Novel tert-Butyl Migration in Copper-Mediated Phenol Ortho-Oxygenation Implicates a Mechanism Involving Conversion of a 6-Hydroperoxy-2,4-cyclohexadienone Directly to an o-Quinone

Article abstract of DOI:10.1021/jo991625m

Copper mediated ortho-oxygenation of phenolates may proceed through the generation of a 6-peroxy-2,4-cyclohexadienone intermediate. To test this theory, we studied the fate of sodium 4-carbethoxy-2,6-di-tert-butylphenolate, where the ortho-oxygenation sit

Full text of DOI:10.1021/jo991625m

4804
J . Org. Chem. 2000, 65, 4804-4809
Novel ter t-Bu tyl Migr a tion in Cop p er -Med ia ted P h en ol
Or th o-Oxygen a tion Im p lica tes a Mech a n ism In volvin g Con ver sion
of a 6-Hyd r op er oxy-2,4-cycloh exa d ien on e Dir ectly to a n o-Qu in on e
Subrata Mandal, Dainius Macikenas, J ohn D. Protasiewicz, and Lawrence M. Sayre*
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078
lms3@po.cwru.edu
Received October 18, 1999
Copper mediated ortho-oxygenation of phenolates may proceed through the generation of a 6-peroxy-
2,4-cyclohexadienone intermediate. To test this theory, we studied the fate of sodium 4-carbethoxy-
2,6-di-tert-butylphenolate, where the ortho-oxygenation sites are blocked by tert-butyl groups. Using
the Cu(I) complex of N,N-bis(2-(N-methylbenzimidazol-2-yl)ethyl)benzylamine, isolation of the major
oxygenated product and characterization by single-crystal X-ray crystallography and NMR
spectroscopy revealed it to be 4-carbethoxy-3,6-di-tert-butyl-1,2-benzoquinone, resulting from a 1,2-
migration of a tert-butyl group. The independently prepared 6-hydroperoxide is transformed by
the Cu(I)- (or Cu(II)-) ligand complex to the same o-quinone. The observed 1,2-migration of the
tert-butyl group appears to reflect an electron demand created by rearrangement of the postulated
peroxy intermediate. A mechanism proceeding alternatively through a catechol and subsequent
oxidation to the o-quinone seems ruled out by a control study demonstrating that the requisite
intermediate to catechol formation would instead eliminate the 2-tert-butyl group.
Sch em e 1
In tr od u ction
Copper catalysis of phenol ortho-oxygenation is being
extensively studied in regard to understanding the mech-
anism of oxidation of tyrosine to dihydroxyphenylalanine
(DOPA) quinone by the cuproenzyme tyrosinase (EC
1.14.18.1)1 and the oxygenation of the active site tyrosine
residue in copper amine oxidases, as the initial step in
cofactor biogenesis.2 In the latter case, oxygenation occurs
spontaneously following binding of Cu(II) to its three
histidine ligands in the vicinity of the active site tyrosine
residue. Synthetic model systems that achieve ligand-
based arene monooxygenation have been characterized
in exquisite detail,3 but model systems achieving re-
giospecific ortho-oxygenation of exogenous phenols4,5 are
mechanistically less defined. In the latter case, it is
unclear whether ultimate o-quinone formation reflects
initial production of catechol with subsequent oxidation,
or a dioxygenase-like generation of a peroxy intermediate
that can convert to o-quinone directly or through inter-
mediacy of catechol (Scheme 1).
subsequent rearrangement would be required to rees-
tablish aromaticity, the properties of this rearrangement
would intimately reflect electronic attributes of the
oxygenation intermediate. The most well-known rear-
rangement accompanying oxygenation chemistry, termed
the “1,2-NIH shift”, occurs for arene monooxygenation
mediated by cytochrome P450 systems. An example of
the 1,2-NIH shift in copper-mediated oxygenation was
reported by Karlin for his m-xylyl-bridged binucleating
dicopper(I) system upon replacing the hydrogen at the
oxygenation site (xylyl C-2 position) with a methyl group.6
Information on the nature of intermediates may be
achieved from a determination of the fate of oxygenation
of a phenol bearing o,o′-dialkyl-substituents. Since a
* To whom correspondence should be addressed. Tel (216) 368-3704.
Fax (216) 368-3006.
(4) (a) Brackman, W.; Havinga, E. Recl. Trav. Chim. Pays-Bas 1955,
74, 937. (b) Tsuji, J .; Takayanagi, H. Tetrahedron 1978, 34, 641. (c)
Demmin, T. R.; Swerdloff, M. D.; Rogic, M. J . Am. Chem. Soc. 1981,
103, 5795. (d) Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1982, 23,
1573, 1577. (e) Casella, L.; Gullotti, M.; Radaelli, R.; Gennaro, P. D.
