Synthetic approach to 4a-methyltetrahydrofluorene-type diterpenoids via an aromatic oxidation of phenol derivatives

Article abstract of DOI:10.1080/00397911.2010.518274

An intramolecular aromatic oxidation of a phenolic compound with a hypervalent iodine reagent afforded the coupling product, in which the coupling took place at the para-position of the methoxy goup of the starting material instead of the desired para-pos

Full text of DOI:10.1080/00397911.2010.518274

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Synthetic Approach to 4a-
Methyltetrahydrofluorene-Type
Diterpenoids via an Aromatic Oxidation
of Phenol Derivatives
Wuhong Chen a , Koichi Kobayashi a , Kazunori Takahashi a & Toshio
Honda a
a Faculty of Pharmaceutical Sciences, Hoshi University , Tokyo ,
Japan
Published online: 26 Jul 2011.
To cite this article: Wuhong Chen , Koichi Kobayashi , Kazunori Takahashi & Toshio Honda (2011)
Synthetic Approach to 4a-Methyltetrahydrofluorene-Type Diterpenoids via an Aromatic Oxidation of
Phenol Derivatives, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:22, 3385-3402, DOI: 10.1080/00397911.2010.518274
To link to this article: http://dx.doi.org/10.1080/00397911.2010.518274
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Synthetic Communications1, 41: 3385–3402, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518274
SYNTHETIC APPROACH TO 4a-
METHYLTETRAHYDROFLUORENE-TYPE
DITERPENOIDS VIA AN AROMATIC OXIDATION
OF PHENOL DERIVATIVES
Wuhong Chen, Koichi Kobayashi, Kazunori Takahashi, and
Toshio Honda
Faculty of Pharmaceutical Sciences, Hoshi University, Tokyo, Japan
GRAPHICAL ABSTRACT
Abstract An intramolecular aromatic oxidation of a phenolic compound with a hypervalent
iodine reagent afforded the coupling product, in which the coupling took place at the para-
position of the methoxy goup of the starting material instead of the desired para-position of
the isopropenyl group, unfortunately.
Keywords Aromatic oxidation; dichroanone; diterpenoid; hypervalent iodine reagent;
4a-methyltetrahydrofluorene skeleton
INTRODUCTION
Recently, several diterpenoids possessing structurally scarce 4a-methyltetra-
(and hexa-) hydrofluorene skeletons, such as taiwaniaquinol A (1), B (2),[1] and C
(3);[2] taiwaniaquinone A (4),[1] D (5),[3] and H (6);[4] dichroanone (7);[5] dichroanal
B (8); and standishinal (9);[6] have been isolated from Taiwania cryptomerioides,[1–4]
Salvia dichroantha,[5] Thuja standishii,[6] and other related plants (Fig. 1).
Some of them exhibit attractive biological activities. For example, taiwaniaqui-
none D (5) is known to show antitumor activity, and standishinal (9) with
aromatase-inhibitory activity is recognized as a promising candidate for the treatment
of breast cancer.[7] Because of their significant biological activities and intriguing
structural features, these diterpenoids have received special attention, and several
synthetic methods have been developed to date.[8]
Received October 13, 2009.
Address correspondence to Toshio Honda, Faculty of Pharmaceutical Sciences, Hoshi University,
Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan. E-mail: honda@hoshi.ac.jp
3385

3386
W. CHEN ET AL.
Figure 1. Structures of 4a-methyltetra- (and hexa-) hydrofluorene-type diterpenes.
As part of our continuing exploitation of an aromatic oxidation strategy with a
hypervalent iodine reagent in the synthesis of bioactive natural products,[9] we are
also interested in developing a general synthetic procedure for these diterpenes.
For the synthesis of these diterpenenes, we focused our attention on the bond
formation between the 4a and 4b positions of the basic skeleton by using an aromatic
oxidation of a phenolic compound with a hypervalent iodine reagent as depicted
in Scheme 1, although there have been several strategies to achieve such a bond
formation.[8]
RESULTS AND DISCUSSION
The starting phenolic compound as a precursor for an aromatic oxidation was
prepared as follows.
The known phenolic ester (10),[10] readily prepared from 2,6-dimethylbenzoic
acid, was protected as its silyl ether (11). Reduction of 11 with diisobutylaluminum
hydride (DIBAL), followed by oxidation of the resulting alcohol (12) with pyridinium
dichromate (PDC) or manganese dioxide, afforded the corresponding aldehyde (13)
in 63% overall yield from 10. A coupling reaction of 13 with the Grignard reagent
(14), derived from the known 5-bromo-1-isopropenyl-2,3-dimethoxybenzene,[11]
was successfully carried out in tetrahydrofuran (THF) at 0 ꢀC to give the alcohol
Scheme 1. Retrosynthetic analysis of the target diterpenes.

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3387
(15) in 80% yield. Deprotection of the silyl group of 15 by treatment with tetrabutyl-
ammonium fluoride (TBAF) in THF gave the resulting phenolic compound (16),
which was then subjected to the key aromatic oxidation. We note in advance that
an aromatic oxidation of a phenolic compound with a hypervalent iodine reagent
in the presence of 2.0 equivalents of base sometimes gives the desired product in better
yield than in the absence of the base.[9d] Therefore, we adopted such reaction
conditions for the oxidation of 10 as follows. Treatment of 16 with 1.1 equivalents
of iodobenzene diacetate (PIDA) in hexafluoroisopropanol (HFIP) in the presence
of 2.0 equivalents of n-BuLi at 0 ꢀC to room temperature for 10 min provided the
oxidation product (17) in 40% yield (Scheme 2). Based on the examination of the
molecular models for the possible two products, we first assumed that the aromatic
oxidation might occur at the para-position of isopropenyl group, providing the
desired compound (18), because the steric hindrance between the isopropenyl group
and the angular methyl group was observed in 17. However, the aromatic oxidation
took place at the para-position of the methoxy group to furnish 17 as the sole coup-
ling product, whose structure was determined by analysis of its NMR spectra. In our
analysis of the nuclear Overhauser effect (NOE) experiment, NOEs between 8-H and
9-H, and also 8-H and the methyl group of the 7-methoxy function, were observed,
unambiguously supporting the structure of 17. The relative stereochemistry of the
hydroxy group and an angular methyl group of 17 were assumed to be cis on the basis
Scheme 2. Aromatic oxidation of the phenolic compound (16) with PIDA.

