Synthesis of methoxy-substituted phenols by peracid oxidation of the aromatic ring

Article abstract of DOI:10.1021/jo050944c

A novel benign protocol for the preparation of hydroxy-methoxybenzene derivatives is disclosed. By utilizing this protocol, activated aromatic compounds such as l,3-dimethoxy-2-methyl-benzene and 1-(2,6-dimethoxyphenyl) ethanone are smoothly converted to the corresponding monohydroxylated compound. The reaction can be considered to be a normal aromatic electrophilic substitution reaction, and the regioselectivity for the reaction thus follows the similar rules as for electrophilic substitutions. The protocol is composed by benign reagents, namely, hydogenperoxide, acetic acid, and p-toluene sulfonic acid, which lead to the production of ethaneperoxoic acid in situ. The ethaneperoxoic acid operates as the hydroxylating reagent. The hydroxylation reaction is completed within a short period and requires moreover only mild experimental conditions, which make this novel protocol a green, cheap, and rapid process leading to hydroxy-methoxybenzene derivatives. The proposed reaction mechanism is supported by density functional theory and NMR spectroscopy experiments. The mechanism is constituted by two discrete steps: (a) addition of OH+ to the most nucleophilic carbon atom of the aromatic ring, which is the rate-determining step, and (b) the loss of the proton from the aromatic ring.

Full text of DOI:10.1021/jo050944c

Synthesis of Methoxy-Substituted Phenols by Peracid Oxidation of
the Aromatic Ring
Hans-Rene´ Bjørsvik,* Giovanni Occhipinti, Cristian Gambarotti, Leonardo Cerasino, and
Vidar R. Jensen
Department of Chemistry, University of Bergen, Alle´gaten 41, N-5007, Bergen, Norway
hans.bjorsvik@kj.uib.no
Received May 11, 2005
A novel benign protocol for the preparation of hydroxy-methoxybenzene derivatives is disclosed.
By utilizing this protocol, activated aromatic compounds such as 1,3-dimethoxy-2-methyl-benzene
and 1-(2,6-dimethoxyphenyl)ethanone are smoothly converted to the corresponding monohydroxy-
lated compound. The reaction can be considered to be a normal aromatic electrophilic substitution
reaction, and the regioselectivity for the reaction thus follows the similar rules as for electrophilic
substitutions. The protocol is composed by benign reagents, namely, hydogenperoxide, acetic acid,
and p-toluene sulfonic acid, which lead to the production of ethaneperoxoic acid in situ. The
ethaneperoxoic acid operates as the hydroxylating reagent. The hydroxylation reaction is completed
within a short period and requires moreover only mild experimental conditions, which make this
novel protocol a green, cheap, and rapid process leading to hydroxy-methoxybenzene derivatives.
The proposed reaction mechanism is supported by density functional theory and NMR spectroscopy
experiments. The mechanism is constituted by two discrete steps: (a) addition of OH+ to the most
nucleophilic carbon atom of the aromatic ring, which is the rate-determining step, and (b) the loss
of the proton from the aromatic ring.
Introduction
as the reacting species for the direct oxidation of the
aromatic ring. Peroxydisulfate4 or peroxydiphosphate5
operate successfully as oxidants for the aromatic ring in
the presence of another oxidant such as Cu(II). Typical
for all of these radical methods is that they operate with
a varying degree of selectivity. Various metal complexes
containing Fe,6 Pt,7 or V8 have been studied for the
oxidation of benzene to phenol as an alternative to the
Hydroxylation of aromatic compounds has for decades
been a research topic of extensive interest from an
academic as well as an industrial standpoint. Direct
hydroxylation of simple aromatic and polycyclic aromatic
hydrocarbons can be performed by means of a plethora
of methods. Free-radical processes utilizing molecular
oxygen or metal-catalyzed hydrogen peroxide oxidation
known as Fenton-type oxidation reactions are examples
(2) Udenfriend, S.; Clark, C. T.; Axelrod, J.; Brodie, B. B. J. Biol.
Chem. 1954, 208, 731-739.
that generate the OH radical as the reactive species.1
•
(3) Hamilton, G. A.; Friedman, J. P. J. Am. Chem. Soc. 1963, 85,
1008-1009.
The Udenfriend2 and the Hamilton3 protocols are two
more methods based on the generation of the •OH radical
(4) Walling, C.; Camaioni, D. M.; Kim, S. S. J. Am. Chem. Soc. 1978,
100, 4814-4818.
(5) Tomizawa K.; Ogata, Y. J. Org. Chem. 1981, 46, 2107-2109.
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Chem. Commun. 1991, 2, 102-104.
