A family of new 1,2,4-trioxanes by photooxygenation of allylic alcohols in sensitizer-doped polymers and secondary reactions

Article abstract of DOI:10.1055/s-2005-872103

Type II photooxygenation (singlet oxygen) is described as a synthetically useful way for the preparation of allylic hydroperoxides and endoperoxides using sensitizer-adsorbed or covalently sensitizer-doped polymeric (macro- or nanosized) containers. Facil

Full text of DOI:10.1055/s-2005-872103

FEATURE ARTICLE
2433
A Family of New 1,2,4-Trioxanes by Photooxygenation of Allylic Alcohols in
Sensitizer-Doped Polymers and Secondary Reactions
1
, 2,4-Trioxanes by
n
Photooxyge
n
nation of Al
a
A
lcohols Bartoschek, Tamer T. El-Idreesy, Axel G. Griesbeck,* Lars-Oliver Höinck, Johann Lex,1 Claus Miara,
Jörg M. Neudörfl1
University of Cologne, Institute of Organic Chemistry, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4705057; E-mail: griesbeck@uni-koeln.de
Received 13 May 2005; revised 8 July 2005
Dedicated to Professor Bernd Giese on the occasion of his 65th birthday
remarkable chemo-, regio-, and stereoselectivity pat-
Abstract: Type II photooxygenation (singlet oxygen) is described
as a synthetically useful way for the preparation of allylic hydro-
peroxides and endoperoxides using sensitizer-adsorbed or covalent-
ly sensitizer-doped polymeric (macro- or nanosized) containers.
terns.3 Recently, even the first enantioselective singlet
oxygen reactions under organocatalytic conditions were
reported.4 The conventional reaction conditions nicely
Facilitated product separation and purification as well as increased correspond to the principles of sustainable ‘green’ chem-
istry,5 i.e. triplet oxygen from air is the reagent and the en-
reactivity are advantages of these techniques in comparison with so-
lution-phase photochemistry. The products generated by Type II
ergy-transfer sensitizers can be as simple as natural
photooxygenation have been used for the syntheses of numerous
porphyrins or xanthene dyes.
polycyclic peroxides with a common 1,2,4-trioxane core as exhibit-
Beside these attractive features, however, singlet oxygen
has unfavorable properties under environmentally clean
conditions, e.g. in aqueous media. The lifetime of the 1Dg
state, an essential parameter for reactions with electroni-
cally excited species, is in the microsecond region in pro-
tic solvents and rises to milliseconds only in chlorinated
or fluorinated solvents.6
ed in the natural antimalarial artemisinin.
Key words: photochemistry, catalytic oxygenation, peroxides, per-
oxyacetals, Lewis acid catalysis
Introduction
In recent publications we have described a relatively sim-
ple approach to improved reaction conditions: the use of
polymeric micro- or nanosized containers with the por-
phyrin sensitizer incorporated either adsorbed in the poly-
mer network or covalently linked during the
polymerization process.7 A favorable dye for the adsorp-
tive approach was tetrakis-4-methylphenylporphyrin
(TTP); for the covalently linked polymers, either tetrakis-
4-vinylphenylporphyrin (TSP) or protoporphyrin IX (PP-
IX) were used (Figure 1).8 The nanosized polymer beads
Photooxygenation processes are classified as Type I, II,
and sometimes also as Type III.2 These codifications
stand for radical-induced oxygenation (with triplet oxy-
gen as the transfer reagent), energy-transfer oxygenation
(with singlet excited oxygen as the reagent), and for elec-
tron-transfer oxygenation (with triplet oxygen or with the
superoxide anion radical as reagent). Especially the Type
II photooxygenation has been used for numerous synthet-
ic applications because singlet oxygen (1Dg) is a highly re-
active and at the same time selective reagent showing
NH
N
N
N
H
N
H
N
HN
N
N
N
H
N
H
N
HOOC
COOH
TSP
PP-IX
TTP
Figure 1 Monomeric dyes for adsorption and linking to polymers.
SYNTHESIS 2005, No. 14, pp 2433–2444
x
x.
x
x
.
