Iodo- And bromo-enolcyclization of 2-(2-propenyl)cyclohexanediones and 2-(2-propenyl)cyclohexenone derivatives using iodine in methanol and pyridinium hydrobromide perbromide in dichloromethane

Article abstract of DOI:10.1039/b505491e

α-Allylcyclohexane-1,3-diones undergo one-pot iodine-methanol promoted iodocyclization and oxidative aromatization to afford variously substituted 2-iodomethyltetrahydrobenzofuran-4-ones (minor) and 2-iodomethyl-4-methoxydihydrobenzofuran derivatives (maj

Full text of DOI:10.1039/b505491e

View Article Online / Journal Homepage / Table of Contents for this issue
A R T I C L E
Iodo- and bromo-enolcyclization of 2-(2-propenyl)cyclohexanediones
and 2-(2-propenyl)cyclohexenone derivatives using iodine in methanol
and pyridinium hydrobromide perbromide in dichloromethane
Malose J. Mphahlele* and Thwanthwadi B. Moekwa
Department of Chemistry, College of Science, Engineering and Technology, University of South
Africa, P.O. Box 392, Pretoria, 0003, South Africa. E-mail: mphahmj@unisa.ac.za;
Fax: +27 12 429 8549; Tel: +27 12 429 8805
Received 19th April 2005, Accepted 11th May 2005
First published as an Advance Article on the web 31st May 2005
a-Allylcyclohexane-1,3-diones undergo one-pot iodine–methanol promoted iodocyclization and oxidative
aromatization to afford variously substituted 2-iodomethyltetrahydrobenzofuran-4-ones (minor) and
2-iodomethyl-4-methoxydihydrobenzofuran derivatives (major). On the other hand, the a-allyl-1,3-
cyclohexanediones react with pyridinium hydrobromide perbromide in dichloromethane to afford mixtures of
2-bromomethyltetrahydrobenzofuran-4-ones (major) and 3-bromomethyltetrahydrobenzopyran-5-ones (minor).
The prepared products and their derivatives were characterized using a combination of NMR, FT-IR and mass
spectroscopic techniques.
benzofuran and 4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxy-
Introduction
late, the products of which were in turn converted to O-
methylated derivatives using iodomethane in acetone in the pres-
ence of potassium carbonate. In 1980 Tamura and Yoshimoto
reported the aromatization of cyclohexenones using iodine in
methanol under reflux.8 We have also applied these reaction
conditions before to 3-(phosphonoalkyl)cyclohexenones and
have prepared a series of benzylphosphonic esters substituted in
the aromatic ring with a methoxy group.9 In a cognate study we
subjected the 3-(phosphonoalkyl)cyclohexenones to pyridinium
tribromide in acetic acid to afford phenol derivatives bearing 3-
phosphonoalkyl moiety.9 A pyridinium tribromide and sodium
bicarbonate mixture in THF has been shown by Trost et al. to
promote bromolactonization in the synthesis of picrotoxinin.10
The main objective of this investigation was to study new
halocyclization reactions of 2-(2-propenyl)cyclohexanediones
with iodine or pyridinium tribromide, in order to assess the
regioselectivity of the reactions and the possibility to obtain
direct one-pot aromatization of the resulting adducts. The
results have been then extended also to some special 2-(2-
propenyl)cyclohexenones. Herein we describe the outcome of
these reactions and further studies of chemical transformation
of the resulting products.
Dihydrofuran and furan moieties constitute important chemi-
cal units in a large number of naturally occurring substances
obtained from plants and marine organisms.1 Although several
methods have been developed for the synthesis of substituted
dihydrobenzofurans and benzofurans,1,2 due to their importance
as pharmaceutical, flavor, insecticidal and fish antifeedant
agents,2e,3 development of simple and efficient methods for their
construction remains a challenge. Kibayashi and coworkers have
previously reported a one-step synthesis of 4-aminodihydro-
benzofurans and 4-hydroxyindoles via mercury(II) acetate-
promoted dehydrogenation–heteromercuration of 2-allyl-3-
aminocyclohexenones.4 Iodoenolcyclization of 2-allylphenol us-
ing SnCl4–I2 in dichloromethane5a or I2–EPZ-105b has been
reported to afford the 2-iodomethyl-2,3-dihydrobenzofurans,
which are important precursors for the synthesis of benzofurans.
Iodine–sodium bicarbonate mixture in dichloromethane, on
the other hand, has recently been shown to promote electro-
philic cyclization of a-allyl-b-cyclohexanediones to afford the 2-
iodomethyltetrahydrobenzofuran-4-ones in good yields.6a Huang
et al.6b recently prepared these derivatives via polymer-supported
selenium-induced electrophilic cyclization of a-(2-propenyl)-1,3-
cyclohexanediones and subsequent cleavage of the selenium
linkers with CH3I–NaI in DMF. Electrophilic reagents such
as p-methoxyphenyltellurium trichloride2,6 and phenylselenenyl
bromide2,5,6 have also been used before to promote cyclization of
a-allyl-b-cyclohexanediones to tetrahydrofuranone derivatives.
Although several methods have been described in literature
for the construction of 2-iodomethyltetrahydrobenzofuranone
moiety,2e,6,7 corresponding data for the synthesis of 2-bromo-
methyl derivatives are considerably less documented. Recourse
to literature revealed only one example for the synthesis of 2-
bromomethyl-6,6-dimethyltetrahydrobenzofuran-4-one (15%)
involving the use of rhodium(II)-catalyzed reaction of 2-diazo-
5,5-dimethylcyclohexane-1,3-dione with allyl bromide.2e
Results and discussion
The readily accessible 2-(2-propenyl)cyclohexane-1,3-diones 1
were subjected to iodine (2 equiv.) in methanol under reflux.
Two products were isolated by column chromatography and
were found by NMR (1H and 13C), IR and mass spectro-
scopic techniques to correspond to the previously reported 2-
iodomethyl-3,5,6,7-tetrahydrobenzofuran-4-ones 2 (minor) and
the 2-iodomethyl-4-methoxy-2,3-dihydrobenzofurans 3 (major)
described here for the first time (Scheme 1). Products 3a,b,d
are the result of initial hemiacetal formation from 2 followed
by dehydration and spontaneous oxidative aromatization. In
the case of 6,6-dimethyl-1,3-cyclohexanedione derivative 1c we
isolated from the cooled reaction mixture a crystalline product
characterized as the benzofuran-4-one 2c. The 1H- and 13C
NMR spectral data of product 2c compare favourably with data
reported in the literature for the compound that was previously
described by Lee et al.2e as liquid and by Ferraz et al.6a and
Huang et al.6b as oil. Its experimentally determined accurate m/z
value (C12H15O2I: 306.0116) represents the closest fit consistent
Only a limited number of methods exist in literature for the
direct aromatization of cyclohexenone moiety of tetrahydro-
benzofuran-4-ones to dihydrobenzofuran derivatives.1c,2b Yam-
aguchi and coworkers2b previously dehydrogenated the 4-oxo-
4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid to 4-hydroxy-
benzofuran-2-carboxylic acid using copper(II) bromide in re-
fluxing methanol. Lee and Morehead,1c on the other hand,
used DDQ in dioxane on 5-acetyl-4-oxo-4,5,6,7-tetrahydro-
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5
2 4 6 9
©

View Article Online
Scheme 1
with the assigned structure. However, the efficient preparation
of compounds of general formula 2 through iodocyclization
reaction was already described previously.6,2e
Prompted by the scant attention paid in the literature to
the bromoenolcyclization of a-allyl-1,3-dicarbonyl compounds,
in the second part of this investigation we subjected sys-
tems 1 to pyridinium tribromide in dichloromethane at room
temperature to afford mixtures of products characterized as
the corresponding 2-bromomethyltetrahydrobenzofuran-4-ones
4 (major) and 3-bromotetrahydrobenzopyran-5-ones 5 (minor)
(Scheme 2). In the case of substrates 1a and d we also isolated
traces of the 2-bromomethyl-4-hydroxy-2,3-dihydrobenzofuran
derivatives 6 substituted with bromine at either C-5 (6a) or C-
5 and C-7 (6b and 6c). Products 6 are the result of oxidative
aromatization of the cyclohexenone moiety of 4 followed by
halogenation of the aromatic ring. On the other hand, from
the crude mixture of 1b we also isolated from silica gel column
a product characterized using a combination of spectroscopic
techniques as the 5,6-dibromo-2-(2,3-dibromopropyl)-5-methyl-
1,3-benzenediol 7 (5%). The latter is presumably the result
of initial halogenation of the propenyl moiety followed by
oxidative aromatization of the ring to a 5-methylresorcinol
derivative which then undergoes further bromination at C-5 and
C-7. Whereas iodocyclization of a-allylcyclohexanediones leads
exclusively to exo-cyclized derivatives according to Baldwin’s
rules,11 bromoenolcyclization on the other hand gives both the
exo-2 and endo-cyclized products 3. Halocyclization reactions of
1,x-alkenones using Br2 are known to be much faster and non-
selective than the I2 reactions and their product mixtures often
contain 1,2-dibromides and bromosolvates as well as cyclized
material.12 Additionally, it is also known that neighbouring
group participation in internal displacements leading to three-
membered halonium ions by iodine is 1000–3000 fold better than
the corresponding bromine participation.12
Scheme 2
Tetrahydrobenzofuranone and tetrahydropyranone moieties
contain several potential reactive centers for further studies of
chemical transformation. Systems 4a,b,d and 5a,b were sub-
jected to iodine (1.5–2 equiv.) in refluxing methanol to afford the
corresponding 2-bromomethyl-4-methoxydihydrobenzofurans
8a–c and 3-bromo-5-methoxydihydrobenzopyran 9a,b all de-
scribed here for the first time (Scheme 3).
