Efficient ortho-oxidation of phenols with diacyl peroxides

Article abstract of DOI:10.1248/cpb.56.239

A stable symmetric diacyl peroxide, m-chlorobenzoyl peroxide (mCBPO), and an asymmetric diacyl peroxide, chloroacetyl m-chlorobenzoyl peroxide (CAMCBPO), were synthesized from m-chloroperbenzoic acid. Both peroxides oxidized phenols selectively at the ortho position predoninantly. CAMCBPO gave para-oxidized compounds as minor products from some phenols. The improvement of the yield of ortho-oxidation of phenols with mCBPO was also reported.

Full text of DOI:10.1248/cpb.56.239

March 2008
Chem. Pharm. Bull. 56(3) 239—242 (2008)
239
Efficient ortho-Oxidation of Phenols with Diacyl Peroxides
Masahiro TADA,* Risa ISHIGURO, and Ryohei IZUMI
Laboratory of Bioorganic Chemistry, Tokyo University of Agriculture and Technology; Fuchu, Tokyo 183–8509, Japan.
Received July 5, 2007; accepted December 22, 2007; published online January 8, 2008
A stable symmetric diacyl peroxide, m-chlorobenzoyl peroxide (mCBPO), and an asymmetric diacyl perox-
ide, chloroacetyl m-chlorobenzoyl peroxide (CAMCBPO), were synthesized from m-chloroperbenzoic acid. Both
peroxides oxidized phenols selectively at the ortho position predoninantly. CAMCBPO gave para-oxidized com-
pounds as minor products from some phenols. The improvement of the yield of ortho-oxidation of phenols with
mCBPO was also reported.
Key words ortho-oxidation; phenol; stable diacyl peroxide; m-chlorobenzoyl peroxide; chloroacetyl m-chlorobenzoyl peroxide;
chloroacetic acid
There are many natural catechols which show various bio- differential thermal analysis, and improvement of the reac-
logical activities, e.g., anti-oxidant,1) anti-methicillin-resis- tion condition using CH2Cl2 solution to avoid the incident.
tant Staphylococcus aureus (MRSA) and vancomycin-resis- Thus we tried the reaction of phenols with mCBPO at reflux-
tant Enterococcus (VRE),2) anti-tubercular,3) anti-bacteri- ing temperature of CH2Cl2 and CHCl3. Phenols were safely
al,4—9) anti-plasmodial,10) anti-viral,11,12) anti-tumor,13—15) and oxidized with mCBPO even at refluxing temperature in chlo-
anti-platelet16) activities. Natural catechol derivatives are eas- roform. The reaction mixtures were reduced with LiAlH4
ily oxidized by oxygen or chemical reagents. Benzenese- (LAH) and then acetylated with acetic anhydride and pyri-
leninic anhydride,17) 2-iodoxybenzoic acid (IBX)18,19) and dine. The mixture was chromatographed on silica gel to give
iodobenzene diacetate20,21) are well known reagents for catechol diacetates that was analyzed by NMR spectroscopy
ortho-oxidation of phenol to give ortho-quinone or ortho-hy- without further purification. The reaction yields were esti-
1
droxy-para-quinone methide, although sometimes a complex mated by measuring the H-NMR spectra of these catechol
mixture is formed. Dibenzoyl peroxide is commonly used as diacetates (Table 1, Fig. 2). The phenols were oxidized at the
an initiator of polymer synthesis and an effective reagent for ortho-position selectively. As mentioned above, small phe-
ortho-oxidation of phenols to give catechol monoesters. nols e.g. o-cresol, m-cresol, p-cresol, 2,4-xylenol and 3,5-
However, dibenzoyl peroxide is unstable and has caused large xylenol, could not be oxidized by the previous experimental
explosions in industrial plants, e.g., at Itabashi in Japan condition at ambient temperature.23) Many phenols, however,
(1990) and in northern Taiwan (2001).22) In the previous syn- were oxidized at refluxing temperature to show the reaction
thesis of abietaquinone methide3) (1) with anti-MRSA and condition at refluxing temperature is superior to that at ambi-
anti-VRE activities, we reported ortho-oxidation of phenols ent temperature. Ferruginol which has three alkyl substitu-
using a stable diacyl peroxide, m-chlorobenzoyl peroxide tents on the phenol ring was oxidized at ambient temperature
(mCBPO, 2) which was synthesized from meta-chloroper- in 50% yield.23) ortho-Substituted phenols, however, were ox-
benzoic acid.23) The ortho-oxidation of a diterpene phenol idized by this reaction (Table 1: entries 5, 8, 11) in less yield.
