2,3-Dioxabicyclo[2.2.2]oct-7-en-5-one: Synthesis and Reactions of the Keto Endoperoxide of Phenol

Article abstract of DOI:10.1021/jo000120p

The photooxygenation of 1,4-cyclohexadiene (3) affords the diastereomeric hydroperoxy endoperoxides exo-4 and endo-4 and the diastereomeric hydroperoxides trans-5 and cis-5 in a ratio of 87: 9:3.5:0.5. Selective reduction of hydroperoxide group in the endoperoxides exo-4 and endo-4 in the presence of titanium tetraisopropoxide-diethyl sulfide gave the corresponding hydroxy endoperoxides exo-7 and endo-7, which on PCC oxidation leads to the phenol-derived keto endoperoxide 2. The triphenylphosphine deoxygenation of the keto endoperoxide 2 produces a 9:1 mixture of 1,2-and 1,4-dihydroxybenzenes 10 and 11, while the CoTPP-catalyzed rearrangement affords the bisepoxide 12, malealdehyde (13), and β-lactone 14. The mechanisms of these transformations are presented.

Full text of DOI:10.1021/jo000120p

5926
J . Org. Chem. 2000, 65, 5926-5931
2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-on e: Syn th esis a n d Rea ction s of
th e Keto En d op er oxid e of P h en ol
Waldemar Adam,† Metin Balci,*,‡ and Hamdullah Kilic¸§
Institute of Organic Chemistry University of Wu¨rzburg Am Hubland, D-97074 Wu¨rzburg, Germany;
Department of Chemistry, Middle East Technical University, 06531 Ankara; and Department of
Chemistry Atatu¨rk University, 25240 Erzurum, Turkey
mbalci@metu.edu.tr
Received J anuary 29, 2000
The photooxygenation of 1,4-cyclohexadiene (3) affords the diastereomeric hydroperoxy endoper-
oxides exo-4 and endo-4 and the diastereomeric hydroperoxides trans-5 and cis-5 in a ratio of 87:
9:3.5:0.5. Selective reduction of hydroperoxide group in the endoperoxides exo-4 and endo-4 in the
presence of titanium tetraisopropoxide-diethyl sulfide gave the corresponding hydroxy endoper-
oxides exo-7 and endo-7, which on PCC oxidation leads to the phenol-derived keto endoperoxide 2.
The triphenylphosphine deoxygenation of the keto endoperoxide 2 produces a 9:1 mixture of 1,2-
and 1,4-dihydroxybenzenes 10 and 11, while the CoTPP-catalyzed rearrangement affords the
bisepoxide 12, malealdehyde (13), and â-lactone 14. The mechanisms of these transformations are
presented.
Sch em e 1
In tr od u ction
Singlet oxygen (1O2) is an effective electrophilic oxidant
for a variety of electron-rich organic compounds.1 Among
these, phenols are of interest because these ubiquitous
organic substances (found in natural waters, drinking
water, and wastewater) are rapidly oxidized by singlet
oxygen. Moreover, phenols occur numerously as anthro-
pogenic pollutants (e.g., industrial solvents, coal- and
petroleum-derived wastes, detergent metabolites, pesti-
cides, and antioxidants), but also in natural products2
(e.g., amino acids, vitamins, lignin, and humic sub-
stances). Previous studies have shown that in the dye-
sensitized photooxygenation of phenols,3 the singlet
oxygen produces hydroperoxides (Scheme 1); however,
the parent phenol does not undergo this reaction because
it physically quenches singlet oxygen efficiently.2,4 In
contrast, the more electron-rich derivatives (catechol and
methoxybenzenes, such as 1,2,3,4-tetramethoxybenzene)
do react chemically with singlet oxygen.1e,5 Plausible
Sch em e 2
the hydroperoxide by way of the superoxide ion and the
phenol radical cation (Scheme 1).6
mechanisms are [π4s + 2s] cycloaddition of the singlet
π
As already stated above, the endoperoxide or its ring-
opened hydroperoxide (Scheme 1, R ) H) of the parent
phenol is to date not known, nor is its regioisomeric
endoperoxide 1 (Scheme 2), which may exist as its
tautomeric endoperoxide 2. Since the later is not directly
accessible through photooxygenation of the parent phe-
nol, in this paper we describe the indirect synthesis of
the hitherto unknown endoperoxide 2 and its chemistry.
We demonstrate that an effective methodology involves
1,4-cyclohexadiene, which allows the introduction of the
three oxygen functionalities at the required positions and
further functionalization.
oxygen to the phenol and subsequent ring-opening of the
labile endoperoxide to its hydroperoxide, or electron-
transfer (ET) between singlet oxygen and phenol to afford
* Corresponding author. Tel: (90) 312 210 5140.
† University of Wu¨rzburg. Tel: (49) 931 8885339. E-mail adam@
chemie.uni-wuerzburg.de.
‡ Middle East Technical University.
§ Atatu¨rk University.
(1) (a) Saito, I.; Matsuura, T. In Singlet Oxygen; Wasserman, H. H.;
Murray, R. W. Eds.; Academic: New York, 1979. (b) Adam, W.; Prein,
M. Acc. Chem. Res. 1996, 29, 275. (c) Adam, W.; Prein, M. Angew.
Chem., Int. Ed. Engl. 1996, 35, 477. (d) Balci, M. Chem. Rev. 1981,
81, 91. (e) Frimer, A. A. Ed. Singlet Oxygen; CRC Press: Boca Raton,
FL, 1985. (f) Frimer, A. A. The Chemistry of Peroxides; J ohn Wiley:
Chichester, 1983, 201.
