Copper(II)-mediated autoxidation of tert-butylresorcinols

Article abstract of DOI:10.1021/jo020582y

Although copper(II)-mediated oxidation of phenols results in oxidative coupling rather than in oxygenation, it was recently reported that naturally occurring 5-alkylresorcinols undergo oxygenation in the presence of copper(II). To explore the generality of this reaction, the copper(II)-mediated autoxidation of 4-tert-butylresorcinol and 4,6-di-tert-butylresorcinol was investigated and was found to result in direct oxygenation at open activated positions and, at the tert-butyl-substituted positions, in oxygenation with competing loss of (as isobutylene) and 1,2-rearrangement of the tert-butyl group. 5-tert-Butyl-2-hydroxy-1,4-benzoquinone is the major product from both starting materials, and the final product mixture reflects, in part, coupling of metastable initially formed electrophilic and nucleophilic side products. Mechanisms that are consistent with the observed products and control reactions are proposed. The key step appears to be equilibration of a copper(II)-resorcinolate with a charge-transfer radical form that reacts regioselectively with O₂ as prescribed by resonance.

Full text of DOI:10.1021/jo020582y

Cop p er (II)-Med ia ted Au toxid a tion of ter t-Bu tylr esor cin ols
Ke-Qing Ling, Younghee Lee, Dainius Macikenas, J ohn D. Protasiewicz, and
Lawrence M. Sayre*
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106
lms3@po.cwru.edu
Received September 4, 2002
Although copper(II)-mediated oxidation of phenols results in oxidative coupling rather than in
oxygenation, it was recently reported that naturally occurring 5-alkylresorcinols undergo oxygen-
ation in the presence of copper(II). To explore the generality of this reaction, the copper(II)-mediated
autoxidation of 4-tert-butylresorcinol and 4,6-di-tert-butylresorcinol was investigated and was found
to result in direct oxygenation at open activated positions and, at the tert-butyl-substituted positions,
in oxygenation with competing loss of (as isobutylene) and 1,2-rearrangement of the tert-butyl group.
5-tert-Butyl-2-hydroxy-1,4-benzoquinone is the major product from both starting materials, and
the final product mixture reflects, in part, coupling of metastable initially formed electrophilic and
nucleophilic side products. Mechanisms that are consistent with the observed products and control
reactions are proposed. The key step appears to be equilibration of a copper(II)-resorcinolate with
a charge-transfer radical form that reacts regioselectively with O2 as prescribed by resonance.
In tr od u ction
definitive demonstration of a copper(II) (as opposed to
copper(I)) mediated arene oxygenation. However, copper-
(II)-mediated oxygenations should be possible for mol-
ecules where coordination to CuII promotes the otherwise
uncatalyzed autoxidation of the compound.
Copper(II)-mediated autoxidation of alkylphenols re-
sults in oxidative coupling rather than in oxygenation.5
However, a recent study reported that CuII can catalyze
autoxidative oxygenation of 5-alkylresorcinols to give
6-alkylbenzene-1,2,4-triols and 6-alkyl-2-hydroxy-1,3-
benzoquinones (eq 1).6 The different behavior may reflect
Copper-mediated oxygenation of phenols1 is of interest
both in terms of commercial production of benzenediols
and quinones and in terms of understanding the mech-
anism of action of copper enzymes that carry out arene
monooxygenation.2 All such reactions that have been
examined in detail require the use of CuI-ligand com-
plexes for initial activation of O2, and the most well
understood examples involve a stoichiometric oxygen-
ation by a binuclear µ-η2:η2-biscopper(II) peroxo core,
leaving a copper(II)-O-copper(II) byproduct.3 The latter
species would have to be reduced back to copper(I) to
make the process catalytic in copper. Although copper-
(II)-mediated oxidation (dehydrogenation) of hydroquino-
nes and especially catechols to the corresponding p- and
o-benzoquinones is well precedented,4 there has been no
the more electron rich nature of resorcinols compared to
phenols. The symmetry of 5-alkylresorcinols and the lack
of substitution at the most activated C4-position (ortho
to one OH and para to the other) result in a fairly clean
reaction in this case. In considering the generality of such
a reaction, it is unclear what the fate would be of
4-alkylresorcinols under such conditions, where one of
the two most activated positions is substituted.
* To whom correspondence should be addressed. Phone: (216) 368-
3704. Fax: (216) 386-3006.
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10.1021/jo020582y CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/23/2003
1358
J . Org. Chem. 2003, 68, 1358-1366

CuII-Mediated Autoxidation of tert-Butylresorcinols
TABLE 1. HMQC a n d HMBC Da ta of P r od u ct 5 in
As part of another study, we recently reported that
4-tert-butylresorcinol readily undergoes CuII-mediated
autoxidation to give mainly 5-tert-butyl-2-hydroxy-1,4-
benzoquinone, as well as a side product.6 The details of
this reaction are now disclosed along with additional
studies identifying another side product of the reaction
and efforts to clarify the mechanistic nature of the CuII-
mediated oxygenations. Oxygenation of 4-tert-butyl-
resorcinol occurs at both the unsubstituted 6-position and
at the 4-position, in the latter case resulting in either
loss or rearrangement of tert-butyl.
DMSO-d 6 (p p m )a
HMQC
HMBC
9.99 T 157.1, 132.5, 99.1
9.90 T 199.5, 152.5, 147.2
-
-
7.01 T 121.2 7.01 T 157.1, 151.1, 51.3, 34.4
6.69 T 99.1
2.77 T 46.0
6.69 T 157.1, 151.1, 132.5, 119.3
2.77 T 199.5, 179.6, 152.5 (w), 147.2, 119.3 (w),
51.3
2.58 T 46.0
1.33 T 29.5
0.97 T 27.4
2.58 T 199.5, 179.6, 152.5 (w), 147.2, 119.3, 51.3
1.33 T 132.5, 34.4, 29.5
0.97 T 147.2, 34.6, 27.4
a
The symbol T denotes the C-H correlation, while “w” in
parentheses means weak C-H correlation.