To further demonstrate the versatility of the iodine–methanol
mixture in the construction of diversely functionalized benzo-
furan derivatives, we prepared the 3-phosphonylmethyl-2-(2-
propenyl)-2-cyclohexenone derivative 10a14 and its previously
undescribed 5-methyl derivative 10b and subjected them to
the above reaction conditions to afford the corresponding 2-
iodomethyl-2,3-dihydrobenzofuran derivatives 11a and b as
sole products, respectively (Scheme 4). Under similar reaction
conditions, the 3-(phosphonoalkyl)cyclohexenones bearing no
substituent at position 2 previously afforded the benzylphos-
phonic esters substituted in the aromatic ring with methoxy
group.9 The mechanism of formation of 11 presumably involves
initial iodocyclization of the hemiacetal followed by expulsion
of methanol to form a conjugated diene which then undergoes
oxidative aromatization.
Although the involvement of a bromonium ion cannot be
completely ruled out, the above reaction in our opinion proceeds
through a 2-(2,3-dibromopropyl)-1,3-cyclohexanedione inter-
mediate to form both the endo- and exo-cyclic derivatives. It
has been demonstrated in literature that variously substituted
allylic alcohols react with bromine in dichloromethane to
afford the 1,2-dibromoalcohols, which can be isolated and
then cyclized under basic conditions to the corresponding 3-
bromotetrahydrobenzofuran derivatives.13 This literature obser-
vation, at least in our opinion, provides further support for
the envisaged involvement of the 2-(2,3-dibromopropyl)-1,3-
cyclohexanedione intermediate A in the proposed mechanism.
The 2-iodomethyl-4-methoxydihydrobenzofuran derivatives
3a–c undergo Arbuzov reaction when heated with triethyl
phosphite to afford the corresponding hitherto unknown phos-
phonate derivatives 12 in moderate yields (Scheme 5).
Systems 3a,b and 11a,b were subjected to DBU in toluene
under reflux to afford the corresponding benzofuran derivatives
2 4 7 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5

View Article Online
Scheme 6
Scheme 3
Scheme 7
for the bromoenolcyclization of a-allylcyclohexane-1,3-diones
to afford tetrahydrobenzofuranones and tetrahydrobenzopyra-
nones. Whereas electrophilic reagents such as iodine,1,2,5 p-
methoxyphenyltellurium trichloride2,6 and phenylselenenyl
bromide2,5,6 promote exo-cyclization of a-allyl-b-cyclohexane-
diones to tetrahydrofuranone derivatives in accordance with
Baldwin’s rules,11 bromocyclization is nonselective and it affords
both the exo- and endo-cyclized derivatives.
Experimental
Scheme 4
Solvents and commercially available reagents were purified by
conventional methods before use. Reactions involving organo-
lithium reagents were carried out in an atmosphere of dry
nitrogen using oven-dried glassware. Melting points were de-
termined on a Gallenkamp melting point apparatus and are
uncorrected. For column chromatography, Merck kieselgel 60
(0.063–0.200 mm) was used as the stationary phase. NMR
spectra were obtained as CDCl3 solutions using Varian Mercury
300 MHz NMR spectrometer and the chemical shifts are quoted
relative to the solvent peaks (dH 7.25 and dC 77.0 ppm). 31P
NMR chemical shift values are given relative to 85% H3PO4 as
external standard. FT-IR spectra were recorded neat (powder or
oil) using a FTS 7000 Series Digilab Win-IR Pro spectrometer.
Low- and high-resolution mass spectra were recorded at an
ionization potential of 70 eV using a Micromass Autospec-TOF
(double focusing high resolution) instrument. Substrates 1a–d16
and 10a14 were prepared according to the procedures described
in the respective literature.
Scheme 5
13 (Scheme 6). These products are easily distinguished from
the corresponding precursors by the presence of the methyl and
olefinic proton signals in their 1H NMR spectra in the region d
2.40–2.50 ppm and d 6.00–6.50 ppm, respectively.
Further functional group modification was made on the
4-methoxy-2-methylbenzofurans 13a,b through demethylation
using boron tribromide in dichloromethane to afford the cor-
responding 4-hydroxy-2-methylbenzofurans 14a,b (Scheme 7)
which are useful intermediates in the synthesis of biologically
active furoquinolinedione derivatives.15
In conclusion, the combined electrophilic and oxidative
properties associated with iodine were exploited to construct
diversely substituted tetrahydrobenzofuranones and dihydro-
benzofuran derivatives. Pyridinium tribromide in dichloro-
methane, on the other hand, provides an effective medium
Preparation of diethyl {[(5-methyl-2-(propen-2-yl)-3-
oxo]methyl}phosphonate 10b
n-Butyl lithium (1.6 M solution in hexane; 1.3 mol equiv.) was di-
luted with THF (3 mL per mmol of diethyl methylphosphonate)
and cooled to −65 ◦C. To this solution was added dropwise with
stirring a solution of diethyl methylphosphonate (1 mol equiv.)
in THF (1 mL per mmol of phosphonate) and the mixture
was stirred at this temperature for 30 min. A solution of 3-
chloro-5-methyl-2-(2-propenyl)-2-cyclohexenone (1 mol equiv.)
in THF (1 mL per mmol of electrophile) was then added and
the reaction mixture was stirred at −65 ◦C for 30 min. The
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5
2 4 7 1

View Article Online
mixture was allowed to warm to room temperature and after
stirring for 1 h at this temperature, the mixture was quenched
with 20% aqueous sulfuric acid. The product was extracted with
chloroform and the combined organic layers were sequentially
washed with water, brine and dried (MgSO4). The solvent was
evaporated under reduced pressure and the residue was purified
by column chromatography RF (3 : 2 EtOAc–hexane, v/v) 0.27,
to afford 10b as an oil (50%); dH (300 MHz, CDCl3) 1.04 (3H,
d, J 6.0 Hz), 1.31 (6H, dt, J 1.8 and 7.1 Hz), 2.02–2.31 (3H,
m), 2.47–2.63 (2H, m), 2.81 (2H, ddd, J 14.1 and 24.2 Hz),
3.04–3.21 (2H, m), 4.04–4.16 (4H, m), 4.91 (1H, dddd, J 1.8,
3.6 and 6.6 Hz), 4.96 (1H, t, J 1.8 Hz), 5.66–5.79 (1H, m); dC
(75 MHz, CDCl3) 16.4 (d, JCP 6.0 Hz), 21.0, 29.1, 29.6, 33.3 (d,
JCP 134.0 Hz), 40.2 (d, JCP 2.0 Hz), 45.8, 62.2 (t, JCP 6.0 Hz),
114.8, 135.3, 135.2 (d, JCP 8.0 Hz), 149.4 (d, JCP 11.1 Hz), 198.3
(d, JCP 3.2 Hz); dP 25.6; mmax/cm−1 964.3, 1022.8, 1241.1, 1664.6;
MS (EI) m/z 300 (M+, 45.1), 162 (100), 147 (33.0). HRMS (EI)
calculated for C15H25O4P: 300.1490. Found: 300.1491.