2
0
0
5
Advanced online publication: 29.07.2005
DOI: 10.1055/s-2005-872103; Art ID: T06105SS
© Georg Thieme Verlag Stuttgart · New York

2434
A. Bartoschek et al.
FEATURE ARTICLE
Biographical Sketches
Anna Bartoschek was born in Tychy, Cologne from 1994 and received her on the use of polymer supports for pho-
Poland, in 1974. She studied chemistry first state examination in 2001. She is tooxygenation reactions under the su-
and mathematics at the University of currently finishing her doctoral thesis pervision of Prof. A. Griesbeck.
Tamer T. El-Idreesy was born in with a Ph.D. long-term scholarship Griesbeck and received his doctoral de-
Cairo, Egypt, in 1975. He studied from the Egyptian government. He car- gree in 2005. He is recipient of the
chemistry at the University of Cairo ried out his doctoral thesis on the syn- Kurt–Alder award of the University of
from 1992 and received his B.Sc. in thesis of novel peroxide compounds Cologne for the best thesis in organic
1996. In 2000 he came to Germany under the supervision of Prof. Axel G. chemistry in 2005.
Axel G. Griesbeck was born in the the Weizmann Institute of Science and two books on organic photochem-
state of Hesse, Germany, in 1958. He (Prof. Ernst Fischer), he performed his istry and is active in the fields of pre-
studied chemistry at the University of Habilitation in 1991 at the University parative and mechanistic organic
Munich from 1976 and received his of Würzburg. He was guest professor at photochemistry,
photooxygenation,
doctoral degree in 1984 on kinetic the University of Wisconsin at Madi- photocycloaddition and photo-induced
studies of singlet oxygen reactions son and the IMCR in Tsukuba, Japan. electron transfer reactions. He received
(Prof. Klaus Gollnick). After three Since 1994 he is professor at the Uni- the Grammatikakis-Neumann prize in
years as post-doc at the University of versity of Cologne. He has published 1999 and is currently chairman of the
Würzburg (Prof. Waldemar Adam), the more than 180 papers on synthetic and photochemistry section of the German
ETH Zürich (Prof. Dieter Seebach) and mechanistic organic photochemistry Chemical Society (GDCh).
Lars-Oliver Höinck was born in Co- and received his diploma degree in Prof. Axel G. Griesbeck. His research
logne, Germany, in 1966. He studied 2005. He is currently working on his topic is the synthesis of hydrophilic an-
chemistry at the University of Cologne doctoral thesis under the supervision of timalarial 1,2,4-trioxanes.
Johann Lex was born in Bottrop, a city Franz Feher) at the Institute of Inorgan- ‘figure eight compounds’ from the re-
near Essen, Germany, in 1942. He ic Chemistry. After moving to the Insti- search group of Emanuel Vogel. He
studied chemistry at the University of tute of Organic Chemistry in 1978 he still continues his activities as service
Cologne from 1963 to 1969 and re- established and built up the X-ray de- crystallographer at the University of
ceived his doctoral degree in 1972 on partment and determined numerous Cologne.
X-ray structural investigations of het- crystal structures, mainly derivatives of
erocyclic sulfur compounds (Prof. octalenes, annulenes, porphyrins and
Claus Miara was born in Bremer- and moved in 1998 to the University of the use of polymer supports within the
haven, Germany, in 1974. He started Cologne, where he finished his Diplo- scope of his Ph.D. thesis under the su-
studying chemistry 1995 at the Carl ma Thesis 2002. Currently, he is exam- pervision of Prof. Axel G. Griesbeck.
von Ossietzky University Oldenburg ining photooxygenation reactions and
Jörg M. Neudörfl was born in Hürth, Prof. Otto Ermer on the structural crystallographer at the Institute of
near Cologne in 1965. He studied chemistry of salts derived from mellitic Organic Chemistry, University of
chemistry at the University of Cologne acid and the inculsion behavior of Cologne.
from 1986 and received his doctoral hexaphenylbenzene
hexacarboxylic
degree in 2002 under the supervision of acid. He is currently working as service
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

FEATURE ARTICLE
1,2,4-Trioxanes by Photooxygenation of Allylic Alcohols
2435
which were obtained from emulsifier-free emulsion poly- and chiral dienes 9 and 11. The syn/anti selectivity in 12
merization of styrene in the presence of PP-IX and divi- of the singlet oxygen addition to 11 was very low, in pro-
nylbenzene, were not as stable as the TSP-derived beads nounced opposition to the reaction with monoalkenes.
