A solvolytic C-C cleavage reaction of 6-acetoxycyclohexa-2,4-dienones: Mechanistic implications for the intradiol catechol dioxygenases

Article abstract of DOI:10.1021/jo001669r

6-Acetoxycyclohexa-2,4-dienones are found to undergo a rapid reaction in methanol/water under mildly basic conditions to give an acyclic ketoester as the major product for 6-phenyl and 6-methyl substrates. Reaction monitoring by UV spectroscopy indicates

Full text of DOI:10.1021/jo001669r

J . Org. Chem. 2001, 66, 2091-2097
2091
A Solvolytic C-C Clea va ge Rea ction of
6-Acetoxycycloh exa -2,4-d ien on es: Mech a n istic Im p lica tion s for th e
In tr a d iol Ca tech ol Dioxygen a ses
Kirstin L. Eley,† Patrick J . Crowley,‡ and Timothy D. H. Bugg*,†
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K., and Syngenta,
J ealott’s Hill Research Station, Bracknell, Berkshire RG42 6ET, U.K.
mssgv@csv.warwick.ac.uk
Received November 27, 2000
6-Acetoxycyclohexa-2,4-dienones are found to undergo a rapid reaction in methanol/water under
mildly basic conditions to give an acyclic ketoester as the major product for 6-phenyl and 6-methyl
substrates. Reaction monitoring by UV spectroscopy indicates the formation of an unsaturated
ketone reaction intermediate (λmax 275 nm, R ) Ph) and the transient appearance of a highly
conjugated species. Reaction of the 6-phenyl substrate (4.95 × 10-6 s-1) is 2-fold faster than the
6-methyl substrate (2.47 × 10-6 s-1). The reaction rate is first order with respect to substrate
concentration, and the final step in the reaction is pH-dependent. No cleavage was observed for a
substrate lacking an acetyl substituent. A reaction mechanism for C-C cleavage is proposed
involving a benzene oxide-oxepin interconversion. The possible relevance to the catalytic mechanism
of the intradiol catechol dioxygenases is discussed.
Sch em e 1
In tr od u ction
The formation of 6-acetoxycyclohexa-2,4-dienones
(“quinol acetates”) from ortho-substituted phenols by
lead(IV) acetate was discovered by Wessely, who synthe-
sized a large range of such compounds.1 These highly
functionalized compounds have found synthetic utility in
recent years due to their participation in intermolecular2
and intramolecular3 Diels-Alder reactions.
The structure of this family of compounds closely
resembles the putative reaction intermediates that have
been proposed for the catalytic mechanisms of the cat-
echol dioxygenases, a family of nonheme iron-dependent
enzymes that catalyze the oxidative cleavage of catechol
and substituted catechols (see Scheme 1).3,4 The intradiol
dioxygenases catalyze the cleavage of the bond situated
between the two catechol hydroxyl groups, utilizing
nonheme iron(III) as cofactor, whereas the extradiol
dioxygenases catalyze the cleavage of the bond adjacent
to the two hydroxyl groups, utilizing nonheme iron(II)
as cofactor.4,5
Mechanistic proposals for the catechol dioxygenases
involve the formation of 6-hydroxy-6-peroxocyclohexa-2,4-
dienone intermediates, which are proposed to undergo
Criegee rearrangements to give either lactone (for ex-
tradiol cleavage) or anhydride (for intradiol cleavage)
products.4,5 Recent studies suggest that the reaction
mechanisms of the extradiol and intradiol dioxygenases
diverge from a common proximal hydroperoxide inter-
mediate, the choice of reaction pathways depending on
alkenyl vs acyl migration in the Criegee rearrangement
step.6,7 Although cyclohexadienone hydroperoxide inter-
mediates have been invoked on many occasions, there
are few studies that give insight into the chemical
reactivity of functionalized 2,4-cyclohexadienones. This
manuscript describes the observation of an unexpected
and unusual C-C cleavage reaction of two 6-acetoxycy-
clohexa-2,4-dienones and studies to investigate the mech-
anism of C-C cleavage, which may relate to the mech-
anism ofC-Ccleavagein theintradiolcatecholdioxygenases.