* To whom correspondence should be addressed. Ph: +47 55 58 34
52. Fax: +47 55 58 94 90.
(1) (a) Fenton, H. J. H. Proc. Chem. Soc. 1893, 9, 113. (b) Fenton,
H. J. H. J. Chem. Soc. 1894, 65, 899. (c) Walling, C. Acc. Chem. Res.
1975, 8, 125-131. (d) Tezuka, T.; Narita, N.; Ando, W.; Oae, S. J. Am.
Chem. Soc. 1981, 103, 3045-3049. (e) Walling, C.; Amarnath, K. J.
Am. Chem. Soc. 1982, 104, 1185-1189.
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4371.
10.1021/jo050944c CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/30/2005
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J. Org. Chem. 2005, 70, 7290-7296

Synthesis of Methoxy-Substituted Phenols
autoxidation process of cumene.9 Some heterogeneous
systems with hydrogen peroxide as the terminal oxidant
have also been established, though one of the more
successful ones utilizes titanium silicalite together with
hydrogen peroxide.10 Electrophilic monohydroxylation of
aromatic compounds was demonstrated using a series of
peroxide reagents,11 although a common characteristic
for these protocols was that they provided rather low
yields of the target phenols. Olah and co-workers have
demonstrated in a series of reports12 how electrophilic
hydroxylation of the aromatic ring can be performed
using hydrogen peroxide and superacid. These protocols
provide good to high yield, although under rather harsh
and cryogenic conditions. In these systems it is supposed
SCHEME 1
+
that the H3O2 ion operates as the reacting species.
Cytochrome P450 catalyzed oxidation of polyaromatic
compounds, a reaction that involves the NIH shift, was
disclosed by Jerina and co-workers.13
A system that attracted our interest was the Lewis acid
promoted electrophilic hydroxylation with peracids as
disclosed by Hart and Buehler14 and in the communica-
tions of Griffin and co-workers.15,16 A similar oxidation
seems to have taken place as a side reaction in a current
project in our laboratory, although with the presence of
a Brønsted rather than a Lewis acid. Our project involves
investigation of new strategies and protocols leading
toward the synthesis of the carbazole framework in
general and of Carbazomycines (A-H)17 in particular. For
this purpose we required access to 2,4-dimethoxy-3-
methylphenol 5 (Scheme 1) and derivatives thereof. In
addition to the preparation of the required compound,
we wanted to perform a “green chemistry improvement”
of existing syntheses,18,19 especially the B-V oxidation
step. Instead of performing B-V oxidation with mCPBA,
we designed a protocol involving hydrogen peroxide,
acetic acid, and p-toluene sulfonic acid (pTSA) as the
oxidizing system. This reagent substitution was foreseen
(1) to improve the atom economy and thus reduce the
quantity of effluents, (2) to avoid handling of chloroor-
ganics, and (3) to utilize benign, cheap, large-scale
industrial chemicals that are easy to handle.
Similar to prior disclosures,18,19 we utilized a synthetic
pathway as outlined in Scheme 1, steps a-c. The com-
mercially available 2,6-dimethoxy-3-methylbenzene 1
was submitted to Friedel-Craft acylation by treatment
with acetyl chloride and aluminum trichloride using
nitroethane as solvent.20 The reaction proceeded with
high yield (96%) to give the acetophenone 2. The next
step was the Baeyer-Villiger oxidation utilizing our new
protocol to successfully achieve the acetate 3 in high
yields (92%) and with the side product (∼7%) acetic acid
5-hydroxy-2,4-dimethoxy-3-methylphenyl ester 4. The
phenol 5 was obtained under hydrolytic conditions,
pathway c, in nearly quantitative yields.
At this stage, our original task was satisfactorily
accomplished. However, the observed results raised three
questions, namely, (1) is the novel B-V oxidation protocol
a general procedure for the transformation of acetophe-
nones to the corresponding phenylacetates, (2) what is
the mechanism that provided the byproduct 4, and (3)
can the observed direct hydroxylation reaction be devel-
oped into a novel route to phenols? The observation of
the phenol 4 turned out to be of special interest, since
compound 4 apparently was produced by direct hydroxy-
lation of the aromatic ring by the action of the peracid
or by protonated hydrogen peroxide.21
(9) (a) Hock, H.; Lang, S. Ber. 1944, 77b, 257-264. (b) Jordan, W.;
Barneveld, H.; Gerlich, O.; Ullrich, J. Cumol-Oxidation (Hock-Process).
In Ullmanns Encyklopa¨die der technischen Chemie, 4th ed.; Verlag
Chemie: Weinheim, 1979, Vol. 18.
