Nucleophilic attack of intramolecular hydroxyl groups on electron-rich aromatics using hypervalent iodine(III) oxidation

Article abstract of DOI:10.1016/j.tet.2007.02.118

The hypervalent iodine(III) reagent, phenyliodine bis(trifluoroacetate) (PIFA)-mediated oxidative nucleophilic substitution of electron-rich aromatics involving aromatic cation radical intermediates was utilized in the direct aromatic carbon-oxygen bond f

Full text of DOI:10.1016/j.tet.2007.02.118

Tetrahedron 63 (2007) 4052–4060
Nucleophilic attack of intramolecular hydroxyl groups on
electron-rich aromatics using hypervalent iodine(III) oxidation
*
€
Kayoko Hata, Hiromi Hamamoto, Yukiko Shiozaki, Simon B. Cammerer and Yasuyuki Kita
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
Received 16 January 2007; revised 26 February 2007; accepted 28 February 2007
Available online 2 March 2007
Abstract—The hypervalent iodine(III) reagent, phenyliodine bis(trifluoroacetate) (PIFA)-mediated oxidative nucleophilic substitution of
electron-rich aromatics involving aromatic cation radical intermediates was utilized in the direct aromatic carbon–oxygen bond formation
reaction, and a novel and simple synthetic method for chroman derivatives was developed. As an extension of this methodology, a facile access
to spirodienone derivatives was also achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
chromans and spirodienones (Scheme 1). Recently, we re-
ported the novel synthesis of chromans using phenyliodine
bis(trifluoroacetate) (PIFA) in 1,1,1,3,3,3-hexafluoro-2-
propanol ((CF3)2CHOH).12 Additionally, the novel use of
the heteropoly acid (HPA) as an activator in the presence of
PIFA caused a different reaction to afford the spirodienone
derivatives, which are also important precursors of many
pharmaceutical compounds.9 In this paper, we provide a full
account of our studies on the direct carbon–oxygen bond
formation of unfunctionalized aromatic substrates based on
the hypervalent iodine(III) reagent-mediated intramolecular
oxidation via single-electron transfer processes.
The construction of the aromatic carbon–oxygen bond is an
important step in the synthesis of many pharmaceutically
and agriculturally valuable compounds.1–3 Much effort has
been made in developing a methodology for this purpose,
and the most predominant process in this field is the metal
(palladium)-catalyzed reaction of the halogenated aromatic
carbons, which generally requires selective insertion steps
for preparation of the substrate.2
On the other hand, although the direct aromatic carbon–
oxygen bond formation reaction of the unfunctionalized
aromatic carbons should be a potential attractive means to
assemble chroman skeletons, only a few facile approaches
are known.4,5
O
OR
OR
OR
R'
or
R'
R'
R'
or
Hypervalent Iodine
Reagent
H
O
Oxidative Coupling Reaction
O
OH
Over the past 20 years, hypervalent iodine(III) reagents have
received much attention due to their low toxicity, ready avail-
ability, easy handling, and reactivity similar to those of heavy
metal reagents.6 As a continuation of our research on the use
of hypervalent iodine(III) reagents in organic synthesis, the
direct nucleophilic substitution of electron-rich phenyl ethers
involving aromatic cation radical intermediates was origi-
nally reported by us7 and has been extensively applied for
the novel synthesis of important aromatic substrates such
as biaryls,8,9 spirodienones,9 quinone imines,10 or sulfur-
containing heterocycles.11 We focused on the hydroxyl group
as a nucleophile to produce two types of products, i.e.,
O
Scheme 1. Intramolecular coupling reaction of phenyl ether derivatives with
hydroxyl group.
2. Results and discussion
The construction of the aromatic carbon–oxygen bond was
achieved through two approaches, a and b (Fig. 1). Ap-
proach a, a two-step synthesis involving a metal-mediated/
catalyzed coupling reaction, is the general and predominant
approach, and several methods for this purpose have been
developed. Although some efficient syntheses were reported
using the palladium-catalyzed reaction,2 these approaches
still require the introduction of a halogen or 4-(trifluorome-
thyl)benzenesulfonyloxy (OTf) group into the aromatic ring
Keywords: Chroman; Spirodienone; Cyclization; Hypervalent iodine(III)
reagent; Heterocycle.
* Corresponding author. Tel.: +81 6 6879 8225; fax: +81 6 6879 8229;
e-mail: kita@phs.osaka-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.118

K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
4053
approach a: two-step synthesis
The reactions of monomethoxy precursors 1b–f with PIFA
were investigated in (CF3)2CHOH in the presence of
MK10 and these results are shown in Table 2. Primary, sec-
ondary, and tertiary alcohols had almost the same reactivity
(entries 1–3). Interestingly, in all cases, no directly cyclized
compound was observed at all, but only the compound in
which the position of the carbon–carbon bond was changed
was produced. The structures of the 2b–f were determined
by comparing the NMR spectra of the compounds synthe-
sized according to the reported method14 and/or the NOE
experiment. The migration reaction of the spiroether 5b
was examined in (CF3)2CHOH in the presence of MK10,
and only the corresponding C-migrated chroman 2b0 was
produced in quantitative yield (Scheme 2).
OH
introduction of X
[metal catalyst]
X
MeO
OH
O
Chroman
H
MeO
MeO
approach b: one-step synthesis
Figure 1. Aromatic C–O bond-forming reaction.
to form the carbon–oxygen bond. In contrast to approach a,
approach b, the direct aromatic carbon–oxygen bond forma-
tion reaction using unfunctionalized aromatics, should be
a potential attractive means to assemble the chroman skele-
tons, but only a few facile approaches are known.4,5 One of
them is the method using an oxygen-centered radical with
the hypervalent iodine(III) reagent, but the chroman was ob-
tained by iodination on the aromatic ring in an undesirable
yield (5–64%).5,13 We planned the one-step chroman synthe-
sis via the cation radical intermediate using the hypervalent
iodine(III) reagent.