3388
W. CHEN ET AL.
of the NOE experiment, where no NOE was observed between the proton underneath
the hydroxy and the methyl groups.
Similar cyclization was also observed in the synthesis of dichroanone and
taiwaniaquinol B.[8i] To obtain the desired coupling compound, we decided to
prepare the bromide (24), in which the para-position of the methoxy group was
blocked with a bromine atom and hence the coupling would be expected to occur
at the para-position of the isopropenyl group.
Thus, the isopropenyl group of 16 was hydrogenated over palladium on carbon
to give the isopropyl derivative (19). After protection of both hydroxy groups by
acetylation in the usual manner, the resulting diacetate (20) was brominated with
N-bromosuccimide (NBS) in acetonitrile to provide the bromide (21). Partial
hydrolysis of 21 with aqueous potassium carbonate in MeOH afforded a phenolic
compound (22). However, oxidation of 22 with PIDA in HFIP, as described pre-
viously, gave none of the coupling product, unfortunately. Interestingly, an addition
of an n-butyl moiety to 22, leading to the formation of the dienone (23) in poor yield,
was observed under these reaction conditions (Scheme 3).
By changing the solvent from TFIP to 2,2,2-trifluoroethanol (TFE) in the
absence of base, an addition of the trifluoroethoxy group to 24 took place at the
para-position of the phenolic hydroxy group to generate the dienone (25) as a mixture
of diastereoisomers in 25% yield.[12]
We thought that the introduction of a bromine atom might decrease the
reactivity of the benzene ring, providing 23 or 25 instead of the desired cyclization
Scheme 3. Aromatic oxidation of the phenolic compounds (22 and 24) with PIDA.

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3389
product; therefore, the preparation of the precursor having an electron-donating
group at the same position as the bromide (22) was investigated next.
Addition of the Grignard reagent (26), derived from the known 1-bromo-3-
isopropyl-2,4,5-trimethoxybenzene,[13] to the aldehyde (13) gave the alcohol (27),
which, on treatment with TBAF in THF, afforded the desired phenolic compound
(28). Again, the oxidation of 28 using PIDA as the oxidant in TFE afforded the
adduct (29) in 16% yield, and none of the coupling product could be isolated under
these reaction conditions (Scheme 4).
The aromatic oxidation was also applied to the acetate of 28; however,
decomposition of the starting material was always observed under a variety of reac-
tion conditions. Again, the oxidation of the ketone (31) produced the adduct (32) as
the sole isolable product in 24% yield. Although the trimethoxybenzene derivative is
superior to the corresponding dimethoxybenzene derivative for the desired aromatic
oxidation in terms of electron density, we speculate that a trimethoxybenzene ring is
unfavorable for the coupling in terms of steric hindrance. Thus, the dimethoxy
derivative was synthesized for further investigation of the oxidation. The precursor
(35) was prepared starting from 1-bromo-3-isopropyl-2,4-dimethoxybenzene[14]
using the same procedure as described for the synthesis of the trimethoxy derivative
(28). Attempted oxidation of 35, however, afforded the dienone (36) in 22% yield as
the sole isolable product (Scheme 5).
In 1998, Kita and coworkers reported that the acetal is an effective protecting
group to give the coupling product, regioselectively, in an intramolecular oxidative
coupling with a hypervalent iodine reagent.[15] Thus, we synthesized the acetal deriva-
tive (39) from the Grignard reagent, prepared from the corresponding bromide,[16] as
the precursor for the oxidation. However, attempted oxidations for 39 under a variety
of reaction conditions all failed to obtain the desired coupling product.
For the synthesis of a core skeleton of the target compounds, we focused on the
bond formation between the 4a- and 4b- positions of the basic structures by using an
aromatic oxidation of a phenolic compound with a hypervalent iodine reagent; how-
ever, none of attempts gave the desired product, unfortunately. Thus, we decided to
Scheme 4. Attempted aromatic oxidation of 28 and 31 with PIDA.

3390
W. CHEN ET AL.
Scheme 5. Attempted aromatic oxidation of 35 and 39 with PIDA.
change the synthetic strategy, in which a benzoquinone derivative derived by
oxidation of the isopropyl-substituted benzene ring would be involved as a key inter-
mediate. Oxidation of 19, a reduction product of 16, with 6 N nitric acid in ethanol at
0 ꢀC gave the ethoxy-substituted compound (40) in 68% yield (Scheme 6). When 28
was treated with 6 N nitric acid in EtOH at 0 ꢀC for 2.5 h, the fragmentation
products, 3-isopropyl-1,2,4-trimethoxy-5-nitrobenzene (41) and 3-hydroxy-2,6-
dimethyl-4-nitrobenzaldehyde (42), were obtained, respectively. The structure of
41 was determined based on the analyses of its spectroscopic data and comparison
with those of the structurally related compounds.[17] The structure of 42 also was
unambiguously confirmed based on its spectroscopic data. An alternative oxidation
of 19, 28, or 31 with silver(II) oxide and 6 N nitric acid[18] in an appropriate solvent,
such as dioxane, ethanol, and acetone, under various reaction conditions gave a
complex mixture of structurally unidentified compounds.
Scheme 6. Attempted oxidation of 19 and 28 with HNO3.

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3391
CONCLUSION
In summary, we disclose the preparation of the basic skeleton of 4a-methyl-
tetrahydrofluorene diterpenes by exploitation of an aromatic oxidation of a phenolic
compound with a hypervalent iodine reagent.
Although it is very hard to rationalize the relationship between the reactivity
and the substitution patterns of the phenolic compounds for the aromatic oxidation
at present, it is worthy of note that the addition of a trifluoroethoxy group to the
phenolic compounds takes place under the aromatic oxidation conditions using
1.1 equivalents of PIDA in TFE. With the suitable substitution pattern of substrate,
the strategy developed here can be applied to the synthesis of this class of diterpenes.
EXPERIMENTAL
Melting points were measured with a Yanagimoto MP apparatus and are uncor-
rected. IR spectra were obtained using a JASCO FT=IR-200 spectrophotometer.
1H- and 13C-NMR spectra were obtained on Bruker AV 400 (1H-NMR: 400 MHz,
13C-NMR: 100 MHz), or JEOL LA-500 (1H-NMR: 500 MHz, 13C-NMR: 125 MHz)
instrument for solutions in CDCl3 unless otherwise noted, and chemical shifts are
reported on the d scale from internal TMS. MS spectra were measured with a JEOL
JMS-D 300 spectrometer. Elemental analyses were performed on a Yanaco-MT5.
Methyl 3-(tert-Butyldimethylsilyloxy)-2,6-dimethylbenzoate (11)
To a stirred solution of 10 (8.3 g, 46 mmol) and imidazole (6.3 g, 92 mmol) in
dry CH2Cl2 (100 mL) was added TBSCl (10.4 g, 69 mmol) in one portion at 0 ꢀC.
The resulting mixture was stirred at room temperature for 3 h, and then poured into
ice water. The whole mixture was extracted with dichloromethane, and the extract
was dried over Na2SO4. Evaporation of the solvent gave a residue, which was pur-
ified by column chromatography eluting with hexane-Et2O (20=1, v=v) to afford
11 (11.0 g, 80%) as a colorless oil. IR: nmax 2954, 2931, 1733, 1287 and 837 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d 0.19 (s, 6H), 1.00 (s, 9H), 2.13 (s, 3H), 2.21
(s, 3H), 3.90 (s, 3H), 6.71 (d, J ¼ 8.0 Hz, 1H), 6.88 (d, J ¼ 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d ꢁ4.2, 13.8, 18.3, 18.9, 25.8, 51.9, 119.5, 125.6, 126.9, 128.0,
135.4, 151.7, 170.4. MS (CI): m=z 295 (Mþ þ 1). HRMS (CI) calcd. for C16H27O3Si:
295.1729; found: 295.1702.
3-(tert-Butyldimethylsilyloxy)-2,6-dimethylbenzyl Alcohol (12)
DIBAL-H (80 mL, 81 mmol, 1.02 mol=L in hexane) was added to a stirred
solution of 11 (11.0 g, 36.8 mmol) in dry CH2Cl2 (150 mL) dropwise at ꢁ78 ꢀC, and
the resulting mixture was stirred at the same temperature for 1 h. HCl (1 mol=L)
and water were successively added to the mixture. The mixture was extracted with
ethyl acetate, and the extract was dried over Na2SO4. Evaporation of the solvent gave
a residue, which was purified by column chromatography, eluting with hexane–Et2O
(5=1, v=v), to afford the desired product 12 (9.2 g, 94%) as a white solid. IR nmax
:
1
3305, 2957, 2929, 1482 and 1273 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.20 (s, 6H),

