P-quinols and p-quinol Ethers from 2,4,6-trialkylphenols

Article abstract of DOI:10.1055/s-0029-1217127

The oxidation of 2,4,6-trialkylphenols with lead(IV) oxide and 70% perchloric acid in water-acetone or in alcohols gives p-quinols or p-quinol ethers, respectively. Some nonmetallic oxidants serve the same purpose. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217127

208
SHORT PAPER
p-Quinols and p-Quinol Ethers from 2,4,6-Trialkylphenols
Preparationof
p
-Q
a
uinols and
n
p
-Quinol Eth
j
ers i Omura*,1
College of Nutrition, Koshien University, Momijigaoka, Takarazuka, Hyogo 665-0006, Japan
Fax +81(72)7668732; E-mail: k.omura@iris.eonet.ne.jp
Received 24 August 2009; revised 28 September 2009
Table 1 Preparation of 2 from 1 in the Presence of Lead(IV) Oxide
and 70% Perchloric Acid
Abstract: The oxidation of 2,4,6-trialkylphenols with lead(IV) ox-
ide and 70% perchloric acid in water–acetone or in alcohols gives
p-quinols or p-quinol ethers, respectively. Some nonmetallic oxi-
dants serve the same purpose.
R1
R1
PbCl2/70% HClO4
R3OH
R2
HO
R2
O
Key words: oxidations, 2,4,6-trialkylphenols, p-quinols, p-quinol
ethers, lead(IV) oxide, perchloric acid, nonmetallic oxidants
OR3
R1
R1
1
2
k: R3 = H
a: R1 = t-Bu, R2 = Me
b: R1 = t-Bu, R2 = Et
c: R1 = R2 = t-Bu
d: R1 = R2 = Me
A variety of oxidants have been exploited for the conver-
sion of phenols into quinols and their derivatives, which
are often important synthetic intermediates. The contribu-
tion of electrochemistry in achieving this purpose has also
been extensive.2 Herein, we report new oxidants for pre-
paring such dienones from phenols.
l: R3 = Me
m: R3 = Et
n: R3 = i-Pr
o: R3 = t-Bu
Run
1
Solvent
2
Yielda
(%)
Mp (°C)
The reactions of 2,4,6-trialkylphenols 1 as model sub-
strates to yield the corresponding p-quinols or p-quinol
ethers 2 were carried out with lead(IV) oxide and 70%
perchloric acid in hydroxylic solvents (R3OH), and the re-
sults are summarized in Table 1.3 The reaction was mildly
exothermic and rapidly completed. For instance, portion-
wise addition of a small excess of lead(IV) oxide to a
stirred solution of 2,6-di-tert-butyl-4-methylphenol (1a)
in methanol containing 70% perchloric acid readily gave
quinol methyl ether 2al in 90% yield after column chro-
matography of the crude reaction product (Table 1, run
2).4 Omission of 70% perchloric acid resulted in the for-
mation of the product of oxidative dimerization of 1a.
Products 2 were generally obtained in high yields after
column-chromatographic purification. In most cases, 2
could also be isolated by recrystallization of the crude re-
action product. Some examples of the isolation by such re-
crystallization are also shown in Table 1. The yields of
quinol tert-butyl ethers 2ao and 2co from the oxidations
of 1a and 2,4,6-tri-tert-butylphenol (1c), respectively, in
tert-butyl alcohol, a sterically hindered alcohol, were ex-
ceptionally low (Table 1, runs 5 and 11).
1
2
1a H2O–acetone 2ak 89 (78) 112–114 (Lit.14 113–114)
1a MeOH
1a EtOH
2al 90 (79) 92.5–93 (Lit.15 94)
b
3
2am 83
–
–
–
b
b
4
1a i-PrOH
1a t-BuOH
2an 83 (70)
2aoc 30
5
6
1b H2O–acetone 2bk 83 (69) 99–100 (Lit.9 99–100)
b
7
1b MeOH
1c MeOH
1c EtOH
2bl 88
2cl 90
2cm 84
2cn 85
2coe 22
2dl 50
–
8
56–57.5 (Lit.9 57–58)
40–42 (Lit.9 39–41)
oild (Lit.9 30)
9
10
11
12
1c i-PrOH
1c t-BuOH
1d MeOH
48–49.5 (Lit.9 37–39)
42–43 (Lit.6 42–44)
a Yield of product purified by column chromatography. Yields shown
in parentheses are of the products isolated by recrystallization of the
crude reaction products.
b For data, including mp data, of quinol ethyl ethers 2am, 2an, 2ao,
and 2bl, see the experimental section.