J . Chem. Soc., Chem. Commun. 1991, 1611. (f) Casella, L.; Monzani,
E.; Gullotti, M.; Cavagnino, D.; Cerina, G.; Santagostini, L.; Renato,
U. Inorg. Chem. 1996, 35, 7516. (g) Monzani, E.; Quinti, L.; Perotti,
A.; Casella, L.; Gullotti, M.; Randaccio, L.; Geremia, S.; Nardin, G.;
Faleschini, P.; Tabbi, G. Inorg. Chem. 1998, 37, 553. (h) Chioccara,
F.; Chiodini, G.; Farina, F.; Orlandi, M.; Rindone, B.; Sebastiano, R.
J . Mol. Catal. A 1995, 97, 187. (i) Maumy, M.; Capdevielle, P. J . Mol.
Catal. A 1996, 113, 159. (j) Chioccara, F.; DiGennaro, P.; La Monica,
G.; Sebastiano, R.; Rindone, B. Tetrahedron 1991, 47, 4429. (k) Reglier,
M.; J orand, C.; Waegell, B. J . Chem. Soc., Chem. Commun. 1990, 1752.
(5) Sayre, L. M.; Nadkarni, D. V. J . Am. Chem. Soc. 1994, 116, 3157.
(1) Espin, J . C.; Varon, R.; Fenoll, L. G.; Gilabert, M. A.; Garcia-
Ruiz, P. A.; Tudela, J .; Garcia-Canovas, F. Eur. J . Biochem. 2000, 267,
1270. Clews, J .; Cooksey, C. J .; Garratt, P. J .; Land, E. J .; Ramsden,
C. A.; Riley, P. A. Chem. Commun. 1998, 77-78 and references therein.
Robb, D. A. Copper Proteins and Copper Enzymes; Lontie, R., Ed., CRC
Press: Boca Raton, FL, 1984; Vol. 2, p 207.
(2) Dooley, D. M. J . Biol. Inorg. Chem. 1999, 4, 1.
(3) Karlin, K. D.; Kaderli, S.; Zuberbu¨hler, A. D. Acc. Chem. Res.
1997, 30, 139. Karlin, K. D., Tyekla´r, Z., Eds. Bioinorganic Chemistry
of Copper; Chapman and Hall: New York, 1993. Gelling, O. J .; Bolhuis,
F. V.; Meetsma, A.; Feringa, B. L. J . Chem. Soc., Chem. Commun. 1988,
552. Menif, R.; Martell, A. E. J . Chem. Soc., Chem. Commun. 1989,
1521. Alzuue, G.; Casella, L.; Villa, M. L.; Carugo, O.; Gullotti, M. J .
Chem. Soc., Dalton Trans. 1997, 4789.
10.1021/jo991625m CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/20/2000

Alkyl Migration in Cu(I)-Mediated Phenol Oxygenation
J . Org. Chem., Vol. 65, No. 16, 2000 4805
However, there have been no reports of alkyl rearrange-
ments in systems that achieve oxygenation of exogenous
phenols. Herein we report a 1,2-shift of a tert-butyl group
that occurs when the sodium salt of ethyl 3,5-di-tert-
butyl-4-hydroxybenzoate (1) is exposed to the Cu(I)
complex of N,N-bis(2-(N-methylbenzimidazol-2-yl)ethyl)-
benzylamine (2) under O2. Companion studies on the
independently prepared 6-hydroperoxy-2,4-cyclohexadi-
enone yield results consistent with a mechanism of
copper-mediated phenolate oxygenation to give o-quinone
via an o-peroxy intermediate without obligate interme-
diacy of catechol.
Resu lts a n d Discu ssion
We previously reported that the reaction of the sodium
salt of 4-carbomethoxyphenol (3, R ) Me) with the
dicopper(I) complex of the binucleating ligand N,N,N′,N′-
tetrakis(2-(N-methylbenzimidazol-2-yl)ethyl)-m-xylylene-
diamine in CH3CN, with subsequent exposure to O2,
affords as the major product catechol 4 (R ) Me),
resulting from coupling of the initial ortho-oxygenation
product with the starting phenolate.5 Casella and co-
workers reported that the copper(I) complex of the simple
mononucleating secondary amine, N,N-bis(2-(N-methyl-
benzimidazol-2-yl)ethyl)amine, was an ineffective oxy-
genation catalyst.4f However, this might be a consequence
of the free NH, since we now report that the copper(I)
complex of the mononucleating tertiary amine 2, obtained
by benzylation of the secondary amine ligand, permits
achieving the conversion of 3 to 4 (R ) Et) in the best
yield so far observed.
