Photooxygenation of masked o-benzoquinones: An efficient entry into highly functionalized cyclopentenones from 2-methoxyphenols

Article abstract of DOI:10.1002/anie.200802130

(Chemical Equation Presented) MOB tactics: A novel oxidation of masked o-benzoquinones (MOBs) 1 occurs by singlet-oxygen-triggered ring contraction to form cyclopentenone derivatives 2 and by [4+2] cycloaddition to give endoperoxides 3. The competing path

Full text of DOI:10.1002/anie.200802130

Angewandte
Chemie
DOI: 10.1002/anie.200802130
Oxidation
Photooxygenation of Masked o-Benzoquinones: An Efficient Entry into
Highly Functionalized Cyclopentenones from 2-Methoxyphenols**
Tzu-Chiao Kao, Gary Jing Chuang, and Chun-Chen Liao*
Singlet oxygen (1O2) is an essential excited molecule in both
Table 1: Photooxygenation of MOBs 1a–f to generate endoperoxides 2a–
f and 4-hydroxy-2-cyclopentenones 3a–c.
organic reactions[1,3] and biological pathways.[2] The reaction
1
of O2 with a 1,3-diene can take three potential pathways:
[4+2] cycloaddition to form endoperoxides, the ene reaction,
and [2+2] cycloaddition to obtain dioxetanes. The type of
reaction is dependent on the solvent, steric, electronic factors
and variations in the structure.[3] Among the few cases of
photooxygenation with electron-deficient 2,4-cyclohexadie-
nones, [4+2] cycloaddition was found to be the major
pathway.[4] We have extensively investigated the [4+2] cyclo-
addition reactions of masked o-benzoquinones (MOBs) with
a wide variety of dienophiles, including electron-rich dien-
ophiles (benzyl vinyl ether, dihydrofuran, styrene, and phenyl
vinyl sulphide), electron-deficient dienophiles (methyl acry-
late, methyl vinyl ketone, and acrylonitrile), nitroso com-
pounds, and N-phenyltriazolinedione. We have also demon-
strated the great potential of MOBs in organic synthesis by
developing various methodologies for the total synthesis of
natural products.[5] We were interested in examining the
substituent effect of the 6,6-dimethoxy groups of MOBs in
photooxygenation, as a comparison with the corresponding
reactions of other 2,4-cyclohexadienones. To our surprise,
upon photoxygenation various MOBs produced not only
endoperoxides, but also 4-hydroxy-2-cyclopentenones by ring
contraction, depending on the solvents employed. We report
herein the novel photooxygenation reactions of MOBs.
All the MOBs utilized in this study were prepared from
oxidation of the corresponding 2-methoxyphenols with diac-
etoxyiodobenzene (DAIB) in methanol. Photooxygenations
were performed on a solution of the appropriate MOB and a
small amount of sensitizer bubbling with oxygen at À158C by
irradiation with five 500 W halogen lamps. The photooxyge-
nation of MOB 1a (0.05m) was carried out in chloroform with
tetraphenylporphyrin (TPP) as the sensitizer. Endoperoxide
2a (26%) and 4-hydroxy-2-cyclopentenone 3a (50%) were
isolated from the irradiated solution after treatment with
Product in
R3 chloroform[a]
(yield[c] [%])
Product in
methanol[b]
(yield[c] [%])
Entry SM
R1
R2
1
2
1a
1b
H
H
iPr
tBu
iPr
H
2a (26)[d]
3a (50)[d]
3a (70)[d]
tBu 2b (68)[d]
3b (78)[d]
3b (17)[d]
3
4
1c
1d
1e
H
Me 2c (87)
3c (75)[d]
Me
Me
H
2d (90)[e]
Recovery of SM[f]
5
6
H
H
H
H
2e (82)[e]
2 f (90)[g]
Recovery of SM[f]
1 f OMe
2 f (92)[f]
[a] Reaction conditions: Irradiation by 5”500 W lamps of a solution
containing MOB (0.05m) and a small amount of tetraphenylporphyrin
(TPP) in chloroform with bubbling oxygen at À158C for entries 1–3 and
at 08C for entries 4–6. [b] Under similar conditions with Rose Bengal
(RB) as a sensitizer (in place of TPP). [c] Yield of isolated product.
[d] After completion of reaction, the mixture was treated with thiourea.
[e] Reaction time: 2 h. [f] Reaction time: 4 h. [g] Reaction time: 1 h.
Similar results were found in the photooxygenation of
MOBs 1b and 1c, (R1 = H, Table 1, entries 2 and 3). The
reactions generated the corresponding 4-hydroxy-2-cyclopen-
tenones 3b and 3c exclusively in methanol, whereas reactions
in chloroform yielded mixtures of endoperoxides (2b and 2c,
respectively) and 4-hydroxy-2-cyclopentenones (3b and 3c,
respectively). As a comparison with 1a, alkyl group substitu-
ents at R3 favored the formation of endoperoxides in the
reactions of 1b and 1c in chloroform. This result is in accord
with those from the reported examples of [4+2] cycloaddition
thiourea (Table 1, entry 1). Interestingly, the reaction gener- of singlet oxygen with 1,4-disubstituted naphthalenes and 4-
ated only 3a in methanol, using Rose Bengal (RB) as the
sensitizer. Initial product distributions clearly indicate the
importance of solvent effects on reaction pathways.[6]
substituted phenol derivates, where endoperoxide products
substituted with electronic-donating groups (alkyl and hy-
droxy) at the bridgehead position of the dienes were
favored.[7]
The reactions of MOBs 1d–f (R1 = CH3 or OCH3, Table 1,
entries 4–6) in chloroform yielded endoperoxides 2d–f exclu-
sively. Interestingly, the reaction of 1 f in methanol was
considerably slower than that in chloroform (4 h vs 1 h), and
gave exclusive formation of the [4+2] adduct 2 f, whereas, in
the cases of 1d and 1e, starting materials were recovered after
4 h, with traces of uncharacterized product. These results