with mCBPO gave the corresponding catechol ester in mod- Asymmetric diacyl peroxides were then prepared and used in
erate yield, but the oxidation of other small phenols gave situ for the oxidation of phenols.
lower yields. We thus planned to improve the ortho-oxidation
ortho-Oxidation of Phenols Using Asymmetric Diacyl
of phenols with diacyl peroxides, a stable and nontoxic Peroxides Various carboxylic acids were treated with meta-
reagent. We report herein a novel ortho-oxidation reaction of chloroperbenzoic acid (mCPBA: content ꢀ68%, product of
phenol using the asymmetric diacyl peroxide which was syn- Tokyo Kasei) and dicyclohexylcarbodiimide (DCC) (Table
thesized from m-chloroperbenzoic acid, together with the im- 2). Asymmetric diacyl peroxides were presumed to be
provement of the yield of ortho-oxidation of phenols with the
symmetric diacyl peroxide, mCBPO.
ortho-Oxidation of Phenols with the Symmetric Di-
acyl Peroxide, mCBPO Previously, we synthesized abi-
etaquinone methide 1, via the ortho-oxidation of ferruginol
(3) with mCBPO at ambient temperature (Fig. 1).23) Some
small phenols, e.g. o-cresol, m-cresol, p-cresol, 2,4-xylenol
and 3,5-xylenol, however, were not oxidized with mCBPO at
ambient temperature. Kubota and Takeuchi reported the un-
expected formation of mCBPO 2 by the heating of mCPBA
in dimethyl formamide (DMF) which was accompanied by
an explosion.24) The formation of mCBPO after the explosion
indicates that mCBPO is stable under high temperatures. In
fact, solid mCBPO melts at over 110 °C and exhibits slow
foaming when heated in a glass tube. They also foresaw that
severe explosion of mCBPO in DMF over 125 °C from the
Fig. 1. ortho-Oxidation of Phenols with mCBPO
∗ To whom correspondence should be addressed. e-mail: tada@cc.tuat.ac.jp
© 2008 Pharmaceutical Society of Japan

240
Vol. 56, No. 3
Fig. 2. Oxidation Products of Various Phenols with mCBPO and Chloroacetyl m-Chlorobenzoyl Peroxide (CAMCBPO)
Fig. 3. Synthesis of Asymmetric Diacyl Peroxides and Oxidation of Phenols with Asymmetric Diacyl Peroxides
Table 1. Oxidation of Phenols with mCBPO and with CAMCBPO
mCBPO CAMCBPO
Table 2. Oxidation of 3-Methoxyphenol with Asymmetric Diacyl Perox-
ides
Entry
R group of RCOOH
pKa25,26)
Yield (%)
Entry
Phenol
Yield
(%)a)
Yield
(%)a)
Products
Products
1
2
3
4
5
6
CH3-
CH2l-
CH2Br-
CH2Cl-
CHCl2-
CCl3-
4.76
2.90
2.82
2.66
1.30
0.46
Trace
17a)
29a)
53a)
n.r.
1
2
3
4
5
6
7
8
9
o-Cresol
m-Cresol
p-Cresol
2,3-Xylenol
3,4-Xylenol
3,5-Xylenol
2,4-Xylenol
3,4,5-Trimethylphenol
4-Isopropylphenol
4
5
5
6
6ꢂ7
8
n.r.