3392
W. CHEN ET AL.
1.01 (s, 9H), 2.29 (s, 3H), 2.35 (s, 3H), 4.71 (s, 2H), 6.67 (d, J ¼ 8.0 Hz, 1H), 6.89 (d,
J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d ꢁ4.2, 12.3, 18.3, 19.0, 25.9, 59.6,
118.3, 128.0, 128.5, 129.7, 137.9, 152.1. MS (CI): m=z 277 (Mþ þ 1). HRMS (CI)
calcd. for C15H27O2Si: 267.1780; found: 267.1788.
3-(tert-Butyldimethylsilyloxy)-2,6-dimethylbenzaldehyde (13)
Pyridinium dichromate (2.1 g, 5.6 mmol) was added to a solution of 12 (1.0 g,
3.7 mmol) in CH2Cl2 (15 mL) at room temperature, and the resulting mixture was
stirred at the same temperature for 3 h. Ethyl acetate and celite were added to this
mixture, and the whole mixture was filtered to remove insoluble materials. The fil-
trate was concentrated and purified by flash column chromatography, eluting with
hexane–Et2O (1=10, v=v), to afford 13 (810 mg, 82%) a colorless oil. IR nmax
:
2957, 2930, 1743 and 1277 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.20 (s, 6H), 1.02
(s, 9H), 2.45 (s, 3H), 2.51 (s, 3H), 6.88 (d, J ¼ 8.0 Hz, 1H), 6.93 (d, J ¼ 8.0 Hz,
1H), 10.58 (s, 1H). 13C NMR (100 MHz, CDCl3): d ꢁ4.3, ꢁ4.2, 12.3, 18.3, 19.9,
25.8, 123.4, 129.4, 131.5, 133.3, 133.8, 152.4, 194.2. MS (CI): m=z 264 (Mþ). HRMS
(CI) calcd. for C15H24O2Si: 264.1546; found: 264.1527.
1
General Procedure for the Grignard Reaction
A solution of the bromide (1.2 eq.) in dry THF was added to a stirred suspension
of magnesium turnings (1.3 eq.) in dry THF in the presence of a small crystal of iodine
at room temperature under argon. The mixture started to reflux during the addition.
After addition of all the bromide, the reaction mixture was refluxed for 30 min. The
Grignard solution thus prepared was added to a solution of the aldehyde (1.0 eq.) in
dry THF at 0 ꢀC, and the resulting mixture was stirred at ambient temperature for 2 h.
The mixture was treated with saturated aqueous ammonium chloride solution and
extracted with Et2O. The ethereal layer was washed with brine and dried over Na2SO4.
Evaporation of the solvent gave a residue, which was subjected to column chromato-
graphy on silica gel. Elution with hexane–Et2O afforded the desired product.
(3-[tert-Butyldimethylsilyloxy]-2,6-dimethylphenyl)(3-isopropenyl-4,
5-dimethyl)methanol (15)
IR nmax: 3480, 2956, 2930, 1479 and 1260 cmꢁ1. 1H NMR (400 MHz, CDCl3): d
0.18 (s, 3H), 0.19 (s, 3H), 0.99 (s, 9H), 2.07 (s, 3H), 2.12 (s, 3H), 2.20 (s, br, 1H), 2.25
(s, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 4.97 (s, 1H), 5.07 (s, 1H), 6.25 (d, J ¼ 4.0 Hz, 1H),
6.59 (s, 1H), 6.70 (d, J ¼ 8.0 Hz, 1H), 6.85 (s, 1H), 6.89 (d, J ¼ 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d ꢁ4.2, ꢁ4.1, 13.5, 18.3, 20.2, 23.5, 25.9, 55.8, 60.7, 71.5, 108.9,
115.2, 118.3, 118.3, 128.3, 128.9, 129.5, 137.4, 138.7, 140.4, 143.7, 152.6, 152.6. MS
(CI): m=z 442 (Mþ). HRMS (EI) calcd. for C26H38O4Si: 442.2539; found: 442.2559.
General Procedure for Removal of Silyl Group with TBAF
To a stirred solution of the silyl ether (1.0 eq.) in dry THF, a solution of TBAF
(1 mol=L in THF, 1.1 eq.) was added at 0 ꢀC, and the resulting mixture was stirred