Table 2. Application to 4-monomethoxy derivatives
OMe
OMe
H
R
R
PIFA, MK10
H
(CF3)2CHOH
0 °C ~ rt
OH
R2
O
R1
R1
R2
1b–f
2b–f
OMe
Entry Substrate
R1
R2
Time (h) Yielda (%)
Previously, the intramolecular aromatic carbon–oxygen
bond formation reaction via the aromatic cation radical
intermediate was reported using the heavy metal reagent,
thallium(III) trifluoroacetate, by McKillop (Table 1, entry
1).4 However, the yield of the coupling step was low
(21%). Alternatively, other heavy metal reagent-mediated
coupling reactions did not provide practical routes to the
chroman derivatives, such as entries 2 and 3. Moreover,
heavy metal reagents are highly toxic and must be handled
with great care. In order to develop a versatile route to the
chroman derivatives via the aromatic cation radical pathway,
the reactivity of the PIFA-mediated cyclization of 3-(3,4-
dimethoxyphenyl)propan-1-ol (1a) was studied under vari-
ous reaction conditions. When the reaction was carried out
in the presence of an acid additive, a low yield was observed
(entry 4). On the other hand, a notable increase in the reaction
yield occurred in poor nucleophilic polar solvents, such as
(CF3)2CHOH (entry 5), and the addition of solid acid addi-
tives, such as montmorillonite K10 (MK10), also caused an
improvement in the yield (entry 6).
R
OMe
1b
2b
3b
1b
1c
1d
H
Me
Me Me
H
H
0.5
4
4
43 (2b)
45 (2c)
46 (2d)
OMe
Me
4
5
1e
1f
H
H
H
H
2.5
3
42 (2e)
47 (2f)
OMe
a
Yield of the isolated products.
In our previous report (Ref. 12), the structures of the products were
missed. C-migrated structure is the real structure.
b
O
OH
O
MK10
Table 1. Intramolecular oxidative cyclization of 1a
(CF3)2CHOH
0 °C, 1 h
97%
OMe
OMe
O
O
MeO
MeO
O
[O]
5b
2b'
O
OH
Scheme 2. Rearrangement of the spirodienone derivative.
1a
2a
From these results, the plausible reaction mechanism is as-
sumed as follows (Scheme 3). The cation radical A is ini-
tially formed by the reaction of the electron-rich aromatic
ring with PIFA as mentioned in our previous study.7 The gen-
eration of the cation radical of 1b under the reaction condi-
tions (PIFA in (CF3)2CHOH) was detected by electron spin
resonance (ESR) spectroscopy (Fig. 2). The intramolecular
hydroxyl group was then attacked on the arylic cation radical
at the para position of methoxy group to generate the spiro-
dienone-type intermediate B. Rearrangement of the spiro
Entry Conditions
Yieldb (%)
1a
2
Tl2O3, BF3$Et2O, CF3CO2H, (CF3CO)2O, CH2Cl2 21
RuO2, BF3$Et2O, CF3CO2H, (CF3CO)2O, CH2Cl2 ndc
3
4
5
VOF3, CF3CO2H, (CF3CO)2O, CH2Cl2
PIFA, BF3$Et2O, CH2Cl2
PIFA, (CF3)2CHOH
ndc
28
40
55
6
PIFA, MK10, (CF3)2CHOH
a
b
c
Ref. 4.
Isolated yield.
nd: not detected.

4054
K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
carbon atom then occurred by the electron donation of the
spiro oxygen. On the other hand, for the rearrangement reac-
tion of 5b, a decrease in the conversion was observed in the
absence of MK10, which means that MK10 contributes to
the migration of the spiro-type intermediate.
hydroxyl one (entry 5). However, other protecting deriva-
tives (e.g., R¼silyl, acetyl, and THP) gave the chromans in
low yield.
Although the chromans 2a, g–i were thought to be produced
via the spirodienone-type intermediate (Scheme 4, route a),
the direct cyclization of the hydroxyl group was also a possi-
ble route (route b), and the reaction mechanism was not clear
from the structures of the products. Therefore, the reactions
using the substrates with methoxy and benzyloxy groups 1k,
l were examined to clarify the reaction mechanism (Scheme
5). Not only C-migrated chroman, but also the regioisomer
chromans were produced in these reactions, and in addition,
their ratio was almost same between 1k and 1l.15
OMe
OMe
OMe
OMe
O
R
R
R
R
PIFA, MK10
(CF3)2CHOH
– e-
– H+
OH
OH
O
A
B
Scheme 3. Plausible reaction mechanism.
Next, the reactions of dialkoxy precursors 1a, g–j with PIFA
were investigated (Table 3). The chroman derivatives 2a, g–i
were produced in moderate yields (entries 1–4). The reactiv-
ity of the methyl ether derivative was similar to that of the
OMe
OMe
OMe
O
BnO
MeO
BnO
BnO
PIFA, MK10
(CF3)2CHOH
+
OH
OH
O
O
0 °C ~ rt
OMe
OH
44%
1k
3
4
(
77
OBn
:
:
23
OBn
)
)
OBn
MeO
MeO
+
PIFA, MK10
(CF3)2CHOH
0 °C ~ rt
46%
O
1l
4
3
1 mT
(
75
25
Scheme 5. Oxidative coupling reaction of the substrates with methoxy and
benzyloxy groups.
Figure 2. ESR spectra of cation radical 1b generated by PIFA in
(CF3)2CHOH.
Table 3. Application to other alcohol derivatives
OR3
R3O
OR3
R3O
PIFA, MK10
(CF3)2CHOH
0 °C ~ rt
OR
R2
R1
O
R2
R1
1a,g–j
2a,g–i
Entry
Substrate
R1
R2
OR3
OR3
R
Time (h)
Yielda (%)
1
2
3
4
5
1a
1g
1h
1i
H
H
H
Me
H
H
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
2
4
4
1
1
55 (2a)
49 (2g)
52 (2h)
57 (2i)
57 (2a)
Me
Me
H
OCH2O
1j
H
OMe
OMe
Me
a
Yield of the isolated products.
OR
OR
RO
RO
(route a)
– e-, – H+
rearrangement
– H+
OR
OR
O
RO
RO
O
OR
PIFA
– e-
b
OH
B
RO
OH
a
(route b)
– e-, – 2H+
O
A
Scheme 4. Assumed reaction mechanism for chroman 2a, g–i.

