Synthesis of aromatic compounds using combinations of ring-closing olefin metathesis, dehydration, oxidation, and tautomerization

Article abstract of DOI:10.1246/bcsj.81.1512

An approach to aromatic compounds using combinations of ring-closing olefin metathesis (RCM), dehydration, oxidation, and tautomerization is reported. The RCM reaction of l,7-diene-3,5-diols, which were readily prepared by the allylation of aldol products, gave corresponding cyclized products, 4-cyclohexene-l,3-diols, in high yields. The subsequent dehydration or oxidation of 4-cyclohexene-1,3-diols led to versatile substituted benzenes including phenol and resorcinol derivatives.

Full text of DOI:10.1246/bcsj.81.1512

1512 Bull. Chem. Soc. Jpn. Vol. 81, No. 11, 1512–1517 (2008)
Ó 2008 The Chemical Society of Japan
Synthesis of Aromatic Compounds Using Combinations of Ring-Closing
Olefin Metathesis, Dehydration, Oxidation, and Tautomerization
ꢀ
ꢀ
Kazuhiro Yoshida, Takeharu Toyoshima, and Tsuneo Imamoto
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522
Received May 21, 2008; E-mail: kyoshida@faculty.chiba-u.jp, imamoto@faculty.chiba-u.jp
An approach to aromatic compounds using combinations of ring-closing olefin metathesis (RCM), dehydration,
oxidation, and tautomerization is reported. The RCM reaction of 1,7-diene-3,5-diols, which were readily prepared by
the allylation of aldol products, gave corresponding cyclized products, 4-cyclohexene-1,3-diols, in high yields. The sub-
sequent dehydration or oxidation of 4-cyclohexene-1,3-diols led to versatile substituted benzenes including phenol and
resorcinol derivatives.
One important aspect of modern organic chemistry is the
development of highly regioselective methods for the synthesis
of substituted aromatic compounds.1 Electrophilic aromatic
substitution is considered to be one of the most powerful and
general methods for the synthesis of aromatic compounds in
industry as well as in the laboratory. However, one weak point
of this method is its lack of regioselectivity. Unless there is
structural bias, the synthesis often gives a mixture of re-
gioisomers. One possible solution to this problem is the direct
construction of aromatic rings from acyclic precursors.2 Al-
though the preparation of acyclic precursors usually requires
several steps, this approach has an advantage to enable perfect
regioselective access to the desired aromatic compounds. Re-
cently, the construction of aromatic rings using ring-closing
olefin metathesis (RCM)3,4 has emerged as an interesting and
efficient method in this field.5–7 We also have reported that
RCM/dehydration and RCM/tautomerization are valuable
processes for the synthesis of benzene and phenol derivatives
(eqs 1 and 2).8 However, from a practical viewpoint, these
processes have a limitation: the selective construction of
an internal cis double bond is required to obtain the acyclic
precursors.
OH
O
M
O
OH
[O]
HO
HO
M = Mg, B, etc.
1
2
O
4
3
RCM
RCM
OH
[O]
[O]
HO
HO
6
dehydration
dehydration
tautomerization
OH
OH
HO
8
7
5
Scheme 1.
OH
4 has cis configuration, this strategy makes it possible to avoid
the requirement of selective synthesis of the internal cis double
bond of the acyclic precursors. In the present paper, we report
further improvement of this methodology. The main improve-
ment is that the cyclization can now be conducted under mild
conditions since 1,7-diene-3,5-diol 2 was chosen as the reac-
tive precursor in preference to 3. First, we describe the cycli-
zation of 2 (route 2–6). Then, we discuss the conversion of 6
into phenol (route 6–4–5), benzene (route 6–7), and resorcinol
(route 6–4–8).
OH
RCM
dehydration
ð1Þ
O
O
OH
RCM
tautomerization
ð2Þ
Very recently, we proposed a facile and improved route to
phenol derivatives, as outlined in one part of Scheme 1 (route
1–2–3–4–5).9 In this strategy, phenol derivatives 5 were syn-
thesized by sequential dehydration and tautomerization of
key intermediates 4, after cyclization of 5-hydroxy-1,7-octa-
dien-3-ones 3 that were easily prepared from aldol products
1. Because the double bond constructed by the dehydration of
Results and Discussion
Electron-deficient dienic systems are known to be weakly
reactive in RCM reactions.10 In this regard, high reaction tem-
peratures (40 to 100 ꢁC) were required to achieve complete
conversion in most of the RCM reactions of 3 into 4 in our pre-
vious study.9 Therefore, we started this investigation with the
Published on the web November 12, 2008; doi:10.1246/bcsj.81.1512

K. Yoshida et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 11 (2008) 1513
Table 1. Synthesis of 4-Cyclohexene-1,3-diols 6 by Ruthenium-Catalyzed Ring-Closing Olefin Metathesisa)
OH
OH
R2
R1
N
N
R2
R1
R5
9 (7.5 mol%)
HO
R3
Cl
HO
Ru
CH2Cl2
Temp., 2 h
R3
Ph
Cl
R4
R4
R5
PCy3
2
6
9
Entry
Substrate
R1
R2
R3
R4
R5
Temp.