(10) (a) Romano, U.; Esposito, A.; Maspero, F.; Neri, C.; Clerici, M.
G. Chim. Ind. (Milan, Italy) 1990, 72, 610-616. (b) Romano, U.;
Esposito, A.; Maspero, F.; Neri, C.; Clerici, M. G. In New Developments
in Selective Oxidation; Centi, G., Trifiro, F., Eds.; Elsevier: Amsterdam
1990; Studies in Surface Science and Catalysis, Vol. 55, p 33.
(11) (a) Derbyshire, D. H.; Waters, W. A. Nature 1950, 165, 401. (b)
Vesely, J. A.; Schmerling, L. J. Org. Chem. 1970, 35, 4028-4034. (c)
McClure, J. D.; Williams, P. H. J. Org. Chem. 1962, 27, 24-26. (d)
Kurz, M. E.; Johnson, G. J. J. Org. Chem. 1971, 36, 3184-3187. (e)
Olah, G. A.; Keumi, T.; Fung, A. P. Synthesis 1979, 7, 536-537. (f)
Hashimoto, S.; Koike, W. Bull. Chem. Soc. Jpn. 1970, 43, 293. (g)
Kovacic, P.; Morneweck, S. T. J. Am. Chem. Soc. 1965, 87, 1566-1572.
(h) Kovacic, P.; Kurz, M. E. J. Am. Chem. Soc. 1965, 87, 4811-4818.
(i) Kovacic, P.; Kurz, M. E. J. Org. Chem. 1966, 31, 2011-2013.
(12) (a) Olah, G. A.; Ohnishi, R. J. Org. Chem. 1978, 43, 865-867.
(b) Olah, G. A.; Fung, A. P.; Keumi, T. J. Org. Chem. 1981, 46, 4305-
4306. (c) Olah, G. A.; Keumi, T.; Lecoq, J. C.; Fung, A. P.; Olah, J. A.
J. Org. Chem. 1991, 56, 6148-6151.
Methods and Results
(13) Guroff, G.; Daly, J. W.; Jerina, D. M.; Renson, J.; Witkop, B.;
Udenfriend, S. Science 1967, 157, 1524-1530.
Reaction and Spectroscopic Experiments. A series
of methoxy-substituted acetophenones were submitted to
the Baeyer-Villiger protocol composed of H2O2, CH3-
COOH, and pTSA. Moreover, for comparison purposes,
(14) (a) Hart, H.; Buehler, C. A. J. Org. Chem. 1964, 29, 2397-2400.
(b) Hart, H.; Buehler, C. A.; Waring, A. J. Adv. Chem. Ser. 1965, 51,
1-9.
(15) Ishikawa, K.; Charles, H. C.; Griffin, G. W. Tetrahedron Lett.
1977, 427-430.
(16) Ishikawa, K.; Griffin, G. W. Angew. Chem. 1977, 89, 181-182.
(17) (a) Sakano, K.; Ishimaru, K.; Nakamura, S. J. Antibiot. 1980,
33, 683-689. (b) Sakano, K.; Nakamura, S. J. Antibiot. 1980, 33, 961-
966. (c) Kaneda, M.; Sakano, K.; Nakamura, S.; Kushi, Y.; Iitaka, Y.
Heterocycles 1981, 15, 993-998. (d) Kondo, S.; Katayama, M.; Marumo,
S. J. Antibiot. 1986, 39, 727-730. (e) Naid, T.; Kitahara, T.; Kaneda,
M.; Nakamura, S. J. Antibiot. 1987, 40, 157-164. (f) Kaneda, M.; Naid,
T.; Kitahara, T.; Nakamura, S.; Hirata, T.; Suga, T. J. Antibiot. 1988,
41, 602-608.
(18) Clive, D. L. J.; Etkin, N.; Joseph, T.; Lown, J. W. J. Org. Chem.
1993, 58, 2442-2445.
(19) Kno¨lker, H.-J.; Fro¨hner, W.; Reddy, K. R. Eur. J. Org. Chem.
2003, 740-746.
(20) Shepard, E. K.; Porter, H. D.; Noth, J. F.; Simmans, C. K. J.
Org. Chem. 1952, 17, 568-576.
(21) Øiestad, A° . M. L.; Petersen, A. C.; Bakken, V.; Vedde, J.;
Uggerud, E. Angew. Chem., Int. Ed. 2001, 40, 1305-1309.
J. Org. Chem, Vol. 70, No. 18, 2005 7291

Bjørsvik et al.