(2) Tratnyek, P. G.; Holgne, J . Environ. Sci. Technol. 1991, 25, 1596.
(3) (a) Matsuura, T.; Omura, K.; Nakashima, R. Bull. Chem. Soc.
J pn. 1965, 38, 1358. (b) Matsuura, T.; Nishinaga, A.; Yoshimura, N.;
Arai, T.; Omura, K.; Matsushima, H.; Kato, S.; Saito, I. Tetrahedron
Lett. 1969, 1673. (c) Saito, I.; Kato, S.; Matsuura, T. Tetrahedron Lett.
1970, 4987.
Resu lts a n d Discu ssion
P r ep a r a tion of th e Keto En d op er oxid e 2. Tetra-
phenylporphine(TPP)-sensitized photooxygenation of 1,4-
(4) Yamaguchi, K.; Ikeda, Y.; Fueno, T. Tetrahedron 1985, 46, 2099.
(5) Thomas, M. J .; Foote, C. S. Photochem. Photobiol. 1978, 27, 325.
(6) Foote, S. C.; J ensen, F. Photochem. Photobiol. 1987, 46, 325.
10.1021/jo000120p CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/25/2000

2,3-Dioxabicyclo[2.2.2]oct-7-en-5-one
J . Org. Chem., Vol. 65, No. 19, 2000 5927
Sch em e 3a
Sch em e 4
endoperoxides exo-4 and endo-4. Alternatively, a second
ene reaction of the monohydroperoxide 8 affords the
bishydroperoxides trans-5 and cis-5.
The hydroperoxy-functionalized endoperoxides exo-4
and endo-4 are suitable substrates for the synthesis of
the phenol-derived endoperoxide 2 since the two oxygen
functionalities are regiomerically properly located in the
six-membered ring as desired for the synthesis of the
phenol endoperoxide. Reduction of the hydroperoxide
group in the endoperoxides endo- and exo-4 and subse-
quent oxidation should afford the desired phenol endo-
peroxide 2 (Scheme 2). However, it is well-known that
both hydroperoxides and endoperoxides are highly sus-
ceptible to reductive cleavage by a variety of reductants.1f
Moreover, since in the present case exo-4 and endo-4
possess both endoperoxide and hydroperoxide linkages,
a selective reduction was required for the preservation
of the endoperoxide functionality. This selective reduction
was achieved by using titanium tetraisopropoxide in the
presence of diethyl sulfide as reductant, which gave the
desired hydroxy endoperoxides exo-7 and endo-7 (Scheme
3, step c).
a
Reagents: (a) O2, TPP, hv, chloroform; product composition:
exo-4 (87%), endo-4 (9%), trans-5 (3.5%), cis-5 (0.5%); (b) PPh3, 20
°C, yield 75%; (c) Et2S (1.2 equiv), Ti(Oi-Pr)4 (5 mol %), CH2Cl2, 5
°C, 4 Å molecular sieves, yield 96%; (d) PCC, CH2Cl2, ca. 20 °C,
yield 52%; (e) PCC, CH2Cl2, ca. 20 °C, yield 48%; (f) m-CPBA (1
equiv), CH2Cl2, rt, (70% conversion).
cyclohexadiene (3) at -20 °C in chloroform solution gave
the two known endoperoxides exo-4 and endo-4,7 and
additionally the two labile bishydroperoxides trans-5 and
cis-5 (Caution! explosive). These products were separated
by silica gel column chromatography at low temperature
(Scheme 3). A pure sample of the bishydroperoxide trans-
5, which eluted together exo-4 and cis-5, was obtained
by means of several crystallizations. All attempts to
isolate the bishydroperoxide cis-5 failed because it was
thermally too labile for isolation and decomposed im-
mediately.
The structures of the hydroxy endoperoxides exo-7 and
endo-7 were assigned by spectroscopic and chemical
methods. For instance, a peroxide test with KI/HOAc
confirmed that the endoperoxide linkage was preserved.
The structural assignment of the bishydroperoxide
trans-5 rests on its spectral and chemical data. Thus, the
elemental analysis confirmed the empirical formula
C6H8O4, while the cyclohexadienyl hydroperoxide struc-
1
The most conspicuous features in the H NMR spectra
of the hydroxy endoperoxides exo-7 and endo-7 are two
distinct AB systems which correspond to two olefinic and
two methylenic protons. The olefinic protons of exo-7 at
δ 6.44-6.71 show further splitting with the adjacent
bridgehead protons. The methylenic protons appear as
an AB system at δ 2.50 and 1.24 and are definitive for
the proposed alcohol structure. The proposed structures
are also in agreement with the 13C NMR spectral data.
For the oxidation of the alcohols exo-7 and endo-7 to
the keto derivative 2, several chromate reagents8-10 were
tried, but the best yield (52% for the conversion of exo-7
and 48% for endo-7) was obtained with pyridinium
chlorochromate (PCC)11 as oxidant (Scheme 3, steps d and
e). The structure assignment of the keto endoperoxide 2
is based on its analytical and spectral data. The elemen-
tal analysis revealed the emprical formula C6H6O3, while
the 13C NMR spectrum displayed the expected six carbon
resonances. The IR band at 1748 cm-1 indicates the
presence of the carbonyl group.