F igu r e 1. ORTEP view (thermal elipsoids at the 30% prob-
ability level) of one of the independent molecules of 5 with
labeling scheme.
ure 1)7 and clearly indicates that migration of a 1,2-tert-
butyl has accompanied the oxygenation.
Stannous chloride reduction of oxygenation product
(quinone 5) afforded authentic catechol 6, which was not
colored, had distinct NMR spectral and TLC elution
properties, and could thereby be excluded as even a minor
product in the oxygenation of 1. The propensity for 5 to
be reduced to 6 in the mass spectrometer may arise from
fragmentation and the supply of hydrogens by the tert-
butyl groups.
The X-ray structural analysis demonstrated that the
bond distances and angles for the two independent
To gain information on the nature of the oxygenation,
we carried out the same reaction substituting the di-tert-
butyl analogue 1 for 3. Compound 1 was synthesized by
acid-catalyzed esterification of the commercially available
acid in ethanol. Reaction of the sodium salt of 1 with the
Cu(I)-2 complex in CH3CN followed by exposure to O2
resulted in a single major product which was shown by
1H and 13C NMR analysis to contain two nonidentical tert-
butyl groups. Although the material was colored, sug-
gestive of quinone structure 5, FAB mass spectral
analysis gave an expected mass peak (M + 1) that was
2.6-fold smaller than a peak at M + 3 reflective of the
reduced catechol analogue 6. Nonetheless, the structure
was confirmed to be 4-carbethoxy-3,6-di-tert-butyl-1,2-
benzoquinone (5) by single-crystal X-ray diffraction (Fig-
(7) C17H24O4: a ) 10.7440(14) Å, b ) 10.5177(13) Å, c ) 30.432(4)
Å, â ) 97.702(4)o, Z ) 8, two independent molecules per asymmetric
unit. X-ray quality crystals were grown by vapor diffusion from
ethanol-water mixtures of 5. A green crystal (0.6 × 0.1 × 0.08 mm3)
was mounted on a glass fiber, and a unit cell was determined based
on 2585 reflections using the data integration program SAINT. Data
were collected at 223(1) K using the Bruker SMART Platform with a
CCD 1K detector and Mo radiation with a graphite monochromator
(using 3 different settings of Φ to cover a hemisphere, 0.3° increment
in omega scans, 2Θ < 58° and 30 s/frame exposure time). Corrections
for absorption and decay were applied in SADABS (Sheldrick, G.M.,
University of Gottingen, 1998) although decay was negligible. The
structure was solved by direct methods in the space group P21/c (No.
14) and refined by a full matrix least squares on F2 using all 8260
independent reflections. All non-hydrogen atoms were located from
Fourier difference maps; hydrogens were placed in ideal calculated
positions. Hydrogen atoms were assigned common thermal parameters.
Refinement converged at final values of R ) 0.0610 and Rw ) 0.1070.
Crystal data and data collection parameters for compound 5 are
available as Supporting Information.
(6) Nasir, M. S.; Cohen, B. I.; Karlin, K. D. J . Am. Chem. Soc. 1992,
114, 2482.

4806 J . Org. Chem., Vol. 65, No. 16, 2000
Mandal et al.
molecules in the unit cell fall into the expected range.8
No significant hydrogen bonding was observed in the
packing diagram. The o-benzoquinone rings are virtually
planar (average rms deviation from the mean least
squares plane 0.027). This planarity and the o-benzo-
quinone CdO bond lengths (1.200(3)-1.213(3) Å) closely
match analogous attributes in the published structure
of the similar compound 2,2′-dimethyl-5,5′-di-tert-butyl-
biphenyl-3,4,3′,4′-diquinone 7 (1.211(4)-1.220(4) Å).9,10
Sch em e 2
On the basis of our proposal that copper-mediated
oxygenation of phenols may proceed through generation
of a 6-peroxy-2,4-cyclohexadienone intermediate5 (e.g., 8),
we hypothesized that the observed tert-butyl migration
could reflect rearrangement to an electron-deficient
center created by structural reorganization of this puta-
tive peroxy intermediate. To test this theory we synthe-
sized the hydroperoxide 8 and studied the fate of its
coordination to copper. Compound 8 was obtained by
filtration over silica gel of the cobalt hydroperoxide
arising from oxygenation of 1 mediated by Co(II)(Salpr).11
We were unable to isolate and characterize the copper
peroxide complex of 8 prior to its structural reorganiza-
tion, but generation of the complex in situ by triethyl-
amine-induced deprotonation of 8 in the presence of
either the Cu(I)- or Cu(II)-complex of 2 under argon
afforded 5 in good yield (eq 1).
