IBS-catalyzed regioselective oxidation of phenols to 1,2-quinones with oxone

Article abstract of DOI:10.3390/molecules17078604

We have developed the first example of hypervalent iodine(V)-catalyzed regioselective oxidation of phenols to o-quinones. Various phenols could be oxidized to the corresponding o-quinones in good to excellent yields using catalytic amounts of sodium salts of 2-iodobenzenesulfonic acids (pre-IBSes) and stoichiometric amounts of Oxone as a co-oxidant under mild conditions. The reaction rate of IBS-catalyzed oxidation under nonaqueous conditions was further accelerated in the presence of an inorganic base such as potassium carbonate (K2CO3), a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate (nBu4NHSO4), and a dehydrating agent such as anhydrous sodium sulfate (Na2SO4).

Full text of DOI:10.3390/molecules17078604

Molecules 2012, 17, 8604-8616; doi:10.3390/molecules17078604
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
IBS-Catalyzed Regioselective Oxidation of Phenols to
1,2-Quinones with Oxone®
Muhammet Uyanik 1, Tatsuya Mutsuga 1 and Kazuaki Ishihara 1,2,
*
1
Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8603, Japan
Japan Science and Technology Agency (JST), CREST, Nagoya University, Furo-cho, Chikusa,
Nagoya 464-8603, Japan
2
* Author to whom correspondence should be addressed; E-Mail: ishihara@cc.nagoya-u.ac.jp;
Tel.: +81-52-789-3331; Fax: +81-52-789-3222.
Received: 25 June 2012; in revised form: 6 July 2012 / Accepted: 12 July 2012 /
Published: 18 July 2012
Abstract: We have developed the first example of hypervalent iodine(V)-catalyzed
regioselective oxidation of phenols to o-quinones. Various phenols could be oxidized to
the corresponding o-quinones in good to excellent yields using catalytic amounts of
sodium salts of 2-iodobenzenesulfonic acids (pre-IBSes) and stoichiometric amounts of
Oxone® as a co-oxidant under mild conditions. The reaction rate of IBS-catalyzed
oxidation under nonaqueous conditions was further accelerated in the presence of an
inorganic base such as potassium carbonate (K2CO3), a phase transfer catalyst such as
tetrabutylammonium hydrogen sulfate (nBu4NHSO4), and a dehydrating agent such as
anhydrous sodium sulfate (Na2SO4).
Keywords: oxidation; phenol; o-quinone; 2-iodoxybenzenesulfonic acid (IBS); Oxone®
1. Introduction
o-Quinones are useful synthetic intermediates for the synthesis of medicinally and biologically
important compounds [1–11]. To date, numerous methods have been reported for the preparation of
p-quinones by the oxidation of phenols or their derivatives [12–14]. For instance, the oxidation of
phenols with Fremy’s radical [15], MeReO3 [16], dimethyldioxirane [17], or benzeneseleninic
anhydride [18] mostly gives p-quinones, unless blocked by a substituent. However, there have been
only a few studies on the direct conversion of a phenol into an o-quinone. In 2002, Pettus and colleagues

Molecules 2012, 17
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reported the regioselective oxidation of phenols with stoichiometric amounts of 2-iodoxybenzoic acid
(IBX) to the o-quinones [19]. After Pettus’ pioneering findings, this method was applied to the
synthesis of biologically active compounds such as catecholestrogen [20], catecholamine [21],
hydroxytyrosol [22], and flavonoid [23] derivatives. In 2010, Harvey and colleagues reported the
regiospecific oxidation of polycyclic aromatic phenols to quinones using hypervalent iodine(III and V)
reagents [24]. Accordingly, oxidation with IBX in non-aqueous DMF gives o-quinones, while
oxidation with bis(trifluoro-acetoxy)iodobenzene in aqueous DMF gives p-quinones selectively.
The hypervalent organoiodine(III or V)-catalyzed oxidation reactions with co-oxidants have also
been extensively investigated over the past seven years [25–29]. From 2007 to 2009, Yakura and
colleagues reported that p-alkoxyphenols or p-arylphenols were oxidized to the corresponding
p-quinones or p-quinols, respectively, in excellent yields using catalytic amounts of 4-iodophenoxyacetic
acid with Oxone® (2KHSO5•KHSO4•K2SO4) as a co-oxidant in aqueous acetonitrile [30–32]. To the
best of our knowledge, however, there are no successful examples of a catalytic hypervalent iodine
system for the regio-selective oxidation of phenols to o-quinones.
We recently reported a highly efficient and chemoselective oxidation of various alcohols to
carbonyl compounds such as aldehydes, carboxylic acids, and ketones with powdered Oxone® in the
presence of catalytic amounts (1–5 mol%) of 2-iodobenzenesulfonic acids (pre-IBSes) or their sodium
salts (1a–c) under nonaqueous conditions (Scheme 1a) [33–36]. 2-Iodoxybenzenesulfonic acids
(IBSes) 2a–c as iodine(V), which are generated in situ from 1a–c and Oxone®, serve as the actual
catalysts for the oxidations (Scheme 1b) [33–36]. According to previous theoretical calculations [33],
the relatively ionic character of the intramolecular hypervalent iodine-OSO2 bond of IBS 2a lowers the
twisting barrier of the alkoxyperiodinane intermediate. In fact, 2a shows much more catalytic activity
than IBX [33]. The oxidation rate in 2a-catalyzed oxidation under nonaqueous conditions is further
accelerated by the use of powdered Oxone® due to its increased surface area. When Oxone® is used
under nonaqueous conditions, Oxone® wastes can be removed by simple filtration. Furthermore, we
developed the oxidative rearrangement of tertiary allylic alcohols to -disubstituted ,-unsaturated
ketones with Oxone® catalyzed by in situ-generated 5-Me-IBS (2b) (Scheme 1c) [37]. The addition of
inorganic bases such as K2CO3, and a phase transfer catalyst such as tetrabutylammonium hydrogen
sulfate (nBu4NHSO4), extended the substrate scope for oxidative rearrangement reactions. Recently, the
IBS/Oxone® catalytic oxidation system was applied to benzylic oxidation [38] and oxidation of fluorinated
alcohols [39]. As part of our continuing interest in the IBS-catalyzed oxidation system, we report here
the in situ-generated IBS-catalyzed regioselective oxidation of phenols to o-quinones with Oxone®.
Scheme 1. In situ generated IBS (2)-catalyzed selective oxidation of alcohols and
oxidative rearrangement of tertiary allylic alcohols with powdered Oxone® under
non-aqueous conditions.