and gave rise to strong bleaching after 3–4 photooxygen-
Especially sensitive with regard to diastereoselectivity,
ation cycles. A scanning electron microscopy (SEM) pic-
however, is the singlet oxygen ene reaction with chiral al-
ture of the former sample (unswollen) is shown in
lylic alcohols: when the reaction is performed in non-po-
Figure 2.
lar solvents, preferentially the threo isomers are formed
with high diastereoselectivites (Scheme 2), in protic
solvents the selectivities drop remarkably.9 We used as
a characteristic selectivity model the ene reaction of
4-methylpent-3-en-2-ol (mesitylol, 13). The dr values
were not only characteristic of the solvent but also on the
initial concentration and the degree of conversion of the
substrate. Additionally, H/D exchange in the starting ma-
terial led to a decrease in selectivity (Scheme 3).
O
OH
O
H
O
R
OH
H
R
R
H
threo
1O2
OOH
R
OH
Figure 2 SEM pictures of protoporhyrin IX containing polymer
R
O
O
beads.
O
erythro
OOH
H
Scheme 2 Diastereoselectivity of the singlet oxygen ene reaction
with chiral allylic alcohols.
Some prototype reactions are illustrated in Scheme 1: the
ene reactions of a- and b-pinene (1 and 3) to give the al-
lylic hydroperoxides 2 and 4, of 2,3-dimethylbut-2-ene
(5) and ethyl tiglate (7) to the allylic hydroperoxides 6 and
8, and the [4+2] cycloaddition of singlet oxygen to achiral
These experiments did clearly provide evidence for non-
covalent interactions between singlet oxygen and the sub-
3O2, hν
3O2, hν
Sens., PS
OOH
Sens., PS
OOH
84%
90%
1
3
2
4
OOH
3O2, hν
3O2, hν
Sens., PS
82%
COOEt
COOEt
OOH
Sens., PS
95%
7
5
8
6
OH
OH
OH
OH
3O2, hν
O
O
O
O
O
O
3O2, hν
Sens., PS
+
OH
Sens., PS
81%
85%
9
10
syn-12
anti-12
11
Scheme 1 Prototype ene reactions and Diels–Alder type cycloadditions of alkenes and dienes with singlet oxygen in polystyrene (PS) matrix.
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

2436
A. Bartoschek et al.
FEATURE ARTICLE
OH
OH
and simultaneously a syn addition is enforced. On the oth-
er hand, the hydroxy group deactivates the alkene by a
factor of roughly ten in comparison with the unsubstituted
alkene.9 The geminal-directing effect is a purely regiocon-
OH
1O2
+
OOH
OOH
14
13
1
trolling phenomenon describing the ene reaction of O2
with a,b-unsaturated carbonyl compounds and analogs
with a substituent bearing allylic hydrogens at the a-car-
bon. To these compounds, 1O2 adds preferentially to the b-
carbon with concomitant hydrogen abstraction resulting
in a-hydroperoxyalkyl acrylate derivatives (Scheme 4).11
CCl4, 4x10-2
CH3OH, 4x10-2
CD3OD, 4x10-2
M
93
73
68
:
7
27
32
:
:
:
:
:
M
M
64
75
86
36
25
14
PEG, max. loading
PS, max. loading (ld.)
PS, 1/10 ld.
We have now investigated substrates which combine
these two effects in order to generate b-hydroperoxy alco-
hols with an additional acrylate function, substrates de-
sired for the synthesis of potential antimalarials
combining 1,2,4-trioxane (vide infra) with the acryl-
amide benzophenone-conjugate pharmacophors. The first
substrate was shikimic acid (15), a cyclohexane carboxy-
lic acid with a properly flanked hydroxyl group. The com-
bination of the two deactivating groups together with the
low solubility in less polar solvents, however, completely
prevented 1O2 addition. A straightforward way to activate
the substrate was the transformation into the acetal-pro-
90
:
10
PS, 1/10 ld., 20% conv.