112.4, 112.5, 176.2, 176.3, 194.9, 194.8; mmax/cm−1 1044.1, 1206.0,
1400.8, 1630.7.
2-Iodomethyl-6,6-dimethyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-
one 3c. The product which crystallised from the cooled
reaction mixture of 1c with I2–MeOH was filtered, washed
with ice-cold ethanol and dried to afford pure 3c, solid (80%)
mp 151–154 ◦C; dH (300 MHz, CDCl3 + 0.5% DMSO-d6)
0.87 (3H, s), 0.88 (3H, s), 1.99 (2H, s), 2.08 (2H, s), 2.34 (1H,
ddt, J 1.8, 6.7 and 14.8 Hz), 2.74 (1H, ddt, J 1.9, 10.0 and
14.8 Hz), 3.16 (2H, dd, J 1.6 and 5.3 Hz), 4.56–4.65 (1H, m); dC
(75 MHz, CDCl3 + 0.5% DMSO-d6) 8.7, 27.9, 28.3, 31.9, 33.5,
37.0, 50.2, 82.8, 110.7, 175.5, 194.0; mmax/cm−1 1036.8, 1217.1,
1401.6, 1629.8; MS (EI) m/z 306 (M+, 75.5), 254 (80.0), 250
(51.5), 179 (100), 123 (45.0), 28 (74.0). HRMS (EI) calculated
for C12H15O2I: 306.0117. Found: 306.0116.
2-Iodomethyl-2-methyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-
one 2d and 2-iodomethyl-4-methoxy-2-methyl-2,3-dihydrobenzo-
furan 3d. Reaction of 1d with I2–MeOH followed by column
chromatography (3 : 2 toluene–EtOAc, v/v) yielded products
3d and 2d in sequence.
General procedure for iodocyclization of 1
A stirred mixture of 1 (1 equiv.) and iodine (2 equiv.) in methanol
(5 mL per mmol of allylcyclohexenone) was boiled under reflux
for 3 h. The solvent was evaporated under reduced pressure and
the residue was taken up into chloroform. The organic solution
was sequentially washed with saturated aqueous sodium thio-
sulfate, sodium bicarbonate and brine and then dried (Na2SO4).
The mixture was filtered, evaporated under reduced pressure and
the residue was purified by column chromatography.
3d (RF 0.96), oil (60%); dH (300 MHz, CDCl3) 1.66, 2.98 (1H,
d, J 15.9 Hz), 3.25 (1H, d, J 15.9 Hz), 3.42 (2H, s), 3.82 (3H, s),
6.40 (1H, d, J 3.6 Hz), 6.43 (1H, d, J 3.0 Hz), 7.09 (1H, t, J
7.8 Hz); dC (75 MHz, CDCl3) 15.6, 26.2, 38.7, 55.3, 87.1, 102.9,
103.0, 113.0, 129.2, 156.6, 159.7; mmax/cm−1 760.3, 1086.4, 1246.0,
1462.0, 1605.6; MS (EI) m/z 304 (M+, 100), 177 (70.0), 163
(28.0). HRMS (EI) calculated for C11H13O2I: 303.9960. Found:
303.9960.
2d (RF 0.36), oil (23%); dH (300 MHz, CDCl3) 159 (3H, s), 2.02
(2H, quint., J 6.3 and 10.1 Hz), 2.33 (2H, t, J 6.9 Hz), 2.38–2.44
(1H, m), 2.66 (1H, tt, J 1.5 and 15.0 Hz), 2.85 (1H, tt, J 2.1
and 14.7 Hz), 3.34 (1H, J 10.5 Hz), 3.38 (1H, d, J 10.2 Hz); dC
(75 MHz, CDCl3) 14.5, 21.6, 23.9, 26.2, 36.4, 37.7, 89.4, 112.8,
175.7, 195.6; mmax/cm−1 1000.9, 1179.0, 1399.5, 1626.6; MS (EI)
m/z 292 (M+, 53.0), 165 (100), 43 (59.0). 39 (93.8). HRMS (EI)
calculated for C10H13O2I: 291.9960. Found: 291.9960.
2-Iodomethyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one 2a and
2-iodomethyl-4-methoxy-2,3-dihydrobenzofuran 3a. Reaction
of 1a with I2–MeOH followed by column chromatography (3 :
2 toluene–EtOAc, v/v) yielded two products 3a and 2a in
sequence.
3a (RF 0.86), oil (75%); dH (300 MHz, CDCl3) 2.96 (1H, dd,
J 6.6 and 15.9 Hz), 3.30 (1H, dd, J 3.9 and 10.5 Hz), 3.33 (1H,
dd, J 3.6 and 11.7 Hz), 3.42 (1H, dd, J 5.1 and 10.2 Hz), 3.82
(3H, s), 4.86–4.95 (1H, m), 6.57 (1H, d, J 6.0 Hz), 6.60 (1H, d,
J 5.7 Hz), 7.09 (1H, t, J 8.4 Hz); dC (75 MHz, CDCl3) 9.0, 33.6,
55.4, 82.2, 102.8, 103.2, 112.7, 129.2, 156.4, 160.3; mmax/cm−1
760.8, 1084.3, 1234.4, 1462.0, 1606.7; MS (EI) m/z 290 (M+,
100), 163 (68.3), 147 (26.0), 91 (29.2). HRMS (EI) calculated for
C10H11O2I: 289.9804. Found: 289.9803.
General procedure for bromocyclization of 1
A stirred mixture of 2-allyl-1,3-cyclohexanedione 1 (1 equiv.)
and pyridinium tribromide (1.2–1.5 equiv.) in dichloromethane
(2.5 mL per mmol of 1) was stirred at room temperature for
1 h. The reaction mixture was poured into ice-cold solution
of saturated aqueous Na2CO3 and the product was extracted
into chloroform. The combined chloroform solutions were
washed with brine, dried (Na2SO4), filtered, evaporated under
reduced pressure and the residue was purified by column
chromatography.
◦
2a (RF 0.29), solid (14%), mp 71–73 C (Lit.2e,6 72–74 ◦C);
dH (300 MHz, CDCl3) 2.03 (2H, quint., J 6.6 and 9.4 Hz), 2.33
(2H, t, J 6.5 Hz), 2.40–2.46 (2H, m), 2.58 (1H, ddt, J 2.0, 6.7
and 14.8 Hz), 2.97 (1H, ddt, J 2.0, 10.2 and 14.8 Hz), 3.33 (2H,
dddd, J 6.0, 8.3 and 14.8 Hz), 4.77–4.87 (1H, m); dC (75 MHz,
CDCl3) 8.25, 21.6, 23.8, 32.5, 36.4, 83.4, 112.9, 176.6, 195.4;
mmax/cm−1 937.4, 1222.9, 1403.4, 1614.2.
2-Bromomethyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-one 4a,
3-bromo-2,3,4,6,7,8-hexahydro-1-benzopyran-5(5H)-one 5a, 5-
bromo-2-bromomethyl-4-hydroxy-2,3-dihydrobenzofuran 6a and
5,7-dibromo-2-bromomethyl-4-hydroxy-2,3-dihydrobenzofuran
6b. Reaction of 1a with pyridinium tribromide followed by
column chromatography (3.5 : 1.5 hexane–EtOAc, v/v) yielded
products 6a,6b,5a and 4a in sequence.
