.74 (s, 3H), 4.30 (q, J¼7.1 Hz, 2H), 4.55 (dd,
J¼2.5, 10.4 Hz, 1H), 6.56 (s, 1H), 6.78 (s, 1H), 7.30–7.36
(m, 1H), 7.45–7.55 (m, 2H), 8.29 (dd, J¼1.1, 8.1 Hz, 1H).
dC (75 MHz, CDCl3) 14.6, 16.2, 22.8, 31.1, 33.5, 34.6, 56.3,
61.9, 74.0, 108.8, 120.0, 121.5, 125.9, 126.9, 127.3, 129.3,
129.4, 133.5, 134.0, 147.6, 152.9, 171.2. Anal. calcd
for C22H25O6NSe: C, 55.22; H, 5.23. Found: C, 54.92; H,
5.18.
Acknowledgements
We gratefully acknowledge financial support from Depart-
ment of Science and Technology, Govt. of India, New
Delhi.
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