Domino Self-Sensitized Photooxygenation of Conjugated Dienones for the Synthesis of 1,2,4-Trioxanes

Article abstract of DOI:10.1021/acs.joc.8b03279

The photochemical behavior of several dienones was studied under aerobic conditions. 2-Allylidene-1,3-cycloalkanediones prepared via Knoevenagel-type condensation between simple readily available 1,3-dicarbonyl substrates and α,β-unsaturated aldehydes aff

Full text of DOI:10.1021/acs.joc.8b03279

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Note
Domino Self-Sensitized Photooxygenation of Conjugated
Dienones for the Synthesis of 1,2,4-Trioxanes
Martin Jorge Riveira, Nadia L. Martiren, and Mirta P. Mischne
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03279 • Publication Date (Web): 26 Feb 2019
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Domino Self-Sensitized Photooxygenation of Conjugated Dienones for the Synthesis of
1,2,4-Trioxanes
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Martín J. Riveira, Nadia L. Martiren and Mirta P. Mischne*
Instituto de Química Rosario, Facultad de Ciencias Bioquímicas y Farmacéuticas,
Universidad Nacional de Rosario-CONICET, Suipacha 531, S2002LRK, Rosario, Argentina.
mischne@iquir-conicet.gov.ar
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ABSTRACT
The photochemical behavior of several dienones was studied under aerobic
conditions.
2-Allylidene-1,3-cycloalkanediones prepared
via
Knoevenagel-type
condensation between simple readily available 1,3-dicarbonyl substrates and ,-unsaturated
aldehydes, afforded 1,2,4-trioxane derivatives upon UVA-irradiation in the presence of
oxygen. This domino self-sensitized photooxygenation cascade of conjugated carbonyl
systems proceeds stereoselectively and involves the formation of two new oxa-cycles, three
new bonds (two C-O) and three stereocenters.
The 1,2,4-trioxane pharmacophore has become famous over the last decades due to
the success of artemisinin (1)-based combination therapies (ACT’s) against malaria’s
etiological agent Plasmodium falciparum, the most dangerous of malaria parasites (Scheme
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1A).1 Indeed, for her discoveries concerning these treatments based on the remarkable
peroxidic sesquiterpene 1, Youyou Tu was awarded the Nobel Prize in Physiology or
Medicine in 2015.2 Although signs of resistance have recently emerged in Southeast Asia,
malaria scientists still rely on newly developed and future peroxides for the fight in the war
against this long-standing problem.3
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From an organic synthesis viewpoint, 1,2,4-trioxanes have been shown to be valuable
as intermediates for the preparation of diverse heterocyclic scaffolds by the use of a variety
of developed rearrangement and reductive processes.4 On the other hand and as regards their
preparation, many methodologies have been made available during the last decades primarily
triggered by the need of new drug candidates.5 One of the most conventional and reliable
methods known as Type II photooxygenation, involves the reaction of singlet oxygen with
olefinic compounds.6 Generally, singlet oxygen is generated by an energy-transfer
mechanism provided a suitable dye sensitizer is excited in the presence of ground-state triplet
oxygen. This reaction has been occasionally used employing 2H-pyrans as substrates, for
example in the synthesis of bicyclic 1,2,4-trioxanes 2 and 3, the former a natural
sesquiterpenoid,7 the latter an intermediate in the total synthesis of phomactin A (Scheme
1B).8
Taking into account that malaria affects the poorest regions of the planet, the most
needed protocols are those that are operationally simple and that involve readily available
inexpensive reagents. In this regard, domino reactions meet these criteria since they allow
the rapid assembly of complex molecules through the combination of multiple bond-forming
transformations without the need to isolate and purify intermediates.9 Our research group
previously established that natural product -ionone 4 affords 1,2,4-trioxane derivative 6
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when toluene solutions are irradiated in the presence of oxygen without the use of an external
singlet oxygen sensitizer (Scheme 1C).10 This domino process involves sequential exocyclic
double bond isomerization, oxa-6-electrocyclic ring closure and eventual Diels-Alder type
[4+2] cycloaddition between 2H-pyran intermediate 5 and singlet oxygen generated in-situ.
Time-resolved laser induced experiments confirmed the formation of the excited triplet state
of 4 as responsible for the generation of singlet oxygen, establishing the ability of dienones
bearing a ionone-type skeleton to act as singlet oxygen sensitizers.11
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Scheme 1. (A) Structure of Artemisinin (1). (B) Singlet Oxygen [4+2]-Cycloaddition
Leading to Bicyclic 1,2,4-Trioxanes. (C) The Self-Sensitized Photooxygenation of -Ionone.
It is known that polyunsaturated substrates are versatile candidates for the efficient
construction of polycyclic molecules via cycloisomerization rearrangements.12 For
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conjugated carbonyl compounds, many aspects of this chemistry have mainly been
investigated with regards to electrocyclization reactions. In this context, taking into account
the rapid assembly of trioxane systems via this unusual and underexplored
cycloisomerization/oxidation sequence, and stimulated by the need and importance of
endoperoxides, we decided to undertake a study aiming to establish the reaction modes of a
series of substituted carbonyl-polyene systems. Herein we wish to report our findings
concerning the photochemical behavior of simple structurally diverse conjugated dienones.