1
ture was established by its 250 MHz H NMR and 63
MHz 13C NMR and IR spectra. The H NMR spectrum
1
displayed a broad singlet at δ 10.75, which was assigned
to the hydroperoxide proton. Olefinic and aliphatic
protons comprise two separate multiplets at δ 6.17 and
4.73, while the IR band at 3381 cm-1 discloses the -OOH
functionality. The suggested structure is in good accord
with the 13C NMR spectrum (one sp2 and one sp3 carbon
atom). For chemical confirmation, the hydroperoxide
group in trans-5 was reduced with triphenylphosphine1d
to the trans-6 diol, whose symmetry is evident by the
expected two-line 13C NMR resonances. To support the
correct configuration of the alcohol and peroxide func-
tionalities in 5 and 6, trans-6 diol was treated with 1 mol
of m-CPBA at 0 °C. The obtained mono-epoxide showed
an asymmetric structure (six lines in the 13C NMR) which
indicates clearly the trans configuration of the starting
material.
Tr a n sfor m a tion s of th e Keto En d op er oxid e 2. The
keto endoperoxide 2 persists at room temperature (ca.
25 °C) and does not decompose to phenol and oxygen
under these conditions. Upon heating at 90-95 °C for
24 h, only 20% of the keto endoperoxide 2 was decom-
The formation of the diastereomeric endoperoxides
exo-4 and endo-4, as well as the diastereomeric hydro-
peroxides trans-5 and cis-5, is outlined in Scheme 4. The
first ene reaction of singlet oxygen leads to the monohy-
droperoxide 8, which reacts subsequently with another
singlet-oxygen molecule by a [4 + 2] cycloaddition to the
(8) Srimivason, R.; Stanley, P.; Balasubramanian, K. Synth. Com-
mun. 1997, 27, 2057.
(7) (a) Sec¸en, H.; Salamci, E.; Su¨tbeyaz, Y.; Balci M. Synlett 1993,
609. (b) Sec¸en, H.; Salamci, E.; Su¨tbeyaz, Y.; Balci, M. J . Org. Chem.
1997, 62, 2453. (c) Sec¸en, H.; Salamci, E.; Su¨tbeyaz, Y.; Balci M. Synth.
Commun. 1997, 27, 2223.
(9) Zhang, G.-S.; Shi, Q.-Z.; Chen, M.-F., Cai, K. Synth. Commun.
1997, 27, 3691.
(10) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(11) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647.

5928 J . Org. Chem., Vol. 65, No. 19, 2000
Adam et al.
Sch em e 5a
Sch em e 6a
a
Reagents: (a) Ph3P (1.0 equiv), CHCl3, 0 °C, 30 min; (b)
pyridine, Ac2O, CHCl3, 20 °C, 10 h, yield 70%.
Sch em e 7a
a
Reagents: (a) t-BuOK (1.0 equiv), DMF, 10 °C, HCl/H2O; (b)
NEt3, Ac2O CHCl3, -60 °C, 2 h and 20 °C, 10 h, yield 60%; (c)
t-BuOK (1.0 equiv), THF, rt, HCl/H2O, yield 70%.
posed and formed polymeric materials; however, when
endoperoxide 2 was treated with potassium tert-butoxide
in DMF at 10 °C (Scheme 5, step a), phenol was the only
isolable product. Thus, the labile phenolate endoperoxide
2a must have been generated in situ as an intermediate,
which readily released O2.12 Presumably, the released
oxygen is again in the singlet state. To determine the
electronic nature of the released oxygen we have carried
the thermolysis as well as the base-promoted reaction of
2 in the presence of tetramethylethylene, which acts as
singlet oxygen trapping agent. We were not able to detect
any reaction (ene-reaction) between the generated oxygen
and tetramethylethylene. But, these results do not
exclude the formation of the singlet oxygen. It is well-
known that phenols are capable of quenching singlet
oxygen. Therefore, we assume that the generated singlet
oxygen may be quenched by the formed phenols.13
Potassium tert-butoxide and triethylamine (Scheme 5,
step a) abstract the bridgehead protons14 of the keto
endoperoxide 2 to form 1,2,4-benzenetriol (9),15a-c which
was treated with acetic anhydride to afford the known
1,2,4-triacetoxybenzene 9a (Scheme 5).15d
a
Reagents: (a) CoTPP 2 mol %, CH2Cl2, 20 °C, 2 h; (b) SiO2,
hexane/EtOAc, 20 °C; (c) pyridine, Ac2O, CHCl3, 20 °C, 4 h, yield
80%.
the rearrangement to the three products 12-14 in a ratio
of 50:32:18, as confirmed by 200 MHz H NMR spectros-
1
copy (Scheme 7, step a). The resulting mixture was
chromatographed on a silica gel from which only the
rearranged product 15 was isolated (Scheme 7, step b).