Possible reaction pathways (omitting details of the role
of the metal) consistent with our experimental observa-
tions are shown in Scheme 2. Direct reorganization of 8
could lead to 5. Alternatively, reaction could proceed
through 9, generated from monooxygenation of 1 or
reduction of 8 by Cu(I); 9 could then undergo rearrange-
ment to catechol 6 analogous to base-mediated rear-
rangement of tertiary ketols,12 and 6 would be oxidized
to 5 by the Cu(II) produced during generation of 9. Both
reactions would have the same net stoichiometry and
would be catalytic (theoretically) with copper.
Nonetheless, if the reaction proceeded through 9, the
latter might alternatively undergo elimination of iso-
butylene to give a catechol missing one of the two tert-
butyl groups. In fact, Nishinaga and co-workers found
that dimethyl sulfide-mediated deoxygenation of the
6-hydroperoxy-2,4-cyclohexadienone obtained from
Co(II)-mediated oxygenation of 2,4,6-tri-tert-butylphenol
1
led to 3,5-di-tert-butylcatechol, shown by H NMR spec-
troscopy at low temperature to involve the intermediacy
of the 6-hydroxy-2,4-cyclohexadienone.13 These workers
also found that 6-hydroperoxy-2,6-di-tert-butyl-4-(tert-
butylcarbonyl)-2,4-cyclohexadienone underwent instant
conversion by Me2S at room temperature to the des-tert-
butyl catechol.14 When we dissolved 8 in Me2S at 0-5
°C, there was immediate evolution of gas, and eventual
workup of the reaction indicated quantitative conversion
of 8 to catechol 10. In analogy to the work of Nishinaga
et al., we propose a mechanism proceeding via the
6-hydroxy intermediate 9 (eq 2). The facile conversion of
9 to 10 must reflect transformation of a strongly elec-
trophilic dienone into an aromatic system with “push-
pull” resonance and could follow the concerted 6-center
reaction shown.
In an effort to demonstrate formation of the copper-8
salt in the Cu(I)-mediated oxygenation of 1, the sodium
salt of 1 was allowed to react with the Cu(I)-2 complex
o
in CH3CN under O2 at -43 C. At this temperature only
5 was obtained even when the reaction was acid-
quenched at short reaction times. Clearly, the intermedi-
ate copper-8 species must be very short-lived. The
freezing point (-45.7 °C) of CH3CN prevented us from
exploring the reaction at even lower temperature.
It is noteworthy that during the synthesis11 of 8 from
1 using Co(II)(Salpr), 5 was also obtained as a side-
product, the yield of which slowly increased with increas-
ing reaction time, with a concomitant decrease in yield
of 8. From this observation, it is clear that although Co-
(II) and/or Co(III)(Salpr) complexes are much less reac-
tive than the above copper complexes toward 8, the tert-
butyl migration appears to be a general phenomenon for
hydroperoxide 8 in the presence of transition metal
complexes.
(8) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen,
A. G.; Taylor, R. J . Chem. Soc., Perkin Trans. 2, 1987, S1.
(9) Abakumov, G. A.; Nevodchikov, V. I.; Druzhkov, N. O.; Zacharov,
L. N.; Abakumova, L. G.; Kurskii, Y. A.; Cherkasov, V. K. Russ. Chem.
Bull. 1997, 46, 771.
(10) Numerous X-ray crystal structures having the 3,6-di-tert-butyl-
1,2-benzoquinone moiety complexed to various metal centers have been
published. The geometry of those quinones, however, is affected by the
metal center; in particular, the CdO bonds are considerably elongated.
The most recent structures of metal 3,6-di-tert-butyl-1,2-benzoquinone
complexes are described in: Lange, C. W.; Pierpont, C. G. Inorg. Chim.
Acta 1997, 263, 219. Attia, A. S.; Conklin, B. J .; Lange, C. W.; Pierpont,
C. G. Inorg. Chem. 1996, 35, 1033. J ung, O.-S.; Pierpont, C. G. J . Am.
Chem. Soc. 1994, 116, 2229.
Since this conversion appears to occur so readily, we
believe that if 9 were an intermediate in the oxygenation
(12) Selman, S.; Eastham, J . F. Quart. Rev. 1960, 14, 221.
(13) Nishinaga, A.; Itahara, T.; Shimizu, T.; Matsuura, T. J . Am.
Chem. Soc. 1978, 100, 1820.
(14) Nishinaga, A.; Shimizu, T.; Matsuura, T. Tetrahedron Lett.
1981, 22, 5293.