Yieldb)/%
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
Me
Me
Me
H
H
H
H
H
Et
H
H
Me
H
H
H
H
H
H
H
Me
rt
rt
rt
rt
rt
40 ꢁC
90 (6a)
80 (6b)
82 (6c)
>99 (6d)
86 (6e)c)
54 (6f)
4-ClC6H4
t
CH2OSiMe2 Bu
H
H
Me
Ph
H
H
CH2OBn
a) Reactions were carried out with 1,7-diene-3,5-diol 2 and ruthenium catalyst 9 (7.5 mol %) in CH2Cl2 for 2 h. b) Isolated
yield by silica gel chromatography. c) When the amount of catalyst 9 was decreased to 2.5 mol %, the isolated yield of 6e
was decreased to 40%.
MnO2, or PCC, could be used for the oxidation of 6. The reac-
OH
OH
Me
HO
Ph
tions proceeded well in most cases, but only the best results are
selected for entry in Table 2.13 For the following dehydration,
we employed a catalytic amount of p-toluenesulfonic acid as
Brønsted acid catalyst, and phenol derivatives 5 were obtained
in high yields. In the case of 4d that has an acid-sensitive silyl
ether, basic conditions (mesylation of the hydroxy group with
t-BuOK, followed by elimination) were required to retain the
silyl group (Table 2, Entry 4).14
Me
HO
9 (7.5 mol%)
CH2Cl2, 15 °C, 2 h
85% yield
Me
Ph
Me
2g
6g
O
O
Me
Me
HO
9 (7.5 mol%)
CH2Cl2, 15 °C, 2 h
21% yield
It is possible to perform the conversion of 2 into 4 sequen-
tially without the isolation of 6. As shown in Scheme 3, RCM
reactions of 2h and 2i, followed by sequential oxidation with
PCC, gave good yields of 4h and 4i, respectively.15 Treatment
of 4h with p-toluenesulfonic acid led to aromatization to give
corresponding phenol 5h quantitatively. On the other hand, the
same process for 4i resulted in isomerization of the carbon–
carbon double bond from terminal to internal at R3 position.
Therefore, basic conditions (t-BuOK, MsCl) were applied to
4i to obtain 5i.
HO
Ph
Me
Ph
Me
3g
4g
Scheme 2.
RCM reaction of 2, which does not have electron-deficient
alkene moieties. The route including cyclization of 2, followed
by oxidation of 6, seemed to be the most practical.
4-Cyclohexene-1,3-diols 6 are promising intermediates be-
cause the sequential dehydrations process of 6 affords benzene
derivatives 7 and the sequential oxidations process of 6 at the
two hydroxy groups affords resorcinol derivatives 8, as outlined
in one part of Scheme 1. In fact, the dehydration of 6 with p-
toluenesulfonic acid proceeded smoothly to give corresponding
benzene derivatives 7 (Table 3). Moreover, it was also proved
that a combination of Dess–Martin and Swern oxidations of 6f
afforded resorcinol derivative 8f via 4f (Scheme 4).16,17
The results of the RCM reaction of 2 are listed in Table 1.
In most cases, the RCM of 2 with Grubbs’ second-generation
catalyst 911 proceeded well to afford cyclized products 6. Irre-
spective of the formation of disubstituted or trisubstituted dou-
ble bond, the RCM reaction was completed in 2 h at room tem-
perature. An exception was found with substrate 2f having a
benzyloxymethyl group as the R5 substituent, which was cy-
clized at high temperature (40 ꢁC) into 6f in moderate yield
(54%). This result is ascribed to the competitive isomerization
of the allylic olefin of 2f to produce a significant amount of the
by-product, 7-benzyloxymethyl-5-hydroxy-7-octen-3-one.12
The RCM reaction of 2g was compared with that of 3g
under the same conditions (15 ꢁC, 2 h) to determine the differ-
ence in reactivities between 2 and 3 (Scheme 2). As a result,
incomplete conversion in the reaction of 3g gave correspond-
ing cyclic product 4g only in 21% yield as predicted, whereas a
high yield (85%) of 6g was obtained from 2g.
Conclusion
We have presented an efficient method for the production of
aromatic compounds from acyclic precursors. The key step
was the RCM reaction of 2 to form 6. The choice of 2 as
the precursor, instead of less reactive intermediate 3 having
electron-deficient olefin, rendered the RCM reaction condi-
tions milder. The formation of a variety of products (benzene,
phenol, and resorcinol), which is attributed to the diversity of
the transformations of 6, and no formation of inseparable re-
gioisomers are proof of the versatility of this method for the
synthesis of aromatic compounds.