TABLE 1. Experimental Results from Two Various Oxidation Systems: (1) mCPBA/pTSA in CH3CN/80 °Ca and (2)
H2O2/pTSA/CH3COOH/80 °Cb
a Acetophenone (1.0 mmol) was dissolved in CH3CN (5.0 mL) followed by addition of p-toluene sulfonic acid monohydrate (0.20 mmol)
and mCPBA (1.0 mmol). The reaction mixture was then leaved under stirring for 1 h at 80 °C (reflux). Another portion (1.0 mmol) of the
oxidant mCPBA was then added and the reaction mixture was then left 1 h under stirring at reflux. b Acetophenone (1.0 mmol) was
dissolved in CH3COOH (5.0 mL) followed by adding p-toluene sulfonic acid monohydrate (0.20 mmol) and hydrogen peroxide (5.0 mmol).
The reaction mixture was then left under stirring and heating at 80 °C for 1 h.
the acetophenones were also submitted to the B-V
protocol that utilizes mCPBA as oxidant. Details con-
cerning the experimental conditions and results obtained
are provided in Table 1.
All of the acetophenones 7-12 were oxidized to afford
the expected phenyl acetates. 3,5-Dimethoxyacetophe-
none 6 was, however, oxidized to only a small extent, only
14% conversion. The expected phenyl acetate was not
observed among the oxidized products from this com-
pound. Only two of the acetophenones, namely, 3,4-
dimethoxyacetophenone 7 and 4-methoxy acetophenone
11 provided the corresponding phenyl acetates (7a and
11a) with a selectivity of ∼100%.
Some of the products obtained form the oxidation of
the acetopheneones 6, 8, 9, and 10 were, however,
unexpected, since these were shown to be oxidized
directly on the aromatic ring to provide the corresponding
hydroxy acetophenone or hydroxyphenyl acetate as oxi-
dation products. The experimental result achieved sug-
gests that the hydroxylation proceeds with a preference
7292 J. Org. Chem., Vol. 70, No. 18, 2005

Synthesis of Methoxy-Substituted Phenols
SCHEME 2
for the para position to the methoxy group. In cases
where this position was blocked by another group,
hydroxylation did not take place on the aromatic ring.
The results attained spurred us on to subject compound
1 to the oxidation conditions in an attempt to produce
the original target 2,4-dimethoxy-3-methylphenol 5 via
direct oxidation. To the best of our knowledge, such a
reaction has not been previously described.
1,3-Dimethoxy-2-methylbenzene 1 was thus submitted
to oxidative conditions constituted by hydrogenperoxide,
acetic acid, and pTSA (Scheme 2). An oxidation experi-
FIGURE 1. 1H NMR monitoring of the oxidation carried out
by means of hydrogen peroxide, acetic acid, and p-toluene
sulfonic acid of 1,3-dimethoxy-2-methylbenzene 1 to 2,4-
dimethoxy-3-methylphenol 5. Chemical shifts are referred to
the CD2HCN peak at δ 1.98 ppm. Spectrum a reveals only
1,3-dimethoxy-2-methylbenzene 1. The labeled peaks (/) of
spectrum d shows 2,4-dimethoxy-3-methylphenol 5 as the
major component of the mixture, while the spectra c and d
shows how those signals steadily are strengthened during the
course of the reaction.
1
ment was monitored by means of H NMR spectroscopy
with the two-fold goal of identifying the structure of the
reaction product and of searching for transient chemical
entities present during the course of the reaction, infor-
mation that subsequently could be used as pieces of the
reaction mechanistic puzzle.
Figure 1 shows details from the regions δ 7.2-6.5, 3.8-
1
3.2, and 2.4-1.9 ppm of the H NMR spectra recorded
during the course of the reaction. The spectrum shown
in Figure 1a was recorded at 298 K after a reaction time
of 10 min. The only visible signals are the aromatic ones
belonging to compound 1, namely, at 7.12 ppm (proton
H,4 triplet) and 6.59 ppm (the protons H3 and H,5
doublet), respectively.
SCHEME 3
The reaction mixture was then heated to 318 K and
left for 1 h after which a spectrum was recorded (Figure
1b). A new chemical entity was now present in the
solution since a new resonance was discerned at δ 6.76
ppm (doublet). The spectrum shown in Figure 1c was
recorded after a reaction time of 2 h, still at a tempera-
ture of 318 K. The new entity was at this time much more
clearly seen in two aromatic signals, one doublet at δ 6.76
ppm, which was already present after 1 h (Figure 1b)
and a second doublet at δ 6.58 ppm that was undetectable
in the spectrum of Figure 1b because it was buried under
the starting compound signal. At this stage of the
reaction, about 45% of the substrate 1,3-dimethoxy-2-
methylbenzene 1 was converted into the new entity.
