A novel synthetic route to 2-arylalkanoic acids by a ruthenium-catalyzed chemoselective oxidation of furan rings

Article abstract of DOI:10.1055/s-0028-1083222

An efficient two-step synthesis of 2-arylalkanoic acids from 1-arylalkanols is described. Firstly, 1-arylalkylfuran derivatives were synthesized in high yields by the metal triflate catalyzed Friedel-Crafts alkylation of 2-methylfuran with 1-arylalkanols without employing anhydrous conditions. The chemoselective oxidation of the furan ring in 1-arylalkylfurans to carboxylic acid was then investigated. In a solvent system of hexane-EtOAc/H₂O (1:3:4), the furan ring was selectively oxidized with 7 equivalents of NaIO ₄ by using 0.5 mol% RuCl₃ as catalyst to give 2-arylalkanoic acids in good yields. The selectivity of ruthenium oxidation was controlled by the solvent ratio of hexane-EtOAc. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083222

PAPER
3835
A Novel Synthetic Route to 2-Arylalkanoic Acids by a Ruthenium-Catalyzed
Chemoselective Oxidation of Furan Rings
Ruthenium-Catalyzed
a
s
tive
O
xid
a
ationof Fu
h
ranRings iro Noji, Haruka Sunahara, Ken-ichi Tsuchiya, Tōru Mukai, Ayako Komasaka, Keitaro Ishii*
Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
Fax +81(42)4958783; E-mail: ishiikei@my-pharm.ac.jp
Received 25 July 2008; revised 29 August 2008
R2
Method 1
R2
Abstract: An efficient two-step synthesis of 2-arylalkanoic acids
R-X
hydrolysis
hydrolysis
Ar
CO2R1
from 1-arylalkanols is described. Firstly, 1-arylalkylfuran deriva-
tives were synthesized in high yields by the metal triflate catalyzed
Friedel–Crafts alkylation of 2-methylfuran with 1-arylalkanols
without employing anhydrous conditions. The chemoselective oxi-
dation of the furan ring in 1-arylalkylfurans to carboxylic acid was
then investigated. In a solvent system of hexane–EtOAc/H2O
(1:3:4), the furan ring was selectively oxidized with 7 equivalents
of NaIO4 by using 0.5 mol% RuCl3 as catalyst to give 2-arylalkano-
ic acids in good yields. The selectivity of ruthenium oxidation was
controlled by the solvent ratio of hexane–EtOAc.
Ar
Ar
CO2H
CO2H
Ar
CO2R1
base
Method 2
R1
R1
R1
NaCN
Ar
X
X: halogen Ar
CN
Method 3
R1
transition metal
CO
R1
R1
hydrolysis
CO2R2
R2OH
Ar
Ar
Ar
Ar
CO2H
Key words: Friedel–Crafts alkylation, 1-arylalkylfurans, rutheni-
um tetroxide, chemoselective oxidation, carboxylic acids
Scheme 1 Synthetic methods for 2-arylalkanoic acids
2-methylfuran
M(OTf)n
R
chemoselective
Ru oxidation
R
R
O
Ar
2-Arylalkanoic acids are known to be a very important
class of nonsteroidal anti-inflammatory agents, and many
synthetic methods have been reported.1 The alkylation of
aryl acetates is the most direct synthetic method though
the starting compounds are not widely available
(Scheme 1, Method 1). The introduction of a carboxylic
group is also achieved by the reaction of CN– or CO,
which are extremely hazardous reagents, with halides or
olefins (Scheme 1, Methods 2 and 3).
CO2H
3-CO2H
Ar
OH
MeNO2
solvent
1
2
Scheme 2 RuO4-catalyzed chemoselective oxidation of furan rings
Chemoselective oxidation of alcohols,7 benzene rings,8
and olefins9 over benzene rings were observed only in
some cases. In addition, only a few examples were known
for the chemoselective oxidation of a furan ring over a
benzene ring.10
We have recently developed a metal triflate catalyzed
Friedel–Crafts-type benzylation system.2 This method
provides a variety of 1-arylalkylfuran derivatives 2 from
readily and commercially available 1-arylalkanols 1.
Chemoselective oxidation of furan ring in 2 over an aro-
matic ring was expected to be a useful synthetic method
for 2-arylalkanoic acids 3-CO2H. (Scheme 2)
In contrast, chemoselective oxidations of olefins have
been studied more often than aromatic compounds. These
investigations are categorized into three approaches: the
addition of ligands,11 selection of a co-oxidant,12 and se-
lection of a reaction solvent.13
Improvement of the solvent system for the aromatic ring
oxidation was also reported in the noncompetitive case. A
halogen-free solvent system, EtOAc–MeCN–H2O, has
been used for a benzene ring oxidation.14 In some cases, a
simple EtOAc/H2O solvent system is better than the
CCl4–MeCN–H2O solvent system for the oxidation of a
benzene ring.15
Sharpless and co-workers reported an efficient ruthenium
oxidation system using a catalytic amount of ruthenium
salt and several equivalents of NaIO4 in CCl4–MeCN–
H2O,3 and this procedure effectively oxidized alcohols,
olefins, and benzene rings.4 For the synthesis of carboxy-
lic acids, ruthenium catalyzed oxidation of aromatic rings
is a very useful method.5 Especially, furan derivatives are
extensively employed as a precursor of carboxylic acids.6
However, the substrates for the ruthenium oxidation have
been limited to furans bearing nonaromatic substituents or
bearing electron-deficient, relatively inert, aromatic
groups.
In this work, various types of new 1-arylalkylfurans 2
were synthesized from 1-arylalkanols 1 with 2-methylfu-
ran. And the chemoselective oxidation of furan rings was
examined with the aim to lower the environmental impact
of the oxidation reaction by a solvent approach.
SYNTHESIS 2008, No. 23, pp 3835–3845
x
x.
x
x
.
2
0
0
8
Advanced online publication: 14.11.2008
DOI: 10.1055/s-0028-1083222; Art ID: F16908SS
© Georg Thieme Verlag Stuttgart · New York

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M. Noji et al.
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Synthesis of Furan Derivatives
Table 1 Reactions of 1a with 2-Methylfuran
M(OTf)n
(0.5 mol%)
2-methylfuran
(2 equiv)a
The reactions of 1-arylalkanols 1 and 2-methylfuran were
performed using 0.5 mol% of La, Yb, Sc, and Hf
trifluoromethanesulfonates16 at 20, 40, and 60 °C in
MeNO2. The optimization of the reaction conditions was
easily attained through catalyst-temperature screening ex-
periments.17 The results of the reactions of 1-phenylcyclo-
hexanol (1a) and 2-methylfuran to give 2a are sum-
marized in Table 1. The reaction at 20 °C gave tertiary-
alkylated furan 2a in moderate yields with the recovery of
the starting alcohol 1a. The best yield of 2a (96%) was ob-
tained in the Yb(OTf)3-catalyzed reaction at 40 °C.
O
MeNO2
Ph
MeNO2
temperature
Ph
OH
Ph
2a
1a
Temp
(°C)
20
Time GC yield of 2a (%)
(h)
24
La
45
92
94
Yb
56
96
94
Sc
63
Hf
67
40
60
13
81 (1 h)
77 (1 h)
1.5
75 (0.5 h)
65 (0.5 h)
A considerable amount of 1-phenylcyclohexene was ob-
tained in the Hf(OTf)4-catalyzed reaction at 60 °C via the
decomposition of the benzylic cation.
a The use of 2 equiv of 2-methylfuran was better suited for the repro-
ducibility of the chemical yields because of the low boiling point of
2-methylfuran.
The generality of this benzylation of 2-methylfuran was
subsequently explored with a variety of benzylic alcohols
1a–r. The results are summarized in Table 2. Tertiary al-
cohols 1b and 1k were highly reactive, and the mild reac-
tion conditions were better to prevent the formation of
olefinic by-products. The formation of dimerized ether
derivatives2 was not observed for the reaction of tertiary
alcohols. The electron-donating alkoxy groups in 1d, 1e,
1m, and 1o efficiently increased the yields. Primary ben-
zylic protecting groups, BnO and CbzNH, were stable
during the reaction. Electron-deficient 4-chloro derivative
1i was considerably less reactive than the alkyl derivative
1g, and the addition of Mg(ClO4)2 was effective in in-
creasing the yield. However, the Hf(OTf)4-catalyzed reac-
tion at 60 °C without Mg(ClO4)2 gave 2i in only 24%
without recovery of 1i.