We next examined the conversion of 6 into phenol deriva-
tives 5. Table 2 summarizes the results of the partial oxidation
of 6 at allylic alcohol position and the dehydration of 4 to form
5. Several oxidizing agents, such as Dess–Martin periodinane,

1514 Bull. Chem. Soc. Jpn. Vol. 81, No. 11 (2008)
Synthesis of Aromatic Compounds
Table 2. Synthesis of 5-Hydroxy-2-cyclohexenones 4 by Oxidation of 6a) and Synthesis of Phenol Derivatives 5 by
Dehydration of 4b)
OH
O
OH
R2
HO
R1
R5
R2
HO
R1
R5
R2
R3
R1
R5
p-TsOH (10 mol%)
[O]
rt
benzene
70 °C
R3
R3
R4
R4
R4
6
4
5
Entry
Substrate
R1
R2
R3
R4
R5
H
H
H
H
Me
CH2OBn
Me
Oxidant
Yieldc)/%
Yieldc)/%
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
H
Me
Me
Me
H
H
H
H
Et
H
H
Me
H
H
H
DMP
MnO2
PCC
98 (4a)
86 (4b)
84 (4c)
86 (4d)
93 (4e)
85 (4f)
97 (4g)
85 (5a)
>99 (5b)
>99 (5c)
88 (5d)d)
>99 (5e)
90 (5f)
4-ClC6H4
t
CH2OSiMe2 Bu
Me
Ph
H
PCC
H
H
H
DMP
DMP
PCC
H
Me
H
H
6g
Ph
97 (5g)
a) 4-Cyclohexene-3,5-diol 6 was treated with Dess–Martin periodinane (2.3 equiv), MnO2 (30 equiv), or PCC (3 equiv).
b) A solution of 5-hydroxy-2-cyclohexenone 4 in benzene was treated with p-toluenesulfonic acid (p-TsOH; 10 mol %)
and stirred overnight at 70 ꢁC. c) Isolated yield by silica gel chromatography. d) The reaction was carried out with 5-hy-
droxy-2-cyclohexenone 4, t-BuOK (4.4 equiv), and MsCl (3.2 equiv) in CH2Cl2 at rt for 2.5 h.
OH
O
OH
Me
9
p-TsOH
(10 mol%)
Me
Me
PCC
(7.5 mol%)
benzene
70 °C
CH2Cl2
40 °C, 2 h
CH2Cl2
rt, 3.5 h
HO
OH
4h (64% yield)
5h (>99% yield)
2h
OH
O
OMs
9
t-BuOK
MsCl
PCC
(7.5 mol%)
HO
HO
CH2Cl2
40 °C, 2 h rt, 3.5 h
Me CH2Cl2
rt
CH2Cl2
Me
Me
Me
Me
Me
2i
4i (65% yield)
Scheme 3.
5i (>99% yield)
Table 3. Synthesis of Benzene Derivatives 7 by Dehydration of 6a)
OH
H
R2
HO
R1
R5
R2
R3
R1
R5
p-TsOH (10 mol%)
benzene
70 °C
R3
R4
R4
6
7
Entry
Substrate
R1
R2
R3
R4
R5
Yieldb)/%
1
2
3
4
6c
6d
6e
6g
Me
CH2OSiMe2 Bu
H
H
H
H
H
Me
4-ClC6H4
H
H
H
H
H
H
Me
Me
>99 (7c)
73 (7d)c)
91 (7e)
t
Me
Ph
Ph
>99 (7g)
a) A solution of 4-cyclohexene-1,3-diol 6 in benzene was treated with p-toluenesulfonic acid (p-TsOH; 10 mol %) and
stirred overnight at 70 ꢁC. b) Isolated yield by silica gel chromatography. c) Desilylated product.
(400 MHz for H and 100 MHz for 13C). Chemical shifts are re-
1
Experimental
1
ported in ꢀ referenced to an internal SiMe4 standard for H NMR
General. All anaerobic and moisture-sensitive manipulations
were carried out with standard Schlenk techniques under predried
nitrogen or glove box techniques under prepurified argon. NMR
spectra were recorded on a JEOL JNM LA-500 spectrometer
(500 MHz for 1H and 125 MHz for 13C) and LA-400 spectrometer
and chloroform-d (ꢀ 77.0) for 13C NMR.
Materials. THF was distilled from sodium benzophenone-
ketyl under argon prior to use. Et2O was distilled from sodium
benzophenone-ketyl under argon prior to use. Dichloromethane
was distilled from CaH2 under nitrogen and stored in a glass

K. Yoshida et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 11 (2008) 1515
OH
O
OH
Dess-Martin
periodinane
ClCOCOCl, DMSO
CH2Cl2
rt, 3 h
85% yield
Et3N, CH2Cl2
−78 °C, 1.5 h
80% yield
HO
HO
HO
OBn
OBn
OBn
6f
4f
8f
Scheme 4.
flask with a Teflon stopcock under nitrogen. Ruthenium complex
(PCy3)(Imes)Cl2Ru=C(H)Ph (9) was prepared according to re-
ported procedures.11b 1,7-Octadiene-3,5-diols 2 were prepared
according to reported procedures.9 Dess–Martin periodinane,18
and activated MnO219 were prepared according to reported proce-
dures. Pyridinium chlorochromate, p-toluenesulfonic acid were
used as received.
Preparation of 4-Cyclohexene-1,3-diols 6. General Proce-
dure A: To a solution of 1,7-octadiene-3,5-diol 2 (0.16 mmol)
in CH2Cl2 (15.5 mL, 0.01 M) was added 7.5 mol % catalyst 9
(0.012 mmol) in one portion under nitrogen at room temperature.