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3393
for 30 min at room temperature. The reaction was treated with water and extracted
with Et2O. The ethereal layer was washed with brine and dried over Na2SO4. Evap-
oration of the solvent gave a residue, which was subjected to column chromato-
graphy on silica. Elution with hexane–Et2O afforded the desired product.
3-[Hydroxyl(3-isopropenyl-4,5-dimethoxyphenyl)methyl]-2,4-
dimethylphenol (16)
IR nmax: 3420, 2934, 1456, 1261 and 1070 cmꢁ1. 1H NMR (400 MHz, CDCl3): d
2.07 (s, 3H), 2.14 (s, 3H), 2.22 (d, J ¼ 4.4 Hz, 1H), 2.26 (s, 3H), 3.77 (s, 3H), 3.80 (s,
3H), 4.75 (s, 1H), 4.98 (s, br, 1H), 5.08 (s, br, 1H), 6.26 (d, J ¼ 4.4 Hz, 1H), 6.59 (s,
1H), 6.69 (d, J ¼ 8.0 Hz, 1H), 6.87 (s, 1H), 6.91 (d, J ¼ 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 12.4, 20.2, 23.4, 55.9, 60.7, 71.3, 109.0, 114.5, 115.2, 118.3,
123.5, 128.5, 129.0, 137.4, 138.6, 140.3, 143.7, 144.8, 152.5, 153.1. MS (CI): m=z
328 (Mþ). HRMS (EI) calcd. for C20H24O4: 328.1674; found: 328.1682.
(4aRꢂ,9Rꢂ)-9-Hydroxy-5-isopropenyl-6,7-dimethoxy-1,4a-dimethyl-
4a,9-dihydro-2H-fluoren-2-one (17)
n-BuLi (0.32 mL, 1.59 mol=L in hexane, 0.52 mmol) was gradually added to
HFIP (2 mL) over 3 min at 0 ꢀC. A solution of 16 (100 mg, 0.26 mmol) in HFIP
was added to that solution at the same temperature, and the resulting mixture was
treated with PIDA (83 mg, 0.26 mmol). After being stirred for a further 10 min at
ambient temperature, the mixture was directly purified by silica-gel column chroma-
tography. Elution with hexane–Et2O (1=1, v=v) gave 17 (40 mg, 40%) as a yellow
powder. IR nmax: 3422, 2930, 1635, 1464 and 1023 cmꢁ1 1H NMR (400 MHz,
.
CDCl3): d 1.75 (s, 3H), 2.04 (s, 3H), 2.06 (s, 3H), 3.77 (s, 1H), 3.81 (s, 3H), 3.90
(s, 3H), 5.05 (s, 1H), 5.42 (s, 1H), 5.57 (d, J ¼ 4.4 Hz, 1H), 6.26 (d, J ¼ 8.0 Hz,
1H), 7.02 (s, 1H), 7.60 (d, J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 11.1,
25.8, 35.2, 50.8, 55.9, 61.4, 72.6, 108.5, 116.5, 117.8, 127.7, 130.1, 133.1, 134.8,
137.3, 141.5, 150.9, 152.9, 162.4, 187.1. MS (CI): m=z 326 (Mþ), 308. HRMS (EI)
calcd. for C20H22O4: 326.1518; found: 326.1545.
3-[Hydroxy(3-isopropyl-4,5-dimethoxyphenyl)methyl]-2,4-
dimethylphenol (19)
A mixture of 16 (50 mg, 0.15 mmol), 10% Pd=C (10 mg), and MeOH (5 mL) was
stirred at room temperature under an atmospheric pressure of hydrogen for 16 h.
The reaction mixture was filtrated through a pad of celite, and the filtrate was
concentrated under reduced pressure to give the desired product 19 (50 mg, 100%)
1
as a white crystal. IR nmax: 3393, 2962, 1488 and 1457 cmꢁ1. H NMR (400 MHz,
CDCl3): d 1.12 (d, J ¼ 6.8 Hz, 3H), 1.15 (d, J ¼ 6.8 Hz, 3H), 2.13 (s, 3H), 2.18 (d,
J ¼ 4.4 Hz, 1H), 2.26 (s, 3H), 3.24–3.34 (m, 1H), 3.77 (s, 3H), 3.80 (s, 3H), 4.68 (s,
1H), 6.27 (d, J ¼ 4.4 Hz, 1H), 6.70 (d, J ¼ 8.0 Hz, 3H), 6.92 (d, J ¼ 8.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3): d 12.4, 20.1, 23.5, 26.9, 55.7, 60.9, 71.5, 107.4, 114.4,
115.4, 123.5, 128.5, 128.9, 138.8, 140.5, 141.9, 144.8, 152.4, 153.1. MS (EI): m=z
330 (Mþ). HRMS (EI) calcd. for C20H26O4: 330.1831; found: 330.1839.

3394
W. CHEN ET AL.
[3-(Acetoxy)-2,6-dimethylphenyl](3-isopropyl-4,5-dimethoxyphenyl)-
methyl Acetate (20)
Acetyl chloride (1.72 mL, 24 mmol) was added to a stirred solution of 19 (1.6 g,
4.8 mmol) and triethylamine (6.7 mL, 48 mmol) in dry CH2Cl2 (20 mL) at 0 ꢀC, and
the resulting mixture was stirred at ambient temperature for 14 h. The mixture was
treated with water and extracted with ethyl acetate. The extract was washed with
brine and dried over anhydrous Na2SO4. Evaporation of the solvent gave a residue,
which was purified by silica-gel column chromatography. Elution with hexane–Et2O
(2=1, v=v) gave 20 (1.5 g, 75%) as a white foam. IR nmax: 2341, 2359, 1761, 1741 and
1219 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d 1.12 (d, J ¼ 6.8 Hz, 3H), 1.14 (d,
J ¼ 6.8 Hz, 3H), 2.08 (s, 3H), 2.17 (s, 3H), 2.30 (s, 3H), 2.36 (s, 3H), 3.25–3.33 (m,
1H), 3.73 (s, 3H), 3.79 (s, 3H), 6.44 (s, 1H), 6.58 (s, 1H), 6.92 (d, J ¼ 8.0 Hz, 1H),
7.06 (d, J ¼ 8.0 Hz, 1H), 7.32 (s, 1H). 13C NMR (100 MHz, CDCl3): d 13.2, 20.4,
20.7, 20.8, 21.1, 23.4, 27.0, 55.7, 60.9, 72.9, 107.8, 116.0, 121.8, 129.2, 130.1, 134.3,
135.5, 137.1, 142.2, 145.6, 148.2, 152.6, 169.3, 170.3. MS (EI): m=z 414 (Mþ). HRMS
(EI) calcd. for C24H30O6: 414.2042; found: 414.2062.
3-[(Acetoxy)-(2-bromo-3-isopropyl-4,5-dimethoxyphenyl)methyl]-2,
4-dimethylphenyl Acetate (21)
NBS (0.47 g, 2.65 mmol) was added to a stirred solution of 20 (1.5 g, 2.4 mmol)
in dry acetonitrile (25 mL) at room temperature. The mixture was stirred at the same
temperature for 4 days, and the solvent was removed under reduced pressure to leave
a residue, which was purified by silica-gel column chromatography, eluting with
hexane–Et2O (2=1, v=v) to give 21 (1.1 g, 61%) as a white foam. IR nmax: 1760,
1743, 1229 and 1194 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d 1.34 (d, J ¼ 6.8 Hz,
3H), 1.37 (d, J ¼ 6.8 Hz, 3H), 2.10 (s, 3H), 2.17 (s, 3H), 2.31 (s, 3H), 2.35 (s, 3H),
3.25–3.33 (m, 1H), 3.59 (s, 3H), 3.84 (s, 3H), 6.46 (s, 1H), 6.92 (d, J ¼ 8.0 Hz, 1H),
7.07 (d, J ¼ 8.0 Hz, 1H), 7.32 (s, 1H). 13C NMR (100 MHz, CDCl3): d 14.0, 20.7,
20.9, 21.0, 23.4, 55.6, 55.7, 60.8, 75.1, 112.8, 121.7, 121.8, 129.5, 129.6, 135.0,
136.1, 141.4, 148.5, 151.77, 169.4, 169.8. MS (EI): m=z 492 (Mþ ꢁ 1). HRMS (EI)
calcd. for C24H29O6 81Br: 492.1147; found: 492.1120.
(2-Bromo-3-isopropyl-4,5-dimethoxyphenyl)(3-hydroxy-2,6-
dimethylphenyl)methyl Acetate (22)
A mixture of 21 (228 mg, 0.46 mmol), K2CO3 (0.19 g, 1.38 mmol), H2O (5 mL),
and MeOH (5 mL) was stirred at room temperature for 2 h, and then the solvent was
removed under reduced pressure. The residue was extracted with Et2O, and the
extract was washed with brine and dried over Na2SO4. Evaporation of the solvent
gave 22 (200 mg, 96%) as a white foam. IR nmax: 3414, 1740, 1273 and 1233 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d 1.35 (d, J ¼ 6.8 Hz, 3H), 1.38 (d, J ¼ 6.8 Hz, 3H),
2.11 (s, 3H), 2.26 (s, 3H), 2.28 (s, 3H), 3.59 (s, 3H), 3.71–3.80 (m, 1H), 3.84 (s, 3H),
4.63 (s, 1H), 6.49 (s, 1H), 6.70 (d, J ¼ 8.0 Hz, 1H), 6.93 (d, J ¼ 8.0 Hz, 1H), 7.30 (s,
1H). 13C NMR (100 MHz, CDCl3): d 13.1, 20.6, 20.8, 21.0, 55.6, 60.8, 75.7, 112.9,