Molecules 2012, 17
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Scheme 1. Cont.
2. Results and Discussion
Initially, we investigated the reactivity and regioselectivity of the oxidation of 1-naphthol (3a)
using conventional hypervalent catalysts under non-aqueous conditions (Table 1). A mixture of 3a,
powdered Oxone® (2 equiv.) and nBu4NHSO4 (10 mol%) as a solid-liquid phase transfer catalyst was
heated in ethyl acetate at 40 °C in the presence of 5 mol% of iodobenzene or Yakura’s pre-catalyst
(4-iodophenoxyacetic acid, 6) [30−32] (entries 2 and 3). However only trace amounts of the desired
products were detected, and more than 80% of 3a was recovered with small amounts of unidentified
side-products. The reaction was somewhat messy, and more than 80% of 3a was recovered.
Additionally, the use of pre-IBX (7) gave both 1,2-naphthoquinone (4a) and 1,4-naphthoquinone (5a)
each in 5% yield, and 80% of 3a was recovered (entry 4). In sharp contrast, and to our delight, when
pre-IBS (1a) was used, 3a was completely consumed in 11 h, and quinones 4a and 5a were obtained in
respective yields of 64% and 5% together with highly polar compounds (entry 5). As expected from
our previous works [33,37], the use of pre-5-Me-IBS (1b) or pre-4,5-Me2-IBS (1c) gave slightly better
results, and the former gave the best results (entries 6 and 7). Interestingly, when the oxidation was
conducted in aqueous acetonitrile, 5a was obtained selectively as a major product in 51% yield (entry 8).
We found that the carbon(1)-carbon(2) bond of o-quinone 4a was oxidatively cleaved under identical
aqueous conditions to highly polar compounds including trans-2-carboxycinnamic acid (8) [40] and
other minor unidentified compounds (Scheme 2). These results indicated that non-aqueous conditions
were essential for the preparation of o-quinones in high yields. According to our previous works, the
selective oxidation of acid-sensitive alcohols could be achieved in the presence of anhydrous sodium
sulfate as a dehydrating agent [33,37]. Additionally, the oxidation rate and selectivity could be further
accelerated with the use of additional base to buffer the acidity of the reaction mixture [37]. Based on
these previous findings, the reaction of 3a was carried out in the presence of 1 equiv. of potassium
carbonate and anhydrous sodium sulfate under the modified conditions in entry 6. Thus, 4a was
obtained in 78% yield after 1 h, when Oxone® and K2CO3 were sufficiently premixed in the presence
of anhydrous Na2SO4 in ethyl acetate at room temperature for 24 h before the addition of 2b, 3a, and