SiO2 is responsible for the isomerization of the keto
bisepoxide 12 (it persists in solution) to the epoxyenone
15, whose structure was elucidated on the basis of NMR
analysis and chemical transformation.17
Thus, acetylation with acetic anhydride in the presence
of pyridine gave the corresponding acetate 15a (Scheme
7, step c), for which the acetoxy functionality was
confirmed by the IR band at 1758 cm-1. The structure of
the labile â-lactone 14, which decomposes during silica
gel chromatography, was determined by means of NMR
data. However, low-temperature flash-chromatography
allowed us to isolate trans-14 in a purity of 80%. The
aldehyde proton gives a doublet at δ 9.55, the olefinic
protons display an AB system, and its large coupling
constant (J ) 16.0 Hz) clearly manifests the trans
configuration of the double bond. Furthermore, the
The triphenylphosphine deoxygenation1d of the keto
endoperoxide 2 in CHCl3 led to a mixture of 1,2- and 1,4-
dihydroxybenzenes 10 and 11, which were confirmed by
comparison with authentic sample (Scheme 6, step a),
e.g., no melting-point depression. Presumably, the reac-
tion mechanism involves triphenylphosphine oxide elimi-
nation to give the corresponding epoxy enones, which can
easily afford the two hydroxybenzenes 10 and 11. For
the characterization, 10 and 11 were converted to the
diacetates 10a and 11a (Scheme 6, step b).
Endoperoxide 2 was submitted to the cobalt meso-
tetraphenylporphine (CoTPP) complex16 which catalyzed
(12) (a) Noh, T.; Yang, N. C. J . Am. Chem. Soc. 1991, 113, 9412. (b)
Schafer-Ridder, M.; Brocker, U.; Vogel, E. Angew. Chem., Int. Ed. Engl.
1976, 15, 228.
(13) (a) Thomas, M. J .; Foote, C. S. Photochem. Photobiol. 1978, 27,
683. (b) Foote, C. S.; Thomas, M. J .; Ching, T.-J . J . Photochem. 1976,
5, 172. (c) Foote, C. S.; Ching, T.-J .; Geller, G. G. Photochem. Photobiol.
1974, 20, 511. (d) Saito, I.; Imuta, M.; Matsuura, T. Tetrahedron 1972,
28, 5307.
3
3
coupling constants of J cis ) 6.3 Hz and J trans ) 4.5 Hz
and the geminal coupling constant (2J ) 16.4 Hz) support
the presence of the four-membered ring. The 1H NMR
data of the cis-14 has been extracted from the reaction
(14) Kornblum, N.; De La Mare, H. E. J . Am. Chem. Soc. 1951, 73,
880.
(15) (a) Callaghan, P. D.; Gibson, M. S. J . Chem. Soc. (C) 1970, 2106.
(b) Kurien, K. C. Robins, P. A. J . Chem. Soc. (B) 1970, 855. (c) Luijkx,
G. A. C.; Rantwijk, F.; Bekkum, H. Recl. Trav. Chim. Pays-Bas 1991,
110, 343. (d) Gent, P. A.; Gigg, R. J . Chem. Soc. (C) 1970, 2253.
(16) (a) Boyd, J . D.; Foote, C. S.; Imagawa, D. K. J . Am. Chem. Soc.
1980, 102, 3641. (b) Su¨tbeyaz, Y.; Sec¸en, H.; Balci, M. J . Org. Chem.
1988, 53, 2312.
(17) For similar rearrangement see: Block, O.; Klein, G.; Altenbach,
H.-J .; Brauer, D. J . Org. Chem. 2000, 65, 716.

2,3-Dioxabicyclo[2.2.2]oct-7-en-5-one
J . Org. Chem., Vol. 65, No. 19, 2000 5929
Sch em e 8
In conclusion, a short and convenient method for the
synthesis of the keto endoperoxide 2 has been developed
starting from cyclohexa-1,2-diene. Upon base treatment,
it decomposes readily through its tautomeric enolate 2a
to generate dioxygen and phenol. Furthermore, the
chemistry of this hitherto unknown keto endoperoxide 2
was explored.
Exp er im en ta l Section
Melting points were determined on a capillary melting point
apparatus. IR spectra were obtained from films on NaCl plates
for liquids or KBr pellets for solids on an infrared recording
spectrometer. 1H and 13C NMR spectra were recorded on 200,
250 (50, 62.5) MHz NMR spectrometers and are reported in δ
units with SiMe4 as internal standard. The column chroma-
tography was performed on silica gel (60 mesh) and florisil
(60-100 mesh).
P h otooxygen a tion of 1,4-Cycloh exa d ien e (3). A sample
of 2.00 g (24.98 mmol) of the olefine 3 and 30 mg of meso-
tetraphenylporphine in 80 mL of chloroform were photolyzed
for 24 h at -20 °C with a 150-W sodium lamp while a slow
stream of oxygen gas was passed through the solution. After
removal of the solvent (25 °C, 15 Torr), the mixture was
chromatographed on silica gel (100 g) at -20 °C by elution
with hexanes-Et2O (3:2) to afford 2.82 g of products exo-4,
trans-5, and cis-5 and 0.27 g of (1.87 mmol, 7.5%) endo-4. The
mixture of exo-4, trans-5, and cis-5 was recrystallized from
chloroform-hexane (4:1) to give 110 mg (0.76 mmol, 3%) of
the bishydroperoxide trans-5. The filtrate was diluted with
hexane and kept in the freezer, and 2.48 g (17.22 mmol, 69%)
of exo-4 was crystallized.