6a (RF 0.71), oil (2%); dH (300 MHz, CDCl3) 3.11 (1H, dd, J
6.3 and 16.2 Hz), 3.38 (1H, dd, J 9.3 and 16.2 Hz), 3.54 (1H,
dd, J 6.6 and 10.5 Hz), 3.59 (1H, dd, J 4.8 and 10.7 Hz), 5.01–
5.10 (1H, m), 5.55 (1H, s), 6.32 (1H, d, J 8.4 Hz), 7.19 (1H,
dd, J 0.6 and 8.5 Hz); dC (75 MHz, CDCl3) 32.3, 34.3, 82.4,
101.1, 103.6, 112.6, 131.2, 148.8, 160.3; mmax/cm−1 791.2, 1031.2,
1259.5, 1452.4, 1607.4, 3489.2; MS (EI) m/z 308 (M+, 100), 306
(48.5), 227 (31.5), 148 (81.5), 134 (77.4). HRMS (EI) calculated
for C9H8O279Br2 305.8891. Found: 305.8893.
2-Iodomethyl-6-methyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-
one 2b and 2-iodomethyl-4-methoxy-6-methyl-2,3-dihydrobenzo-
furan 3b. Reaction of 1b with I2–MeOH followed by column
chromatography (3 : 2 toluene–EtOAc, v/v) yielded two
products 3b and 2b in sequence.
3b (RF 0.96), oil (70%); dH (300 MHz, CDCl3) 2.29 (3H, s), 2.91
(1H, dd, J 6.6 and 15.6 Hz), 3.27 (1H, dd, J 9.9 and 15.0 Hz), 3.31
(1H, dd, J 7.5 and 9.9 Hz), 3.41 (1H, dd, J 5.1 and 10.2 Hz), 3.80
(3H, s), 4.83–4.92 (1H, m), 6.24 (1H, s), 6.27 (1H, s); dC (75 MHz,
CDCl3) 9.2, 22.0, 33.4, 55.3, 82.3, 103.4, 104.2, 109.7, 139.8,
156.1, 160.4; mmax/cm−1 978.0, 1094.3, 1220.9, 1336.7, 1602.9;
MS (EI) m/z 304 (M+, 100), 177 (68.0), 28 (72.5). HRMS (EI)
calculated for C11H13O2I: 303.9960. Found: 303.9969.
2b (RF 0.37), (Equal mixture of diastereomers by 13C NMR),
oil (20%); dH (300 MHz, CDCl3) 1.09 (3H, dd, J 1.6 and 6.5 Hz),
2.00–2.59 (4H, m), 2.90–3.00 (1H, m), 3.32 (2H, dd, J 5.7
and 6.9 Hz), 4.76–4.86 (1H, m); dC (75 MHz, CDCl3) 8.2, 8.3,
20.9, 21.0, 29.6, 29.8, 31.7, 31.8, 32.3, 32.4, 44.9, 83.5, 83.6,
6b (RF 0.62), oil (1.5%); dH (300 MHz, CDCl3) 3.24 (1H,
dddd, J 0.9, 6.6 and 16.2 Hz), 3.47 (1H, dddd, J 0.9, 9.5 and
16.2 Hz), 3.53 (1H, dd, J 7.2 and 10.5 Hz), 3.64 (1H, dd, J
4.5 and 10.5 Hz), 5.10–5.19 (1H, m), 5.53 (1H, s), 7.37 (1H,
t, J 1.8 Hz); dC (75 MHz, CDCl3) 33.3, 33.8, 82.6, 93.6, 101.6,
2 4 7 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5

View Article Online
113.3, 133.0, 148.3, 157.4; mmax/cm−1 717.5, 964.4, 1039.9, 1155.4,
1263.3, 1316.3, 1442.8, 1611.2, 3488.0; m/z 388 (100), 384 (M+,
34.0), 307 (55.5), 228 (60.5), 226 (53.0), 147 (33.4). HRMS (EI)
calculated for C9H7O279Br3: 383.7996. Found: 383.7996.
5a (RF 0.29), oil (15%); dH (300 MHz, CDCl3) 2.03 (2H, quint.,
J 6.9 and 9.8 Hz), 2.32 (2H, dt, J 3.6 and 6.5 Hz), 2.40–2.46 (2H,
m), 3.42 (1H, dd, J 8.1 and 9.5 Hz), 3.64–3.73 (1H, m), 3.73 (1H,
dd, J 3.0 and 10.2 Hz), 4.46 (1H, dd, J 5.4 and 9.9 Hz), 4.60 (1H,
t, J 9.9 Hz); dC (75 MHz, CDCl3) 21.6, 24.0, 35.3, 36.4, 36.6,
41.8, 77.5, 113.9, 179.5, 195.1; mmax/cm−1 935.9, 1182.2, 1236.6,
1401.6, 1623.4; MS (EI) m/z 230 (M+, 25.0), 151 (56.0), 137
(58.5), 130 (44.5), 41 (42.5), 28 (85.0). HRMS (EI) calculated
for C9H11O279Br: 229.9942. Found: 229.9945.
(40.0), 179 (47.0), 165 (100), 123 (51.5). HRMS (EI) calculated
for C11H15O279Br: 258.0255. Found: 258.0256.
4c (RF 0.29),6 oil (50%); dH (300 MHz, CDCl3) 1.09 (6H, s),
2.21 (2H, s), 2.29 (2H, t, J 1.8 Hz), 2.69 (1H, ddt, J 1.8, 6.6 and
14.8 Hz), 2.98 (1H, ddt, J 1.8, 10.5 and 14.4 Hz), 3.49 (1H, dd,
J 4.8 and 9.9 Hz), 3.54 (1H, dd, J 4.8 and 9.9 Hz), 5.01 (1H,
doublet of quint., J 3.9, 5.4 and 8.1 Hz); dC (75 MHz, CDCl3)
28.5, 28.8, 30.6, 34.1, 34.5, 37.5, 50.8, 83.2, 111.4, 175.8, 194.7;
mmax/cm−1 1216.9, 1400.3, 1631.8; MS (EI) m/z 258 (M+, 42.3),
204 (95.5), 202 (100), 179 (87.6), 53 (28.7), 41 (36.5). HRMS
(EI) calculated for C9H11O279Br: 258.0255. Found: 258.0256.
2-Bromomethyl-2-methyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-
one 4d and 5,7-dibromo-2-bromomethyl-4-hydroxy-2-methyl-
2,3-dihydrobenzofuran 6d. Reaction of 1d with pyridinium
tribromide followed by column chromatography (3.5 : 1.5
hexane–EtOAc, v/v) yielded products 6d and 4d in sequence.
6d (RF 0.74), oil (10%), dH (300 MHz, CDCl3) 1.67 (3H, s), 3.09
(1H, dd, J 0.9 and 16.2 Hz), 3.47 (1H, dd, J 0.9 and 16.7 Hz),
3.54 (1H, s), 3.56 (1H, s), 7.37 (1H, t, J 0.9 Hz); dC (75 MHz,
CDCl3) 25.4, 38.8, 38.9, 89.5, 93.8, 101.3, 113.6, 133.0, 148.3,
156.8; mmax/cm−1 1001.4, 1182.3, 1400.4, 1627.2; MS (EI) m/z
402 (63.0), 398 (M+, 20.5), 242 (100), 240 (91.5), 63 (47.4), 39
(86.5). HRMS (EI) C10H9O279Br3: 397.9942. Found: 397.9942.
4d (RF 0.24), oil (54%); dH (300 MHz, CDCl3) 1.53 (3H, s),
2.01 (2H, quint., J 6.3 and 9.5 Hz), 2.31 (2H, t, J 6.9 Hz), 2.37–
2.43 (2H, m), 2.61 (1H, dd, J 1.8 and 14.9 Hz), 2.88 (1H, tt, J 1.5
and 15.0 Hz), 3.44 (1H, d, J 11.1 Hz), 3.48 (1H, d, J 10.8 Hz); dC
(75 MHz, CDCl3) 21.5, 23.8, 25.3, 36.3, 36.5, 39.3, 89.6, 112.6,
175.7, 195.5; mmax/cm−1 1001.4, 1182.3, 1400.4, 1627.2; MS (EI)
m/z 244 (M+, 22.0), 165 (100), 137 (27.0), 41 (53.5), 39 (50.8).