Resu lts
Ba se-Ca ta lyzed Clea va ge of 6-Acetoxy-cycloh exa -
2,4-d ien on es. The method of Wessely,1 namely treat-
ment of a 2-substituted phenol with lead(IV) acetate in
acetic acid, was used to synthesize 6-phenyl-6-acetoxy-
cyclohexa-2,4-dienone (1a ) and 6-methyl-6-acetoxycyclo-
hexa-2,4-dienone (1b), shown in Scheme 1. The major
byproduct of the reaction was the 2-substituted 6,6-
* To whom correspondence should be addressed. Tel: 44-2476-
573018. Fax: 44-2476-524112.
† University of Warwick.
‡ Syngenta.
(1) Wessely, F.; Sinwel, F. Monatsch. Chem. 1950, 81, 1055.
(2) Singh, V. Acc. Chem. Res. 1999, 32, 324 and references therein.
(3) Bichan, D. J .; Yates, P. Can. J . Chem. 1975, 53, 2057. Yates, P.;
Auksi, H. Can. J . Chem. 1979, 57, 2853.
(6) Spence, E. L.; Langley, G. J .; Bugg, T. D. H. J . Am. Chem. Soc.
1996, 118, 8336.
(4) Que, L., J r.; Ho, R. Y. N. Chem. Rev. 1996, 96, 2607.
(5) Bugg, T. D. H.; Winfield, C. J . Nat. Prod. Rep. 1998, 15, 513.
(7) Winfield, C. J .; Al-Mahrizy, Z.; Gravestock, M.; Bugg, T. D. H.
J . Chem. Soc., Perkin Trans. 1 2000, 3277.
10.1021/jo001669r CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/16/2001

2092 J . Org. Chem., Vol. 66, No. 6, 2001
Eley et al.
Sch em e 2
diacetoxycyclohexa-2,4-dienone (2a ,b) formed by consecu-
tive oxidation in the unsubstituted ortho position. Treat-
ment of of 2-tert-butylphenol and 2-trifluoromethylphenol
under the same conditions failed to give the desired
6-substituted 6-acetoxycyclohexa-2,4-dienone products, in
the first case yielding only 6,6-diacetoxy-2-tert-butylcy-
clohexadienone and in the second case giving a complex
mixture of products.
Attempts to hydrolyze the acetate ester functional
group of 1a or 1b under mildly basic conditions gave none
of the corresponding alcohol. Treatment of 1a with
sodium carbonate in methanol/water (1:1) gave an im-
mediate color change and a rapid reaction as observed
by thin-layer chromatography. The major isolated prod-
uct was an acyclic ester, methyl 4-methoxy-6-keto-6-
phenylhexanoate (3a ). The 1H NMR spectrum of 3a
showed two 3H singlets at 3.60 and 3.26 ppm, a multiplet
for H-4 at 3.85 ppm, diastereotopic H-5 signals at 3.25
and 2.87 ppm, and signals for H-2 and H-3 at 2.38 and
1.83 ppm. The 13C NMR spectrum of 3a showed evidence
of two carbonyl carbons at 198.8 and 174.3 ppm, and the
mass spectrum showed a molecular ion at m/z 250.
Treatment of 6-methyl-6-acetoxycyclohexa-2,4-dienone
(1b) under the same conditions gave the analogous acyclic
ester methyl 4-methoxy-6-ketoheptanoate (3b) as the
major isolated product (see Scheme 2).
The acyclic ester products 3a and 3b are at the same
oxidation state as the starting materials but correspond
to the addition of 2 equiv of methanol, and their forma-
tion requires a reaction mechanism involving cleavage
of the C-C bond between the oxygenated carbons C-1
and C-6, analogous to intradiol catechol cleavage. The
same reaction products were observed when the reaction
was carried out in the dark, thus ruling out a photo-
chemical reaction, which has been observed for other 2,4-
cyclohexadienones.8
F igu r e 1. (A) UV spectra vs time for reaction of 1a , showing
the formation of intermediate 4a (0-120 s). (B) UV spectra vs
time for subsequent reaction of 1a , showing the formation of
final product 3a (120-240 s). C. UV spectra vs time for
reaction of 2a , showing the formation of intermediate 4b (0-
120 s). Experiments were carried out in 50 mM Na2CO3 in
methanol/water (1:1) at 20 °C; scans were recorded every 10
s.