R1 R2
RuCl3 (0.5 mol%)
R1 R2
NaIO4
Ar
Ar
CO2H
hexane–EtOAc/H2O
or
CCl4–MeCN–H2O
O
3-CO2H
2
R1 R2
Ar CO2Me
TMSCHN2
PhH–MeOH
3
Scheme 3 Ruthenium-catalyzed chemoselective oxidation of furan
derivatives
with the careful tuning of the oxidation conditions. To
control the reactivity of active ruthenium species, we em-
ployed a hexane–EtOAc/H2O solvent system with vari-
able ratios. The addition of less polar hexane may
decrease the rate of the oxidation, and slower oxidation
may increase the selectivity of the oxidation reaction. The
reaction is outlined in Scheme 3.
The addition of such an inorganic salt increases the ionic
strength of the reaction medium and could stabilize18 the
benzylic cation. The addition of Mg(ClO4)2 was also ef-
fective for the reaction of 1g, 1l, 1n.
The reaction of (S)-ferrocenylethanol (1r, 100% ee) gave
the desired furan derivative (S)-2r in 93% yield and 100%
ee. 1-Ferrocenylethyl cations are known to be rotationally
stable, and the substitution reaction of a leaving group of
1-ferrocenylethyl compounds occur with the retention of
configuration in many cases.19
The furan derivative 2 was dissolved in hexane–EtOAc or
CCl4–MeCN, and 0.25 mol/L of NaIO4 solution in water
was added. After stirring the mixture at 20 °C for 5–10
min, 0.1 mol/L of RuCl3 solution in water was added, and
the mixture vigorously stirred at 20 °C for 24 hours. After
the extraction of the carboxylic acid with EtOAc, esterifi-
cation with trimethylsilyldiazomethane (TMSCHN2)
gave the desired ester 3.
The reuse of the catalyst was examined with 1a under the
optimized reaction conditions [Yb(OTf)3, 40 °C]. The cat-
alyst was recycled by extraction with water from the reac-
tion mixture. In the first run, 2a was isolated in 97% yield,
and the yields of the second and third runs were 96% and
94%, respectively.
Examination of the Solvent Ratio of Hexane–EtOAc
First, we examined the chemoselective oxidation of 2m
that had the 2-methylfuran and 2-methoxynaphthalene
moieties. This compound is a challenging substrate be-
cause 2m has a large electron-rich aromatic ring, and the
desired product 3m-CO2H is one of the pharmaceutically
important classes of nonsteroidal anti-inflammatory
agents,20 naproxen. The oxidation was performed with 7
equivalents of NaIO4 using 0.5 mol% of RuCl3 as catalyst
in a two-phase system of hexane–EtOAc/H2O at 20 °C.
Chemoselective Oxidation of the Furan Ring
A furan ring is more electron-rich than the majority of the
alkyl-substituted benzenes and naphthalenes. The
chemoselective oxidation of a furan ring may be possible
Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

PAPER
Ruthenium-Catalyzed Chemoselective Oxidation of Furan Rings
3837
Table 2 Reaction of 1-Arylalkanols 1 with 2-Methylfuran
R1 R2
R1 R2
Ar OH
M(OTf)n (0.5 mol%)
O
+
Ar
MeNO2
20–60 °C
O
1
2 equiv
2
R1 R2
R1 R2
Catalyst
0.5 mol%
Temp Time
R
Yield (%)a
O
(°C)
(h)
Ar
Ar
OH
R1 R2
OH
1a
1b
1c
R1, R2 = -(CH2)5-
R1 = R2 = Me
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
40
60
60
14
2
0.5
2a
2b
2c
97
99
93
R1 = H, R2 = Ph
1d
1e
1f
1g
1h
1i
MeO
BnO
CbzNH
Me
Ph
Cl
Yb(OTf)3
Yb(OTf)3
La(OTf)3
Yb(OTf)3
Hf(OTf)4
Yb(OTf)3
40
60
40
40
60
40
23
2d
95
0.08 2e
9
1
1
99b
2f
93
90 (78)d
91
c
c
2g
2h
2i
OH
24
58 + 5e
(47 + 4e)d
R
R
1j
1k
H
Me
La(OTf)3
Sc(OTf)3
60
20
0.75 2j
0.33 2k
99
93
OH
c
c
1l
1m
H
MeO
Yb(OTf)3
Yb(OTf)3
40
20
0.5
4
2l
2m
84 (75)f
99
OH
R
OH
1n
1o
H
MeO
Yb(OTf)3
Sc(OTf)3
40
20
0.5
2
2n
2o
88 (75)f
91
R
1p
–
Hf(OTf)4
20
0.5
0.5
0.17 2r
0.5
2p
2q
84
OH
S
R
g
1q
1r
H
Me
Hf(OTf)4
La(OTf)3
La(OTf)3
20
20
20
79
94
93
g
OH
(S)-1rh Me
(S)-2rh
g
Fe
a Isolated yield.
b GC yield.
c Mg(ClO4)2 (0.2 equiv) was added.
d Yb(OTf)3, 60 °C, without Mg(ClO4)2.
e A regioisomer was obtained.
f La(OTf)3, 60 °C, without Mg(ClO4)2.
g One mol% of catalyst was used.
h 100% ee.
The reaction in the conventional CCl4–MeCN–H2O The oxidation of 2m with KBrO3, NaOCl, H2O2, and t-
(2:2:3) solvent system gave 3m in only 20% yield, and 2m BuOOH was also examined in hexane–EtOAc/H2O
was recovered in 12%. This result indicates that the oxi- (1:3:4). In the reaction with KBrO3, NaOCl, and t-
dation was nonselective, and not only the furan ring but BuOOH, more than 90% of 2m disappeared, but the
also the naphthalene ring also consumed NaIO4. The best yields of 3m were less than 5%. And 88% of 2m was re-
solvent system for the oxidation of 2m was hexane– covered in the reaction with H2O2. Interestingly, the reac-
EtOAc/H2O (1:3:4), and the yield of 3m was 65%. The tion of 2m with t-BuOOH gave 6-methoxy-2-
addition of an excess amount of hexane decreased the acenaphthone, a methylketone-type degradation prod-
yields, and 12% of 2m was recovered in the reaction using uct,21 as the main product in 25% yield. This degradation
the hexane–EtOAc/H2O (3:1:4) system (Table 3).
might have occurred via the C–H oxidation of 2m.22
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M. Noji et al.
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Table 3 Oxidation of 2m in Hexane–EtOAc/H2O or CCl4–MeCN–
Table 4 NaIO4 Equivalents for Furan Ring Oxidation
H2O
RuCl3 (0.5 mol%)
NaIO4 (1–8 equiv)
RuCl3 (0.5 mol%)
NaIO4 (7 equiv )
TMSCHN2
O
O
CO2Me
PhH–MeOH
hexane–EtOAc/H2O
(1:3:4)
solvent
20 °C, 24 h
2j
3j
MeO
20 °C, 24 h
2m
TMSCHN2
NaIO4 (equiv)
1
7
2
3
4
5
6
7
8
CO2Me
PhH–MeOH
r.t., 10 min
Yield of 3j (%)a
22 35 53 80 86 85 86
MeO
3m
Recovery of 2j (%) 92 70 44 20
1
0
0
0
Solvent
hexane–EtOAc/H2O
CCl4–MeCN–H2O
a GC yield.
Ratio
3:1:4 2:2:4 1:3:4 0:4:4
2:2:3
20
the CCl4–MeCN–H2O system. In the majority of the cas-
es, the best solvent ratio was hexane–EtOAc/H2O (1:3:4).
The oxidation of 2a, 2b, and 2k, which have quaternary
carbons, proceeded smoothly, and the best yields were ob-
tained for the solvent ratio of hexane–EtOAc/H2O (2:2:4).