The first series of unsaturated precursors is depicted in Figure 1. All substrates 7a-h
were prepared via classical aldol and Knoevenagel condensation reactions.13 All of these
dienones have been previously synthetized and the photochemical behavior of many have
also been studied under anaerobic conditions.13,14 In particular, dienones 7a and 7b, lacking
a conjugated aromatic ring at the end of the polyene chain, turned out to be quite unstable
resulting in complex mixtures due to decomposition even after a few days of storage.
According to our previously reported photooxidation protocol used for the oxidation of -
ionone 4, all unsaturated carbonyl compounds 7a-h were dissolved in toluene and their 10
mM solutions irradiated using black light fluorescent tubes (λmax = 350 nm) with the bubbling
of oxygen gas. Substrate 7a structurally related to -ionone (4), and also 7b suffered thorough
decomposition upon irradiation. Only cis/trans photoisomerization processes were found to
take place for dienones 7c-g, affording in these cases inseparable mixtures of stereoisomers.
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Figure 1. Initially screened conjugated dienones 7a-h
After prolonged irradiation, cinnamylidene dimedone (7h), less structurally related to
-ionone (4) than compound 7a, afforded the corresponding 1,2,4-trioxanes 8h and 8’h in
20% and 2% yield, respectively (Scheme 2). Stereochemical assignments could be drawn
from NOE experiments, minor product being assigned as 8’h particularly based on a NOE
correlation between the olefinic and benzylic hydrogen atoms suggesting the pseudo-axial
position of the latter in the bicyclic system. This stereoselective character of the reaction is
not only in agreement with recently reported results on the dye-sensitized photooxygenation
of 2H-pyrans,15 but also in line with mechanistic grounds. Photooxygenations of the [4+2]-
type involving singlet oxygen are known to be highly sensitive to steric control.16
Accordingly, singlet oxygen, generated in-situ, would approach the pyran system 12 from
the less hindered face opposite to the substituent phenyl group. Additionally, it should be
noticed that the chemical shift of the benzylic proton (Ha) in the anti-isomer 8h appears more
downfield which could be attributed to a deshielding effect provided by the proximate
peroxide linkage (Scheme 2).
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Scheme 2. Self-sensitized photooxygenation of 2-cinnamylidene 1,3-dicarbonyl substrate 7h
Motivated by this finding, we then explored some adjustments to the reaction
conditions in order to achieve better yields of trioxanes 8 production. In particular, the
evaluation of other concentrations did not provide any improvement. In addition,
replacement of actinic lamps by a mercury medium pressure lamp using an immersion well
apparatus was not fruitful either. Our attention was then focused on the evaluation of other
solvents in order to find suitable conditions for the preparation of trioxanes 8. Whereas no
reaction was observed in methanol, in dichloromethane extensive decomposition was
evidenced for substrate 7h. When acetonitrile was assayed, the yield of products 8h was
slightly increased (33%) and the reaction was complete in 19 hours instead of the 40 hours
required in toluene to achieve an 85% conversion of substrate 7h (Scheme 2). This
improvement was particularly beneficial since, although trioxanic products 8h were shown
to be stable over years of storage, they were found to be sensitive to the UV-irradiation used
for their formation. In this context, under these same conditions but using hydroquinone as
additive, the yield could be increased to 45%. One particular observation that caught our
attention was that unlike the photooxygenation of -ionone, 2H-pyran intermediate 9h could
not be observed by TLC or NMR monitoring nor found when the reaction was run with
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exclusion of oxygen. We then reasoned that a short lifetime of this putative intermediate 9h
could account for this observation being the valence-equilibrium rapidly shifted towards the
starting dienone open-form in the absence of oxygen. In view of this, we then contemplated
the use of carbon tetrachloride as solvent as the lifetime of reactive intermediate singlet
oxygen is considerably longer in this halogenated solvent being thus readily available for
capturing the putative unstable intermediate 9h. In this manner, dienone 7h underwent
successful photooxygenation towards trioxanes 8h in 60% overall yield and taking only 8
hours for reaction completion (Scheme 3). Remarkably, both in carbon tetrachloride and
acetonitrile, the same diastereoselectivity found in toluene was observed and hence the
stereoselectivity of the process seems to be independent of the polarity of the solvent and
mainly governed by steric factors.