UV Sp ectr oscop ic Stu d ies. The reaction of 1a with
sodium carbonate in methanol/water (1:1) was monitored
by UV spectroscopy. Scanning from 200 to 600 nm at 10
s intervals revealed an immediate and rapid reaction,
resulting in the gradual disappearance of 1a at 317 nm,-
and the appearance of a new species at 275 nm over the
time period 0-2 min (Figure 1A). At longer reaction
times, the species at 275 nm decreased, and a third
species at 250 nm was formed (Figure 1B), which matches
the UV spectrum of the final product 3a . The UV
spectrum of the reaction intermediate with λmax 275 nm
matches that expected for an R,â-unsaturated ketone 4a ,
which would be converted to the product 3a by conjugate
addition of methoxide (Scheme 2).
The reaction of 1a was monitored by UV scanning over
pH range 8.0-10.8, at 18 and 37 °C (Figure 2). At 18 °C,
the predominant feature is the formation of intermediate
4a at λmax 275 nm. At pH 10.77, the formation of product
3a at λmax 250 nm is also apparent, indicating that the
conversion of 4a to 3a is faster under basic conditions.
At 37 °C, the formation of product 3a at λmax 250 nm is
much faster, with little of the intermediate species
observed at higher pH. Under these conditions, a linear
decrease at 317 nm is visible, whose rate is independent
of pH, although the rate is approximately 2-fold higher
(8) Quinkert, G.; Scherer, S.; Reichert, D.; Nestler, H. P.; Wenne-
mers, H.; Ebel, A.; Urbahns, K.; Wagner, K.; Michaelis, K. P.; Wiech,
G.; Prescher, G.; Bronstert, B.; Freitag, B. J .; Wicke, I.; Lisch, D.; Belik,
P.; Crecelius, T.; Horstermann, D.; Zimmermann, G.; Bats, J . W.;
Rehm, D. Helv. Chim. Acta 1997, 80, 1683.

C-C Cleavage Reaction of 6-Acetoxycyclohexa-2,4-dienones
J . Org. Chem., Vol. 66, No. 6, 2001 2093
F igu r e 2. pH and temperature dependence for the ring cleavage of 1a . Experiments were carried out as described in the
Experimental Section, at the pH and temperature indicated; scans were recorded every 10 s.
at 37 °C than 18 °C (the rate of appearance of 4a shows
no apparent change with temperature, due to the in-
creased rate of conversion to 3a ). (Observed rate con-
stants from Figures 2 and 3 are submitted as Supporting
Information.) It therefore appears that the conversion of
intermediate 4a to 3a is accelerated by higher pH and
by temperature, as would be expected for the base-
catalyzed addition of methanol to an R,â-unsaturated
ketone. In contrast, the rate of conversion of 1a to
intermediate 4a appears to be temperature-dependent
but pH-independent.
The reaction of 1b was monitored in the same way
(Figure 1C). In this case, a linear disappearance of 1b
was also observed at 300 nm over 1-5 min. A new species
was observed as a shoulder at 240 nm, which was
assigned to intermediate 4b.
Scans were carried at at short reaction times, to
identify early reaction intermediates. At 10 and 20 s time

2094 J . Org. Chem., Vol. 66, No. 6, 2001
Eley et al.
Sch em e 3. P r op osed Mech a n ism s for Con ver sion
of 1 to 3a
F igu r e 3. Rate dependence for ring cleavage of 1a and 1b vs
reactant concentration. Reactions were carried out in 50 mM
Na2CO3 in methanol/water (1:1), at 20 °C.
intervals in the reaction of 1a a weak absorbance peak
was detected at λmax 550 nm, which disappeared at longer
reaction times, suggesting the existence of a further
short-lived reaction intermediate that has a highly
conjugated structure.