Resu lts a n d Discu ssion
P r od u ct Id en t ifica t ion . A mixture of 4-tert-butyl-
resorcinol (1) and 0.1 equiv of Cu(ClO4)2‚6H2O in air-
equilibrated acetonitrile-water was found to generate
5-tert-butyl-2-hydroxy-1,4-benzoquinone (2) and a side
product (3) in a 3:1 ratio,7 along with another, nonisolable
minor side product. Product 3 formed red crystals in the
NMR tube (CD3CN) and was isolated as such. The
structure could not be assigned using NMR spectroscopy
and mass spectral data, though it was clear that it
contained the equivalents of two mol of 1 minus one tert-
butyl group, suggesting the generation of 2-hydroxy-1,4-
benzoquinone (4) from 1. The same reaction run at a 10-
fold dilution afforded much reduced levels of 3 relative
to 2 (along with a substantial amount of unreacted 1),
implicating 3 as derived from bimolecular coupling of
initial products. The identity of 3 as 3-(4-(1,1-dimethyl-
ethyl)-5-hydroxy-2-oxo-(5H)-furan-5-yl)-5-hydroxybenzo-
furan-2,6-dione was revealed by X-ray diffraction. Com-
pound 3 incorporates the elements of a des-tert-but-
ylquinone nucleus joined as a quinone methide to a
muconic acid oxidative cleavage product apparently
derived from 2. Details of the structural determination
are provided in the Supporting Information. Although 3
contains a chiral center, crystals of 3 are racemic and
contain both enantiomeric forms. Hydrogen bonding in
the molecule involves carbonyl oxygen O6 forming proxi-
mate contacts with both H7-O7 (O6-O7 ) 2.762(2) Å)
and H2-O2 (O6-O2 ) 2.735(2) Å) in different molecules.
The unusual structure of 3 inspired a preliminary
examination of its mode of formation. The reaction rate
increased over the pH range 7-11, but the 2:3 product
ratio was unchanged. Importantly, the starting resorcinol
1 was recovered from the reaction run in the presence of
a metal chelator (diethylenetriaminepentaacetic acid) or
in the strict absence of either CuII or O2. The reaction
outcome was also solvent dependent: the same reaction
in pH 11 phosphate buffer in the absence of CH3CN gave
no 3 and instead 2 as the major product, along with an
increased amount of the side product seen in the aqueous
CH3CN reaction. Although the reaction in buffer alone
was more complex, and several polar neutral products
were present that could not be identified, the side product
could now be isolated and was shown by HRMS to derive
from two molecules of resorcinol 1, one molecule of O2,
loss of one H2O, and a further dehydrogenation (or
3
addition of /2O2 and loss of two waters).
The new dimer could not be crystallized, but its 1H
NMR spectrum exhibited two different tert-butyl groups
(0.97 and 1.32 ppm), an isolated diastereotopic methylene
(2.58 and 2.77 ppm, J ) 18.7 Hz), and only two aryl
singlets (6.69 and 7.01 ppm), suggesting the presence of
only one of the original two aromatic rings, containing
two para protons. The 13C NMR spectrum displayed only
two carbonyl groups, and two carbonyl absorptions are
found in the IR spectrum at 1802 and 1706 cm-1. The IR
spectrum also showed a broad hydroxy band at 3404
cm-1, but no absorption corresponding to a carboxyl group
(∼2500 cm-1). Considering the molecular formula and
various mechanisms for oxygenative dimerization, sev-
eral isomeric structures could be drawn that fit the above
findings to varying degrees. HMQC and HMBC data in
CDCl3 permitted elimination of all structures except for
three, 5-7. Using the phenolic and enolic protons as
structural probes, HMQC and HMBC experiments in
DMSO-d6 (Table 1) ruled out structure 7. The key
evidence was the observation of a three-bond correlation
of the enol proton (9.90 ppm) with the carbonyl carbon
(199.5 ppm) in the HMBC spectrum (see Figure 1 and
the Supporting Information). If the structure were 7, this
correlation would have been with the quaternary carbon
at 51.3 ppm. Finally, the structure was assigned as 5
rather than 6 on the basis of NOE difference experiments.
Irradiation of the tert-butyl protons at 0.97 ppm resulted
in strong enhancements of the aryl signal at δ 7.01
(0.32%) and the enolic OH signal at δ 9.90 (0.25%) and a
(7) Lee, Y.; J eon, H.-B.; Huang, H.; Sayre, L. M. J . Org. Chem. 2001,
66, 1925-1937.
J . Org. Chem, Vol. 68, No. 4, 2003 1359

Ling et al.
TABLE 2. Cop p er (II)-Med ia ted Oxid a tion of Resor cin olsa
phenol
(concn, mM)
copper(II)
(concn, mM)
solvent
(pH)
reaction
time (h)
conversion
(%)
productsb
(yield, %)
atmosphere
1 (10)
1 (10)
1 (10)
1 (10)
1 (10)
9 (10)
9 (10)
Cu(ClO4)2 (1)
Cu(ClO4)2 (10)
Cu(ClO4)2 (10)
CuSO4 (1)
Cu(ClO4)2 (1)
Cu(ClO4)2 (1)
CuSO4 (1)
MeCN/H2O (10)c
MeCN/H2O (10)c
MeCN/H2O (10)c
buffer (11)d
air
air
argon
air
air
1.5
0.5
3
1.5
1.5
1.5
1.5
98
100
47
38
39
2 (57), 3 (13), 5 (8)
2 (53), 3 (12), 5 (7)
11 (62), 12 (19)
2 (27), 5 (17)
2 (30), 5 (13)
2 (45), 10 (12)
2 (40), 10 (13)
buffer (11)d
MeCN/H2O (10)c
buffer (11)d
air
air
99
89
a
The conversion of substrates and the product distribution were determined by 1H NMR using 1,4-dimethoxybenzene as an internal
standard. Based on consumed resorcinols. c The ratio for MeCN/H2O was 1:1 (v/v), and the pH was controlled by adding aqueous NaOH
and monitored using a pH meter. 0.1 M phosphate buffer.
b
d
a stoichiometric concentration of CuII (Table 2). Although
no reaction of 1 was apparent in the absence of O2 using
0.1 mol equiv of CuII, the use of stoichiometric CuII under
argon did accomplish a slow conversion of 1 in pH 10
aqueous acetonitrile. The major products in this case
were shown to be dimer 11 and the Pummerer’s ketone
12 (Table 2), while the other two possible dimers (13 and
14) were not found. The finding that this latter reaction
F IGURE 1. 1H and 13C chemical shifts of product 5.
weak enhancement of the aryl signal at δ 6.99 (0.06%),
but only very weak enhancement of the methylene
signals at δ 2.58 and 2.77 (both 0.02%). The latter should
be the most strongly enhanced if the structure is 6.
