Synthesis of substituted phenols by using the ring-closing metathesis/isoaromatization approach

Article abstract of DOI:10.1002/chem.200800943

Ring-closing olefin metathesis (RCM) of 4-methylene-1,7-octadien-3-ones 2, followed by isomerization of the carbon-carbon double bond of 6-methylene-2-cyclohexenones 3 from exo to endo, produced various phenols 4. As an application of the method, the RCM/

Full text of DOI:10.1002/chem.200800943

DOI: 10.1002/chem.200800943
Synthesis of Substituted Phenols by Usingthe Ring-ClosingMetathesis/
Isoaromatization Approach
Kazuhiro Yoshida,* Rintaro Narui, and Tsuneo Imamoto*[a]
Abstract: Ring-closing olefin metathesis (RCM) of 4-methylene-1,7-octadien-3-
À
ones 2, followed by isomerization of the carbon carbon double bond of 6-methyl-
Keywords: isoaromatization · meta-
thesis · phenols · ring closure ·
tautomerization
ene-2-cyclohexenones 3 from exo to endo, produced various phenols 4. As an ap-
plication of the method, the RCM/Mizoroki–Heck reaction of 2 was proven to be
also effective for the synthesis of phenols having an additional substituent at
ortho-benzylic position.
Introduction
The development of a regiospecific method for the synthesis
of substituted aromatic compounds remains a difficult task
in organic chemistry.[1] One promising solution is the direct
construction of aromatic rings from acyclic precursors.[2] If
the acyclic precursors were prepared selectively, exact regio-
control of substituents on the aromatic rings would be real-
ized with this approach. On the other hand, ruthenium-cata-
lyzed ring-closing olefin metathesis (RCM) has become one
of the most important reactions for the construction of
cyclic compounds due to its operational simplicity and re-
markable functional group tolerance.[3,4] Therefore, the fact
that much attention has been recently paid to the synthesis
of aromatic compounds using RCM of acyclic precursors is
to be expected.[5–7]
Herein we report an efficient method for the synthesis of
phenols by using the RCM/isoaromatization[9] approach.
The use of new acyclic precursors, 4-methylene-1,7-octa-
À
dien-3-ones 2, containing an external carbon carbon double
bond simplifies the overall synthesis of 2. The combination
À
of RCM of 2 and isomerization of the carbon carbon
double bond of resulting cyclized products 3 from exo to
endo, followed by spontaneous tautomerization, is expected
to produce a wide variety of phenols 4 [Eq. (2)].
In the last few years, we have devoted much of our
effort[8] to this field and reported that phenols can be ob-
tained by RCM/tautomerization of 1,4,7-trien-3-ones 1 via
cyclohexa-2,5-dienones[8a,c] [Eq. (1)]. Although various phe-
nols could be synthesized without the formation of re-
gioisomers, this approach was limited by the difficulty of
preparing 1. In particular, the construction of the internal
cis double bond of 1 was the bottleneck in the process.
Results and Discussion
Our retrosynthetic analysis represented in Scheme 1 suggest-
ed that 2 might arise from the oxidation of 4-methylene-1,7-
octadien-3-ols 5. The basic structure of 5 was envisioned to
come from two synthetic routes. One involves the vinylation
of 2-methylene-5-hexenals 6, which can be obtained by the
Mannich/Hofmann degradation or aldol/dehydration of 5-
hexenals 7. The other involves the coupling of a,b-unsatu-
rated aldehydes with 2-halo-1,5-hexadienes 8, which can be
obtained by the allylation of 2,3-dihalopropenes 9. In fact, a
series of 2 with various substitution patterns could be readily
prepared with these routes.[10]
[a] Prof. Dr. K. Yoshida, R. Narui, Prof. Dr. T. Imamoto
Department of Chemistry, Graduate School of Science
Chiba University, Yayoi-cho, Inage-ku
Chiba 263-8522 (Japan)
Fax: ( +81)43-290-2791
E-mail: kyoshida@faculty.chiba-u.jp
imamoto@faculty.chiba-u.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800943.
9706
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Chem. Eur. J. 2008, 14, 9706 – 9713

FULL PAPER
As an important part of this study, we next examined the
isoaromatization step to phenols and chose 3d as the model
substrate (Table 2). When we tested basic conditions using
DBU, which were reported by Kleinman and co-workers,[9d]
desired phenol 4d was obtained in moderate yield (68%)
(Table 2, entry 1). Acidic conditions using p-toluenesulfonic
acid (Table 2, entry 2) and transition-metal-catalyzed iso-
merization conditions using Pd/C[14] or RhCl3 (Table 2, en-
[15]
tries 3 and 4) also afforded 4d in moderate yields (62–
79%). After screening numerous reaction conditions, we fi-
nally found that 4d could be successfully obtained in high
Scheme 1. Retrosynthetic analysis of substrates 2.
yield (92%) using [RhCl(cod)]2 (1 mol% Rh) and Cs2CO3
A
The results of RCM of 2 are summarized in Table 1.[11]
When the reaction of 2a was
Table 1. Synthesis of 6-methylene-2-cyclohexenones 3 by RCM.[a]
performed
with
1.5 mol%
Grubbsꢁ second-generation cat-
alyst 10[12] at 408C for 2 h, cor-
responding cyclized product 3a
was formed in high yield, as ex-
pected (Table 1, entry 1). Simi-
larly, 3b and 3c were obtained
by reacting 2b and 2c under
the same conditions, respective-
ly (Table 1, entries 2 and 3).
The reaction of 2d that has a
phenyl group at R1 position
also proceeded smoothly to
give 3d (Table 1, entry 4). How-
ever, decreasing the amount of
catalyst from 1.5 to 0.5 mol%
for the same reaction lowered
the yield of 3d to half (Table 1,
entry 4 vs 5). The RCM of 2e
and 2 f, both of which have an-
other substituent at R1 position,
furnished corresponding 3e and
f in good yields, respectively
(Table 1, entries 6 and 7). In
contrast, introduction of a sub-
stituent at R5 position consider-
ably retarded the reaction.
When RCM of 2g having a
phenyl group at the R5 position
was carried out, cyclized prod-
uct 3g was obtained in only
31% yield despite the high cat-
alyst load (7.5 mol%) (Table 1,
entry 8). However, employing
Entry
1
Substrate
Product
Conditions
Yield [%][b]
10 (1.5 mol%), 408C
84
2
3
10 (1.5 mol%), 408C
10 (1.5 mol%), 408C
79
95
4
5
10 (1.5 mol%), 408C
10 (0.5 mol%), 408C
92
46
6
7
10 (1.5 mol%), 408C
10 (1.5 mol%), 408C
81
99
2.5 mol%
Hoveyda–Grubbs
catalyst [(H2Imes)Cl2Ru=CH(o-
iPrO-C6H4)] (11),[13] which is
known to be effective for elec-
tron-deficient dienic systems, at
elevated temperature improved
product yield to 86% (Table 1,
entry 9).
8
9
10 (7.5 mol%), 408C
11 (2.5 mol%), 1008C
31
86
[a] The reaction was carried out with 2 and ruthenium catalyst 10 in toluene for 2 h. [b] Isolated yield by silica
gel chromatography.
