Copper-catalyzed oxidative aromatization of 2-cyclohexen-1-ones to phenols in the presence of catalytic hydrogen bromide under molecular oxygen

Article abstract of DOI:10.1039/c3ra43071e

Catalytic oxidative aromatization has been achieved using 2-cyclohexen-1-ones to obtain phenol derivatives in the presence of a catalytic amount of copper salt and aqueous HBr under molecular oxygen. The amount of HBr was successfully reduced to a catalytic quantity, and the other additive such as a ligand and an oxidant as well as inert conditions were unnecessary. Various mono-, di-, and trisubstituted phenols with substituents at the desired positions could be synthesized under cheap and simple conditions. An oxidative aromatization/bromination sequence was also demonstrated to obtain bromophenols with excess HBr. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra43071e

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Copper-catalyzed oxidative aromatization of
2-cyclohexen-1-ones to phenols in the presence of
Cite this: RSC Adv., 2013, 3, 20150
catalytic hydrogen bromide under molecular oxygen†
*
*
Kotaro Kikushima and Yuta Nishina
Catalytic oxidative aromatization has been achieved using 2-cyclohexen-1-ones to obtain phenol
derivatives in the presence of a catalytic amount of copper salt and aqueous HBr under molecular
oxygen. The amount of HBr was successfully reduced to a catalytic quantity, and the other additive such
as a ligand and an oxidant as well as inert conditions were unnecessary. Various mono-, di-, and
trisubstituted phenols with substituents at the desired positions could be synthesized under cheap and
simple conditions. An oxidative aromatization/bromination sequence was also demonstrated to obtain
bromophenols with excess HBr.
Received 19th June 2013
Accepted 16th August 2013
DOI: 10.1039/c3ra43071e
www.rsc.org/advances
development of highly efficient catalytic aromatization proce-
dures is therefore desirable, and could provide useful synthetic
Introduction
Phenol derivatives are among the most important chemicals
used for industrial materials, including polymers and plastics,
and are core structures of many biologically active compounds
and pharmaceuticals.1 Additionally, recent developments in
dearomatization strategies2 and transition-metal-catalyzed
cross-coupling using phenol derivatives3 have been reminders
that phenol derivatives are useful precursors in total synthesis
and materials science. Typical electrophilic aromatic substitu-
tion reactions produce ortho- and/or para-substituted phenols,
promoted by the strong electronic directing effect of the hydroxy
group. In contrast, preparation of meta-substituted phenol
derivatives is still a challenge, despite efforts to achieve meta
substitution through C–H functionalization induced by transi-
tion-metal catalysts.4 Hydroxylation of a functional group such
as a boron4e,5a or halogen5b–g moiety, and direct oxidation of
aromatic C–H bonds using directing groups,6 are useful ways of
introducing hydroxy groups into arenes to give phenol deriva-
tives. In these synthetic methods, however, preinstallation of
leaving groups or directing groups is necessary. Oxidative
aromatization of 2-cyclohexen-1-one derivatives is an attractive
alternative synthetic approach to produce various customized
phenol derivatives, allowing installation of substituents at the
desired positions.7–13 Much effort has been focused on oxidative
aromatization procedures, but some of these are low yields7 and
most of the reactions require stoichiometric amounts of
oxidants,8 a high temperature,9 or a long reaction time.10 The
methods. Phenols have been produced under acceptable
conditions by transition-metal-catalyzed oxidative aromatiza-
tion reactions using vanadium11 or palladium salts12 as cata-
lysts. The former reaction proceeds via bromination/
dehydrobromination induced by a system consisting of a
vanadium salt and a sub-stoichiometric amount of HBr
(>50 mol%), and the latter requires a combination of a palla-
dium salt and a pyridine ligand; the reactions were performed
at a relatively high temperature (80 ꢀC) in both cases. Very
recently, Li's group reported the preparation of an aryl ether
from 2-cyclohexen-1-one and an aliphatic alcohol in the pres-
ence of a stoichiometric amount of copper, or a copper catalyst
combined with a radical source and stoichiometric amounts of
additives.13 The palladium-catalyzed aromatization of cyclic
ketones with amines to aryl amines has also been reported by
Yoshikai's group and Li and Deng's group.14 However, these
reactions are expensive and require high temperatures. Here we
describe the preparation of various mono-, di-, and trisubsti-
tuted phenols, with the substituents at the desired positions, via
an oxidative aromatization reaction that uses a cheap and
Research Core for Interdisciplinary Sciences, Okayama University, Tsushimanaka,
Kita-ku, Okayama 700-8530, Japan. E-mail: nisina-y@cc.okayama-u.ac.jp; kixy@
okayama-u.ac.jp; Fax: +81-86-251-8718; Tel: +81-86-251-8718
† Electronic supplementary information (ESI) available: General procedure,
additional screening, and spectral data. See DOI: 10.1039/c3ra43071e
Scheme 1 This work.