After stirring for 2 h, the reaction mixture was concentrated under
reduced pressure and purified by PTLC on silica gel to give 4-
cyclohexene-1,3-diols 6.
1-Ethyl-2-methyl-4-cyclohexene-1,3-diol (6a): The reaction
was carried out according to General Procedure A; purified by
PTLC (hexane/EtOAc = 1/1) (diastereomeric mixture: 90%
yield); Two of the diastereomers (0.50/0.50) were separated to
clarify the spectral characterization. 1H NMR (CDCl3): ꢀ 0.83
(d, J ¼ 6:8 Hz, 1.5H), 0.90 (t, J ¼ 7:6 Hz, 1.5H), 0.94 (t, J ¼
7:6 Hz, 1.5H), 1.10 (d, J ¼ 6:8 Hz, 1.5H), 1.42 (br s, 1.0H),
1.50–1.60 (m, 3.0H), 1.67 (br s, 1.0H), 1.89–2.16 (m, 1.5H),
2.28 (dq, J ¼ 18:3, 2.5 Hz, 0.5H), 3.97–4.03 (m, 0.5H), 4.63–
4.69 (br m, 0.5H), 5.59–5.79 (m, 2.0H). 13C NMR (CDCl3): ꢀ
6.45, 8.02, 9.13, 10.56, 32.29, 32.57, 35.07, 36.40, 41.04, 43.44,
68.33, 71.78, 74.26, 75.10, 125.27, 125.65, 129.51, 130.46.
HRMS (FAB) calcd for C9H15O (Mþ ꢂ OH) 139.1123, found
139.1120.
0.25H), 4.20–4.38 (m, 2.0H), 4.54–4.60 (m, 0.75H), 5.58–5.63
(m, 0.75H), 5.68–5.73 (m, 0.25H). 13C NMR (CDCl3): ꢀ ꢂ5:50,
ꢂ5:48, ꢂ5:44, ꢂ5:42, 18.16, 18.20, 25.82, 29.88, 29.98, 39.52,
39.83, 40.80, 44.26, 66.71, 66.81, 67.47, 67.63, 68.38, 69.91,
122.67, 123.88, 136.25, 137.33. HRMS (FAB) calcd for
C14H27O2Si (Mþ ꢂ OH) 255.1780, found 255.1788.
5-Methyl-1-phenyl-4-cyclohexene-1,3-diol (6e): The reac-
tion was carried out according to General Procedure A; purified
by PTLC (hexane/EtOAc = 1/1) (86% yield); One of the diaster-
eomers of 2e was used for this reaction. 1H NMR (CDCl3): ꢀ 1.46
(d, J ¼ 5:5 Hz, 1H), 1.77 (s, 3H), 1.85 (s, 1H), 1.99 (dd, J ¼ 12:9,
8.9 Hz, 1H), 2.19 (d, J ¼ 18:2 Hz, 1H), 2.34 (dd, J ¼ 13:0, 6.2 Hz,
1H), 2.51 (d, J ¼ 18:2 Hz, 1H), 4.55–4.65 (m, 1H), 5.62 (s, 1H),
7.29 (t, J ¼ 7:1 Hz, 1H), 7.38 (t, J ¼ 8:0 Hz, 2H), 7.50 (d, J ¼
8:0 Hz, 2H). 13C NMR (CDCl3): ꢀ 23.12, 43.60, 44.84, 66.71,
74.02, 124.43, 124.83, 127.23, 128.44, 134.01, 147.39. HRMS
(FAB) calcd for C13H15O (Mþ ꢂ OH) 187.1123, found 187.1118.
5-Benzyloxymethyl-4-cyclohexene-1,3-diol (6f): The reac-
tion was carried out according to General Procedure A; purified
by PTLC (hexane/EtOAc = 1/4) (diastereomeric mixture: 54%
yield); The following data are for a mixture of two diastereomers
1
(0.50/0.50). H NMR (CDCl3): ꢀ 1.78–1.82 (m, 0.5H), 1.93–2.07
(m, 1.5H), 2.15–2.43 (m, 2.5H), 2.52 (dd, J ¼ 16:4, 8.6 Hz, 0.5H),
2.62 (dd, J ¼ 17:6, 4.2 Hz, 0.5H), 2.73 (dd, J ¼ 16:1, 3.4 Hz,
0.5H), 3.96 (s, 1.0H), 4.12 (s, 1.0H), 4.23–4.37 (m, 2.0H), 4.51
(s, 1.0H), 4.57 (s, 1.0H), 5.92–5.95 (m, 0.5H), 6.21–6.23 (m,
0.5H), 7.28–7.40 (m, 5.0H). 13C NMR (CDCl3): ꢀ 34.72, 35.07,
37.62, 39.73, 64.00, 64.80, 65.01, 65.47, 72.14, 72.28, 73.37,
73.66, 125.37, 126.14, 127.67, 127.72, 127.76, 127.83, 128.37,
128.45, 134.19, 136.08, 137.98, 137.99. HRMS (FAB) calcd for
C14H17O2 (Mþ ꢂ OH) 217.1229, found 217.1230.