HRMS (EI) C10H13O279Br: 244.0099. Found: 244.0098.
4a (RF 0.14), solid (40%), m.p. 82–84 ◦C; dH (300 MHz, CDCl3)
2.03 (2H, quint., J 6.3 and 9.8 Hz), 2.34 (2H, t, J 6.3 Hz), 2.44
(2H, t, J 6.3 Hz), 2.67 (1H, dd, J 6.9 and 15.0 Hz), 2.97 (1H,
dd, J 10.2 and 14.4 Hz), 3.37 (2H, d, J 6.7 Hz), 4.96–5.02 (1H,
m); dC (75 MHz, CDCl3) 21.6, 23.7, 30.8, 34.2, 36.4, 83.2, 112.9,
176.9, 195.4; mmax/cm−1 950.9, 1226.2, 1404.6, 1615.3; MS (EI)
m/z 230 (M+, 41.0), 204 (77.0), 151 (100), 81 (25.5). HRMS (EI)
calculated for C9H11O279Br: 229.9942. Found: 229.9943.
2-Bromomethyl-6-methyl-3,5,6,7-tetrahydrobenzofuran-4(2H)-
one 4b, 3-bromo-2,3,4,6,7,8-hexahydro-7-methyl-1-benzopyran-
5(5H)-one 5b and 4,6-dibromo-2-(2,3-dibromopropyl)-5-methyl-
1,3-benzenediol 7. Reaction of 1b with pyridinium tribromide
followed by column chromatography (3.5 : 1.5 hexane–EtOAc,
v/v) yielded products 7,5b and 4b in sequence.
7 (RF 0.85), solid (5%), m.p. 130–132 ◦C; dH (300 MHz,
CDCl3) 2.55 (3H, s), 3.35 (1H, dd, J 8.4 and 14.1 Hz), 3.55
(1H, dd, J 5.4 and 14.1 Hz), 3.73 (1H, dd, J 7.5 and 10.8 Hz),
3.84 (1H, dd, J 5.4 and 10.7 Hz), 4.55–4.65 (1H, m), 5.82
(1H, s); dC (75 MHz, CDCl3) 24.3, 33.3, 37.1, 51.0, 104.7, 110.2,
135.7, 150.5; mmax/cm−1 883.4, 1076.3, 1161.7, 1244.1, 1316.4,
1387.7, 1599.0, 3440.5; MS (EI) m/z 478 (M+, 31.4), 297 (50.5),
295 (100), 293 (54.5). HRMS (EI) calculated for C10H10O279Br3
477.7414. Found: 477.7416.
General procedure for oxidative aromatization of 4 and 5 using
iodine
A stirred mixture of 4 or 5 (1 equiv.) and iodine (2 equiv.) in
methanol (5 mL per mmol of 4 or 5) was boiled under reflux for
2 h. The solvent was evaporated under reduced pressure and the
residue was taken up into chloroform. The organic solution was
sequentially washed with saturated aqueous sodium thiosulfate,
sodium bicarbonate and brine and then dried (Na2SO4). The
mixture was filtered, evaporated under reduced pressure and the
residue was purified by column chromatography.
5b (RF 0.37), (equal mixture of diastereomers by 13C NMR),
oil (8%); dH (300 MHz, CDCl3) 1.10 (3H, dd, J 2.4 and 6.5 Hz),
2.00–2.20 (2H, m), 2.22–2.35 (1H, m), 2.40–2.53 (2H, m), 3.44
(1H, dddd, J 8.4, 10.0 and 11.4 Hz), 3.63–3.72 (1H, m), 3.42
(1H, dd, J 2.4 and 10.2 Hz), 4.47 (1H, dddd, J 5.4, 6.6 and
9.5 Hz), 4.61 (1H, dt, J 3.1 and 10.1 Hz); dC (75 MHz, CDCl3)
20.8, 20.9, 29.7, 29.8, 31.9, 32.0, 35.3, 35.4, 41.6, 41.7, 45.0,
45.2, 77.6, 77.8, 113.4, 113.7, 179.0, 179.3, 194.7; MS (EI) m/z
244 (M+, 39.2), 204 (25.0), 165 (53.0), 151 (100), 109 (26.2), 69
(27.0), 53 (32.6), 41 (43.0), 39 (50.8). HRMS (EI) calculated for
C10H13O2Br: 244.0099. Found: 244.0098.
2-Bromomethyl-4-methoxy-2,3-dihydrobenzofuran 8a. Reac-
tion of 4a with I2–MeOH followed by column chromatography
RF (toluene) 0.70, yielded 8a, oil (72%); dH (300 MHz, CDCl3)
3.04 (1H, dd, J 6.3 and 15.9 Hz), 3.31 (1H, dd, J 9.3 and
16.1 Hz), 3.50 (1H, dd, J 6.6 and 10.5 Hz), 3.59 (1H, dd, J
5.2 and 10.4 Hz), 3.82 (3H, s), 5.02 (1H, m, J 1.5, 2.7, 5.4 and
8.6 Hz), 6.42 (1H, d, J 8.4 Hz), 6.46 (1H, d, J 8.4 Hz), 7.10
(1H, t, J 8.1 Hz); dC (75 MHz, CDCl3) 32.0, 34.6, 55.3, 81.8,
102.7, 103.2, 112.6, 129.3, 156.5, 160.3; mmax/cm−1 761.5, 1084.8,
1232.5, 1462.0, 1606.7; MS (EI) m/z 242 (M+, 100), 163 (80.0),
149 (96.5), 147 (49.0), 107 (69.8), 91 (85.2), 77 (49.0). HRMS
(EI) calculated for C10H11O279Br: 241.9942. Found: 241.9943.
4b (RF 0.20), (equal mixture of diastereomers by 13C NMR),
oil (44%); dH (300 MHz, CDCl3) 1.11 (3H, d, J 6.3 Hz), 2.03–
2.23 (2H, m), 2.25–2.36 (1H, m), 2.47 (2H, J 3.6 and 16.5 Hz),
2.68 (1H, dd, J 6.9 and 14.7 Hz), 2.98 (1H, J 10.6 and 14.7 Hz),
3.51 (2H, dd, J 5.4 and 6.6 Hz), 4.97–5.06 (1H, m); dC (75 MHz,
CDCl3) 20.8, 20.9, 29.7, 29.8, 31.9, 32.0, 35.3, 35.4, 41.6, 41.7,
45.0, 45.2, 77.6, 77.8, 113.4, 113.7, 179.0, 179.3, 194.7; mmax/cm−1
1210.9, 1394.5, 1610.6; MS (EI) m/z 244 (M+, 34.0), 202 (77.0),
165 (100), 140 (31.0), 41 (31.8). HRMS (EI) calculated for
C9H11O279Br: 244.0099. Found: 244.0099.
2-Bromomethyl-4-methoxy-5-methyl-2,3-dihydrobenzofuran
8b. Reaction of 4b with I2–MeOH followed by column
chromatography RF (toluene) 0.72, yielded 8b, oil (65%); dH
(300 MHz, CDCl3) 2.30 (3H, s), 2.99 (1H, dd, J 6.3 and
15.8 Hz), 3.26 (1H, dd, J 9.3 and 15.6 Hz), 3.48 (1H, dd, J 6.9
and 10.4 Hz), 3.56 (1H, dd, J 5.4 and 10.5 Hz), 4.95–5.05 (1H,
m), 6.24 (1H, s), 6.29 (1H, s); dC (75 MHz, CDCl3) 22.0, 31.9,
34.7, 55.3, 81.9, 103.4, 104.3, 109.6, 139.9, 156.1, 160.4, 166.6;
mmax/cm−1 810.1, 987.2, 1094.9, 1220.9, 1336.9, 1603.1; MS (EI)
m/z 256 (M+, 100), 177 (85.6), 163 (85.0), 121 (69.0), 105 (71.4),
91 (80.0). HRMS (EI) calculated for C11H13O279Br: 256.0099.