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Results from evaluating other dienones related to 7h are shown in Scheme 3. All
substrates 7g-7r were readily prepared via Knoevenagel condensation catalyzed by Tietze
base EDDA (ethylenediammonium diacetate).13a As shown, in carbon tetrachloride,
previously considered unreactive substrate 7g did undergo transformation towards the
corresponding trioxane derivatives 8g. Unfortunately, low conversion was achieved even
after 22 hours of irradiation. An inspection of Scheme 3 reveals the yields of trioxane
formation were in general moderate and no other products could be identified in the reaction
mixtures. Photoisomerization was only observed for acyclic dienones 7g and 7o, which
underwent incomplete transformations after prolonged irradiation, the recovered material
being a mixture of starting dienones 7g and 7o contaminated with the corresponding ,-cis
isomers. Interestingly, reactions of these two dienones along with that of trienedione
substrate 7p which does not bear an aromatic ring, were less diastereoselective giving rise to
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the corresponding trioxanes as 3:1 stereoisomeric mixtures. In every case, whereas main
peroxidic products 8 were readily isolated after column chromatography purification, minor
components 8’ could not be obtained in pure form. Their structures and relative abundance
were determined, however, by analyses of the spectral data of crude mixtures and comparison
with data gathered for isolated 8’h. The fastest transformations were observed for those
cyclic substrates not bearing the phenyl substituent or having one featuring an electron-
withdrawing halogen atom on it. Among these, bromoderivative 7n underwent complete
conversion in 2 hours giving the highest yield of peroxide formation (73%), a result that we
attributed to a facilitated intersystem crossing event due to the presence of the heavy atom
favoring in this way the required singlet oxygen sensitization step. Curiously, whereas 2-
cinnamylidene-1,3-cyclohexanedione 7i successfully afforded the corresponding trioxane
derivatives 8i in 56% yield after 4 h of irradiation, analogous cyclopentanedione derivative
7r did not participate in the domino sequence even after prolonged irradiation (> 20 h).
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Scheme 3. Self-sensitized photooxygenation of 2-allylidene-1,3-cycloalkanediones 7
It should be noted that when -alkyl substituted enals were used as electrophilic
partners in the Knoevenagel condensation reactions carried out for the preparation of
substrates 7, no conjugated dienone 7 was obtained as product. Instead, only the 2H-pyran
valence isomers were isolated as products of a formal [3+3]-cycloaddition, which comprises
a Knoevenagel condensation followed by a spontaneous oxa-6-electrocyclization.17 For
example, the condensation between 5,5-dimethyl-1,3-cyclohexanedione (10) and trans-2-
pentenal (11) catalyzed by EDDA yields 2H-pyran 9s exclusively, albeit in low yield
(Scheme 4). Curiously, when 2H-pyrans such as 9s were submitted to our new
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photooxygenation protocol, no trioxane could be identified in the reaction mixtures. Instead
thorough decomposition of the starting materials was only observed.18 It should be noted that
from these species, 1,2,4-trioxanes can still be synthesized by using the conventional dye-
sensitized photooxygenation. For example, irradiation of 9s using a tungsten lamp and rose
bengal as singlet-oxygen sensitizer led to the production of peroxides 8s which were obtained
as an inseparable mixture of stereoisomers in a 3.5:1 ratio. Pyran 9t, prepared according to J.
L. Renaud and co-workers,19 also underwent dye-sensitized [4+2] photooxygenation to
afford polycyclic peroxide 8t which was isolated as a single stereoisomer in low yield and
proved to be very unstable.
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Scheme 4. Dye-sensitized photooxygenation of 2H-pyrans 9
In summary, we have reported a stereoselective methodology for the synthesis of
1,2,4-trioxanes from simple precursors through self-sensitized photooxygenation.
Undoubtedly, this one-pot approach stands as a complementary strategy for the preparation
of valuable 1,2,4-trioxane derivatives which may encourage future biological studies on these
remarkable peroxidic scaffolds.
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EXPERIMENTAL SECTION
Materials and methods
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Unsaturated precursors 7 have been previously prepared in the literature.13 All other
chemical reagents were purchased from commercial suppliers and used without further
purification. Solvents were analytical grade or were purified by standard procedures prior to
use. Yields were calculated for material judged homogeneous by thin layer chromatography
(TLC) and nuclear magnetic resonance (1H NMR). All reactions were monitored by thin layer
chromatography performed on silica gel 60 F254 pre-coated aluminum sheets, visualized by
a 254 nm UV lamp, and stained with an ethanolic solution of 4-anisaldehyde. Column flash
chromatography was performed using silica gel 60 (230 – 400 mesh). Melting points (M.p.)
were taken on an electrothermal melting point apparatus and are uncorrected. Nuclear
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1
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magnetic resonance spectra were acquired at 300 MHz for H and 75 MHz for C using
CDCl3 as solvent. Chemical shifts for proton nuclear magnetic resonance spectra are reported
in parts per million relative to the signal of tetramethylsilane (TMS) at 0 ppm (internal
standard) and coupling constants (J) are reported in hertz (Hz). Chemical shifts for carbon
nuclear magnetic resonance (13C NMR) spectra are reported in parts per million relative to
the center line of the CDCl3 triplet at 77.0 ppm. The following abbreviations are used to
indicate the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, quint
= quintet, h = sextet, b = broad signal. IR spectra were obtained using an FT-IR spectrometer
and only partial spectral data are listed. High resolution mass spectra (HRMS) were obtained
on a Q-TOF mass spectrometer and detection of the ions was performed in electrospray
ionization, positive ion mode. The structure of the products were determined by a
combination of spectroscopic methods such as IR, 1D and 2D NMR (including NOE, DEPT,
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COSY, HSQC and HMBC experiments) and HRMS. NMR signals assignments were based
on 2D NMR experiments performed.
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Representative procedure for the self-sensitized photooxidation of dienones 7
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A Pyrex vessel containing a solution of dienone 7 (1 mmol) in carbon tetrachloride
(100 mL, 0.01 M) was irradiated (photochemical reactor with 16 BLB lamps, max = 350 nm,
distance to the irradiation vessel = 10 cm, no added filter) with a gentle bubbling of oxygen.