4,6-Dimethyl-4-cyclohexene-1,3-diol (6b): The reaction was
carried out according to General Procedure A; purified by PTLC
(hexane/EtOAc = 1/1) (diastereomeric mixture: 80% yield);
The following data are for a mixture of two diastereomers
(0.50/0.50). 1H NMR (CDCl3): ꢀ 0.98 (d, J ¼ 7:3 Hz, 1.5H),
1.11 (d, J ¼ 7:1 Hz, 1.5H), 1.70–1.83 (m, 3.0H), 1.78 (s, 3.0H),
2.00–2.15 (m, 1.5H), 2.41 (br m, 0.5H), 3.55–3.62 (m, 0.5H),
4.08–4.13 (m, 1.0H), 4.18–4.22 (m, 0.5H), 5.26–5.28 (m, 0.5H),
5.32–5.35 (m, 0.5H). 13C NMR (CDCl3): ꢀ 14.70, 18.51, 20.24,
20.56, 35.50, 37.70, 39.67, 40.53, 67.98, 68.90, 69.68, 70.33,
128.86, 129.90, 134.25, 134.60. HRMS (FAB) calcd for C8H13O
(Mþ ꢂ OH) 125.0966, found 125.0967.
2,5-Dimethyl-1-phenyl-4-cyclohexene-1,3-diol (6g): The re-
action was carried out according to General Procedure A; purified
by PTLC (hexane/EtOAc = 1/1) (diastereomeric mixture: >99%
yield); One of the diastereomers was separated to clarify the spec-
tral characterization. 1H NMR (CDCl3): ꢀ 0.84 (d, J ¼ 6:8 Hz,
3H), 1.56 (br s, 1H), 1.73 (s, 3H), 1.85 (s, 1H), 2.01 (dq, J ¼
8:6, 6.8 Hz, 1H), 2.12 (d, J ¼ 18:2 Hz, 1H), 2.61 (d, J ¼ 18:2
Hz, 1H), 4.07–4.14 (m, 1H), 5.59 (s, 1H), 7.25 (tt, J ¼ 7:4,
1.6 Hz, 1H), 7.36 (dd, J ¼ 8:3, 7.4 Hz, 2H), 7.43 (dd, J ¼ 8:3,
1.6 Hz, 2H). 13C NMR (CDCl3): ꢀ 11.69, 22.96, 44.76, 46.93,
72.50, 76.82, 124.64, 124.84, 126.65, 128.29, 133.73, 146.03.
HRMS (FAB) calcd for C14H17O (Mþ ꢂ OH) 201.1279, found
201.1269.
1-(4-Chlorophenyl)-4-methyl-4-cyclohexene-1,3-diol (6c):
The synthesis of 6c was already reported in our previous commu-
nication.9
4-(tert-Butyldimethylsilanyloxymethyl)-1-methyl-4-cyclohex-
ene-1,3-diol (6d): The reaction was carried out according to
General Procedure A; purified by PTLC (hexane/EtOAc = 1/1)
(diastereomeric mixture: >99% yield); The following data are
for a mixture of two diastereomers (0.75/0.25). 1H NMR (CDCl3):
ꢀ 0.10–0.11 (m, 6.0H), 0.91 (s, 2.25H), 0.91 (s, 6.75H), 1.29 (s,
0.75H), 1.34 (s, 2.25H), 1.68 (dd, J ¼ 13:2, 8.1 Hz, 1.5H), 1.70–
1.73 (m, 0.5H), 2.05–2.15 (m, 2.0H), 2.21–2.35 (m, 1.0H),
3.28–3.32 (m, 0.75H), 3.66–3.68 (m, 0.25H), 3.93–3.96 (m,
Preparation of 5-Hydroxy-2-cyclohexenones 4.
General
Procedure B: To a solution of 6 (0.0588 mmol) in CH2Cl2
(1.1 mL) was added Dess–Martin periodinane (0.135 mmol) in
one portion under air. The reaction mixture was stirred for 3 h
at room temperature. After removal of the solvent in vacuo, the
residue was passed through a short silica gel pad (eluent: Et2O).
The solution was concentrated under reduced pressure and puri-
fied by PTLC on silica gel to give 5-hydroxy-2-cyclohexenone 4.

1516 Bull. Chem. Soc. Jpn. Vol. 81, No. 11 (2008)
Synthesis of Aromatic Compounds
General Procedure C: To a solution of 6 (0.136 mmol) in
hexane (5.0 mL) was added MnO2 (4.07 mmol) in one portion un-
der air. The reaction mixture was stirred for 37 h at room temper-
ature and passed through Celite. The residue was washed with
CH2Cl2 thoroughly. The filtrate was concentrated under reduced
pressure and purified by PTLC on silica gel to give 5-hydroxy-
2-cyclohexenone 4.
was characterized by comparison of the spectroscopic data with
those reported previously.9
5-Hydroxy-3-methyl-5-(2-methylallyl)-2-cyclohexenone (4i):
The reaction was carried out according to General Procedure E
and purified by PTLC (hexane/EtOAc = 1/1) (65% yield); This
product was characterized by comparison of the spectroscopic
data with those reported previously.9
General Procedure D: To a mixture of 6 (0.128 mmol) and
˚
molecular sieve 4 A (powder, 135 mg) in CH2Cl2 (4.0 mL) was
added PCC (0.383 mmol) under air. After stirring for 3.5 h at room
temperature, the reaction mixture was filtered through Celite, con-
centrated under reduced pressure, and purified by PTLC on silica
gel to give 5-hydroxy-2-cyclohexenone 4.