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3395
114.8, 123.2, 129.0, 129.2, 135.8, 141.3, 151.7, 152.5, 170.1. MS (EI): m=z 451 (Mþ).
HRMS (EI) calcd. For C22H27O5 81Br: 451.1120; found: 451.1140.
(2-Bromo-3-isopropyl-4,5-dimethoxyphenyl)(6-butyl-2,6-
dimethylphenyl-3-oxocyclohexa-1,4-dien-1-yl)methyl Acetate (23)
n-BuLi (0.27 mL, 1.59 mol=L in hexane, 0.44 mmol) was gradually added to
HFIP (2 mL) over 3 min at 0 ꢀC. A solution of 22 (100 mg, 0.22 mmol) in HFIP
(3 mL) was added to this solution at 0 ꢀC, and the resulting mixture was treated with
PIDA (78 mg, 0.24 mmol). After being stirred for 10 min at ambient temperature, the
mixture was directly purified by flash silica-gel column chromatography, eluting with
hexane–Et2O (2=1, v=v) to give 23 (15 mg, 13%) as a yellow foam. IR nmax: 1748,
1
1667 and 1227 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.86–0.89 (m, 2H), 1.24–1.40
(m, 13H), 1.77 (s, 3H), 2.10 (s, 3H), 2.18 (s, 3H), 3.74 (s, 3H), 3.77–3.80 (m, 1H),
3.86 (s, 3H), 6.23 (d, J ¼ 8.0 Hz, 1H), 6.77 (s, 1H), 6.88 (d, J ¼ 8.0 Hz, 1H), 6.99
(s, 1H). MS (EI): m=z C26H35O5 81Br 507 (Mþ ꢁ 1).
3-[(2-Bromo-3-isopropyl-4,5-dimethoxyphenyl)(hydroxyl)methyl]-
2,4-dimethylphenol (24)
A mixture of 22 (500 mg, 1.1 mmol), 2 N NaOH (1.1 mL), and MeOH (5 mL)
was refluxed for 1 h. After removal of the solvent under reduced pressure, the residue
was acidified with 2 N HCl, and the mixture was extracted with Et2O. The extract
was washed with brine and dried over Na2SO4. Evaporation of the solvent gave a
residue, which was purified by silica-gel column chromatography, eluting with hex-
ane–Et2O (1=1, v=v), to give 24 (410 mg, 91%) as a white foam. IR nmax: 3380, 2961,
1
2872, 1462 and 771 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.35 (d, J ¼ 6.8 Hz, 6H),
2.23 (s, 3H), 2.24 (s, 3H), 2.69 (s, 1H), 3.66 (s, 3H), 3.71–3.80 (m, 1H), 3.84 (s,
3H), 4.63 (s, 1H), 6.37 (s, 1H), 6.69 (d, J ¼ 8.0 Hz, 1H), 6.76 (s, 1H), 6.90 (d,
J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 12.8, 20.8, 21.0, 55.6, 60.9, 73.7,
111.6, 114.4, 123.4, 128.9, 129.2, 138.5, 140.8, 151.8, 152.5. MS (EI): m=z 409
(Mþ þ 1). HRMS (EI) calcd. for C20H26O4 79Br: 409.1014; found: 409.1043.
3-[(2-Bromo-3-isopropyl-4,5-dimethoxyphenyl)(hydroxyl)methyl]-2,
4-dimethyl-4-(2,2,2-trifluoroethoxy)cyclohexa-2,5-dien-1-one (25)
A solution of PIDA (50 mg, 0.15 mmol) in TFE (2 mL) was added to a solution
of 24 (57.5 mg, 0.14 mmol) in TFE (2 mL) at ꢁ40 ꢀC, and the mixture was stirred for
4 h at the same temperature. The solvent was removed under reduced pressure, and the
residue was purified by column chromatography, eluting with hexane–Et2O (1=1, v=
v), to give 25 (18 mg, 25%) as a yellow foam. IR nmax: 1670, 1639 and 1160 cmꢁ1
.
1H NMR (400 MHz, CDCl3): d 1.19 (s, 3H), 1.37 (d, J ¼ 6.8 Hz, 6H), 2.20 (s, 3H),
3.17 (d, J ¼ 4.0 Hz, 1H), 3.70 (s, 3H), 3.65–3.71 (m, 1H), 3.86 (s, 3H), 6.14
(d, J ¼ 4.0 Hz, 1H), 6.45 (d, J ¼ 8.0 Hz, 1H), 6.69 (s, 1H), 6.75 (d, J ¼ 8.0 Hz, 1H).
13C NMR (100 MHz, CDCl3): d 14.7, 21.0, 21.2, 25.8, 29.7, 55.9, 61.0, 63.0 (q),
71.1, 75.0, 111.0, 123.7 (q), 130.0, 139.6, 141.9, 149.0, 151.5, 152.0, 185.7. MS (EI):
m=z 506 (Mþ). HRMS (EI) calcd. for C22H26O5F37 79Br: 506.0915; found: 506.0914.