The reaction was monitored by TLC. After the time indicated in Scheme 3, the solvent was
evaporated under reduced pressure and the residue was purified by flash column
chromatography on silica gel (eluent hexanes/ethyl acetate = 10:1, v/v) to afford the
following 1,2,4-trioxanes 8/8’.
(2R*,3S*,8aR*)-7,7-dimethyl-2-phenyl-2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-
one (8h)
Prepared according to the general procedure. Colorless solid (156 mg,
0.545 mmol, 54%). mp 96.0-97.0 ºC. IR (film) (cm-1): 3055, 2959, 1692,
1
1623, 1267, 1025. H NMR (CDCl3, 300 MHz):  7.34-7.24 (m, 3H, Ar-H), 7.26
(overlapping d, J = 5.8 Hz, 1H, 4-H), 7.12-7.07 (m, 2H, Ar-H), 5.58 (d, J = 2.1 Hz, 1H, 2-
H), 4.98 (dd, J = 5.7 Hz, J = 2.2 Hz, 1H, 3-H), 2.43 (bs, 2H, 6-H), 2.19 (dAB, J = 15.3 Hz,
1H, 8-H), 2.03 (dAB, J = 15.3 Hz, 1H, 8-H), 1.17 (s, 3H, 7-CH3), 1.07 (s, 3H, 7-CH3). 13C
NMR (CDCl3, 75 MHz):  193.3 (C, C-5), 139.1 (C, C-4a), 136.0 (C, Ar), 131.8 (CH, C-4),
128.6 (2  CH, Ar), 128.4 (CH, Ar), 126.0 (2  CH, Ar), 98.5 (C, C-8a), 75.9 (CH, C-2), 74.5
(CH, C-3), 52.1 (CH2, C-6), 43.0 (CH2, C-8), 31.1 (C, C-7), 29.3 (CH3, C7-CH3), 28.4 (CH3,
C7-CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19O4 287.1278; Found 287.1281.
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(2S*,3S*,8aR*)-7,7-dimethyl-2-phenyl-2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-
one (8’h)
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Prepared according to the general procedure. Colourless solid (16 mg,
0.055 mmol, 6%). mp 134.0-135.0 ºC. IR (KBr) (cm-1): 3063, 3034, 2965,
2934, 1692, 1624, 1267, 1053. 1H NMR (CDCl3, 300 MHz):  7.67 (d, J
= 5.7 Hz, 1H, 4-H), 7.61-7.54 (m, 2H, Ar-H), 7.48-7.27 (m, 3H, Ar-H), 4.69 (dd, J = 5.7 Hz,
J = 0.9 Hz, 1H, 3-H), 4.68 (bs, 1H, 2-H), 2.39 (bs, 2H, 6-H), 2.13 (dAB, J = 15.1 Hz, 1H, 8-
H), 2.06 (dAB, J = 15.1 Hz, 1H, 8-H), 1.08 (s, 3H, 7-CH3), 1.07 (s, 3H, 7-CH3). 13C NMR
(CDCl3, 75 MHz):  193.6 (C, C-5), 137.5 (C, C-4a), 136.9 (C, Ar), 133.3 (CH, C-4), 128.5
(2  CH, Ar), 128.4 (CH, Ar), 127.1 (2  CH, Ar), 98.1 (C, C-8a), 75.6 (CH, C-2), 73.8 (CH,
C-3), 52.0 (CH2, C-6), 43.0 (CH2, C-8), 31.1 (C, C-7), 28.8 (CH3, C7-CH3), 28.6 (CH3, C7-
CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H19O4 287.1278; Found 287.1287.
(2R*,3S*,8aR*)-2-phenyl-2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-one (8i)
Prepared according to the general procedure. Colourless liquid (132 mg, 0.51
mmol, 51%). 1H NMR (CDCl3, 300 MHz):  7.34-7.26 (m, 3H, Ar-H), 7.20
(d, J = 6.0 Hz, 1H, 4-H), 7.12-7.07 (m, 2H, Ar-H), 5.58 (d, J = 2.1 Hz, 1H, 2-H), 4.97 (dd, J
= 5.7, J = 2.4 Hz, 1H, 3-H), 2.58-2.51 (m, 2H, 6-H), 2.29-1.94 (m, 4H, 7-H, 8-H). 13C NMR
(CDCl3, 75 MHz):  193.4 (C, C-5), 140.1 (C, C-4a), 135.9 (C, Ar), 131.9 (CH, C-4), 128.6
(2  CH, Ar), 128.4 (CH, Ar), 125.9 (2  CH, Ar), 98.7 (C, C-8a), 75.5 (CH, C-2), 74.4 (CH,
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C-3), 38.4 (CH2, C-6), 30.2 (CH2, C-8), 18.2 (CH2, C-7). HRMS (ESI-TOF) m/z: [M + H]+
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Calcd for C15H15O4 259.0965; Found 259.0972.