Found: 256.0099.
2-Bromomethyl-6,6-dimethyl-3,5,6,7-tetrahydrobenzofuran-
4(2H)-one 4c and 3-bromo-2,3,4,6,7,8-hexahydro-7,7-dimethyl-
1-benzopyran-5(5H)-one 5c. Reaction of 1c with pyridinium
tribromide followed by column chromatography (3.5 : 1.5
hexane–EtOAc, v/v) yielded products 5c and 4c in sequence.
5c (RF 0.43), oil (10%); dH (300 MHz, CDCl3) 1.09 (3H, s),
1.10 (3H, s), 2.20 (2H, s), 2.28 (2H, d, J 0.6 Hz), 3.52 (1H, dd,
J 8.1 and 11.1 Hz), 3.69 (1H, dd, J 3.0 and 9.9 Hz), 3.65–3.75
(1H, m), 4.48 (1H, dd, J 5.4 and 9.9 Hz), 4.61 (1H, t, J 9.9 Hz);
dC (75 MHz, CDCl3) 28.2, 29.1, 35.5, 37.8, 41.5, 51.0, 77.5,
112.5, 178.5, 194.4; MS (EI) m/z 258 (M+, 29.5), 204 (37.0), 202
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5
2 4 7 3

View Article Online
2-Bromomethyl-4-methoxy-2-methyl-2,3-dihydrobenzofuran
8c. Reaction of 4d with I2–MeOH followed by column
chromatography RF (3.5 : 1.5 hexane–EtOAc v/v) 0.85, yielded
8c, oil (86%); dH (300 MHz, CDCl3) 1.62 (3H, s), 2.96 (1H, d,
J 15.9 Hz), 3.29 (1H, d, J 15.9 Hz), 3.53 (2H, s), 3.82 (3H, s),
6.41 (1H, d, J 4.8 Hz), 6.44 (1H, d, J 4.2 Hz), 7.09 (1H, t,
J 8.1 Hz); dC (75 MHz, CDCl3) 25.3, 37.7, 39.8, 55.3, 87.5,
102.9, 103.0, 112.9, 129.3, 156.6, 159.7; mmax/cm−1 761.1, 1053.5,
1089.9, 1249.9, 1462.0, 1606.4; MS (EI) m/z 256 (M+, 81.0), 177
(83.5), 163 (100), 135 (40.0), 39 (41.5). HRMS (EI) calculated
for C11H13O279Br: 256.0099. Found: 256.0098.
JCP 138.0 Hz), 34.9, 62.1 (t, JCP 6.5 Hz), 81.7, 108.9 (d, JCP
4.0 Hz), 122.9 (d, JCP 6.6 Hz), 123.2 (d, JCP 5.6 Hz), 127.9 (d,
JCP 10.0 Hz), 138.6 (d, JCP 3.4 Hz), 159.3 (d, JCP 3.4 Hz); dP
27.5; mmax/cm−1 960.9, 1020.9, 1234.1, 1597.1; MS (EI) m/z 424
(M+, 100), 297 (64.0), 283 (31.5), 159 (96.0), 145 (44.0). HRMS
(EI) calculated for C15H22O4IP: 424.0300. Found: 424.0301.
Arbuzov’s reaction of 3 with triethyl phosphite to form 12.
General procedure
A stirred mixture of 3 (1 equiv.) and triethyl phosphite (4 equiv.)
was heated under reflux for 8 h. The crude mixture was purified
by column chromatography to afford pure 12.
3-Bromo-5-methoxy-3,4-dihydro-2H-1-benzopyran 9a. Re-
action of 5a with I2–MeOH followed by column chromatography
RF (toluene) 0.69, yielded analytically pure 9a, oil (85%); dH
(300 MHz, CDCl3) 3.39 (1H, t, J 9.9 Hz), 3.82 (3H, s), 3.86 (1H,
ddd, J 0.9, 3.3 and 9.9 Hz), 3.91–4.01 (1H, m), 4.53 (1H, dd,
J 5.1 and 9.6 Hz), 4.62 (1H, dt, J 0.9 and 9.3 Hz), 6.40 (1H,
dd, J 0.6 and 8.3 Hz), 6.45 (1H, dd, J 0.6 and 8.9 Hz), 7.12
(1H, dt, J 0.6 and 8.2 Hz); dC (75 MHz, CDCl3) 34.8, 43.8, 55.7,
77.8, 103.4, 103.7, 114.5, 131.0, 157.4, 162.0; mmax/cm−1 773.6,
1083.4, 1238.4, 12271.1, 1455.8, 1606.5; MS (EI) m/z 242 (M+,
66.0), 163 (90.5), 149 (100), 91 (75.5). HRMS (EI) calculated for
C10H11O279Br: 2412.9942. Found: 2412.9942.
2-[(Diethoxyphosphono)methyl]-4-methoxy-2,3-dihydrobenzo-
furan 12a. Reaction of 3a with triethyl phosphite followed by
column chromatography RF (3 : 2 toluene–EtOAc, v/v) 0.19,
afforded pure 12a, oil (66%); dH (300 MHz, CDCl3) 1.29–1.37
(6H, m), 2.15 (1H, dd, J 7.5 and 18.3 Hz), 2.20 (1H, dd, J 7.5
and 18.3 Hz), 2.36 (1H, dd, J 6.3 and 18.8 Hz), 2.41 (1H, dd,
J 6.0 and 18.6 Hz), 2.95 (1H, dd, J 7.2 and 15.9 Hz), 3.34 (1H,
dd, J 9.0 and 15.8 Hz), 4.03–4.22 (4H, m), 5.02–5.15 (1H, m),
6.38 (1H, d, J 4.2 Hz), 6.41 (1H, d, J 3.9 Hz), 7.06 (1H, t, J
8.1 Hz); dC (75 MHz, CDCl3) 16.4 (d, JCP 2.3 Hz), 32.4 (d, JCP
129.2 Hz), 33.9, 55.3, 61.8 (dd, JCP 6.5 and 17.6 Hz), 78.4, 102.7,
103.1, 113.1, 129.1, 156.5, 160.1; dP 27.5; mmax/cm−1 762.6, 951.5,
1021.9, 1234.4, 1464.0, 1606.7; MS (EI) m/z 300 (M+, 59.5),
152 (100), 125 (94.5), 108 (37.0), 97 (44.0), 29 (29.9). HRMS
(EI) calculated for C14H21O5P: 300.1127. Found: 300.1127.
3-Bromo-5-methoxy-7-methyl-3,4-dihydro-2H-1-benzopyran
9b. Reaction of 5b with I2–MeOH followed by column
chromatography RF (toluene) 0.73, yielded analytically pure 9b,
solid (89%), m.p. 83–85 ◦C; dH (300 MHz, CDCl3) 2.29 (3H, s),
3.35 (1H, t, J 10.2 Hz), 3.80 (3H, s), 3.81–3.93 (2H, m), 4.51
(1H, dd, J 5.0 and 9.6 Hz), 4.61 (1H, dt, J 0.9 and 9.2 Hz),
6.22 (1H, s), 6.27 (1H, d, J 0.3 Hz); dC (75 MHz, CDCl3) 22.1,
34.6, 43.3, 55.2, 76.3, 103.9, 104.0, 111.2, 141.3, 156.6, 161.7;
mmax/cm−1 812.7, 1097.9, 1219.0, 1456.3, 1597.1; MS (EI) m/z
256 (M+, 30.0), 177 (100), 163 (68.0); HRMS (EI) calculated for
C11H13O279Br: 256.0099. Found: 256.0099.
