Novel generation of an o-quinone methide from 2-(2′-cyclohexenyl)phenol by excited state intramolecular proton transfer and subsequent C-C fragmentation

Article abstract of DOI:10.1039/b207545h

Formation of an o-quinone methide via C-C fragmentation of a zwitterion formed by intramolecular excited state proton transfer from an o-allylphenol derivative is reported for the first time.

Full text of DOI:10.1039/b207545h

Novel generation of an o-quinone methide from 2-(2A-cyclohexenyl)phenol
by excited state intramolecular proton transfer and subsequent C–C
fragmentation
Julio Delgado, Amparo Espinós, M. Consuelo Jiménez and Miguel A. Miranda*
Departamento de Química-Instituto de Tecnología Química UPV-CSIC, Camino de vera s/n, 46071
Valencia, Spain. E-mail: mmiranda@qim.upv.es; Fax: +34 963879349; Tel: +34 963877340
Received (in Cambridge, UK) 1st August 2002, Accepted 1st October 2002
First published as an Advance Article on the web 10th October 2002
Formation of an o-quinone methide via C–C fragmentation
of a zwitterion formed by intramolecular excited state proton
transfer from an o-allylphenol derivative is reported for the
first time.
These species are relatively stable intermediates; they have
been detected by means of laser flash photolysis of both o-
hydroxybenzyl alcohols and o-hydroxystyrene precursors and
display characteristic transient absorption at 400 nm.3–5 o-
Allylphenols such as 1a are closely related to o-hydroxystyr-
enes and are also known to undergo ESIPT upon photolysis; the
resulting zwitterions photocyclise to 5- (or 6-) membered ring
products.6–9 The b-cyclodextrin inclusion complexes undergo
photohydration of the olefin as the major process.10 Thus,
insertion of a methylene group between the phenol and the
olefin moieties appears to prevent formation of o-quinone
methides, which have never been generated in the photolysis of
o-allylphenols.
We wish now to report on the use of an o-allylphenol
analogue as the source of an o-quinone methide. Thus, 2-(2A-
cyclohexenyl)phenol 1b6 was irradiated for 6 h in several
organic solvents using the quartz-filtered light of a medium
pressure mercury lamp. The photomixtures were analysed by
GC, GC-MS and 1H-NMR, using adequate standards for
quantitation. The major products were isolated and spectroscop-
ically characterised. Their structures are shown in Chart 1, and
their yields are summarised in Table 1.
o-Quinone methides (6-alkylidenecyclohexa-2,4-dienones) are
very useful synthetic intermediates with both electrophilic and
nucleophilic properties.1 Their biological activity is also very
interesting, as they appear to be the ultimate cytotoxins
responsible for the effect of some antitumor drugs, antibiotics
and DNA alkylators.2
Intermediates of this type have been generated in the past by
several routes, including light-induced water elimination from
o-hydroxybenzyl alcohols or excited state intramolecular pro-
ton transfer (ESIPT) in o-hydroxystyrenes (Fig. 1).3–5
Fig. 1 Generation of o-quinone methides by dehydration of o-hydrox-
ybenzyl alcohols or ESIPT in o-hydroxystyrenes.
When 1b was photolysed in methanol (Table 1, entry 1), the
major product exhibited a MS with molecular ion M+ at m/z 206,
In aqueous solution, o-quinone methides undergo hydro-
nium-ion catalyzed hydration by a reaction mechanism that
involves rapid equilibrium protonation of the substrate on its
carbonyl oxygen followed by rate-determining nucleophilic
capture of the ensuing carbocation by water. The only
photoproducts are the corresponding benzyl alcohols. Trapping
can also be achieved with other nucleophiles (MeOH, SCN2,
Br2, etc.) and with electron rich alkenes, to give [4 + 2]
cycloaddition products (Fig. 2).4,5
Fig. 2 Trapping of o-quinone methides by nucleophiles and dienophiles.
Table 1 Photochemistry of 1ba
Chart 1
Product yield (%)
Entry
Solventa
Conversion (%)
Mass balance (%)
2 (or 5)
3 + 4
Others
1
2
3
4
A
B
C
D
91
54
75
38
68
40
45
78
93
67
—
—
2
27
91
97
5b
6b
9c
3b
a A: methanol; B: ethyl vinyl ether; C: benzene; D: cyclohexane. b Unidentified products. c Includes a benzene addition product and a 1b dimer.14
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This journal is © The Royal Society of Chemistry 2002