The reaction mixture was cooled to 306 K, and a
spectrum was recorded after an additional 1 h of reaction
time (3 h); see Figure 1d. The new entity was now more
abundant than the starting material 1 (65% conversion).
The new oxidation product showed two aromatic
protons that gave rise to an AB system in which JAB is
8.8 Hz (A, δ 6.74 ppm; B, δ 6.59 ppm). This is typical of
vicinal protons. Together with these signals, two new
O-methyl resonances (δ 3.67 ppm and δ 3.66 ppm) and a
C-methyl (δ 2.06 ppm) emerged. The presence of only two
aromatic protons (on adjacent carbons) and the two
distinct methoxy signals indicate that the oxidation
product is 2,4-dimethoxy-3-methylphenol 5. Moreover, a
singlet integrating for one proton at δ 3.32 ppm accounts
for the OH group of the phenol 5.
oxide species similar to the mechanism for the arene
oxidation catalyzed by cytochrome P450 (involving the
NIH shift).13 Signal peaks of the vicinal protons of such
an arene oxide were expected to be found in the region
of δ 3.25 ppm. However, such a signal was absent in all
of the recorded spectra.
It is known that H3O2 can act as a source of HO.+ 22
+
The hydroxylation conditions we utilized here, that is,
with the presence of the strong acid pTSA, provide
conditions for the formation of the H3O2+ ion. This species
may thus be the source of the cation acting in place of or
in mutual action with the ethaneperoxoic acid formed in
situ. An experiment was thus designed for the resolution
of this problem: acetonitrile was used as reaction me-
dium in place of acetic acid. A large quantity of pTSA
(0.3 equiv) and the oxidant hydrogen peroxide (6 equiv)
was mixed, and the substrate 1,3-dimethoxy-2-methyl-
benzene 1 (3 equiv) was added and heated at 75 °C for 1
h. Samples were analyzed on GC-MS, but only traces of
the expected phenol were detected. In contrast, when
acetic acid was used as the solvent under otherwise
similar conditions, a yield of 85% of the phenol was
achieved. From these experiments we can conclude that
the H3O2+ ion eventually formed in the reaction mixture
(pathway b of Scheme 3) acts only to a very small extent
as the hydroxylation reagent and that the ethaneperoxoic
acid formed in situ operates as the hydroxylation reagent
(pathway a of Scheme 3).
In addition to the structure elucidation of the oxidizing
product, we looked for intermediates of this reaction. One
of our initial, mechanistic proposals embraces an arene
(22) Olah, G. A.; Yoneda, N.; Parker, D. G. J. Am. Chem. Soc. 1977,
99, 483-488.
J. Org. Chem, Vol. 70, No. 18, 2005 7293

Bjørsvik et al.
SCHEME 5
This interpretation suggests considering the peracid
as a soft electrophile,26-28 which is capable of transferring
OH+ to soft nucleophiles, such as alkenes. Aromatic
compounds, for example, benzene, are able to react with
several relatively strong electrophiles in order to undergo
electrophilic substitution.
FIGURE 2. (a) Structure of protonated ethene epoxide. (b)
Transition state for epoxidation of ethene by etheneperoxoic
acid.
SCHEME 4
Our experimental data (Table 1) reveal that activated
aromatic compounds such as 1-(2,6-dimethoxyphenyl)-
ethanone 9 and 1,3-dimethoxy-2-methylbenzene 1 react
with the peracid to produce the corresponding phenols
in high yields. In both cases, the OH group is introduced
in the para position to a methoxy group. It is reasonable
to believe that the course of the reaction can proceed in
a similar way as in the case of alkenes, namely through
an OH+ transfer to two vicinal nucleophilic carbons,
namely, C3 and C,4 and to possess a similar transition
state as well. Although another workable mechanism is
that the HO+ transfer proceeds only to the most nucleo-
philic and thus the most electron-rich carbon, which is
C3 for the two studied compounds 1 and 9.
Scheme 5 outlines a reaction pathway for the hydroxy-
lation of the aromatic ring, here exemplified by benzene.
Geometry optimization of protonated benzene oxide A (7-
oxonia-bicyclo[4.1.0]hepta-2,4-diene) results in a very
shallow minimum with a barrier to formation of the
hydroxylation that vanishes upon inclusion of thermal
corrections. Rearrangement to the much more stable
hydroxyl cation B can thus be expected to be rapid.
Obviously, this also suggests that the hydroxylation of
benzene proceeds via a transition state involving the
cation (Figure 3b) and not an intermediate or a transition
state involving protonated benzene oxide (TS) (Figure 3a).