3396
W. CHEN ET AL.
(3-[tert-Butyldimethylsilyloxy]-2,6-dimethylphenyl)(3-isopropyl-2,4,
5-trimethyl)methanol (27)
The alcohol 27 was prepared from 26 and 13 by the same procedure as
described for the synthesis of 15, in 72% yield. IR nmax: 3470, 2956, 2933, 1479
1
and 1268 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.18 (s, 3H), 0.19 (s, 3H), 1.00 (s,
9H), 1.34 (d, J ¼ 6.8 Hz, 3H), 1.38 (d, J ¼ 6.8 Hz, 3H), 2.19 (s, 3H), 2.27 (s, 3H),
3.34–3.37 (m, 1H), 3.61 (s, 6H), 3.84 (s, 3H), 6.41 (s, 1H), 6.43 (s, 1H), 6.69 (d,
J ¼ 8.0 Hz, 1H), 6.89 (d, J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d ꢁ4.2,
ꢁ4.1, 13.8, 18.3, 20.7, 21.9, 21.9, 25.9, 26.0, 55.8, 60.6, 61.7, 69.9, 109.9, 118.1,
128.5, 128.9, 129.9, 130.1, 135.0, 138.8, 148.5, 149.2, 149.7, 152.4. MS (EI): m=z
474 (Mþ). HRMS (EI) calcd. for C27H42O5Si: 474.2801; found: 474.2825.
3-[Hydroxyl(3-isopropyl-2,4,5-trimethoxyphenyl)methyl]-2,4-
dimethylphenol (28)
The phenol 28 was derived from 27 by the same procedure as described for the
1
preparation of 16, in 93% yield. IR nmax: 3401, 2958, 1480, 1218 and 772 cmꢁ1. H
NMR (400MHz, CDCl3): d 1.34 (d, J ¼ 6.8 Hz, 3H), 1.38 (d, J ¼ 6.8 Hz, 3H), 2.23 (s,
3H), 2.27 (s, 3H), 3.34–3.38 (m, 1H), 3.47 (s, 1H), 3.62 (s, 3H), 3.64 (s, 3H), 3.85 (s,
3H), 4.69 (s,1H), 6.40 (s, 1H), 6.44 (s, 1H), 6.68 (d, J ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 8.0 Hz,
1H). 13C NMR (100MHz, CDCl3): d 12.8, 20.5, 21.8, 21.9, 25.9, 55.8, 60.5, 61.7, 69.6,
110.0, 114.2, 123.9, 128.6, 128.9, 130.2, 134.9, 138.8, 149.2, 149.6, 153.1. MS (EI): m=z
360 (Mþ). HRMS (EI) calcd. for C21H28O5: 360.1937; found: 360.1936.
3-[(2-Bromo-3-isopropyl-4,5-dimethoxyphenyl)(hydroxyl)methyl]-
2,4-dimethyl-4-(2,2,2-trifluoroethoxy)cyclohexa-2,5-dien-1-one (29)
A solution of PIDA (98 mg, 0.30 mmol) in TFE (3 mL) was added to a solution
of 28 (100 mg, 0.28 mmol) in TFE (3 mL) at ꢁ40 ꢀC, and the mixture was stirred for
15 h at the same temperature. The solvent was removed under reduced pressure, and
the residue was purified by column chromatography, eluting with hexane–Et2O (1=1,
v=v), to give 29 (20 mg, 16%) as a yellow foam. IR nmax: 3499, 2988, 2938, 1671, 1641
and 1279 cmꢁ1. 1H NMR (400 MHz, CDCl3): d 1.32 (s, 3H), 1.35 (d, J ¼ 6.8 Hz, 3H),
1.40 (d, J ¼ 6.8 Hz, 3H), 2.04 (s, 3H), 3.37–3.41 (m, 1H), 3.65–3.71 (m, 1H), 3.68 (s,
3H), 3.75 (s, 1H), 3.84 (s, 3H), 3.87 (s, 3H), 3.99–4.06 (m,1H), 6.04 (s, 1H), 6.39 (s,
1H), 6.45 (d, J ¼ 8.0 Hz, 1H), 6.79 (d, J ¼ 8 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 14.5, 21.8, 21.8, 26.0, 26.2, 29.7, 56.2, 60.7, 61.9, 63.2 (q), 67.0, 75.1, 109.6, 123.8
(q), 127.6, 130.1, 136.0, 140.1, 149.1, 149.4, 149.5, 150.6, 151.6, 185.7. MS (EI): m=
z 458 (Mþ). HRMS (EI) calcd. for C23H29O6F3: 458.1916; found: 458.1890.
(3-[tert-Butyldimethylsilyloxy]-2,6-dimethylphenyl)(3-isopropenyl-
2,4,5-trimethylphenyl)methanone (30)
Manganese dioxide (1.19 g, 13.5 mmol) was added to a solution of 27 (0.64 g,
1.35 mmol) in CH2Cl2 (30 mL), and the resulting mixture was heated at reflux for
12 h. The mixture was filtered to remove insoluble materials, and the filtrate was