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K. Yoshida, T. Imamoto and R. Narui
Table 2. Survey of isoaromatization conditions for the synthesis of 4d.
of 2, by which the formation of
undesirable regioisomers could
be completely excluded. The
employment of 2 as key acyclic
precursor paved the way to
smoothly accessing phenols
from commercially available
compounds. Moreover, the exo-
Entry
Reagents
Conditions
Yield [%][a]
1
2
3
4
5
6
7
8
DBU (1.0 equiv)
toluene, 708C, 24 h
toluene, 708C, 24 h
iPrOH, 708C, 24 h
iPrOH/DMF, 1008C, 24 h
dioxane/H2O 2:1, 608C, 5 h
dioxane/H2O 2:1, 608C, 5 h
dioxane/H2O 2:1, 708C, 3 h
dioxane/H2O 2:1, 708C, 3 h
68
79
63
62
92
0
pTsOH·H2O (10 mol%)
10 mol% Pd/C (10 mol% Pd)
RhCl3 (10 mol%)
À
cyclic carbon carbon double
bond of products 3 could be uti-
lized effectively in the Mizoro-
ki–Heck reaction to introduce
A
N
A
N
0
0
[a] Isolated yield by silica gel chromatography.
Table 3. Synthesis of phenols 4 by isoaromatization.[a]
(1 equiv) in dioxane/H2O (2:1) at 608C (Table 2, entry 5).
Interestingly, the employment of RhCl3 instead of [RhCl-
A
N
(1 mol% Rh) or Cs2CO3 (Table 2, entries 7 and 8) under
similar conditions resulted in no reaction.[16]
The results of the isoaromatization of 3 with these condi-
tions to synthesize phenols 4 are summarized in Table 3.
The optimal conditions found in Table 2, namely, [RhCl-
Entry
1
Substrate
Product
Yield [%][b]
93
(cod)]2 (1 mol% Rh) and Cs2CO3 (1 equiv) in dioxane/H2O
(2:1) at 608C, were proved to be effective for most of the
isoaromatization reactions of 3, and various phenols 4 could
be obtained in high yields. One exception was the reaction
of 3 having a substituent at the R3 position. The complete
absence of products was observed in both reactions of 3c
and f (Table 3, entries 3 and 7). Applying the same isomeri-
zation conditions to 3c and f but using p-toluenesulfonic
acid and Pd/C as alternatives, respectively, successfully pro-
duced corresponding phenols 4c and f, respectively (Table 3,
entries 4 and 8).
2
75
3
0
77
4[c]
Finally, we conducted the Mizoroki–Heck reaction[17] of
3d with p-methoxybenzenediazonium tetrafluoroborate (12)
5
6
92
69
in the presence of a catalytic amount of Pd(OAc)2, because
G
introduction of an additional p-methoxyphenyl substituent
at the ortho benzylic position and aromatization to the
phenol was expected to occur simultaneously with this ap-
proach. As a result, corresponding phenol 4h was successful-
ly produced (Scheme 2).
7
0
86
8[d]
9
95
Scheme 2. Preparation of 4h by the Mizoroki–Heck reaction of 3d with
12.
[a] The reaction was carried out with 3, [RhCl(cod)]2 (1 mol% Rh), and
G
Cs2CO3 (1 equiv) in dioxane/H2O at 608C for 5 h. [b] Isolated yield by
silica gel chromatography. [c] The reaction was carried out with 3c and
pTsOH·H2O (10 mol%) in toluene at 708C for 24 h. [d] The reaction was
carried out with 3 f and 10 mol% Pd/C (10 mol% Pd) in iPrOH at 708C
for 24 h.
Conclusions
In summary, we have developed an efficient method for the
synthesis of substituted phenols by RCM/isoaromatization
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Chem. Eur. J. 2008, 14, 9706 – 9713

Synthesis of Substituted Phenols
FULL PAPER
4-Benzylidene-1,7-octadien-3-ol (5a): The reaction was carried out ac-
cording to the GPA (see also Scheme S1 in Supporting Information). 2-
Benzylidene-5-hexenal (6a) (1.65 mmol) and vinylmagnesium chloride
(3.29 mmol) were used. The reaction mixture was stirred for 1 h, The
crude mixture was purified by silica gel column chromatography (hexane/
EtOAc 4:1) and gel permeation chromatography (273 mg, 77%).
1H NMR (CDCl3): d = 1.72 (d, J=3.4 Hz, 1H), 2.22–2.49 (m, 4H), 4.73
(d, J=4.6 Hz, 1H), 4.96 (ddt, J=10.1, 1.8, 1.3 Hz, 1H), 5.01 (dq, J=17.1,
1.6 Hz, 1H), 5.23 (dt, J=10.1, 1.5 Hz, 1H), 5.38 (dt, J=17.1, 1.6 Hz, 1H),
5.80 (ddt, J=16.8, 10.1, 6.4 Hz, 1H), 5.94 (ddd, J=17.1, 10.4, 6.1 Hz,
1H), 6.63 (s, 1H), 7.22 (tt, J=7.3, 1.8 Hz, 1H), 7.27 (d, J=7.0 Hz, 2H),
7.33 ppm (t, J=7.4 Hz, 2H); 13C NMR (CDCl3): d = 27.66, 32.84, 76.93,
114.71, 115.75, 126.63, 126.69, 128.22, 128.60, 137.33, 138.13, 139.20,
142.67 ppm; HRMS (FAB): m/z: calcd for C15H18O: 214.1358, found
214.1355 [M]+.
an additional substituent onto the ortho benzylic position of
the phenols.
Experimental Section
General: All anaerobic and moisture-sensitive manipulations were car-
ried out with standard Schlenk techniques under predried nitrogen or
glove boxtechniques under prepurified argon. NMR Spectra were re-
corded on a JEOL JNM LA-500 spectrometer (500 MHz for 1H and
125 MHz for 13C) and LA-400 spectrometer (400 MHz for 1H and
100 MHz for 13C). Chemical shifts are reported in d ppm referenced to
an internal SiMe4 standard for 1H NMR and chloroform-d (d 77.0) for
13C NMR.
4-(4-Chlorobenzylidene)-1,7-octadien-3-ol (5b): The reaction was carried
out according to the GP A (see also Scheme S1 in Supporting Informa-
tion): 2-(4-Chlorobenzylidene)-5-hexenal (6b) (0.691 mmol) and vinyl-
magnesium chloride (9.36 mmol) were used: The reaction mixture was
stirred for 30 min. The crude mixture was purified by silica gel column
chromatography (hexane/EtOAc 5:1) (156 mg, 91%). 1H NMR (CDCl3):
d = 1.77 (d, J=2.9 Hz, 1H), 2.20–2.46 (m, 4H), 4.71 (ddt, J=4.9, 2.9,
1.2 Hz, 1H), 4.96 (ddt, J=10.1, 1.8, 1.3 Hz, 1H), 5.01 (dq, J=17.1,
1.8 Hz, 1H), 5.24 (dt, J=10.4, 1.2 Hz, 1H), 5.37 (dt, J=17.1, 1.6 Hz, 1H),
5.78, (ddt, J=16.8, 10.4, 6.5 Hz, 1H), 5.92 (ddd, J=17.4, 10.4, 6.4 Hz,
1H), 6.57 (s, 1H), 7.19 (d, J=8.3 Hz, 2H), 7.29 ppm (d, J=8.6 Hz, 2H);
13C NMR (CDCl3): d = 27.63, 32.71, 76.75, 114.89, 116.05, 125.39, 128.40,
129.90, 132.35, 135.80, 137.88, 139.04, 143.35 ppm; HRMS (FAB): m/z:
calcd for C15H17ClO: 248.0968, found 248.0959 [M]+.