2-[(Diethoxyphosphono)methyl]-4-methoxy-6-methyl-2,3-dihy-
drobenzofuran 12b. Reaction of 3b with triethyl phosphite
followed by column chromatography RF (3 : 2 toluene–EtOAc,
v/v) 0.14, afforded pure 12b, oil (55%); dH (300 MHz, CDCl3)
1.33 (6H, tt, J 3.3 and 7.1 Hz), 2.15 (1H, dddd, J 7.5, 15.0
and 18.3 Hz), 2.28 (3H, s), 2.37 (1H, dddd, J 6.0, 15.0 and
18.6 Hz), 2.90 (1H, dd, J 6.9 and 15.6 Hz), 3.29 (1H, dd, J 9.0
and 15.6 Hz), 3.78 (3H, s), 4.02–4.21 (4H, m), 5.01–5.13 (1H,
m), 6.22 (1H, s), 6.24 (1H, s); dC (75 MHz, CDCl3) 16.4 (dd, JCP
2.6 and 5.8 Hz), 21.9, 33.1 (d, JCP 138.0 Hz), 33.7 (d, J 7.7 Hz),
55.3, 61.8 (dd, JCP 6.5 and 18.5 Hz), 78.5, 104.1, 103.4, 110.1,
139.7, 156.1, 160.1; dP 27.6; mmax/cm−1 762.3, 958.9, 1022.8,
1242.2, 1462.0, 1606.5; MS (EI) m/z 314 (M+, 68.0), 175 (50.0),
152 (100), 125 (90.5), 97 (40.5). HRMS (EI) calculated for
C15H23O5P: 314.1283. Found: 314.1283.
General procedure for iodocyclization of 10
A stirred mixture of 10 (1 equiv.) and iodine (2 equiv.) in
methanol (5 mL per mmol of 10) was boiled under reflux for
5 h. The solvent was evaporated under reduced pressure and the
residue was taken-up into chloroform. The organic solution was
sequentially washed with saturated aqueous sodium thiosulfate,
sodium bicarbonate and brine and then dried (Na2SO4). The
mixture was filtered, evaporated under reduced pressure and the
residue was purified by column chromatography to afford pure
11.
2-[(Diethoxyphosphono)methyl]-4-methoxy-2-methyl-2,3-dihy-
drobenzofuran 12c. Reaction of 3d with triethyl phosphite
followed by column chromatography RF (3 : 2 toluene–EtOAc,
v/v) 0.19, afforded pure 12c, oil dH (300 MHz, CDCl3) 1.31
(6H, tt, J 4.5 and 7.1 Hz), 1.62 (3H, s), 2.31 (2H, d, J 19.2 Hz),
2.95 (1H, d, J 15.9 Hz), 3.34 (1H, d, J 15.9 Hz), 3.79 (3H, s),
4.01–4.16 (4H, m), 6.36 (1H, d, J 1.8 Hz), 6.39 (1H, d, J 2.4 Hz);
7.06 (1H, t, J 8.4 Hz); dC (75 MHz, CDCl3) 16.3 (d, JCP 6.3 Hz),
27.4 (d, J 3.5 Hz), 37.3 (d, JCP 137.2 Hz), 39.5 (d, J 4.8 Hz),
55.3, 61.6 (t, JCP 6.2 Hz), 86.5, 102.8, 102.9, 113.5, 129.0, 156.7,
159.3; dP 26.9; mmax/cm−1 763.1, 960.4, 1023.7, 1244.1, 1464.7,
1606.8; MS (EI) m/z 314 (M+, 90.8), 175 (127.0), 152 (100),
125 (88.0), 108 (32.9). HRMS (EI) calculated for C15H23O5P:
314.1283. Found: 314.1283.
4-[(Diethoxyphosphonyl)methyl]-2-iodomethyl-2,3-dihydro-
benzofuran 11a. Reaction of 10a with I2–MeOH followed
by column chromatography RF (EtOAc) 0.57, yielded 11a, oil
(69%); dH (300 MHz, CDCl3) 1.25 (6H, dt, J 3.0 and 7.1 Hz),
2.26 (3H, s), 3.01 (2H, d, J 21.9 Hz), 3.31 (2H, dd, J 7.2 and
9.9 Hz), 3.41 (2H, dd, J 4.5 and 10.1 Hz), 4.81–4.91 (1H,
m), 3.95–4.08 (4H, m), 6.49 (1H, s), 6.60 (1H, d, J 0.6 Hz);
dC (75 MHz, CDCl3) 9.0, 16.4 (d, JCP 5.7 Hz), 31.7 (d, JCP
138.3 Hz), 35.2, 62.2 (t, JCP 6.6 Hz), 81.6, 108.2 (d, JCP 3.7 Hz),
122.4 (d, JCP 5.7 Hz), 126.0 (d, JCP 6.5 Hz), 128.4 (d, JCP 3.5 Hz),
128.6, 138.6 (d, JCP 3.4 Hz), 159.2; dP 27.2; mmax/cm−1 960.6,
1022.1, 1049.6, 1234.4, 1454.3, 1597.2; MS (EI) m/z 410 (M+,
72.0), 283 (72.2), 269 (42.0), 145 (100), 28 (88.0). HRMS (EI)
calculated for C14H20O4IP: 410.0143. Found: 410.0143.
General procedure for the dehydrohalogenation of 3 and 11
A stirred solution of the iodomethyl derivative 3 or 11 (1 equiv.)
in toluene (5 mL per mmol of iodo derivative) was treated with
DBU (3 equiv.). The mixture was refluxed for 18 h, cooled
and then quenched with water. The solution was extracted with
chloroform and the combined organic extracts were washed with
saturated ammonium chloride solution, dried (Na2SO4), filtered
and then evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel to afford the
product.
4-[(Diethoxyphosphonyl)methyl]-2-iodomethyl-6-methyl-2,3-
dihydrobenzofuran 11b. Reaction of 10b with I2–MeOH
followed by column chromatography RF (EtOAc) 0.60, yielded
11b, oil (65%); dH (300 MHz, CDCl3) 1.25 (6H, dt, J 3.0 and
7.1 Hz), 2.26 (3H, s), 3.01 (2H, d, J 21.9 Hz), 3.31 (2H, dd, J
7.2 and 9.9 Hz), 3.41 (2H, dd, J 4.5 and 10.1 Hz), 4.81–4.91
(1H, m), 3.95–4.08 (4H, m), 6.49 (1H, s), 6.60 (1H, d, J 0.6 Hz);
dC (75 MHz, CDCl3) 9.2, 16.4 (d, JCP 6.0 Hz), 21.4, 31.6 (d,
2 4 7 4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5

View Article Online
4-Methoxy-2-methylbenzofuran 13a2a. Reaction of 3a with
DBU followed by column chromatography RF (toluene) 0.76,
yielded 13a, oil (74%); dH (300 MHz, CDCl3) 2.44 (3H, d, J
1.0 Hz), 3.92 (3H, s), 6.45 (1H, d, J 1.0 Hz), 6.62 (1H, d, J
8.0 Hz), 7.05 (1H, d, J 7.8 Hz), 7.13 (1H, t, J 7.8 Hz); dC (75 MHz,
CDCl3) 14.0, 55.5, 99.9, 103.1, 104.1, 119.1, 123.6, 152.7, 153.9,
155.9.
7.01–7.05 (2H, m); dC (75 MHz, CDCl3) 14.0, 99.1, 103.9,
107.7, 118.0, 123.7, 148.3, 154.2, 156.3; mmax/cm−1 767.7, 1017.6,
1228.7, 1287.3, 1460.1, 1602.8, 3339.8; HRMS (EI) calculated
for C9H8O2: 148.0524. Found: 148.0524.
4-Hydroxy-2,6-dimethylbenzofuran 14b. Reaction of 13b
with BBr3 followed by column chromatography RF (toluene)
0.11, yielded 14b, solid (80%), mp 86–88 ◦C; dH (300 MHz,
CDCl3) 2.37 (3H, s), 2.40 (3H, d, J 0.9 Hz), 4.96 (1H, s), 6.35
(1H, t, J 1.1 Hz), 6.42 (1H, s), 6.82 (1H, d, J 0.3 Hz); dC (75 MHz,
CDCl3) 14.0, 21.6, 98.9, 104.3, 109.1, 115.5, 134.2, 147.7, 153.5,
156.7; mmax/cm−1 823.6, 976.0, 1056.7, 1205.8, 1315.4, 1428.5,
1587.6, 3300.9; MS (EI) m/z 162 (M+, 100), 147 (27), 28
(40.5). HRMS (EI) calculated for: C10H11O2 162.0681. Found:
162.0680.