Sch em e 9
exo-2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-yl Hyd r op er oxid e
(exo-4).7b Colorless powder from chloroform-hexane (3:2), mp
1
53-54 °C; H NMR (250 MHz, CDCl3) δ 8.43 (br s, 1H), 6.75
(ddd, J ) 11.3, 6.2, 1.5 Hz, 1H), 6.60-6.54 (m, 1H), 5.09-5.04
(m, 1H), 4.74-4.65 (m, 2H), 2.52 (ddd, J ) 14.0, 8.5, 3.9 Hz,
1H), 1.19 (dm, J ) 14.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ
133.8, 129.0, 74.7, 70.7, 70.5, 29.3; IR (KBr, cm-1) 3352, 2943,
1379, 1335, 1275, 1216, 1065, 1009, 971.
en d o-2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-yl Hyd r op er ox-
id e (en d o-4).7b Colorless powder from chloroform-hexane (3:
2), mp 92-93 °C; 1H NMR (250 MHz, CDCl3) δ 8.82 (br.s, 1H),
6.74 (ddd, J ) 8.2, 5.8, 1.5 Hz, 1H), 6.63 (ddd, J ) 8.2, 6.4, 1.8
Hz, 1H), 5.46 (dq, J ) 6.4, 1.8 Hz, 1H), 4.64 (m, 1H), 4.21 (ddd,
J ) 10.0, 3.9, 1.8 Hz, 1H), 1.96 (ddd, J ) 14.3, 10.0, 2.4 Hz,
1H), 1.83 (dt, J ) 14.3, 3.6 Hz, 1H); 13C NMR (63 MHz, CDCl3)
δ 134.9, 130.0, 77.4, 72.4, 70.8, 27.3; IR (KBr, cm-1) 3321, 2926,
1424, 1374, 1069, 992, 915. Anal. Calcd for C6H8O4: C, 50.03;
H, 5.55. Found: C, 49.85, H, 5.56.
tr a n s-4-H yd r op er oxycycloh exa -2,5-d ien -1-yl H yd r o-
p er oxid e (tr a n s-5). Colorless plates from chloroform-hexane,
decomposition above 40 °C without melting; 1H NMR (200
MHz, CD3COCD3) δ 10.75 (br. s, 2H), 6.17 (m, 4H), 4.73 (m,
2H); 13C NMR (50 MHz, CD3COCD3) δ 131.9, 77.3; IR (KBr,
cm-1) 3381, 2786, 1397, 1279, 1013, 903. Anal. Calcd for
C6H8O4: C, 50.03; H, 5.55. Found: C, 49.76, H, 5.72.
tr a n s-2,5-Cycloh exadien e-1,4-diol (tr a n s-6).21 To a stirred
solution of 200 mg (1.38 mmol) of hydroperoxide trans-5 in 50
mL of dichloromethane was added 0.73 g (2.76 mmol) of
triphenylphosphine at 20 °C and stirred for 20 min. After
removal of the solvent (ca. 20 °C and 15 Torr), the mixture
was dissolved in hot chloroform and kept in the freezer, and
100 mg (1.04 mmol, 75%) of diol 6 as colorless plates was
crystallized, mp 138-139 °C; 1H NMR (200 MHz, CD3COCD3)
δ 5.93 (m, 4H), 4.31 (m, 2H), 3.89 (m, 2H); 13C NMR (50 MHz,
CD3COCD3) δ 133.3, 64.3; IR (KBr, cm-1) 3336, 3285, 2902,
1446, 1421, 1268, 1063, 1038, 961.
mixture. Especially, the determined coupling constant
between the olefinic protons (J 3 ) 11.0 Hz) indicates
clearly the cis configuration. The spectral data of the
dialdehyde 13 are in agreement with the reported
ones.18a-c
The mechanism of the CoTPP-catalyzed decomposition
of the keto endoperoxide 2 involves radical pathways
(Scheme 9).16 The alkoxyl radical that results from
electron transfer between the Co(ll) complex and the
endoperoxide 2 serves as a key intermediate (Scheme 8).
By scission of the C-C bond, the acyl radical is gener-
ated, which on cyclization produces the â-lactone 14 with
cis configuration. The double bond in the â-lactone cis-
14 isomerizes partly to the trans-14 under the reaction
conditions. The scission of another C-C bond in the acyl
radical forms malealdehyde 13 and radicals collapse into
the double bond to give bisepoxide 12. Related CoTPP-
catalyzed decompositions have recently been observed,
e.g., for the cycloheptatriene endoperoxide 1619 and
cyclobutanone-annelated cycloheptadiene endoperoxide
17,20 which give the corresponding radical-cyclization
products 18 and 19.
(18) (a) Adam, W.; Erden, I. J . Am. Chem. Soc. 1979, 101, 5692. (b)
Chipman, D. M.; Chauhan, S. M.-S.; George, M. V. J . Org. Chem. 1980,
45, 3187. (c) Adger, B. M.; Barrett, C.; Brennan, J .; McKervey, M. A.;
Murray, R. W. J . Chem. Soc., Chem. Commun. 1991, 1553.
(20) S¸ engu¨l, M. E.; S¸ ims¸ek, N.; Balci, M. Eur. J . Org. Chem. 2000,
1359.
(21) Pan, X.-M.; Schuchmann, M. N.; von Sonntag, C. J . Chem. Soc.,
Perkin Trans. 2 1993, 289.