implied that non-hydrogen substituents at R1 prohibit the
rearrangement pathway for photooxygenation. MOBs 1d and
[*] T.-C. Kao, Dr. G. J. Chuang, Prof. Dr. C.-C. Liao
Department of Chemistry, National Tsing Hua University
Hsinchu 300 (Taiwan)
Fax: (+886)3572-8123
E-mail: ccliao@mx.nthu.edu.tw
[**] Financial support from the National Science Council of Taiwan is
gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802130.
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1e, which are less electron-rich than 1 f, are inert towards
process. Hydroperoxide 4b could also be isolated at À58C,
and was subsequently transformed to 5b upon warming up,
presumably by 1,4-addition (Scheme 2). The structural infor-
mation for cyclopentenones 4 and 5 gives indirect evidence of
the existence of intermediate II (Scheme 1).
To further expand the scope of the new photooxygena-
tion-rearrangement reaction, two work-up treatments were
applied to the photooxygenated solution to furnish cyclo-
pentenones with structural variations (Table 2). Method A, as
previously described, with the addition of thiourea to the
photooxygenated product in methanol, afforded 4-hydroxy-2-
cyclopentenones 3a–c, g–j, isolated in good yield (50–79%).
Method B, treating the photooxygenated solutions with
excess sodium bicarbonate at À158C, led to the formation
of the epoxycyclopentenones bearing orthoester groups, 6a–c,
photooxygenation in methanol, in which the lifetime of
singlet oxygen is considerably shorter than in chloroform.[8]
A proposed mechanism of competing reaction pathways,
depicted in Scheme 1, explains the above substituent and
solvent effects in the photooxygenation of MOBs. For MOBs
containing an electron-donating group at R1, [4+2] cyclo-
Scheme 1. Proposed reaction pathways for formation of endoperoxide
2 and cyclopentenone 3.
addition, to form the corresponding endoperoxide 2, is
preferred. This tendency could be explained by the nature
of MOB in the [4+2] cycloaddition, where the bond next to
the dimethoxy group is formed prior to that adjacent to the
carbonyl group in a concerted reaction.[5a] Thus an alkyl group
at R1, would promote the formation of endoperoxide 2.
Conversely, electron-deficient MOBs with R1 = H tend to
yield 4-hydroxy-2-cyclopentenones 3 as the major products of
photooxygenation. This ring-contraction reaction to form a 5-
membered ring is likely to be the result of a rare [1,2] acyl
Scheme 2. Generation of hydroperoxide 4b and cyclic peroxy-
orthoester 5a,b from photooxygenation of 1a,b.
Table 2: Examples of post-treatments of photooxygenation to form 3, 6,
and 7b.
1
shift,[9] in which the initial attachment of O2 provoked the
rearrangement process from intermediate I (Scheme 1, with
resonance structures Ia and Ib); the stabilization of the
carbocation II by the dimethoxy group would drive a [1,2]
shift. The cis-relationship of R1 and R2 in cyclopentenone 3
hinted at a back-side-attack during the migration, and the
prohibition of the rearrangement by installation of R1
substituents could be rationalized by the potential steric
hindrance in forming two fully substituted carbon centers
adjacent to each other in II. Past research has supported the
Product A[b]
(yield[d] [%])
Product B[c]
(yield[d] [%])
Entry SM[a]
R2
R3
H
1
2
1a
1b
iPr
3a (73)
6a (92)
tBu
tBu 3b (72)
1
tendency of O2 to undergo [4+2] cycloaddition in nonpolar
7b (90)
6c (95)
solvents. According to previous research in our group,[5a]
[4+2] reactions of MOBs are considered to be concerted
and, therefore, less affected by solvent polarity.[10] The high
solvent preference for the formation of rearrangement
product 3 in methanol (rather than CHCl3) could be
rationalized by the greater solvation of the proposed inter-
mediates in polar solvents.[3e,l,11]
3
4
1c
1g
iPr
Me
H
3c (70)
3g (75)
6g (92)
5
6
1h
1i
n-C16H33
H
H
3h (65)[e]
3i (79)
6h (85)
6i (90)
7
1j
Cl
3j (50)
6j (70)
[a] Irradiation by 5”500 W lamps of a solution of MOB (0.01m) and
Rose Bengal in methanol at À158C with bubbling oxygen. [b] After
completion of reaction, the mixture was treated with thiourea at 08C;
[c] After completion of reaction, the mixture was treated with excess
sodium bicarbonate at À158C. [d] Yield of isolated product. [e] 3h is
untenone A.
After the photooxygenated solutions of MOBs 1a and 1b
were kept at À58C overnight and then warmed to room
temperature, cyclic peroxyorthoesters 5a and b were obtained
respectively in excellent yields (90, 85%), offering further
evidence for the proposed mechanism of the rearrangement
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[2.2.2]octane (dabco) and 2,4,6-tri-tert-butylphenol (TBP) were
used to examine the reaction of MOB 1a (0.05m) in chloroform.
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Figure 1. Selected examples of natural products containing 4-hydroxy-
2-cyclopentenone moiety.
In summary, this investigation on the photooxygenation of
substituted MOBs has shown intriguing results of novel
reactions. The reaction allows access to a variety of function-
alized cyclopentenones resulting from controlling solvent and
substituent effects.
Received: May 7, 2008
Published online: August 8, 2008
Keywords: cycloaddition · oxygenation · peroxides · quinones ·
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