Scheme 3 Diastereoselectivity of the mesitylol ene reaction; 100%
conversion if not mentioned.
strate as well as the product of the ene reaction. At very
high concentrations (e.g. under solvent-free conditions in
polymeric matrices), the diastereoselectivity drops due to
intermolecular hydrogen-bonding between substrate mol-
ecules; at higher degrees of conversion, the diastereose-
lectivity drops because of stronger hydrogen-bonding
between the more polar b-hydroperoxy alcohols and the
substrate. This complex reaction behavior could be nicely
investigated in the polymeric reaction containers. Reduc-
ing the amount of substrate loaded to the polymer leads to
increased selectivity at low conversions and again drops
with increasing conversion.10 The lowest diastereoselec-
tivity was observed either in protic solvents or in polar
polymer films such as poly(ethylene glycol) (PEG).
1
tected diene 16. Cycloaddition with O2 resulted in the
endoperoxide 17 which could be further modified
(Scheme 5).12
HO
HO
COOH
COOMe
O
O
15
16
As already mentioned, we routinely use two approaches to
singlet oxygen production and application to oxygen-
ation: (a) a purely adsorptive approach where non-polar
OH
1O2
1O2
95%
1
singlet oxygen sensitizers with high O2 quantum yields
OOH
are embedded into polymeric matrices by a wetting/dry-
ing process, and (b) covalent linking of functionalized
sensitizer dye monomers during the polymerization pro-
cess. In both cases, the polymer particles are subsequently
swollen with the substrate dissolved in a volatile polar sol-
vent (see experimental procedures).
COOMe
O
HO
COOH
O
O
O
HO
17
OH
Scheme 5 Intended photooxygenation of shikimic acid 15 and its
derivative 16.
Two Directing Effects: Two Case Studies
The second substrate was the 4-hydroxy tiglate 18 ob-
tained from the ‘C5-aldehyde’ (an important intermediate
in the industrial synthesis of vitamin A).13 This compound
reacted slowly with singlet oxygen to give the allylic hy-
droperoxide 19 with high regioselectivity. This compound
The hydroxy-directing effect has been extensively used
for control of the regio- and diastereoselectivity of the ene
reaction of singlet oxygen with chiral allylic alcohols: a
hydroxy group in an allylic position directs the 1O2 attack
towards the proximate position of the C=C double bond
Y
Y
OH
OH
1O2
1O2
HOO
X
X
88%
>95%
OOH
Y = COOR, COR, CN, SOnR
geminal-directing
hydroxy-directing
Scheme 4 Regioselectivity control by hydroxy and gem effects.
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

FEATURE ARTICLE
1,2,4-Trioxanes by Photooxygenation of Allylic Alcohols
2437
was converted into trioxanes 20 by Lewis acid catalyzed
peroxyacetalization with ketones (Scheme 6).14 Adaman-
tanone as the carbonyl component gave the spiroperoxide
20a that was also analyzed by X-ray crystal determina-
tion.14 One major driving force for introducing acrylate
side-chains to the 1,2,4-trioxane skeleton was a recent re-
port on the antimalarial activity of acrylamide-benzophe-
none conjugates15 which we currently try to compare with
acrylate-trioxane conjugates. The cooperative directing of
hydroxy and gem effect in 18 is thus a valuable tool for the
synthesis of properly substituted hydroperoxides.
H
O
O
HO
O
H
HO
O
O
O
O
artemisinin
yingzhaosu A
OH
OOH
O
O
HO
COOMe
HO
COOMe
1O2
yingzhaosu C
Figure 3 Natural antimalarials: artemisinin, yingzhaosu A and C.
PS-TTP
90%
18
19
BF3⋅Et2O
R1R2C=O
30–86%
droxy substituent or vice versa. The best process for this
goal is the singlet oxygen ene reaction with allylic alco-
hols directed by the hydroxy effect regio- and diastereose-
lectively. The subsequent peroxyacetalization can be
catalyzed by Brönsted23 or Lewis acids24 such as concen-
trated sulfuric acid or boron trifluoride, respectively
(Scheme 7).
O
O
R2
R1
O
COOMe
O
O
O
COOMe
20a
20
Scheme 6 Photooxygenation of the allylic alcohol 18 and subse-
quent trioxane synthesis.
R1
1O2
R2
OH
OH
cat.