K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
4055
OMe
These results indicated that dialkoxyl chromans were also
produced via the spirodienone intermediate. When the
dimethoxy substrates were used, the driving force of the rear-
rangement from the spirodienone intermediate was assumed
to be not only the electron donation of the spiro oxygen, but
also that of the second alkoxyl group on the aromatics. The
electron donation of the spiro oxygen produced the C-migra-
tion, and that of the second alkoxyl group on the aromatics
favored O-migration,16 therefore, two kinds of chromans
were thought to be produced (Scheme 7).
MeO
O
6
Figure 3.
When the dihydrobenzofuran synthesis using this method
was examined, the corresponding product 6 (Fig. 3) was
only slightly produced. This is probably because it was diffi-
cult to form the spirodienone-type intermediate. In addition,
the other condition for producing the cation radical, the com-
bination of PIFA and HPA, which allows the spirodienone-
type compounds to be produced, were applied to 1a. The
spirodienone ether 5a was produced as a major product
together with the chroman 2a (Scheme 6). These results
can be regarded as the support for the formation of the spiro-
dienone-type intermediate during the chroman synthesis.
Recently, we developed an alternative method for the cation
radical formation, i.e., the combination of a hypervalent io-
dine(III) reagent and HPA,8c,9,17 which is a readily available,
inexpensive, easy to handle, non-corrosive, and odorless
solid acid. This method has a characteristic behavior that
the hydration water of HPA produces spirodienones by
a non-phenolic coupling reaction.9,17 Previously, we devel-
oped the hypervalent iodine oxidation of phenol derivatives
into spirodienone ethers.18 However, the use of phenyl ether
derivatives for the hypervalent iodine oxidation is consid-
ered to be valuable, since the phenyl ether derivatives are
more stable and easier to handle than the phenol derivatives
themselves under the various reaction conditions. In fact, the
spirodienone ether 5a was obtained using HPA as an activa-
tor of PIFA in Scheme 6. Therefore, this spirodienone ether
synthesis can be applied to the various alcohols.
O
OMe
OMe
PIFA
H4[SiW12O40
MeO
MeO
MeO
]
+
wet CH3CN
1h
OH
O
O
2a
5a
1a
20%
34%
Scheme 6. C–O bond formation reaction using PIFA–HPA.
We examined the spirodienone synthesis using 1m as a sub-
strate to produce a stable spirodienone compound by the
combination of PIFA and HPA (H4[SiW12O40]). The corre-
sponding spirodienone 5m was obtained in 50% yield in ace-
tonitrile (Table 4, entry 1). The reactions of other compounds
having terminal hydroxyl groups were investigated under the
similar PIFA–HPA conditions and the results are summarized
in Table 4. When a symmetrical spirodienone was produced,
the yield was good (entries 1–6). Even when the substrate
contains other functional groups (alcohol, ester), the corre-
sponding spirodienone was obtained in a moderate yield
(entries 7 and 8). Products 5s and 5t are possible analogues
of the gryndelic acid derivatives, which were isolated from
Grindelia nana, and the ethanol extract demonstrated invitro
an inhibitory effect on the HIV-1 reverse transcriptase.19 We
O-migration path
R1
OR1
O
OR1
R2O
–H+
R2O
R2O
H
O
O
B
O
C-migration path
R1
OR1
O
OR1
O
R2O
R2O
R2O
–H+
H
B
O
O
Scheme 7. Plausible migration mechanism.
Table 4. Synthesis of spirodienone derivatives
O
OMe
R4
R5
R4
R5
R4
R5
R4
R5
PIFA
H4[SiW12O40
]
CH3CN-H2O
0 °C ~ rt
O
OH
R7
R7
R6
1m-t
R6
5m-t
Entry
Substrate
R4
R5
R6
R7
H2O (%)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
1m
1n
1o
1p
1q
1r
1s
Me
H
H
H
OMe
H
H
H
H
Me
Me
H
H
H
H
Me
H
H
Me
Me
0
0.5
0.5
0.5
2
0.1
1.5
0.5
2.0
50 (5m)
79 (5n)
83 (5o)
68 (5p)
85 (5q)
63 (5r)
52 (5s)
39 (5t)
Me
Me
Me
H
OMe
Me
Me
2.5
2.5
5
5
5
H
H
H
CH2CH2OH
CH2CO2Et
5
5
1t
a
Yield of the isolated products.

4056
K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
H2O
OMe
O
O
OMe
OMe
HO OMe
R
R
R
R
R
PIFA
– e-
– e-
+ H2O
– H+
– H+
– MeOH
OH
OH
O
O
Scheme 8. Plausible mechanism of the spirodienone ether synthesis.
1
with KBr pellets. The H and 13C NMR spectra were mea-
sured in CDCl3 using JEOL JNM-AL 300 spectrometers
with TMS or CHCl3 as the internal standard. The ESR spec-
tra were taken using a JEOL JES-TE 200 spectrometer.
Merck silica gel 60 (70–230 mesh ASTM) and Fuji Silysia
Chemical silica gel BW-300 were used for the column chro-
matography and flash column chromatography, respectively.
PIFA is commercially available. H4[SiW12O40] was pur-
chased from the Kanto Chemical Company.
OMe
OH
1 mT
Figure 4. ESR spectra of cation radical 1b generated by PIFA–HPA.
4.1.1. Measurement of electron spin resonance (ESR)
spectra in (CF3)2CHOH. PIFA (1.0 equiv) was added
at room temperature to a 0.05 M solution of 1b in
(CF3)2CHOH. An aliquot from this mixture was then placed
on a flat cell and inserted into the ESR cavity. The spectra
were recorded at room temperature using a JEOL JES-TE
200 spectrometer. The instrument conditions were as fol-
lows: magnetic field, 335.5ꢀ5.0 mT; modulation frequency,
9.42 GHz; output power, 1.0 mW; time constant, 0.03 s;
sweep time, 0.5 min.
think this approach for the spirodienone could be applied to
the synthetic study of many natural products.
The plausible mechanism for the spirodienone ether is as-
sumed as follows (Scheme 8). The spiro-type nucleophilic
attack of the hydroxyl group on the cation radical formed
by the reaction with PIFA initially occurs. Next, the water at-
tack on the cationic intermediate occurs and the spiroether is
produced by the cleavage of the methoxy group. Under this
reaction condition, the generation of the cation radical 1b
was also detected by electron spin resonance (ESR) spec-
troscopy (Fig. 4).