4
5
5
Trace
Trace
25
35
75
11
6ꢂ13 27 (2 : 1)
26 (1 : 6)
8ꢂ14 45 (2 : 1)
8
9
10
11
12
n.r.
39 (1 : 3) 6ꢂ7
32
n.r.
56
29
17
n.r.
7
8
4.19
3.83
n.r.
18
25
32
53
51
9
10
11
Trace
10 4-tert-Butylphenol
11 2,4-di-tert-Butylphenol
9
3.47
3.43
Trace
Trace
CAMCBPO: chloroacetyl m-chlorobenzoyl peroxide. a) Estimated by 1H-NMR of
the diacetate. n.r.: no reaction.
10
a) Estimated by 1H-NMR of the diacetate. n.r.: no reaction
formed as the intermediate (B) by condensation with the
corresponding acids (Fig. 3). The oxidation of 3-methoxy- reagent quantities (chloroacetic acid, mCPBA and DCC),
phenol was examined in situ using the synthesized asym- temperature and reaction times for the oxidation of 4-tert-
metric diacyl peroxides. The reaction mixtures were re- butylphenol. A moderate yield was obtained under the reac-
duced with LiAlH4 and then acetylated with acetic anhydride tion conditions using 2.0 eq of chloroacetic acid, 2.2 eq of
and pyridine. The reaction yields were estimated by DCC and 2.8 eq of mCPBA, at 0 °C to room temperature for
1
measuring the H-NMR spectra of the catechol diacetate 66 h. The oxidation of various phenols was subsequently ex-
(4-methoxyphenylene-1,2-diacetate18)) produced. Chloroacetic amined using these conditions (Tables 1, 3).
acid (pKa 2.66)25,26) gave a moderate yield. The formation of
The yields and products with these reaction conditions
chloroacetyl meta-chlorobenzoyl peroxide (CAMCBPO) was were different from those by mCBPO. mCBPO could be
1
presumed from the H-NMR spectrum of the reaction mix- formed in Table 2 entry 8, but the yield was lower than previ-
ture of chloroacetic acid, DCC and mCPBA in CDCl3. The ous result by this reaction condition. Bicyclic phenols and
1H-NMR (CDCl3, 600 MHz) of the reaction mixture showed phenols with bulky alkyl groups gave increased yields. The
the signals due to CAMCBPO [d: 8.07 (1H, br s), 7.98 (1H, majority of phenols were oxidized predominantly at the ortho
br d, Jꢁ8.1 Hz), 7.59 (1H, br d, Jꢁ8.1 Hz), 7.42 (1H, t, position, but some were oxidized at both the ortho and para
Jꢁ8.1 Hz) , 4.13 (2H, s)] and meta-chlorobenzoic anhydride positions (Table 1: entries 4, 6; Table 3: entry 1). We previ-
[d: 8.11 (0.6H, t, Jꢁ1.8, 1.8 Hz), 8.04 (0.8H, br d, ously proposed the mechanism of the oxidation with mCBPO
Jꢁ8.1 Hz), 7.67 (0.8H, br d, Jꢁ8.1 Hz), 7.50 (0.8H, t, through a [3,3] sigmatropic rearrangement of the peroxyacid
Jꢁ8.1 Hz)], whereas the signals due to chloroacetic meta- ester of phenol to give the catechol ester selectively.23) These
chlorobenzoic anhydride were not observed under this reac- results, however, suggested that the reaction mechanism of
tion condition.