R2
O
R1
R2
R1
Synthesis of 1,2,4-Trioxanes Using the Photooxygen-
ation Route
R3
R4
O
OOH
O
The quest for the synthesis of a broad series of structurally
diverse compounds with a central 1,2,4-trioxane skeleton
results from the ongoing struggle for active and reliable
antimalarials which do not show resistance against the
most problematic form of Malaria tropica, resulting from
infection by the Plasmodium falciparum parasite.16 There
are numerous potential drugs and derivatives which are
currently investigated. Besides the well established quin-
oline derivatives, compounds that are currently tested as
pharmaceutical leads include those that interact with dif-
ferent locations of infected erythrocytes. Classes of com-
pounds having in common the structural motif of cyclic
peroxides play a special role both because of their struc-
tures and the possible mode of action. Many of these com-
pounds are structurally derived from the naturally
occurring sesquiterpene lactone artemisinin (qinghaosu),
a compound with a 1,2,4-trioxane core structure
(Figure 3).17 But also 1,2-dioxanes as present in yingzha-
osu A and C show high antimalarial activities.18
Scheme 7 Access to 1,2,4-trioxanes by the singlet oxygen route.
Peroxyacetalization with Symmetric Ketones
The photooxygenation of chiral allylic alcohols in poly-
mer matrices delivers the b-hydroxy allylic hydroperox-
ides in moderate diastereoselectivity but in good yields
and with much less impurities than the traditional solu-
tion-phase reaction. When treating these products with
symmetric ketones in the presence of catalytic amounts of
BF3, the trans 5,6-substituted 1,2,4-trioxanes were formed
in good to moderate yields. Volatile ketones such as ace-
tone, cyclopentanone or cyclohexanone were applied in
10–20-fold excess and high yields of trioxanes were ob-
tained. More problematic was the use of adamantanone
which was applied in stoichiometric amounts and compli-
cated product separation.
A typical reaction protocol is shown in Scheme 8: the cy-
clopropane 21 is available from aldol condensation of cy-
clopropylmethylketone with acetone,25 photooxygenation
in polymer beads results in a 62:38 mixture of diastereo-
isomeric hydroperoxides 22 in 80% yield (combined, only
the major isomer shown). Subsequent treatment with 1–20
equivalents of ketone in the presence of catalytic BF3 af-
forded the trioxanes 23 in yields of 8–41% (adaman-
Extensive work has been published on the total synthesis
of artemisinin,19 the preparation of its derivatives20 as well
as on the elucidation of the peroxide-specific mode of ac-
tion.21 Semisynthetic derivatives have been reported from
several research groups as well as fully synthetic spirobi-
cyclic peroxides and ‘dual systems’, with 1,2,4-trioxanes
linked to quinolines.22 One straightforward process is the
introduction of a hydroperoxy group b to a preexisting hy-
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

2438
A. Bartoschek et al.
FEATURE ARTICLE
OH
BF3⋅Et2O
O
R1R2C=O
O
R2
OOH
22
O
R1
24
R1
R2
yield
dr
a
b
Et
Et
Me
H
62%
21%
72:28
> 98:2
Scheme 9 C-4 chiral, 5-cyclopropanated 1,2,4-trioxanes from 22.
The C3-Naphthyl Series
Scheme 8 5-Cyclopropanated 1,2,4-trioxanes, for R and yields see
text; X-ray structure of 23a (for X-ray data, see Table 1 in experimen-
tal part).
A special feature in the peroxyacetalization runs was the
application of naphthaldehyde derivatives. These experi-
ments were performed in order to approach trioxane-quin-
oline conjugates that might act cooperatively in their
antimalarial activities. Therefore, we investigated the re-
action of b-hydroperoxy alcohols with b-naphthaldehyde
(equimolar amounts) as a model compound and obtained
the corresponding trioxanes in good yields indicating that
the reactivity of the naphthaldehyde was higher than in the
adamantanone series (Scheme 10).
tanone: 8%, cyclohexane-1,4-dione: 17%, acetone: 41%).
In most cases, the trioxane resulting from the minor hy-
droperoxide diastereomer could not be isolated after puri-
fication. The currently most active trioxane of this series
in the antimalarial in vitro test against P. falciparum was
compound 23a.26
Non-Symmetric Ketones and Aldehydes
Acid-Catalyzed Cleavage Followed by Cross-Peroxy
Acetalization
When using non-symmetric ketones or aldehydes, a third
stereogenic center was created at C-3. In most cases the
configuration of this center was perfectly controlled dur-
ing the reaction with the major diastereoisomeric (threo)
hydroperoxides. In these cases, the products (e.g. in
Scheme 9 the trioxanes 24 from the cyclopropyl deriva-
tive 22) were formed as sole diastereoisomers in an all-
equatorial substituent pattern (from NOE measurements).