General Procedure E: To a solution of 1,7-octadiene-3,5-diol
2 (0.169 mmol) in CH2Cl2 (16.9 mL) was added 7.5 mol % cata-
lyst 9 (0.0127 mmol) in one portion under nitrogen at room tem-
perature. After stirring for 2 h, the reaction mixture was concen-
trated under reduced pressure. To a mixture of the residue and mo-
Preparation of Phenol Derivatives 5. The synthesis of 5
from 4 was already reported in our previous communication.9
Preparation of Benzene Derivatives 7. General Procedure
F: To a solution of 4-cyclohexene-1,3-diol 6 (0.0558 mmol)
in benzene (1.0 mL) was added p-toluenesulfonic acid (0.00558
mmol) at room temperature under air. The reaction mixture was
warmed to 70 ꢁC and stirred overnight. The resulting mixture
was concentrated under reduced pressure and purified by PTLC
on silica gel to give benzene derivative 7.
4-Chloro-40-methylbiphenyl (7c): The reaction was carried
out according to General Procedure F and purified by PTLC (hex-
ane/EtOAc = 4/1) (>99% yield); This product was characterized
by comparison of the spectroscopic data with those reported pre-
viously.20
p-Tolylmethanol (7d): The reaction was carried out accord-
ing to General Procedure F and purified by PTLC (hexane/
EtOAc = 10/1) (73% yield); This product was characterized by
comparison of the spectroscopic data with those reported previ-
ously.21
3-Methylbiphenyl (7e): The reaction was carried out accord-
ing to General Procedure F and purified by PTLC (hexane only)
(91% yield); This product was characterized by comparison of
the spectroscopic data with those reported previously.22
2,5-Dimethylbiphenyl (7g): The reaction was carried out
according to General Procedure F and purified by PTLC (hexane
only) (86% yield); This product was characterized by comparison
of the spectroscopic data with those reported previously.23
Preparation of 5-Benzyloxymethyl-1,3-benzenediol (8f).
The synthesis of 8f from 4f was already reported in our previous
communication.9
˚
lecular sieve 4 A (powder, 178.5 mg) in CH2Cl2 (5.0 mL) was add-
ed PCC (0.506 mmol). After stirring for 3.5 h, the reaction mixture
was filtered through Celite, concentrated under reduced pressure,
and purified by PTLC on silica gel to give 5-hydroxy-2-cyclohex-
enone 4.
5-Ethyl-5-hydroxy-6-methyl-2-cyclohexenone (4a): The re-
action was carried out according to General Procedure B and pu-
rified by PTLC (hexane/EtOAc = 1/1) (98% yield); This product
was characterized by comparison of the spectroscopic data with
those reported previously.9
5-Hydroxy-2,4-dimethyl-2-cyclohexenone (4b): The reac-
tion was carried out according to General Procedure C and puri-
fied by PTLC (hexane/EtOAc = 1/1) (86% yield); This product
was characterized by comparison of the spectroscopic data with
those reported previously.9
5-(4-Chlorophenyl)-5-hydroxy-2-methyl-2-cyclohexenone (4c):
The reaction was carried out according to General Procedure D
and purified by PTLC (hexane/EtOAc = 1/1) (84% yield); This
product was characterized by comparison of the spectroscopic
data with those reported previously.9
2-(tert-Butyldimethylsilanyloxymethyl)-5-hydroxy-5-meth-
yl-2-cyclohexenone (4d): The reaction was carried out accord-
ing to General Procedure D and purified by PTLC (hexane/
EtOAc = 1/1) (86% yield); This product was characterized by
comparison of the spectroscopic data with those reported previ-
ously.9
We appreciate the financial support from the Sumitomo
Foundation, the Mitsubishi Chemical Corporation Fund, the
Research for Promoting Technological Seeds from JST, and
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information
5-Hydroxy-3-methyl-5-phenyl-2-cyclohexenone (4e): The
reaction was carried out according to General Procedure B and pu-
rified by PTLC (hexane/EtOAc = 1/2) (93% yield); This product
was characterized by comparison of the spectroscopic data with
those reported previously.9
1H NMR and 13C NMR spectra of new compounds, and
1H NMR spectra of known compounds. This material is available
free of charge on the Web at: http://www.csj.jp/journals/bcsj/.
3-Benzyloxymethyl-5-hydroxy-2-cyclohexenone (4f): The
reaction was carried out according to General Procedure B and pu-
rified by PTLC (hexane/EtOAc = 1/1) (85% yield); This product
was characterized by comparison of the spectroscopic data with
those reported previously.9
References
1
For a comprehensive review, see: Modern Arene Chemis-
try, ed. by D. Astruc, Wiley-VCH, Weinheim, 2002.
