Bromide-assisted oxidation of substituted phenols with hydrogen peroxide to the corresponding p-quinol and p-quinol ethers over WO4 2--exchanged layered double hydroxides

Article abstract of DOI:10.1002/anie.200461555

A simple and efficient one-pot synthesis of p-quinols and their ethers occurs over tungstate-exchanged layered double hydroxides (WO₄ ^2--LDHs), which catalyze the bromide-assisted oxidation of substituted phenols to the corresponding 4-alkoxy- and 4-hydroxycyclohexa-2,5- dienones in high yields (see scheme).

Full text of DOI:10.1002/anie.200461555

Communications
Synthetic Methods
Bromide-Assisted Oxidation of Substituted
Phenols with Hydrogen Peroxide to the
Corresponding p-Quinol and p-Quinol Ethers
over WO42À-Exchanged Layered Double
Hydroxides**
B. F. Sels, D. E. De Vos, and P. A. Jacobs*
The selective oxidation of substituted phenols to yield 4-
hydroxycyclohexa-2,5-dienones (p-quinols) and their ethers
has been intensely investigated in view of their applications as
antioxidants, antibiotics, and antitumor agents.[1,2] Besides
electrolytic[3] and photosensitized[4] approaches, procedures
for quinol preparation require stoichiometric amounts of
oxidants, such as BiIII or TlIII salts,[5,6] oxygen at high
pressure,[7] hydrogen peroxide,[8] or particularly electrophilic
halogens,[9] such as IIII reagents, chlorine, or bromine. In view
of the risks associated with handling such reactive species,
much attention has recently been devoted to the in situ
generation of halonium species from harmless halides by
using oxygen or hydrogen peroxide.[10] As with haloperoxi-
dase enzymes, this halide oxidation requires a catalyst. Most
haloperoxidase mimics reported until now are only effective
at extremely low pH values. However, we developed a
2À
heterogeneous haloperoxidase-like catalyst based on WO4
-
exchanged layered double hydroxides (WO42À-LDH), which
strongly accelerates the halide oxidation with hydrogen
[*] Prof. B. F. Sels, Prof. D. E. De Vos, Prof. P. A. Jacobs
Department of Interphase Chemistry
Centre for Surface Chemistry and Catalysis
Katholieke Universtiteit Leuven
Kasteelpark Arenberg 23, 3001, Heverlee (Belgium)
Fax: (+32)16-321-998
E-mail: bert.sels@agr.kuleuven.ac.be
[**] The authors thank the FWO-Vlaanderen (BFS) for a postdoctoral
fellowship and Roeland Vancutsem for skilful technical assistance.
This work was performed in the frame of the IAP program
“Supramolecular Chemistry and Catalysis” of the Belgian Federal
government.
310
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DOI: 10.1002/anie.200461555
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Angewandte
Chemie
peroxide even at mild pH values.[11] Based on this method, we
anticipated the overall transformation of substituted phenols
to quinol ethers with hydrogen peroxide in the presence of a
bromide salt, the WO42À-LDH catalyst, and the appropriate
alcohol. If successful, this one-pot synthesis could provide a
new route towards the highly valuable p-quinol ethers:
Initial investigations focused on the oxidative methoxyla-
tion of mesitol (1) with hydrogen peroxide in methanol in the
presence of a bromide source and 1 mol% WO42À exchanged
on LDH (Table 1). Hydrogen peroxide was added slowly to
Scheme 1. Bromide-assisted oxidation of mesitol with H2O2 to the
corresponding p-quinol (ether) over WO42À-exchanged layered double
hydroxide.
Table 1: BrÀ-assisted oxidation of mesitol (1) to 4-methyoxy-4-methyl-
cyclohexa-2,5-dienone (1a).[a]
charged reaction partners BrÀ and peroxotungstate. As a
result, the bromide-oxidation rate is increased tremendously.
In the absence of either WO42À-LDH or BrÀ, no product was
observed after 12 h (Table 1, entries 5–6). As a solvent, a
methanol/ethyl acetate mixture proved suitable, though
satisfactory yields were also obtained in pure methanol or
other methanol-containing mixtures (73–85%, data not
shown). However, when acetone is used or when the water
content is too high, the yields of 1a drastically drop to lower
values (32 and 72%; Table 1, entries 7–8).