This solvent ratio was also effective for the oxidation of
unsubstituted naphthalene derivatives (2l and 2n). A
marked difference in the solvent effect was observed for
the oxidation of electron-rich naphthalene derivatives 2m
and 2o and thienyl derivative 2p. The selective oxidation
of 2o was difficult even with the use of 6 or 7 mol equiv-
alents of NaIO4. A methoxy group at the ortho position
might have inhibited the catalytic cycle, because 22% of
2o was recovered under the reaction using 7 equivalents
of NaIO4. The ferrocene ring reacted more rapidly than
the furan ring under the reaction conditions. The non-
selective oxidation reaction consumed a considerable
amount of NaIO4, and 2q and 2r were recovered.
Yield (%)a
a GC yield.
15
58
65
46
Examination of the Equivalents of NaIO4
Next, we investigated the requirement of NaIO4 equiva-
lents for the oxidative conversion of a furan ring to a car-
boxylic acid. To accurately estimate the requirement of
NaIO4, we used the compound 2j with a less electron-rich
aromatic ring that was expected to have a better chemose-
lectivity than 2m. After the optimization of the solvent
ratio to hexane–EtOAc/H2O (1:3:4) for 2j, 1–8 mol equiv-
alents of NaIO4 was examined for the oxidation reaction
(Table 4).
The yields of the desired product 3j increased from 7 to
86% as the amount of NaIO4 was increased from 1 to 6
mol equivalents. Although the starting compound 2j al-
most disappeared when 5 mol equivalents of NaIO4 was
used, the best yield was observed for more than 6 mol
equivalents of NaIO4. These results indicated that the net
requirement of NaIO4 for the oxidative conversion of the
furan ring to the carboxylic acid would be 6 mol equiva-
lents.
Ruthenium tetroxide is known to oxidize a methylene
group at the alpha position of a heteroatom.3,24 Benzyl
ethers are additionally sensitive to oxidation under the
conditions employed by Sharpless than the benzene rings.
In our case, the BnO and CbzNH moieties of 2e and 2f
were stable, and the furan ring was chemoselectively
oxidized25 under the reaction conditions.
The origin of chemoselectivity can be rationalized by con-
sidering the solubility of the products. After a more elec-
tron-rich furan ring is predominantly oxidized, the
generated carboxylic acid shifts into an aqueous phase.26
Ruthenium tetroxide is soluble in the organic phase. In our
solvent system, the oxidation would occur in the hexane–
EtOAc phase. The solubility of the carboxylic acid can be
controlled by the ratio of hexane–EtOAc. The hexane-rich
solvent is preferred for the migration of the carboxylic
acid to the aqueous phase, but it reduces the concentration
of ruthenium tetroxide in the organic phase. In the Sharp-
less procedure, a more polar MeCN solvent helps the in-
active ruthenium-carboxylate complex return to the
catalytic cycle. A considerably more polar dimethylfor-
mamide was also been employed for the same reason.27
Therefore, the rate of oxidation in the less polar hexane-
rich solvent decreases, and a considerable amount of the
starting material was recovered in our case.
The pH of the aqueous phase of the reaction mixture was
slightly acidic (pH 3–4). The hydrolysis of ethyl acetate
could have occurred during the reaction, and the generat-
ed ethanol consumes NaIO4.23 In addition, the consump-
tion of NaIO4 by the nonselective oxidation was also
considered. We chose 7 mol equivalents of NaIO4 and ex-
amined the oxidation of furan derivatives 2. The results
are summarized in Table 5.
The optimization of the solvent ratio of hexane–EtOAc/
H2O was attained for all furan derivatives 2a–r, and the
best solvent ratio and the best yield are indicated in
Table 5. The yield data of the oxidation reaction in the
CCl4–MeCN–H2O (2:2:3) solvent system are also shown
for comparison.
The desired 2-arylalkanoic acid esters 3a–p were obtained
in moderate to good yields both in the hexane–EtOAc/
H2O and CCl4–MeCN–H2O systems. In all the productive
cases, the yields of the oxidation of 2a–p in the hexane–
EtOAc/H2O system giving 3a–p were better than those in
In summary, various types of 1-arylalkylfurans 2 were
easily synthesized in high yields from secondary and ter-
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Ruthenium-Catalyzed Chemoselective Oxidation of Furan Rings
3839
Table 5 Ruthenium-Oxidation of Furan Derivatives 2
R1 R2
R1 R2
TMSCHN2
RuCl3 (0.5 mol%), NaIO4 (7 equiv)
O
Ar
Ar
CO2Me
PhH–MeOH
hexane–EtOAc/H2O (3:1:4 to 0:4:4)
or
2
3
CCl4–MeCN–H2O (2:2:3)
20 °C, 24 h
R1 R2
R1 R2
Ar
CO2Me
R
CCl4–MeCN–H2O
(2:2:3)
O
hexane–EtOAc/H2O
Ratio
Ar
Yield (%)a
Yield (%)a
R1 R2
2a
2b
2c
R1, R2 = -(CH2)5- 3a
2:2:4
2:2:4
1:3:4
81
88
87
60
65
80
O
R1 = R2 = Me
3b
3c
R1 = H, R2 = Ph
2d
2e
2f
2g
2h
2i
MeO
BnO
CbzNH
Me
Ph
Cl
3d
3e
3f
3g
3h
3i
1:3:4
1:3:4
1:3:4
1:3:4
1:3:4
2:2:4
92
96
86
74
89
77
87
86
85
68
78
71
O
R
R
2j
2k
H
Me
3j
3k
1:3:4
2:2:4
85
90
73
59
O
2l
H
3l
3m
2:2:4
1:3:4
80
65
51
21
O
2m MeO
R
O
R
2n
2o
H
MeO
3n
3o
2:2:4
2:2:4
88
70
8
27b
O
2p
–
3p
0:4:4
51
11
S
R
2q
2r
H
Me
3q
3r
0
0
0
0
3:1:4 – 0:4:4
O
Fe
a GC yield.
b Isolated yield.
tiary arylalkanols 1 by a metal triflate catalyzed Friedel– oxidation in view of the yields and environmental require-
Crafts reaction with 2-methylfuran. The furan derivatives ments.
2 were chemoselectively oxidized into arylalkanoic acid
derivatives 3 by the RuCl3–NaIO4 catalytic system in hex-
Melting points were measured on a Yanako MP-J3 melting point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded on Jeol JNM-AL400 and JNM-AL300 spectrometers in
CDCl3. IR spectra were recorded on Hitachi 260-10 and Jasco FT/
IR 4100 spectrometers. Low- and high-resolution mass spectra
(LRMS, GC-LRMS, HRMS, and GC-HRMS) were measured with
a JMS-700 mass spectrometer. Optical rotation was measured on a
Jasco P-1020 polarimeter. High performance liquid chromatogra-
phy (HPLC) was carried out with a Jasco PU-2089 pump equipped
ane–EtOAc/H2O. The chemoselectivity of the ruthenium
oxidation was controlled by the hexane–EtOAc ratio. The
ratio of hexane–EtOAc can be easily optimized for vari-
ous types of arylalkylfuran derivatives, and in the majori-
ty of the cases, the best ratio was hexane–EtOAc/H2O =
1:3:4. This procedure can be a good alternative to the con-
ventional CCl4–MeCN–H2O solvent system for furan ring
Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

3840
M. Noji et al.
PAPER
with a Jasco UV-2075 and JASCO CD-2095 spectrophotometer.
GC analysis was performed with a Shimadzu GC-14A, GC-2014
(flame ionization detection) with Phenomenex ZB-1 (100% meth-
ylpolysiloxane, 30 m length, 0.25 mm inner diameter, 0.50 mm film
thickness). Elemental analyses were done with a Yanako CHN
Corder MT-6, PerkinElmer Model 240B elemental analyzer. Pre-
parative TLC was performed on Wakogel B5-F. Column chroma-
tography was performed on silica gel 60 (40–50 mm, Kanto
Chemical). For analytical TLC, precoated F254 silica gel 60 plates
(Merck) were used. RuCl3 was purchased from Wako Pure Chemi-
cal Industries. The syntheses of 1e, 1k, 1m, 1o, 1p, 2j, 2k, 2l, 2m,
2o, and 2p are reported in the literature.2
The aqueous extract was concentrated under a reduced pressure and
dried under vacuum (1 Torr) at r.t. for 10 min and then heated for 3
min using a heating gun at ca. 200 °C to give a white to light-brown
crystalline Yb(OTf)3 catalyst. The catalyst was used for the next
run. For the second run, 1a (612 mg, 3.48 mmol), MeNO2 (3.48 mL)
and 2-methylfuran (627 mL, 6.95 mmol) were stirred at 40 °C for 14
h. After chromatographic purification, 802 mg of 2a (96%) was ob-
tained. For the third run, 1a (626 mg, 3.55 mmol), MeNO2 (3.40
mL), and 2-methylfuran (641 mL, 7.10 mmol) were stirred at 40 °C
for 14 h. After chromatographic purification, 799 mg (94%) of 2a
was obtained.