For example, see: a) R. L. Danheiser, S. K. Gee, J. Org.
2
5-Hydroxy-3,6-dimethyl-5-phenyl-2-cyclohexenone (4g): The
reaction was carried out according to General Procedure D and
purified by PTLC (hexane/EtOAc = 1/1) (97% yield); This prod-
uct was characterized by comparison of the spectroscopic data
with those reported previously.9
6-Hydroxy-3-methylbicyclo[4,4,0]-3-decen-2-one (4h): The
reaction was carried out according to General Procedure E and pu-
rified by PTLC (hexane/EtOAc = 1/1) (64% yield); This product
Chem. 1984, 49, 1672. b) P. Turnbull, H. W. Moore, J. Org.
Chem. 1995, 60, 644. c) T. Takahashi, Z. Xi, A. Yamazaki, Y.
Liu, K. Nakajima, M. Kotora, J. Am. Chem. Soc. 1998, 120,
1672. d) K. H. Dotz, P. Tomuschat, Chem. Soc. Rev. 1999, 28,
¨
187. e) A. R. Katritzky, J. Li, L. Xie, Tetrahedron 1999, 55,
8263. f) S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901.
g) D. Suzuki, H. Urabe, F. Sato, J. Am. Chem. Soc. 2001, 123,
7925. h) C. B. de Koning, A. L. Rousseau, W. A. L. van Otterlo,

K. Yoshida et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 11 (2008) 1517
Tetrahedron 2003, 59, 7. i) Y. Yamamoto, T. Arakawa, R. Ogawa,
K. Itoh, J. Am. Chem. Soc. 2003, 125, 12143. j) T. Shibata, T.
Fujimoto, K. Yokota, K. Takagi, J. Am. Chem. Soc. 2004, 126,
8382. k) X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao, B. Li,
J. Am. Chem. Soc. 2005, 127, 4578. l) N. Asao, Synlett 2006,
1645. m) K. Tanaka, T. Osaka, K. Noguchi, M. Hirano, Org. Lett.
2007, 9, 1307. n) S. Serra, C. Fuganti, E. Brenna, Chem.—Eur. J.
2007, 13, 6782. o) M. Gayral, J. M. Brown, Synlett 2007, 2823.
M. Nakagawa, J. Organomet. Chem. 2006, 691, 5109. b) T. J.
Donohoe, N. M. Kershaw, A. J. Orr, K. M. P. Wheelhouse,
L. P. Fishlock, A. R. Lacy, M. Bingham, P. A. Procopiou, Tetra-
hedron 2008, 64, 809.
8
a) K. Yoshida, T. Imamoto, J. Am. Chem. Soc. 2005, 127,
10470. b) K. Yoshida, F. Kawagoe, N. Iwadate, H. Takahashi,
T. Imamoto, Chem. Asian J. 2006, 1, 611. c) K. Yoshida, S.
Horiuchi, N. Iwadate, F. Kawagoe, T. Imamoto, Synlett 2007,
1561. d) K. Yoshida, Y. Shishikura, H. Takahashi, T. Imamoto,
Org. Lett. 2008, 10, 2777.
3
For a comprehensive review, see: a) Handbook of Metathe-
sis, ed. by R. H. Grubbs, Wiley-VCH, Weinheim, 2003. For
reviews, see: b) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54,
9 K. Yoshida, T. Toyoshima, T. Imamoto, Chem. Commun.
2007, 3774.
4413. c) A. Furstner, Angew. Chem. 2000, 112, 3140; Angew.
¨
Chem., Int. Ed. Engl. 2000, 39, 3012. d) T. M. Trnka, R. H.
Grubbs, Acc. Chem. Res. 2001, 34, 18. e) A. H. Hoveyda, A. R.
Zhugralin, Nature 2007, 450, 243.
10 a) J. A. Love, J. P. Morgan, T. M. Trnka, R. H. Grubbs,
Angew. Chem., Int. Ed. 2002, 41, 4035. b) A. K. Chatterjee,
T.-L. Choi, D. P. Sanders, R. H. Grubbs, J. Am. Chem. Soc.
2003, 125, 11360. c) A. H. Hoveyda, D. G. Gillingham, J. J.
Van Veldhuizen, O. Kataoka, S. B. Garber, J. S. Kingsbury,
J. P. A. Harrity, Org. Biomol. Chem. 2004, 2, 8.
11 a) M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett.
1999, 1, 953. b) T. M. Trnka, J. P. Morgan, M. S. Sanford, T. E.
Wilhelm, M. Scholl, T.-L. Choi, S. Ding, M. W. Day, R. H.
Grubbs, J. Am. Chem. Soc. 2003, 125, 2546.
12 For a discussion on the mechanism of olefin isomerization
in metathesis reactions, see: C. D. Edlin, J. Faulkner, D. Fengas,
C. K. Knight, J. Parker, I. Preece, P. Quayle, S. N. Richards,
Synlett 2005, 572.
13 It must be noted that two-step yields of 4 from 2 via 6 were
better than those via 3 with the exception of the special case of 4f,
see: Ref. 9.