Molecules 2012, 17
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nBu4NHSO4 (entry 9). Notably, the use of nBu4NHSO4 was essential for the present oxidation, since
almost no reaction occurred in its absence (entry 10).
Table 1. Hypervalent iodine-catalyzed oxidation of 1-naphthol 3a.
Entry
Pre-cat. Additive (equiv.) Time (h)
4a, Yield (%) a
5a, Yield (%) a
1
2
3
4
5
–
–
–
–
–
–
–
–
24
24
24
24
11
8
trace b
trace b
trace b
5 b
trace b
PhI
6 f
7 g
1a
1b
1c
trace b
trace b
5 b
64
69
67
5
6
6
6
7
9
8 c
9 d
10 e
1b
1b
1b
–
3.5
1
24
trace b
78
51
K2CO3 (1)
K2CO3 (1)
6
trace b
trace b
a Isolated yield; b 1H-NMR analysis; c The reaction was performed in CH3CN-H2O (2:1, v/v) instead
of EtOAc; After a mixture of Oxone® and K2CO3 in ethyl acetate was vigorously stirred in the
d
e
presence of Na2SO4 for 24 h at room temperature, 1a, 3a and nBu4NHSO4 were added; In the
absence of nBu4NHSO4; f 6: 4-Iodophenoxyacetic acid; g 7: 2-Iodobenzoic acid.
Scheme 2. Oxidative carbon-carbon bond cleavage of 4a to dicarboxylic acid 8 under
aqueous conditions.
To explore the generality of the in situ-generated 5-Me-IBS-catalyzed oxidation of phenols with
Oxone®, various naphthols, phenanthrols, and phenols 3b–l were examined as substrates under the
optimized conditions: powdered Oxone® (2 equiv.) and potassium carbonate (1 equiv.) in ethyl acetate
were vigorously stirred at room temperature for 24 h in the presence of anhydrous sodium sulfate, and
then 1b (5 mol%), 3a and nBu4NHSO4 (10 mol%) were added and the resulting mixture was heated to
40 °C (Table 2). As expected, 4a was obtained in slightly better yield by the oxidation of 2-naphthol
3b than by the oxidation of 3a (Table 2, entry 1 versus Table 1, entry 9). 4-Bromo- or chloro-substituted
1-naphthols 3c and 3d gave the corresponding o-quinones in high yields (entries 2 and 3). Notably, the
desired 1,2-quinones were obtained as a major product under our catalytic conditions even with the
oxidation of 4-methoxy-1-naphthol (3e) and 4-methoxyphenol (3j) (entries 4 and 9). Accordingly, the
previous iodine(III)-mediated oxidation of para-alkoxy phenols gave 1,4-quinones exclusively [30–32].

Molecules 2012, 17
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Additionally, the oxidation of phenanthrols 3g and 3h gave the desired 1,2-quinones in excellent yields
(entries 6 and 7). These polycyclic aromatic quinones were obtained in only moderate yields by
stoichiometric oxidations with IBX [24]. The oxidation of 2,4-di-tert-butylphenol (3k) gave desired
o-quinone 4k in 73% yield after 24 h (entry 10). In contrast, the oxidation of 3-methoxy-1-naphthol
(3l) gave 1,4-quinone 5l rather than 1,2-quinone 4l as a major product (Scheme 3). Additionally, the
oxidation of 3l with Oxone® even in the absence of 1b also gave 5l selectively, but in lower yield
(63%) after 6 h.
Table 2. 5-Me-IBS-catalyzed oxidation of naphthols, phenanthrols and phenols 3 a.
Entry
3
4
Time (h)
Yield (%) b
1
4a
4
84
3b
2
3
4
3c (R = Cl)
3d (R = Br)
3e (R = OMe)
4c
4d
4e
5
3
2
80
75
50 c
5
4a
2
72
90
3f
6
2
3g
3h
4g
4h
7
2
97

Molecules 2012, 17
8609
Table 2. Cont.
Entry
3
4
Time (h)
Yield (%) b
8
5
63
3i
3j
3k
4i
4j
4k
9
5
66 d
10
24
73
a Reaction conditions: 3 (1 mmol), powdered Oxone® (2 mmol), K2CO3 (1 mmol), 1b (0.05 mmol),
nBu4NHSO4 (0.1 mmol), Na2SO4 (1 g), EtOAc (10 mL), 40 °C. Oxone® and K2CO3 were
pre-treated in EtOAc for 24 h at room temperature in the presence of anhydrous Na2SO4; b Isolated
yield; c 1,4-Naphthoquinone (5a) was obtained in 15% yield; d 2-tert-Butyl-1,4-quinone 5j obtained
in 16% yield.
Scheme 3. Oxidation of 3-methoxy-1-naphthol 3i.
Based on previous studies [24,33–37], a proposed reaction mechanism is depicted in Scheme 4.
In situ-generated IBS (2) reversibly combines with 3 to give IBS-phenol complex 10, which serves to
transfer oxygen from an iodoxy group (IV = O) to the ortho-site of the phenol through concerted
intramolecular [2,3]-rearrangement. During this process, the iodine(V) atom is concurrently reduced to
the iodine(III)-catechol complex 11, which gives o-quinones 4 and pre-IBS 1. The catalytic cycle of
IBS 2 can be accomplished by the regeneration of 2 through the successive oxidations of 1 and 9 with
tetrabutylammonium peroxymonosulfate, nBu4NHSO5, which can be generated in situ from KHSO5
and nBu4NHSO4.