The fact that the dimer exists in enol form 5 rather
than its keto tautomer 5a is consistent with reports on
1,2-cyclopentanedione derivatives, which were shown by
NMR to exist in the enol form in most solvents.8 With
the identification of 5, the product profile of the CuII-
promoted autoxidations of 1 can be summarized as in
Table 2. Although the perchlorate salt of CuII was used
is so slow indicates that simple CuII-induced oxidation
in most cases for convenience, the observed oxidation is
of the resorcinol or the coordinated resorcinolate to a
not derived from ClO4-, as CuSO4 gave the same results
radical that can either couple or react with O2 is not a
(compare entries 4 and 5 in Table 2).
kinetically competent step in the normal CuII-catalyzed
The finding that CuII-mediated autoxidation of 1
autoxidation pathway. This assertion and the observed
advantage of higher pH suggest that the rate-limiting
step of autoxidation is direct reaction of O2 with a copper-
(II)-resorcinolate complex, which otherwise dimerizes
only slowly on its own.
The finding that 2 was the major product arising from
resulted in partial loss of the 4-tert-butyl group ortho/
para to the hydroxyls and in oxygenation apparently only
at the other ortho/para-position (i.e., there was no
evidence for oxygenation at C2 to give 8) led us to
investigate the same reaction with 4,6-di-tert-butylresor-
cinol (9). The question is whether 9 might be forced to
9 shows that dealkylation at the most activated ortho/
react at least partly at C2 now that both activated ortho/
para-position is preferred over oxygenation at the less
para-positions are tert-butyl substituted. In fact, 9 was
activated but unsubstituted ortho/ortho-position, at least
found to afford the suspected o-quinone 10 (minor) and
in the case of tert-butyl. A unified depiction of the reaction
pathways for 1 and 9 that rationalizes the observed
product outcome is shown in Scheme 1. For the purposes
of discussion, we have depicted the key copper(II)-
resorcinolate 15 to be in unfavorable equilibrium with a
the des-tert-butylquinone 2 (major) as the only isolable
products, regardless of reaction solvent (Table 2). When
the autoxidation of 9 was run in a closed air-equilibrated
system with CCl4 added as a second solvent phase,
1
analysis of the CCl4 layer by H NMR in CDCl3 revealed
charge-transfer complex that has three resonance forms,
the presence of isobutylene, suggesting this was the
16-18. This analysis leads to oxygenation of the complex
at three possible sites on the benzene ring to give peroxy
radicals 19-21, respectively, in analogy to what was
major fate of the tert-butyl group.
Stu d ies on Rea ction Mech a n ism . Consumption of
1 was found to proceed to completion using 0.1 mol equiv
proposed in the CuII-mediated oxygenation of 5-alkyl-
of CuII, implicating a catalytic role of copper. However,
resorcinols.6 It should be noted that, for 1, there are two
possible starting copper(II)-resorcinolates, though the
identical outcome shown in Scheme 1 arises if copper is
autoxidation of 1 was found to occur more rapidly using
(8) Ponaras, A. A. Tetrahedron Lett. 1980, 21, 4803-4806 and
references therein.
coordinated alternatively to the 3-hydroxy group.
1360 J . Org. Chem., Vol. 68, No. 4, 2003

CuII-Mediated Autoxidation of tert-Butylresorcinols
SCHEME 1
For resorcinol 1, oxygenation at the site indicated by
resonance structure 16 gives rise to the ipso-substituted
hydroperoxide intermediate 22, which is precedented in
cobalt(II)-mediated autoxidation of 2,6-di-tert-butylphe-
nol.9 This intermediate can undergo a cyclic electronic
reorganization to generate the des-tert-butylquinone 4
along with isobutylene and water.10 In the case of 9,
resonance structures 16 and 17 (R ) tert-butyl) are
identical and lead to the major des-tert-butyl product 2
by the same mechanism. At the same time, we have
shown that ipso-peroxy intermediates arising from cop-
per-mediated oxygenation of tert-butylated phenols can
rearrange to quinones with 1,2-migration of the tert-butyl
group.11 In the case of resorcinol 1, 22 (R ) H) should
thus lead to quinone 25, whereas the same rearrange-
ment starting with resorcinol 9 would lead to a sterically
unfavorable o-di-tert-butyl-substituted quinone, and was
not observed. In addition to the mechanisms previously
discussed,11 rearrangement of 22 (R ) H) to 25 could
proceed via a dioxirane intermediate (eq 2). Further
precedent for the simultaneous oxygenative loss and 1,2-
rearrangement of the tert-butyl group is found in the
previously studied base-catalyzed autoxidation of 9,
which was reported to give both 2 and 5,6-di-tert-butyl-
2-hydroxy-2-cyclohexene-1,4-dione.12
dehydrate to give 2. Oxygenation at the remaining site,
indicated by resonance structure 18, is evidently less
favorable, since the predicted product 8 from 1 was not
found. In the case of 9, however, since the only other
alternative requires expulsion of tert-butyl, the pathway
through 24 can now compete, and o-quinone 10 is now
seen as a minor product. It is interesting to note that
dimers 13 and 14, which represent oxidative coupling at
the 2-position of one or both molecules of resorcinol, were
not found in the stoichiometric CuII-mediated anaerobic
coupling of 1. This result and the apparent absence of 8
in the oxidation of 1 together suggest that the resonance
form 18, representing localization of unpaired electron
density at C2 of the resorcinoxy radical, is a minor
contributor to the resonance hybrid. Overall, although
we depict the reactions in Scheme 1 in terms of a
mononuclear CuII-resorcinolate species, we have no data
that bear on the nature of the actual complex undergoing
reaction with O2, and binuclear or higher order complexes
could well be involved, possibly linking both coordination
sites in the reactant.
