Synthesis of quinones from hydroquinone dimethyl ethers. Oxidative demethylation with cobalt(III) fluoride

Article abstract of DOI:10.1055/s-1999-2875

The oxidative demethylation of 1,4-dimethoxynaphthalene and 1,4- dimethoxybenzene derivatives with cobalt(III) fluoride proceeded in good to excellent yield to afford the corresponding naphthoquinone and benzoquinone derivatives.

Full text of DOI:10.1055/s-1999-2875

1474
LETTER
Synthesis of Quinones from Hydroquinone Dimethyl Ethers. Oxidative
Demethylation with Cobalt(III) Fluoride
Ayumi Tomatsu, Syunji Takemura, Kimiko Hashimoto, Masaya Nakata*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522,
Japan
Fax +81-45-563-0446; E-mail: msynktxa@applc.keio.ac.jp
Received 25 June 1999
added ca. 60 equiv of H2O. After being stirred for 4 d at rt,
Abstract: The oxidative demethylation of 1,4-dimethoxynaphtha-
1,4-naphthoquinone (2) was obtained in 60% yield along
with the recovered 1 (ca. 20%). After several experiments,
lene and 1,4-dimethoxybenzene derivatives with cobalt(III) fluo-
ride proceeded in good to excellent yield to afford the
we found that the amount of H2O proved to be crucial for
this oxidative demethylation. Therefore, we examined in
dioxane (0.5 M for 1) the effect of the amount of H2O on
the reaction time (Table 1). The best result was obtained
when 10 equiv of H2O was used, giving 2 after 1 h in 86%
yield (entry 4, Table 1). Acetonitrile could also be used as
the solvent (entry 7, Table 1).13 It was necessary to use 4
equiv of CoF3 for the complete consumption of 1, excess
CoF3 probably being consumed during the oxidation of
methoxy fragments and/or solvent.3
corresponding naphthoquinone and benzoquinone derivatives.
Key words: oxidative demethylation, cobalt(III) fluoride, hydro-
quinone dimethyl ethers, quinones, reduction potential
Quinones are a large class of chemically and biologically
important compounds.1 With respect to organic synthesis,
hydroquinone dimethyl ethers are most often used as ver-
satile precursors of quinones because they are stable under
a variety of reaction conditions and they can be converted
to quinones by oxidative demethylation during the later
stage of the quinone synthesis (Figure 1). This oxidative
demethylation has been accomplished using nitric acid,2
silver(II) oxide (AgO)-mineral acid,3 ammonium ceri-
um(IV) nitrate (CAN),4 AgO- or CAN-pyridinecarboxylic
acid,5 silver(II) dipicolinate,6 manganese dioxide-nitric
acid-Celite,7 and AgNO3-ammonium peroxodisulfate.8
Among them, AgO and CAN have most frequently been
used. In order to synthesize the structurally complex
quinones, it is desirable to develop milder methods for the
oxidative demethylation. We now report in this letter a
new and convenient procedure for the oxidative demethy-
lation of hydroquinone dimethyl ethers to quinones using
cobalt(III) fluoride (CoF3).9 Judging from the standard re-
duction potential table,10 Co(III) has a comparable value
to that of Ag(II) and a larger value than that of Ce(IV).
Moreover, HF liberated as the reaction proceeds is a weak
acid and hence a milder medium would be anticipated
throughout the reaction.
Table 1 Oxidative Demethylation of 1 with CoF3
in the Presence of the Various Amount of H2O
OMe
O
CoF3 (4 equiv),
dioxane
(0.5 M for 1), rt
1
OMe
2
O
H2O (equiv)
time / h
yield / %
entry
1
2
3
4
5
6
7
2
24
53a
87
4
6
8
3
85
10
15
50
10
1
86
6
87
24
1
64a
83b
OMe
O
R3
R4
R1
R2
R3
R4
R1
R2
oxidative
aStarting material was recovered in ca. 20% yield.
bAcetonitrile was used as the solvent.
demethylation
OMe
O
Encouraged by this success, we next investigated the oxi-
dative demethylation of several 2-substituted 1,4-
dimethoxynaphthalene derivatives 311 with CoF3. Con-
Figure 1
We chose 1,4-dimethoxynaphthalene (1)11 as a represen- centration of the reaction depended on the substrate used,
tative substrate. Following the procedure for the AgO- varying from 0.1 M to 0.5 M. For comparative purposes,