Furan Derivatives; 2-Methyl-5-(1-phenylcyclohexyl)furan (2a);
Typical Procedure
Optimizing Reaction Conditions; Typical Procedure Using
1-Phenylcyclohexanol (1a)
To a mixture of Sc(OTf)3 (30.4 mg, 61.8 mmol) and 1a (2.179 g,
12.37 mmol) in MeNO2 (12.19 mL) was added 2-methylfuran (2.23
mL, 24.7 mmol) at r.t. The resulting mixture was stirred at 40 °C for
1 h using a Dimroth condenser with a rubber balloon stopper. After
filtering the mixture through a short silica gel pad with EtOAc (70
mL), the filtrate was concentrated under a reduced pressure and the
residue was purified by column chromatography (silica gel, hex-
ane–EtOAc, 10:1) to afford 2a (2.730 g, 92%) as a colorless liquid
(Table 2).
A nitromethane solution (10 mL) of 1-phenylcyclohexanol (1a;
1.772 g, 10.05 mmol, 1.005 mol/L) and nitrohexane (339 mg, 2.59
mmol, as an internal standard, 0.2–0.4 mol/L) was prepared. The so-
lution was mixed with catalysts and 2-methylfuran in 20 mL test
tubes equipped with glass stoppers as follows at 20 °C: 2.5 mg of
La(OTf)3, 832 mL of the solution, and 151 mL of 2-methylfuran; 2.1
mg of Yb(OTf)3, 680 mL of the solution, and 123 mL of 2-methylfu-
ran; 2.1 mg of Sc(OTf)3, 861 mL of the solution, and 156 mL of 2-
methylfuran; 2.7 mg of Hf(OTf)4, 698 mL of the solution, and 127
mL of 2-methylfuran. The reactions at 40 and 60 °C were carried out
in the same manner. The mixtures in the test tubes were stirred at
the corresponding temperatures. The reactions were followed by
TLC. After the complete consumption of 1a (and the symmetrical
ethers for secondary benzylic alcohols), 35 mL of the reaction mix-
ture was filtered through a short silica gel pad with 1 mL of EtOAc
to remove insoluble materials. The filtrates were analyzed by GC
and GC-MS. The programmed GC analysis temperature condition
was 150 °C for 2 min, 10 °C/min, and 260 °C for 17 min. The yields
were determined using the calibration line prepared from nitrohex-
ane and 2a using GC.
The analytical and spectral data of 2a are given above.
2-Methyl-5-(2-phenyl-2-propyl)furan (2b)
Pure 2b was obtained by column chromatography (hexane–EtOAc,
30:1) as a colorless oil; Rf = 0.77 (hexane–EtOAc, 4:1).
IR (neat): 2960, 1450, 1230, 1030, 790, 770, 700 cm–1.
1H NMR (400 MHz): d = 7.28–7.17 (5 H, m), 5.96 (1 H, d, J = 4.0
Hz), 5.87–5.86 (1 H, m), 2.22–2.21 (3 H, m), 1.61 (6 H, s).
13C NMR (100 MHz): d = 160.3, 150.4, 148.0, 127.9, 125.82,
125.76, 105.6, 105.0, 40.2, 28.7, 13.7.
MS (EI, 70 eV): m/z (%) = 200 (M+, 26), 185 (100).
Reuse of the Catalyst; Typical Procedure for 2-Methyl-5-(1-
phenylcyclohexyl)furan (2a)
HRMS-EI: m/z calcd for C14H16O [M]+: 200.1201; found: 200.1204.
Anal. Calcd for C14H16O: C, 83.96; H, 8.05. Found: C, 83.87; H,
8.12.
To a mixture of Yb(OTf)3 (10.5 mg, 17.0 mmol) and 1a (621 mg,
3.52 mmol) in MeNO2 (3.52 mL) was added 2-methylfuran (635
mL, 7.03 mmol) at r.t. The resulting mixture was stirred at 40 °C for
14 h using a Dimroth condenser with a rubber balloon stopper. After
cooling to r.t., the Yb(OTf)3 catalyst was extracted with H2O (6 × 3
mL) (upper phase) from the reaction mixture of MeNO2 solution
(lower phase). When the phase separation became difficult, a small
amount of CHCl3 was added. The trace amount of contaminated
MeNO2 in the aqueous phase was extracted with EtOAc (2 × 5 mL)
and combined with the MeNO2 layer. The combined organic layers
were concentrated under reduced pressure, and the resulting oil was
purified by column chromatography (silica gel, hexane–EtOAc,
20:1) to afford 2a (817 mg, 97%) as colorless needles; mp 38–41
°C; Rf = 0.53 (hexane–EtOAc, 4:1).
2-Diphenylmethyl-5-methylfuran (2c)28
Pure 2c was obtained by column chromatography (hexane–EtOAc,
10:1) as a colorless oil; Rf = 0.67 (hexane–EtOAc, 10:1).
IR (neat): 3030, 1600, 1490, 1450, 1220, 1020, 780, 750, 700 cm–1.
1H NMR (300 MHz): d = 7.31–7.15 (10 H, m), 5.88–5.86 (1 H, m),
5.74–5.73 (1 H, m), 5.38 (1 H, s), 2.24 (3 H, s).
13C NMR (100 MHz): d = 154.6, 151.3, 141.9, 128.6, 128.2, 126.5,
109.0, 105.8, 51.0, 13.8.
EI-MS: m/z (%) = 248 (M+, 100), 205 (81), 171 (85).
HRMS-EI: m/z calcd for C18H16O [M]+: 248.1201; found: 248.1206.
IR (neat): 2910, 2850, 1600, 1550, 1490, 1450, 1220, 1120, 1020,
970, 780, 750, 700 cm–1.
1H NMR (400 MHz): d = 7.29–7.13 (5 H, m), 5.94 (1 H, d, J =3.2
Hz), 5.88–5.87 (1 H, m), 2.33–2.28 (2 H, m), 2.22 (3 H, s), 2.05–
1.99 (2 H, m), 1.60–1.35 (6 H, m).
13C NMR (100 MHz): d = 158.1, 150.1, 147.7, 128.0, 126.2, 125.6,
106.7, 105.6, 44.4, 35.9, 26.2, 23.1, 13.7.
Anal. Calcd for C18H16O: C, 87.06; H, 6.49. Found: C, 86.83; H,
6.67.
2-[1-(4-Methoxyphenyl)ethyl]-5-methylfuran (2d)28
Pure 2d was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.83 (hexane–EtOAc, 10:1).
IR (neat): 2940, 1610, 1500, 1450, 1240, 1220, 1170, 1030, 1020,
830, 780 cm–1.
MS (EI, 70 eV): m/z (%) = 240 (M+, 97), 184 (20), 171 (25), 155
1H NMR (300 MHz): d = 7.16–7.10 (2 H, m with doublet charac-
ter), 6.86–6.81 (2 H, m with doublet character), 5.88–5.83 (2 H, m),
4.01 (1 H, q, J = 7.2 Hz), 3.78 (3 H, s), 2.22 (3 H, s), 1.53 (3 H, d,
J = 7.2 Hz).
(10), 141 (11), 115 (13).
HRMS-EI: m/z calcd for C17H20O [M]+: 240.1514; found: 240.1516.
Anal. Calcd for C17H20O: C, 84.96; H, 8.39. Found: C, 85.24; H,
8.64.
Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

PAPER
Ruthenium-Catalyzed Chemoselective Oxidation of Furan Rings
3841
13C NMR (100 MHz): d = 157.9, 157.3, 150.5, 136.5, 128.1, 113.7,
13C NMR (100 MHz, CDCl3): d = 156.9, 153.2, 150.6, 139.7, 135.9,
105.6, 105.2, 55.3, 38.5, 20.9, 13.7.
135.8, 128.5, 128.2, 128.1, 127.8, 118.8, 105.6, 150.4, 67.0, 38.7,
20.7, 13.7.
MS (EI, 70 eV): m/z (%) = 216 (M+, 26), 201 (100).
HRMS-EI: m/z calcd for C14H16O2 [M]+: 216.1150; found:
MS (EI, 70 eV): m/z (%) = 335 (M+, 8), 227 (28), 212 (100), 108
(10), 91 (17).
HRMS-EI: m/z calcd for C21H21NO3 [M]+: 335.1521; found:
335.1517.
216.1147.
Anal. Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.68; H,
7.27.
Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31. Found: C, 75.38; H,
6.47.
2-[1-(4-Benzyloxyphenyl)ethyl]-5-methylfuran (2e)
Pure 2e was obtained by column chromatography (hexane–EtOAc,
40:1) as a colorless oil; Rf = 0.77 (hexane–EtOAc, 4:1).
2-Methyl-5-[1-(4-Methylphenyl)ethyl]furan (2g)
Pure 2g was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.57 (hexane–EtOAc, 4:1).
IR (neat): 2970, 2930, 1570, 1520, 1460, 1230, 1020, 805, 790 cm–1.
1H NMR (300 MHz): d = 7.12–7.08 (4 H, m), 5.89–5.88 (1 H, m),
5.85–5.84 (1 H, m), 4.02 (1 H, q, J = 7.2 Hz), 2.31 (3 H, s), 2.21 (3
H, s), 1.54 (3 H, d, J = 7.2 Hz).
IR (neat): 2960, 1610, 1510, 1460, 1380, 1240, 1220, 1180, 1020,
830, 790, 720, 700 cm–1.
1H NMR (300 MHz): d = 7.43–7.28 (5 H, m), 7.14–7.10 (2 H, m
with doublet character), 6.91–6.89 (2 H, m with doublet character),
5.87–5.83 (2 H, m), 5.02 (2 H, s), 4.01 (1 H, q, J = 7.2 Hz), 2.21 (3
H, s), 1.53 (3 H, d, J = 7.3 Hz).
13C NMR (100 MHz): d = 157.3, 157.2, 150.5, 137.0, 136.8, 128.4,
128.2, 127.7, 127.3, 114.6, 105.6, 105.3, 70.1, 38.5, 20.9, 13.7.
13C NMR (100 MHz): d = 157.2, 150.5, 141.4, 135.7, 128.9, 127.0,
105.6, 105.3, 39.0, 21.1, 20.9, 13.7.
MS (EI, 70 eV): m/z (%) = 292 (M+, 59), 277 (58), 91 (100).
MS (EI, 70 eV): m/z (%) = 200 (M+, 29), 185 (100).
HRMS-EI: m/z calcd for C20H20O2 [M]+: 292.1463; found:
HRMS-EI: m/z calcd for C14H16O [M]+: 200.1201; found: 200.1203.
292.1471.
Anal. Calcd for C14H16O: C, 83.96; H, 8.05. Found: C, 83.81; H,
8.19.
Anal. Calcd for C20H20O2: C, 82.16; H, 6.89. Found: C, 82.12; H,
6.96.
2-[1-(4-Biphenylyl)ethyl]-5-methylfuran (2h)
Pure 2h was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.63 (hexane–EtOAc, 10:1).
Benzyl 4-(1-Hydroxyethyl)phenylcarbamate (1f)
To a solution of benzyl 4-acetylphenylcarbamate29 (5.190 g, 19.27
mmol) in propan-2-ol (19.3 mL) and THF (19.3 mL) was added
NaBH4 (365 mg, 9.64 mmol) at r.t. The mixture was stirred for 1 h.
To the mixture was then added MeOH (10 mL) and after stirring for
1 h, another portion of NaBH4 (185 mg, 4.90 mmol) was added and
stirred for 1 h. The whole was concentrated, and the residue was
partitioned between H2O (100 mL) and EtOAc (100 mL). The aque-
ous phase was extracted with EtOAc (2 × 100 mL). The combined
organic layers were washed with brine (1 × 100 mL), dried over
MgSO4, filtered, and the filtrate was concentrated to give a colorless
solid (5.130 g, 98%). The solid was recrystallized from propan-2-ol
to afford colorless prisms; mp 101–102 °C; Rf = 0.32 (hexane–
EtOAc, 1:1).
IR (neat): 2960, 1560, 1480, 1220, 1020, 840, 780, 770, 740, 700
cm–1.
1H NMR (300 MHz): d = 7.58–7.56 (2 H, m with doublet charac-
ter), 7.53–7.51 (2 H, m with doublet character), 7.44–7.39 (2 H, m
with triplet character), 7.40–7.27 (3 H, m), 5.95 (1 H, d, J = 2.8 Hz),
5.88–5.87 (1 H, m), 4.11 (1 H, q, J = 7.2 Hz), 2.44 (3 H, s), 1.60 (3
H, d, J = 7.2 Hz).
13C NMR (100 MHz): d = 156.8, 150.7, 143.5, 140.9, 139.2, 128.6,
127.6, 127.0, 126.91, 126.90, 105.7, 105.5, 39.0, 20.8, 13.7.
MS (EI, 70 eV): m/z (%) = 262 (M+, 33), 247 (100).
HRMS-EI: m/z calcd for C19H18O [M]+: 262.1358; found: 262.1362.
IR (KBr): 3441, 3253, 1699, 1601, 1539, 1419, 1239, 1048, 741
cm–1.
1H NMR (300 MHz): d = 7.40–7.25 (9 H, m), 6.76 (1 H, br), 5.18 (2
H, s), 4.84 (1 H, q, J = 6.4 Hz), 1.91(1 H, br), 1.46 (3 H, d, J = 6.6
Hz).
MS (EI, 70 eV): m/z (%) = 271 (M+, 22), 253 (16), 212 (22), 148
(17), 91 (100).
Anal. Calcd for C19H18O: C, 86.99; H, 6.92. Found: C, 87.08; H,
7.00.
2-[1-(4-Chlorophenyl)ethyl]-5-methylfuran (2i)
A mixture of 2i and 2i¢ was obtained by column chromatography
(hexane–EtOAc, 20:1) as a colorless oil; Rf = 0.67 (hexane–EtOAc,
4:1).
HRMS-EI: m/z calcd for C16H17NO3 [M]+: 271.1208; found:
271.1209.
IR (neat) (mixture of 2i and 2i¢): 2970, 1570, 1500, 1230, 1100,
1020, 840, 790 cm–1.
1H NMR (300 MHz,): d = 7.26–7.23 (2 H, m), 7.15–7.11 (2 H, m),
5.91–5.89 (1 H, m), 5.86–5.85 (1 H, m), 4.03 (1 H, q, J = 7.2 Hz),
2.21 (3 H, s), 1.53 (3 H, d, J = 6.9 Hz).
13C NMR (100 MHz): d = 156.3, 150.8, 142.8, 131.9, 128.5, 128.4,
105.67, 105.63, 38.8, 20.7, 13.7.
GC-MS (EI, 70 eV): m/z (%) = 222 (M+ + 2, 28), 220 (77), 207 (78),
205 (100), 141 (14).
GC-HRMS-EI: m/z calcd for C13H13ClO [M]+: 220.0655; found:
220.0658.
Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.99; H, 6.38; N, 5.25.
Benzyl N-[4-(1-(5-Methyl-2-furyl)ethyl)phenyl]carbamate (2f)
Pure 2f was obtained by column chromatography (hexane–EtOAc,
15:1) as a colorless oil; Rf = 0.45 (hexane–EtOAc, 4:1).
IR (neat): 3330, 2960, 1710, 1600, 1530, 1420, 1320, 1220, 1070,
1030, 840, 790, 750, 710 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40–7.25 (7 H, m), 7.15 (2 H, d,
J = 8.4 Hz), 6.63 (1 H, br), 5.88 (1 H, d, J = 2.8 Hz), 5.85–5.84 (1
H, m), 5.19 (2 H, s), 4.02 (1 H, q, J = 6.8 Hz), 2.21 (3 H, s), 1.53 (3
H, d, J = 6.8 Hz).