Molecules 2012, 17
Scheme 4. Possible mechanism for the IBS-catalyzed oxidation of phenols.
8610
While, the reason for the para-selective oxidation of 3l is not yet clear, a plausible mechanism is
depicted in Scheme 5. The peroxo-IBS complex 12 might be generated reversibly in situ from IBS and
ammonium Oxone®. Electrophilic aromatic oxidation at the highly nucleophilic carbon(4) position of
3l with 12 gives 13, which easily tautomerizes to IBS-hydroquinone complex 14. Finally, the oxidation
of hydroquinone gives 1,4-quinone 5l and iodine(III) 9. Notably, 5l was also obtained by the oxidation
of 3l with only Oxone® (Scheme 3) [41]. The reactivity of Oxone® should be accelerated by
complexation with IBS [42]. Thus, the oxidation was faster and the chemical yield of 5l was higher in
the presence of IBS (Scheme 3).
Scheme 5. Possible mechanism for the para-selective oxidation of 3l.

Molecules 2012, 17
8611
3. Experimental
3.1. General
1
Infrared (IR) spectra were recorded on a Jasco FT/IR 460 plus spectrometer. H-NMR spectra
(400 MHz) and 13C-NMR spectra (100 MHz) were measured on a Jeol ECS-400 spectrometer at
ambient temperature. Data were recorded as follows: chemical shift in ppm from internal tetramethylsilane
on the  scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet), coupling
constant (Hz), integration, and assignment. Chemical shifts were recorded in ppm from the resonance
of the solvent used as the internal standard (deuterochloroform at 77.0 ppm). For thin-layer
chromatography (TLC) analysis throughout this work, Merck precoated TLC plates (silica gel 60 GF254
0.25 mm) were used. The products were purified by column chromatography on silica gel (E. Merck
Art. 9385). High-resolution mass spectral analysis (HRMS) and elemental analysis were performed at
the Chemical Instrument Center, Nagoya University. Pre-catalysts 1a–c were prepared according to
known procedures [33]. Additionally, 1a and 1b (as potassium salts) are also commercially available
from Junsei Chemical Japan, TCI and Sigma-Aldrich. Starting materials 3d [43], 3f [44], 3g [24], and
3l [45] were prepared according to known procedures. In experiments that required solvents, ethyl
acetate, acetonitrile, and nitromethane were purchased from Wako Pure Chemical Industries, Ltd. in
“anhydrous” form and used without any purification. Other simple chemicals were analytical-grade
and obtained commercially.
3.2. General Procedure for the Oxidation Phenol to Quinone
A mixture of powdered Oxone® (1.2 g, 2.0 mmol), potassium carbonate (0.14 g, 1.0 mmol) and
anhydrous sodium sulfate (1.0 g, dried by a heat-gun under vacuum before use), in ethyl acetate
(4.0 mL) was vigorously stirred at room temperature for 24 h. To the resulting mixture were added 3
(1.0 mmol), nBu4NHSO4 (34 mg, 0.10 mmol), 1b (17 mg, 0.050 mmol), and EtOAc (6.0 mL), and the
resulting mixture was stirred vigorously at 40 °C. The reaction was monitored by TLC analysis. After
the reaction was completed, the reaction mixture was cooled to room temperature and the solids were
filtered-off and washed with EtOAc. The filtrate was washed with water, and the aqueous layers were
extracted with EtOAc. The combined organic layers were washed by water and brine, and dried over
anhydrous Na2SO4. The solvents were removed under vacuo, and the residue was purified by column
chromatography on silica gel (hexane-EtOAc as eluent) to give the corresponding quinones 4 or 5.
1,2-Naphthoquinone (4a) [46]. Brown solid; TLC, Rf = 0.21 (hexane–EtOAc = 4:1); 1H-NMR (CDCl3)
 6.45 (d, J = 10 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.53 (dd, J = 6.4, 7.8 Hz,
1H), 7.66 (ddd, J = 1.4, 5.9, 6.4 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H); 13C-NMR (CDCl3)  128.0, 130.0,
130.3, 131.0, 131.7, 134.9, 136.0, 145.6, 179.0, 181.0.
1,4-Naphthoquinone (5a) [47]. Yellow solid; TLC, Rf = 0.41 (hexane–EtOAc = 4:1); 1H-NMR (CDCl3)
 6.99 (s, 1H), 7.77 (m, 2H), 8.10 (m, 2H); 13C-NMR (CDCl3)  126.6, 132.0, 134.1, 138.8, 185.2.
trans-2-Carboxycinnamic acid (8) [40]. Pale yellow solid; 1H-NMR (DMSO-d6)  6.43 (d, J = 16 Hz,
1H), 7.51 (t, J = 7.5 Hz, 1H), 7.60 (t, J = 6.8 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.88 (dd, J = 0.9, 7.8 Hz,