(11) Nishinaga, A.; Shimizu, T.; Toyoda, Y.; Matsuura, T. J .; Hirotsu,
K. J . Org. Chem. 1982, 47, 2278 and references therein.

Alkyl Migration in Cu(I)-Mediated Phenol Oxygenation
Sch em e 3
J . Org. Chem., Vol. 65, No. 16, 2000 4807
of 1 according to Scheme 2, the product observed would
be 10 rather than 5. However, not even a trace amount
of 10 was seen in the copper-mediated oxygenation of 1.
It should be noted that if 9 were the immediate product
of copper-mediated oxygenation of 1, it would probably
be produced as the corresponding Cu(II)-alkoxide; but
this should not affect the choice between rearrangement
to give 6 and elimination to give 10. We are forced to
conclude that observation of 5 as the exclusive identifi-
able product from copper-mediated oxygenation of 1
implicates a mechanism involving direct reorganization
of the 6-hydroperoxide 8 to quinone 5.
tant reactions mediated by copper-containing enzymes.
In addition, although we have depicted the reactions as
There are no simple mechanisms that would justify
such reorganization, but a similar conversion is prece-
dented by the outcome of base-mediated autoxidation of
4,6-di-tert-butylguaiacol.15 In analogy with this work, we
consider the intermediacy of a dioxetane that decays to
an epoxide, opening of which would provide the “driving”
force for migration of the tert-butyl group. This mecha-
nism as well as a possible scenario for initial oxygenation
are depicted in Scheme 3.16
One aspect of Scheme 3 that appears problematic is
the putative intermediacy of a Cu(I) peroxide, since Cu-
(I) might be expected to mediate reductive fission of the
O-O bond. However, we argued above that if reduction
of the 6-hydroperoxy intermediate 8 to the 6-hydroxy
intermediate 9 occurred, the latter would evolve to a
different product (10) than what is observed (5). Thus,
although the two-electron reduction of 8 to 9 cannot be
on the pathway for generation of 5, one potential mecha-
nistic alternative consistent with redox predictions would
call for Cu(I)-induced reductive cleavage of 8 to the
radical 11, which could undergo migration of the tert-
butyl group to produce another radical 12 that would in
turn be oxidized to 5 by the Cu(II) generated in the
peroxide reductive cleavage (eq 3). Although we know of
no precedent for such putative homolytic 1,2-alkyl shift,
this mechanism would avoid having to invoke a meta-
stable Cu(I)-peroxy intermediate.
being mediated by mononuclear copper, we cannot ex-
clude a possible binuclear copper involvement. Notwith-
standing the need for further mechanistic definition in
this system, we note that the 1,2-migration of a tert-butyl
group driven by a metal ion-mediated oxygenation event
is unprecedented. To the best of our knowledge, the
present account represents the first example of any
copper/O2-mediated 1,2-alkyl migration within an exog-
enous substrate.
Exp er im en ta l Section
Gen er a l. All reagents and solvents were obtained from
commercial sources and used as received unless otherwise
noted. Acetonitrile was dried according to published proce-
dure17 and distilled under argon immediately prior to use. All
air-sensitive reactions were performed under argon. The salt
[Cu(CH3CN)4][BF4]18 was prepared by suspending 10% excess
Cu2O in 95% aq CH3CN (v/v) containing 2 M HBF4, heating
at reflux under argon, hot filtration under argon, cooling to 0
°C, and recrystallization of the resulting colorless crystals from
CH3CN. The monosodium salt of ethyl 3,5-di-tert-butyl-4-
hydroxybenzoate (1) was prepared by using 1 equiv of aqueous
NaOH solution in EtOH, followed by solvent evaporation, with
azeotropic removal of traces of water using EtOH-toluene. The
Cu(II)-2 complex was prepared by using equimolar amounts
of Cu(BF4)2‚xH2O, 19.6% Cu, and 2 in CH3CN, followed by
removal of solvent under reduced pressure at 40 °C and
azeotropic removal of traces of water using EtOH-toluene.
Triethylamine was dried by refluxing over LiAlH4, distilled,
and stored over NaOH. All reactions were carried out at room
temperature (25 °C) with magnetic stirring unless otherwise
Further studies will be required to determine whether
the mechanistic argument presented here pertains also
to phenolate oxygenation in systems lacking blocking
ortho substituents. If the reactions are judged to be
electronically similar, our finding is consistent with
possible direct o-quinone production from phenols, with-
out the intermediacy of catechols, in biologically impor-
(15) Gierer, J .; Imsgard, F. Acta Chim. Scand. B 1977, 31, 546.
(16) Direct formation of the putative dioxetane by a photosensitized
production of 1O2 and its reaction with the starting phenolate seems
unlikely in that the reaction shows no dependence on light.