According to the oxygenation mechanism in Scheme
1, the new oxygen atom in the major product 2 during
autoxidation of 1 and 9 derives from O2. Although O2 is
absolutely required to get 2, a theoretically possible
alternate mechanism might involve O2 only as the
oxidant required to induce a copper-mediated addition
(9) Nishinaga, A.; Shimizu, T.; Toyoda, Y.; Matsuura, T. J .; Hirotsu,
K. J . Org. Chem. 1982, 47, 2278-2285 and references therein.
(10) Loss of tert-butyl could also proceed by Criegee rearrangement
of 22 to give a tert-butyl hemiketal that cyclodehydrates to quinone 4
and isobutylene, though simple dissociation to 4 and tert-butyl alcohol
might also be expected.
(11) Mandal, S.; Macikenas, D.; Protasiewicz, J . D.; Sayre, L. M. J .
Org. Chem. 2000, 65, 4804-4809.
(12) Musso, H.; Maassen, D. Liebigs Ann. Chem. 1965, 689, 93-
108.
For resorcinol 1, oxygenation of resonance form 17
would lead to species 23 (R ) H), which would simply
J . Org. Chem, Vol. 68, No. 4, 2003 1361

Ling et al.
SCHEME 2
5, respectively. In the case of 25 (6-tert-butyl-2-hydroxy-
1,4-benzoquinone), the C5-position is electrophilic and
could couple to the activated C6-position of starting
resorcinol 1 by a Friedel-Crafts-like aromatic substitu-
tion (Michael addition of 1 to 25)14 to give 27 (Scheme
3). This same reaction with 1 might be considered for
major product 2, except that the electrophilic position in
2 is tert-butyl substituted. Intermediate 27 would be
subject to oxidation and intramolecular cyclization, lead-
ing to a benzilic ester-like rearrangement15 to the enol
tautomer of observed product 5 (Scheme 3).
The potential for 4 to be the precursor of the des-tert-
butyl portion of 3 was shown by the finding that the
reaction of independently prepared 4 with 2, to some
extent, or especially triol 26 in the presence of a catalytic
amount of CuII at pH 10 afforded 3 in a higher yield
(comparable to that of recovered 2) than was obtained
from 1 under the same conditions (eq 3). The formation
of 3 was strictly CuII dependent; in the absence of CuII,
4 was decomposed to unidentified products and only 2
could be isolated.
of H2O to resorcinol, either by activation of the water (to
a species with HO+ or HO• character) or by activation of
the resorcinol toward nucleophilic water addition. To
distinguish whether the new oxygen in 2 derives from
O2 or from H2O, an 18O-labeling experiment was con-
ducted. Thus, both 1 and 9 were allowed to undergo CuII-
mediated autoxidation to 2 using 18O2 in the presence of
excess 16OH2. The caveat of this experiment is that 2 is
known to undergo carbonyl oxygen exchange in water at
the position where the new oxygen is incorporated,
especially at elevated pH levels.13 Although this exchange
can be suppressed by conducting the autoxidation in
anhydrous media, the final product 2 in this case would
be 18O labeled regardless of mechanism, since any water
becoming available (from reduction of O2) would also be
labeled. To minimize exchange, we had to find conditions
that achieved a compromise in converting 1 and 9 to 2
in a reasonably short time, but at a modest basic pH.
The reaction conditions chosen involved conducting the
autoxidation with 18O2 in acetonitrile in the presence of
10 equiv of 16OH2 (with respect to resorcinol) using
anhydrous Cu(CF3SO3)2 and NaOMe as base (aqueous
NaOH was insufficiently miscible with CH3CN). To
ensure minimal carbonyl oxygen exchange in 2, a short
reaction time (10 min), a stoichiometric amount of Cu-
(CF3SO3)2, and a minimum amount of NaOMe were used,
and the major product 2 was characterized in its reduced
form 26 by a reductive quench of the reaction (NaBH4),
at which point no further exchange would occur (Scheme
2). Higher pH (initially 11, dropping to 8) was needed
for sufficient conversion of 1 to 2 than of 9 to 2 (initial
pH 9, dropping to 7), so we expected in the former case
a greater degree of exchange in 2 during the 10 min
reaction time prior to reductive quenching. Our finding
that the abundance of 18O-labeled 26 was 28% for
autoxidation of 1 and 75% for autoxidation of 9 (see the
Experimental Section) is consistent with the oxygenation
mechanism in Scheme 1. If the source of new oxygen were
from water, the 18O incorporation should have been no
more than ∼9% since, using 10 equiv of 16OH2, the 18O
content of the water would have reached only 1 part in
11 by the end of the reaction.
On the basis of the above findings, Scheme 4 outlines
proposed mechanisms for generation of 3 from 2 and 4.
Any mechanism must provide for the oxygenative cleav-
age of 2 to provide the tert-butylmuconic acid portion of
3. We propose Baeyer-Villiger formation of muconic
anhydride 28 initiated by addition of one of the peroxide
intermediates generated in the oxygenation of 1 to the
electrophilic carbonyl of 2. Enol 28 could then undergo
conjugate addition to the electrophilic C5-position of 4
to give 29 (Scheme 4, path A). Nucleophilic carbon
addition to 4 has been observed previously.16 Intra-
molecular lactonization of 29 followed by two-electron
oxidation of the vinylogous hydroquinone 31 in equilib-
rium with 30 would generate the ring-opened tautomer
32 of observed product 3. Alternatively, since 4 is also
well-known to undergo conjugate addition of heteroatom
nucleophiles,17 anhydride 28 could first hydrolyze (Scheme
4, path B), followed by conjugate addition of the more
nucleophilic carboxylate of 33 to the C5-position of 4 to
give benzenetriol ester 34. Oxidation of the 34 would
generate ester intermediate 35 that would be expected
to cyclocondense to give 32. Since either pathway requires
a two-electron autoxidation expected to generate H2O2,
the key oxygenative cleavage of 2 would likely be effected
mainly by H2O2 rather than by ROOH after a short period
(14) Musso, H.; Gizycki, U. v.; Zahorszky U. I.; Bormann, D. Liebigs
Ann. Chem. 1964, 676, 10-20.