Anal. Calcd for C13H13ClO (mixture of 2i and 2i¢): C, 70.75; H,
5.94. Found: C, 70.75; H, 6.11.
Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

3842
M. Noji et al.
PAPER
3-[1-(4-Chlorophenyl)ethyl]-5-methylfuran (2i¢)
1H NMR (300 MHz): d = 7.26–7.23 (2 H, m), 7.15–7.11 (2 H, m),
6.22 (1 H, br), 5.90–5.85 (1 H, m), 3.92 (1 H, q, J = 7.2 Hz), 2.15
(3 H, s), 1.50 (3 H, d, J = 7.5 Hz).
(S)-1-(Ferrocenyl)ethanol [(S)-1r]
(S)-1r was prepared by the (R)-oxazaborolidine-catalyzed asym-
metric borane reduction of acetylferrocene.22 The crude product
was recrystallized from cyclohexane to afford (S)-1r with 100% ee.
13C NMR (100 MHz): d = 146.8, 144.6, 139.8, 131.4, 128.4, 128.3,
(S)-2-(1-Ferrocenyl)ethyl-5-methylfuran [(S)-2r]
122.7, 109.8, 35.0, 22.2, 11.9.
100% ee, DAICEL CHIRALCEL OD-H, hexane–propan-2-ol
(30:1), 1 mL/min, 254 nm detection; [a]D26 +57.4 (c = 0.935,
CHCl3).
GC-MS (EI, 70 eV): m/z (%) = 222 (M+ + 2, 11), 220 (34), 207 (32),
205 (100), 141 (8).
GC-HRMS-EI: m/z calcd for C13H13ClO [M]+: 220.0655; found:
220.0650.
Ruthenium Oxidation of Furan Derivatives; Methyl 1-Phenyl-
1-cyclohexanecarboxylate (3a);30 Typical Procedures
For GC Analysis
2-Methyl-5-[1-(1-naphthyl)ethyl]furan (2n)
Furan derivative 2a (20.0 mg, 83.2 mmol) was dissolved in hexane–
EtOAc (3:1, 2.33 mL) in a 20 mL test tube. A 0.25 mol/L solution
of NaIO4 in H2O (2.33 mL, 583 mmol, 7 equiv) was added and the
mixture was stirred for 5 min at 20 °C. A 0.1 mol/L solution of
RuCl3·nH2O (calculated as 3 H2O) in H2O (4.2 mL, 0.42 mmol, 0.5
mol%) was added. The mixture was vigorously stirred at 20 °C for
24 h. NaCl was added to saturate the aqueous layer and the mixture
was extracted with EtOAc (5 × 2 mL). The combined extracts were
dried (MgSO4) and filtered. The filtrate was concentrated under re-
duced pressure, and the residue was dissolved in benzene–
MeOH (2:7, 832 mL). A 2.0 mol/L solution of trimethylsilyldiazo-
methane (TMSCHN2) in hexane (250 mL, 1.5 equiv) was added, and
stirred for 5 min at r.t. A 0.1 mol/L solution of AcOH in MeOH was
added to consume the excess of TMSCHN2, and the mixture was
concentrated under reduced pressure to give the methyl ester 3a.
Octadecane (13.0 mg, 2/3–3/4 weight of the starting material) was
added, and dissolved in EtOAc (26 mL). The solution was analyzed
by GC and GC-MS. The yields were determined using the calibra-
tion line prepared from octadecane and 3a using GC. The yield of
3a was 69%. The carboxylic acids (3-CO2H) can be obtained by
preparative TLC (CH2Cl2–MeOH, 10:1) after the extraction of the
crude products.
Pure 2n was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.67 (hexane–EtOAc, 4:1).
IR (neat): 2960, 1560, 1450, 1380, 1220, 1020, 780 cm–1.
1H NMR (300 MHz): d = 8.13 (1 H, d, J = 8.4 Hz), 7.86 (1 H, d,
J = 7.6 Hz), 7.72 (1 H, d, J = 8.0 Hz), 7.52–7.44 (2 H, m), 7.40 (1
H, t, J = 7.7 Hz), 7.27–7.23 (1 H, m), 5.95–5.94 (1 H, m), 5.89–5.87
(1 H, m), 4.90 (1 H, q, J = 7.1 Hz), 2.23 (3 H, s), 1.70 (3 H, d,
J = 7.2 Hz).
13C NMR (100 MHz): d = 156.8, 150.6, 140.2, 133.8, 131.2, 128.7,
126.9, 125.8, 125.5, 125.2, 124.0, 123.2, 106.3, 105.7, 34.8, 20.4,
13.7.
MS (EI, 70 eV): m/z (%) = 236 (M+, 50), 221 (100), 193 (11), 178
(17).
HRMS-EI: m/z calcd for C17H16O [M]+: 236.1201; found: 236.1200.
Anal. Calcd for C17H16O: C, 86.40; H, 6.82. Found: C, 86.47; H,
7.02.
2-(Ferrocenyl)methyl-5-methylfuran (2q)
Pure 2q was obtained by preparative TLC (hexane–CHCl3, 4:1) as
an orange solid; mp 33–34 °C; Rf = 0.45 (hexane–CHCl3, 4:1).
1 mmol Scale
IR (KBr): 3100, 1568, 1419, 1217, 1105, 1027, 1001, 969, 950, 817,
788, 491 cm–1.
Furan derivative 2a (280.8 mg, 1.168 mmol) was dissolved in hex-
ane–EtOAc (1:1, 32.7 mL) in a 100 mL flask. A 0.25 mol/L solution
of NaIO4 in H2O (32.7 mL, 8.18 mmol, 7 equiv) was added and the
mixture was stirred for 10 min at 20 °C. A 0.1 mol/L solution of
RuCl3⋅nH2O (calculated as 3 H2O) in H2O (58.4 mL, 5.84 mmol, 0.5
mol%) was added. The mixture was stirred vigorously at 20 °C for
24 h. NaCl was added to saturate the aqueous layer and the mixture
was extracted with EtOAc (4 × 40 mL). The combined extracts were
dried (MgSO4) and filtered. The filtrate was concentrated under re-
duced pressure, and the residue was dissolved in benzene–MeOH
(2:7, 20 mL). A 2.0 mol/L solution of trimethylsilyldiazomethane
(TMSCHN2) in hexane (3.51 mL, 1.5 equiv) was added, and stirred
for 10 min at r.t. A 0.1 mol/L solution of AcOH in MeOH was added
to consume the excess of TMSCHN2, and the mixture was concen-
trated under reduced pressure to give crude methyl ester 3a. Pure 3a
was obtained by column chromatography (hexane–EtOAc, 20:1) as
a pale yellow oil; yield: 191.4 mg (75%); Rf = 0.45 (hexane–EtOAc,
10:1).
1H NMR (400 MHz): d = 5.86–5.84 (2 H, m), 4.13–4.06 (9 H, m),
3.61 (2 H, s), 2.27 (3 H, s).
13C NMR (100 MHz): d = 152.8, 150.1, 106.0, 105.8, 85.7, 68.7,
68.4, 67.4, 28.5, 13.7.
MS (EI, 70 eV): m/z (%) = 281 (M+ + 1, 20), 280 (100), 214 (7).
HRMS-EI: m/z calcd for C16H16FeO [M]+: 280.0551; found:
280.0549.
Anal. Calcd for C16H16FeO: C, 68.60; H, 5.76. Found: C, 68.62; H,
5.87.
2-(1-Ferrocenyl)ethyl-5-methylfuran (2r)
Pure 2r was obtained by preparative TLC (hexane–CHCl3, 4:1) as
an orange solid; mp 55–56 °C; Rf = 0.45 (hexane–CHCl3, 4:1).
IR (neat): 3100, 2960, 1560, 1450, 1220, 1105, 1020, 820, 790 cm–1.
1H NMR (400 MHz): d = 5.84–5.80 (2 H, m), 4.12–4.06 (9 H, m),
3.80 (1 H, q, J = 7.2 Hz), 2.27 (3 H, s), 1.53 (3 H, d, J = 7.2 Hz).