Molecules 2012, 17
8612
1H), 8.31 (d, J = 16 Hz, 1H), 13C-NMR (DMSO-d6)  121.4, 127.8, 129.8, 130.4, 131.1, 132.2, 134.9,
142.6, 167.5, 168.2.
4-Chloro-1,2-naphthoquinone (4c). Brown solid; TLC, Rf = 0.58 (hexane–EtOAc = 1:1); IR (KBr)
1,658, 1,582, 1,322, 1,287, 1,242, 936, 769 cm−1; 1H-NMR (CDCl3)  6.76 (s, 1H), 7.63 (t, J = 7.8 Hz,
13
1H), 7.77 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H); C-NMR (CDCl3)
 127.7, 128.0, 130.2, 130.6, 132.2, 132.7, 135.9, 152.8, 178.1, 178.4; HRMS (FAB+) m/z calcd for
C11H14O3 (M+H) 193.0056, found 193.0054.
4-Bromo-1,2-naphthoquinone (4d) [48]. Brown solid; TLC, Rf = 0.62 (hexane–EtOAc = 1:1); 1H-NMR
(CDCl3)  7.05 (s, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.77 (t, J = 7.3 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H),
8.15 (d, J = 7.3 Hz, 1H); 13C-NMR (CDCl3)  130.1, 130.6, 130.9, 132.1, 133.6, 136.0, 145.9, 178.2.
4-Methoxy-1,2-naphthoquinone (4e) [49]. Yellow solid; TLC, Rf = 029 (hexane–EtOAc = 1:1);
1H-NMR (CDCl3)  4.08 (s, 3H), 5.99 (s, 1H), 7.59 (dd, J = 7.3, 7.8 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H),
13
7.87 (d, J = 8.2 Hz, 1H), 8.13 (d, J = 7.3 Hz, 1H); C-NMR (CDCl3)  57.0, 103.2, 124.9, 129.2,
130.4, 131.7, 132.1, 135.1, 168.8, 179.5, 179.6.
1
1,2-Phenanthraquinone (4g) [24]. Red solid; TLC, Rf = 0.54 (hexane–EtOAc = 1:1); H-NMR
(CDCl3)  6.59 (d, J = 10 Hz, 2H), 7.70 (m, 2H), 7.91 (m, 1H), 7.98 (d, J = 8.2 Hz, 1H), 8.17 (d,
13
J = 8.2 Hz, 1H), 8.31 (m, 2H); C-NMR (CDCl3)  123.6, 124.4, 127.7, 128.6, 129.4, 129.7, 129.8,
131.4, 132.0, 137.3, 139.6, 179.5, 180.8.
1
9,10-Phenanthraquinone (4h) [50]. Yellow solid; TLC, Rf = 0.50 (hexane–EtOAc = 1:1); H-NMR
(CDCl3)  7.47 (dd, J = 7.3, 7.8 Hz, 2H), 7.72 (ddd, J = 1.4, 6.9, 7.3 Hz, 2H), 8.03 (d, J = 8.3 Hz, 2H),
8.20 (dd, J = 1.4, 6.4 Hz, 2H); 13C-NMR (CDCl3)  124.1, 129.7, 130.5, 131.0, 135.9, 136.2, 180.3.
4-tert-Butyl-1,2-benzoquinone (4i) [51]. Brown solid; TLC, Rf = 0.38 (hexane–EtOAc = 1:1); 1H-NMR
(CDCl3)  1.24 (s, 9H), 6.29 (d, J = 2.2 Hz, 1H), 6.40 (d, J = 10 Hz, 1H), 7.19 (dd, J = 2.5, 10 Hz, 1H);
13C-NMR (DMSO-d6)  27.4, 35.3, 123.2, 129.4, 140.2 161.5, 180.0.
3-tert-Butyl-5-methoxy-1,2-benzoquinone (4j). Red solid; TLC, Rf = 0.42 (hexane–EtOAc = 1:1);
1
IR (KBr) 1,649, 1,630, 1,589, 1,440, 1,367, 1,228, 1,007, 900, 783; H-NMR (CDCl3)  1.26 (s, 9H),
3.84 (s, 3H), 5.73 (d, J = 2.7 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H); 13C-NMR (CDCl3)  28.9, 35.2 56.7,
101.0, 133.0, 151.5, 170.0, 178.6, 179.9; HRMS (FAB+) m/z calcd for C11H14O3 (M+H) 195.1021,
found 195.1013.
2-tert-Butyl-1,4-benzoquinone (5j) [52]. Brown solid; TLC, Rf = 0.71 (hexane–EtOAc = 4:1); 1H-NMR
13
(CDCl3, 400 MHz)  1.30 (s, 9H), 6.61 (d, J = 1.4 Hz, 1H), 6.69 (d, J = 1.4 Hz, 2H); C-NMR
(CDCl3, 100 MHz)  29.2, 35.3, 131.6, 135.0, 138.7, 156.1, 188.5.
3,5-Di-tert-Butyl-1,2-benzoquinone (4k) [52]. Brown solid; TLC, Rf = 0.71 (hexane–EtOAc = 1:1);
1H-NMR (CDCl3)  1.23 (s, 9H), 1.27 (s, 9H), 6.22 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H);
13C-NMR (CDCl3)  28.0, 29.3, 35.6, 36.1, 122.2, 133.6, 150.0, 163.4, 180.2, 181.2.