(15) Cuntze, U.; Maassen, D.; Musso, H. Chem. Ber. 1969, 102,
2851-2861.
(16) Butsugan, Y.; Muto, Masao, M.; Kawai, M.; Araki, S.; Murase,
Y.; Saito, K. J . Org. Chem. 1989, 54, 4215-4217. Cheng, A. C.; Shulgin,
A. T.; Castagnoli, N., J r. J . Org. Chem. 1982, 47, 5258-5262.
(17) Alt, C.; Eyer, P. Chem. Res. Toxicol. 1998, 11, 1223-1233.
Manthey, M. K.; Pyne, S. G.; Truscott, R. J . W. Aust. J . Chem. 1989,
42, 365-373.
P r op osed P a th w a ys to P r od u cts 5 a n d 3. Although
quinones 4 and 25, postulated to be generated from 1,
are not observed as isolated products of the reaction, they
are the key species proposed to result in products 3 and
(13) Mandal, S.; Lee, Y.; Purdy, M. M.; Sayre, L. M. J . Am. Chem.
Soc. 2000, 122, 3574-3584.
1362 J . Org. Chem., Vol. 68, No. 4, 2003

CuII-Mediated Autoxidation of tert-Butylresorcinols
SCHEME 3
SCHEME 4
of reaction.18 Also, if the initial peroxide adding to 2 were
22 (R ) H), the byproduct would be 5-tert-butyl-1,2,4-
benzenetriol (26), which would be oxidized to 2 as part
of Scheme 1, generating H2O2 from O2.
phile, so that these two species react preferentially with
each other.
The structure of 3 shares its benzofuran-2,6-dione core
with that of a family of structurally characterized red
pigments called xylerythrins from the fungus Peniophora
sanguinea.19 The latter represent formally the lactone
form of quinone methide Perkin-like condensation prod-
ucts of 3,6-diaryl-2,5-dihydroxy-1,4-benzoquinones with
arylacetic acids (eq 4), which have been synthesized by
The proposed routes for generation of 3 and 5 in the
same reaction bring up the question of potential compet-
ing reactions. In both cases, the initial bimolecular
coupling involves a nucleophile-electrophile combina-
tion, 28 with 4 in the case of 3 and 1 with 25 in the case
of 5. The alternate pairing of the two possible nucleo-
philes and two possible electrophiles would lead to two
additional products that were not observed, though there
were several minor unidentified products generated in
the reaction. It is possible that the reaction outcome is
controlled by the fact that 28 is expected to be the more
reactive nucleophile and 4 is the more reactive electro-
(18) The requirement for peroxide-induced cleavage of 2 (Scheme
4) explains why 3 was obtained in much higher yield from reaction of
4 with triol 26 as opposed to 2: autoxidation of triol 26 would give
both the required 2 and H2O2.
such a route.20 We thus considered that 3 might arise
alternatively from such a condensation. If so, the ret-
J . Org. Chem, Vol. 68, No. 4, 2003 1363

Ling et al.
50% Ag2CO3 on Celite in 200 mL of refluxing toluene for 10
min, cooling, filtering, concentrating until a solid appeared,
and then collecting the yellow solid which crystallized. 4,6-
Di-tert-butylresorcinol (9) was prepared by mixing resorcinol
and 2 equiv of tert-butyl alcohol in phosphoric acid.23 All other
reagents and solvents were obtained from commercial sources
and used as received unless otherwise noted. Reactions in
aqueous solution were carried out using Millipore purified
water. All reactions were carried out at room temperature (25
°C) with magnetic stirring unless otherwise noted, and all
evaporations were carried out at reduced pressure with a
rosynthetic analysis shown in eq 4 would suggest con-
densation of the des-tert-butyl precursor 2,5-dihydroxy-
1,4-benzoquinone (36) with a ring-opened â-keto acid
derived from oxidative cleavage of 2 (eq 5). However,
1
rotary evaporator. The H NMR spectra were obtained at 200
or 300 MHz (13C NMR at 50 or 75 MHz), with chemical shifts
being referenced to the TMS or solvent peak(s), expressed on
the δ scale. Attached proton test (APT) designations for 13C
NMR spectra are given in parentheses. Two-dimensional
HMQC and HMBC spectra were recorded using a 600 MHz
spectrometer. High-resolution mass spectroscopy (HRMS) was
done in either electron impact (EI) mode (24 eV) or fast atom
bombardment (FAB) mode (glycerol matrix). Thin-layer and
preparative-layer chromatographies were run on silica gel 60
plates with a 254 nm indicator.
Cop p er (II)-Ca ta lyzed Oxid a tion of 4-ter t-Bu tylr esor -
cin ol (1) in Aqu eou s Aceton itr ile. A mixture of 1 (166 mg,
1 mmol) and Cu(ClO4)2‚6H2O (37 mg, 0.1 mmol) in 100 mL of
acetonitrile-water (1:1) was adjusted to pH 10.0 by adding 4
N NaOH. The solution was stirred vigorously in an open 250
mL Erlenmeyer flask at 25 °C with monitoring of the pH. As
the reaction progressed, the pH dropped and was readjusted
to pH 10 by addition of 4 N NaOH. After 1.5 h of stirring, the
reaction mixture was acidified with HCl to pH 3.0, concen-
trated to remove the CH3CN, and extracted with EtOAc (50
mL). The organic layer was dried (Na2SO4) and evaporated,
and the residue was dissolved in CD3CN. The 1H NMR
spectrum showed a mixture of 2 and 3 in a ratio of 3:1. Red
crystals that formed in the NMR tube after 2 days at room
temperature were filtered and washed with CH3CN to give
pure 3-(4-(1,1-dimethylethyl)-5-hydroxy-2-oxo-(5H)-furan-5-yl)-
5-hydroxybenzofuran-2,6-dione (3; 27 mg, 9%): 1H NMR
(DMSO-d6) δ 1.13 (s, 9H), 6.27 (s, 1H), 6.32 (s, 1H), 6.88 (s,
1H), 8.69 (br s, 1H, OH); 13C NMR (APT, DMSO-d6) δ 29.4
(-), 33.8 (+), 100.1 (-), 104.5 (+), 104.6 (-), 118.4 (-), 121.4
(+), 144.8 (+), 153.7 (+), 158.8 (+), 164.4 (+), 169.3 (+), 174.8
(+), 181.6 (+); FAB HRMS exhibited the M + 1 ion for the
reduced form of 3,24 m/z calcd for C16H17O7 321.0974 found
321.0987.