Entry
Catalyst,
conditions
Yield[b]
(Conversion) [%]
t [h]
p/o[c]
2À
1
2
3
4
5
6
7
8
NiAl[NO3À, WO4
]
91 (100)
84 (97)
86 (92)
21 (28)
0 (<1)
0 (<1)
72 (95)
32 (34)
0.5
0.5
0.5
6
12
12
1
25:1
24:1
21:1
23:1
–
–
24:1
24:1
NiAl[ClÀ, WO4
]
2À
MgAl[NO3À, WO4
]
2À
Na2WO4·2H2O
no WO42À catalyst
no NH4Br
5 vol% water
acetone instead of
ethyl acetate
1
The synthetic utility of this heterogeneous tungstate-
catalyzed oxidation was evaluated with a wide range of
variously substituted phenols (Table 2). Alkylated phenols
undergo the BrÀ-assisted oxidative methoxylation in moder-
ate to excellent yields, especially when the ortho and para
positions are substituted (Table 2, 1–4; 81–91%). However,
when the ortho or para positions are unsubstituted, stable
brominated phenols are the main products (5–6). This
limitation does not hold for the p-alkoxylated phenols (7–
10), and high yields of the p-benzoquinone monoketals are
obtained, irrespective of the substitution pattern. A consid-
erable benefit of the catalytic procedure is that the products
are not transketalized. Thus, the WO42À-LDH can be used for
the synthesis of mixed ketal 4-ethoxy-4-methoxycyclohexa-
2,5-dienone (8a). When Tl salts are used as the oxidant, 8a is
not accessible because of TlIII-induced transketalization.[6,13]
Reactions with o-alkoxylated phenols, 11, are less selective
and give rise to a mixture of products, including the o-quinone
monoketal 11b. The latter is unstable and dimerizes through a
Diels–Alder mechanism.[9f]
[a] Conditions, unless mentioned otherwise: WO42À-LDH (Ni0.64Al0.36
-
À
(OH)2[(WO42À
)
0.045(NO3
)0.27]·0.6H2O) (17 mg), MeOH/EtOAc/H2O
(10 mL; 30:68.5:1.5 vol%), NH4Br (0.15m), 1 (0.06m), aqueous H2O2
(35 wt%; added at 2.8 mmolhÀ1), 608C. Product yields and identities
were determined by GC and GC–MS, and, after product extraction with
1
diethyl ether, by H and 13C NMR spectroscopic analysis. [b] Yield of p-
and o-quinol ethers. [c] Molar ratio of p- and o-quinol ethers.
the reaction mixture. We employed LDHs as supports with
)
xy/2(AÀ)x(1Ày)]·
II
1Àx
2À
varying compositions M MIxII(OH)2[(WO4
mH2O (MII = ZnII, NiII, MgII; MIII = AlIII, GaIII; AÀ = ClÀ,
À
NO3 ).[12] In our experience, the oxidative bromination
proceeds fastest with LDHs with a large degree of isomor-
phous substitution (x = 0.37) and with tungstate contents of
20–25% of the total anion exchange capacity (y = 0.25–0.30).
NiII- and NO3 -containing LDHs have especially high pro-
À
ductivities: quinol ether 1a was produced in 87% yield within
30 min (Table 1, entry 1). With MgII in the hydroxide layers or
with ClÀ as the counterion, the yield of 1a is only slightly
lower (Table 1, entries 2–3). In contrast, with the homoge-
neous catalyst Na2WO4, only 21% of 1a is formed after 6 h
(Table 1, entry 4). This result highlights the importance of the
LDH support in facilitating the bromide oxidation
(Scheme 1). Indeed, the cationic surface, decorated with
peroxotungstate anions, attracts bromide anions and thus
compensates for the repulsion between the negatively
Finally, the use of various alcohol nucleophiles was
evaluated in Table 3. If the bromide salt is sufficiently soluble
in the solvent mixture and the alcohol is not too bulky (as for
example, tert-butyl alcohol), many alcohol reagents lead to
the quinol ether products in good yields (75–91%). The
oxidative alkoxylation is highly para-selective, with p/o ratios
> 20:1, in contrast to most existing procedures.[9,14]
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Communications
Table 2: Oxidation of substituted phenols to quinol ethers.[a]
conditions, this compound rapidly reacts
with the alcohol to form the quinol
ether,[15,17] and the eliminated HBr can
participate in a new catalytic cycle. Under
acidic conditions, the same 4-Br compound
rearranges into the stable 3-bromomesi-
tol.[9e] Clearly, for the success of the overall
transformation, it is essential to avoid acid-
ity, which underlines again the need for a
haloperoxidase mimic capable of halide
oxidation under neutral conditions.