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Table 2 Synthesis of monosubstituted phenolsa
ligand-free copper catalyst combined with catalytic HBr under
mild conditions (Scheme 1).
Results and discussion
Initial studies and reaction optimization
We began our investigation of efficient oxidative aromatization
by examining the reaction of 2-cyclohexen-1-one (1a) with
various copper salts and a stoichiometric amount of HBr (1.05
equiv.) at room temperature under molecular oxygen (see ESI,
Table S1†). Aer the several screenings, the reaction using
CuBr2 as a catalyst in 1,4-dioxane was found to be the best
combination, giving phenol (1b) in 80% yield (Table 1, entry 1),
although all the copper salts tested exhibited similar catalytic
activities for oxidative aromatization under the present condi-
tions. This reaction system did not work in the absence of
molecular oxygen or HBr (Table 1, entries 2 and 3). The use of
HCl instead of HBr afforded 1b in moderate yield (Table 1, entry
4). The reaction using CF3COOH/Bu4NBr resulted in a low yield
(Table 1, entry 5). These results show that molecular oxygen and
HBr are essential for the reaction to proceed. When CuBr2 was
used as a catalyst, the amount of HBr used was successfully
reduced to 20 mol%, producing 1b in 90% yield (Table 1, entry
6), whereas other copper salts were less effective as catalysts
(Table 1, entries 7–13).
Substrate scope
The present reaction system was used in the oxidative aroma-
tization of various 2-cyclohexen-1-one derivatives to phenols
Table 1 Optimization of reaction conditionsa
Entry Cu salt
Additive/mol%
Time/h Yieldb (%)
1
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl2
48% HBr aq. (105)
48% HBr aq. (105)
—
36% HCl aq. (105)
CF3COOH (105)/Bu4NBr (105) 10
10
10
10
10
80
2
3
43
2
90
71
17
29
8
35
9
65
2c
3
4
5
6
7
8
9
10
11
12
13
48% HBr aq. (20)
48% HBr aq. (20)
20
20
20
20
20
20
20
20
Cu(OAc)2 48% HBr aq. (20)
CuSO4
CuO
48% HBr aq. (20)
48% HBr aq. (20)
48% HBr aq. (20)
48% HBr aq. (20)
48% HBr aq. (20)
Cu2Od
CuI
a
CuBr
Conditions: 0.25 mmol of substrate, 0.0125 mmol of CuBr2, 0.050
b
mmol of 48% HBr aq., 1,4-dioxane (0.50 mL), rt. In the presence of
a
Conditions: 0.50 mmol of 2-cyclohexen-1-one (1a), 0.025 mmol of
c
d
0.25 mmol of 48% HBr aq. for 10 h. Reaction at 100 ꢀC. For 10 h.
b
copper salt, additive, 1,4-dioxane (1.0 mL) at rt. Determined by GC
e
f
For 30 h. For 40 h.
c
using dodecane as an internal standard. Under argon atmosphere.
d
0.0125 mmol of Cu2O was used.
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Table 3 Synthesis of di- or trisubstituted phenolsa
(Table 2). First, the oxidative aromatization reactions of 3-aryl-2-
cyclohexen-1-ones were examined; the desired reaction pro-
ceeded to give the corresponding meta-substituted phenols in
almost quantitative yields. 3-Phenylphenol (2b) and 3-tolyl-
phenols (3b, 7b, and 8b) were smoothly synthesized from the
corresponding 2-cyclohexen-1-ones in quantitative yields.
Substrates bearing various functional groups underwent
aromatization to furnish the corresponding phenols 4–6b, 9b,
and 10b in high yields. It should be noted that 2-cyclohexen-1-
one bearing a heteroarene, namely a thienyl group, was also
successfully aromatized to give the corresponding phenol 11b
in high yield, without deactivation of the catalyst. 3-Butyl-2-
cyclohexen-1-one also reacted with high efficiency and alkyl-
phenol 12b was obtained, although heating or a stoichiometric
amount of HBr was required. We then tested 2-substituted-2-
cyclohexen-1-ones, and good to excellent yields were obtained
with various ortho-arylphenols. 2-Phenylphenol (13b) was iso-
lated in 96% yield. The reactions of 2-aryl-2-cyclohexen-1-ones
with a methyl, methoxy, or chlorine substituents proceeded to
give the corresponding phenols 14–16b in quantitative yields.
Substrates bearing cyano, nitro, or acetyl groups were also
converted to the functionalized biphenyls 17–19b, which could
undergo further transformations. 2-(2-Benzofuranyl)phenol
(20b) was also easily obtained in high yield. The reaction of
2-alkyl-2-cyclohexen-1-one also proceeded and 2-benzylphenol
(21b) was afforded in 99% yield under heating conditions.