(19) Balci, M.; Su¨tbeyaz, Y. Tetrahedron Lett. 1983, 24, 4135.

5930 J . Org. Chem., Vol. 65, No. 19, 2000
Adam et al.
Ep oxid a tion of tr a n s-6 d iol. To a stirred solution of
trans-6 diol (50 mg, 0.44 mmol) in 10 mL of CH2CI2 at room
temperature was added 83 mg (0.48 mmol) of m-CPBA, and
the resulting mixture was stirred for 24 h. The precipitate was
removed by filtration, and the solvent was removed under
reduced pressure. The 200 MHz 1H and 50 MHz 13C NMR
analyses indicated 70% conversion of diol to mono-epoxide
trans-6a . 1H NMR (200 MHz, CD3COCD3) δ 5.65 (ddd, J )
8.2, 6.1, 1.8 Hz, A-part of the AB-system, 1H), 5.5 (dm, J )
8.2, B-part of the AB-system, 1H), 4.4 (m, 1H), 4.25 (m, 1H),
3.25 (m, 1H), 3.2 (m, 1H). 13C NMR (50 MHz, CD3COCD3) δ
131.29, 128.98, 59.37, 57.57, 56.78, 56.12.
exo-2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-ol (exo-7). To a
stirred solution of 270 mg (1.87 mmol) of hydroperoxide exo-4
and 2 g of molecular sieves (4°) in 10 mL of dichloromethane
at 5 °C were added 200 mg (2.22 mmol) of Et2S and 26.0 mg
(0.09 mmol) of titanium tetraisopropoxide. Five minutes later,
the reaction was stopped by the addition of 40 µL of water,
and the solids were removed by filtration. After removal of
the solvent (ca. 20 °C and 15 Torr), the mixture was loaded
on a short silica gel column (20 g), and elution with Et2O-
hexane (4:1) gave 220 mg (1.71 mmol; 92%) of exo-7, which
was recrystallized from Et2O-hexane, colorless prisms, mp
106-107 °C; 1H NMR (250 MHz, CDCl3) δ 6.71 (ddd, J ) 8.2,
6.1, 1.8 Hz, 1H), 6.48-6.42 (m, 1H), 4.64-4.55 (m, 2H), 4.28-
4.20 (m, 1H), 2.50 (ddd, J ) 14.0, 7.9, 3.6 Hz, 1H), 1.75 (br d,
1H), 1.24 (dm, J ) 14.0, 1H); 13C NMR (63 MHz, CDCl3) δ
134.8, 129.0, 73.0, 70.8, 62.5, 35.0; IR (KBr, cm-1) 3424, 2936,
1337, 1319, 1282, 1077, 1012, 970. Anal. Calcd for C6H8O3:
C, 56.02; H, 6.24. Found: C, 55.93, H, 6.00.
mmol) of the keto endoperoxide 2 in 15 mL of DMF at 10 °C
was added within 10 min 141 mg (1.26 mmol) of potassium
tert-butoxide in 10 mL of DMF. The resulting mixture was
stirred for 1.5 h and hydrolyzed with 5 mL HCl (5 N). The
solution was extracted with Et2O (2 × 100 mL) and dried over
MgSO4. After evaporation of the solvent (20 °C and 15 Torr),
the residue was chromatographed on a silica gel column (15
g) by elution with hexanes-Et2O (1:1). The first fraction gave
12.0 mg (0.12 mmol, 10%) of phenol.
2,4-Bis(a cetyloxy)p h en yl Aceta te (9a ).15d To a stirred
solution of 0.30 g (2.34 mmol) of the keto endoperoxide 2 in
50 mL of chloroform at -60 °C were added within 2 h 470 mg
(4.68 mmol) of NEt3 and 3 mL of acetic anhydride. The mixture
was allowed to reach room temperature (ca. 25 °C), and at this
temperature the solution was stirred for 10 h. The mixture
was poured into 50 mL of a saturated aqueous NaHCO3
solution. The aqueous organic layer was extracted with Et2O
(2 × 100 mL), and the combined organic layers were dried over
CaCl2. Evaporation of the solvent (20 °C and 15 Torr) gave
0.35 g (1.38 mmol, 60%) of product 9a , which was recrystallized
1
from hexane, colorless plates, mp 100-101 °C; H NMR (250
MHz, CDCl3) δ 7.19-6.97 (m, 3H), 2.27 (s, 9H); 13C NMR (63
MHz, CDCl3) δ 168.8, 168.1, 167.8, 148.1, 142.2, 139.6, 123.5,
119.4, 117.1, 21.0, 20.6 (2C); IR (KBr, cm-1) 3108, 2948, 1765,
1609, 1498, 1425, 1372, 1270, 1180, 1098, 1045, 962.
Th e Rea ction of Keto En d op er oxid e 2 w ith P ota ssiu m
ter t-Bu toxid e in THF . To a stirred solution of 50 mg (0.39
mmol) of the keto endoperoxide 2 in 10 mL of THF at room
temperature was added 50 mg (0.4 mmol) of potassium tert-
butoxide in 10 mL of THF. The resulting mixture was stirred
for 3 h. The resulting mixture was hydrolyzed with 1 mL of
HCl (5 N), and the solvent was evaporated. The residue was
dissolved in 1 mL of acetic anhydride, and 1-2 drop of pyridine
was added. The mixture was stirred for 6 h and poured into
saturated NaHCO3 solution and extracted with diethyl ether
(2 × 20 mL). The organic layer was washed with water and
dried over MgSO4. After evaporation of the solvent, the residue
was chromatographed on a silica gel column (5 g) by elution
with hexanes-Et2O (7:3) giving 68 mg (0.27 mmol) of benzene-
triacetate in 70% yield.