(17) Perrin, D. D.; Armarego, W. L. F., Eds. Purification of Labora-
tory Chemicals; Pergamon Press: New York, 1988.
(18) Hathaway, B. J .; Holah, D. G.; Postlethwaite, J . D. J . Chem.
Soc. 1961, 3215.

4808 J . Org. Chem., Vol. 65, No. 16, 2000
Mandal et al.
noted, and all evaporations were carried out at reduced
raphy (CH2Cl2-hexane, 3:2, v/v), affording analytical quality
5: 1H NMR (CDCl3) δ 1.24 (s, 9H), 1.29 (s, 9H), 1.41 (t, 3H, J
) 7.17 Hz), 4.36 (q, 2 H, J ) 7.18 Hz), 6.52 (s, 1H); 13C NMR
(CDCl3) δ 13.78, 28.80, 29.41, 35.01, 36.37, 62.16, 134.73,
138.36, 146.61, 149.73, 169.11, 180.50, 183.72; HRMS (FAB)
m/z calcd for C17H25O4 (M + 1)+ 293.1754, found 293.1744 (rel
intensity 38.1). Apart from the molecular ion peak, (M + 2)+
and (M + 3)+ peaks were also observed with relative intensities
of 37.69 and 100.00, respectively. X-ray quality crystals were
grown at room temperature from an ethanolic solution of 5 in
an open vial, which was placed in a closed vial containing
water.
The same reaction, when carried out for a longer period of
time, produced many unidentified products, along with a lower
yield of 5. In control reactions performed with omission of
either ligand 2 or Cu(I), 5 was not detected. Using 2 rather
than 1 equiv of the Cu(I)-2 complex per equivalent of
phenolate 1 resulted in an increase in yield of 5 by only 2-3%,
whereas 4-6% more starting phenolate was converted to
unidentified products.
1
pressure with a rotary evaporator. The H NMR spectra were
obtained at 300 MHz (13C NMR at 75 MHz), with chemical
shifts being referenced to TMS or the solvent peak(s). Thin-
layer and preparative-layer chromatography were run on
Merck silica gel 60 plates with a 254 nm indicator.
P r ep a r a tion of Eth yl 3,5-Di-ter t-bu tyl-4-h yd r oxyben -
zoa te (1). To a solution of 3,5-di-tert-butyl-4-hydroxybenzoic
acid (3.8 g, 15.2 mmol) in EtOH (60 mL) was added concen-
trated H2SO4 (20 µL), and the mixture was heated at reflux
for 9 days. The solvent was removed, and the solid was
triturated with a saturated aqueous solution of NaHCO3 to
removed unreacted acids. A CH2Cl2 solution of the remaining
solid was washed with saturated NaHCO3 and then with
water. On evaporation of CH2Cl2, 119 was obtained in 92% yield
in pure form. 1H NMR (CDCl3) δ 1.37 (t, 3H, J ) 7.12 Hz),
1.46 (s, 18H), 4.36 (q, 2H, J ) 7.12 Hz), 5.79 (s, 1H), 7.94 (s,
2H); 13C NMR (CDCl3) δ 14.37, 30.05, 34.21, 60.36, 121.41,
126.86, 135.61, 157.99, 167.07.
P r ep a r a tion of N,N-Bis(2-(N-m eth yl ben zim id a zol-2-
yl)eth yl)ben zyla m in e (2). According to a previously de-
scribed procedure,4e benzyl bromide (1.80 g, 10.5 mmol) and
dry sodium carbonate (1.75 g, 16.5 mmol) were added to a
solution of N,N-bis[2-(N-methylbenzimidazol-2-yl)ethyl]amine
(3.5 g, 10.5 mmol) in anhydrous DMF (60 mL). The mixture
was heated with rapid stirring for 42 h at 70 °C. After removal
of DMF, the residue was treated with chloroform, the inorganic
salts were filtered off, and the solvent was removed. Compound
2 was isolated as a light pink crystals from ethanol-water
(1:1, v/v, 0 °C) in 55% yield: 1H NMR (CDCl3) δ 2.97-3.17
(m, 8H), 3.50 (s, 6H), 3.79 (s, 2H), 7.18-7.25 and 7.67-7.68
(m, 13H); 13C NMR (CDCl3) δ 25.96, 29.39, 51.81, 58.97, 108.82,
118.83, 121.60, 121.82, 126.93, 128.13, 128.55, 135.52, 139.12,
142.41, 153.55; HRMS (EI) m/z calcd for C27H29N5 423.2423,
found 423.2410.