Materials: Dichloromethane and anhydrous N,N-dimethylformamide
were used without further purification. Tetrahydrofuran and diethyl ether
were distilled from sodium benzophenone-ketyl under nitrogen prior to
use. 2-Propanol was distilled from magnesium under nitrogen and stored
in a glass flask with a three-way cock under nitrogen. Toluene and diox-
ane were distilled from sodium benzophenone-ketyl under nitrogen and
stored in glass flasks with Teflon stopcocks under nitrogen. Ruthenium
complexes,
[(H2Imes)Cl2Ru=CH(o-iPrO-C6H4)] (11)[18] were prepared according to
the reported procedures. A rhodium complex, [RhCl(cod)]2 was prepared
[(PCy3)
A
(10)[12b]
and
AHCTREUNG
according to the reported procedure.[19] 2-Methylene-5-hexenals 6 were
prepared by Mannich/Hofmann degradation from corresponding 5-hexe-
nals 7 according to the reported procedures.[20] 2-Bromo-5-phenyl-1,5-
hexadiene (8g) was prepared by allylation of 2,3-dibromo-1-propene with
2-phenylallylmagnesium bromide and copper cyanide analogously to the
reported procedure.[21] 2-Bromo-3-indol-1-yl-propene was prepared by al-
kylation of indole with 2,3-dibromopropene according to the reported
procedure.[22] 5-Hexenal,[23] 4-cyclohexyl-3-phenyl-5-hexenol,[24] (E)-3-
allyl-2-iodocyclononene (8 f),[25] activated MnO2,[26] Dess–Martin periodi-
nane,[27] and p-methoxybenzenediazonium tetrafluoroborate (12)[28] were
prepared according to the reported procedures. a-Bromostyrene, 2,3-di-
bromopropene, indole, tert-butyllithium solution, vinylmagnesium chlo-
ride solution, DBU, palladium diacetate, rhodium trichloride, and cesium
carbonate were used as received.
6-Cyclohexyl-4-methylene-5-phenyl-1,7-octadien-3-ol (5c): The reaction
was carried out according to the GPA (see also Scheme S1 in Supporting
Information):
2-Methylene-4-cyclohexyl-3-phenyl-5-hexenal
(6c)
(5.47 mmol) and vinylmagnesium chloride (6.01 mmol) were used. The
reaction mixture was stirred for 1.5 h. The crude mixture was purified by
silica gel column chromatography (hexane/EtOAc 5:1) (diastereomeric
mixture: 1.47 g, 90%). One of the diastereomers was separated for the
spectral characterization. M.p. 83–868C; 1H NMR (CDCl3): d = 0.81–
1.33 (m, 7H), 1.48–1.71 (m, 5H), 2.53 (ddd, J=11.6, 9.8, 2.5 Hz, 1H),
3.41 (d, J=11.6 Hz, 1H), 4.34 (dd, J=5.5, 3.7 Hz, 1H), 4.95 (ddd, J=
17.4, 2.2, 0.4 Hz, 1H), 5.10 (dd, J=10.4, 2.2 Hz, 1H), 5.11 (ddd, J=10.4,
1.6, 1.2 Hz, 1H), 5.18 (s, 1H), 5.23 (dt, J=17.1, 1.5 Hz, 1H), 5.32 (t, J=
0.9 Hz, 1H), 5.52 (dt, J=16.8, 10.1 Hz, 1H), 5.61 (ddd, J=17.1, 10.4,
Procedures for the preparation of 4-methylene-1,7-octadien-3-ols 5
6.7 Hz, 1H), 7.17–7.30 ppm (m, 5H); 13C NMR (CDCl3): d
= 26.51,
General procedure
A (GP A): Vinylmagnesium chloride solution
(1.44 molLÀ1 solution in THF, 3.29 mmol) was added at À788C to a solu-
tion of 2-methylene-5-hexenal 6 (1.65 mmol) in Et2O (9.2 mL). The reac-
tion mixture was warmed up to 08C. After stirring for 30 min, the reac-
tion mixture was quenched by addition of water and extracted with Et2O
several times. The organic phases were combined, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography or PTLC on silica gel to give 5.
General procedure B (GP B): tBuLi (1.59 molLÀ1 solution in pentane,
2.60 mmol) was added at À788C to a solution of vinylhalide (1.31 mmol)
in Et2O (3.0 mL). After 1 h, 6 (1.19 mmol) in Et2O (3.0 mL) was added
to the mixture and it was stirred for 15 min at the same temperature.
Then, the reaction mixture was quenched by addition of water and ex-
tracted with Et2O three times. The organic phases were combined, dried
over Na2SO4, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography or PTLC on silica gel to
give 5.
General procedure C (GP C): tBuLi (1.57 molLÀ1 solution in pentane,
7.16 mmol) was added at À788C to a solution of 2-halo-1,5-hexadiene 8
(3.58 mmol) in Et2O (25 mL). After 30 min, the mixture was added a,b-
unsaturated aldehyde (3.94 mmol) and stirred for 15 min at the same
temperature. Then, the reaction mixture was quenched by addition of
water and extracted with EtOAc three times. The organic phases were
combined, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography or PTLC
on silica gel to give 5.
26.54, 26.67, 26.70, 32.61, 38.42, 49.59, 52.86, 75.49, 111.75, 116.09, 117.02,
126.46, 128.47, 128.75, 139.11, 139.19, 142.48, 151.82 ppm; HRMS (FAB):
m/z: calcd for C21H27: 279.2113, found 279.2109 [MÀOH]+.
4-Methylene-2-phenyl-1,7-octadien-3-ol (5d): The reaction was carried
out according to the GP B (see also Scheme S1 in Supporting Informa-
tion). a-Bromostyrene (1.31 mmol), tBuLi (2.60 mmol), and 2-methylene-
5-hexenal (6d) (1.19 mmol) were used. The reaction mixture was stirred
for 15 min: The crude mixture was purified by PTLC on silica gel
(hexane/EtOAc 4:1) and gel permeation chromatography (125 mg, 49%).
1H NMR (CDCl3): d = 1.95 (d, J=4.1 Hz, 1H), 2.00–2.25 (m, 4H), 4.92–
5.02 (m, 3H), 5.07 (d, J=3.2 Hz, 1H), 5.17, (d, J=0.8 Hz, 1H), 5.44 (t,
J=1.2 Hz, 1H), 5.46 (dd, J=1.2, 0.5 Hz, 1H), 5.78 (ddt, J=17.3, 10.2,
7.1 Hz, 1H), 7.24–7.34 (m, 3H), 7.36–7.43 ppm (m, 2H); 13C NMR
(CDCl3): d = 30.98, 31.90, 76.93, 112.19, 114.43, 114.74, 126.85, 127.63,
128.19, 138.21, 139.53, 148.48, 148.90 ppm; HRMS (FAB): m/z: calcd for
C15H17: 197.1330, found 197.1326 [MÀOH]+.
4-Benzylidene-2-indol-1-ylmethyl-1,7-octadien-3-ol (5e): The reaction
was carried out according to the GP B (see also Scheme S1 in Supporting
Information).
2-Bromo-3-indol-1-yl-propene
(1.38 mmol),
tBuLi
(2.67 mmol), and 2-benzylidene-5-hexenal (6a) (1.14 mmol) were used.