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(2R*,3S*,8aR*)-6,6-dimethyl-2-phenyl-2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-
one (8j)
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Prepared according to the general procedure. Colourless liquid (49 mg,
0.17 mmol, 17%). 1H NMR (CDCl3, 300 MHz):  7.33-7.27 (m, 3H, Ar-
H), 7.23 (d, J = 6.0 Hz, 1H, 4-H), 7.11-7.07 (m, 2H, Ar-H), 5.58 (d, J = 2.1 Hz, 1H, 2-H),
4.97 (dd, J = 6.0 Hz, J = 2.4 Hz, 1H, 3-H), 2.34 (ddd, J = 15.1 Hz, J = 9.6 Hz, J = 5.1 Hz,
1H, 8-H), 2.14 (ddd, J = 15.2 Hz, J = 6.9 Hz, J = 4.5 Hz, 1H, 8-H), 1.92-1.82 (m, 2H, 7-H),
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1.28 (s, 3H, 6-CH3), 1.21 (s, 3H, 6-CH3). C NMR (CDCl3, 75 MHz):  198.0 (C, C-5),
139.5 (C, C-4a), 136.0 (C, Ar), 132.7 (CH, C-4), 128.6 (2  CH, Ar), 128.5 (CH, Ar), 125.9
(2  CH, Ar), 98.9 (C, C-8a), 75.6 (CH, C-2), 74.6 (CH, C-3), 41.9 (C, C-6), 32.4 (CH2, C-
7), 26.6 (CH2, C-8), 24.6 (CH3, C6-CH3), 24.2 (CH3, C6-CH3). HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C17H19O4 287.1278; Found 287.1287.
1-((1S*,4R*,6R*)-4-methyl-6-phenyl-2,3,5-trioxabicyclo[2.2.2]oct-7-en-8-yl)ethan-1-one
(8g)
Prepared according to the general procedure. Colourless liquid (61.5 mg,
0.25 mmol, 25%). 1H NMR (CDCl3, 300 MHz):  7.39-7.27 (m, 3H), 7.17-
7.07 (m, 2H), 7.03 (d, J = 6.1 Hz, 1H), 5,58 (d, J = 2.3 Hz, 1H), 4.92 (dd, J = 6.0 Hz, J = 2.4
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Hz, 1H), 2.36 (s, 3H), 1.89 (s, 3H). C NMR (CDCl3, 75 MHz):  194.0 (C), 143.9 (C),
136.4 (C), 133.9 (CH), 128.6 (2  CH), 128.3 (CH), 125.8 (2  CH), 98.2 (C), 74.5 (CH),
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73.8 (CH), 26.7 (CH3), 19.6 (CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H15O4
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247.0965; Found 247.0961.
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(2R*,3S*,8aR*)-2-(4-methoxyphenyl)-7,7-dimethyl-2,3,7,8-tetrahydro-3,8a-
epidioxychromen-5(6H)-one (8k)
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Prepared according to the general procedure. Colourless liquid (174
mg, 0.55 mmol, 55%). IR (film) (cm-1): 2961, 1696, 1613, 1515,
1253, 1174, 1028. 1H NMR (CDCl3, 300 MHz):  7.29 (d, J = 5.7
Hz, 1H), 7.04-6.98 (m, 2H), 6.85-6.80 (m, 2H), 5.51 (d, J = 2.1 Hz, 1H), 4.93 (dd, J = 5.7
Hz, J =2.1 Hz, 1H), 3.77 (s, 3H), 2.42 (bs, 2H), 2.16 (dAB, J = 15.2 Hz, 1H), 2.02 (dAB, J
= 15.2 Hz, 1H), 1.16 (s, 3H), 1.07 (s, 3H). 13C NMR (CDCl3, 75 MHz):  193.3 (C), 159.7
(C), 139.2 (C), 132.1 (CH), 128.1 (C), 127.4 (2  CH), 114.0 (2  CH), 98.5 (C), 75.7 (CH),
74.5 (CH), 55.2 (CH3), 52.1 (CH2), 43.0 (CH2), 31.1 (C), 29.2 (CH3), 28.4 (CH3). HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C18H21O5 317.1384; Found 317.1385.
(2R*,3S*,8aR*)-2-(4-methoxyphenyl)-2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-one
(8l)
Prepared according to the general procedure. Colourless liquid (158 mg,
0.55 mmol, 55%). IR (film) (cm-1): 2956, 2937, 1694, 1623, 1515,
1
1252. H NMR (CDCl3, 300 MHz):  7.25 (d, J = 6.0 Hz, 1H), 7.05-
6.99 (m, 2H), 6.87-6.81 (m, 2H), 5.53 (d, J = 2.4 Hz, 1H), 4.93 (dd, J = 5.7 Hz, J = 2.4 Hz,
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1H), 3.78 (s, 3H), 2.60-2.51 (m, 2H), 2.28-1.92 (m, 4H). C NMR (CDCl3, 75 MHz): 
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193.5 (C), 159.7 (C), 140.3 (C), 132.2 (CH), 127.9 (C), 127.4 (2  CH), 114.0 (2  CH), 98.8
(C), 75.4 (CH), 74.6 (CH), 55.3 (CH3), 38.5 (CH2), 30.3 (CH2), 18.3 (CH2). HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C16H17O5 289.1071; Found 289.1068.