4.1.2. Measurement of electron spin resonance (ESR)
spectra under PIFA–HPA. H4[SiW12O40] (0.50 g mmolꢁ1
)
and PIFA (1.0 equiv) were added at room temperature to
a 0.025 M solution of 1b in CH3CN. An aliquot from this
mixture was then placed on a flat cell and inserted into the
ESR cavity. The spectra were recorded at room temperature
using a JEOL JES-TE 200 spectrometer. Instrument condi-
tions were as follows: magnetic field, 335.5ꢀ5.0 mT; mod-
ulation frequency, 9.42 GHz; output power, 1.0 mW; time
constant, 0.03 s; sweep time, 0.5 min.
3. Conclusion
We have developed a novel and direct synthetic method for
chroman and spirodienone derivatives via the cation radical
pathway using a hypervalent iodine reagent. The reaction
mechanism was investigated in detail. Under dry reaction
conditions, the rearrangement reaction removed off the
cation of the spirodienone-type intermediate. On the other
hand, under the water containing conditions using HPA,
the cation of the spirodienone-type intermediate was readily
attacked by the water, and the spirodienone compounds were
produced from the phenyl ethers. Selection of the reaction
conditions (the dry condition using (CF3)2CHOH or the
water containing condition using HPA) allows us to control
synthesis of desired compounds, i.e., the chromans or spiro-
dienones. The simplicity of the reaction protocol employing
unfunctionalized aromatics in mild reaction systems may
find many advantages for its application to the synthesis of
various types of natural and synthesized products.
4.1.2.1.
3-(4-Methoxy-3-methylphenyl)propan-1-ol
(1e). Colorless crystals; mp 44.8–44.9 ꢂC; IR (KBr): 3360,
2941, 2860 cmꢁ1; 1H NMR (CDCl3) d: 1.82–1.91 (2H, m),
2.21 (3H, s), 2.62 (2H, t, J¼7.5 Hz), 3.67 (2H, t,
J¼6.3 Hz), 3.81 (3H, s), 6.75 (1H, d, J¼8.7 Hz), 6.97–7.00
(2H, m); 13C NMR (CDCl3) d: 16.2, 31.1, 34.5, 55.3, 62.3,
109.9, 126.3, 126.5, 130.8, 133.4, 156.0; elemental analysis
calcd (%) for C11H16O2: C 73.30; H 8.95; found: C 73.38;
H 8.84.
4.1.2.2. 3-(3,4-Dimethoxyphenyl)propyl methyl ether
1
(1j). Colorless oil; IR (KBr): 2935, 2866, 2831 cmꢁ1; H
NMR (CDCl3) d: 1.82–1.92 (2H, m), 2.64 (2H, t,
J¼7.8 Hz), 3.35 (3H, s), 3.39 (2H, t, J¼6.5 Hz), 3.86 (3H,
s), 3.87 (3H, s), 6.72–6.81 (3H, m); 13C NMR (CDCl3) d:
31.5, 31.9, 55.8, 55.9, 58.6, 71.9, 111.2, 111.8, 120.2,
134.6, 147.1, 148.8; elemental analysis calcd (%) for
C12H18O3: C 68.54; H 8.63; found: C 68.75; H 8.59.
4. Experimental section
4.1. General information
€
All melting points were measured using a Buchi 545 appara-
4.1.2.3. 3-(3,5-Dimethyl-4-methoxyphenyl)propan-
1-ol (1m). Colorless oil; IR (KBr): 3356, 2937,
tus and are corrected. The infrared (IR) absorption spectra
were recorded using a Shimadzu FT/IR-8400 spectrometer
1
2862 cmꢁ1; H NMR (CDCl3) d: 1.81–1.91 (2H, m), 2.26

K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
4057
(6H, s), 2.60 (2H, t, J¼6.2 Hz), 3.67 (2H, t, J¼6.0 Hz), 3.70
(3H, s), 6.84 (2H, s); 13C NMR (CDCl3) d: 16.0, 31.3, 34.3,
59.7, 62.4, 128.7, 130.6, 137.0, 155.0; elemental analysis
calcd (%) for C12H18O2: C 74.19; H 9.34; found: C 74.35;
H 9.31.
3.76 (3H, s), 4.19 (2H, qd, J¼7.1, 1.6 Hz), 6.58 (2H, s);
13C NMR (CDCl3) d: 14.1, 19.9, 23.3, 26.4, 40.9, 44.7,
55.0, 60.7, 70.8, 113.4, 130.8, 137.2, 157.1, 173.1.
4.1.3. A typical procedure for the preparation of 6,7-di-
methoxychroman (2a). To a stirred solution of the alcohol
(1a, 39.2 mg, 0.20 mmol) in (CF3)2CHOH (4.0 mL) were
added MK10 (100 mg) and PIFA (90.3 mg, 0.21 mmol) at
0 ꢂC. Stirring was continued for 2 h at 0 ꢂC to rt. The solution
was then filtered and concentrated in vacuo. Purification of
the residue by column chromatography on silica gel gave
the corresponding chroman 2a (21.5 mg, 55%) as colorless
crystals; mp 52.6–52.7 ꢂC (lit.4 mp 51.5–52 ꢂC); IR (KBr):
4.1.2.4.
3-(2,6-Dimethyl-4-methoxyphenyl)propan-
1-ol (1n). Colorless crystals; mp 51.8–51.9 ꢂC; IR (KBr):
3394, 2949, 2878 cmꢁ1; H NMR (CDCl3) d: 1.68–1.77
1
(2H, m), 2.32 (6H, s), 2.62–2.68 (2H, m), 3.73 (2H, t,
J¼6.3 Hz), 3.77 (3H, s), 6.58 (2H, s); 13C NMR (CDCl3)
d: 20.2, 25.3, 32.4, 55.1, 63.0, 113.3, 130.8, 137.2, 156.9;
elemental analysis calcd (%) for C12H18O2: C 74.19; H
9.34; found: C 73.85; H 9.27.