All of our attempts to obtain a transition state involv-
ing a symmetric protonated oxide (structure A, Scheme
5) for each of the two derivatives 1,3-dimethoxy-2-
methylbenzene 1 and 1-(2,6-dimethoxyphenyl)ethanone
9 failed. Similar efforts with benzene led instead to a
second-order saddle point (see Figure 3a), with one
imaginary frequency (-421 cm-1) due to a mode that
leads to the symmetric epoxide, and one imaginary
frequency at (-112 cm-1) due to a mode that leads to the
asymmetric cation transition state (structure B, Scheme
5). The cation transition state is easily obtained and the
optimized geometries for benzene, 2,6-dimethoxybenzne,
and 1-(2,6-dimethoxyphenyl)ethanone are shown in Fig-
ure 3b, c, and d, respectively.
To unravel the importance of the presence of the strong
acid (pTSA), an experiment was conducted in acetic acid
without the presence of the pTSA, heating at 75-80 °C
for 6 h to obtain a yield of 65%. Prolonging the reaction
time to 8 h resulted in a higher conversion, but a minor
decomposition of the phenol was also observed as well.
This experiment demonstrates that the hydroxylation
rate is promoted by the presence of a Brønsted acid, but
the excess of the Brønsted acid is not required to operate
the reaction.
DFT Calculations. Density functional theory calcula-
tions were performed in our endeavor to establish further
mechanistic information for the direct oxidation of the
aromatic ring of the methoxybenzene derivatives shown
in Table 1. The calculations were performed on three
different reactant pairs: (1) 1,3-dimethoxy-2-methylben-
zene 1 and ethaneperoxoic acid, (2) 1-(2,6-dimethoxyphe-
nyl)ethanone 9 and ethaneperoxoic acid, and for com-
parison purposes (3) benzene and ethaneperoxoic acid.
It is known that peracids can act as electrophiles in
the epoxidation of alkenes,23-25 a reaction that proceeds
through a concerted transition state to provide directly
the epoxide with the corresponding carboxylic acid as a
side product. The transition state for the epoxidation of
ethene with ethaneperoxoic acid (see Figure 2b) shows a
H-O bond length (∼1 Å) similar to those of the corre-
sponding protonated epoxide (see Figure 2a), which
indicates that the deprotonation has not yet been initi-
ated in the transition state and hence may suggest that
the epoxidation proceeds over two consecutive steps. The
first step is OH+ transfer from the peracid to the double
bond [step a, Scheme 4], producing the protonated
epoxide as an intermediate (strong acid). A straightfor-
ward deprotonation by means of the carboxylate ion [step
b, Scheme 4] concludes the epoxidation.
(23) Bartlett, P. D. Rec. Chem. Prog. 1950, 11, 47-51.
(24) Bach, R. D.; Canepa, C.; Winter, J. E.; Blanchette, P. E. J. Org.
Chem. 1997, 62, 5191-5197.
(25) Freccero, M.; Gandolfi, R.; Sarzi-Amade`, M.; Rastelli, A. J. Org.
Chem. 2004, 69, 7479-7485.
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3533-3539.
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7294 J. Org. Chem., Vol. 70, No. 18, 2005

Synthesis of Methoxy-Substituted Phenols
FIGURE 3. (a) Second-order saddle point structure for benzene and s-cis ethaneperoxoic acid. (b) Saddle point (transition state,
TS) structure for benzene and s-cis ethaneperoxoic acid. (c) TS structure for 1,3-dimethoxy-2-methylbenzene and s-cis ethaneperoxoic
acid. (d) TS structure for 1-(2,6-dimethoxyphenyl)ethanone and s-cis ethaneperoxoic acid.
TABLE 2. Calculated Energies for Direct Oxidation of
Aromatics Compounds with Peracid (Calculated for s-cis
Ethaneperoxoic Acid)
SCHEME 6. Proposal for Mechanism for
Hydroxylation of the Aromatic Ring with a
Peroxoic Acid
On the basis of the above considerations and spectro-
scopic and experimental results, our proposal for the
reaction mechanism is as follows. The reaction appears
to take place over two steps. The first one is the OH+
transfer from the peracid to the aromatic carbon in the
para position to a methoxy group. The second step is a
concerted process involving the proton loss and rearo-
matization to yield the corresponding phenols. An outline
for the reaction of 1 f 5 is given in Scheme 6. The first
step, pathway a, is the rate-limiting step, and analysis
of the transition state energies can provide information
about the relative rates of different substrates; see Table
2. Our experimental data show that the 1,3-dimethoxy-
2-methylbenzene 1 is slightly more reactive than 1-(2,6-
dimethoxyphenyl)ethanone 9 and that benzene did not
react under these reaction conditions. These experimen-
tal results are in agreement with the relative order of
the transition state energy, namely, ∆Gq298K (benzene) >
∆Gq298K (9) > ∆Gq298K (1); for details see Table 2. It is also
evident that this trend in barrier heights follows Ham-
monds postulate.29 The early TS found for 1 (Figure 3c),
as judged from, for example, the length of the O-H bond
to be broken, is also associated with the lowest barrier.