The yields with aliphatic aldehydes were generally low
due to competitive 1,3,5-trioxane formation and could be
increased by using acetal derivatives. Orthoesters could
also be applied and gave rise to different stereochemical
results (C3-OR in an axial position) indicating strong ano-
meric effects (vide infra).
Lewis- and Brönsted acids slowly decompose b-hydroxy
allylic hydroperoxides in a Hock-type cleavage to give
two carbonyl fragments. This reaction can efficiently
compete with the regular peroxyacetalization as described
above if (a) sterically demanding carbonyl compounds are
used and/or (b) only stoichiometric amounts of the carbo-
nyl compounds could be used. In case of adamantanone
both effects act cooperatively and the yields of spiroada-
mantane peroxides were generally low. On the other hand,
controlled acid-catalyzed peroxide cleavage in the ab-
sence of external carbonyls generates minute amounts of
Scheme 10 3-b-Naphthyl-substituted 1,2,4-trioxanes, X-ray structure of 26d (for X-ray data, see Table 1 in experimental part).
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

FEATURE ARTICLE
1,2,4-Trioxanes by Photooxygenation of Allylic Alcohols
2439
OH
BF3⋅OEt2
O
O
+
r.t.
O
O
OOH
22
33%
O
O
27
28
Scheme 11 Lewis acid catalyzed cleavage and cross-peroxyacetalization of the b-hydroxy hydroperoxide 22.
carbonyl fragments in the presence of the b-hydroxy hy-
A Diverse Family of 1,2,4-Trioxanes
droperoxides and thus cross-peroxyacetalization is initiat-
ed. This process allows the access to a series of new Following the procedures described above, a family of
trisubstituted 1,2,4-trioxanes with high diastereoselectiv- mono-, bi-, spiro- and dispirocyclic 1,2,4-trioxanes were
itiy. A typical example is shown in Scheme 11 with the generated in recent years. A sample collection is shown in
BF3-catalyzed decomposition of the cyclopropyl deriva- Scheme 13, demonstrating that a broad substituent pattern
tive 22.
is available at positions C3 and C5 of the 1,2,4-trioxane
ring. The two methods already mentioned are also com-
pared here: the trans-peroxyacetalization of acetals
(Method B, for the synthesis of trioxanes 30a) is superior
over the direct use of volatile aldehydes (Method A). This
Bis-Trioxanes: Doubled Peroxyacetalization
The peroxyacetalization of 1,2-hydroperoxy alcohols method is also described for the synthesis of the 1,2,4-tri-
with cyclohexane-1,4-dione has been already investigated oxane 24b in the experimental section. When triethyl
by several research groups including us (see compounds orthoformate was used as component, the first examples
23).22,27 In all cases reported in literature, the second car- of orthoperacetals with the trioxane substructure (e.g. 30g
bonyl group was used as anchor functionality for intro- as a 3:1 diastereoisomeric mixture) were obtained in ex-
ducing amino groups, e.g. for the synthesis of the dual cellent yields.
trioxaquines developed by the Meunier group.22,27b The
bifunctional ketone can in principle also be used as a basis
for the synthesis of dispiroperoxides by application of an
excess of hydroperoxide. The yields for these processes
were in all cases low (4–20%) and diastereoisomeric mix-
tures of dispiroperoxides 29 were isolated (Scheme 12).28
The X-ray structure analyses revealed that the syn com-
pounds have the two peroxide bridges freely exposed to
one side of the molecule and might therefore exhibit inter-
esting pharmacological properties. Highly active antima-
larial trioxane dimers have already been synthesized from
artemisinin derivatives by bridging reactions.29
Polymer-Bound Porphyrin Dyes; PP-S-DVB; Typical Proce-
dure
Deionized H2O (200 mL), acidified with H2SO4 to pH 2.3, was
purged with N2 and heated to 70 °C for 20 min in a 500-mL three-
necked flask equipped with a stopper, a reflux condenser and a gas
inlet. Subsequently, freshly distilled styrene (10 g), divinylbenzene
(DVB, 100 mg) and protoporphyrin IX (10 mg) were added rapidly
and the system was sealed in order to prevent contamination with
air. While the mixture was being vigorously stirred, potassium per-
oxodisulfate (120 mg) in H2O (10 mL) was added at once. As the
polymerization proceeds, the color of the reaction mixture turned
Scheme 12 Synthesis of dispiro compounds 29 from cyclohexane-1,4-dione (CHD) and 25, X-ray structure of tat-29a (for X-ray data, see
Table 1 in experimental part).