Kin etic Stu d ies. Monitoring of reaction rate for 1a
and 1b was carried out in 50 mM sodium carbonate (pH
8.9) at 20 °C using methanol/water (1:1) as solvent. The
rate of reaction, as monitored by the rate of disappear-
ance of substrate, or the disappearance of the first
product (at 275 or 236 nm, respectively) was found to be
linear versus time. Comparison of the reaction rates for
1a and 1b versus concentration revealed that in both
cases the reaction appears to be first order with respect
to the concentration of the starting cyclohexa-2,4-dienone
but that the first-order rate constant for reaction of 1a
(4.95 × 10-6 s-1) is approximately 2-fold higher than the
that of 1b (2.47 × 10-6 s-1) (Figure 3). (Observed rate
constants from Figures 2 and 3 are submitted as Sup-
porting Information.)
To investigate whether the presence of the acetyl ester
was essential for C-C cleavage, a further cyclohexadi-
enone was synthesized, which contained methoxy sub-
stituents rather than an acetoxy substituent. Treatment
of 2-phenyl phenol with diacetoxy-iodosobenzene9 (DAIB)
in methanol gave 2-phenyl-6,6-dimethoxy-cyclohexa-2,4-
dienone (5). Incubation of 5 in methanol/water (1:1)
containing 50 mM sodium carbonate gave no reaction on
a 5-10 min time scale as observed by UV spectroscopy
or thin-layer chromatography.
a
Mechanism A proposed by Wessely;10 mechanism B described
in the text.
Wessely proposed a reaction mechanism involving nu-
cleophilic attack of solvent on the ketone group, followed
by an electrocyclic ring opening of the diene (Scheme 3,
mechanism A).10 Mechanism A does not fully account for
the observed data in this paper, since nucleophilic attack
at the C-1 ketone would be disfavored by increased steric
bulk at the adjacent C-6 quaternary center. Hence, if
mechanism A is followed, one would predict that the
phenyl-substituted 1a would react slower than the meth-
yl-substituted analogue 1b, whereas the opposite is
found.
An alternative mechanism (B) is presented in Scheme
3. Since we have been unable to isolate any of the alcohol
6 resulting from acetyl ester hydrolysis, we propose that
this alcohol is formed under basic conditions and under-
goes a rapid rearrangement, involving attack onto the
adjacent C-1 ketone, forming a benzene oxide intermedi-
ate (7), which undergoes rapid electrocyclic ring opening
to the corresponding seven-membered oxepin (8). This
oxepin might then be converted to a lactone, or might
undergo internal C-O bond cleavage to give a ketene (9),
either of which species could be attacked by methanol to
give R,â-unsaturated ketone 4. Conjugate addition of
methanol then yields the final â-methoxy ketone product
3.
Discu ssion
An investigation of the solvolytic cleavage of 2-acetoxy-
cyclohexa-2,4-dienes has not previously been reported,
although in one report by Wessely a derivative of such a
ring cleavage product was observed.10 For this reaction,
Our experimental observations provide some support
for mechanism B. The involvement of ester hydrolysis is
supported by the observation that dimethoxy derivative
5 does not undergo reaction under the same reaction
conditions. The observation that reaction of 1a is twice
as fast as reaction of 1b implies that the phenyl sub-
stituent of 1a provides some assistance to the rate-
(9) Hsu, D. S.; Rao, P. D.; Liao, C. C. J . Chem. Soc., Chem. Commun.
1998, 1795.
(10) Siegel, A.; Wessely, F.; Stockhammer, P.; Antony, F.; Klezl, P.
Tetrahedron 1958, 4, 49.