Moreover, 2-cyclohexen-1-ones with substituents at 4-position
also served as reaction substrates for the present aromatization
reaction. para-Alkyl- and benzylphenols (22–25b) were obtained
under the standard conditions in satisfactory yields.
Substrate
Product
Yield (%)
26b
92
27b
28b
66, 93b,c
66
29b
30b
88
Di- or trisubstituted cyclohexenones were also used as reac-
tion substrates in the present system, giving the corresponding
phenols (Table 3). The reaction of commercially available
4-methoxy-carbonyl-3-methyl-2-cyclohexen-1-one afforded the
corresponding phenol 26b, despite the presence of an ester
group. Dialkylphenol such as 3,5-dimethylphenol (27b) and
86c
a
Conditions: 0.25 mmol of substrate, 0.0125 mmol of CuBr2,
b
3-butyl-6-methylphenol (28b) were obtained in moderate yields, 0.050 mmol of 48% HBr aq., 1,4-dioxane (0.50 mL), rt. Reaction
using 0.25 mmol of 48% HBr aq. at 100 ꢀC. c For 30 h.
respectively. The use of a stoichiometric amount of HBr
improved the yield of 27b under heating conditions. When 3-
phenyl-4-methyl-2-cyclohexen-1-one was used as the substrate,
the corresponding phenol 29b was afforded in high yield at
room temperature. Trisubstituted phenol such as 30b was also
successfully synthesized by copper-catalyzed aromatization.
Oxidative aromatization/bromination sequence
The present reaction system was found to provide an oxidative
aromatization/bromination reaction sequence in the presence
of excess amounts of HBr at high temperatures (Scheme 2). The
reaction of 1a with 5 mol% CuBr2 and 2.0 equiv. of HBr at 60 ꢀC
furnished 4-bromophenol (1c) in moderate yield (Scheme 2, eqn
(a)). The dibromide 27c was obtained from 27a in the presence
of 4.0 equiv. of HBr (Scheme 2, eqn (b)). Copper-catalyzed
bromination of arenes with a bromide salt in acetic acid has
already been reported by Stahl's group.15 It is suggested that the
bromination reaction proceeded aer oxidative aromatization
Scheme 2 Oxidative aromatization/bromination sequence.
under the present conditions.
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Table 5 Aromatization under several bromination conditionsa
Reaction pathway
A plausible reaction pathway for the oxidative aromatization
reaction is illustrated in Scheme 3. Initially, copper(II) species
would generate molecular bromine along with reduced cop-
per(I) species, as reported in the literature.15 Bromination of
2-cyclohexen-1-one occurs to give the a-bromination product,
which undergoes dehydrobromination followed by trans-
formation to a phenol. The reduced copper(I) would be oxidized
by molecular oxygen and HBr to regenerate the copper(II)
species.
To gain insight into the reaction pathway, we investigated
whether the present aromatization involves a-bromination of
2-cyclohexen-1-one. 6-Bromo-2-cyclohexen-1-one (8d) was
synthesized separately in two steps, and treated with CuBr2 and/
or HBr (Table 4). As expected, the aromatization reaction
occurred to give the phenol 8b in 30 min under the present
conditions (Table 4, entry 1), whereas the bromide 8d was
unchanged in the absence of HBr (Table 4, entries 2 and 4).
These results suggest that the present aromatization proceeds
by the above-mentioned reaction pathway: the bromination
reaction occurs rst, then the dehydrobromination of the
bromide occurs, followed by tautomerization to give the corre-
sponding phenol. The mechanistic details of the bromination
and dehydrobromination steps are currently unknown. Further
Entry
Conditions
Yield (%), 2a : 2b : 2c
15 : 42 : 43
1
2
3
Bromine (105 mol%),b
1,4-dioxane, rt, 20 h
AIBN (5 mol%), NBS (105 mol%),
cyclohexane, 85 ꢀC, 30 h
CuBr2 (5 mol%), 48%
HBr aq. (105 mol%),
22 : 76 : 0
0 : 99 : 0
1,4-dioxane, rt, 30 h
a
b
0.25 mmol of 3-phenyl-2-cyclohexen-1-one (2a) was used. Slow
addition.
studies are therefore clearly needed to conrm this proposed
mechanism, and other mechanisms cannot be ruled out.