Molecules 2012, 17
8613
3-Methoxy-1,4-naphthoquinone (5l) [53]. Yellow solid; TLC, Rf = 0.46 (hexane–EtOAc = 1:1);
13
1H-NMR (CDCl3)  3.90 (s, 3H), 6.17 (s, 1H); C-NMR (CDCl3)  56.6, 110.0, 126.3, 126.8, 131.1,
132.1, 133.4, 134.5, 160.5, 180.2, 185.0.
4. Conclusions
We have demonstrated the in situ-generated IBS-catalyzed regioselective oxidation of phenols to
o-quinones with Oxone®. The reaction rate is accelerated with the use of inorganic bases such as
K2CO3, a phase transfer catalyst such as tetrabutylammonium hydrogen sulfate (nBu4NHSO4), and
dehydrating agent such as Na2SO4. Various phenols are oxidized to the corresponding o-quinones in
good to excellent yields. To the best of our knowledge, this is the first example of the hypervalent
iodine-catalyzed oxidation of phenols to o-quinones.
Acknowledgments
Financial support for this project was provided in part by JSPS.KAKENHI (24245020, 22750087).
T.M. thanks “the Nagoya University IGER Program in Green Natural Sciences for Leading Graduate
Schools from MEXT” for a research fellowship.
References
1. Quideau, S.; Pouységu, L. Synthetic uses of orthoquinone monoketals and their orthoquinols
variants. A review. Org. Prep. Proced. Int. 1999, 31, 617–680.
2. Scott, J.D.; Williams, R.M. Chemistry and biology of the tetrahydroisoquinoline antitumor
antibiotics. Chem. Rev. 2002, 102, 1669–1730.
3. Magdziak, D.; Meek, S.J.; Pettus, T.R.R. Cyclohexadienone ketals and quinols: Four building
blocks potentially useful for enantioselective synthesis. Chem. Rev. 2004, 104, 1383–1430.
4. Pouységu, L.; Deffieux, D.; Quideau, S. Hypervalent iodine-mediated phenol dearomatization in
natural product synthesis. Tetrahedron 2010, 66, 2235–2261.
5. Danishefsky, S.J.; Mazza, S.; McCurry, P. Diels-Alder reactions of o-benzoquinones. J. Org.
Chem. 1974, 39, 3610–3611.
6. Omote, Y.; Tomotake, A.; Kashima, C. Reaction of 1,2-benzoquinones with enamines. J. Chem.
Soc. Perkin Trans. 1 1988, 2, 151−156.
7. Nair, V.; Maliakal, D.; Treesa, P.M.; Rath, N.P.; Eigendorf, G.K. [4+2] Cycloaddition reactions
of o-benzoquinones with styrenes: A facile synthesis of bicyclo[2.2.2]octenediones. Synthesis
2000, 850−856.
8. Stavber, S.; Zupan, M. The effect of heteroatoms on the reactions of organic molecules with
cesium fluoroxysulphate. Tetrahedron 1992, 48, 5875–5882.
9. Osman, F.H.; Abd El-Rahman, N.M.; El-Samahy, F.A. Reaction of phosphonium ylides with
4-triphenylmethyl-1,2-benzoquinone. Tetrahedron 1993, 49, 8691−8704.
10. Viallon, L.; Reinaud, O.; Capdevielle, P.; Maumy, M. Synthesis of new 4-alkylamino-5-methoxy-
2H-pyran-2-ones. Tetrahedron Lett. 1995, 36, 6669−6672.