For quantitative analysis of the percent conversion of 1 and
the yield of products, the same reaction was repeated, and the
final EtOAc extract was concentrated to 10 mL. A 5 mL aliquot
(corresponding to 0.5 mmol of starting 1) was utilized for the
1H NMR spectral determination (CDCl3), with 138 mg (1 mmol)
of 1,4-dimethoxybenzene being added as an internal standard
(Table 2).
The same reaction described above occurred over the pH
range 7.0-11.0, giving the same ratio of products (2:3 in a ratio
of 3:1), except that the reaction was slower at lower pH. The
addition of 1 equiv of 2,2′-bipyridine (based on copper) to the
reaction did not alter the results. However, CuII was found to
be essential for this reaction, because a separate reaction
performed without CuII for 1.5 h at pH 10 resulted in recovery
of starting 1.
reaction of independently generated 36 with either 2 or
its reduced triol form 26 in the presence of air and CuII
did not afford any 3, giving instead 2 as the only organic
extractable material (no significant reaction occurred in
the absence of CuII). Thus, even if 36 were formed in the
CuII-mediated oxidation of 1, it evidently would not lead
to 3 under the reaction conditions. As far as why 36 did
not serve as a precursor to 3, it should be noted that the
xylerythrin syntheses are conducted under acidic condi-
tions, and under the basic conditions used here, 36 likely
becomes an inactive electrophile relative to competing
base decomposition processes.
In conclusion, facile CuII-mediated oxygenation of 1 has
been shown to afford 2 as the main product, reflecting
oxygenation at the unsubstituted position ortho/para to
the two resorcinol hydroxyls. In addition, on the basis of
the isolation of two side products (3 and 5), oxygenation
also evidently occurs at the ortho/para-position bearing
the tert-butyl group. This can result in either loss of tert-
butyl, leading to quinone 4 that serves as a precursor to
3, or a 1,2-shift of the tert-butyl group to give the quinone
25, proposed as the precursor to 5. Although oxygenation
at the ortho/ortho-position (C2) of 1 is not observed, C2
oxygenation does compete as a minor pathway in the
reaction of 9, where both ortho/para-positions (identical)
are tert-butyl substituted. The observed facile CuII-
mediated oxygenation of 4-alkylresorcinols parallels the
reaction seen for 5-alkylresorcinols, and is notable in that
CuII-mediated autoxidation of simple phenols results only
in oxidative coupling, whereas phenol oxygenation re-
quires the involvement of CuI-ligand catalysis. The
difference is probably due to greater ease of one-electron
oxidation of resorcinols compared to phenols, permitting
CuII to activate the resorcinol, through charge-transfer
coordination, toward reaction with O2. The resorcinol
oxygenations appear worthy of additional investigation.
Exp er im en ta l Section
Gen er a l In for m a tion . 5-tert-Butyl-2-hydroxy-1,4-benzo-
quinone (2) was prepared according to our previous work.21
2-Hydroxy-1,4-benzoquinone22 (4) was prepared freshly before
use by stirring 1,2,4-benzenetriol (2.5 mmol) with 2 equiv of
Cop p er (II)-Ca t a lyzed Oxid a t ion of 1 in P h osp h a t e
Bu ffer . To a well-stirred 0.1 M pH 11 sodium phosphate buffer
solution (500 mL) were added a clear solution of 1 (830 mg, 5
mmol) in 2 mL of methanol and then 500 µL (0.5 mmol) of 1
M aqueous CuSO4. The mixture was stirred vigorously in air
for 1.5 h, acidified with concentrated HCl to pH 2, and then
(19) Abrahamsson, S.; Innes, M. Acta Crystallogr. 1966, 21, 948-
956. Gripenberg, J .; Hiltunen, L.; Pakkanen, T.; Pakkanen, T. Acta
Chem. Scand., B 1980, 34, 575-578.
(20) Pattenden, G.; Pegg, Neil A.; Kenyon, R. W. J . Chem. Soc.,
Perkin Trans. 1 1991, 2363-2372.
(23) Halfpenny, P. J .; J ohnson, P. J .; Robinson, M. J . T.; Ward, M.
G. Tetrahedron 1976, 32, 1873-1879.
(24) It is not uncommon for tert-butyl-containing quinones or
quinone-like substances to undergo reduction in the mass spectrometer;
see ref 11.
(21) Lee, Y.; Sayre, L. M. J . Am. Chem. Soc. 1995, 117, 3096, 11823-
11828.
(22) Musso, H.; Do¨pp, D.; Kuhls, J . Chem. Ber. 1965, 98, 3937-
3951.