Substrate
Product
R1
R2
R3
H2O2
[equiv]
Yield
(Conv.) [%]
1
2
3
4
5
1a
2a
3a
4a
5a
Me
iPr
tBu
tBu
H
Me
iPr
tBu
tBu
Me
Me
Me
Me
tBu
Me
2.3
3.0
3.2
6.0
4.0
91 (100)
88 (100)
87 (96)
81 (94)
21 (100)[b]
Regarding the efficiency of hydrogen
peroxide, it is important to avoid the
unproductive reduction of OBrÀ by excess
hydrogen peroxide, which yields singlet
oxygen. Whether this occurs depends on
the hydrogen peroxide concentration, the
pH value of the reaction conditions, and the
reactivity of the phenol. In the case of 1 in
0.15m NH4Br, dropwise addition of hydro-
2.3
71 (100)[c]
gen peroxide at
a maximum rate of
7
8
9
10
7a
8a
9a
10a
H
H
H
Me
H
H
Cl
Me
OMe
OEt
OMe
OMe
2.3
2.3
2.3
2.3
94 (100)
92 (100)
92 (99)
500 mol(mol W)À1 hÀ1 resulted in reasona-
ble yields based on the concentration of
hydrogen peroxide.
89 (100)
Careful analysis of the products from 1
showed that the p-quinol 4-hydroxy-2,4,6-
trimethylcyclohexa-2,5-dienone (1c) was
always formed in small amounts. Since 1b
is a drug and vitamin E precursor,[2] we
briefly investigated its formation. In reac-
tion conditions similar to those given in
Table 3, and in a water/THF solvent mixture
(9:1), 1c is produced in 91% yield, with only
2,6-dimethylquinone as a minor byproduct.
4.0
56 (96)[d]
[a] Conditions as in Table 1; 0.5–1 h. [b] 2-Brominated product (m/z=200–202): 59% yield. [c] m/z=
214–216. [d] p/oꢀ8:1; to be taken with caution because of considerable dimerization of the ortho
product.
Table 3: WO42À-LDH-catalyzed oxidative alkoxylation of mesitol (1) with
various alcohols.[a]
Entry
Alcohol
(ROH)
Products
H2O2
[equiv]
p/o
Yield
(Conv.) [%]
1
2
3
4
5
6
7
8
9
MeOH
EtOH
2.3
2.3
2.3
3.2
3.2
3.2
3.2
3.2
3.2
3.2
25:1
26:1
24:1
25:1
n.d.
n.d.
n.d.
27:1
30:1
n.d.
91 (100)
89 (100)
86 (100)
84 (100)
21 (68)
81 (100)
82 (98)
75 (99)
78 (95)
3 (85)
nPrOH
nBuOH
nHexOH
AllylOH
AmylOH
iPrOH
In conclusion, we have designed a one-pot metal-cata-
lyzed procedure for the synthesis of 4-alkoxy- or 4-hydroxy-
substituted cyclic 2,5-dienones in good yields from a broad
range of phenol substrates. Although this particular class of
phenol oxidations has often been performed with stoichio-
metric oxidants, we propose a metal-catalyzed route based on
the clean oxidant hydrogen peroxide. A unique feature of the
WO42À-LDH/NH4Br/H2O2 catalytic system is that high bro-
mide-oxidation rates are decoupled from strong acidity which
allows a high chemoselectivity for the desired quinol products
to be reached.
iBuOH
tBuOH
10
[a] Conditions as in Table 1, except that methanol is replaced by other
alcohols.
As is known from previous mechanistic work,[11b] hydro-
gen peroxide is activated by the tungstate to give peroxo-
tungstates, which in turn oxidize BrÀ into hypobromite. As
shown in Scheme 1 and in agreement with literature
reports,[15,16] subsequent electrophilic bromination of mesitol
(1) by HOBr generates the 4-bromocyclohexa-2,5-dienone
intermediate, which in some reactions was detected as a
transient product in small amounts by GC–MS. Under neutral
Received: August 5, 2004
Revised: September 2, 2004
Keywords: heterogeneous catalysis ·
.
hydroxycyclohexadienones · oxidation · peroxides · tungsten
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