12
promoted oxidative demethylation,3 4 equiv of CoF3
we carried out at the same time the oxidation experiments
was added at rt to 1 in dioxane (0.1 M for 1) to which was using AgO-nitric acid and CAN under the reported
Synlett 1999, No. 9, 1474–1476 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Quinones from Hydroquinone Dimethyl Ethers
1475
conditions3,4 (Table 2). Although longer reaction times In order to evaluate the applicability of the CoF3 method
were required in the case of CoF3, the isolated yield of the to acid-sensitive compounds, the oxidative demethylation
1,4-naphthoquinone derivatives 414 were comparable to of acetal compounds, 76,11 and 811, was examined (Table
that in the case of AgO or CAN.
4). In the case of the naphthalene derivative 7 (entry 1, Ta-
ble 4), all three oxidants, AgO, CAN, and CoF3, were ef-
fective with regard to yield. In the case of the benzene
derivative 8 (entry 2, Table 4), the oxidative demethyla-
tion with AgO or CAN afforded complex mixture (the
yield of the quinone was only 20 ~ 30%); whereas we
were delighted to find that CoF3 could be preparatively
used [55% isolated yield along with ca. 20% yield of 12
(vide infra)].14
Table 2 Oxidative Demethylation of 2-Substituted
1,4-Dimethoxynaphthalenes with AgO, CAN, and CoF3
OMe
O
R
R
oxidant, rt
3a ~ 3d OMe
4a ~ 4d
O
AgO (dioxane) CAN (acetonitrile) CoF3 (dioxane)
Table 4 Oxidative Demethylation of 7 and 8 with AgO, CAN,
entry
R
and CoF3
time / yield
time / yield
time / yield
5 min / 87%
7 min / 92%
7 min / 88%
OMe
O
OMe
O
1
2
3
4
H
30 min / 93%
10 min / 94%
8 min / 93%
8 min / 95%
1 h / 86%a
6 h / 92%b
1.5 h / 82%a
7 h / 75%a
(3a = 1)
O
O
Me
(3b)
Me
CH2OH
(3c)
7
OMe
8
OMe
AgO (dioxane) CAN (acetonitrile)
CoF3
time / yield
CH2OAc 7 min / 85%
(3d)
entry
compd
time / yield
time / yield
aThe reaction was carried out in 0.5 M solution for 3. bThe reaction was
carried out in 0.1 M solution for 3.
1
2
7
8
2 min / 78%
2 min / 66%
20 min / 66%a
2 min / 20~30% 2 min / 20~30% 25 min / 55%a
The oxidative demethylation of 2,5-disubstituted 1,4-
dimethoxybenzene derivatives 511 using AgO-nitric acid,
CAN, and CoF3 was next examined (Table 3). In the case
of the halogenated derivatives, the oxidation yield from 5
to 6 using CoF3 was slightly superior to that using AgO-
nitric acid (entries 3 and 4, Table 3).14
aThe reaction was carried out in 0.3 M solution for 7 and 0.5 M solution for
8 in acetonitrile.
Generally, when monosubstituted 1,4-dimethoxybenzene
derivatives are subjected to oxidative demethylation with
AgO or CAN, the dimerization products are obtained as
the major products.4,15 When the monosubstituted 1,4-
dimethoxybenzene derivatives, 9 and 10, were subjected
to oxidative demethylation with AgO, CAN or CoF3,
dimerization products were obtained as the major prod-
ucts (Figure 2). Furthermore, when the electron withdraw-
ing groups, the nitro or aldehyde group, were attached to
the aromatic nuclei (compounds 11,11,16 12,11,17 and
1311,18), the reaction with each of the three oxidants result-
ed in decomposition or no reaction.
Table 3 Oxidative Demethylation of 2,5-Disubstituted
1,4-Dimethoxybenzenes with AgO, CAN, and CoF3
OMe
O
R2
R2
oxidant, rt
R1
5a ~ 5d OMe
R1
6a ~ 6d
O
AgO (dioxane) CAN (acetonitrile)
CoF3
entry R1, R2
time / yield
time / yield
time / yield
OMe
OMe
1
R1 = Me
9 min / 80%
8 min / 96%
5 h / 79%a
0.5 h / 84%b
8 h / 76%b
(5a)
R
2 = Me
R1 = Me
R2 = CH2OAc
2
(5b)
7 min / 90%
7 min / 71%
5 min / 62%
8 min / 95%
10 min / 90%
5 min / 90%
MeO
Me
R
1 = Me
R2 = Br
1 = NHAc
2 = Cl
3
(5c)
OMe
10
OMe
9
4
(5d)
2.5 h / 70%c
R
OMe
OMe
OMe
R
CHO
NO2
CHO
aThe reaction was carried out in 0.1 M (for 5) solution in dioxane. bThe
reaction was carried out in 0.5 M (for 5) solution in acetonitrile. cThe
reaction was carried out in 0.1 M (for 5) solution in acetonitrile.
Me
AcHN
OMe
12
OMe
11
OMe
13
Figure 2
Synlett 1999, No. 9, 1474–1476 ISSN 0936-5214 © Thieme Stuttgart · New York