Cop p er (I)/O2-Med ia ted Oxygen a tion of Eth yl 4-Hy-
d r oxyben zoa te (3). To the degassed solution of 2 (0.339 g,
0.80 mmol) in 120 mL of CH3CN was added [Cu(CH3CN)4][BF4]
(0.252 g, 0.80 mmol) under argon. The sodium salt of 3 (0.150
g, 0.80 mmol) was then added anaerobically to the resulting
solution, and stirring was continued until it dissolved com-
pletely. Dry O2 was then admitted into the flask for 35 min at
room temperature. The reaction mixture was then quenched
with dilute HCl (0.4 M, 20 mL), followed by removal of solvent.
The remaining residue was taken up in ethyl acetate (100 mL)
and washed with dilute HCl (0.4 M, 3 × 20 mL) and then with
water (3 × 20 mL). The crude product was subjected to
preparative thin-layer silica gel chromatography (ethyl acetate-
hexane, 2:3, v/v), affording the product ethyl 2-(4-carbethoxy-
phenoxy)-3,4-dihydroxybenzoate (4) in 84% yield (42% oxy-
genation): 1H NMR (CDCl3) δ 1.05 (t, 3H, J ) 7.15 Hz), 1.38
(t, 3H, J ) 7.11 Hz), 4.08 (q, 2H, J ) 7.10 Hz), 4.35 (q, 2 H, J
) 7.14 Hz), 6.88 (d, 2H, J ) 8.82 Hz), 6.92 (d, 1H, J ) 8.70
Hz), 7.62 (d, 1H, J ) 8.70 Hz), 7.98 (d, 2H, J ) 8.82 Hz); 13C
NMR (CDCl3) δ 13.78, 14.17, 60.91, 61.09, 112.4, 114.5, 115.9,
123.7, 124.1, 131.5, 137.7, 141.2, 150.4, 161.9, 165.2, 166.7;
HRMS (EI) m/z calcd for C18H18O7 346.1052, found 346.1053.
Cop p er (I)/O2-Med ia ted Oxygen a tion of 1. To a degassed
solution of 2 (0.254 g, 0.6 mmol) in 20 mL of CH3CN was added
[Cu(CH3CN)4][BF4] (0.188 g, 0.6 mmol) under argon. The
sodium salt of 1 (0.180 g, 0.6 mmol) was added to the resulting
solution, and stirring was continued until 1 dissolved com-
pletely. Dry O2 was then admitted into the flask for 15 min at
room temperature. The reaction mixture was then quenched
by glacial acetic acid (0.108 g, 1.8 mmol), followed by removal
of solvent. The remaining solid residue was taken up in CH2-
Cl2 (20 mL), and the mixture was filtered through a short silica
gel column to remove the metal complex. After removal of CH2-
Cl2, the 1H NMR spectrum of the crude product indicated
(average of three experiments) ∼40% 4-carbethoxy-3,6-di-tert-
butyl-1,2-benzoquinone (5) and ∼55% starting phenol (1).
Although we see no evidence of any significant single minor
product, integration of the tert-butyl signals indicates the
presence of ∼5% of unidentified products. The crude product
was subjected to preparative thin-layer silica gel chromatog-
P r ep a r a tion of Eth yl 2,5-Di-ter t-bu tyl-3,4-d ih yd r oxy-
ben zoa te (6). A room-temperature SnCl2 reduction of 5 under
argon atmosphere in a mixed solvent system (0.2 M aqueous
HCl:MeOH 1:2, v/v) afforded catechol 6, which was purified
by preparative thin-layer silica gel chromatography (CH2Cl2).
1H NMR (CDCl3) δ 1.37 (t, 3H, J ) 7.13 Hz), 1.39 (s, 9H), 1.49
(s, 9H), 4.31 (q, 2H, J ) 7.13 Hz), 5.59 (s, 2H), 6.70 (s, 1H);
HRMS (EI) m/z calcd for C17H26O4 294.1832, found 294.1830.
P r ep a r a tion of 2,6-Di-ter t-bu tyl-4-ca r beth oxy-6-h yd r o-
p er oxy-2,4-cycloh exa d ien on e (8). Co(II)(Salpr) was pre-
pared and isolated from the reaction of bis(salicylaldehydato)-
cobalt(II) dihydrate with bis(3-aminopropyl)amine under N2.20
To a degassed solution of Co(II)(Salpr) (0.436 g, 1.1 mmol) in
20 mL CH2Cl2 was added 1 (0.278 g, 1.0 mmol) under argon.