1
2934, 2855, 2837, 1620 cmꢁ1; H NMR (CDCl3) d: 1.94–
2.02 (2H, m), 2.71 (2H, t, J¼6.5 Hz), 3.81 (6H, s), 4.13
(2H, t, J¼5.0 Hz), 6.37 (1H, s), 6.53 (1H, s); 13C NMR
(CDCl3) d: 22.6, 24.3, 55.8, 56.4, 66.3, 100.8, 112.5, 112.6,
142.9, 148.1, 148.6.
4.1.2.5. 4-(2,6-Dimethyl-4-methoxyphenyl)butan-2-ol
(1o). Colorless crystals; mp 69.4–69.5 ꢂC; IR (KBr): 3350,
2960, 2916 cmꢁ1 1H NMR (CDCl3) d: 1.26 (3H, d,
;
J¼6.3 Hz), 1.57–1.62 (2H, m), 2.31 (6H, s), 2.51–2.77
(2H, m), 3.76 (3H, s), 3.87–3.93 (1H, m), 6.58 (2H, s); 13C
NMR (CDCl3) d: 20.1, 23.5, 25.2, 38.8, 55.1, 68.4, 113.5,
131.1, 137.2, 157.1; elemental analysis calcd (%) for
C13H20O2: C 74.96; H 9.68; found: C 75.15; H 9.63.
4.1.3.1. 6-Methoxychroman (2b).2c,d Obtained in 43%
yield as colorless oil; IR (KBr): 3153, 2937, 2868,
1
1790 cmꢁ1; H NMR (CDCl3) d: 1.95–2.02 (2H, m), 2.77
(2H, t, J¼6.5 Hz), 3.74 (3H, s), 4.13 (2H, t, J¼5.1 Hz),
6.58 (1H, d, J¼2.7 Hz), 6.66 (1H, dd, J¼8.8, 2.7 Hz), 6.72
(1H, d, J¼8.8 Hz); 13C NMR (CDCl3) d: 22.4, 25.1, 55.7,
66.3, 113.2, 114.3, 117.2, 122.7, 149.0, 153.2; elemental
analysis calcd (%) for C10H12O2: C 73.15; H 7.37; found:
C 73.36; H 7.37.
4.1.2.6. 4-(2,6-Dimethyl-4-methoxyphenyl)-2-methyl-
butan-2-ol (1p). Colorless crystals; mp 59.3–59.4 ꢂC; IR
1
(KBr): 3440, 2966, 2920 cmꢁ1; H NMR (CDCl3) d: 1.32
(6H, s), 1.55–1.60 (2H, m), 2.31 (6H, s), 2.61–2.67 (2H,
m), 3.76 (3H, s), 6.58 (2H, s); 13C NMR (CDCl3) d: 19.9,
23.7, 29.0, 43.0, 55.1, 71.0, 113.5, 131.1, 137.1, 157.1;
elemental analysis calcd (%) for C14H22O2: C 75.63;
H 9.97; found: C 75.76; H 9.87.
4.1.3.2. 6-Methoxy-2-methylchroman (2c). Obtained in
45% yield as colorless oil; IR (KBr): 3153, 2977, 2936,
1
2879, 2835, 1794, 1614 cmꢁ1; H NMR (CDCl3) d: 1.38
(3H, d, J¼6.2 Hz), 1.63–1.77 (1H, m), 1.92–2.00 (1H, m),
2.67–2.75 (1H, m), 2.80–2.91 (1H, m), 3.74 (3H, s), 4.05–
4.11 (1H, m), 6.59 (1H, d, J¼2.8 Hz), 6.66 (1H, dd,
J¼8.7, 2.8 Hz), 6.72 (1H, d, J¼8.7 Hz); 13C NMR
(CDCl3) d: 21.3, 25.2, 29.3, 55.7, 72.0, 113.2, 114.1,
117.2, 122.3, 149.1, 153.1; elemental analysis calcd (%)
for C11H14O2: C 74.13; H 7.92; found: C 74.34; H 7.87.
4.1.2.7. 3-(2,4,6-Trimethoxyphenyl)propan-1-ol (1r).
1
Colorless oil; IR (KBr): 3354, 2939, 2837 cmꢁ1; H NMR
(CDCl3) d: 1.69–1.77 (2H, m), 2.69 (2H, t, J¼6.6 Hz),
3.47 (2H, t, J¼5.6 Hz), 3.80 (9H, s), 6.14 (2H, s); 13C
NMR (CDCl3) d: 17.9, 31.6, 55.3, 55.7, 61.4, 90.5, 109.6,
158.6, 159.2; elemental analysis calcd (%) for C12H18O4:
C 63.70; H 8.02; found: C 63.52; H 7.92.
4.1.3.3. 2,2-Dimethyl-6-methoxychroman (2d). Ob-
tained in 46% yield as colorless oil; IR (KBr): 3153, 2978,
4.1.2.8. 3-(3,4,5-Trimethoxyphenyl)propan-1-ol (1q).
1
1
Colorless oil; IR (KBr): 3379, 2939, 2839 cmꢁ1; H NMR
2941, 2835, 1774, 1612 cmꢁ1; H NMR (CDCl3) d: 1.31
(CDCl3) d: 1.84–1.94 (2H, m), 2.66 (2H, t, J¼7.6 Hz),
3.69 (2H, t, J¼6.6 Hz), 3.82 (3H, s), 3.84 (6H, s), 6.42
(2H, s); 13C NMR (CDCl3) d: 32.6, 34.3, 56.0, 60.9, 62.2,
105.1, 135.9, 137.5, 152.9; elemental analysis calcd (%)
for C12H18O4: C 63.70; H 8.02; found: C 63.79; H 7.97.
(6H, s), 1.79 (2H, t, J¼6.8 Hz), 2.76 (2H, t, J¼6.8 Hz),
3.74 (3H, s), 6.62 (1H, s), 6.69–6.70 (2H, m); 13C NMR
(CDCl3) d: 22.8, 26.7, 32.8, 55.7, 73.8, 113.4, 113.9,
117.7, 121.4, 147.9, 152.9; elemental analysis calcd (%)
for C12H16O2: C 74.97; H 8.39; found: C 75.15; H 8.41.