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3397
concentrated under reduced pressure to leave a residue, which was purified by flash
silica-gel column chromatography, eluting with hexane–Et2O (5=1, v=v), to give the
ketone 30 (620 mg, 97%) as a colorless oil. IR nmax: 2957, 2932, 1476, 1328 and
1
1275 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.19 (s, 6H), 1.00 (s, 9H), 1.32 (s, 3H),
1.33 (s, 3H), 2.03 (s, 3H), 2.09 (s, 3H), 3.40–3.47 (m, 1H), 3.48 (s, 3H), 3.73 (s, 3H),
3.92 (s, 3H), 6.72 (d, J ¼ 8.0 Hz, 1H), 6.89 (d, J ¼ 8.0 Hz, 1H), 7.04 (s, 1H). 13C
NMR (100 MHz, CDCl3): d ꢁ4.2, 13.8, 19.0, 21.7, 25.6, 25.8, 55.9, 60.8, 62.4,
112.8, 118.8, 125.0, 126.4, 126.5, 128.0, 136.3, 142.2, 149.2, 151.7, 153.7, 153.9. MS
(EI): m=z 472 (Mþ). HRMS (EI) calcd. for C27H40O5Si: 472.2645; found: 472.2643.
(3-Hydroxy-2,6-dimethylphenyl)(3-isopropenyl-2,4,5-trimethyl-
phenyl)methanone (31)
Deprotection of the silyl group of 30 was carried out by the same procedure as
described for the preparation of 16 to give 32 in 94% yield. IR nmax: 3398, 2958, 2937,
1649, 1479 and 1329 cmꢁ1. 1H NMR (400 MHz, CDCl3): d 1.32 (s, 3H), 1.33 (s, 3H),
2.07 (s, 3H), 2.09 (s, 3H), 3.38–3.45 (m, 1H), 3.46 (s, 3H), 3.75 (s, 3H), 3.92 (s, 3H),
4.68 (s, 1H), 6.72 (d, J ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 8.0 Hz, 1H), 7.09 (s, 1H). 13C
NMR (100 MHz, CDCl3): d 12.7, 18.9, 21.5, 25.6, 55.8, 60.7, 62.4, 112.9, 115.3,
120.5, 125.5, 126.1, 128.1, 136.3, 142.7, 149.2, 152.0, 153.7, 154.1. MS (EI): m=z
359 (Mþ þ 1), HRMS (EI) calcd. for C21H27O5: 359.1858; found: 359.1886.
3-(3-Isopropyl-2,4,5-trimethoxybenzoyl)-2,4-dimethyl-4-(2,2,2-
trifluoroethoxy)cyclohexa-2,5-dien-1-one (32)
A solution of PIDA (130 mg, 0.40 mmol) in TFE (3 mL) was added to a
solution of 31 (132 mg, 0.37 mmol) in TFE (3 mL) at ꢁ40 ꢀC, and the mixture was
stirred for 4 h at the same temperature. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography, eluting with hex-
ane–Et2O (1=1, v=v), to give 32 (40 mg, 24%) as a yellow foam. IR nmax: 2958, 2933,
1
1642, 1479 and 1332 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.31 (d, J ¼ 6.8 Hz, 3H),
1.35 (d, J ¼ 6.8 Hz, 3H), 1.47 (s, 3H), 1.91 (s, 3H), 3.42–3.49 (m, 1H), 3.51–3.59 (m,
1H), 3.71 (s, 3H), 3.79 (s, 3H), 3.93 (s, 3H), 4.08–4.16 (m,1H), 6.43 (d, J ¼ 8.0 Hz,
1H), 6.72 (d, J ¼ 8.0 Hz, 1H), 6.99 (s, 1H). 13C NMR (100 MHz, CDCl3): d 13.5,
21.5, 21.6, 25.7, 26.8, 29.7, 56.1, 60.9, 63.0, 63.1 (q), 74.6, 112.6, 123.7 (q), 125.0,
129.9, 133.7, 136.9, 149.2, 153.2, 154.1, 154.5, 185.2, 193.8. MS (EI): m=z 456
(Mþ). HRMS (EI) calcd. for C23H27O6F3: 456.1759; found: 456.1774.
(3-[tert-Butyldimethylsilyloxy]-2,6-dimethylphenyl)(3-isopropenyl-2,
4-dimethyl)methanol (34)
The alcohol 34 was synthesized from the Grignard reagent 33 and 13 by the
same procedure as described for the preparation of 15 in 80% yield. IR nmax
:
3503, 2956, 2932, 1593, 1263 and 1106 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.19
(s, 6H), 1.00 (s, 9H), 1.32 (d, J ¼ 6.8 Hz, 3H), 1.37 (d, J ¼ 6.8 Hz, 3H), 2.17 (s,
3H), 2.24 (s, 3H), 3.40–3.44 (m, 2H), 3.74 (s, 3H), 3.76 (s, 3H), 6.41 (s, 1H), 6.48
(d, J ¼ 8.0 Hz, 1H), 6.64 (d, J ¼ 8.0 Hz, 1H), 6.69 (d, J ¼ 8.0 Hz, 1H), 6.88 (d,
1

3398
W. CHEN ET AL.
J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d ꢁ4.2, ꢁ4.1, 13.9, 18.3, 20.8, 20.89,
20.93, 25.6, 25.9, 55.2, 61.8, 70.0, 106.8, 117.8, 125.9, 127.3, 128.6, 128.7, 129.5,
129.8, 138.8, 152.4, 156.8, 159.5. MS (EI): m=z 444 (Mþꢁ1); HRMS (CI) calcd.
for C26H41O4Si: 445.2774; found: 445.2770.
(3-Hydroxy-2,6-dimethylphenyl)(3-isopropenyl-2,4-dimethyl)-
methanol (35)
Deprotection of the silyl group of 34 was carried out by the same procedure as
described for the preparation of 16 to give 35 in 93% yield. IR nmax: 3391, 2957, 1593,
1
1263 and 1106 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.33 (d, J ¼ 6.8 Hz, 3H), 1.38
(d, J ¼ 6.8 Hz, 3H), 2.21 (s, 3H), 2.24 (s, 3H), 3.40–3.49 (m, 2H), 3.55 (s, 1H), 3.77
(s, 6H), 6.42 (s, 1H), 6.48 (d, J ¼ 8.0 Hz, 1H), 6.62 (d, J ¼ 8.0 Hz, 1H), 6.69 (d,
J ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 13.0,
20.6, 20.87, 20.90, 25.6, 55.2, 61.8, 69.9, 106.9, 114.3, 124.0, 125.9, 127.0, 128.87,
128.91, 129.5, 138.4, 152.8, 156.7, 159.6. MS (EI): m=z 330 (Mþ). HRMS (CI) calcd.
for C20H27O4 (Mþ þ 1): 331.1909; found: 331.1887.
3-[3-Isopropyl-2,4-dimethoxyphenyl)(hydroxyl)methyl]-2,4-
dimethyl-4-(2,2,2-trifluoroethoxy)cyclohexa-2,5-dien-1-one (36)
The oxidation of 35 was carried out by the same procedure as described for the
preparation of 29 to give 36 in 22% yield. IR nmax: 3514, 2958, 1641, 1483 and
1
1218 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.28 (s, 3H), 1.33 (d, J ¼ 6.8 Hz, 3H),
1.40 (d, J ¼ 6.8 Hz, 3H), 2.02 (s, 3H), 3.43–3.50 (m, 1H), 3.63–3.69 (m, 1H), 3.80
(s, 3H), 3.88 (s, 3H), 4.01–4.05 (m, 1H), 6.00 (s, 1H), 6.44 (d, J ¼ 8.0 Hz, 1H), 6.54
(d, J ¼ 8.0 Hz, 1H), 6.76 (d, J ¼ 8.0 Hz, 1H), 6.77 (d, J ¼ 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 14.3, 20.7, 20.8, 25.7, 25.8, 29.7, 55.3, 61.8, 63.2 (q), 66.9,
75.1, 106.9, 123.7 (q), 125.3, 129.9, 130.4, 140.1, 149.5, 151.5, 157.2, 160.2, 185.8.
MS (EI): m=z 429 (Mþ þ 1). HRMS (CI) calcd. for C22H28O5F3: 429.1889; found:
429.1859.
(3-[tert-Butyldimethylsilyloxy]-2,6-dimethylphenyl)(7-isopropenyl-
2,2-diphenyl-1,3-benzodioxol-5-yl)methanol (38)
The alcohol 38 was synthesized from the Grignard reagent 37 and 13 by the
same procedure as described for the preparation of 15 in 51% yield. IR nmaxꢁ:
1
2955, 2929, 2361, 1480 and 1255 cmꢁ1. H NMR (400 MHz, CDCl3): d 0.19 (s,
6H), 0.99 (s, 9H), 2.11 (s, 3H), 2.13 (s, 1H), 2.14 (s, 3H), 2.22 (s, 3H), 5.24 (s,
1H), 5.68 (s, 1H), 6.18 (s, 1H), 6.64 (s, 1H), 6.68 (d, J ¼ 8.0 Hz, 1H), 6.86 (s, 1H),
6.87 (d, J ¼ 8.0 Hz, 1H), 7.33–7.35 (m, 6H), 7.55–7.58 (m, 4H). 13C NMR
(100 MHz, CDCl3): d ꢁ4.2, 13.5, 18.3, 20.3, 22.5, 25.9, 71.8, 105.6, 116.0, 117.4,
118.2, 122.9, 126.2, 127.9, 128.2, 128.3, 128.9, 129.0, 129.4, 136.5, 139.3, 140.4,
140.6, 140.7, 143.1, 147.4, 152.6. MS (EI): m=z 578 (Mþ); HRMS (EI) calcd. for
C37H42O4Si: 578.2852; found: 578.2882.