Among the effective oxidants for the conversion of phe-
nols into quinols and their derivatives are periodic acid
(H5IO6),5 (diacetoxyiodo)benzene [PhI(OAc)2],6 and thal-
lium(III) nitrate trihydrate [Tl(NO3)3·3H2O; TTN].7 Oxi-
dation of 1a and/or 1c with these reagents in methanol has
been reported to provide 2al and/or quinol methyl ether
2cl, respectively, in good to high yields. Attempted prep-
aration of quinol isopropyl ether 2an by treatment of 1a
c In addition, 3,5-di-tert-butyl-4-hydroxybenzyl tert-butyl ether
(31%) was obtained.
d Attempts at obtaining crystals at r.t. (25 °C) were unsuccessful.16
e In addition, 2ck (72%) was obtained; mp 86–128 °C (Lit.4,17 82–124).
with any of these oxidants in isopropyl alcohol, a moder-
ately hindered alcohol, was, however, not quite successful
(Table 2, runs 1–3), whereas the same oxidation with
lead(IV) oxide and 70% perchloric acid afforded 2an in
high yield (Table 2, run 4). Similarly, the oxidation of 1a
in tert-butyl alcohol and of 1c in isopropyl alcohol with
SYNTHESIS 2010, No. 2, pp 0208–0210
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Advanced online publication: 20.11.2009
DOI: 10.1055/s-0029-1217127; Art ID: F17409SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Preparation of p-Quinols and p-Quinol Ethers
209
periodic acid, (diacetoxyiodo)benzene, or thallium(III) ni- yield was intermediate and formation of quinol 2ak as a
trate trihydrate provided 2ao and quinol isopropyl ether byproduct was substantial (Table 2, run 7).13 The similar
2cn, respectively, in lower or much lower yields than oxidation of 1a with iodine and 30% hydrogen peroxide in
those from the oxidation with lead(IV) oxide/70% per- methanol gave 2al in a chromatographic yield (82%)
chloric acid (Table 1, runs 5 and 10) (see experimental higher than that of 2an obtained from the above-men-
section).8
tioned same oxidation in isopropyl alcohol. The reaction
of 1c with iodine and 30% hydrogen peroxide in methanol
gave 2cl, also in a good chromatographic yield (71%).
Possibly, the oxidation with iodine and 30% hydrogen
peroxide, which proved catalytic in nature with respect to
iodine, can be improved by modifying the reaction condi-
tions.
Table 2 Preparation of 2an from 1a with Various Oxidants
Run Oxidant
Solvent
i-PrOH
i-PrOH
i-PrOH
Yield of 2ana (%)
1
2
3
4b
5
6
7
H5IO6
47
PhI(OAc)2
TTN
14
The present results indicate that there are cases where
lead(IV) oxide with 70% perchloric acid and the new non-
metallic oxidants are better reagents than the previously
employed oxidants in preparing p-quinols and p-quinol
ethers, possibly especially the sterically hindered ethers,
from phenols.
33
PbO2/70% HClO4 i-PrOH
NaIO3/70% HClO4 i-PrOH
83 (70)
78 (68)
79 (62)
45c
Br2/NIS
i-PrOH–MeCN
i-PrOH
I2/30% H2O2
1H NMR (90 MHz) spectra were obtained of samples in CDCl3 with
TMS as reference on a Hitachi R-1900 spectrometer. IR spectra
were recorded of samples in CHCl3 on a Shimadzu FTIR-8300
spectrophotometer. Column chromatography was conducted on
Merck silica gel 60. Unless otherwise specified, reagents were pur-
chased from WAKO and used as received.
a Yield of product purified by column chromatography. Yields shown
in parentheses are of 2an isolated by recrystallization of the crude re-
action product.
b Identical to run 4 in Table 1.
c In addition, 2ak (32%) was obtained.