4.1.2.9. 5-(2,6-Dimethyl-4-methoxyphenyl)-3-methyl-
pentane-1,3-diol (1s). Colorless oil; IR (KBr): 3339,
4.1.3.4. 6-Methoxy-7-methylchroman (2e). Obtained in
42% yield as colorless oil; IR (KBr): 2934, 2856,
1
1
2961, 2920 cmꢁ1; H NMR (CDCl3) d: 1.37 (3H, s), 1.59–
1504 cmꢁ1; H NMR (CDCl3) d: 1.94–2.02 (2H, m), 2.15
1.65 (2H, m), 1.74–1.88 (2H, m), 2.31 (6H, s), 2.59–2.66
(2H, m), 3.76 (3H, s), 3.92–3.98 (2H, m), 6.58 (2H, s); 13C
NMR (CDCl3) d: 20.0, 23.3, 26.5, 41.5, 41.8, 55.1, 59.9,
73.7, 113.5, 130.9, 137.1, 157.2; elemental analysis calcd
(%) for C15H24O3: C 71.39; H 9.59; found: C 70.65; H 9.46.
(3H, s), 2.75 (2H, t, J¼6.6 Hz), 3.76 (3H, s), 4.12 (2H, t,
J¼5.1 Hz), 6.49 (1H, s), 6.60 (1H, s); 13C NMR (CDCl3)
d: 15.9, 22.6, 24.9, 55.9, 66.3, 111.2, 118.7, 119.2, 125.8,
148.3, 151.5; elemental analysis calcd (%) for C11H14O2:
C 74.13; H 7.92; found: C 73.17; H 7.91.
4.1.2.10.
3-Hydroxy-5-(2,6-dimethyl-4-methoxy-
4.1.3.5. 6-Methoxybenzo[h]chroman (2f). Obtained in
47% yield as colorless oil; IR (KBr): 2934, 2856,
phenyl)-3-methylpentanoic acid ethyl ester (1t). Colorless
oil; IR (KBr): 3521, 2976, 2835, 1713, 1606, 1585 cmꢁ1; 1H
NMR (CDCl3) d: 1.29 (3H, t, J¼7.1 Hz), 1.35 (3H, s), 1.62
(2H, dd, J¼10.6, 6.8 Hz), 2.30 (6H, s), 2.50–2.69 (4H, m),
1
1597 cmꢁ1; H NMR (CDCl3) d: 2.06–2.16 (2H, m), 2.88
(2H, t, J¼6.5 Hz), 3.97 (3H, s), 4.33 (2H, t, J¼5.1 Hz),
6.47 (1H, s), 7.41–7.51 (2H, m), 8.09–8.18 (2H, m);

4058
K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
13C NMR (CDCl3) d: 27.8, 25.4, 55.7, 66.4, 105.5, 114.8,
120.9, 121.5, 124.9, 125.8, 125.9, 143.5, 148.6; elemental
analysis calcd (%) for C14H14O2: C 78.48; H 6.59; found:
C 78.21; H 6.69.
4.1.5.2. 7-Benzyloxy-6-methoxychroman (4). 7-Benzyl-
oxy-6-methoxychromen was synthesized by the reported
method.14 Following hydrogenation using 5% Rh on alu-
mina as catalyst, 7-benzyloxy-6-methoxychroman was ob-
tained as colorless crystals; mp 87.7–87.8 ꢂC; IR (KBr):
4.1.3.6. 6,7-Dimethoxy-2-methylchroman (2g).20 Ob-
tained in 49% yield as colorless crystals; mp 45.6–45.9 ꢂC
(lit.20 mp 47–48 ꢂC); IR (KBr): 3153, 2936, 2835,
2936, 2868, 1512 cmꢁ1; H NMR (CDCl3) d: 1.90–2.00
1
(1H, m), 2.67 (2H, t, J¼6.5 Hz), 3.80 (3H, s), 4.07 (2H, t,
J¼5.3 Hz), 5.07 (2H, s), 6.38 (1H, s), 6.54 (1H, s), 7.23–
7.42 (5H, m); 13C NMR (CDCl3) d: 22.5, 24.3, 56.7, 66.2,
70.9, 103.2, 113.3, 113.4, 127.2, 127.7, 128.5, 137.1,
143.5, 147.4, 148.6; elemental analysis calcd (%) for
C17H18O3: C 75.53; H 6.71; found: C 75.56; H 6.84.
1
1792 cmꢁ1; H NMR (CDCl3) d: 1.38 (3H, d, J¼6.2 Hz),
1.63–1.77 (1H, m), 1.93–2.00 (1H, m), 2.60–2.69 (1H, m),
2.74–2.86 (1H, m), 3.81 (6H, s), 4.02–4.12 (1H, m), 6.39
(1H, s), 6.54 (1H, s); 13C NMR (CDCl3) d: 21.3, 24.4, 29.5,
55.8, 56.4, 72.1, 100.8, 112.2, 112.3, 142.8, 148.2, 148.8.
4.1.6. A typical procedure for the preparation of 7,9-di-
methyl-1-oxaspiro[4.5]deca-6,9-dien-8-one (5m). To a
stirred solution of the alcohol (1m, 21.8 mg, 0.112 mmol)
in CH3CN (4.4 mL) were added H4[SiW12O40] (88 mg)
and PIFA (58 mg, 0.134 mmol) at 0 ꢂC. After 0.5 h of stir-
ring at 0 ꢂC to rt, the reaction mixture was diluted with
EtOAc. EtOAc containing 3.0% Et3N (5.0 mL) was then
added. The precipitate was observed and the solution was fil-
tered through kieselguhr and concentrated in vacuo. Purifi-
cation of the residue by column chromatography on silica
gel produced the corresponding spirodienone derivatives
(5m, 10.0 mg, 50%) as yellow oil; IR (KBr): 2955, 2874,
4.1.3.7. 6,7-Dimethoxy-2,2-dimethylchroman (2h).21
Obtained in 52% yield as colorless crystals; mp 58.9–
59.0 ꢂC (lit.21 mp 59–60 ꢂC, lit.21 mp 59–60 ꢂC, lit.21 mp
1
60 ꢂC); IR (KBr): 2936, 2853, 2833, 1776 cmꢁ1; H NMR
(CDCl3) d: 1.32 (6H, s), 1.78 (2H, t, J¼6.8 Hz), 2.69 (2H,
t, J¼6.8 Hz), 3.81 (6H, s), 6.37 (1H, s), 6.55 (1H, s); 13C
NMR (CDCl3) d: 22.2, 26.8, 33.0, 55.8, 56.4, 73.9, 101.1,
111.1, 112.1, 142.4, 147.7, 148.2.