The reaction mixture was stirred for 1 h: The crude mixture was purified
by silica gel column chromatography (hexane/EtOAc 5:1) (264 mg,
67%). 1H NMR (CDCl3): d = 1.85 (d, J=2.5 Hz, 1H), 2.14–2.50 (m,
4H), 4.67 (s, 1H), 4.71 (d, J=16.5 Hz, 1H), 4.81 (d, J=18.0 Hz, 1H),
4.83 (s, 1H), 4.94 (dq, J=9.2, 1.3 Hz, 1H), 4.97 (dq, J=15.6, 1.6 Hz, 1H),
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9709

K. Yoshida, T. Imamoto and R. Narui
5.32 (s, 1H), 5.75 (ddt, J=17.1, 10.4, 6.5 Hz, 1H), 6.52 (dd, J=3.4,
0.7 Hz, 1H), 6.66 (s, 1H), 7.07 (d, J=3.4 Hz, 1H), 7.09 (ddd, J=8.0, 7.0,
0.9 Hz, 1H), 7.17 (ddd, J=8.3, 7.0, 1.2 Hz, 1H), 7.21–7.29 (m, 4H), 7.32–
7.38 (m, 2H), 7.62 ppm (dt, J=7.9, 0.9 Hz, 1H); 13C NMR (CDCl3): d =
27.49, 32.86, 47.76, 76.80, 101.57, 109.64, 113.81, 114.90, 119.43, 120.92,
121.58, 126.55, 126.88, 127.83, 128.33, 128.37, 128.60, 136.24, 136.93,
137.91, 140.99, 145.10 ppm; HRMS (FAB): m/z: calcd for C24H25NO:
343.1936, found 343.1951 [M]+.
column chromatography (hexane/EtOAc 10:1) (122 mg, 86%). 1H NMR
(CDCl3): d = 2.22 (tdt, J=7.9, 6.7, 1.6, Hz, 2H), 2.68 (t, J=8.2 Hz, 2H),
4.97 (ddt, J=10.4, 1.9, 1.2 Hz, 1H), 5.02 (dq, J=17.1, 1.9 Hz, 1H), 5.80
(ddt, J=17.1, 10.4, 6.7 Hz, 1H), 5.82 (dd, J=10.7, 1.9 Hz, 1H), 6.31 (dd,
J=17.1, 1.9 Hz, 1H), 6.96 (dd, J=17.1, 10.7 Hz, 1H), 7.32 (d, J=8.3 Hz,
2H), 7.37–7.40 ppm (m, 3H); 13C NMR (CDCl3): d
= 26.23, 32.67,
115.19, 128.85, 128.98, 130.47, 132.70, 133.96, 134.58, 137.53, 138.29,
142.49, 193.20 ppm; HRMS (FAB): m/z: calcd for C15H16ClO: 247.0890,
found 247.0887 [M+H]+.
1-(9-Allyl-1-cyclononenyl)-2-ethyl-2-propen-1-ol (5 f): The reaction was
carried out according to the GP C (see also Scheme S1 in Supporting In-
formation). 3-Allyl-2-iodocyclononene (8 f) (0.558 mmol), tBuLi
(1.12 mmol), and 2-ethylacrolein (1.70 mmol) were used. The reaction
mixture was stirred for 30 min: The crude mixture was purified by silica
gel column chromatography (hexane/EtOAc 20:3) (diastereomeric mix-
ture: 102 mg, 73%). The following data are for a mixture of two diaste-
reomers (0.5:0.5); 1H NMR (CDCl3): d = 1.04 (t, J=7.5 Hz, 1.5H), 1.07
(t, J=7.5 Hz, 1.5H), 1.30–2.44 (m, 16H), 2.52 (s, 0.5H), 2.71 (s, 0.5H),
4.46 (d, J=3.4 Hz, 0.5H), 4.48 (d, J=2.4 Hz, 0.5H), 4.93–5.02 (m, 2.5H),
5.05 (ddt, J=17.2, 2.2, 1.4 Hz, 0.5H), 5.16 (t, J=1.2 Hz, 0.5H), 5.23 (t,
J=1.2 Hz, 0.5H), 5.64 (t, J=10.1 Hz, 0.5H), 5.66 (t, J=10.1 Hz, 0.5H),
5.74 (ddt, J=16.4, 10.4, 7.2 Hz, 0.5H), 5.84ppm (ddt, 17.1, 10.1, 6.8 Hz,
0.5H); 13C NMR (CDCl3): d = 11.98, 12.06, 23.89, 24.61, 24.95, 25.13,
26.16, 26.30, 26.43, 26.56, 26.82, 27.09, 27.18, 31.44, 31.79, 37.97, 38.42,
39.16, 39.63, 77.20, 108.55, 108.67, 115.25, 115.40, 129.54, 129.77, 137.85,
138.43, 141.49, 141.58, 151.83, 151.86 ppm; HRMS (FAB): m/z: calcd for
C17H28OK: 287.1777, found 287.1780 [M+K]+.
6-Cyclohexyl-4-methylene-5-phenyl-1,7-octadien-3-one (2c): The reaction
was carried out according to the GP D (see also Scheme S1 in Supporting
Information). 6-Cyclohexyl-4-methylene-5-phenyl-1,7-octadien-3-ol (5c)
(0.478 mmol) and Dess–Martin periodinane (0.574 mmol) were used. The
reaction mixture was stirred for 1 h, as being warmed from 08C to room
temperature. The crude mixture was purified by PTLC on silica gel
(hexane/EtOAc 5:1) (93.6 mg, 67%). The following data are for a mix-
ture of two diastereomers (0.85:0.15). 1H NMR (CDCl3): d = 0.80–1.80
(m, 11H), 2.55 (ddd, J=11.6, 10.1, 1.5 Hz, 0.85H), 2.59 (td, J=10.1,
3.4 Hz, 0.15H), 4.26, (d, J=10.5 Hz, 0.15H), 4.28 (d, J=11.9 Hz, 0.85H),
4.74 (ddd, J=17.1, 2.2, 0.6 Hz, 0.15H), 4.86 (dd, J=10.4, 2.2 Hz, 0.15H),
4.92 (ddd, J=17.1, 2.2, 0.7 Hz, 0.85H), 5.02 (dd, J=10.4, 2.1 Hz, 0.85H),
5.43 (dt, J=17.1, 10.1 Hz, 0.15H), 5.51 (dt, J=17.1, 10.1 Hz, 0.85H), 5.67
(dd, J=10.4, 1.8 Hz, 0.85H), 5.72 (dd, J=10.4, 1.8 Hz, 0.15H), 5.83 (d,
J=0.9 Hz, 0.85H), 5.91 (d, J=0.6 Hz, 0.15H), 6.01 (s, 0.85H), 6.07 (s,
0.15H), 6.13 (dd, J=17.1, 1.8 Hz, 0.85H), 6.18 (dd, J=17.1, 1.9 Hz,
0.15H), 6.72 (dd, J=17.1, 10.7 Hz, 0.85H), 6.78 (dd, J=17.1, 10.7 Hz,
0.15H), 7.09–7.14 (m, 0.15H), 7.15–7.31 ppm (m, 4.85H); 13C NMR
(CDCl3): d = 26.32, 26.40, 26.54, 26.57, 26.61, 26.67, 27.43, 32.38, 32.46,
38.30, 38.80, 46.23, 46.83, 52.67, 53.22, 116.98, 117.27, 124.39, 125.41,
126.05, 126.22, 128.00, 128.33, 128.55, 128.75, 129.06, 129.22, 132.71,
138.10, 138.26, 141.88, 141.95, 150.96, 151.28, 192.51, 192.60 ppm; HRMS
(FAB): m/z: calcd for C21H27O: 295.2062, found 295.2077 [M+H]+.
4-Methylene-7-phenyl-1,7-hexadien-3-ol (5g): The reaction was carried
out according to the GP C (see also Scheme S1 in Supporting Informa-
tion). 2-Bromo-5-phenyl-1,5-hexadiene (8g) (3.58 mmol), tBuLi
(7.16 mmol), and acrolein (3.94 mmol) were used: The reaction mixture
was stirred for 15 min. The crude mixture was purified by silica gel
column chromatography (hexane/EtOAc 5:1) (513 mg, 67%). 1H NMR
(CDCl3): d = 1.71 (s, 1H), 2.18 (td, J=15.3, 8.3 Hz, 1H), 2.24 (td, J=
15.3, 7.9 Hz, 1H), 2.68 (td, J=7.6, 1.1 Hz, 2H), 4.56 (d, J=5.8 Hz, 1H),
4.93 (s, 1H), 5.08 (d, J=1.2 Hz, 1H), 5.14 (d, J=0.9 Hz, 1H), 5.15 (dt,
J=10.1, 1.2 Hz, 1H), 5.26 (dt, J=17.4, 1.6 Hz, 1H), 5.29 (d, J=1.1 Hz,
1H), 5.82 (ddd, J=17.1, 10.4, 6.4 Hz, 1H), 7.26 (tt, J=7.6, 1.6 Hz, 1H),
7.32 (td, J=7.9, 1.5 Hz, 2H), 7.40 ppm (d, J=7.4 Hz, 2H); 13C NMR
(CDCl3): d = 30.61, 33.84, 76.20, 110.40, 112.46, 115.65, 126.06, 127.37,
128.26, 139.08, 141.04, 148.01, 149.81 ppm; HRMS (FAB): m/z: calcd for
C15H17: 197.1330, found 197.1338 [MÀOH]+.