C-C Cleavage Reaction of 6-Acetoxycyclohexa-2,4-dienones
J . Org. Chem., Vol. 66, No. 6, 2001 2095
Sch em e 4. Tr a n sfor m a tion of Wa sa bid en on e B1
Rep or ted by Soga et a l.,14 w ith Mech a n ism
P r oceed in g via Ben zen e Oxid e-Oxep in
In ter con ver sion
determining step, which in mechanism B could come
about either by lowering the pKa of the neighboring
hydroxyl group (which might, for example, accelerate 8
to 9) or through some steric influence (for example, in
promoting the formation of 7).
The effects of pH and temperature on the reaction
(Figure 2) are also informative. The intermediate ob-
served experimentally at λmax 275 matches the expected
UV spectrum for R,â-unsaturated ketone 4, and its
conversion to 3 is base-catalyzed and temperature-
dependent, consistent with a bimolecular reaction of
methoxide with 4. The conversion of 1 to 4 shows no
apparent pH dependence, but does show temperature
dependence. The lack of pH dependence is contrary to
expectations, since the ester hydrolysis step should be
base-catalyzed. We suggest that the UV spectra of ester
1 and alcohol 6 will be very similar; hence, the conversion
of 1 to 6 is not observable by UV spectroscopy. The
observation that the disappearance of the initial peak at
317 nm is not strongly influenced by changes in pH would
therefore imply that ester hydrolysis is faster than the
subsequent reaction of 6 via this mechanism and, fur-
thermore, that the rate-limiting step between 6 and 4 is
not influenced by pH in the range 9-11.
The proposed oxepin intermediate (8) may correspond
to the species observed transiently at λmax 550 nm. There
are no literature reports of stable 1-O-substituted ox-
epins; however, 1,6-dimethyl-oxepin is reported to absorb
at 290-400 nm.11 Studies of the benzene oxide intercon-
version have found that this electrocyclic ring opening
occurs at room temperature.11 It is known that pericyclic
reactions such as the oxy-Cope rearrangement are greatly
accelerated by the presence of an adjacent oxyanion;12
thus, one would predict that the electrocyclic ring opening
of 7 would be a rapid process. Two possible mechanisms
are drawn in Scheme 3 for decomposition of oxepin 8,
via C-protonation to give a seven-membered lactone, or
C-O cleavage to give a ketene 9. Formation of ketenes
from activated esters via C-O cleavage is known in the
case of esters with acidic CR-protons.13
Soga et al. have reported the conversion of cyclohexa-
dienone natural product wasibidienone B1 (10) to cyclo-
pentenone 11, effected by heating 10 in benzene at reflux
overnight, as shown in Scheme 4.14 Although no mech-
anism was proposed by Soga et al., the application of
mechanism B, via a benzene-oxepin interconversion,
could rationalize this transformation. Conversion of the
oxepin intermediate to product (11) can be explained by
C-O cleavage to give a ketene, followed by intermolecu-
lar reaction with an enolate anion to form the five-
membered ring (see Scheme 4).
from Acinetobacter sp. ADP1.16 In both cases, the non-
heme iron(III) cofactor is ligated by two tyrosine residues
and two histidine residues. The proposed mechanism for
this family of enzyme involves the rearrangement of a
6-hydroxy-6-peroxocyclohexa-2,4-dienone, via acyl migra-
tion, to give an anhydride, which is then hydrolyzed to
give a muconic acid product.4,5
To date, it has been assumed that the acyl migration
step in this reaction mechanism occurs by direct Criegee
rearrangement.4,5 In support of this proposal is the
observation that Baeyer-Villiger oxidation of 1,2-dike-
tones gives anhydride products,17 via acyl migration.
However, studies on the Baeyer-Villiger oxidation of
benzil using 17O labeling have implicated a reaction
mechanism involving intramolecular attack of an alkox-
ide ion on the adjacent ketone prior to O-O bond
cleavage,18 similar to our proposed mechanism. As shown
in Scheme 5, a cyclohexadienone intermediate in which
the alcohol substituent is positioned axially with respect
to the ring could react via this mechanism to give an
oxepin, which can undergo O-O cleavage to yield an
anhydride and, hence, the muconic acid product. Thus,
the studies in this paper provide a chemical basis for an
alternative mechanism for intradiol cleavage, which
remains to be investigated for the enzyme-catalyzed
reaction.