Next, the reactions of 2a under several bromination condi-
tions were conducted (Table 5). When 2a was treated with
molecular bromine, the oxidative aromatization reaction
occurred, giving the phenol (2b, 42%) and bromophenol (2c,
43%), with recovery of 2a (Table 5, entry 1). Molecular bromine
is considered to serve as an oxidant and/or brominating
reagent, inducing aromatization and bromination. This result
indicates that the present aromatization reaction proceeds
through the above-mentioned bromination/dehydrobromina-
tion reaction sequence. A catalytic combination of azobisiso-
butyronitrile (AIBN) and N-bromosuccinimide (NBS) also
produced 2b, although the yield was moderate, even at high
temperatures (Table 5, entry 2), showing that the reaction was
induced by molecular bromine generated in situ rather than by
bromine radicals. Compared with these results, the present
reaction system provided 2b in 99% yield, with a trace amount
of 2c, even in the presence of a stoichiometric amount of HBr
(Table 5, entry 3). Under the present conditions, it is considered
that the bromination species generates slowly and the forma-
tion of bromophenol might be suppressed.
Scheme 3 Proposed reaction pathway.
Table 4 Dehydrobromination under several conditionsa
Conclusions
48%
HBr aq.
In conclusion, we have developed the rst copper-catalyzed
phenol synthesis through oxidative aromatization of 2-cyclo-
hexen-1-one derivatives in the presence of catalytic HBr and
molecular oxygen. This reaction system efficiently produces
various phenols under cheap and simple conditions. Further
investigations into the mechanism of this transformation and
its application to other organic synthetic reactions are currently
underway in our laboratory.
Entry
CuBr2
8b
1
2
3
4
B
B
—
—
B
—
B
—
Quant.
No reaction
Quant.
No reaction
a
Conditions: 0.20 mmol of 8d, 0.010 mmol of CuBr2, 0.040 mmol of 48%
HBr aq., and 1,4-dioxane (0.50 mL) at rt for 30 min.
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Hz, 1H), 7.13 (dd, J ¼ 0.8, 7.7 Hz, 1H), 7.03 (dd, J ¼ 1.7, 2.3 Hz,
1H), 6.84 (dd, J ¼ 2.4, 7.9 Hz, 1H), 5.19 (s, 1H); 13C NMR (100
MHz, CDCl3) d 155.81, 141.71, 139.08, 133.53, 130.12, 128.86,
128.29, 119.59, 114.51, 113.91.
Experimental
General
All 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded
using a JEOL JNM-LA400 spectrometer. Proton chemical shis
are reported relative to residual solvent peak CDCl3 at d 7.26 ppm.
Carbon chemical shis are reported relative to CDCl3 at d 77.00
ppm. NMR spectra are reported as follows: chemical shi
(multiplicity, coupling constants, number of hydrogens). High-
resolution mass spectrometry was performed on a JEOL JMS-700
MStation at the Mass Spectrometry Facility (Okayama University).
Gas chromatographic analysis was conducted with Shimadzu GC-
2014 equipped with FID detector and the chemical yields were
determined using dodecane as an internal standard. Flash
chromatography separations were performed on KANTO
CHEMICAL Silica Gel 60 (spherical, 40–50 mesh). Thin layer
chromatography was performed using Merck TLC silica gel 60
F254 Aluminum sheets and visualized by UV irradiation, phos-
phomolybdic acid, and iodine staining. All commercially avail-
able compounds were purchased and used as received. Solvents
1,4-dioxane, MeCN, THF, Et2O, toluene, dichloromethane, and
cyclohexane were purchased from Wako Pure Chemical Indus-
tries and used as received. Diisopropylamine and chloro-
trimethylsilane were distilled over calcium hydride prior to use.
40-(Triuoromethyl)biphenyl-3-ol (6b). 1H NMR (400 MHz,
CDCl3) d 7.68 (d, J ¼ 8.8 Hz, 2H), 7.65 (d, J ¼ 8.8 Hz, 2H), 7.35 (t,
J ¼ 8.0 Hz, 1H), 7.18 (ddd, J ¼ 0.7, 0.8, 7.7 Hz, 1H), 7.08 (dd, J ¼
1.7, 2.3 Hz, 1H), 6.89 (dd, J ¼ 2.5, 8.0 Hz, 1H), 5.12 (s, 1H); 13
C
NMR (100 MHz, CDCl3) d 155.86, 144.15 (JCF ¼ 1.2 Hz), 141.51,
130.26, 129.52 (JCF ¼ 32.3 Hz), 127.35, 125.68 (JCF ¼ 3.7 Hz),
124.24 (JCF ¼ 270.5 Hz), 119.93, 115.11, 114.22.
30-Methylbiphenyl-3-ol (7b). 1H NMR (400 MHz, CDCl3) d
7.24–7.22 (m, 3H), 7.21–7.17 (m, 2H), 6.86 (ddd, J ¼ 1.1, 1.5, 7.6
Hz, 1H), 6.80–6.76 (m, 2H), 5.09 (s, 1H), 2.24 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 155.09, 143.63, 141.43, 135.27, 130.27,
129.57, 129.26, 127.32, 125.69, 121.87, 116.16, 113.69, 20.37.