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(2R*,3S*,8aR*)-2-(4-fluorophenyl)-7,7-dimethyl-2,3,7,8-tetrahydro-3,8a-
epidioxychromen-5(6H)-one (8m)
Prepared according to the general procedure. Colourless solid (122
mg, 0.40 mmol, 40%). mp 126.5-127.5 ºC. IR (KBr) (cm-1): 3085,
2980, 2961, 1692, 1625, 1512, 1268, 1222. 1H NMR (CDCl3, 300 MHz):  7.26 (d, J = 5.8
Hz, 1H), 7.13-7.04 (m, 2H), 7.04-6.95 (m, 2H), 5.53 (d, J = 2.1 Hz, 1H), 4.96 (dd, J = 5.7
Hz, J = 2.4 Hz), 2.43 (bs, 2H), 2.17 (dAB, J = 15.4 Hz, 1H), 2.03 (dAB, J = 15.1 Hz, 1H),
1.16 (s, 3H), 1.07 (s, 3H). 13C NMR (CDCl3, 75 MHz):  193.2 (C), 162.6 (C, d, J = 246.8
Hz), 139.3 (C), 131.9 (C, d, J = 2.7 Hz), 131.6 (CH), 127.8 (2  CH, d, J = 8.2 Hz), 115.6 (2
 CH, d, J = 21.7 Hz), 98.6 (C), 75.3 (CH), 74.4 (CH), 52.1 (CH2), 43.0 (CH2), 31.1 (C), 29.3
(CH3), 28.4 (CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C17H18FO4 305.1184; Found
305.1178.
(2R*,3S*,8aR*)-2-(4-bromophenyl)-7,7-dimethyl-2,3,7,8-tetrahydro-3,8a-
epidioxychromen-5(6H)-one (8n)
Prepared according to the general procedure. Colourless solid (233 mg,
0.64 mmol, 64%). mp 129.0-130.0 ºC. IR (KBr) (cm-1): 3082, 3063,
2961, 1693, 1625, 1488, 1268, 1070. 1H NMR (CDCl3, 300 MHz):  7.46-7.41 (m, 2H), 7.23
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(d, J = 6.0 Hz, 1H), 7.02-6.95 (m, 2H), 5.53 (d, J = 2.1 Hz, 1H), 4.96 (dd, J = 5.7 Hz, J = 2.4
Hz), 2.42 (bs, 2H), 2.17 (dAB, J = 15.4 Hz, 1H), 2.03 (dAB, J = 15.1 Hz, 1H), 1.16 (s, 3H),
1.07 (s, 3H). 13C NMR (CDCl3, 75 MHz):  193.0 (C), 139.2 (C), 135.1 (C), 131.8 (2  CH),
131.4 (CH), 127.6 (2  CH), 122.5 (C), 98.5 (C), 75.2 (CH), 74.1 (CH), 52.1 (CH2), 42.9
(CH2), 31.1 (C), 29.3 (CH3), 28.4 (CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C17H18BrO4 365.0383; Found 365.0380.
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1-((1S*,4R*,6R*)-6-(4-bromophenyl)-4-methyl-2,3,5-trioxabicyclo[2.2.2]oct-7-en-8-
yl)ethan-1-one (8o)
Prepared according to the general procedure. Colourless liquid (97 mg,
1
0.30 mmol, 30%). H NMR (CDCl3, 300 MHz):  7.47-7.43 (m, 2H),
7.02-6.98 (overlapping m, 3H), 5.52 (d, J = 2.4 Hz, 1H), 4.90 (dd, J = 6.0 Hz, J = 2.4 Hz,
1H), 2.35 (s, 3H), 1.88 (s, 3H). 13C NMR (CDCl3, 75 MHz):  193.9 (C), 144.0 (C), 135.5
(C), 133.4 (CH), 131.7 (2  CH), 127.4 (2  CH), 122.3 (C), 98.2 (C), 73.9 (CH), 73.4 (CH),
26.7 (CH3), 19.5 (CH3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C14H14BrO4 325.0070;
Found 325.0058.
(2R*,3S*,8aR*)-7,7-dimethyl-2-((E)-prop-1-en-1-yl)-2,3,7,8-tetrahydro-3,8a-
epidioxychromen-5(6H)-one (8p)
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Prepared according to the general procedure. Colourless solid (75 mg,
0.30 mmol, 30%). mp 73.0-74.0 ºC. IR (KBr) (cm-1): 2963, 2936,
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1692, 1624, 1081. 1H NMR (CDCl3, 300 MHz):  7.42 (d, J = 5.9 Hz,
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1H, 4-H), 5.75 (dqd, J = 15.2 Hz, J = 6.7 Hz, J = 0.9 Hz, 1H, 2’-H), 5.04 (ddq, J = 15.3 Hz,
J = 7.6 Hz, J = 1.7 Hz, 1H, 1’-H), 4.89 (bdd, J = 7.4 Hz, J = 2.3 Hz, 1H, 2-H), 4.78 (dd, J =
6.1 Hz, J = 2.6 Hz, 1H, 3-H), 2.36 (bs, 2H, 6-H), 2.03 (dAB, J = 15.2 Hz, 1H, 8-H), 1.92
(dAB, J = 15.2 Hz, 1H, 8-H), 1.66 (ddd, J = 6.7 Hz, J = 1.5 Hz, J = 0.7 Hz, 3H, 2’-CH3),
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1.08 (s, 3H, 7-CH3), 1.03 (s, 3H, 7-CH3). C NMR (CDCl3, 75 MHz):  193.5 (C, C-5),
139.1 (C, C-4a), 131.8 (CH, C-4), 131.6 (CH, C-2’), 125.9 (CH, C-1’), 97.8 (C, C-8a), 75.7
(CH, C-2), 73.3 (CH, C-3), 52.0 (CH2, C-6), 42.9 (CH2, C-8), 31.0 (C, C-7), 29.0 (CH3, C7-
CH3), 28.5 (CH3, C7-CH3), 17.7 (CH3, C2’-CH3).