This reaction mechanism also provides a new, alterna-
tive reaction pathway for the later stages of the reaction
catalyzed by the intradiol catechol dioxygenases. X-ray
crystal structures have been solved for two members of
this family, namely protocatechuate 3,4-dioxygenase from
Pseudomonas aeruginosa15 and catechol 1,2-dioxygenase
Exp er im en ta l Section
Reagents and solvents were purchased from Acros or Sigma-
Aldrich and were used as received. Reactions were followed
by the use of thin-layer chromatography (aluminum sheets
precoated with Merck 60 F254 silica) and products were
visualized using UV absorption (254 nm) and dinitrophenyl
hydrazine. Silica flash chromatography columns were per-
formed using Merck silica 60 (230-400 mesh). UV/visible
(11) Vogel, E.; Gunther, H. Angew. Chem., Int. Ed. Engl. 1967, 6,
385.
(12) Evans, D. A.; Baillargeon, D. J .; Nelson, J . V. J . Am. Chem.
Soc. 1978, 100, 2242.
(13) Holmquist, B.; Bruice, T. C. J . Am. Chem. Soc. 1969, 91, 2993
& 3003.
(14) Soga, O.; Iwamoto, H.; Takuwa, A.; Takata, T.; Tsugiyama, Y.;
Hamada, K.; Fujiwara, T.; Nakayama, M. Chem. Lett. 1988, 1535.
(15) Ohlendorf, D. H.; Lipscomb, J . D.; Weber, P. C. Nature 1988,
336, 403.
(16) Vetting, M. W.; Ohlendorf, D. H. Structure 2000, 8, 429.
(17) Krow, G. R. Org. React. 1993, 43, 251.
(18) Cullis, P. M.; Arnold, J . R. P.; Clarke, M.; Howell, R.; de Mira,
M.; Naylor, M.; Nicholls, D. J . Chem. Soc., Chem. Commun. 1987, 1088.

2096 J . Org. Chem., Vol. 66, No. 6, 2001
Eley et al.
Sch em e 5. P ossible Mech a n ism for th e Acyl Migr a tion Step of th e In tr a d iol Ca tech ol Dioxygen a se
Rea ction Mech a n ism , In volvin g th e Con ver sion of a Cycloh exa d ien on e Hyd r op er oxid e to Mu con ic
An h yd r id e via a Ben zen e Oxid e-Oxep in In ter con ver sion
spectra were recorded on a Beckman Coulter DU7400 spec-
trophotometer.
products were purified by silica column chromatography (1:1
diethyl ether/petroleum ether) to give a yellow oil (67 mg, 63%
yield): δH (300 MHz, CDCl3) 7.89 (2H, d, J ) 9.2 Hz), 7.50
(1H, tt, J ) 7.7, 1.7 Hz), 7.39 (2H, t, J ) 7.7 Hz), 3.85 (1H, qn,
J ) 6.1 Hz, -CH(OMe)-), 3.60 (3H, s, -COOCH3), 3.26 (3H,
s, -OCH3), 3.25 (1H, dd, J ) 18.0, 6.1 Hz, H-5), 2.87 (1H, dd,
J ) 18.0, 6.1 Hz, H-5′), 2.38 (2H, td, J ) 7.7, 3.1 Hz, H-2),
1.93-1.73 (2H, m, H-3) ppm; δC (75 MHz, CDCl3) 198.86,
174.33, 137.50, 133.63, 129.23, 128.55, 76.93, 57.80, 52.03,
43.32, 30.31, 29.90 ppm; m/z (CI) 251 (MH+); HRMS 251.1287,
P r ep a r a tion of 6-Acetoxy-6-p h en ylcycloh exa -2,4-d i-
en on e (1a ). Glacial acetic acid (10 mL) was added to lead(IV)
acetate (10.03 g, 20 mmol), and the slurry was stirred at room
temperature under nitrogen. A solution of 2-hydroxybiphenyl
(1.72, 10 mmol) in glacial acetic acid (10 mL) was added very
slowly, over 20-30 min, and the dark red/brown mixture
stirred for 2 h at room temperature and under nitrogen. The
reaction was quenched with water (50 mL), and the mixture
was extracted with ether, both phases being filtered to remove