4-Methoxy-2,6-dimethylbenzofuran 13b. Reaction of 3b with
DBU followed by column chromatography RF (toluene) 0.81,
yielded 13b, solid (93%), m.p. 54–56 ◦C; dH (300 MHz, CDCl3)
2.41 (3H, d, J 0.9 Hz), 2.44 (3H, s), 3.90 (3H, s), 6.39 (1H, d, J
0.9 Hz), 6.46 (1H, s), 6.86 (1H, d, J 0.6 Hz); dC (75 MHz, CDCl3)
14.0, 22.0, 55.5, 99.6, 104.3, 104.7, 116.5, 134.0, 152.2, 153.2,
156.2; mmax/cm−1 804.3, 825.5, 1211.3, 1410.0, 1591.2; HRMS
(EI) calculated for C11H12O2: 176.0837. Found: 176.0836.
Acknowledgements
4-[(Diethoxyphosphono)methyl)]-2-methylbenzofuran
13c.
Reaction of 11a with DBU followed by column chromatography
RF (EtOAc) 0.49, yielded 13c, oil (85%); dH (300 MHz, CDCl3)
1.19 (6H, t, J 6.9 Hz), 2.44 (3H, t, J 0.9 Hz), 3.32 (2H, J
21.6 Hz), 3.89–4.03 (4H, m), 6.49 (1H, t, J 1.2 Hz), 7.06–7.11
(1H, m), 7.13 (1H, t, J 7.7 Hz), 7.29–7.30 (1H, m); dC (75 MHz,
CDCl3) 14.1, 16.3 (d, JCP 5.9 Hz), 31.5 (d, JCP 138.6 Hz), 62.1 (d,
JCP 6.8 Hz), 101.7, 109.3 (d, JCP 4.0 Hz), 123.1 (d, JCP 3.4 Hz),
123.4 (d, JCP 9.7 Hz), 123.9 (d, JCP 6.8 Hz), 129.5, 154.6, 155.4;
dP 27.2; mmax/cm−1 791.1, 1013.1, 1084.0, 1258.5; MS (EI) m/z
282 (M+, 72.0), 205 (44.5), 145 (100). HRMS (EI) calculated for
C14H19PO4: 282.1021. Found: 282.1021.
We thank the University of South Africa for financial assistance
and Dr L. Fourie of the University of NorthWest (Potchefstroom
campus) for mass spectral data. We are also grateful to the ref-
erees who reviewed this manuscript for their valuable criticisms
and suggestions.
References
1 (a) J. Lee, J. Li, S. Oya and J. K. Snyder, J. Org. Chem., 1992, 57,
5301; (b) B. B. Kinnel, A. J. Duggan, T. Eisner and J. Meinwald,
Tetrahedron Lett., 1982, 104, 4011; (c) Y. R. Lee and A. T. Morehead,
Jr., Tetrahedron, 1995, 51, 4909; (d) M. Cse´kei, Z. Nova´k, G. Tima´ri
and A. Kotschy, Arkivoc, 2004, 285.
4-[(Diethoxyphosphono)methyl)]-2,6-dimethylbenzofuran 13d.
Reaction of 11b with DBU followed by column chromatography
RF (EtOAc) 0.54, yielded 13d, oil (65%); dH (300 MHz, CDCl3)
1.20 (6H, t, J 7.2 Hz), 2.41 (3H, d, J 3.3 Hz), 3.27 (2H, J
21.6 Hz), 3.91–4.00 (4H, m), 6.42 (1H, t, J 1.2 Hz), 6.92 (1H,
d, J 2.4 Hz), 7.09 (1H, s); dC (75 MHz, CDCl3) 14.1, 16.3 (d,
JCP 5.9 Hz), 16.4, 30.5, 32.4, 62.1 (d, JCP 6.5 Hz), 101.4, 109.8
(d, JCP 4.0 Hz), 122.5, 122.6, 125.2 (d, JCP 6.9 Hz), 126.9 (d, JCP
5.5 Hz), 133.1 (d, JCP 1.3 Hz), 154.9; dP 27.4; mmax/cm−1 787.0,
960.9, 1021.8, 1246.0, 1588.4; MS (EI) m/z 296 (M+, 59.3), 159
(100), 28 (28.0). HRMS (EI) calculated for C15H21PO4: 296.1177.
Found: 296.1177.
2 (a) A. A. Alemagna, C. Baldoli, P. Del Buttero, E. Licarndro and S.
Maiorana, Synthesis, 1987, 192; (b) S. Yamaguchi, K. Yamamoto, T.
Ueda, T. Morikawa and K. S. Kawase, Bull. Chem. Soc. Jpn., 1989,
62, 4066; (c) K. S. Feldman, C. C. Mechem and L. Nader, J. Am.
Chem. Soc., 1982, 104, 4011; (d) A. Fu¨rstener and D. N. Jumbam,
Tetrahedron, 1992, 48, 5991; (e) Y. K. Lee and J. Y. Suk, Tetrahedron,
2002, 58, 2359.
3 G. Brader, S. Vajrodaya, H. Greger, M. Bacher, H. Kalchhauser and
O. Hofer, J. Nat. Prod., 1998, 61, 1482.
4 H. Iida, Y. Yuasa and C. Kibayashi, Tetrahedron Lett., 1982, 23,
3591.
5 (a) K. Orito, T. Hatakeyama, M. Takeo, H. Suginome and M.
Tokuda, Synthesis, 1997, 23; (b) V. A. Maharaj, P. D. Shinde, A. S.
Gajare, M. Karthikeyan and R. D. Wakharkar, Green Chem., 2002,
4, 325.
6 (a) H. M. C. Ferraz, M. K. Sano, M. R. S. Nunesand and G. G.
Bianco, J. Org. Chem., 2002, 67, 4122; (b) E. Tang, X. Huang and
W. - M . X u , Tetrahedron, 2004, 60, 9963.
General procedure for the demethylation of 13a and 13b with
BBr3
A stirred solution of 13a or b (1 equiv.) in dichloromethane (5 mL
per mmol) at 0 ◦C was treated dropwise with BBr3 (1.5 equiv.).
The mixture was then allowed to warm to room temperature
for 24 h. The mixture was cooled to 0 ◦C and quenched
with ice-cold water and the aqueous phase was extracted with
dichloromethane. The combined organic phases were dried
(MgSO4), filtered and evaporated under reduced pressure. The
residue was purified by column chromatography to afford 14.
7 J. W. Lee and D. H. Oh, Heterocycles, 1990, 31, 1417.
8 Y. Tamura and Y. Yoshimoto, Chem. Ind., 1980, 888.
9 M. J. Mphahlele, A. Pienaar and T. A. Modro, J. Chem. Soc., Perkin
Trans. 2, 1996, 1455.
10 B. M. Trost, C. D. Haffner, D. J. Jebaratnam, M. J. Krische and A. P.
Thomas, J. Am. Chem. Soc., 1999, 121, 6183.
11 J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734.
12 A. A. Neverov and R. S. Brown, J. Org. Chem., 1996, 61, 962.
13 M. V. Chirskaya, A. A. Vasil’e, N. L. Sergovskaya, S. V. Shorshnev
and N. L. Sviridov, Tetrahedron Lett., 2004, 45, 8811.
14 M. J. Mphahlele and T. A. Modro, J. Org. Chem., 1995, 60, 8236.
15 O. Cheraoui, P. Nebois and H. Fillion, Tetrahedron, 1996, 52, 9499.
16 M. J. Bullivant and G. Pattenden, J. Chem. Soc., Perkin Trans. 2,
1976, 249.
4-Hydroxy-2-methylbenzofuran 14a. Reaction of 13a with
BBr3 followed by column chromatography RF (toluene) 0.08,
yielded 14a, oil (91%); dH (300 MHz, CDCl3) 2.43 (3H, s),
6.42 (1H, s), 5.10 (1H, br s), 6.58 (1H, dd, J 2.4 and 6.2 Hz),
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 4 6 9 – 2 4 7 5
2 4 7 5