4.1.3.8. 7,8-Dihydro-6H-[1,3]dioxolo[4.5-g]chromene
(2i). Obtained in 57% yield as colorless crystals; mp 44.9–
45.8 ꢂC; IR (KBr): 2934, 2876, 2772, 1626 cmꢁ1; 1H NMR
(CDCl3) d: 1.92–2.00 (2H, m), 2.68 (2H, t, J¼6.5 Hz), 4.11
(2H, t, J¼5.1 Hz), 5.85 (2H, s), 6.34 (1H, s), 6.48 (1H, s);
13C NMR (CDCl3) d: 22.4, 24.8, 66.3, 98.5, 100.7, 108.4,
113.5, 141.2, 146.3, 149.4; elemental analysis calcd (%)
for C10H10O3: C 67.41; H 5.66; found: C 67.46; H 5.77.
1
1676, 1641 cmꢁ1; H NMR (CDCl3) d: 1.87 (6H, s), 1.98–
2.03 (2H, m), 2.08–2.22 (2H, m), 4.04 (2H, t, J¼6.6 Hz),
6.55 (2H, s); 13C NMR (CDCl3) d: 15.7, 26.7, 36.5, 68.8,
77.9, 133.7, 145.0, 187.5; elemental analysis calcd (%) for
C11H14O2: C 74.13; H 7.92; found: C 74.16; H 7.92.
4.1.6.1. 7-Methoxy-1-oxaspiro[4.5]deca-6,9-dien-8-
one (5a). Obtained in 34% yield as yellow oil; IR (KBr):
4.1.3.9. Chroman-6-ol (2b0).22 Obtained in 97% yield as
colorless crystals; mp 97.9–98.0 ꢂC (lit.22 mp 99–100 ꢂC); IR
(KBr): 3315, 3028, 2936, 2866 cmꢁ1; 1H NMR (CDCl3) d:
1.94–2.02 (2H, m), 2.73 (2H, t, J¼6.5 Hz), 4.14 (2H, t,
J¼5.2 Hz), 6.53 (1H, d, J¼2.8 Hz), 6.58 (1H, dd, J¼8.6,
2.8 Hz), 6.67 (1H, d, J¼8.6 Hz); 13C NMR (CDCl3) d:
22.3, 24.9, 66.3, 114.3, 115.8, 117.2, 123.0, 148.7, 148.8.
1
3153, 2936, 2874, 1794, 1678 cmꢁ1; H NMR (CDCl3) d:
2.07–2.23 (4H, m), 3.67 (3H, s), 4.02–4.14 (2H, m), 5.70
(1H, d, J¼2.7 Hz), 6.14 (1H, d, J¼10.0 Hz), 6.81 (1H, dd,
J¼10.0, 2.7 Hz); 13C NMR (CDCl3) d: 26.8, 37.7, 54.9,
68.9, 79.4, 116.6, 126.2, 149.7, 150.2, 181.0; elemental anal-
ysis calcd (%) for C10H12O3: C 66.65; H 6.71; found: C
66.90; H 6.77.
4.1.4. The reaction of 1k with PIFA–MK10 in (CF3)2-
CHOH. Obtained in 44% yield as an inseparable mixture
of 3 and 4. The unknown authentic samples 3 and 4
were prepared by the reported method and following
hydrogenation.14
4.1.6.2. 6,10-Dimethyl-1-oxaspiro[4.5]deca-6,9-dien-
8-one (5n). Obtained in 79% yield as colorless crystals;
mp 98.5–98.6 ꢂC; IR (KBr): 2959, 2876, 1672,
1
1632 cmꢁ1; H NMR (CDCl3) d: 2.00 (6H, s), 2.01–2.26
(4H, m), 4.20 (2H, t, J¼6.5 Hz), 5.94 (2H, s); 13C NMR
(CDCl3) d: 18.8, 27.6, 37.4, 72.2, 83.1, 125.3, 162.6,
185.8; elemental analysis calcd (%) for C11H14O2: C
74.13; H 7.92; found: C 74.14; H 7.87.
4.1.5. The reaction of 1l with PIFA–MK10 in (CF3)2-
CHOH. Obtained in 46% yield as an inseparable mixture of
3 and 4. The unknown authentic samples 3 and 4 were pre-
pared by the reported method and following hydrogenation.14
4.1.6.3.
2,6,10-Trimethyl-1-oxaspiro[4.5]deca-6,9-
4.1.5.1. 6-Benzyloxy-7-methoxychroman (3). 6-Benzyl-
oxy-7-methoxychromen was synthesized by the reported
method.14 Following hydrogenation using 5% Rh on alumina
as catalyst, 6-benzyloxy-7-methoxychroman was obtained as
colorless crystals; mp 52.5–53.0 ꢂC; IR (KBr): 2936, 2868,
dien-8-one (5o). Obtained in 83% yield as yellow oil; IR
(KBr): 2972, 2925, 1670, 1632 cmꢁ1; 1H NMR (CDCl3) d:
1.36 (3H, d, J¼5.7 Hz), 1.65–1.79 (1H, m), 1.97–2.06
(7H, m), 2.15–2.27 (2H, m), 4.34–4.45 (1H, m), 5.91 (2H,
s); 13C NMR (CDCl3) d: 18.5, 19.3, 20.3, 34.9, 37.9, 79.4,
83.1, 124.9, 125.4, 162.4, 163.1, 185.8; elemental analysis
calcd (%) for C12H16O2: C 74.97; H 8.39; found: C 75.02;
H 8.38.