Deoxygen a t ion of t h e Ket o E n d op er oxid e 2 b y Tr i-
p h en ylp h osp in e. To a stirred solution of 0.45 g (3.57 mmol)
of the keto endoperoxide 2 in 50 mL of chloroform at 0 °C was
added within 30 min 0.93 g (3.57 mmol) of PPh3; the tri-
phenylphosphine oxide, a white solid precipitated. After
evaporation of the solvent (20 °C and 15 Torr), the residue
was redissolved in 10 mL of acetic anhydride containing 50
mg of pyridine and stirred at room temperature (ca. 25 °C)
for 12 h. The mixture was poured into 50 mL of saturated
aqueous NaHCO3 solution, extracted with Et2O (2 × 50 mL),
and dried over MgSO4. After removal of the solvent (20 °C, 15
Torr), the residue was chromatographed on silica gel (10 g)
by eluting with hexane:EtOAc (4:1) to afford 0.48 g (2.49 mmol,
70%) of a 9:1 mixture of the diacetates 10a and 11a , identified
by comparison 1H NMR spectra and GC retention times with
the authentic materials.
Decom p osition of th e Keto En d op er oxid e 2 Ca ta lyzed
by th e Coba lt Com p lex of m eso-Tetr a p h en ylp or p h in e
(CoTP P ). To a stirred solution of 0.50 g (3.9 mmol) of the keto
endoperoxide 2 in 50 mL of CH2Cl2 at room temperature (ca.
25 °C) was added 50 mg (0.078 mmol) of CoTPP. The resulting
mixture was stirred for 3 h, and the solvent was removed (5
°C, 15 Torr). 1H NMR analysis indicated that the products 12-
14 were present in the mixture in a ratio of 50:32:18. The
mixture was chromatographed on silica gel (30 g) by elution
with hexane:EtOAc (1:1) to afford 150 mg (1.19 mmol, 30%)
of the keto epoxy alcohol 15 as a brown oil.
cis-2-Bu ten d ia l (13).18 1H NMR (200 MHz, CDCl3) δ 10.61
(AA′ part of AA′XX system, 2H), 6.68 (XX′ part of AA′XX′
system, 2H); 13C NMR (50 MHz, CDCl3) 192.9, 142.0.
syn -5-Hyd r oxy-7-oxa bicylo[4.1.0]h ep t-3-en -2-on e (15).21
1H NMR (200 MHz, CDCl3) δ 6.51 (dt, J ) 10.5, 2.8 Hz, 1H),
5.88 (dt, J ) 10.5, 2.1 Hz, 1H), 4.66 (m, 1H), 3.83 (dd, J ) 3.9,
2.1 Hz, 1H), 3.46 (dd, J ) 3.9, 2.1 Hz, 1H), 2.80 (bs, 1H); 13C
en d o-2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-ol (en d o-7). To a
stirred solution of 190 mg (1.31 mmol) of hydroperoxide endo-4
and 1 g of molecular sieves (4°) in 10 mL of dichloromethane
at 5 °C were added 142 mg (1.57 mmol) of Et2S and 19.0 mg
(0.065 mmol) of titanium tetraisopropoxide. The reaction was
stopped by the addition of 30 µL of water and 5 min later, the
solid material was removed by filtration. After evaporation of
the solvent (20 °C and 15 Torr), the mixture was loaded on a
short silica gel column (20 g) and elution with Et2O-hexane
(4:1) gave 160 mg (1.25 mmol, 95%) of solid endo-7, which was
recrystallized from Et2O-hexane, colorless needles, mp 91-
1
92 °C; H NMR (250 MHz, CDCl3) δ 6.72-6.60 (m, 2H), 4.46
(m, 1H), 4.55 (m, 1H), 3.85 (m, 1H), 2.80 (br. d, 1H), 2.04 (ddd,
J ) 14.3, 9.4, 2.1 Hz, 1H), 1.91 (dt, J ) 14.3, 3.3 Hz, 1H); 13
C
NMR (63 MHz, CDCl3) δ 135.5, 131.4, 78.3, 72.7, 65.0, 33.8;
IR (KBr, cm-1) 3213, 2922, 1432, 1390, 1291, 1256, 1086, 998.
Anal. Calcd for C6H8O3: C, 56.02; H, 6.24. Found: C, 56.30,
H, 6.14.