Molecules 2012, 17
8614
11. Takuwa, A.; Kai, R.; Kawasaki, K.I.; Nishigaichi, Y.; Iwamoto, H. New formal [3+2]
photoaddition of vinyl ethers to o-benzoquinones. J. Chem. Soc. Chem. Commun. 1996, 703−704.
12. Dudfield, P.J. Synthesis of quinones. In Comprehensive Organic Synthesis; Trost, B.M.,
Flemming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Volume 7, pp. 345–356.
13. Gallagher, P.T. The synthesis of quinones. Contemp. Org. Synth. 1996, 3, 433−446.
14. Akai, S.; Kita, Y. Review of recent progress in the synthesis of p-quinones and p-dihydroquinones
through oxidation of phenol derivatives. Org. Prep. Proced. Int. 1998, 30, 603−629.
15. Deya, P.M.; Dopico, M.; Raso, A.G.; Morey, J.; Saa, J.M. On the regioselectivity of the Fremy’s
salt oxidation of phenols. Tetrahedron 1987, 43, 3523−3532.
16. Saladino, R.; Neri, V.; Mincione, E.; Marini, S.; Coletta, M.; Fiorucci, C.; Filippone, P. A new
and efficient synthesis of ortho- and para-benzoquinones of cardanol derivatives by the catalytic
system MeReO3-H2O2. J. Chem. Soc. Perkin Trans. 1 2000, 4, 581−586.
17. Crandall, J.K.; Zucco, M.; Kirsch, R.S.; Coppert, D.M. The formation of orthoquinones in the
dimethyldioxirane oxidation of phenols. Tetrahedron Lett. 1991, 32, 5441−5444.
18. Barton, D.H.R.; Finet, J.P.; Thomas, M. Comparative oxidation of phenols with benzeneseleninic
anhydride and with benzeneseleninic acid. Tetrahedron 1988, 44, 6397−6406.
19. Magdziak, D.; Rodriguez, A.A.; van de Water, R.W.; Pettus, T.R.R. Regioselective oxidation of
phenols to o-quinones with o-iodoxybenzoic acid (IBX). Org. Lett. 2002, 4, 285−288.
20. Pezzella, A.; Lista, L.; Napolitano, A.; d’Ischia, M. An expedient one-pot entry to catecholestrogens
and other catechol compounds via IBX-mediated phenolic oxygenation. Tetrahedron Lett. 2005,
46, 3541–3544.
21. Bernini, R.; Crisante, F.; Barontini, M.; Fabrizi, G. A new and efficient route for the synthesis of
naturally occurring catecholamines. Synthesis 2009, 2009, 3838–3842.
22. Bernini, R.; Mincione, E.; Crisante, F.; Barontini, M.; Fabrizi, G. A novel use of the recyclable
polymer-supported IBX: An efficient chemoselective and regioselective oxidation of phenolic
compounds. The case of hydroxytyrosol derivatives. Tetrahedron Lett. 2009, 50, 1307–1310.
23. Barontini, M.; Bernini, R.; Crisante, F.; Fabrizi, G. Selective and efficient oxidative modifications
of flavonoids with 2-iodoxybenzoic acid (IBX). Tetrahedron 2010, 66, 6047–6053.
24. Wu, A.; Duan, Y.; Xu, D.; Penning, T.M.; Harvey, R.G. Regiospecific oxidation of polycyclic
aromatic phenols to quinones by hypervalent iodine reagents. Tetrahedron 2010, 66, 2111–2118.
25. Richardson, R.D.; Wirth, T. Hypervalent iodine goes catalytic. Angew. Chem. Int. Ed. Engl. 2006,
45, 4402–4404.
26. Zhdankin, V.V.; Stang, P.J. Chemistry of polyvalent iodine. Chem. Rev. 2008, 108, 5299–5358.
27. Ochiai, M.; Miyamoto, K. Catalytic version of and reuse in hypervalent organo-λ3- and -λ5-iodane
oxidation. Eur. J. Org. Chem. 2008, 2008, 4229–4239.
28. Dohi, T.; Kita, Y. Hypervalent iodine reagents as a new entrance to organocatalysts. Chem.
Commun. 2009, 2009, 2073–2085.
29. Uyanik, M.; Ishihara, K. Catalysis with in situ-generated (hypo)iodite ions for oxidative coupling
reactions ChemCatChem 2012, 4, 177–185.
30. Yakura, T.; Konishi, T. A novel catalytic hypervalent iodine oxidation of p-alkoxyphenols to
p-quinones using 4-iodophenoxyacetic acid and Oxone®. Synlett 2007, 2007, 765–768.