1
1512 cmꢁ1; H NMR (CDCl3) d: 1.92–2.00 (1H, m), 2.65
(2H, t, J¼6.3 Hz), 3.82 (3H, s), 4.12 (2H, t, J¼5.3 Hz),
5.05 (2H, s), 6.39 (1H, s), 6.57 (1H, s), 7.29–7.45 (5H, m);
13C NMR (CDCl3) d: 22.5, 24.2, 55.9, 66.3, 72.2, 101.2,
112.8, 116.3, 127.4, 127.7, 128.4, 137.6, 142.0, 149.2,
149.4; elemental analysis calcd (%) for C17H18O3: C 75.53;
H 6.71; found: C 75.56; H 6.79.
4.1.6.4. 2,2,6,10-Tetramethyl-1-oxaspiro[4.5]deca-6,9-
dien-8-one (5p). Obtained in 68% yield as yellow oil; IR
1
(KBr): 2980, 2930, 1666, 1626 cmꢁ1; H NMR (CDCl3)

K. Hata et al. / Tetrahedron 63 (2007) 4052–4060
4059
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Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
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Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566.
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5105–5108; (b) Birkett, M. A.; Knight, D. W.; Little, P. B.;
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4. Taylor, E. C.; Andrade, J. G.; Rall, G. J. H.; Turchi, I. J.;
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1996, 37, 2441–2444; (b) Togo, H.; Muraki, T.; Hoshina, Y.;
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d: 1.46 (6H, s), 2.08 (1H, t, J¼6.9 Hz), 2.10 (6H, s), 2.22
(1H, t, J¼6.9 Hz), 5.97 (2H, s); 13C NMR (CDCl3) d:
20.8, 29.5, 38.6, 39.3, 85.1, 85.5, 126.0, 163.3, 125.4,
163.3, 185.7; elemental analysis calcd (%) for C13H18O2:
C 75.69; H 8.80; found: C 75.69; H 8.83.
4.1.6.5. 7,9-Dimethoxy-1-oxaspiro[4.5]deca-6,9-dien-
8-one (5q). Obtained in 85% yield as colorless crystals;
mp 130.4–130.5 ꢂC; IR (KBr): 2937, 2847, 1682, 1657,
1
1622 cmꢁ1; H NMR (CDCl3) d: 2.02–2.23 (4H, m), 3.66
(6H, s), 4.06 (2H, t, J¼6.5 Hz), 5.73 (2H, s); 13C NMR
(CDCl3) d: 26.8, 38.7, 55.3, 68.5, 78.7, 117.1, 149.1,
176.6; elemental analysis calcd (%) for C11H14O4: C
62.85; H 6.71; found: C 62.88; H 6.65.
4.1.6.6. 6,10-Dimethoxy-1-oxaspiro[4.5]deca-6,9-dien-
8-one (5r). Obtained in 63% yield as colorless crystals; mp
113.6–113.7 ꢂC; IR (KBr): 2939, 2849, 1658, 1629,
1
1597 cmꢁ1; H NMR (CDCl3) d: 2.12–2.27 (4H, m), 3.73
(6H, s), 4.15 (2H, t, J¼6.0 Hz), 5.37 (2H, s); 13C NMR
(CDCl3) d: 27.7, 36.2, 56.1, 72.2, 79.6, 99.9, 173.0, 187.5;
elemental analysis calcd (%) for C11H14O4: C 62.85; H
6.71; found: C 62.62; H 6.72.
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4.1.6.7. 2-(2-Hydroxyethyl)-2,6,10-trimethyl-1-oxa-
spiro[4.5]deca-6,9-dien-8-one (5s). Obtained in 52% yield
as colorless oil; IR (KBr): 3408, 2966, 2931, 1666,
1
1620 cmꢁ1; H NMR (CDCl3) d: 1.69 (3H, s), 1.83–2.04
(1H, m), 2.05–2.39 (5H, m), 2.10 (3H, d, J¼1.2 Hz), 2.14
(3H, d, J¼1.2 Hz), 3.75–3.81 (1H, m), 3.96–4.04 (1H, m),
5.95 (1H, s), 5.99 (1H, m); 13C NMR (CDCl3) d: 20.5,
21.4, 26.5, 37.6, 40.1, 43.4, 59.9, 85.7, 88.1, 125.9, 126.7,
162.3, 162.9, 185.6; HRMS (FAB) calcd for C14H21O3
(M++H): 237.1491; found: 237.1495.
4.1.6.8. 2-(Ethoxycarbonylmethyl)-2,6,10-trimethyl-
1-oxaspiro[4.5]deca-6,9-dien-8-one (5t). Obtained in 39%
yield as colorless crystals; mp 70.1–70.2 ꢂC; IR (KBr): 3153,
1
2984, 2903, 1728, 1666, 1626 cmꢁ1; H NMR (CDCl3) d:
1.28 (3H, t, J¼7.1 Hz), 1.56 (3H, s), 2.11 (6H, s), 2.1–2.4
(4H, m), 2.78 (2H, ABq, J¼17.7 Hz), 4.17 (2H, q,
J¼7.1 Hz), 5.98 (2H, m); 13C NMR (CDCl3) d: 14.2, 20.9,
21.0, 26.9, 38.1, 38.2, 46.6, 60.6, 85.3, 85.6, 126.2, 126.4,
157.2, 162.6, 162.7, 170.5, 185.5; elemental analysis calcd
(%) for C16H22O4: C 69.04; H 7.97; found: C 69.00; H 7.88.
7. Kita, Y.; Tohma, H.; Hatanaka, K.; Takada, T.; Fujita, S.;
Mitoh, S.; Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116,
3684–3691.
8. (a) Kita, Y.; Gyoten, M.; Ohtsubo, M.; Tohma, H.; Takada,
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Arisawa, M.; Gyoten, M.; Hamada, R.; Tohma, H.; Kita,
Y. J. Org. Chem. 1998, 63, 7698–7706; (c) Hamamoto, H.;
Anilkmar, G.; Tohma, H.; Kita, Y. Chem. Commun. 2002,
450–451.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research (A) (no. 18209002-00) from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
K.H. acknowledges the JSPS Research Fellowship for
Young Scientists.
9. Hamamoto, H.; Anilkmar, G.; Tohma, H.; Kita, Y. Chem.—Eur.
J. 2002, 8, 5377–5383.
10. Kita, Y.; Egi, M.; Okajima, A.; Ohtsubo, M.; Takada, T.;
Tohma, H. Chem. Commun. 1996, 1491–1492.
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