20-Methylbiphenyl-3-ol (8b). 1H NMR (400 MHz, CDCl3) d
7.40–7.38 (m, 2H), 7.36–7.30 (m, 2H), 7.20–7.17 (m, 2H), 7.08
(dd, J ¼ 1.9, 2.3 Hz, 1H), 6.83 (ddd, J ¼ 0.9, 2.4, 8.0 Hz, 1H), 5.14
(s, 1H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3) d 155.71, 143.10,
140.66, 138.30, 129.90, 128.62, 128.20, 127.88, 124.17, 119.77,
114.08, 21.48.
20,50-Diuorobiphenyl-3-ol (9b). 1H NMR (400 MHz, CDCl3) d
7.33 (t, J ¼ 7.9 Hz, 1H), 7.15–7.07 (m, 3H), 7.03–6.97 (m, 2H),
6.88 (ddd, J ¼ 0.8, 2.7, 8.1 Hz, 1H), 5.09 (s, 1H); 13C NMR (100
MHz, CDCl3) d 158.70 (JCF ¼ 2.5, 241.3 Hz), 155.65 (JCF ¼ 2.5,
241.3 Hz), 155.50, 136.30 (JCF ¼ 1.6 Hz), 129.84 (JCF ¼ 8.0 Hz),
129.83, 121.44 (JCF ¼ 3.1 Hz), 117.15 (JCF ¼ 8.8, 25.9 Hz), 116.80
General procedure for the copper-catalyzed oxidative
aromatization
A screw-capped test tube (20 mL) was charged with CuBr2 (JCF ¼ 3.7, 24.3 Hz), 115.88 (JCF ¼ 3.5 Hz), 115.31 (JCF ¼ 8.8, 23.9
(0.0125 mmol, 2.79 mg, 5 mol%), 1,4-dioxane (1.0 mL), 2- Hz), 115.19; HRMS (EI): m/z calcd for C12H8OF2 ([M]+) 206.0543,
cyclohexen-1-one, and 48% HBr aq. (0.05 mmol, 6.0 mL, 20 mol found 206.0551.
%). The tube was lled with oxygen gas and then sealed. The
3-(Naphthalen-2-yl)phenol (10b). 1H NMR (400 MHz, CDCl3)
reaction mixture was stirred at room temperature for 20 h and d 8.03 (s, 1H), 7.92–7.87 (m, 3H), 7.72 (dd, J ¼ 1.9, 8.5 Hz, 1H),
then the solvent was removed under vacuum. The residue was 7.55–7.49 (m, 2H), 7.37 (t, J ¼ 7.7 Hz, 1H), 7.33 (tt, J ¼ 1.3, 7.7 Hz,
directly charged onto a chromatography column (SiO2, 1 cm ꢁ 1H), 7.20 (dd, J ¼ 1.6, 2.4 Hz, 1H), 6.88 (ddd, J ¼ 2.4, 2.5, 7.9 Hz,
10 cm, AcOEt–hexane ¼ 1 : 25), and the desired product was 1H), 5.12 (s, 1H); 13C NMR (100 MHz, CDCl3) d 155.80, 142.86,
obtained.
137.97, 133.55, 132.68, 130.07, 128.38, 128.19, 127.60, 126.29,
1
Biphenyl-3-ol (2b). H NMR (400 MHz, CDCl3) d 7.58 (d, J ¼ 125.99, 125.80, 125.42, 120.05, 114.31, 114.28; HRMS (EI): m/z
8.0 Hz, 2H), 7.44 (t, J ¼ 8.0 Hz, 2H), 7.38 (t, J ¼ 8.0 Hz, 1H), 7.32 calcd for C16H12O ([M]+) 220.0888, found 220.0876.
1
(t, J ¼ 8.0 Hz, 1H), 7.19 (dd, J ¼ 0.9, 7.7 Hz, 1H), 7.08 (dd, J ¼ 1.6,
3-(Thiophen-2-yl)phenol (11b). H NMR (400 MHz, CDCl3) d
2.4 Hz, 1H), 6.84 (dd, J ¼ 2.4, 8.0 Hz, 1H), 5.15 (s, 1H); 13C NMR 7.30–7.20 (m, 4H), 7.10 (t, J ¼ 2.0 Hz, 1H), 7.07 (ddd, J ¼ 0.5, 3.6,
(100 MHz, CDCl3) d 155.77, 142.98, 140.68, 129.97, 128.72, 5.1 Hz, 1H), 6.76 (ddd, J ¼ 1.2, 2.3, 7.9 Hz, 1H), 5.09 (s, 1H); 13
C
127.46, 127.08, 119.76, 114.18, 114.08.
NMR (100 MHz, CDCl3) d 155.74, 143.82, 135.94, 130.14, 127.95,
40-Methylbiphenyl-3-ol (3b). 1H NMR (400 MHz, CDCl3) d 124.95, 123.33, 118.65, 114.43, 112.78.