the lead oxide precipitate. The ether was washed first with
NaHCO3 (aqueous, saturated), to remove excess acetic acid,
and then brine (2 × 20 mL) and dried over MgSO4. The ether
was removed in vacuo to give the crude product as a red oil
and solid. The oil was dissolved in 20% ether in petroleum
ether leaving the solid undissolved. This was then filtered and
the solid washed in warmed 20% ether in petroleum ether,
filtered again, and dried to give a yellow solid (0.649 g, 29%
yield): δH (300 MHz, CDCl3) 7.49-7.56 (2H, m), 7.31 (3H, dd,
J ) 5.5, 1.1 Hz), 7.05 (1H, ddd, J ) 9.6, 5.8, 2.2 Hz, H-3), 6.50
(1H, ddd, J ) 9.6, 6.0, 2.2 Hz, H-4), 6.36 (1H, dd, J ) 9.6, 2.2
Hz, H-2), 6.15 (1H, d, J ) 9.6, H-5), 2.24 (3H, s, -COCH3)
ppm; δC (75 MHz, CDCl3) 196.88, 170.01, 141.34, 140.96,
134.16, 129.46, 129.32, 126.69, 125.93, 123.76, 82.45, 21.10
ppm; m/z (EI) 228 (M+); HRMS 228.0786, C14H12O3 requires
228.0779.
P r ep a r a tion of 6-Acetoxy-6-m eth ylcycloh exa -2,4-d i-
en on e (1b). Glacial acetic acid (10 mL) was added to lead-
(IV) acetate (10.73 g, 21 mmol), and the slurry was stirred at
room temperature under nitrogen. A solution of O-hydroxy-
biphenyl (1.12 g, 11 mmol) in glacial acetic acid (10 mL) was
added very slowly, over 20-30 min, and the dark red/ brown
mixture stirred for 2 h still at room temperature and under
nitrogen. The reaction was quenched with water (50 mL) and
filtered, and the mixture was extracted with ether. The ether
was washed first with NaHCO3 (aqueous, saturated), to
remove excess acetic acid, and then brine (2 × 20 mL) and
dried over MgSO4. The ether was removed in vacuo to give
the crude product as a brown/red oil. The product was purified
by silica column chromatography (10% ether in petroleum
ether) to give a yellow solid (0.386 g, 23% yield): δH (300 Hz,
CDCl3) 6.98 (1H, ddd, J ) 9.8, 4.5, 3.0 Hz, H-3), 6.17 (2H, d,
J ) 2.9 Hz, H-4 + H-5), 6.11 (1H, d, J ) 9.8 Hz, H-2), 2.02
(3H, s, -COCH3), 1.35 (3H, s, -CH3) ppm; δC (75 MHz, CDCl3)
199.01, 164.08, 142.97, 140.99, 126.72, 122.10, 79.43, 23.85,
20.88 ppm; m/z (EI) 166 (M+); HRMS 166.0629, C9H10O3
requires 166.0630.
C
14H19O4 requires 251.1283.
P r ep a r a tion of Meth yl 6-Keto-4-m eth oxyh ep ta n oa te
(3b). Potassium carbonate (0.35 g, 2.1 mmol) was dissolved
in water (10 mL) and methanol (10 mL). 6-Acetyl-6-methyl-
cyclohexa-2,4-dienone (66 mg, 0.29 mmol) was then dissolved
in methanol (10 mL) and added to the aqueous solution with
stirring. The brown/red solution was stirred overnight. The
solvents were removed in vacuo, and the products were
purified silica column chromatography (1:1 diethyl ether/
petroleum ether) to give a yellow oil (35 mg, 46% yield): δH
(300 MHz, CDCl3) 3.59-3.72 (1H, m, -CH(OMe)-), 3.67 (3H,
s, -COOCH3), 3.63 (3H, s, -OCH3), 2.65 (1H, dd, J ) 15.5,
7.7 Hz), 2.52-2.45 (2H, m), 2.41-2.33 (2H, m), 2.24 (3H, s,
CH3CO-), 1.98-1.70 (2H, m) ppm; δC (75 MHz, CDCl3) 207.71,
174.33, 76.38, 57.49, 52.06, 48.15, 31.42, 29.16, 27.88 ppm; m/z
(CI) 189 (MH+); HRMS 189.1128, C9H17O4 requires 189.1127.