(2R*,3S*,8aR*)-7,7-dimethyl-2-((E)-styryl)-2,3,7,8-tetrahydro-3,8a-epidioxychromen-
5(6H)-one (8q)
Prepared according to the general procedure. Colourless to pale
yellow solid (62 mg, 0.20 mmol, 20%). mp 122.0-123.0 ºC. IR
-1
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(KBr) (cm ): 3080, 3059, 2965, 2928, 1690, 1618, 1273. H NMR (CDCl3, 300 MHz): 
7.45 (d, J = 5.9 Hz), 7.33-7.25 (m, 5H), 6.58 (dd, J = 15.9 Hz, J = 1.2 Hz, 1H), 5.72 (dd, J =
15.9 Hz, J = 7.4 Hz, 1H), 5.12 (ddd, J = 7.3 Hz, J = 2.5 Hz, J = 1.2 Hz, 1H), 4.90 (dd, J =
5.9 Hz, J = 2.6 Hz, 1H), 2.39 (bs, 2H), 2.11 (dAB, J = 15.2 Hz, 1H), 1.96 (dAB, J = 15.2 Hz,
1H), 1.12 (s, 3H), 1.05 (s, 3H). 13C NMR (CDCl3, 75 MHz):  193.4 (C), 139.2 (C), 135.5
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(C), 134.4 (CH), 131.6 (CH), 128.6 (2  CH), 128.4 (CH), 126.7 (2  CH), 123.4 (CH), 97.9
(C), 75.7 (CH), 73.2 (CH), 52.1 (CH2), 42.9 (CH2), 31.1 (C), 29.1 (CH3), 28.5 (CH3). HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C19H20NaO4 335.1254; Found 335.1242.
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Preparation of 2-ethyl-7,7-dimethyl-2,6,7,8-tetrahydro-5H-chromen-5-one (9s)
A mixture of dimedone (10, 140 mg, 1 mmol), trans-2-pentenal (11, 0.1
mL, 1 mmol, 1 equiv) and ethylenediammonium diacetate (36.0 mg, 0.2
mmol, 0.2 equiv) in dichloromethane (5.0 ml, 0.2 M) was heated at reflux for 4 hours. Solvent
was then evaporated under reduced pressure and the residue was purified by flash column
chromatography on silica gel (hexanes:ethyl acetate = 10:1, v/v) to afford 9s as a pale yellow
liquid (62 mg, 0.3 mmol, 30%). IR (film) (cm-1): 2961, 2937, 1643, 1597, 1422, 1219, 1138.
1H NMR (CDCl3, 300 MHz):  6.47 (dd, J = 10.0 Hz, J = 1.3 Hz, 1H), 5.28 (dd, J = 10.0
Hz, J = 3.2 Hz, 1H), 4.86 (tdd, J = 5.9 Hz, J = 3.2 Hz, J = 1.6 Hz, 1H), 2.37-2.21 (m, 4H),
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1.72 (bp, J = 7.4 Hz, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.98 (t, J = 7.4 Hz, 3H). C NMR
(CDCl3, 75 MHz):  194.5 (C), 171.1 (C), 117.6 (CH), 117.2 (CH), 110.2 (C), 78.8 (CH),
50.4 (CH2), 42.1 (CH2), 32.2 (C), 28.8 (CH2), 28.43 (CH3), 28.38 (CH3), 8.5 (CH3). HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C13H19O2 207.1380; Found 207.1375.
Representative procedure for the dye-sensitized photooxidation of 2H-pyrans
2H-Pyran 9 (1.5 mmol) and rose bengal (30 mg) were dissolved in CH2Cl2 or CCl4
(130 ml), CH3OH (20 ml) before being irradiated with a 1000W tungsten halogen lamp
(distance to the irradiation vessel = 15 cm, no filter) under bubbling of oxygen for
approximately 1 hour. The solvent was then removed under reduced pressure to afford a pink
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residue that was purified by column chromatography (SiO2, hexanes/ethyl acetate = 9:1, v/v)
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to give the following 1,2,4-trioxanes 8/8’.
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(2R*,3S*,8aR*)-2-ethyl-7,7-dimethyl-2,3,7,8-tetrahydro-3,8a-epidioxychromen-5(6H)-one
(8s) and (2S*,3S*,8aR*)-2-ethyl-7,7-dimethyl-2,3,7,8-tetrahydro-3,8a-epidioxychromen-
5(6H)-one (8’s)
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Prepared according to the general procedure.