7.48 (d, J ¼ 8.0 Hz, 2H), 7.31 (t, J ¼ 8.0 Hz, 1H), 7.25 (d, J ¼ 8.0
3-Butylphenol (12b). 1H NMR (400 MHz, CDCl3) d 7.15 (t, J ¼
Hz, 2H), 7.17 (dd, J ¼ 0.8, 7.6 Hz, 1H), 7.06 (t, J ¼ 2.0 Hz, 1H), 7.7 Hz, 1H), 6.77 (d, J ¼ 7.7 Hz, 1H), 6.70–6.63 (m, 2H), 4.88 (s,
6.81 (dd, J ¼ 2.5, 8.0 Hz, 1H), 5.09 (s, 1H), 2.41 (s, 3H); 13C NMR 1H), 2.57 (t, J ¼ 7.7 Hz, 2H), 1.59 (tt, J ¼ 7.2, 7.7 Hz, 1H), 1.36 (qt,
(100 MHz, CDCl3) d 155.71, 142.90, 137.77, 137.26, 129.92, J ¼ 7.2, 7.5 Hz, 2H), 0.93 (s, J ¼ 7.4 Hz, 1H); 13C NMR (100 MHz,
129.44, 126.90, 119.57, 113.88, 113.86, 21.06.
CDCl3) d 155.34, 144.91, 129.35, 120.99, 115.30, 112.45, 35.47,
1
40-Methoxylbiphenyl-3-ol (4b). H NMR (400 MHz, CDCl3) d 33.40, 22.31, 13.92.
7.48 (d, J ¼ 8.0 Hz, 2H), 7.31 (t, J ¼ 8.0 Hz, 1H), 7.25 (d, J ¼ 8.0
Biphenyl-2-ol (13b). H NMR (400 MHz, CDCl3) d 7.52–7.48
1
Hz, 2H), 7.18 (dd, J ¼ 0.9, 7.9 Hz, 1H), 7.06 (dd, J ¼ 1.9, 2.1 Hz, (m, 4H), 7.44–7.40 (m, 1H), 7.31–7.27 (m, 2H), 7.05–7.01 (m,
1H), 6.82 (dd, J ¼ 2.4, 8.0 Hz, 1H), 5.09 (s, 1H), 2.41 (s, 3H); 13
C
2H), 5.28 (s, 1H); 13C NMR (100 MHz, CDCl3) d 152.37, 137.04,
NMR (100 MHz, CDCl3) d 159.13, 155.79, 142.50, 133.25, 129.92, 130.21, 129.22, 129.11, 129.06, 128.09, 127.82, 120.81, 115.79.
128.08, 119.27, 114.17, 113.61, 113.59, 112.73, 55.34.
20-Methylbiphenyl-2-ol (14b). 1H NMR (400 MHz, CDCl3) d
40-Chlorobiphenyl-3-ol (5b). 1H NMR (400 MHz, CDCl3) d 7.35–7.33 (m, 2H), 7.32–7.21 (m, 4H), 7.12 (dd, J ¼ 1.6, 7.7 Hz,
7.48 (d, J ¼ 8.0 Hz, 2H), 7.39 (d, J ¼ 8.0 Hz, 2H), 7.31 (t, J ¼ 7.9 1H), 7.01–6.96 (m, 2H), 4.74 (s, 1H), 2.18 (s, 3H); 13C NMR (100
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MHz, CDCl3) d 152.46, 137.39, 135.67, 130.64, 130.45, 130.12, (s, J ¼ 8.1 Hz, 2H), 4.58 (s, 1H), 3.91 (s, 2H); 13C NMR (100 MHz,
129.09, 128.49, 127.67, 126.42, 120.42, 115.27, 19.72.
CDCl3) d 153.76, 141.48, 130.05, 128.80, 128.42, 125.99, 115.25,
1
40-Methoxybiphenyl-2-ol (15b). H NMR (400 MHz, CDCl3) d 41.00.
7.39 (d, J ¼ 8.3 Hz, 2H), 7.24–7.20 (m, 2H), 7.02 (d, J ¼ 8.3 Hz,
4-(4-Bromobenzyl)phenol (25b). 1H NMR (400 MHz, CDCl3) d
2H), 6.99–6.96 (m, 2H), 5.15 (s, 1H), 3.86 (s, 3H); 13C NMR (100 7.40 (d, J ¼ 8.7 Hz, 2H), 7.05 (d, J ¼ 6.8 Hz, 1H), 7.03 (d, J ¼ 6.8
MHz, CDCl3) d 159.22, 152.47, 130.22, 13021, 129.17, 128.72, Hz, 2H), 6.77 (d, J ¼ 8.7 Hz, 2H), 4.98 (s, 1H), 3.86 (s, 2H); 13C
127.79, 120.71, 116.67, 115.63, 114.62, 55.29.