Dry O2 was admitted into the flask at room temperature for
4.5 h, at which time the mixture was filtered through a short
silica gel column to remove the metal complex. Upon removal
1
of CH2Cl2, 8 was obtained (65% yield as determined by the H
NMR analysis) as a mixture with recovered starting material
1 (35%). 8: 1H NMR (CDCl3) δ 0.98 (s, 9H), 1.25 (s, 9H), 1.36
(t, 3H, J ) 7.05 Hz), 4.31 (q, 2 H, J ) 7.05 Hz), 7.21 (d, 1H, J
) 2.26 Hz), 7.53 (d, 1H, J ) 2.26 Hz), 9.34 (s, 1H). When the
reaction was allowed to proceed for longer than 4.5 h, there
was a slow transition of the product mixture to one reflecting
less 8, accompanied by the appearance of 5 and unidentified
1
products. By 5.5 h, the yield (by H NMR analysis, CDCl3) of
8 decreased to 55%, with 9% 5 appearing, whereas by 10 h,
the yield of 8 was 47%, with 23% 5 appearing.
Rea ction of 8 w ith th e Cu (I)- or Cu (II)-2 Com p lexes.
To a degassed solution of 2 (0.127 g, 0.3 mmol) in 10 mL of
CH3CN was added [Cu(CH3CN)4][BF4] (0.094 g, 0.3 mmol)
under argon. Triethylamine (0.030 g, 0.3 mmol) and the crude
hydroperoxide product 8 (0.091 g of the mixture of 65% 8 and
35% 1, 0.3 mmol) in 10 mL of CH3CN was then added to the
Cu(I)-2 complex solution under argon. The resulting solution
was stirred for 2 min anaerobically and was quenched with
glacial acetic acid (0.054 g, 0.9 mmol), followed by evaporation
of solvents. The residue was taken up into CH2Cl2, and the
mixture was filtered through a short silica gel column to
remove the metal complex. Upon removal of CH2Cl2, 1H NMR
(CDCl3) analysis of the crude product showed the complete
absence of 8, while compound 5 was detected as a major
product along with unreacted 1 and minor amounts of uni-
dentified materials. A control experiment, performed under
the identical conditions except for exclusion of the Cu(I)-2
complex, showed that 8 was unaffected by Et3N, and conver-
sion of 8 to 5 occurred smoothly in the absence of Et3N anyway.
Another experiment, performed under O2 using the Cu(II)-2
complex, also indicated complete conversion of 8 to 5 within
90 s.
(19) Cohen, L. A. J . Org. Chem. 1957, 22, 1333.
(20) Nishinaga, A.; Tomita, H.; Nishizawa, K.; Matsuura, T.; Ooi,
S.; Hirotsu, K. J . Chem. Soc., Dalton Trans. 1981, 1504.

Alkyl Migration in Cu(I)-Mediated Phenol Oxygenation
J . Org. Chem., Vol. 65, No. 16, 2000 4809
Deoxygen a tion of 8 w ith Dim eth yl Su lfid e. The crude
hydroperoxide product 8 (0.182 g of the mixture of 65% 8 and
35% 1, 0.6 mmol) was placed in an ice-cooled flask. Excess
dimethyl sulfide (3 mL) was then added dropwise with stirring.
The resulting solution was stirred for 30 min followed by
removal of the ice bath and continued stirring for 40 min at
room temperature (25 °C). Upon evaporation of dimethyl
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: For compound 5,
tables (six) listing detailed crystal data structure refinement,
atomic coordinates, bond lengths and angles, anisotropic
displacement parameters, hydrogen coordinates and isotropic
displacement parameters, torsion angles; an ORTEP view of
both independent molecules in the unit cell with labeling
scheme; 1H and 13C (expect 6 and 8) NMR spectra of 1, 2, 4-6,
8, and 10. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
sulfide under reduced pressure, the crude H NMR spectrum
(CDCl3) revealed the complete disappearance of 8 and quan-
titative appearance of ethyl 5-tert-butyl-3,4-dihydroxybenzoate
(10), while the fraction of 1 present remained unchanged. The
crude product 10 was purified by preparative thin-layer silica
gel chromatography (hexanes-ethyl acetate, 3:2, v/v): 1H
NMR (CD3OD) δ 1.34 (t, 3H, J ) 7.11 Hz), 1.39 (s, 9H), 4.28
(q, 2 H, J ) 7.11 Hz), 7.34 (d, 2H, J ) 2.04 Hz), 7.50 (d, 2H,
J ) 2.04 Hz); 13C NMR (CD3OD) δ 14.74, 29.84, 35.65, 61.64,
114.56, 121.05, 121.20, 136.69, 145.83, 150.76, 168.95; HRMS
(EI) m/z calcd for C13H18O4 238.1205, found 238.1204 (rel
intensity 100).
J O991625M