4-Methylene-2-phenyl-1,7-octadien-3-one (2d): The reaction was carried
out according to the GP D (see also Scheme S1 in Supporting Informa-
tion): 4-Methylene-2-phenyl-1,7-hexadien-3-ol (5d) (0.489 mmol) and
Dess–Martin periodinane (0.923 mmol) were used. The reaction mixture
was stirred for 4 h. The crude mixture was purified by PTLC on silica gel
(hexane/EtOAc 5:1) (97.3 mg, 94%). 1H NMR (CDCl3): d = 2.26 (dtt,
J=8.2, 7.0, 1.2 Hz, 2H), 2.51 (t, J=6.8 Hz, 2H), 4.99, (ddt, J=10.1, 1.9,
1.2 Hz, 1H), 5.04 (dq, J=17.1, 1.4 Hz, 1H), 5.82 (ddt, J=17.1, 10.4,
6.8 Hz, 1H), 5.86 (td, J=1.4, 0.8 Hz, 1H), 5.55 (d, J=0.5 Hz, 1H), 5.91
(d, J=0.5 Hz, 1H), 5.96 (d, J=0.5 Hz, 1H), 7.27–7.37 ppm (m, 5H);
Procedures for the preparation of 4-methylene-1,7-octadien-3-ones 2
13C NMR (CDCl3): d
= 30.23, 32.25, 115.23, 119.96, 126.79, 128.27,
General procedure D (GP D): Dess–Martin periodinane (0.923 mmol)
was added at room temperature to a solution of 4-methylene-1,7-octa-
dien-3-ol (5; 0.489 mmol) in CH2Cl2 (48 mL). After 4 h, the reaction mix-
ture was quenched by addition of saturated aq. NaHCO3 and saturated
aq. Na2S2O3, and extracted with EtOAc several times. The organic phases
were combined, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography
or PTLC on silica gel to give 2.
128.48, 128.54, 137.12, 137.70, 147.85, 148.16, 199.14 ppm; HRMS (FAB):
m/z: calcd for C15H17O: 213.1279, found 213.1258 [M+H]+.
4-Benzylidene-2-indol-1-ylmethyl-1,7-octadien-3-one
(2e):
MnO2
(21.0 mmol) was added to a solution of 4-benzylidene-2-indol-1-ylmethyl-
1,7-octadien-3-ol (5e) (0.563 mmol) in CH2Cl2 (5.6 mL). The resulting
mixture was stirred for 2.5 h at room temperature. The mixture was
passed through Celite and concentrated under reduced pressure. The res-
idue was purified by column chromatography and PTLC on silica gel
(hexane/EtOAc 5:1) to give 2e (146 mg, 76%); 1H NMR (CDCl3): d =
2.19 (tdt, J=7.9, 6.7, 1.3 Hz, 2H), 2.69 (t, J=7.9 Hz, 2H), 4.95 (ddt, J=
10.1, 1.9, 1.3 Hz, 1H), 4.99 (dq, J=17.1, 1.6 Hz, 1H), 5.08 (t, J=1.6 Hz,
2H), 5.38, (t, J=1.6 Hz, 1H), 5.70 (s, 1H), 5.78 (ddt, J=17.1, 10.4,
6.7 Hz, 1H), 6.51 (dd, J=3.1, 0.9 Hz, 1H), 7.04 (s, 1H), 7.11 (d, J=3.1,
1H), 7.12 (ddd, J=8.0, 7.0, 0.9 Hz, 1H), 7.18, (d, J=7.6 Hz, 1H), 7.22
(dd, J=8.3, 7.0, 1.2 Hz 1H), 7.28 (tt, J=7.3, 1.6 Hz, 1H), 7.31–7.37 (m,
3H), 7.63 ppm (ddd, J=8.0, 1.3, 0.7 Hz, 1H); 13C NMR (CDCl3): d =
26.38, 32.53, 47.79, 101.90, 109.56, 115.29, 119.59, 121.07, 121.77, 124.09,
128.49, 128.56, 128.62, 128.74, 129.14, 135.13, 136.02, 137.54, 141.03,
141.32, 144.31, 198.82 ppm; HRMS (FAB): m/z: calcd for C24H23NO:
341.1780, found 341.1775 [M]+.
4-Benzylidene-1,7-octadien-3-one (2a): The reaction was carried out ac-
cording to the GP D (see also Scheme S1 in Supporting Information). 4-
Benzylidene-1,7-octadien-3-ol (5a) (0.460 mmol) and Dess–Martin peri-
odinane (0.826 mmol) were used. The reaction mixture was stirred for
1.5 h: The crude mixture was purified by silica gel column chromatogra-
phy (hexane/EtOAc 11:1) (72.3 mg, 74%); 1H NMR (CDCl3): d = 2.25
(tdt, J=8.0, 6.5, 1.2 Hz, 2H), 2.71 (t, J=7.7 Hz, 2H), 4.97 (ddt, J=10.1,
1.9, 1.2 Hz, 1H), 5.03 (dq, J=17.2, 1.3 Hz, 1H), 5.82 (ddt, J=16.9, 10.8,
6.5 Hz, 1H), 5.82 (dd, J=10.6, 1.9 Hz, 1H), 6.31 (dd, J=17.2, 1.9 Hz,
1H), 6.99 (dd, J=17.1, 10.6 Hz, 1H), 7.32–7.45 (m, 5H), 7.46 ppm (s,
1H); 13C NMR (CDCl3): d = 26.18, 32.74, 114.98, 128.55, 128.61, 128.72,
129.20, 132.75, 135.46, 137.72, 139.90, 141.91, 193.44 ppm; HRMS (FAB):
m/z: calcd for C15H17O: 213.1279, found 213.1273 [M+H]+.
1-(9-Allyl-1-cyclononenyl)-2-ethylpropenone (2 f): The reaction was car-
ried out according to the GP D (see also Scheme S1 in Supporting Infor-
4-(4-Chlorobenzylidene)-1,7-octadien-3-one (2b): The reaction was car-
ried out according to the GP D (see also Scheme S1 in Supporting Infor-
mation). 4-(4-Chlorobenzylidene)-1,7-octadien-3-ol (5b) (0.571 mmol)
and Dess–Martin periodinane (1.58 mmol) were used: The reaction mix-
ture was stirred for 2 h: The crude mixture was purified by silica gel
mation):
1-(9-Allyl-1-cyclononenyl)-2-ethyl-2-propen-1-ol
(5 f)
(0.279 mmol) and Dess–Martin periodinane (0.362 mmol) were used: The
reaction mixture was stirred for 30 min at 08C. The crude mixture was
9710
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9706 – 9713

Synthesis of Substituted Phenols
FULL PAPER
purified by PTLC on silica gel (hexane/EtOAc 10:1) (55.6 mg, 81%);
1H NMR (CDCl3): d = 1.04 (t, J=7.6 Hz, 3H), 1.23–1.62 (m, 8H), 1.67–
1.77 (m, 1H), 1.94–2.05 (m, 1H), 2.25–2.40 (m, 5H), 2.90–2.99 (m, 1H),
4.90 (dq, J=10.1, 1.2 Hz, 1H), 4.95 (dq, J=17.1, 1.5 Hz, 1H), 5.47 (d, J=
0.9 Hz, 1H), 5.52 (q, J=1.5 Hz, 1H), 5.70 (ddt, J=17.4, 10.1, 6.7 Hz,
1H), 6.41 ppm (t, J=8.9 Hz, 1H); 13C NMR (CDCl3): d = 12.31, 24.76,
25.33, 25.91, 26.09, 26.61, 27.18, 32.74, 38.08, 38.41, 115.54, 121.52, 137.81,
143.05, 145.37, 150.80, 201.13 ppm; HRMS (EI): m/z: calcd for C17H26O:
246.1984, found 246.1977 [M]+.