P r ep a r a tion of 6,6-Dim eth oxy-2-p h en ylcycloh exa -2,4-
d ien on e (5). To a stirred solution of diacetoxyiodobenzene
(1.14 g, 3.3 mmol) in dry methanol (25 mL) was added
dropwise a solution of 2-hydroxybiphenyl (0.51 g, 3.0 mmol)
in dry methanol (25 mL) and the reaction stirred overnight at
room temperature. The solvent was then removed in vacuo,
and the products were re-suspended in diethyl ether. The
white solid produced was filtered off and the ether removed
in vacuo. The crude product was then purified using silica
column chromatography (3:1 f 1:1 petroleum ether/diethyl
ether) to give a yellow oil (20 mg, 4% yield): δH (300 MHz,
CDCl3) 7.38 (5H, m), 6.88 (2H, dd, J ) 8.0, 3.7 Hz), 6.38 (1H,
dd, J ) 11.0, 1.5 Hz), 3.38 (6H, s, OCH3) ppm; m/z (CI) 231
(MH+).
UV Sca n n in g of C-C Clea va ge Rea ction s. To a 1:1
mixture of methanol/water (960 µL) in a quartz cuvette was
added 100 mM aqueous Na2CO3 solution (20 µL) and a
methanol solution (20 µL) of either compound 1a (49 mM) or
compound 1b (63 mM), and the UV/visible spectrum was
scanned between 200 and 700 nm every 10 s. Reaction rates
were measured by recording absorbance at 305 nm (for 1a ) or
274 nm (for 1b) versus time.
P r ep a r a tion of Meth yl 6-Keto-6-p h en yl-4-m eth oxy-
h exa n oa te (3a ). Potassium carbonate (0.143 g, 1 mmol) was
dissolved in water (10 mL) and methanol (10 mL). 6-Acetyl-
6-phenylcyclohexa-2,4-dienone (97 mg, 0.43 mmol) was then
dissolved in methanol (10 mL) and added to the aqueous
solution with stirring. The brown/red solution was stirred
overnight. The solvents were removed in vacuo, and the
Dependence of reaction rate upon substrate concentration
was determined by measurement of reaction rates at a final
concentrations of 20-200 µM 1a or 1b in 50 mM sodium
carbonate (pH 8.9) in 1:1 methanol/water at 20 °C. Extinction
coefficients of 4160 and 2215 M-1cm-1 were measured for 1a
and 1b, respectively, under these conditions, which were used
to calculate reaction rates in µM/s.

C-C Cleavage Reaction of 6-Acetoxycyclohexa-2,4-dienones
J . Org. Chem., Vol. 66, No. 6, 2001 2097
p H a n d Tem p er a tu r e Dep en d en ce in th e UV Sca n n in g
of C-C Clea va ge Rea ction s. Aqueous solutions (100 mM)
of Na2CO3 and NaHCO3 were mixed to prepare 100 mM
carbonate buffers of pH 8.9-10.8. To a mixture of methanol
(480µL) and buffer (500µL) in a quartz cuvette was added a
20 µL aliquot of 1a in methanol (2 mM stock), and the UV/
visible spectrum was scanned between 200 and 700 nm every
10 s. Assays and reagents were maintained at either 18 or 37
°C.
Ack n ow led gm en t. We thank Stephen J ones (Uni-
versity of Southampton) for preliminary work, the
University of Warwick and Syngenta for financial
support, and Prof. A. Kirby (University of Cambridge)
for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O001669R