Metal-free oxidative aromatization of 2-aryloxycyclohex-2-en-1-ones to 2-aryloxyphenols using DDQ/Amberlyst-15

Article abstract of DOI:10.1134/S1070428014090115

Efficient metal-free oxidative aromatization of 2-aryloxycyclohex-2-en-1-ones was achieved by a combination of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and Amberlyst-15. The conditions for oxidative aromatization are mild and applicable for a variety of substrates, and Amberlyst-15 can be successfully recovered and recycled.

Full text of DOI:10.1134/S1070428014090115

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 9, pp. 1301–1305. © Pleiades Publishing, Ltd., 2014.
Metal-Free Oxidative Aromatization of 2-Aryloxycyclohex-2-en-
1-ones to 2-Aryloxyphenols Using DDQ/Amberlyst-15*
B. G. Jadhav and S. D. Samant
Department of Chemistry, Institute of Chemical Technology, Matunga, Mumbai, 400019 Maharashtra, India
e-mail: samantsd@yahoo.com; sd.samant@ictmumbai.edu.in
Received December 18, 2013
Abstract—Efficient metal-free oxidative aromatization of 2-aryloxycyclohex-2-en-1-ones was achieved by
a combination of 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and Amberlyst-15. The conditions for
oxidative aromatization are mild and applicable for a variety of substrates, and Amberlyst-15 can be
successfully recovered and recycled.
DOI: 10.1134/S1070428014090115
2-Aryloxyphenols constitute an important structural
motif in medicinal chemistry, which shows a wide
spectrum of therapeutic applications. For example,
2-phenoxyphenol (I) and Triclosan (II) are antibacte-
rial drugs [1], while 2-aryloxyphenol containing bio-
logically active peptides viz. vancomycin family
member isodityrosine (III) [2], K-13, [3] OF-4949-
I-IV [4], Bouvardin [5], and RA I-IV [6] exhibit anti-
tumor activity. Besides these important applications,
2-aryloxyphenols are important building blocks for the
synthesis of polycyclic furans like IV [7].
above methods suffer from such drawbacks as the use
of metals, high temperatures, complex reaction sys-
tems, poor yields, and limited scope of substrates.
Oxidative aromatization of cyclohexenones to
phenols is an important transformation in organic syn-
thesis, so metal-free oxidative aromatization is highly
desirable. The best choice of reagents for oxidative
aromatization of substituted cyclohexenones would be
iodine and DDQ (2,3-dichloro-5,6-dicyano-p-benzo-
quinone). However, oxidative aromatization of substi-
tuted cyclohexenones with iodine in methanol afforded
directly aryl phenyl ethers instead of 2-aryloxyphenols
[17]. DDQ has been investigated as a powerful oxidant
by several research groups [18] and was proved to be
useful for a wide range of reactions. This prompted us
to use DDQ for oxidative aromatization of 2-aryloxy-
cyclohex-2-en-1-ones to 2-aryloxyphenols. DDQ can
be activated by Brønsted acids like concd. HCl, concd.
H2SO4, and TsOH, but these acids are corrosive.
Replacement of these acids by solid acids is always
desirable.
OH
Cl
OH
O
O
Cl
Cl
I
II
OH
O
O
CO2H
H2N
CO2H
Herein we report for the first time the use of
a combination of DDQ and a solid acid, Amberlyst-15,
for efficient and metal-free oxidative aromatization
of 2-aryloxycyclohexenones to 2-aryloxyphenols.
Amberlyst-15 has been recovered and recycled suc-
cessfully. The reaction conditions are mild, and 2-aryl-
oxyphenols are obtained in good yield. 2-Aryloxycy-
clohex-2-en-1-ones Va–Vj were prepared by ring
opening of 2,3-epoxycyclohexanone with phenols
using K2CO3 in acetonitrile under reflux.
NH2
III
IV
In spite of their tremendous importance in medici-
nal chemistry, much less attention was given for their
efficient synthesis. Known syntheses of 2-aryloxy-
phenols can be broadly classified into three categories
such as metal-catalyzed couplings [8–11], condensa-
tion of phenols [12, 13], and oxidative aromatization of
2-aryloxycyclohex-2-en-1-ones using metals like cop-
per [14], palladium [15], and vanadium [16]. All the
Oxidative aromatization was attempted in the pres-
ence of various well known oxidants. Oxidative aro-
* The text was submitted by the authors in English.
1301