6.3, 1.9 Hz, 2H), 5.06 (q, J=1.9 Hz, 2H), 6.23 (tt, J=4.4, 1.5 Hz, 1H),
6.53 (dd, J=3.2, 0.7 Hz, 1H), 7.11 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 7.14 (d,
J=3.2 Hz, 1H), 7.19 (ddd, J=8.0, 7.0, 1.4 Hz, 1H), 7.25–7.41 (m, 6H),
7.64 (dt, J=8.0, 0.8 Hz, 1H), 7.68 ppm (t, J=1.9 Hz, 1H); 13C NMR
(CDCl3): d = 24.76, 26.13, 45.36, 101.64, 109.58, 119.47, 120.98, 121.69,
128.42, 128.46, 128.59, 128.72, 129.71, 134.61, 135.62, 135.68, 136.08,
136.41, 144.58, 187.88 ppm; HRMS (FAB): m/z: calcd for C22H19NO:
313.1467, found 313.1474 [M]+.
2-Ethyl-4,4a,5,6,7,8,9,10-octahydrobenzocyclononen-1-one (3 f): Purified
by PTLC on silica gel (hexane/EtOAc 10:1) (99%); 1H NMR (CDCl3):
d = 1.03 (t, J=7.3 Hz, 3H), 1.13–1.27 (m, 1H), 1.29–1.50 (m, 6H), 1.59–
1.70 (m, 2H), 1.76–1.88 (m, 1H), 2.12–2.36 (m, 5H), 2.62–2.72 (m, 1H),
3.26–3.32 (m, 1H), 6.59 (ddq, J=6.4, 2.4, 1.2 Hz, 1H), 6.93 ppm (dd, J=
4-Methylene-7-phenyl-1,7-octadien-3-one (2g): The reaction was carried
out according to the GP D (see also Scheme S1 in Supporting Informa-
tion): 4-Methylene-7-phenyl-1,7-hexadien-3-ol (5g) (2.38 mmol) and
Dess–Martin periodinane (2.86 mmol) were used: The reaction mixture
was stirred for 30 min: The crude mixture was purified by silica gel
column chromatography (hexane/EtOAc 5:1) (457 mg, 91%). 1H NMR
(CDCl3): d = 2.48 (t, J=6.8 Hz, 2H), 2.63 (t, J=7.1 Hz, 2H), 4.99 (t, J=
1.2 Hz, 1H), 5.24 (d, J=1.2 Hz, 1H), 5.67 (t, J=1.2 Hz, 1H), 5.70 (dd,
J=10.5, 1.7 Hz, 1H), 5.90 (s, 1H), 6.21 (dd, J=17.1, 1.7 Hz, 1H), 6.80
(dd, J=17.1, 10.5 Hz, 1H), 7.19 (tt, J=7.3, 1.5 Hz, 1H), 7.26 (t, J=
8.3 Hz, 2H), 7.34 ppm (d, J=7.3 Hz, 2H); 13C NMR (CDCl3): d = 30.45,
33.95, 112.91, 125.18, 126.12, 127.39, 128.29, 128.87, 132.10, 140.77, 147.55,
148.19, 192.28 ppm; HRMS (FAB): m/z: calcd for C15H17O: 213.1279,
found 213.1281 [M+H]+.
10.1, 7.6 Hz, 1H); 13C NMR (CDCl3): d
= 12.79, 22.68, 22.89, 24.76,
25.48, 26.25, 26.94, 32.12, 33.08, 33.84, 137.84, 138.42, 140.98, 141.13,
187.81 ppm; HRMS (FAB): m/z: calcd for C15H23O: 219.1749, found
219.1742 [M+H]+.
6-Methylene-3-phenyl-2-cyclohexen-1-one (3g): The reaction was carried
out with 7.5 mol% 10 at 408C; the crude mixture was purified by silica
gel column chromatography (hexane/EtOAc 5:1) (31%): The reaction
was also carried out with 2.5 mol% 11 at 1008C; the crude mixture was
purified by PTLC on silica gel (hexane/EtOAc 4:1) (86%); m.p. 54–
1
558C; H NMR (CDCl3): d = 2.86–2.88 (m, 4H), 5.35 (td, J=0.9, 0.7 Hz,
1H), 6.05 (t, J=0.9 Hz, 1H), 6.54 (d, J=0.7 Hz, 1H), 7.39–7.43 (m, 3H),
Procedure for the preparation of 6-methylene-2-cyclohexenones 3
7.52–7.57 ppm (m, 2H); 13C NMR (CDCl3): d
= 28.58, 31.01, 119.76,
General procedure: A solution of 2 (0.263 mmol) in toluene (26 mL,
0.01m) was treated with 1.5 mol% catalyst 10 (0.00395 mmol) in one por-
tion under nitrogen and stirred for 2 h at 408C. The reaction mixture was
concentrated under reduced pressure and purified by PTLC on silica gel
or silica gel column chromatography to give 3.
126.12, 128.77, 130.08, 138.68, 141.97, 159.68, 188.72 ppm; HRMS (FAB):
m/z: calcd for C13H12O: 185.0966, found 185.0972 [M+H]+.
Procedures for the preparation of phenols 4
General procedure
E (GP E, Table 2, entry 1): To a solution of 3
(0.170 mmol) in toluene (0.68 mL) was added DBU (0.170 mmol) under
nitrogen. After stirring at 708C for 24 h, the reaction mixture was con-
centrated under reduced pressure. The residue was worked up with 1n
aq HCl and extracted with EtOAc several times. The organic phases
were combined, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by PTLC on silica gel to give 4.
6-Benzylidene-2-cyclohexen-1-one (3a): Purified by PTLC on silica gel
(hexane/EtOAc 8:3) (84%); m.p. 70–748C; 1H NMR (CDCl3): d = 2.43
(tdd, J=6.4, 4.3, 2.1 Hz, 2H), 3.03 (td, J=6.4, 1.8 Hz, 2H), 6.25 (dt, J=
10.1, 2.1 Hz, 1H), 7.04 (dt, J=10.1, 4.3 Hz, 1H), 7.30–7.43 (m, 5H),
7.61 ppm (t, J=1.8 Hz, 1H); 13C NMR (CDCl3): d = 25.42, 26.26, 128.27,
128.34, 129.66, 130.73, 134.88, 135.06, 135.64, 149.20, 188.78 ppm; HRMS
(FAB): m/z: calcd for C13H13O: 185.0966, found 185.0963 [M+H]+.
General procedure F (GP F): A mixture of 3 (0.170 mmol) and 10 mol%
p-toluenesulfonic acid monohydrate (0.017 mmol) in toluene (1.7 mL)
was stirred at 708C for 24 h. The reaction mixture was concentrated
under reduced pressure and the residue was purified by PTLC on silica
gel to give 4.