13C NMR (100 MHz): d = 157.5, 149.7, 105.6, 104.4, 92.5, 68.6,
67.5, 67.2, 67.0, 66.5, 33.1, 20.2, 13.7.
MS (EI, 70 eV): m/z (%) = 295 (M+ + 1, 22), 294 (M+, 100), 279
(21).
Note: For the isolation of the methyl ester derivative 3, the concen-
tration process should be carried out below 30 °C, because some
methyl ester derivative 3 is significantly volatile.
IR (neat): 2930, 2860, 1730, 1450, 1310, 1220, 1140, 1000, 740,
700 cm–1.
1H NMR (300 MHz): d = 7.40–7.22 (5 H, m), 3.64 (3 H, s), 2.53–
2.45 (2 H, m), 1.78–1.22 (8 H, m).
MS (EI, 70 eV): m/z (%) = 218 (M+, 19), 159 (100), 91 (63).
HRMS-EI: m/z calcd for C14H18O2 [M]+: 218.1307; found:
HRMS-EI: m/z calcd for C17H18FeO [M]+: 294.0707; found:
294.0704.
Anal. Calcd for C17H18FeO: C, 69.41; H, 6.17. Found: C, 69.44; H,
6.33.
218.1308.
Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

PAPER
Ruthenium-Catalyzed Chemoselective Oxidation of Furan Rings
3843
Methyl 2-Methyl-2-phenylpropionate (3b)31
Pure 3b was obtained by column chromatography (hexane–EtOAc,
20:1) as a pale yellow oil; Rf = 0.53 (hexane–EtOAc, 4:1).
13C NMR (100 MHz): d = 174.7, 153.1, 136.6, 135.9, 135.5, 128.5,
128.22, 128.17, 128.0, 118.8, 67.1, 52.1, 44.8, 18.7.
MS (EI, 70 eV): m/z (%) = 313 (M+, 18), 210 (25), 205 (29), 146
IR (neat): 2950, 1730, 1470, 1450, 1440, 1260, 1200, 1150, 1105,
850, 770, 700 cm–1.
1H NMR (300 MHz): d = 7.34–7.22 (5 H, m), 3.65 (3 H, s), 1.58 (6
H, s).
(100), 128 (16), 108 (14), 91 (55), 79 (12), 77 (10).
HRMS-EI: m/z calcd for C18H19NO4 [M]+: 313.1314; found:
313.1309.
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
69.11; H, 6.31; N, 4.12.
MS (EI, 70 eV): m/z (%) = 178 (M+, 24), 119 (100), 91 (40).
HRMS-EI: m/z calcd for C11H14O2 [M]+: 178.0994; found:
178.0991.
Methyl 2-(4-Methylphenyl)propionate (3g)34
Pure 3g was obtained by column chromatography (hexane–EtOAc,
30:1) as a colorless oil; Rf = 0.25 (hexane–EtOAc, 10:1).
IR (neat): 2930, 1730, 1430, 1200, 1160, 1060, 820 cm–1.
Methyl Diphenylacetate (3c)32
Pure 3c was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.33 (hexane–EtOAc, 10:1).
IR (neat): 3030, 1730, 1430, 1280, 1200, 1150, 1010, 750, 700 cm–1.
1H NMR (300 MHz): d = 7.20–7.11 (4 H, m), 3.69 (1 H, q, J = 7.2
Hz), 3.65 (3 H, s), 2.33 (3 H, s), 1.48 (3 H, d, J = 7.2 Hz).
1H NMR (300 MHz): d = 7.82–7.22 (10 H, m), 5.03 (1 H, s), 3.74
MS (EI, 70 eV): m/z (%) = 178 (M+, 23), 119 (100).
HRMS-EI: m/z calcd for C11H14O2 [M]+: 178.0994; found:
(3 H, s).
MS (EI, 70 eV): m/z (%) = 226 (M+, 21), 167 (100).
178.0992.
HRMS-EI: m/z calcd for C15H14O2 [M]+: 226.0994; found:
226.0995.
Methyl 2-(4-Biphenyl)propionate (3h)35
Pure 3h was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.29 (hexane–EtOAc, 10:1).
IR (neat): 2940, 1730, 1490, 1210, 760, 700 cm–1.
1H NMR (300 MHz): d = 7.58–7.52 (4 H, m), 7.46–7.30 (5 H, m),
3.78 (1 H, q, J = 7.2 Hz), 3.69 (3 H, s), 1.54 (3 H, d, J = 7.2 Hz).
Methyl 2-(4-Methoxyphenyl)propionate (3d)33,40
Pure 3d was obtained by column chromatography (hexane–EtOAc,
40:1) as a colorless oil; Rf = 0.26 (hexane–EtOAc, 10:1).
IR (neat): 2930, 1730, 1610, 1510, 1460, 1250, 1210, 1170, 1040,
840, 790 cm–1.
1H NMR (300 MHz): d = 7.24–7.19 (2 H, m), 6.88–6.84 (2 H, m),
3.79 (3 H, s), 3.67 (1 H, q, J = 7.2 Hz), 3.65 (3 H, s), 1.47 (3 H, d,
J = 7.2 Hz).
MS (EI, 70 eV): m/z (%) = 240 (M+, 41), 181 (100).
HRMS-EI: m/z calcd for C16H16O2 [M]+: 240.1150; found:
240.1150.
MS (EI, 70 eV): m/z (%) = 194 (M+, 23), 135 (100).
Methyl 2-(4-Chlorophenyl)propionate (3i)33
Pure 3i was obtained by column chromatography (hexane–EtOAc,
20:1) as a pale yellow oil; Rf = 0.26 (hexane–EtOAc, 10:1).
HRMS-EI: m/z calcd for C11H14O3 [M]+: 194.0943; found:
194.0939.
IR (neat): 2950, 1730, 1490, 1440, 1330, 1210, 1170, 1090, 1020,
830, 770 cm–1.
Methyl 2-(4-Benzyloxyphenyl)propionate (3e)33
Pure 3e was obtained by column chromatography (hexane–EtOAc,
40:1) as a colorless oil; Rf = 0.53 (hexane–EtOAc, 4:1).
IR (neat): 1730, 1605, 1500, 1450, 1250, 1180, 1020, 830, 740 cm–1.
1H NMR (400 MHz): d = 7.43–7.32 (5 H, m), 7.23–7.21 (2 H, m
with doublet character), 6.95–6.91 (2 H, m with doublet character),
5.04 (2 H, s), 3.67 (1 H, q, J = 7.2 Hz), 3.65 (3 H, s), 1.47 (3 H, d,
J = 7.2 Hz).
1H NMR (300 MHz): d = 7.71–7.21 (4 H, m), 3.70 (1 H, q, J = 7.2
Hz), 3.66 (3 H, s), 1.48 (3 H, d, J = 6.9 Hz).
MS (EI, 70 eV): m/z (%) = 200 (M+ + 2, 8), 198 (M+, 24), 141 (34),
139 (100), 103 (38).
HRMS-EI: m/z calcd for C10H11ClO2 [M]+: 198.0448; found:
198.0445.
13C NMR (100 MHz): d = 175.0, 157.7, 136.9, 132.8, 128.44,
Methyl 1,2,3,4-Tetrahydronaphthalene-1-carboxylate (3j)36
Pure 3j was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.38 (hexane–EtOAc, 10:1).
128.36, 127.8, 127.3, 114.8, 70.1, 52.0, 44.6, 18.8.
MS (EI, 70 eV): m/z (%) = 270 (M+, 38), 211 (11), 91 (100).
IR (neat): 2930, 1720, 1450, 1435, 1250, 1205, 1195, 1060, 1070,
1000, 750 cm–1.
1H NMR (300 MHz): d = 7.19–7.08 (4 H, m), 3.84 (1 H, t, J = 5.9
Hz), 3.71 (3 H, s), 2.89–2.70 (2 H, m), 2.20–1.73 (4 H, m).
13C NMR (100 MHz): d = 175.1, 137.0, 133.1, 129.2, 129.1, 126.7,
125.6, 52.0, 44.9, 29.2, 26.7, 20.7.
MS (EI, 70 eV): m/z (%) = 190 (M+, 20), 131 (100).