Molecules 2012, 17
8615
31. Yakura, T.; Yamauchi, Y.; Tian, Y.; Omoto, M. Catalytic hypervalent iodine oxidation of
p-dialkoxybenzenes to p-quinones using 4-iodophenoxyacetic acid and Oxone®. Chem. Pharm. Bull.
2008, 56, 1632–1634.
32. Yakura, T.; Tian, Y.; Yamauchi, Y.; Omoto, M.; Konishi, T. Catalytic hypervalent iodine
oxidation using 4-iodophenoxyacetic acid and Oxone®: Oxidation of p-alkoxyphenols to
p-benzoquinones. Chem. Pharm. Bull. 2009, 57, 252−256.
33. Uyanik, M.; Akakura, M.; Ishihara, K. 2-Iodoxybenzenesulfonic acid as an extremely active
catalyst for the selective oxidation of alcohols to aldehydes, ketones, carboxylic acids, and enones
with Oxone®. J. Am. Chem. Soc. 2009, 131, 251–262.
34. Uyanik, M.; Ishihara, K. Hypervalent iodine-mediated oxidation of alcohols. Chem. Commun.
2009, 2009, 2086–2099.
35. Uyanik, M.; Ishihara, K. 2-Iodoxybenzenesulfonic acid (IBS) catalyzed oxidation of alcohols.
Aldrichim. Acta 2010, 43, 83–91.
36. Uyanik, M.; Ishihara, K. 2-Iodoxy-5-methylbenzenesulfonic acid-catalyzed selective oxidation
of 4-bromobenzyl alcohol to 4-bromobenzaldehyde or 4-bromobenzoic acid with Oxone®.
Org. Syn. 2012, 89, 105–114.
37. Uyanik, M.; Fukatsu, R.; Ishihara, K. IBS-catalyzed oxidative rearrangement of tertiary allylic
alcohols to enones with Oxone®. Org. Lett. 2009, 11, 3470–3473.
38. Cui, L.C.; Liu, K.; Zhang, C. Effective oxidation of benzylic and alkane C-H bonds catalyzed by
sodium o-iodobenzenesulfonate with Oxone® as a terminal oxidant under phase-transfer
conditions. Org. Biomol. Chem. 2011, 9, 2258–2265.
39. Tanaka, Y.; Ishihara, T.; Konno, T. A new entry for the oxidation of fluoroalkyl-substituted
methanol derivatives: Scope and limitation of the organoiodine(V) reagent-catalyzed oxidation.
J. Fluor. Chem. 2012, 137, 99–104.
40. Giurg, M.; Syper, L.; Mlochowski, J. Hydrogen peroxide oxidation of naphthalene derivatives
catalyzed by poly(bis-1,2-diphenylene) diselenide. Pol. J. Chem. 2004, 78, 231–238.
41. Carreño, M.C.; Gonzáles-López, M.; Urbano, A. Oxidative de-aromatization of para-alkyl
phenols into para-peroxyquinols and para-quinols mediated by Oxone® as a source of singlet
oxygen. Angew. Chem. Int. Ed. Engl. 2006, 45, 2737–2741.
42. Ojha, L.R.; Kudugunti, S.; Maddukuri, P.P.; Kommareddy, A.; Gunna, M.R.; Dokuparthi, P.;
Gottam, H.B.; Botha, K.K.; Parapati, D.R.; Vinod, T.K. Benzylic carbon oxidation by an in situ
formed o-iodoxybenzoic acid (IBX) derivative. Synlett 2009, 2009, 117.
43. Ding, Z.; Xue, S.; Wulff, W.D. A succinct synthesis of the vaulted biaryl kigand vanol via a
dienone-phenol rearrangement. Chem. Asian J. 2011, 6, 2130–2146.
44. Ludwik, S. The Baeyer-Villiger oxidation of aromatic aldehydes and ketones with hydrogen
peroxide catalyzed by selenium compounds. A convenient method for the preparation of phenols.
Synthesis 1989, 1989, 167–172.
45. Bell, K.H.; McCaffery, L.F. Regioselective monomethylation of unsymmetrical naphthalenediols
with methanolic hydrogen chloride. Aust. J. Chem. 1993, 46, 731–737.
46. Crich, D.; Zou, Y. Catalytic oxidation adjacent to carbonyl groups and at benzylic positions with a
fluorous seleninic acid in the presence of iodoxybenzene. J. Org. Chem. 2005, 70, 3309–3311.

Molecules 2012, 17
8616
47. Suchard, O.; Kane, R.; Roe, B.J.; Zimmermann, E.; Jung, C.; Waske, P.A.; Mattay, J.;
Oelgemöller, M. Photooxygenations of 1-naphthols: An environmentally friendly access to
1,4-naphthoquinones. Tetrahedron 2006, 62, 1467–1473.
48. Perumal, P.T.; Bhatt, M.V. Oxidation of halophenols and highly substituted phenols with lead(IV)
acetate. Synthesis 1980, 1980, 943–945.
49. Ogata, T.; Okamoto, I.; Kotani, E.; Takeya, T. Biomimetic synthesis of the dinaphthofuranquinone
violet-quinone, utilizing oxidative dimerization with the ZrO2/O2 system. Tetrahedron 2004, 60,
3941–3948.
50. Bernd, P.; Meike, N.; Anja, P. The acid accelerated ruthenium-catalyzed dihydroxylation. Scope
and limitations. Org. Biomol. Chem. 2004, 2, 1116–1124.
51. Ratnikov, M.O.; Farkas, L.E.; McLaughlin, E.C.; Chiou, G.; Choi, H.; El-Khalafy, S.H.;
Doyle, M.P. Dirhodium-catalyzed phenol and aniline oxidations with T-HYDRO. Substrate scope
and mechanism of oxidation. J. Org. Chem. 2011, 76, 2585–2593.
52. Miyamura, H.; Shiramizu, M.; Matsubara, R.; Kobayashi, S. Aerobic Oxidation of Hydroquinone
Derivatives Catalyzed by Polymer-Incarcerated Platinum Catalyst. Angew. Chem. Int. Ed. Engl.
2008, 47, 8093–8095.
53. Lebrasseur, N.; Fan, G.J.; Oxoby, M.; Looney, M.A.; Quideau, S. 3-Iodane-mediated arenol
dearomatization. Synthesis of five-membered ring-containing analogues of the aquayamycin ABC
tricyclic unit and novel access to the apoptosis inducer menadione. Tetrahedron 2005, 61, 1551–1562.
Sample Availability: Samples of the compounds 1a–c are available from the authors.
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