AROMATIC OXIDATION WITH A HYPERVALENT IODINE
3399
3-[Hydroxy(7-isopropenyl-2,2diphenyl-1,3-benzodioxol-5-yl)methyl-
2,4-dimethylphenol (39)
Deprotection of the silyl group of 38 was carried out by the same procedure as
described for the preparation of 16 to give 39 in 96% yield. IR nmax: 3393, 2360, 2341,
1
and 1217 cmꢁ1. H NMR (400 MHz, CDCl3): d 2.12 (s, 3H), 2.15 (s, 3H), 2.17 (d,
J ¼ 4.4 Hz, 1H), 2.24 (s, 3H), 4.59 (s, 1H), 5.25 (s, 1H), 5.69 (s, 1H), 6.20 (d,
J ¼ 4.4 Hz, 1H), 6.63 (s, 1H), 6.68 (d, J ¼ 8.0 Hz, 1H), 6.88 (s, 1H), 6.90 (d,
J ¼ 8.0 Hz, 1H), 7.32–7.38 (m, 6H), 7.54–7.59 (m, 4H). 13C NMR (100 MHz,
CDCl3): d 12.5, 20.2, 22.5, 71.6, 105.6, 114.5, 116.1, 117.5, 123.0, 123.3, 126.2,
128.3, 128.9, 129.0, 129.1, 136.3, 139.3, 140.3, 140.55, 140.63, 147.4, 152.7. MS
(EI): m=z 464 (Mþ). HRMS (EI) calcd. for C31H28O4: 464.1987; found: 464.2011.
3-[Ethoxy(3-isopropyl-4,5-dimethoxyphenyl)methyl]-2,4-
dimethylphenol (40)
To a stirred solution of 19 (50 mg, 0.15 mmol) in EtOH (2 mL) 6 N HNO3
(1 mL), was added at 0 ꢀC, and the resulting mixture was stirred at the same tempera-
ture for 5 h. The mixture was treated with saturated NaHCO3 solution, and the
whole was extracted with EtOAc. The organic layer was dried over Na2SO4. Evap-
oration of the solvent gave a residue, which was purified by column chromato-
graphy, eluting with hexane–EtOAc (10=1, v=v), to afford 40 (37.0 mg, 68%) as a
colorless oil. IR nmax: 3407, 2964, 1589 and 1487 cmꢁ1. 1H NMR (400 MHz, CDCl3):
5 1.11 (d, J ¼ 7.0 Hz, 3H), 1.13 (d, J ¼ 7.0 Hz, 3H), 1.26 (t, J ¼ 7.0, 3H), 2.14 (s, 3H),
2.24 (s, 3H), 3.22–3.33 (m, 1H), 3.42–3.60 (m, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 5.14 (br
s, 1H), 5.85 (s, 1H), 6.66 (d, J ¼ 8.0 Hz, 1H), 6.67 (s, 1H), 6.71 (s, 1H), 6.87 (d,
J ¼ 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3) 5 12.1, 15.5, 20.2, 23.4, 26.9, 55.6,
60.9, 64.2, 78.7, 108.0, 114.2, 116.1, 123.8, 128.6, 129.5, 137.5, 138.4, 141.6, 144.8,
152.2, 152.5. MS (CI): m=z 358 (Mþ). HRMS (CI) calcd. for C22H30O4: 358.2144;
found: 358.2155.
3-Isopropyl-L,2,4-trimethoxy-5-nitrobenzene (41) and 3-Hydroxy-2,
6-dimethyl-4-nitrobenzaldehyde (42)
To a stirred solution of 28 (50 mg, 0.14 mmol) in EtOH (2 mL) 6 N HNO3
(1 mL) was added at 0 ꢀC, and the resulting mixture was stirred at the same tempera-
ture for 2.5 h. The mixture was treated with saturated NaHCO3 solution, and the
whole was extracted with EtOAc. The organic layer was dried over Na2SO4. Evap-
oration of the solvent gave a residue, which was purified by column chromato-
graphy, eluting with hexane–EtOAc (10=1, v=v), to afford 41 (25.9 mg, 73%) as a
1
pale yellow oil. IR nmax: 1522 and 296 cmꢁ1. H NMR (400 MHz, CDCl3): d 1.34
(d, J ¼ 7.1 Hz, 6H), 3.47–3.54 (m, 1H), 3.82 (s, 3H) 3.88 (s, 3H), 3.92 (s, 3H), 7.33
(s, 1H). 13C NMR (100 MHz, CDCl3) d 21.3, 25.9, 56.1, 61.0, 63.0, 106.6, 137.3,
139.9, 146.9, 148.8, 153.3. MS (CI): m=z 256 (Mþ). HRMS (CI) calcd. for
C12H18NO5: 256.1173; found: 256.1185. Further elution with the same solvent sys-
tem gave 42 (19.2 mg, 71%) as a pale yellow oil. IR nmax: 3235, 1703, and
1
1524 cmꢁ1. H NMR (400 MHz, CDCl3): d 2.53 (s, 3H), 2.54 (s, 3H), 7.86 (s, 1H),

3400
W. CHEN ET AL.
10.61 (s, 1H), 10.85 (s, 1H). 13C NMR (100 MHz, CDCl3) d 11.4, 19.5, 124.0, 129.7,
130.9, 131.8, 139.9, 151.9, 193.3. MS (CI): m=z 196 (Mþ). HRMS (CI) calcd. for
C9H10NO4: 196.0594; found: 196.0610.
ACKNOWLEDGMENTS
This research was supported financially in part by a grant for the Open
Research Center Project and a grant-in-aid from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan.
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