1476
A. Tomatsu et al.
LETTER
5b20: (i) 9, DMF, POCl3, 60 °C, 1 d (1217 was obtained); (ii)
NaBH4, aq NaOH, THF, rt, 0.5 h;17 (iii) Ac2O, pyridine, rt, 1 d.
5c21: 9, (n-Bu) 4NBr3, MeOH/CH2Cl2, rt, 1 d.22
The present method could become one of the effective
procedures for the oxidative demethylation of hydro-
quinone dimethyl ethers to quinones and could be applied
to the syntheses of the structurally complex quinones.
5d23: (i) 2,5-dimethoxy-4-nitroaniline, AcOH, NaNO2,
H2SO4, 40 °C, 0.5 h, then CuCl, HCl, 80 °C, 20 min;24,25 (ii)
FeCl3∑6H2O, NH2NH2∑H2O, activated carbon, MeOH, 65 °C,
1 h;25,26 (iii) Ac2O, pyridine, rt, 1 d.
A typical experimental procedure is as follows: To a solu-
tion of 1 (61.0 mg, 0.324 mmol) in dioxane (0.65 ml) CoF3
(151 mg, 1.30 mmol) was added at rt. To this H2O (0.0583
ml, 3.24 mmol) was added at rt and the heterogeneous
mixture was vigorously stirred at rt for 1 h. H2O was add-
ed and the mixture was extracted with ethyl acetate. The
extracts were washed with saturated aqueous NaCl, dried,
and concentrated. The residue was chromatographed on
silica gel (3 g) with 5 : 1 hexane-ethyl acetate to afford 2
(44.1 mg, 86%) as yellow crystals.
76: 13, 1,2-ethanediol, TsOH, benzene, reflux, 2 h.
8: 12, 1,2-ethanediol, TsOH, benzene, reflux, 4 h.
1116: 2,5-dimethoxy-4-nitroaniline, Ac2O, pyridine, rt, 1 d.
(12) We handled CoF3 (Aldrich) in a glove bag under an argon
atmosphere.
(13) Besides dioxane and acetonitrile, nitromethane could also be
used as the solvent. Acetone and t-BuOH could also be used
although longer reaction times were required.
(14) The obtained quinones were characterized by analytical data
(NMR, IR, and MS spectra and mp). The known quinones are
as follows: 4a (= 2), commercially available; 4b,
commercially available; 4c, see ref 19; 4d, see ref 27; 6a,
commercially available; 6b, see ref 20, 28; 6c, see ref 29; 6d,
see ref 30; quinone derived from 7, see ref 6.
References and Notes
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40, 2548.
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(9) CoF3 has previously been used for oxidative couplings to
biaryls (in trifluoroacetic acid, reflux), see: McKillop, A.;
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(10) According to CRC Handbook of Chemistry and Physics (79th
ed.; Lide, D. R., Ed.; CRC Press: Boca Raton, Florida, 1998-
1999; p 8-21), standard reduction potentials are as follows:
Ag(II) + e = Ag(I), 1.98 V; Co(III) + e = Co(II), 1.92 V;
Ce(IV) + e = Ce(III), 1.72 V.
(22) Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Nakamura, H.;
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(11) The hydroquinone dimethyl ethers used in this study were
characterized by analytical data (NMR, IR, and MS spectra
and mp) and were prepared from the commercially available
compounds as follows.
1: (i) 2, H2, Pd/C, acetone, rt, 1 d; (ii) Me2SO4, K2CO3,
acetone, rt, 2 h.
3b5: (i) 4b, H2, Pd/C, acetone, rt, 1 d; (ii) Me2SO4, K2CO3,
acetone, rt, 2.5 h.
3c19: (i) 1, DMF, POCl3, 60 °C, 1 d17 (1318 was obtained); (ii)
NaBH4, aq NaOH, THF, rt, 0.5 h.17
3d: 3c, Ac2O, pyridine, rt, 1 d.
Article Identifier:
1437-2096,E;1999,0,09,1474,1476,ftx,en;Y13499ST.pdf
5a4,5: (i) 6a, H2, Pd/C, acetone, rt, 1 d; (ii) Me2SO4, K2CO3,
acetone, rt, 1 d.
Synlett 1999, No. 9, 1474–1476 ISSN 0936-5214 © Thieme Stuttgart · New York