HRMS-EI: m/z calcd for C12H14O2 [M]+: 190.0994; found:
HRMS-EI: m/z calcd for C17H18O3 [M]+: 270.1256; found:
270.1255.
Anal. Calcd for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.75; H,
6.86.
Methyl 2-[4-(Benzyloxycarbonylamino)phenyl]propionate (3f)
Pure 3f was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless solid; mp 71.5–72.5 °C; Rf = 0.29 (hexane–
EtOAc, 4:1).
190.0991.
IR (KBr): 3368, 1739, 1709, 1594, 1536, 1454, 1436, 1417, 1316,
1210, 1172, 1069, 840, 738 cm–1.
1H NMR (400 MHz): d = 7.39–7.32 (7 H, m), 7.24–7.22 (2 H, m
with doublet character), 6.65 (1 H, br), 5.19 (2 H, s), 3.68 (1 H, q,
J = 7.2 Hz), 3.65 (3 H, s), 1.47 (3 H, d, J = 7.2 Hz).
Anal. Calcd for C12H14O2: C, 75.76; H, 7.42. Found: C, 75.53; H,
7.65.
Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

3844
M. Noji et al.
PAPER
Methyl 1-Methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylate
(3k)37
Pure 3k was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.42 (hexane–EtOAc, 4:1),
IR (neat): 2920, 1720, 1450, 1440, 1260, 1200, 1120, 770, 740 cm–1.
1H NMR (300 MHz): d = 7.23–7.26 (4 H, m), 3.65 (3 H, s), 2.29–
2.72 (2 H, m), 2.35–2.26 (1 H, m), 1.94–1.69 (3 H, m), 1.55 (3 H, s).
IR (neat): 1736, 1263, 1210, 1095, 809, 747 cm–1.
1H NMR (300 MHz): d = 7.84 (1 H, d, J = 8.7 Hz), 7.80 (1 H, d,
J = 7.5 Hz), 7.79 (1 H, d, J = 9.0 Hz), 7.48 (1 H, dd, J = 6.6, 1.5
Hz), 7.34 (1 H, dd, J = 6.9, 1.2 Hz), 7.27 (1 H, d, J = 9.0 Hz), 4.54
(1 H, q, J = 6.9 Hz), 3.92 (3 H, s), 3.63 (3 H, s), 1.54 (3 H, d, J = 6.9
Hz).
13C NMR (100 MHz): d = 175.8, 153.7, 131.9, 129.4, 128.71,
128.70, 126.65, 123.3, 123.1, 122.2, 113.5, 56.6, 51.9, 36.7, 16.3.
13C NMR (100 MHz): d = 177.5, 139.0, 136.2, 129.1, 127.8, 126.3,
1258, 52.2, 46.4, 35.3, 30.0, 27.8, 19.9.
MS (EI, 70 eV): m/z (%) = 244 (M+, 51), 185 (100), 155 (9).
MS (EI, 70 eV): m/z (%) = 204 (M+, 13), 145 (100), 129 (10).
HRMS-EI: m/z calcd for C15H16O3 [M+]: 244.1099; found:
244.1102.
HRMS-EI: m/z calcd for C13H16O2 [M]+: 204.1150; found:
204.1152.
Methyl 2-(2-Thienyl)propionate (3p)38
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C, 76.46; H,
8.16.
A mixture of 3p and 3p¢ was obtained by column chromatography
(hexane–EtOAc, 20:1) as a pale yellow oil. The ratio of 3p/3p¢ was
1
determined by H NMR spectroscopy; Rf = 0.30 (hexane–EtOAc,
Methyl 2-(2-Naphthyl)propionate (3l)38
Pure 3l was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.22 (hexane–EtOAc, 10:1).
10:1).
IR (neat) (5.3:1 mixture of 3p/3p¢): 1739, 1455, 1435, 1327, 1200,
1171, 1059, 852, 702 cm–1.
IR (neat): 2950, 1730, 1440, 1330, 1250, 1200, 1170, 820, 750 cm–1.
1H NMR (300 MHz): d = 7.20 (1 H, t, J = 3.3 Hz), 6.95 (2 H, d,
J = 3.0 Hz), 4.02 (1 H, q, J = 7.2 Hz), 3.71 (3 H, s), 1.59 (3 H, d,
J = 7.2 Hz).
13C NMR (100 MHz): d = 173.7, 142.7, 126.5, 124.6, 124.2, 52.3,
40.8, 19.5.
GC-MS (EI, 70 eV): m/z (%) = 170 (M+, 29), 111 (100).
GC-HRMS-EI: m/z calcd for C8H10O2S [M]+: 170.0402; found:
1H NMR (300 MHz): d = 7.82–7.79 (3 H, m), 7.73–7.74 (1 H, m),
7.49–7.41 (3 H, m), 3.90 (1 H, q, J = 7.2 Hz), 3.67 (3 H, s), 1.59 (3
H, d, J = 7.2 Hz).
13C NMR (100 MHz): d = 174.7, 137.8, 133.3, 132.4, 128.2, 127.7,
127.5, 126.01, 125.98, 125.7, 125.6, 52.1, 45.6, 18.7.
MS (EI, 70 eV): m/z (%) = 214 (M+, 42), 155 (100).
HRMS-EI: m/z calcd for C14H14O2 [M]+: 214.0994; found:
170.0408.
214.0991.
Methyl 2-(4-Iodo-2-thienyl)propionate (3p¢)
1H NMR (300 MHz): d = 7.08 (1 H, d, J = 3.6 Hz), 6.63 (1 H, d,
J = 3.6 Hz), 3.98 (1 H, q, J = 6.9 Hz), 3.71 (3 H, s), 1.55 (3 H, d,
J = 7.5 Hz).
13C NMR (100 MHz): d = 173.2, 148.7, 136.3, 126.4, 71.9, 52.4,
41.2, 19.4.
GC-MS (EI, 70 eV): m/z (%) = 296 (M+, 39), 237 (100).
GC-HRMS-EI: m/z calcd for C8H9IO2S [M]+: 295.9368; found:
Methyl 2-(6-Methoxy-2-naphthyl)propionate (3m)39
Pure 3m was obtained by column chromatography (hexane–EtOAc,
20:1) as colorless fine needles; mp 64–65 °C (propan-2-ol);
Rf = 0.41 (hexane–EtOAc, 4:1).
IR (KBr): 2977, 1736, 1605, 1449, 1333, 1332, 1266, 1230, 1198,
1174, 1029, 857, 824, 480 cm–1.
1H NMR (300 MHz): d = 7.69 (1 H, d, J = 8.4 Hz), 7.69 (1 H, d,
J = 8.4 Hz), 7.65 (1 H, d, J = 0.9 Hz), 7.39 (1 H, dd, J = 8.4, 1.8
Hz), 7.15–7.09 (2 H, m), 3.00 (3 H, s), 3.85 (1 H, q, J = 7.2 Hz),
3.66 (3 H, s), 1.57 (3 H, d, J = 7.2 Hz).
295.9369.
MS (EI, 70 eV): m/z (%) = 244 (M+, 52), 185 (100).
HRMS-EI: m/z calcd for C15H16O3 [M]+: 244.1099; found:
Acknowledgment
This work was supported, in part, by the Ministry of Education,
Culture, Sports, Science and Technology, a Grant-in-Aid for Young
Scientists (B) (No. 18790016).
244.1093.
Methyl 2-(1-Naphthyl)propionate (3n)33,40
Pure 3n was obtained by column chromatography (hexane–EtOAc,
20:1) as a colorless oil; Rf = 0.42 (hexane–EtOAc, 4:1).
IR (neat): 2950, 1730, 1440, 1200, 1180, 790 cm–1.
1H NMR (300 MHz): d = 8.07 (1 H, d, J = 8.1 Hz), 7.88–7.85 (1 H,
m), 7.79–7.75 (1 H, m), 7.56–7.48 (2 H, m), 7.47–7.40 (2 H, m),
4.51 (1 H, q, J = 7.2 Hz), 3.65 (3 H, s), 1.66 (3 H, d, J = 7.2 Hz).
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Synthesis 2008, No. 23, 3835–3845 © Thieme Stuttgart · New York

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