Pale yellow liquid (ratio = 3.5:1, 268 mg, 1.12
mmol, 75%). IR (film) (cm-1): 2963, 2937,
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1695, 1624, 1265. 8s: H NMR (CDCl3, 300 MHz):  7.41 (d, J = 5.9 Hz, 1H, 4-H), 4.83
(dd, J = 5.9 Hz, J = 2.3 Hz, 1H, 3-H), 4.36 (td, J = 7.2 Hz, J = 2.3 Hz, 1H, 2-H), 2.42-2.28
(m, 2H, 6-H), 2.10-1.78 (m, 2H, 8-H), 1.34-1.18 (m, 2H, 1’-H), 1.06 (bs, 3H, 7-CH3), 1.03
(bs, 3H, 7-CH3), 0.90 (t, J = 7.4 Hz, 3H, 2’-H). 13C NMR (CDCl3, 75 MHz):  193.5 (C, C-
5), 138.9 (C, C-4a), 131.4 (CH, C-4), 97.6 (C, C-8a), 76.3 (CH, C-2), 72.8 (CH, C-3), 52.0
(CH2, C-6), 42.7 (CH2, C-8), 30.9 (C, C-7), 28.7 (CH3, C7-CH3), 28.6 (CH3, C7-CH3), 25.3
(CH2, C-1’), 9.1 (CH3, C-2’). 8’s: 1H NMR (CDCl3, 300 MHz):  7.56 (d, J = 6.1 Hz, 1H, 4-
H), 4.66 (dd, J = 6.1 Hz, J = 0.8 Hz, 1H, 3-H), 3.42 (bt, J = 7.0 Hz, 1H, 2-H), 2.42-2.28 (m,
2H, 6-H), 2.10-1.78 (m, 4H, 8-H, 1’-H), 1.10-0.98 (overlapping signals, 9H, 7-CH3, 7-CH3,
2’-H). 13C NMR (CDCl3, 75 MHz):  193.8 (C, C-5), 137.5 (C, C-4a), 133.1 (CH, C-4), 97.8
(C, C-8a), 74.6 (CH, C-2), 71.2 (CH, C-3), 52.0 (CH2, C-6), 43.1 (CH2, C-8), 30.9 (C, C-7),
28.8 (CH3, C7-CH3), 28.5 (CH3, C7-CH3), 25.2 (CH2, C-1’), 9.7 (CH3, C-2’). HRMS (ESI-
TOF) m/z: [M + Na]+ Calcd for C13H18NaO4 261.1097; Found 261.1096.
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(4aR,6R,8R,8aR,10aR)-7,7-dimethyl-3,4,5,7,8,10a-hexahydro-6H-4a,8a-epidioxy-6,8-
methanoxanthen-1(2H)-one (8t)
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Prepared according to the general procedure. Colourless liquid (83 mg,
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-1
1
0.3 mmol, 20%). IR (film) (cm ): 2982, 2949, 2932, 1692, 1624. H
NMR (CDCl3, 300 MHz):  7.20 (s, 1H, 9-H), 4.82 (dd, J = 10.5 Hz, J
= 8.7 Hz, 1H, 10a-H), 2.54 (dtd, J = 18.1 Hz, J = 4.5 Hz, J = 1.2 Hz, 1H, 2-H), 2.40 (ddd, J
= 18.2 Hz, J = 11.4 Hz, J = 5.3 Hz, 1H, 2-H), 2.36-1.78 (m, 9H, 3-H, 4-H, 5-H, 6-H, 8-H,
13-H), 1.50 (dd, J = 13.1 Hz, J = 10.8 Hz, 1H, 5-H), 1.40 (s, 3H, 7-CH ), 0.92 (s, 3H, 7-

3
13
CH ). C NMR (CDCl , 75 MHz):  194.1 (C, C-1), 137.5 (CH, C-9), 137.1 (C, C-9a),

3
3
101.5 (C, C-4a), 81.1 (C, C-8a), 71.6 (CH, C-10a), 44.0 (CH, C-8), 42.7 (C, C-7), 40.8 (CH,
C-6), 38.4 (CH , C-2), 30.2 (CH , C-4), 27.5 (CH , C7-CH ), 26.3 (CH , C-5), 23.4 (CH ,

2
2
3
3
2
3
C7-CH ), 22.7 (CH , C-13), 18.2 (CH , C-3). HRMS (ESI-TOF) m/z: [M + H]+ Calcd for

3
2
2
C16H21O4 277.1434; Found 277.1428.
AUTHOR CONTRIBUTIONS
The manuscript was written through contributions of all authors. / All authors have given
approval to the final version of the manuscript.
NOTES
The authors declare no competing financial interest.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H and 13C NMR spectra of all products, 2D NMR spectra of key products (PDF).
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ACKNOWLEDGEMENTS
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8
9
Support from CONICET (PUE-2016), ANPCyT (PICT.2014-0408), Agencia Santafesina de
Ciencia, Técnica e Innovación (ASACTEI) (AC – 2015-00005) and Universidad Nacional
de Rosario (BIO 426, BIO 514). N.L.M thanks CONICET for fellowships. We also wish to
thank Dr. G.R. Labadie and Dr. C.M.J. Delpiccolo for HRMS measurements.
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