the oxidation with asymmetric the diacyl peroxide (CAM-
The reaction conditions were optimized by adjusting CBPO) is different. The products suggested the formation of

March 2008
241
The reaction mixture was evaporated. The residue was dissolved in tetrahy-
drofuran (THF) (3 ml) and LAH (228 mg, 6 mmol) was added. After stirring
at 0 °C for 1 h, the reaction was stopped with methanol and EtOAc. The or-
ganic layer was successively washed with 1 M HCl, saturated aqueous
NaHCO3 and brine, dried over MgSO4 and evaporated. The residue was dis-
solved in pyridine (2 ml) and Ac2O (1 ml) and the solution was stirred at am-
bient temperature for 1—2 h. The progress of the reaction was followed by
thin layer chromatography. The reaction was quenched with methanol and
the organic layer was successively washed with 1 M HCl, saturated aqueous
NaHCO3 and brine, dried over MgSO4 and evaporated. The reaction mixture
was chromatographed on a silica gel column with EtOAc–hexane to give di-
acetates. The yields were estimated by comparing the integration of the sig-
nals in the 1H-NMR spectra of the diacetates to that of the additive standard,
dioxane.
a radical intermediate that can oxidize at either the ortho or
para positions (Fig. 4). It is expected that CAMCBPO is
more reactive than mCBPO towards decomposition into radi-
cal intermediates. However, the oxidation of 4-tert-butyl-
anisole was attempted unsuccessfully with these reaction
conditions, with no oxidation product observed. While the
reaction mechanism of the ortho-oxidation of phenols with
symmetric or asymmetric diacyl peroxides are still unknown,
the utility of this reaction to prepare catechols from phenols
is clear.
Conclusion
Oxidation of Phenol with Chloroacetic Acid, meta-Chloroperbenzoic
Acid and Dicyclohexylcarbodiimide A solution of chloroacetic acid
(283 mg, 3.0 mmol) and DCC (680 mg, 3.3 mmol) in CH2Cl2 (15 ml) was
The ortho-oxidation of phenols with the stable diacyl per-
oxide, mCBPO was improved. An asymmetric diacyl perox-
ide, CAMCBPO was prepared and oxidized phenols in situ stirred for 15 min and mCPBA (725 mg, less than 4.2 mmol: content ꢀ68%:
Tokyo Kasei) was added. The solution was stirred for an additional 30 min
and phenol (1.5 mmol) was added. After stirring at 0 °C to room temperature
for 66 h, the reaction mixture was filtered to remove solids of dicyclohexy-
safely. These results warrant further investigation of these
reagents for organic reactions and polymer syntheses.
lurea. The filtrate was evaporated and the residue was dissolved in EtOAc.
The EtOAc solution was successively washed with saturated aqueous
Experimental
General Procedures NMR spectra were measured on a JEOL Alpha-
NaHCO3 and brine, dried over MgSO4 and evaporated. The residue was dis-
600 (1H: 600 MHz, 13C: 150.8 MHz) spectrometer in CDCl3 using tetram-
solved in THF (3 ml) and LAH (228 mg, 6 mmol) was added. After stirring
ethylsilane as an internal standard (J-values in Hz). IR spectra were meas-
at 0 °C for 1 h, the reaction was stopped with methanol and EtOAc. The or-
ured on a JEOL JIR-WINSPEC 50 infrared spectrometer. Mass spectra were
ganic layer was successively washed with 1 M HCl, saturated aqueous
recorded on a JEOL JMS-K9 UltraQuad GC/MS spectrometer. Melting
NaHCO3 and brine, dried over MgSO4 and evaporated. The residue was dis-
points (mp) were measured on a MEL-TEMP (Laboratory Device) and were
solved in pyridine (2 ml) and Ac2O (1 ml) and the solution was stirred at am-
uncorrected. TLC was carried out on silica gel 60 (0.25-mm thickness) with
bient temperature for 1—2 h. The progress of the reaction was followed by
fluorescent indicator (Macherey-Nagel). Silica gel (6 nm, BW-127ZH, Fuji
thin layer chromatography. The reaction was quenched with methanol and
Silysia Chemical Ltd.) was used for column chromatography.
the organic layer was successively washed with 1 M HCl, saturated aqueous
ortho-Oxidation of Phenols with mCBPO under Reflux To a solution
of substituted phenol (0.25 mmol) in CHCl3 (3 ml), was added mCBPO
NaHCO3 and brine, dried over MgSO4 and evaporated. The reaction mixture
was chromatographed on a silica gel column with EtOAc–hexane to give di-
(0.3 mmol) and the solution was heated under reflux for 16 h under argon.
acetate. The yields were estimated by comparing the integration of the sig-
nals in the 1H-NMR spectra of the diacetates to that of the additive standard,
Table 3. Oxidation of Phenols with CAMCBPO
dioxane.