1364 J . Org. Chem., Vol. 68, No. 4, 2003

CuII-Mediated Autoxidation of tert-Butylresorcinols
extracted with EtOAc (3 × 50 mL). The combined organic layer
was dried (Na2SO4), evaporated to a small volume, and diluted
to 50 mL with EtOAc. A 5 mL aliquot of the latter solution
(corresponding to 0.5 mmol of starting 1) was utilized for the
1H NMR spectral determination (CDCl3) of the percent conver-
sion of 1 and the yield of products, with 138 mg (1 mmol) of
1,4-dimethoxybenzene being added as an internal standard
(Table 2). The remainder of the EtOAc solution (45 mL) was
evaporated and separated by silica gel column chromatography
using hexanes and EtOAc as eluents to give 5, 1, and 2. Data
for compound 5: white amorphous solid; IR (KBr) νmax/cm-1
3404 (br, OH), 1802 (s, CdO), 1706 (s, CdO); 1H NMR (DMSO-
d6) δ 0.97 (s, 9H), 1.33 (s, 9H), 2.58 (d, 1H, J ) 18.7 Hz), 2.77
(d, 1H, J ) 18.7 Hz), 6.69 (s, 1H), 7.01 (s, 1H), 9.90 (s, 1H,
OH), 9.99 (s, 1H, OH); 13C NMR (APT, DMSO-d6) δ 27.4 (-),
29.5 (-), 34.4 (+), 34.6 (+), 46.0 (+), 51.3 (+), 99.1 (-), 119.3
(+), 121.2 (-), 132.5 (+), 147.2 (+), 151.1 (+), 152.5 (+), 157.1
(+), 179.6 (+), 199.5 (+); HRMS (EI) m/z calcd for C20H24O5
344.1624, found 344.1630 (rel intens 52).
HRMS (EI) m/z calcd for C14H20O3 236.1412, found 236.1419
(rel intens 60).
Essentially the same result was obtained when the above
reaction was carried out in 1:1 acetonitrile-water with pH 10
(Table 2). No reaction occurred in the presence of diethylene-
triaminepentaacetic acid.
Cop p er (II)-Ca ta lyzed Oxid a tion of 1 a n d 9 in Aceto-
n itr ile Usin g 18O2. To a 50 mL round-bottomed two-necked
flask fitted with a vacuum line and a septum was injected 20
mL of a CH3CN solution of either 1 or 9 (10 mM) containing
100 mM 16OH2. The solution was deaerated by three freeze-
pump-thaw cycles under argon, with 18O2 (95% 18O mixed 4:1
with N2, 1 atm, Icon Services, Summit, NJ ) being admitted in
the fourth cycle. Argon was further admitted to maintain a
slightly positive pressure. After vigorous stirring for 5 min,
0.5 mL of a degassed solution of Cu(CF3SO3)2 (400 mM) in CH3-
CN was injected through the septum, and the reaction was
initiated by injecting a degassed methanolic solution of 2 M
NaOMe (0.30 mL for 1 or 0.25 mL for 9). The reaction mixture
was vigorously stirred for 10 min before quenching by injection
of a degassed aqueous solution of NaH2PO4 (40 mM, 20 mL)
followed immediately by addition of NaBH4 in small portions
over 1 min with vigorous stirring until the red color of the
quinone faded. The mixture was then adjusted to pH 2 with
0.1 N aqueous HCl, diluted with 50 mL of water, and then
extracted with CH2Cl2 (50 mL). The combined organic layer
was dried (Na2SO4) and evaporated. TLC analysis showed that
triol 26 was the major product in both cases. The crude product
mixtures were then subjected to mass spectral analysis. HRMS
(FAB) m/z (rel intens) calcd for C10H1416O3 and C10H1418O16O2
(M+), 182.0943 and 184.0986, found 182.0931 (100) and
184.0980 (39) for reaction of 1 and 182.0930 (34) and 184.0982
Essentially the same results were obtained using Cu(ClO4)2‚
6H2O instead of CuSO4 as catalyst (Table 2).
An a er obic Oxid a tion of 1 by Cop p er (II) in Aqu eou s
Aceton itr ile. A solution of 1 (332 mg, 2 mmol) and Cu(ClO4)2‚
6H2O (740 mg, 2 mmol) in 200 mL of acetonitrile-water (1:1,
v/v) was placed in a three-necked round-bottom flask with an
electromagnetic stirrer, fitted with a dropping funnel contain-
ing 0.1 M aqueous NaOH and a pH electrode with a septum
seal. The middle neck contained a septum with inlet and outlet
needles. The solution was first bubbled with argon for 30 min
under continuous stirring, and then aqueous NaOH was slowly
introduced from the dropping funnel until the pH reached 10.
The mixture immediately turned to yellow-brown, and the pH
was maintained at 10 throughout the reaction course by
adding NaOH. After 3 h, the mixture was acidified with 1 M
aqueous HCl to pH 2 and then evaporated under reduced
pressure to remove the acetonitrile. The aqueous solution was
extracted with EtOAc (3 × 20 mL), and the organic layer was
dried (Na2SO4) and concentrated to 50 mL. A 5 mL aliquot
was removed for NMR spectral analysis. The remainder of the
solution was evaporated and separated by silica gel column
chromatography with hexanes and EtOAc as eluent to afford
(100) for reaction of 9. The mass peak representing C10H14
18O16O2 was distinct from the expected M + 2 satellite of
10H1416O3 so that no correction was needed. A control experi-
-
C
ment using air instead of 18O2 confirmed the absence of
C
10H1418O16O2 by HRMS in both cases.