The loss of proton from the aromatic ring, step b, can
take place following several pathways, but all involve the
participation of a base, and a series of DFT calculations
of such processes have in all cases given reaction barriers
that are substantially lower than those of pathway a.
Several entities in the reaction mixture can intervene
during this proton loss: the acetate ion, the p-toluensul-
fonate ion, and water. A detailed discussion regarding
this deprotonation, however, goes beyond the scope of the
present study.
a ∆Ε, ∆H, and ∆G are in kcal mol-1 and ∆Sq is in cal mol-1
K-1 b Restricted DFT (RB3LYP) calculations were performed
.
throughout, except for the TS of the oxidation of benzene for which
a triplet instability was detected. This TS was therefore optimized
using unrestricted formulation (UB3LYP). Details are given in
Experimental Section.
Discussion and Conclusion
A novel reaction for the hydroxylation of methoxyben-
zene derivatives utilizing peracids is presented. The
reaction proceeds through electrophilic substitution of the
aromatic ring with HO+ provided from a peracid. In
electrophilic substitution reactions, the methoxy group
operates as strongly activating, which thus leads to
electrophilic attack in the ortho or para positions to itself.
The two compounds 1 and 9 that have been thoroughly
investigated in the present study possess methoxy groups
in the 2- and 6-positions that correspond to the meta
position relative to the 4-position of the molecule. The
consequence is a strong deactivation toward electrophilic
attack on the 4-position of the two molecules. Thus, the
obtained oxidation products of 1 and 9 utilizing the
disclosed protocol provide the corresponding phenols
where the hydroxyl group is introduced in the 3-position.
The proposed reaction mechanism is supported by
density functional theory and is constituted by two
discrete steps: (a) the addition of OH+ to the aromatic
(29) Hammond, G. S. J. Am. Chem. Soc. 1955, 77, 334-338.
J. Org. Chem, Vol. 70, No. 18, 2005 7295

Bjørsvik et al.
(298 K) for a period of 10 min. From this mixture, a sample of
ca. 1 mL volume was withdrawn and transferred to a NMR
tube, whereas a spectrum was immediately recorded. The
temperature was then raised to 45 °C (318 K). After reaction
times of 1 and 2 h, NMR spectra were recorded. The temper-
ature was then decreased to 33 °C (306 K) and left for 1 h,
when a spectrum was recorded. The 1H NMR spectra were
recorded on a Bruker DPX 400 MHz Spectrometer. 1D spectra
were acquired accumulating 128 transients into 32 k data
points over a spectral width of 8.0 kHz.
Computational Details. Geometry optimizations were
performed using the B3LYP hybrid functional,30 as imple-
mented in the Gaussian 03 set of programs,31 in conjunction
with 6-311+G(d,p) basis sets.32,33 The latter basis sets imply
the contractions [4s,1p] for H atoms and [5s,4p,1d] for carbon
and oxygen atoms.
Thermochemical corrections to obtain enthalpies and Gibbs
free energies were computed within the harmonic-oscillator,
rigid-rotor, and ideal-gas approximations using the same
method and basis sets as in the geometry optimizations. A
restricted formulation, i.e., RB3LYP, was initially used through-
out and all the thus obtained solutions were tested for triplet
instabilities. A triplet instability was only detected for the
transition state of oxidation of benzene with peracid and thus
an unrestricted formulation was used for the optimization of
this structure. The spin expectation value before ( sˆ2 ) 0.185)
and after ( sˆ2 ) 0.005) anhilation of the first (S + 1) spin
contaminant showed that the resulting mixed state was only
marginally contaminated by higher spin states and almost
exclusively by the triplet state.
ring, which is also the rate-determining step, and (b) the
loss of the proton from the aromatic ring. The transition
state of step (a) essentially has a O-H bond distance
equal to that of the resulting hydroxyl cation, which
shows that this step proceeds as a direct addition of HO+
to the most nucleophilic carbon atom of the aromatic ring.
Moreover, a mechanism of oxidation through formation
of a peroxide transition state or intermediate is found
not to be viable. The reaction can be considered to be a
normal aromatic electrophilic substitution reaction, and
thus the regioselectivity follows the similar rules as for
electrophilic substitutions.