3,4-Dimethylphenylene-1,2-diacetate (6) and 2,3-Dimethylphenylene-1,4-
Entry
1
Phenol
Product
Yield (%)a)
31 (5 : 1)
diacetae (13): Yellow oil; 1H-NMR (CDCl3, 600 MHz) d: 7.05 (1H, d,
Jꢁ8.4 Hz), 6.92 (1H, d, Jꢁ8.4 Hz), 6.88 (0.5H, s), 2.32 (4.5H, s), 2.27 (6H,
s), 2.09 (1.5H, s), 2.08 (3H, s); 13C-NMR (CDCl3, 150 MHz) d: 169.34,
168.69, 168.26, 146.77, 140.63, 140.29, 135.75, 130.37, 127.43, 119.84,
20.81, 20.63, 20.33, 19.80, 13.02, 12.82; IR cmꢃ1 (KBr) 2929, 2856, 1762,
1650, 1461, 1367, 1211, 1178, 1078, 1027; LR-EI-MS m/z (relative intensity
%) 222 (Mꢂ, 8), 180 (25), 138 (100), 123 (13), 107 (5), 91 (11), 79 (15), 65
(13); HR-ESI-MS m/z: 245.0840 (Calcd for C12H14O4Na(MꢂNa)ꢂ
245.0790).
2
3
67 (1 : 2)
29 (1 : 3)
4,5-Dimethylphenylene-1,2-diacetate (7) and 3,4-Dimethylphenylene-1,2-
diacetate (6): Yellow oil; 1H-NMR (CDCl3, 400 MHz) d: 7.04 (0.3H, d,
Jꢁ8.3 Hz), 6.93 (2H, s), 6.91 (0.3H, d, Jꢁ8.3 Hz), 2.32 (1H, s), 2.27 (8H, s),
2.22 (6H, s), 2.08 (1H, s); 13C-NMR (CDCl3, 100 MHz) d: 168.43, 168.04,
140.50, 140.17, 139.36, 135.58, 135.10, 130.41, 127.28, 123.94, 119.72,
20.59, 20.32, 19.79, 19.36; IR cmꢃ1 (KBr) 2971, 2933, 2850, 1766, 1633,
1504, 1371, 1214. 1178, 1081; LR-EI-MS m/z (relative intensity %) 222
(Mꢂ, 8), 180 (38), 138 (100), 123 (20), 109 (5), 91 (18), 79 (22), 65 (19));
HR-ESI-MS m/z: 245.0833 (Calcd for C12H14O4Na(MꢂNa)ꢂ 245.0790).
4-Isopropylphenylene-1,2-diacetate (10): Yellow oil; 1H-NMR (CDCl3,
400 MHz) d: 7.10 (1H, dd, Jꢁ8.1, 2.0 Hz), 7.01 (1H, d, Jꢁ8.1 Hz), 2.40
(1H, sept, Jꢁ6.8 Hz), 2.29 (3H, s), 2.28 (3H, s), 1,24 (6H, d, Jꢁ6.8 Hz);
13C-NMR (CDCl3, 100 MHz) d: 168.21, 168.07, 147.41, 141.56, 139.64,
124.37, 122.79, 121.05, 33.50, 23.76, 20.56, 20.54; IR cmꢃ1 (NaCl) 2950,
4
27
a) Estimated by 1H-NMR of the diacetate.
Fig. 4. Presumed Reaction Mechanism of Oxidation of Phenols with CAMCBPO

242
Vol. 56, No. 3
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