Preparation of 2 from 1 by Use of Lead(IV) Oxide and 70% Per-
chloric Acid (Table 1); General Procedure
The above-cited results obtained by us and other workers
appear to indicate that the ease of the oxyfunctionalization
of 1 giving 2 with an oxidant and an alcohol, in general,
tends to depend on the steric bulk of the alcohol. Regard-
ing such dependency, it is worth adding that the thalli-
um(III) nitrate trihydrate oxidation of 1c in tert-butyl
alcohol is reported to yield no 2co (and a low yield of
quinol 2ck), as compared with a high yield of 2cl from the
same oxidation in methanol, the smallest alcohol,7 and
that the yields of quinol ethers 2c obtained by electro-
chemical oxidation of 1c in alcohol–acetonitrile mixtures
decrease in the order 2cl (95%) > quinol ethyl ether 2cm
(78%) > 2cn (62%) > 2co (12%).9
PbO2 (1.195 g, 5 mmol; Aldrich) was added portionwise over 3 min
to a stirred soln of 1 (4 mmol) in an alcohol R3OH (30 mL) contain-
ing 70% HClO4 (1 mL), after which the mixture was kept stirring
for 5 min. In runs 1 and 6 (Table 1), a mixture of H2O (3 mL) and
acetone (27 mL) was employed in place of the alcohol. The mixture
was filtered, and the filtrate was poured into H2O and subjected to
extractive workup with Et2O. The crude product thus obtained was
chromatographed to give 2. Runs 1, 2, 4, and 6 were repeated, and
the crude reaction products were recrystallized from hexane or
MeOH to give 2ak, 2al, 2an, and quinol 2bk, respectively.
2,6-Di-tert-butyl-4-ethoxy-4-methylcyclohexa-2,5-dienone
(2am)
Colorless crystals (MeOH); mp 69.5–71 °C.
Some nonmetallic oxidants (including the sodium salt)
were explored for conversion of phenols into quinols and
quinol ethers. As a model reaction, the conversion of 1a
into 2an was studied, and the results are also shown in
Table 2. Treatment of 1a with sodium iodate and 70%
perchloric acid in isopropyl alcohol for three hours yield-
ed 2an (Table 2, run 5). No reaction of 1a took place if
70% perchloric acid was omitted.10 Addition of bromine
followed by N-iodosuccinimide (NIS) to a solution of 1a
in an isopropyl alcohol–acetonitrile solvent mixture also
afforded 2an readily (Table 2, run 6).11 The yields of 2an
from the above two runs were almost as high as that from
the oxidation with lead(IV) oxide and 70% perchloric acid.
If carried out in methanol and in methanol–acetonitrile,
respectively, the reactions of 1a with sodium iodate and
70% perchloric acid and with bromine and N-iodosuccin-
imide gave 2al in 87% and 85% chromatographic yields,
respectively. Reaction of 1a with iodine and 30% hydro-
gen peroxide,12 both of which are inexpensive, in isopro-
pyl alcohol for 1.5 hours also produced 2an, although the
IR (CHCl3): 1663, 1643 cm–1.
1H NMR (90 MHz, CDCl3): d = 1.15 (shoulder, t, J = 7.0 Hz, 3 H),
1.24 (s, 18 H), 1.36 (s, 3 H), 3.28 (q, J = 7.0 Hz, 2 H), 6.46 (s, 2 H).
Anal. Calcd for C17H28O2: C, 77.22; H, 10.67. Found: C, 76.94; H,
10.68.
2,6-Di-tert-butyl-4-isopropoxy-4-methylcyclohexa-2,5-dienone
(2an)
Colorless crystals (MeOH); mp 70–73.5 °C.
IR (CHCl3): 1661, 1643 cm–1.
1H NMR (90 MHz, CDCl3): d = 1.09 (d, J = 6.1 Hz, 6 H), 1.24 (s,
18 H), 1.33 (s, 3 H), 3.39 (sept, J = 6.1 Hz, 1 H), 6.48 (s, 2 H).
Anal. Calcd for C18H30O2: C, 77.65; H, 10.86. Found: C, 77.35; H,
10.68.
2,6-Di-tert-butyl-4-tert-butoxy-4-methylcyclohexa-2,5-dienone
(2ao)
Colorless crystals (EtOH); mp 64.5–66.5 °C.
IR (CHCl3): 1659, 1639, 1630 cm–1.