clearly indicating incorporation of the solvent. In principle, we
would have expected simple addition of methanol to the double
bond, as previously described in the literature for o-allylphenol
arise from 1b via benzene addition and dimerization. This is
compatible with the reactivity expected for the cationic
character of the proposed zwitterionic intermediate I.
In cyclohexane (Table 1, entry 4) the only photoproducts
were the cyclic ethers 3 and 4.
1
derivatives.11 However, the H-NMR spectrum of the isolated
photoproduct indicated that its structure was that of the open
chain terminal olefin 2.12 Although the reaction was clean, the
quantum yield (as determined by potassium ferrioxalate
actinometry) was ca. 0.02. Traces of the cyclic ethers 3 and 4
(previously reported as the main photoproducts of 1b in
benzene)6 were also found. In a control experiment, a mixture of
3 and 4 was irradiated under the same conditions; the lack of
formation of 2 allowed us to rule out a possible secondary
photoreaction as the origin of this product.
The proposed mechanism to explain formation of 2 is shown
in Fig. 3. Initial ESIPT from the phenolic subunit to the double
bond would lead to the zwitterionic intermediate I. Subsequent
C–C bond fragmentation with concomitant ring opening
explains generation of the o-quinone methide II. In the presence
of methanol, II would be trapped by the solvent giving rise to
2.
In summary, a new route to 6-alkylidenecyclohexa-2,4-die-
nones (o-quinone methides) via intramolecular excited state
proton transfer of o-allylphenols derivatives and subsequent C–
C fragmentation has been observed for the first time. These
intermediates have been trapped by methanol and ethyl vinyl
ether and detected by laser flash photolysis. At the moment, the
reason why 1b exhibits this behaviour is not clear. It could be
due to the combined effect of three factors: (a) enhanced
protonation at the a-carbon, to give the secondary carbocation
I (instead of a primary carbocation, as would have occurred with
the parent allyl phenol 1a and related compounds), (b) higher
stability of II, due to substitution of the double bonds and (c)
conformational effects associated with the cyclohexene ring.
Our ongoing studies in this field are directed to gain further
mechanistic insight and to elucidate the scope and limitations of
this new photogeneration of o-quinone methides.
We thank financial support from the Spanish MCYT (BQU
2001-2725) and Dr. F. Boscá for his advice in laser flash
photolysis measurements.
Notes and references
Fig. 3 Mechanism explaining formation of 2 upon photolysis of 1b in
methanol.
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If the o-quinone methide were actually formed, it should be
possible to achieve its trapping using ethyl vinyl ether as
dienophile.5 As a matter of fact (Table 1, entry 2), the major
photoproduct in neat ethyl vinyl ether as solvent was dihy-
drobenzopyran 5, whose structure was established based on the
spectral data of the isolated compound.13 The two possible
isomers of 5 (cis and trans) were obtained in comparable
amounts. Again, the usual photocyclisation products 3 and 4
were formed, with yields somewhat higher than in the methanol
irradiation.
Direct evidence for the involvement of an o-quinone methide
was provided by laser flash photolysis. Using 266 nm as the
excitation wavelength and acetonitrile as solvent, a well defined
signal with two maxima around 300 and 400 nm was recorded.
The spectrum (shown in Fig. 4) is in agreement with those
previously reported for similar intermediates.3–5
For comparison, irradiation of 1b was also carried out in
benzene and cyclohexane. In benzene (Table 1, entry 3), a
mixture of 3 and 4 was obtained, confirming previous
observations by Fráter and Schmid.6 Besides, trace amounts of
non-reported byproducts were detected by GC-MS:14 the m/z
values of their molecular ions indicate that these byproducts
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12 Compound 2: 1H-NMR (CDCl3, TMS as internal standard) d (ppm):
1.30–2.10 (m, 6H, CH2CH2CH2), 3.37 (s, 3H, OCH3), 4.25 (m, 1 H,
CHOCH3), 4.95 (m, 2H, CHNCH2), 5.75 (m, 1H, CHNCH2),
6.76–6.96–7.21 (m, 4H, ArH); MS (m/z, %): 206 (M+, 10), 174 (29), 159
(14), 145 (20), 137 (100), 133 (58), 131 (25), 120 (22), 107 (21), 105
(20).
13 Compound 5: 1H-NMR, (CDCl3, TMS as internal standard) d (ppm):
1.22–1.27 (t, 3H, J = 7.1 Hz, CH3), 1.38–2.20 (m, 6H, CH2CH2CH2),
2.89 (m, 1H, CHCH2CH2CH2), 3.60 + 4.00 (m + m, 2 H, trans + cis
OCH2CH3), 4.90–5.20 (m, 3H, CHNCH2 + OCHO), 5,82 (m, 1H,
CHNCH2), 6.80–7.20 (m, 4H, ArH); MS (m/z, %): 246 (M+, 10), 201 (6),
200 (8), 177 (100), 174 (15), 149 (16), 133 (22), 131 (35), 121 (30), 120
(17), 91 (15).
14 Benzene addition product: MS (m/z, %): 252 (M+, 100), 211 (40), 198
(18), 183 (32), 165 (19), 145 (21), 144 (19), 115 (19), 91 (16); 77 (20);
1b dimer: MS (m/z, %): 348 (M+, 21), 279 (100), 173 (19), 145 (13), 133
(12), 131 (18), 115 (8), 107 (45), 91 (10).
Fig. 4 Transient absorption spectrum obtained upon laser flash photolysis
(266 nm) of 1b in acetonitrile.
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