2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-on e (2). To a stirred
solution of 250 mg (1.95 mmol) of alcohol exo-7 in 75 mL of
dichloromethane was added 0.47 g (2.61 mmol) of pyridine
chlorochromate (PCC) at room temperature (ca. 25 °C). The
resulting mixture was stirred for 3 h and diluted with 50 mL
of Et2O, and the solid material was removed by filtration. After
evaporation of the solvent (20 °C and 15 Torr), the residue
was chromatographed on a silica gel (20 g) by elution with
hexanes-Et2O (1:4). The first fraction gave 100 mg (0.75 mmol,
52% based on converted starting material) of the keto endo-
peroxide 2 as a light yellow oil and 50 mg of unreacted alcohol
exo-7.1H NMR (200 MHz, CDCl3) δ 6.95 (dm, J ) 8.3 Hz, 1H),
6.70 (dm, J )8.3 Hz, 1H), 5.17-5.10 (m, 1H), 4.61 (dm, J )
6.5 Hz, 1H), 2.80 (dd, J ) 18.1, 3.2 Hz, 1H), 2.34 (dd, J ) 18.1,
2.4 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 201.0, 140.3, 129.7,
81.7, 75.6, 38.5; IR (film, cm-1) 3072, 2989, 2931, 1748, 1396,
1354, 1307, 1178, 1020, 967. Anal. Calcd for C6H6O3: C, 57.17;
H, 4.76. Found: C, 56.75, H, 5.02.
2,3-Dioxa bicyclo[2.2.2]oct-7-en -5-on e (2) fr om en d o-
Alcoh ol 7. To a stirred solution of 55 mg (0.43 mmol) of alcohol
endo-7 in 15 mL of dichloromethane was added 0.1 g (0.55
mmol) of pyridine chlorocromate (PCC) at room temperature
(ca. 25 °C). The reaction was carried out as described above.
Chromatography on a silica gel (5 g) gave as the first fraction
17 mg (48%) of 2 based on converted starting material.
Th e Rea ction of Keto En d op er oxid e 2 w ith P ota ssiu m
ter t-Bu toxid e in DMF . To a stirred solution of 160 mg (1.26

2,3-Dioxabicyclo[2.2.2]oct-7-en-5-one
J . Org. Chem., Vol. 65, No. 19, 2000 5931
NMR (50 MHz, CDCl3) δ 194.6, 147.3, 127.3, 66.9, 56.4, 55.5;
IR (film, cm-1) 3387, 2953, 1707, 1421, 1446, 1293, 1268, 1089,
1063.
(dd, J ) 16.0, 6.4 Hz, 1H), 3.28 (dd, J ) 16.0, 4.5 Hz, 1H); 13
C
NMR (63 MHz, CDCl3) δ 195.5, 168.7, 147.5, 146.9, 132.0, 68.7,
47.5.
1
syn -5-Oxa-7-oxabicylo[4.1.0]h ept-3-en -2-yl Acetate (15a).
To a stirred solution of 100 mg (0.79 mmol) of 15 in 2 mL of
acetic anhydride at room temperature (ca. 20 °C) was added
a drop of pyridine, the resulting mixture was stirred for 4 h,
and the solvent was evaporated (40 °C, 15 Torr). The residue
was chromatographed on silica gel (30 g) by elution with
hexane:EtOAc (4:1) to yield 85.0 mg (0.50 mmol, 80%) of
(E)-3-(4-Oxooxeta n -2-yl)p r op -2-en a l (14). H NMR (250
MHz, CDCl3) δ 9.55 (d, J ) 7.5 Hz, 1H), 6.81 (dd, J ) 16.0,
6.0 Hz, 1H), 6.36 (dd, J ) 16.0, 7.5 Hz, 1H), 5.11 (m, 1H), 3.78
(dd, J ) 16.4, 6.3 Hz, 1H), 3.28 (dd, J ) 16.4, 4.5 Hz, 1H); 13
C
NMR (63 MHz, CDCl3) δ 192.1, 167.8, 147.9, 133.1, 67.7, 44.6.
Ack n ow led gm en t. This work was supported by the
Department of Chemistry (Atatu¨rk University) and
Deutsche Forschungsgemeinschaft (SFB 347 “Selektive
Reaktion metall-aktivierter Moleku¨le”; Schwerpunkt-
programm: “Peroxidchemie: Mechanistische und pra¨-
parative Aspekte des Sauerstoff-Transfers”) and Fonds
der Chemischen Industrie. H.K. thanks the Technical
and Scientific Council of Turkey (TUBITAK) for a
fellowship to conduct some of this work in Wu¨rzburg.
1
acetate 15a as a yellow oil and 20 mg unreacted 15. H NMR
(200 MHz, CDCl3) δ 6.51 (dt, J ) 10.5, 2.4 Hz, 1H), 5.96 (dt,
J ) 10.5, 2.1 Hz, 1H), 5.76 (dd, J ) 5.0, 2.4 Hz, 1H), 3.85 (m,
1H), 3.44 (dd, J ) 4.1, 2.1 Hz, 1H), 2.20 (s, 3H); 13C NMR (50
MHz, CDCl3) δ 193.8, 171.7, 142.9, 128.7, 68.6, 54.3, 53.4, 22.6;
IR (NaCl film, cm-1) 3055, 2927, 1758, 1702, 1395, 1268, 1165,
1063, 910. Anal. Calcd for C8H8O4: C, 57.17; H, 4.76. Found:
C, 56.96, H, 4.93.
1
(Z)-3-(4-Oxooxeta n -2-yl)p r op -2-en a l (14). H NMR (250
MHz, CDCl3) δ 9.84 (d, J ) 5.0 Hz, 1H), 6.58 (dd, J ) 11.0,
7.0 Hz, 1H), 6.36 (dd, J ) 11.0, 5.0 Hz, 1H), 5.66 (m, 1H), 3.62
J O000120P