Synthesis 2010, No. 2, 208–210 © Thieme Stuttgart · New York

210
K. Omura
SHORT PAPER
1H NMR (90 MHz, CDCl3): d = 1.19 (s, 9 H), 1.23 (s, 18 H), 1.29
yields, respectively. The reactions of 1c (1.050 g, 4 mmol) in place
of 1a with H5IO6, PhI(OAc)2, and TTN in i-PrOH gave 2cn in 22%,
25%, and 4% chromatographic yields, respectively.
(s, 3 H), 6.69 (s, 2 H).
Anal. Calcd for C19H32O2: C, 78.03; H, 11.03. Found: C, 77.77; H,
10.95.
Acknowledgment
2,6-Di-tert-butyl-4-methoxy-4-ethylcyclohexa-2,5-dienone (2bl)
Colorless crystals (MeOH); mp 46.5–48 °C.
IR (CHCl3): 1665, 1643 cm–1.
1H NMR (90 MHz, CDCl3): d = 0.73 (t, J = 7.5 Hz, 3 H), 1.25 (s, 18
H), 1.71 (q, J = 7.5 Hz, 2 H), 3.16 (s, 3 H), 6.36 (s, 2 H).
The author is thankful to Takahiro Ohshiro, Kaori Kojima, Mayumi
Fujiyoshi, and Yoshiko Iwamitsu (students) for experimental con-
tributions.
References
Anal. Calcd for C17H28O2: C, 77.22; H, 10.67. Found: C, 76.95; H,
10.66.
(1) Current address: 4-5-2, Matsuodai, Inagawa, Hyogo 666-
0261, Japan.
3,5-Di-tert-butyl-4-hydroxybenzyl tert-Butyl Ether
Colorless crystals (hexane); mp 68–69.5 °C.
IR (CHCl3): 3641 cm–1.
1H NMR (90 MHz, CDCl3): d = 1.29 (s, 9 H), 1.43 (s, 18 H), 4.33
(s, 2 H), 5.09 (s, 1 H), 7.13 (s, 2 H).
(2) (a) Yamamura, S. In The Chemistry of Phenols, Part 1;
Rappoport, Z., Ed.; Wiley: Chichester, 2003, 1153.
(b) Stavber, S.; Jereb, M.; Zupan, M. ARKIVOC 2001, (v),
98. (c) Stavber, S.; Zupan, M. Acta Chim. Slov. 2005, 52,
13. (d) Sels, B. F.; De Vos, D. E.; Jacobs, P. A. Angew.
Chem. Int. Ed. 2005, 44, 310. (e) Quideau, S.; Pouységu, L.;
Deffieux, D. Synlett 2008, 467.
(3) Oxidation of phenols to p-benzoquinones with PbO2/70%
HClO4 has been reported. See: Omura, K. Synthesis 1998,
1145.
(4) Oxidation of 1a with PbO2/70% HClO4 in MeOH under
conditions different from those employed in this study has
recently been reported. The mechanism of the formation of
2al was shown. Thus, the phenoxyl radical as a poor base,
generated by dehydrogenation of 1a with PbO2, is
protonated by the strong acid giving the phenol cation
radical, which can efficiently abstract an electron from more
of the phenoxyl radical, thus yielding the phenoxyl cation
that adds MeOH. See: Omura, K. J. Org. Chem. 2008, 73,
858.
(5) Becker, H.-D.; Gustafsson, K. J. Org. Chem. 1979, 44, 428.
(6) Pelter, A.; Elgendy, S. M. A. J. Chem. Soc., Perkin Trans. 1
1993, 1891.
(7) McKillop, A.; Perry, D. H.; Edwards, M. J. Org. Chem.
1976, 41, 282.
(8) More recently, an N–F reagent has been shown to slowly
oxidize 1 (except 1b) in MeCN–protic solvent (H2O, MeOH,
and primary alcohols) mixtures affording the p-quinols and
p-quinol ethers. An attempt to prepare 2an, 2ao, or 2cn by
the use of the reagent was not made in this laboratory. See
ref. 2b.
Anal. Calcd for C19H32O2: C, 78.03; H, 11.03. Found: C, 77.78; H,
11.30.
Preparation of 2an from 1a by Use of Various Oxidants (Table
2)
Run 1: A soln of H5IO6 (913 mg, 4 mmol) in i-PrOH (20 mL) was
added in one portion to a soln of 1a (881 mg, 4 mmol) in i-PrOH (20
mL) in a bottle under N2. The bottle was screw-capped and the mix-
ture was allowed to stand at 20 °C for 24 h in the dark. The mixture
was poured into aq NaHSO3, and extractive workup with Et2O af-
forded a residual crude product.