NMR (100 MHz, CDCl3) d 153.92, 140.47, 132.69, 131.44, 130.51,
40-Chlorobiphenyl-2-ol (16b). 1H NMR (400 MHz, CDCl3) d 129.99, 119.80, 115.37, 40.34; HRMS (EI): m/z calcd for
7.46 (d, J ¼ 8.8 Hz, 2H), 7.42 (d, J ¼ 8.8 Hz, 2H), 7.29–7.22 (m,
C
13H11OBr ([M]+) 261.9993, found 261.9966.
5-Butyl-2-methylphenol (28b). H NMR (400 MHz, CDCl3) d
1
2H), 7.00 (dt, J ¼ 1.2, 3.5 Hz, 1H), 6.96 (dd, J ¼ 1.1, 8.1 Hz, 1H),
5.09 (s, 1H); 13C NMR (100 MHz, CDCl3) d 152.27, 135.61, 7.03 (d, J ¼ 7.6 Hz, 1H), 6.69 (dd, J ¼ 1.1, 7.6 Hz, 1H), 6.62 (d, J ¼
133.79, 130.47, 130.24, 129.37, 129.23, 127.01, 121.05, 116.01.
1.1 Hz, 1H), 4.72 (s, 1H), 2.54 (t, J ¼ 7.7 Hz, 2H), 2.22 (s, 3H),
40-Cyanobiphenyl-2-ol (17b). 1H NMR (400 MHz, CDCl3) d 1.62–1.54 (m, 2H), 1.40–1.31 (m, 2H), 0.93 (t, J ¼ 7.3 Hz, 3H); 13
C
7.75 (d, J ¼ 8.5 Hz, 2H), 7.66 (d, J ¼ 8.5 Hz, 1H), 7.32–7.26 (m, NMR (100 MHz, CDCl3) d 153.50, 142.23, 130.68, 120.73, 120.59,
2H), 7.04 (dt, J ¼ 0.9, 7.7 Hz, 1H), 6.95 (d, J ¼ 8.1 Hz, 1H), 5.03 (s, 114.92, 35.10, 33.53, 22.29, 15.26, 13.91; IR (ATR) n cmꢂ1; HRMS
1H); 13C NMR (100 MHz, CDCl3) d 152.35, 142.59, 132.41, (EI): m/z calcd for CHO ([M]+) 164.1201, found 164.1175.
130.42, 130.07, 129.93, 126.49, 121.39, 118.82, 116.39, 110.95;
6-Methylbiphenyl-3-ol (29b). 1H NMR (400 MHz, CDCl3) d
HRMS (EI): m/z calcd for C13H9ON ([M]+) 195.0684, found 7.43–7.40 (m, 2H), 7.37–7.34 (m, 1H), 7.33–7.31 (m, 2H), 7.14 (d,
195.0703.
J ¼ 8.1 Hz, 1H), 6.78–6.74 (m, 2H), 4.83 (s, 1H), 2.20 (s, 3H); 13
C
40-Acethylbiphenyl-2-ol (18b). 1H NMR (400 MHz, CDCl3) d NMR (100 MHz, CDCl3) d 153.26, 143.03, 141.58, 131.34, 128.99,
8.05 (d, J ¼ 8.3 Hz, 2H), 7.63 (d, J ¼ 8.3 Hz, 2H), 7.31–7.27 (m, 128.04, 127.50, 126.85, 116.57, 114.06, 19.45; HRMS (EI): m/z
2H), 7.02 (t, J ¼ 7.5 Hz, 1H), 6.98 (d, J ¼ 8.3 Hz, 1H), 5.45 (s, 1H), calcd for C13H12O ([M]+) 184.0888, found 184.0872.
2.64 (s, 3H); 13C NMR (100 MHz, CDCl3) d 197.92, 152.51,
Ethyl-4-hydroxy-2-methyl-3-phenethylbenzoate (30b). 1H
142.55, 135.97, 130.31, 129.74, 129.35, 128.93, 127.12, 121.10, NMR (400 MHz, CDCl3) d 7.66 (d, J ¼ 8.5 Hz, 1H), 7.32–7.22 (m,
116.25, 26.64.