JADHAV, SAMANT
1302
Scheme 1.
O
OH
DDQ, Amberlyst-15
dioxane
O
O
R
R
Va–Vj
VIa–VIj
For substituents R, see Table 2.
matization of 2-phenoxycyclohex-2-en-1-one (Va,
R1 = R2 = H) with iodine in MeOH under reflux
afforded 2-phenoxyphenol (VIa, R1 = R2 = H) only in
10% yield among other products (Table 1, run no. 1).
Compound Va was also treated with iodine in aprotic
solvents like acetonitrile both at room temperature and
under reflux, but no desired phenoxyphenol VIa was
formed, and the starting material was recovered in
good yield. The reaction of Va with CuBr2/LiBr in
dimethylformamide at 90°C (10 h) afforded 30% of
VIa (Table 1, run no. 2) as reported by Bondon et al.
[14]. The reaction of Va with palladium on carbon [19]
in ethylene glycol under reflux (2 h) gave VIa in
10% yield together with some unidentified products
(Table 1, run no. 3). No compound VIa was obtained
in the reaction of Va with o-iodoxybenzoic acid (IBX)
[20] at room temperature to 80°C, and initial cyclohex-
enone Va was recovered almost completely (Table 1,
run no. 4). The use of excess IBX up to 4.0 equiv was
also inefficient for the oxidative aromatization of Va
(Table 1, run no. 5).
(Table 1, no. 6), and the initial compound remained
almost unchanged. Since DDQ alone was inefficient
for the oxidative aromatization, some additives were
tried. The reaction of Va with DDQ in presence of
tert-butyl(chloro)dimethylsilane (TBDMS-Cl) [21] in
methylene chloride at room temperature for 12 h
(Table 1, run no. 7) resulted in complete conversion of
the substrate, but a mixture containing a number of
products was obtained. Compound VIa was not
formed when a catalytic amount of concentrated aque-
ous HCl was added to the reaction mixture in dioxane
(Table 1, run no. 8), at room temperature or under
reflux. Likewise, the reaction of cyclohexenone Va
with DDQ (1.0 equiv) in the presence of Amberlyst-15
(100 wt %) in dioxane at room temperature (Table 1,
run no. 9) afforded no product VIa. Interestingly, in
the reaction of Va with DDQ (1.0 equiv) at 90°C we
isolated 50% of VIa (Table 1, run no. 10) and 40% of
Va was recovered. The reaction of Va with DDQ
(1.0 equiv) in presence of Amberlyst-15(100 wt %) in
dioxane under reflux gave only 20% of VIa (Table 1,
run no. 11) and some unidentified products. This
result showed that the reaction temperature was critical
In our first experiments, the reaction of Va with
DDQ in boiling dioxane afforded no phenol VIa
Table 1. Oxidative aromatization of 2-phenoxycyclohex-2-en-1-one (Va) to 2-phenoxyphenol (VIa)
Run no.
Reagent (equiv)
Additive (equiv)
Solvent
MeOH
Temperature, °C Time, h Yield,a %
01
02
03
04
05
06
07
08
09
10
11
12
Iodine (1.0)
CuBr2 (1.0)
10% Pd/C (10 wt. %)
IBX (2.0)
–
68
90
02
10
02
12
12
12
12
12
12
12
12
10
10
30
LiBr (1.0)
DMF
–
Ethylene glycol
DMSO
Reflux
80
10
–
NR
NR
NR
NR
NR
NR
50
IBX (4.0)
–
DMSO
80
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.2)
–
Dioxane
CH2Cl2
Reflux
25
TBDMS-Cl (1.0)
HCl (0.1 mL)
Dioxane
Reflux
25
Amberylst-15 (100 wt %) Dioxane
Amberylst-15 (100 wt %) Dioxane
Amberlyst-15 (100 wt %) Dioxane
Amberlyst-15 (100 wt %) Dioxane
90
1010
90
20
81
a
Yield of the isolated product; NR stands for no reaction.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 9 2014