The hydroxylation reaction needs as substrates acti-
vated aromatic compounds such as 1,3-dimethoxy-2-
methylbenzene 1 and 1-(2,6-dimethoxyphenyl)ethanone
9. Benign reagents and mild conditions make this novel
protocol a green, cheap, and rapid process to hydroxyl-
methoxybenzene derivatives, which can be utilized in the
synthesis of numerous natural compounds, and for
example, compound 5 is used in the synthesis of the
Carbazomycins G and H.19
Experimental Section
Oxidation of 1,3-Dimethoxy-2-methylbenzene (1) with
H2O2 as Terminal Oxidant. 1,3-Dimethoxy-2-methylbenzene
1 (0.456 g, 3 mmol) was dissolved in glacial acetic acid (15
mL) and thereafter were added p-toluene sulfonic acid mono-
hydrate (57 mg, 0.3 mmol) and hydrogenperoxide (30%, 0.68
mL, 6 mmol). The reaction mixture was heated at 70 °C for 1
h under vigorously stirring with a magnetic stirrer bar. The
reaction mixture was cooled to room temperature, and the
acetic acid was evaporated under vacuum. Water (50 mL) was
added and extracted with dichloromethane (2 × 50 mL). The
organic layer was dried over anhydrous sodium sulfate,
filtered, and evaporated under vacuum to achieve the phenol
5 (crude 0.218 g, GC purity >99%, ∼1.3 mmol).
Acknowledgment. Economic support from the Re-
search Council of Norway (G.O.), Politecnico di Milano
and Department of Chemistry at University of Bergen
(C.G.) is gratefully acknowledged. We also acknowledge
CPU resources granted by the Research Council of
Norway through the NOTUR supercomputing program.
Professor George Francis is thanked for linguistic
assistance.
Oxidation of 1-(2,4-Dimethoxy-3-methylphenyl)-etha-
none (2) with H2O2 as Terminal Oxidant. 1-(2,4-Dimethoxy-
3-methylphenyl)-ethanone 2 (1.27 g crude product, GC purity
96%, ∼6.29 mmol) was dissolved in glacial acetic acid (15 mL)
and thereafter were added p-toluene sulfonic acid monohydrate
(300 mg, 1.6 mmol) and hydrogenperoxide (40%, 2.0 mL, 26
mmol). The reaction mixture was heated at 70 °C for 2 h under
high speed stirring with a magnetic stirrer bar. The reaction
mixture was cooled to room temperature, and the acetic acid
was evaporated under vacuum. Water (50 mL) was added and
extracted with dichloromethane (2 × 50 mL). The organic layer
was dried over anhydrous sodium sulfate, filtered, and evapo-
rated under vacuum to achieve the ester 3 (crude 1.33 g, GC
purity 92%, ∼5.8 mmol).
Supporting Information Available: General experimen-
tal information, analytical data, copies of 1H and 13C NMR
spectra for compounds 5, 8d, and 9b, and the Cartesian
coordinates of geometry optimized species shown in Figures
2a,b and 3a-d. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO050944C
(30) B3LYP is a three-parameter hybrid density functional method
by Becke (see Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652.)
(31) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.;
Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.;
Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai,
H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P.
Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,
O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
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Wallingford CT, 2004.
Oxidation of 1-(2,4-Dimethoxy-3-methylphenyl)-etha-
none (2) with mCPBA as Terminal Oxidant. The ac-
etophenone 2 (1.0 mmol) was dissolved in CH3CN (5.0 mL)
followed by adding p-toluene sulfonic acid monohydrate (0.2
mmol) and mCPBA (1.0 mmol). The reaction mixture was then
left under stirring for 1 h at 80 °C (reflux). Another portion
(1.0 mmol) of the oxidant mCPBA was then added and the
reaction mixture was then left for 1 h at reflux. A sample (0.1
mL) was withdrawn from the reaction mixture, dichlo-
romethane (2 mL) was added, and analysis was carried out
by GC-MS.
NMR Experiment 1 f 5. 1,3-Dimethoxy-2-methylbenzene
1 (456 mg, 3.0 mmol) was dissolved in glacial acetic acid (3
mL). p-Toluene sulfonic acid monohydrate (57 mg, 0.3 mmol),
hydrogenperoxide (0.68 mL 30%, 6 mmol), and 25% (v/v) of
CD3CN (1.0 mL) were then added to the reaction mixture
under good agitation and heated at a temperature of 25 °C
(32) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem.
Phys. 1980, 72, 650-654.
(33) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P.
v. R. J. Comput. Chem. 1983, 4, 294-301.
7296 J. Org. Chem., Vol. 70, No. 18, 2005