5H), 6.62 (d, J ¼ 8.5 Hz, 1H), 4.85 (s, 1H), 4.32 (q, J ¼ 7.2 Hz, 2H),
30-Nitrobiphenyl-2-ol (19b). 1H NMR (400 MHz, CDCl3) d 8.43 3.01–2.97 (m, 2H), 2.81–2.77 (m, 2H), 2.54 (s, 3H), 1.38 (t, J ¼ 7.2
(t, J ¼ 1.9 Hz, 1H), 8.22 (ddd, J ¼ 1.1, 2.3, 8.3 Hz, 1H), 7.89 (ddd, Hz, 3H); 13C NMR (100 MHz, CDCl3) d 168.60, 156.73, 142.01,
J ¼ 1.2, 1.6, 7.7 Hz, 1H), 7.63 (t, J ¼ 8.0 Hz, 1H), 7.34–7.29 (m, 140.19, 129.86, 128.45, 128.35, 127.77, 126.03, 123.63, 112.39,
2H), 7.06 (dt, J ¼ 1.2, 7.2 Hz, 1H), 6.95 (dd, J ¼ 1.1, 8.1 Hz, 1H), 60.68, 35.12, 28.61, 16.50, 14.30; HRMS (EI): m/z calcd for
4.96 (s, 1H); 13C NMR (100 MHz, CDCl3) d 152.31, 139.38,
135.32, 130.58, 129.98, 129.43, 125.98, 124.25, 122.16, 121.48,
116.36; HRMS (EI): m/z calcd for C12H9O3N ([M]+) 215.0582,
found 215.0561.
C
18H20O3 ([M]+) 284.1412, found 284.1411.
Acknowledgements
1
2-(Benzofuran-2-yl)phenol (20b). H NMR (400 MHz, CDCl3)
Financial support for this study was provided by the Develop-
ment of Human Resources in Science and Technology, and
Ministry of Education, Culture, Sports, Science, and Technology
of Japan.
d 7.74 (dd, J ¼ 1.6, 8.0 Hz, 1H), 7.62 (dd, J ¼ 1.6, 6.7 Hz, 1H), 7.55
(dd, J ¼ 1.6, 7.2 Hz, 1H), 7.35–7.27 (m, 3H), 7.18 (s, 1H), 7.11 (d,
J ¼ 0.9 Hz, 1H), 7.04–7.00 (m, 2H); 13C NMR (100 MHz, CDCl3) d
154.27, 153.95, 153.29, 130.26, 128.48, 127.14, 124.43, 123.41,
120.98, 120.76, 117.37, 116.05, 110.98, 103.31.
2-Benzylphenol (21b). 1H NMR (400 MHz, CDCl3) d 7.33–7.30
(m, 2H), 7.26–7.22 (m, 3H), 7.17–7.13 (m, 2H), 6.91 (m, 1H), 6.79
(d, J ¼ 7.5 Hz, 1H), 4.82 (s, 1H), 4.02 (s, 2H); 13C NMR (100 MHz,
CDCl3) d 153.66, 139.86, 130.94, 128.66, 128.59, 127.78, 126.97,
126.29, 120.90, 115.66, 36.27; HRMS (EI): m/z calcd for C13H12O
([M]+) 184.0888, found 184.0881.
Notes and references
1 For example, see: J. H. P. Tyman, Synthetic and Natural
Phenols, Elsevier, New York, 1996.
2 For recent reviews, see: (a) L. Puysegu, D. Deffieux and
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S. Quideau, Tetrahedron, 2010, 66, 2235–2261; (b)
S. P. Roche and J. A. Porco Jr, Angew. Chem., 2011, 123,
4154–4179; Angew. Chem., Int. Ed., 2011, 50, 4068–4093; (c)
C.-X. Zhuo, W. Zhang and S.-L. You, Angew. Chem., 2012,
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3 For recent reviews, see: (a) B. M. Rosen, K. W. Quasdorf,
D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K. Garg and
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4-Ethlyphenol (22b). 1H NMR (400 MHz, CDCl3) d 7.07 (d, J ¼
8.4 Hz, 2H), 6.77 (d, J ¼ 8.4 Hz, 2H), 4.85 (s, 1H), 2.59 (q, J ¼ 7.5
Hz, 2H), 1.21 (t, J ¼ 7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
153.29, 136.55, 128.88, 115.09, 27.93, 15.84.
4-Hexylphenol (23b). 1H NMR (400 MHz, CDCl3) d 7.05 (d, J ¼
8.5 Hz, 2H), 6.75 (d, J ¼ 8.5 Hz, 2H), 2.53 (t, J ¼ 7.9 Hz, 2H), 1.61–
1.52 (m, 2H), 1.33–1.27 (m, 6H), 0.89 (t, J ¼ 6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 153.33, 135.20, 129.41, 115.02, 35.03, 31.71,
31.69, 28.90, 22.60, 14.08; HRMS (EI): m/z calcd for C12H18O
([M]+) 178.1358, found 178.1352.
1
4-Benzylphenol (24b). H NMR (400 MHz, CDCl3) d 7.28 (t,
J ¼ 7.1 Hz, 2H), 7.21–7.16 (m, 3H), 7.06 (d, J ¼ 8.1 Hz, 2H), 6.75
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