Run 2: PhI(OAc)2 (1.29 g, 4 mmol; Aldrich) was added portionwise
over 20 min to a soln of 1a (4 mmol) in i-PrOH (35 mL) in a bottle
under N2. The bottle was screw-capped, and the mixture was stirred
at 20 °C for 40 min. The mixture was evaporated under reduced
pressure to give a residue.
Run 3: TTN (1.79 g, 4 mmol) was added in one portion to a stirred,
cooled (–20 °C) soln of 1a (4 mmol) in i-PrOH (30 mL). After 2
min, the stirred mixture was allowed to warm to r.t. PE was added
to the mixture, the resulting mixture was filtered, and the filtrate
was evaporated under reduced pressure to leave a residue.
Run 5: NaIO3 (1.59 g, 8 mmol) was added in one portion to a soln
of 1a (4 mmol) in i-PrOH (30 mL) containing 70% HClO4 (1 mL),
and the mixture was stirred for 3 h at 20 °C. The mixture was poured
into aq NaHSO3, and extractive workup with Et2O afforded a resid-
ual crude product.
(9) Rieker, A.; Drehher, E.-L.; Geisel, H.; Khalifa, M. H.
Synthesis 1978, 851.
(10) The mechanism of the NaIO3/70% HClO4 oxidation awaits
further investigation.
Run 6: A soln of Br2 (640 mg, 4 mmol) in MeCN (10 mL) was added
dropwise over 2 min to a stirred soln of 1a (4 mmol) in a mixture of
i-PrOH (6 mL) and MeCN (54 mL) at 18 °C. After 1 min, NIS (900
mg, 4 mmol; TCI) was added in one portion to the stirred mixture.
After 3 min, the mixture was poured into aq NaHSO3, and extractive
workup with Et2O left a residual crude product.
(11) The reaction involves a bromination–debromination
mechanism. Details will be discussed in a subsequent paper.
(12) Oxidation of phenols with I2 and aq H2O2 in hydroxylic
solvents giving products including p-benzoquinones has
been studied. See: (a) Cressman, H. W. J.; Thirtle, J. R.
J. Org. Chem. 1966, 31, 1279. (b) Minisci, F.; Citterio, A.;
Vismara, E.; Fontana, F.; De Bernardinis, S. J. Org. Chem.
1989, 54, 728. (c) Omura, K. J. Org. Chem. 1996, 61, 2006.
(13) The reaction would involve an iodination–deiodination
mechanism. See ref. 12c.
Run 7: A soln of I2 (2.03 g, 8 mmol) in i-PrOH (60 mL) containing
30% H2O2 (2 mL) was added in one portion to a soln of 1a (4 mmol)
in i-PrOH (20 mL), and the mixture was stirred for 1.5 h at 20 °C.
The mixture was poured into aq NaHSO3, and extractive workup
with Et2O left a residual crude product.
(14) Ronlán, A.; Parker, V. D. J. Chem. Soc. C 1971, 3214.
(15) Coppinger, G. M.; Campbell, T. W. J. Am. Chem. Soc. 1953,
75, 734.
The residue from each run was chromatographed to afford 2an. A
small amount (11%) of 1a was recovered unchanged from run 2.
Runs 5 and 6 were repeated. The crystalline residue from run 5 was
washed with cold hexane, the washing was evaporated, and the res-
idue was recrystallized (MeOH), yielding 2an. The crystalline resi-
due from run 6 was recrystallized (MeOH) to yield 2an.
(16) 1H NMR (90 MHz, CDCl3): d = 0.92 (s, 9 H), 1.09 (d, J = 6.2
Hz, 6 H), 1.24 (s, 18 H), 3.40 (sept, J = 6.2 Hz, 1 H), 6.59 (s,
2 H). The 1H NMR spectrum of 2cn in CCl4 has been
reported. See ref. 9.
The reactions of 1a with H5IO6, PhI(OAc)2, and TTN in t-BuOH in
place of i-PrOH gave 2ao in 0%, 21%, and <3% chromatographic
(17) For purification and identification of the product, see ref. 4.
Synthesis 2010, No. 2, 208–210 © Thieme Stuttgart · New York