6-(4-Chlorobenzylidene)-2-cyclohexen-1-one (3b): Purified by PTLC on
silica gel (hexane/EtOAc 5:1) (79%); mp=45–478C; 1H NMR (CDCl3):
d = 2.43 (tdd, J=6.3, 4.4, 1.9 Hz, 2H), 2.98 (td, J=6.3, 1.9 Hz, 2H), 6.24
(dt, J=10.1, 1.9 Hz, 1H), 7.04 (dt, J=10.1, 4.4 Hz, 1H), 7.30 (d, J=
8.7 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.54 ppm (s, 1H); 13C NMR
(CDCl3): d = 25.35, 26.25, 128.63, 130.71, 130.94, 133.73, 134.08, 134.19,
135.39, 149.29, 188.46 ppm; HRMS (FAB): m/z: calcd for C13H12ClO:
219.0577, found 219.0561 [M+H]+.
General procedure G (GP G): To a solution of 3 (0.170 mmol) in 2-prop-
anol (1.7 mL) was added 10 mol% Pd/C (0.017 mmol Pd). The resulting
mixture was stirred for 24 h at 708C. The mixture was passed through
Celite and concentrated under reduced pressure. The residue was puri-
fied by PTLC on silica gel to give 4.
4-Cyclohexyl-6-methylene-5-phenyl-2-cyclohexen-1-one (3c): Purified by
PTLC on silica gel (hexane/EtOAc 5:1) (diastereomeric mixture: 95%);
one of the diastereomers was separated to clarify the spectral characteri-
zation; 1H NMR (CDCl3): d = 0.80–1.47 (m, 6H), 1.60–1.78 (m, 5H),
2.67 (dtd, J=6.3, 4.6, 1.9 Hz, 1H), 4.02, (d, J=6.3 Hz, 1H), 5.02–5.04 (m,
1H), 6.16 (t, J=1.7 Hz, 1H), 6.25 (dd, J=10.4, 1.7 Hz, 1H), 6.99 (dd, J=
10.4, 4.1 Hz, 1H), 7.15 (dd, J=7.2, 1.5 Hz, 2H), 7.24 (tt, J=7.0, 1.5 Hz,
1H), 7.32 ppm (t, J=7.0 Hz, 2H); 13C NMR (CDCl3): d = 26.21, 26.33,
26.38, 28.72, 31.25, 40.64, 48.26, 49.58, 123.10, 126.76, 128.17, 128.58,
129.94, 141.77, 145.65, 152.14, 188.12 ppm; HRMS (FAB): m/z: calcd for
C19H22KO: 305.1308, found 305.1307 [M+K]+.
General procedure
H (GP H): A mixture of 3 (0.180 mmol) and
10 mol% RhCl3 (0.018 mmol) in 2-propanol (0.6 mL) and DMF (1.2 mL)
was stirred at 1008C for 24 h. The reaction mixture was added to Et2O
and washed with water. The organic phase was dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by PTLC
on silica gel to give 4.
General procedure I (GP I): A solution of [RhCl(cod)]2 (0.00089 mmol)
R
in dioxane (1 mL) was added to a solution of Cs2CO3 (0.180 mmol) in
H2O (0.6 mL). To the mixture were added 3 (0.178 mmol) and dioxane
(0.2 mL). After stirring at 608C for 5 h, the reaction mixture was worked
up with brine and extracted with EtOAc several times. The organic
phases were combined, dried over Na2SO4, and concentrated under re-
duced pressure. The residue was purified by PTLC on silica gel to give 4.
6-Methylene-2-phenyl-2-cyclohexen-1-one (3d): Purified by PTLC on
silica gel (hexane/EtOAc 5:1) (92%): The reaction was also carried out
with 0.5 mol% 10; the crude mixture was purified by PTLC on silica gel
(hexane/EtOAc 5:1) (46%); mp=63–668C; 1H NMR (CDCl3): d = 2.60
(td, J=6.5, 4.6 Hz, 2H), 2.83 (t, J=6.5 Hz, 2H), 5.36 (q, J=1.4 Hz, 1H),
6.07 (d, J=1.5 Hz, 1H), 7.11 (t, J=4.6 Hz, 1H), 7.28–7.38 ppm (m, 5H);
2-Benzyl phenol (4a): The reaction was carried out according to the
GP I; purified by PTLC on silica gel (hexane/EtOAc 4:1) (93%). The
product was characterized by comparison of the spectroscopic data with
those reported previously.[29]
13C NMR (CDCl3): d
= 26.42, 31.09, 120.62, 127.65, 127.97, 128.69,
136.50, 141.02, 143.40, 147.95, 187.28 ppm; HRMS (FAB): m/z: calcd for
C13H13O: 185.0966, found 185.0962 [M+H]+.
2-(4-Chlorobenzyl)phenol (4b): The reaction was carried out according
to the GP I; purified by PTLC on silica gel (hexane/EtOAc 5:2) (75%).
1
2-Indol-1-ylmethyl-6-benzylidene-2-cyclohexen-1-one (3e): Purified by
PTLC on silica gel (hexane/EtOAc 5:1) (81%); m.p. 103–1108C;
1H NMR (CDCl3): d = 2.26 (tdt, J=6.3, 4.4, 1.9 Hz, 2H), 2.84 (td, J=
M.p. 56–608C; H NMR (CDCl3): d = 3.95 (s, 2H), 4.67 (s, 1H), 6.76 (d,
J=7.9 Hz, 1H), 6.89 (td, J=7.4, 1.2 Hz, 1H), 7.09 (d, J=7.3 Hz, 1H),
7.12 (dd, J=7.9, 1.6 Hz, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.24 ppm (d, J=
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K. Yoshida, T. Imamoto and R. Narui
8.3 Hz, 2H); 13C NMR (CDCl3):
d
=
35.52, 115.57, 121.03, 126.66,
[2] For examples, see: a) P. Bamfield, P. F. Gordon, Chem. Soc. Rev.
1984, 13, 441–488; b) R. L. Danheiser, S. K. Gee, J. Org. Chem.
1984, 49, 1672–1674; c) P. Turnbull, H. W. Moore, J. Org. Chem.
1995, 60, 644–649; d) T. Takahashi, Z. Xi, A. Yamazaki, Y. Liu, K.
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i) C. B. de Koning, A. L. Rousseau, W. A. L. van Otterlo, Tetrahe-
dron 2003, 59, 7–36; j) Y. Yamamoto, T. Arakawa, R. Ogawa, K.
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Fujimoto, K. Yokota, K. Takagi, J. Am. Chem. Soc. 2004, 126, 8382–
8383; l) X. Bi, D. Dong, Q. Liu, W. Pan, L. Zhao, B. Li, J. Am.
Chem. Soc. 2005, 127, 4578–4579; m) N. Asao, Synlett 2006, 1645–
1656; n) K. Tanaka, T. Osaka, K. Noguchi, M. Hirano, Org. Lett.
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2823–2826.
127.92, 128.57, 130.03, 130.89, 131.93, 138.65, 153.46 ppm; HRMS (FAB):
m/z: calcd for C13H11ClO: 218.0498, found 218.0504 [M]+.
4-Cyclohexyl-2-methyl-3-phenylphenol (4c): The reaction was carried out
according to the GP F; purified by PTLC on silica gel (hexane/EtOAc
9:1) (77%). M.p. 58–618C; 1H NMR (CDCl3): d = 0.96–1.20 (m, 3H),
1.32 (qd, J=12.5, 3.1 Hz, 2H), 1.55–1.68 (m, 5H), 1.88 (s, 3H), 2.15 (tt,
J=12.2, 3.1 Hz, 1H), 4.73 (s, 1H), 6.79 (d, J=8.5 Hz, 2H), 7.06 (d, J=
8.2 Hz, 1H), 7.11 (dd, J=8.0, 1.6 Hz, 2H), 7.34 (tt, J=7.6, 1.6 Hz, 1H),
7.40 ppm (t, J=7.4 Hz, 2H); 13C NMR (CDCl3): d = 13.49, 26.10, 26.83,
34.69, 40.29, 114.07, 121.81, 123.99, 126.58, 128.09, 129.18, 138.57, 140.66,
142.30, 151.33 ppm; HRMS (FAB): m/z: calcd for C19H22O: 266.1671,
found 266.1676 [M]+.