METAL-FREE OXIDATIVE AROMATIZATION OF 2-ARYLOXYCYCLOHEX-2-EN-1-ONES
1303
Table 2. Oxidative aromatization of 2-aryloxycyclohex-2-
en-1-ones Va–Vj to 2-aryloxyphenols VIa–VIj with DDQ
in dioxane in the presence of Amberlyst-15a
and that better result was obtained at 90°C. Using
a slight excess of DDQ (1.2 equiv) in dioxane at 90°C
we succeeded in isolating phenol VIa in 81% yield
(Table 1, run no. 12).
Initial
comp. no.
Reaction
time, h
Product
R
(yield,b %)
It should be noted that Amberlyst-15 can be reused
up to 2 cycles. We also studied the effect of solvent
on the oxidative aromatization of Va to VIa with
DDQ (1.2 equiv) in the presence of Amberlyst-15
(100 wt %). Polar solvents like DMF, MeOH, and
AcOH did not ensure an appreciable increase in the
yield of VIa, whereas in nonpolar solvents like toluene
the yield was very low; thus, the use of dioxane was
highly beneficial.
H
10
11
11
12
10
10
08
12
10
81
75
75
71
77
77
78
73
79
Va
Vb
Vc
Vd
Ve
Vf
4-Me
4-t-Bu
4-OMe
4-Br
4-Cl
4-O2N
2-Cl
Vg
Vh
Vi
To establish the reaction scope, various 2-aryloxy-
cyclohex-2-en-1-ones were subjected to oxidative aro-
matization under the optimized conditions (Table 1,
run no. 12); the results are summarized in Table 2.
Substituents like halogen had no any effect on the
reaction. Electron-donating substituents like Me, t-Bu,
and OMe showed no appreciable effect on the yield of
the aromatization product. However, the reaction with
compound Vg having electron-withdrawing nitro
group required a shorter time with no significant effect
on the yield. The reaction was equally efficient with
ortho- (Vh) and ortho/para-substituted substrates (Vj,
Table 2).
3,4-Benzo
4-Cl-2-Me
12
75
Vj
a
Reaction conditions: V, 1.0 mmol; DDQ, 1.2 mmol; Amberlyst-
15, 100 wt %; dioxane, 4 mL; temperature 90°C.
Yield of the product isolated by column chromatography.
b
tron impact, 70 eV) were obtained on a Shimadzu
QP2010 mass spectrometer.
General procedure for the preparation of 2-aryl-
oxycyclohex-2-en-1-ones Va-Vj. The corresponding
phenol (1.5 mmol) and potassium carbonate (1.2 mmol)
were added to a solution of 2,3-epoxycyclohexan-1-
one (1.0 mmol) in 4 mL of acetonitrile, and the mix-
ture was heated for 12–18 h under reflux. When the
reaction was complete, the mixture was cooled to room
temperature, diluted with water, and extracted with
tert-butyl methyl ether (20×2 mL). The combined
extracts were washed with aqueous sodium hydroxide,
dried over anhydrous sodium sulfate, and evaporated
under reduced pressure, and the residue was purified
by column chromatography on silica gel using ethyl
acetate–petroleum ether (10:90 or 20:80) as eluent.
In conclusion, we have developed a metal-free
procedure for the oxidative aromatization of 2-aryloxy-
cylclohex-2-en-1-ones to 2-aryloxyphenols in good
yield using DDQ/Ambelyst-15. Amberlyst-15 was
recovered and recycled successfully. A number of
2-aryloxyphenols were prepared with good overall
yields by this procedure. The synthesis of various bio-
active molecules containing 2-aryloxyphenol moiety
using this methodology is under progress.
EXPERIMENTAL
General procedure for aromatization of 2-aryl-
oxycyclohex-2-en-1-ones Va-Vj. 2,3-Dichloro-5,6-di-
cyano-p-benzoquinone (DDQ, 1.2 mmol) and
Amberlyst-15 (100 wt %) were added to a solution of
compound Va–Vj (1.0 mmol) in dioxane (4 mL), and
the mixture was heated for 8–12 h at 90°C under nitro-
gen. When the reaction was complete, the mixture was
cooled to room temperature and filtered, the precipitate
was washed with methylene chloride, the filtrate was
combined with the washings and evaporated under
reduced pressure, and the residue was purified by
column chromatography on silica gel using ethyl
acetate–petroleum ether (10:90 or 20:80) as eluent.
All reactions were monitored by TLC using Merck
60F254 plates; spots were visualized by UV irradiation
or treatment with iodine vapor. Column chromatog-
raphy was performed on silica gel (60–120 mesh).
Petroleum ether boiling in the range 60–80°C and
1
acetonitrile of analytical grade were used. The H and
13C NMR spectra were recorded on Bruker Avance
1
instruments at 300 or 400 MHz for H and at 75 or
100 MHz for 13C using CDCl3 as solvent and tetra-
methylsilane (TMS) as internal standard. The IR spec-
tra were obtained on a Perkin Elmer Spectrum 100
spectrometer as neat liquids or KBr pellets. The melt-
ing points are not corrected. The mass spectra (elec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 9 2014