Cop p er (II)-Ca ta lyzed Rea ction of Hyd r oxyqu in on e 2
or Tr iol 26 w ith 4 in Aqu eou s Aceton itr ile. A mixture of
either 2 (36.0 mg, 0.20 mmol) or 26 (36.4 mg, 0.20 mmol) with
4 (25.2 mg, 0.20 mmol) and Cu(ClO4)2‚6H2O (7.5 mg, 0.02
mmol) in 10 mL of acetonitrile-water (1:1) was adjusted to
pH 10.0 with 4 N NaOH and was maintained at pH 10 with
stirring for 30 min before quenching with dilute HCl to pH
3.0. The solution was extracted with EtOAc (15 mL). The
organic layer was dried (Na2SO4) and concentrated to give a
1
1, 11, and 12. Data for dimer 11: white amorphous solid; H
NMR (CDCl3) δ 1.38 (s, 18H), 5.25 (br, 2H, OH), 5.75 (br, 2H,
OH), 6.36 (s, 2H), 7.08 (s, 2H); 13C NMR (APT, CDCl3) δ 29.9
(-), 34.2 (+), 104.6 (-), 115.0 (+), 129.8 (-), 130.0 (+), 151.7
(+), 155.3 (+); HRMS (FAB) m/z calcd for C20H26O4 (M+)
330.1831, found 330.1826 (rel intens 93). Data for Pummerer’s
ketone 12: white amorphous solid; 1H NMR (CDCl3) δ 1.05
(s, 9H), 1.36 (s, 9H), 2.75 (dd, 1H, J ) 4.0, 15.5 Hz), 2.92 (dd,
1H, J ) 6.2, 15.5 Hz), 3.18 (d, 1H, J ) 19.5 Hz), 3.33 (d, 1H,
J ) 19.5 Hz), 5.24 (dd, 1H, J ) 4.0, 6.2 Hz), 5.32 (br, 1H, OH),
6.36 (s, 1H), 7.21 (s, 1H); 13C NMR (APT, CDCl3) δ 26.0 (-),
29.9 (-), 34.4 (+), 37.3 (+), 46.9 (+), 55.7 (+), 67.7 (+), 81.8
(-), 98.9 (-), 117.1 (+), 125.0 (-), 129.6 (+), 156.4 (+), 158.3
(+), 202.5 (+), 203.1 (+); HRMS (FAB) m/z calcd for C20H26O4
(M+) 330.1831, found 330.1825 (rel intens 15).
1
crude product mixture. H NMR spectral analysis revealed 2
and 3 in a ratio of 1:1 as the only identified products. Starting
with 26, the yield of the mixture of 2 and 3 was 66%, on the
basis of integration of the eight tert-butyl signals observed in
the crude 1H NMR spectrum (estimated from peak heights;
none of the unidentified products were present to an extent of
>10%). Starting with 2, the yield was 3-fold lower, and when
either reaction was conducted under identical conditions but
the starting concentrations were reduced by 13-fold, the yield
of the 1:1 mixture of 2 and 3 was reduced in each case more
than 2-fold, and the unidentified side products became much
more numerous. The same reaction as described above in the
absence of CuII gave 2 as the major product by far, only a trace
of 3, and several unidentified products.
Cop p er (II)-Ca ta lyzed Oxid a tion of 9. A mixture of 0.1
M pH 11 sodium phosphate buffer solution (500 mL), 9
(dihydrate, 1.29 g, 5 mmol, first dissolved in a small volume
of methanol), and 500 µL (0.5 mmol) of 1 M aqueous CuSO4
was stirred vigorously in air for 1.5 h, titrated with 0.1 M
aqueous HCl to pH 2, and then extracted with EtOAc (3 × 50
mL). The combined organic layer was dried (Na2SO4), evapo-
rated to a small volume, and diluted to 50 mL with EtOAc. A
Cop p er (II)-Ca ta lyzed Rea ction of Hyd r oxyqu in on e 2
or Tr iol 26 w ith 2,5-Dih yd r oxy-1,4-ben zoqu in on e (36) in
Aqu eou s Aceton itr ile. An equimolar mixture of either 2 or
26 with 36 in acetonitrile-water (1:1) at a final concentration
of either 1.5 or 20 mM, in the absence or presence of 0.1 equiv
of Cu(ClO4)2‚6H2O, was adjusted to and maintained at pH 10.0
by addition of 4 N NaOH. After 30 min, the reaction was
directly extracted (20 mM reaction) with EtOAc or first
concentrated and then extracted (1.5 mM reaction), and the
organic layer was dried (Na2SO4) and concentrated to give a
1
small aliquot was applied for H NMR spectral determination
as shown above, while the remainder of the solution was
separated by column chromatography on silica gel using
hexanes and EtOAc as eluents to afford 2 and 10. Data for
compound 10: red oil; 1H NMR (CDCl3) δ 1.28 (s, 9H), 1.37 (s,
9H), 6.50 (s, 1H), 7.20 (s, exchangeable by D2O, 1H, OH); 13C
NMR (APT, CDCl3) δ 29.6 (-), 30.3 (-), 35.5 (+), 36.2 (+),
125.1 (-), 129.2 (+), 148.9 (+), 162.4 (+), 184.5 (+), 189.3 (+);
1
crude product mixture. H NMR spectral analysis revealed 2
J . Org. Chem, Vol. 68, No. 4, 2003 1365

Ling et al.
(or, in the case starting with 26, a little 26) as the major and
only identifiable product.
1.2 times those of associated carbon or oxygen. All non-
hydrogen atoms were refined anisotropically. The bond lengths
and angles in the molecule are within established norms,25 and
selected values are listed in the Supporting Information.
X-r a y Cr ysta llogr a p h y. Single crystals of 3 were grown
from CD3CN. Data were collected on a Siemens P4 diffracto-
meter (Mo KR radiation, λ ) 0.71073 Å). A red block-shaped
crystal having approximate dimensions 0.40 × 0.24 × 0.14
mm3 was glued to the end of a glass fiber. The crystal was
judged to be acceptable on the basis of ω scans and rotation
photography. A random search located reflections to generate
a reduced primitive cell. Cell lengths were confirmed by axial
photographs. Additional reflections with higher 2θ values were
appended to the reflection array and yielded the refined cell
constants reported in the Supporting Information. Data were
corrected for absorption (empirical ψ scans). Direct methods
(Siemens SHELXTL PLUS, version 5.0) revealed all non-
hydrogen atoms. Hydrogen atoms were located from a Fourier
map and their positional parameters refined, while thermal
parameters were restricted to isotropic thermal parameters
Ack n ow led gm en t. We are grateful to the National
Institutes of Health for support of this work through
Grant GM 48812.
Su p p or tin g In for m a tion Ava ila ble: ORTEP diagram
1
and crystallographic data for 3, H and 13C NMR spectra for
compounds 3, 5, and 10-12, and HMBC and HMQC spectra
for 5. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O020582Y
(25) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen,
A. G.; Taylor, R. J . Chem. Soc., Perkin Trans. 2 1987, S1-S17.
1366 J . Org. Chem., Vol. 68, No. 4, 2003