2-Methyl-6-phenylphenol (4d): The reaction was carried out according to
the GP I; purified by PTLC on silica gel (hexane/EtOAc 4:1) (92%);
This product was characterized by comparison of the spectroscopic data
with those reported previously.[30]
2-Indol-1-ylmethyl-6-benzylphenol (4e): The reaction was carried out ac-
cording to the GP I; purified by PTLC on silica gel (hexane/EtOAc 5:1)
(69%). M.p. 728C; 1H NMR (CDCl3): d = 3.97 (s, 2H), 4.77 (s, 1H),
5.28 (s, 2H), 6.52 (dd, J=3.2, 0.5 Hz, 1H), 6.73–6.82 (m, 2H), 7.03–7.35
(m, 10H), 7.63 ppm (d, J=7.8 Hz, 1H); 13C NMR (CDCl3): d = 36.89,
45.49, 77.27, 101.70, 109.79, 119.53, 120.98, 121.67, 124.65, 126.46, 127.04,
127.52, 128.30, 128.56, 128.71, 129.11, 130.50, 136.40, 138.61, 151.88 ppm;
HRMS (FAB): m/z: calcd for C22H19NO: 313.1467, found: 313.1476 [M]+.
[3] For a comprehensive review, see: a) Handbook of Metathesis, (Ed.:
R. H. Grubbs), Wiley-VCH, Weinheim, 2003. For reviews, see:
b) R. H. Grubbs, S. Chang, Tetrahedron 1998, 54, 4413–4450; c) A.
Fꢂrstner, Angew. Chem. 2000, 112, 3140–3172; Angew. Chem. Int.
Ed. 2000, 39, 3012–3043; d) T. M. Trnka, R. H. Grubbs, Acc. Chem.
Res. 2001, 34, 18–29; e) A. H. Hoveyda, A. R. Zhugralin, Nature
2007, 450, 243–251.
4-Cyclohexyl-2-methyl-3-phenylphenol (4 f): The reaction was carried out
according to the GP G. purified by PTLC on silica gel (hexane/EtOAc
10:1) (86%). 1H NMR (CDCl3): d = 1.23 (t, J=7.5 Hz, 3H), 1.27–1.50
(m, 6H), 1.64–1.79 (m, 4H), 2.59 (q, J=7.5 Hz, 2H), 2.70–2.74 (m, 2H),
2.78–2.84 (m, 2H), 4.65 (s, 1H), 6.66 (d, J=7.8 Hz, 1H), 6.93 ppm (d, J=
7.7 Hz, 1H); 13C NMR (CDCl3): d = 13.90, 22.91, 24.09, 24.94, 25.34,
26.62, 27.44, 29.15, 33.27, 121.78, 126.21, 126.39, 126.88, 141.33,
151.02 ppm; HRMS (FAB): m/z: calcd for C15H22O: 218.1671, found
218.1672 [M]+.
[4] For reports on the pharmaceutical application of RCM in multi-kilo-
gram scale (>400 kg of cyclized product), see: a) T. Nicola, M.
Brenner, K. Donsbach, P. Kreye, Org. Process Res. Dev. 2005, 9,
513–515; 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, 7133–7145; 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, 5163–5171.
2-Methyl-5-phenylphenol (4g): The reaction was carried out according to
the GP I; purified by PTLC on silica gel (hexane/EtOAc 7:3) (95%);
This product was characterized by comparison of the spectroscopic data
with those reported previously.[31]
[5] For a review, see: T. J. Donohoe, A. J. Orr, M. Bingham, Angew.
Chem. 2006, 118, 2730–2736; Angew. Chem. Int. Ed. 2006, 45, 2664–
2670.
2-(4-Methoxybenzyl)-6-phenylphenol (4h) by Mizoroki–Heck reaction:
To
a
mixture of 6-methylene-2-phenyl-2-cyclohexen-1-one (3d)
[6] For reports on the direct synthesis of carbocyclic aromatic com-
pounds using RCM, see: a) A. Iuliano, P. Piccioli, D. Fabbri, Org.
Lett. 2004, 6, 3711–3714; b) E. R. Walker, S. Y. Leung, A. G. M.
Barrett, Tetrahedron Lett. 2005, 46, 6537–6540; c) M. C. Bonifacio,
C. R. Robertson, J.-Y. Jung, B. T. King, J. Org. Chem. 2005, 70,
8522–8526; d) S. C. Pelly, C. J. Parkinson, W. A. L. Van Otterlo,
C. B. De Koning, J. Org. Chem. 2005, 70, 10474–10481; e) S. K. Col-
lins, A. Grandbois, M. P. Vachon, J. Cꢃtꢄ, Angew. Chem. 2006, 118,
2989–2992; Angew. Chem. Int. Ed. 2006, 45, 2923–2926. For reports
on the RCM/elimination protocol, see: f) P. Evans, R. Grigg, M. I.
Ramzan, V. Sridharan, M. York, Tetrahedron Lett. 1999, 40, 3021–
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6157; h) Y. Chen, H. V. R. Dias, C. J. Lovely, Tetrahedron Lett. 2003,
44, 1379–1382; 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,
2824–2828. For reports on the RCM/oxidation protocol, see: j) S.
Kotha, K. Mandal, Tetrahedron Lett. 2004, 45, 2585–2588; k) S. Ma,
F. Yu, J. Zhao, Synlett 2007, 583–586; l) S. Kotha, V. R. Shah, K.
Mandal, Adv. Synth. Catal. 2007, 349, 1159–1172. For a report on
the RCM/tautomerization protocol, see: m) W. A. L. van Otterlo,
E. L. Ngidi, E. M. Coyanis, C. B. de Koning, Tetrahedron Lett. 2003,
44, 311–313.
(0.180 mmol) and 5 mol% palladium diacetate (9.0 mmol) in H2O
(0.36 mL) were added 4-methoxyphenyldiazonium tetrafluoroborate (12)
(0.273 mmol) and acetonitrile (0.36 mL). After stirring at 608C for 12 h,
the mixture was added water and extracted with EtOAc several times.
The combined organic phases were dried over Na2SO4 and concentrated
under reduced pressure. The residue was purified by PTLC on silica gel
(hexane/EtOAc 5:1) to give 4h (31.5 mg, 60%). 1H NMR (CDCl3): d =
3.78 (s, 3H), 3.99 (s, 2H), 5.27 (s, 1H), 6.84 (dt, J=7.3, 2.3 Hz, 2H), 6.92
(t, J=7.7 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.11 (dd, J=7.7, 1.5 Hz, 1H),
7.19 (d, J=8.2 Hz, 2H), 7.43–7.50 ppm (m, 4H); 13C NMR (CDCl3): d =
35.47, 55.19, 113.86, 120.39, 127.81, 128.12, 128.13, 128.27, 129.16, 129.24,
129.82, 130.10, 132.47, 137.25, 150.32, 157.95 ppm; HRMS (FAB): m/z:
calcd for C20H18O2: 290.1370, found 290.1303 [M]+.
Acknowledgements
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 Re-
search from the Ministry of Education, Culture, Sports, Science and
Technology, Japan.
[7] For selected recent reports on the synthesis of heterocyclic aromatic
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Astruc), Wiley-VCH, Weinheim, 2002.
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Synthesis of Substituted Phenols
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Received: May 17, 2008
Published online: September 9, 2008
Chem. Eur. J. 2008, 14, 9706 – 9713
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9713