JADHAV, SAMANT
1304
1
2-Aryloxyphenols VIa–VIj were identified by IR,
IR spectrum (KBr): ν 3521 cm–1 (OH). H NMR spec-
1H NMR, and mass spectra.
trum (300 MHz), δ, ppm: 7.47 d (1H, Harom, J =
6.6 Hz), 7.00–7.22 m (5H, Harom), 6.76–6.99 m (2H,
2-Phenoxyphenol (VIa) [12]. mp 104–105°C; pub-
lished data [12]: mp 104.5–106°C; Rf 0.58 (hereinafter,
hexane–ethyl acetate, 8 : 2). IR spectrum (KBr):
H
arom), 5.65 br.s (1H, OH). Mass spectrum:
m/z 220/222 (3:1) [M]+.
1
ν 3430 cm–1 (OH). H NMR spectrum (300 MHz), δ,
2-(Naphthalen-2-yloxy)phenol (VIi) [7]. mp 104–
105°C; published data [7]: mp 105–106°C; Rf 0.62. IR
spectrum (KBr): ν 3604 cm–1 (OH). 1H NMR spectrum
(300 MHz), δ, ppm: 7.82–7.86 m (2H, Harom), 7.70 d
(1H, Harom, J = 8.1 Hz), 7.39–7.49 m (1H, Harom), 7.31–
7.32 m (3H, Harom), 6.84–7.10 m (4H, Harom), 5.63 br.s
(1H, OH). Mass spectrum: m/z 236 [M]+.
2-(2-Chloro-4-methylphenoxy)phenol (VIj).
Rf 0.64. IR spectrum (neat): ν 3522 cm–1 (OH).
1H NMR spectrum (400 MHz), δ, ppm 7.24–7.26 m
(1H, Harom), 7.12 d (1H, Harom, J = 6.4 Hz), 6.98–
7.05 m (2H, Harom), 6.80 m (2H, Harom), 6.65 d (1H,
ppm: 7.13 m (2H, Harom), 7.01–7.09 m (5H, Harom),
6.80–6.90 m (2H, Harom), 5.52 br.s (1H, OH). Mass
spectrum: m/z 186 [M]+.
2-(4-Methylphenoxy)phenol (VIb) [13]. mp 58–
60°C; published data [13]: mp 61.5–62°C; Rf 0.60. IR
spectrum (KBr): ν 3454 cm–1 (OH). 1H NMR spectrum
(300 MHz), δ, ppm: 7.13–7.16 d (2H, Harom, J =
8.4 Hz), 7.01–7.05 m (2H, Harom), 6.91–6.98 m (2H,
Harom), 6.78–6.85 m (2H, Harom), 5.61 s (1H, OH),
2.33 s (3H, CH3). Mass spectrum: m/z 200 [M]+.
2-(4-tert-Butylphenoxy)phenol (VIc) [12]. Rf 0.62.
1
IR spectrum (neat): ν 3483 cm–1 (OH). H NMR spec-
H
arom, J = 8.0 Hz), 5.59 s (1H, OH), 2.25 s (3H, CH3).
13C NMR spectrum (100 MHz), δC, ppm: 152.85
(C–O), 146.75 (C–O), 144.17 (C–O), 131.42 (C–Cl),
131.40 (CCH3); 129.26, 127.30, 124.29, 120.75,
120.01, 116.88, 116.18 (Carom); 16.17 (CH3). Mass
spectrum: m/z 234/236 (3:1) [M]+.
trum (300 MHz), δ, ppm: 7.35 d (2H, Harom, J =
8.7 Hz), 6.82–7.04 m (6H, Harom), 5.59 s (1H, OH),
1.32 s (9H, t-Bu). Mass spectrum: m/z 242 [M]+.
2-(4-Methoxyphenoxy)phenol (VId) [12]. mp 76–
77°C; published data [12]: mp 76.5–77°C; Rf 0.55. IR
spectrum (KBr): ν 3454 cm–1 (OH). 1H NMR spectrum
(300 MHz), δ, ppm: 6.99–7.04 m (4H, Harom), 6.97–
6.99 m (2H, Harom), 6.75–6.79 m (2H, Harom), 5.41 br.s
(1H, OH), 3.80 s (3H, OCH3). Mass spectrum:
m/z 216 [M]+.
B.G. Jadhav is grateful to the University Grants
Commission (UGC), New Delhi, for a fellowship
under UGC-SAP DRS-I program.
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