14 The mesylated phenol was obtained under the conditions.
15 The reason why we chose 2h and 2i as substrates to inves-
tigate these sequential experiments is that we observed that both
intermediates 6h and 6i were somewhat unstable to isolation.
16 Attempts to obtain 8f from 6f at once were unsuccessful.
For example, Swern oxidation of 6f gave a mixture of 4f, 5f (ma-
jor), and 8f.
17 The cyclized product 6b is also a potential precursor of
resorcinol derivative. However, the synthesis of 8b from 6b was
unfortunately unsuccessful. Although we have screened various
oxidation conditions, the formation of phenol derivative 5b pref-
erentially occurred.
18 a) R. E. Ireland, L. Liu, J. Org. Chem. 1993, 58, 2899.
b) R. K. Boeckman, Jr., P. Shao, J. J. Mullins, Org. Synth.
2000, 77, 141.
19 J. Attenburrow, A. F. B. Cameron, J. H. Chapman, R. M.
Evans, B. A. Hems, A. B. A. Jansen, T. Walker, J. Chem. Soc.
1952, 1094.
4
For reports on the pharmaceutical application of RCM in
multi-kilogram scale (>400 kg of cyclized product), see: a) T.
Nicola, M. Brenner, K. Donsbach, P. Kreye, Org. Process Res.
Dev. 2005, 9, 513. b) N. K. Yee, V. Farina, I. N. Houpis, N.
Haddad, R. P. Frutos, F. Gallou, X.-j. Wang, X. Wei, R. D.
Simpson, X. Feng, V. Fuchs, Y. Xu, J. Tan, L. Zhang, J. Xu,
L. L. Smith-Keenan, J. Vitous, M. D. Ridges, E. M. Spinelli, M.
Johnson, K. Donsbach, T. Nicola, M. Brenner, E. Winter, P.
Kreye, W. Samstag, J. Org. Chem. 2006, 71, 7133. c) Y. S.
Tsantrizos, J.-M. Ferland, A. McClory, M. Poirier, V. Farina,
N. K. Yee, X.-j. Wang, N. Haddad, X. Wei, J. Xu, L. Zhang,
J. Organomet. Chem. 2006, 691, 5163.
5
For a review, see: T. J. Donohoe, A. J. Orr, M. Bingham,
Angew. Chem. 2006, 118, 2730; Angew. Chem., Int. Ed. Engl.
2006, 45, 2664.
6
For reports on the direct synthesis of carbocyclic aromatic
compounds using RCM, see: a) A. Iuliano, P. Piccioli, D. Fabbri,
Org. Lett. 2004, 6, 3711. b) E. R. Walker, S. Y. Leung, A. G. M.
Barrett, Tetrahedron Lett. 2005, 46, 6537. c) M. C. Bonifacio,
C. R. Robertson, J.-Y. Jung, B. T. King, J. Org. Chem. 2005,
70, 8522. d) S. C. Pelly, C. J. Parkinson, W. A. L. van Otterlo,
C. B. de Koning, J. Org. Chem. 2005, 70, 10474. e) S. K. Collins,
ˆ ´
A. Grandbois, M. P. Vachon, J. Cote, Angew. Chem. 2006, 118,
2989; Angew. Chem., Int. Ed. 2006, 45, 2923. For reports using
RCM/elimination protocol, see: f) P. Evans, R. Grigg, M. I.
Ramzan, V. Sridharan, M. York, Tetrahedron Lett. 1999, 40,
3021. g) K. S. Huang, E. C. Wang, Tetrahedron Lett. 2001, 42,
6155. h) Y. Chen, H. V. R. Dias, C. J. Lovely, Tetrahedron Lett.
2003, 44, 1379. i) P.-Y. Chen, H.-M. Chen, L.-Y. Chen, J.-Y.
Tzeng, J.-C. Tsai, P.-C. Chi, S.-R. Li, E.-C. Wang, Tetrahedron
2007, 63, 2824. For reports using RCM/oxidation protocol, see:
j) S. Kotha, K. Mandal, Tetrahedron Lett. 2004, 45, 2585. k)
S. Ma, F. Yu, J. Zhao, Synlett 2007, 583. l) S. Kotha, V. R. Shah,
K. Mandal, Adv. Synth. Catal. 2007, 349, 1159. For a report using
RCM/tautomerization protocol, see: m) W. A. L. van Otterlo,
E. L. Ngidi, E. M. Coyanis, C. B. de Koning, Tetrahedron Lett.
2003, 44, 311.
20 Z. Xiong, N. Wang, M. Dai, A. Li, J. Chen, Z. Yang, Org.
Lett. 2004, 6, 3337.
21 M. S. Abaee, R. Sharifi, M. M. Mojtahedi, Org. Lett. 2005,
7, 5893.
22 T. Chen, J. Gao, M. Shi, Tetrahedron 2006, 62, 6289.
23 D. Liu, W. Gao, Q. Dai, X. Zhang, Org. Lett. 2005, 7,
4907.
7 For selected recent reports on the synthesis of heterocyclic
aromatic compounds using RCM, see: a) M. Arisawa, A. Nishida,