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

2440
A. Bartoschek et al.
FEATURE ARTICLE
(1RS,2SR)-1-Cyclopropyl-2-hydroperoxy-3-methylbut-3-en-1-
ol; Minor Isomer
R1
OH
1H NMR (300 MHz, CDCl3): d (additional significant signals) =
1.82 (m, 3 H, CH3C=), 3.14 (dd, 1 H, J = 4.3, 8.8 Hz, CHOH), 4.41
(d, 1 H, J = 4.3 Hz, CHOOH).
BF3⋅Et2O
O
R1
R2R3C=O or
R2R3C(OR4)2
R3
R2
O
OOH
13C NMR (75.5 MHz, CDCl3): d = 2.6 (t, CH2CH2), 2.9 (t,
CH2CH2), 13.3 (d, CH), 19.6 (q, CH3C=), 75.6 (d, CHOH), 91.2 (d,
CHOOH), 115.4 (t, CH2=C), 141.3 (s, C=CH2).
O
30
25
R1
R2
R3
R4
yield
a
b
c
d
e
f
n-Bu Ph
i-Bu ß-Naph
H
H
Me 48%
The diastereomeric mixture of allylic hydroperoxides was applied
for peroxyacetalization without further purification.
-
-
-
-
-
21%
10%
12%
34%
22%
Me
i-Bu
- Ada -
- Ada -
(5′RS,6′RS)-5′-Cyclopropyl-6′-(prop-1-en-2-yl)-spiro{tricyc-
lo[3.3.1.13,7]decane-2,3′-[1,2,4]-trioxane} (23a)
Me Fu
Et o-Cl-Ph
Me OEt
H
H
H
g
OEt 70%
A solution of 22 (1.88 g, 11.9 mmol) and adamantanone (1.78 g,
11.9 mmol) in CH2Cl2 were treated with catalytic amounts of
BF3·OEt2 (0.2 mL). Usual work-up and further purification of the
crude product by preparative thick-layer chromatography (SiO2,
EtOAc–n-hexane, 1:10, Rf 0.81) afforded the pure 1,2,4-trioxane
23a as a faint yellow oil which crystallized upon standing (0.25 g,
8%); mp 79–81 °C.
Scheme 13 Diverse 1,2,4-trioxane structures from reaction of 1,2-
hydroperoxy alcohols with ketones and aldehydes (Method A) or ace-
tals and orthoesters (Method B).
faint red and after a polymerization period of 7–9 h, the mixture was
quenched with MeOH (200 mL) and then cooled to r.t. The polymer
particles were separated by centrifugation at 3500 rpm, and any free
(non-polymerized) sensitizer particles were removed by extraction
with CH2Cl2 several times, until the dye in the washing solvent was
no longer detectable. The beads were dried at 40 °C under vacuum
to afford 3.25 g (33%) of the polymer-bound sensitizer. PP-S-DVB
was obtained as a sandy solid.
IR (film): 3079, 2931, 2917, 1653, 1112, 1079, 1025, 926, 910, 891
cm–1.
1H NMR (300 MHz, CDCl3): d = 0.31–0.49 (m, 4 H, CH2CH2), 0.78
[m, 1 H, CH(CH2)2], 1.50–2.19 (m, 13 H, CH and CH2), 1.79 (m, 3
H, CH3C=), 2.82 (m, 1 H, CH), 3.33 (dd, 1 H, J = 7.4, 9.4 Hz,
OCH), 4.38 (d, 1 H, J = 9.4 Hz, OOCH), 5.04 (m, 2 H, CH2=).
13C NMR (75.5 MHz, CDCl3): d = 1.9 (t, CH2), 3.1 (t, CH2), 12.2 [d,
CH(CH2)2], 21.0 (q, CH3C=), 27.5 (d, CH), 27.6 (d, CH), 30.2 (d,
CH), 36.9 (d, CH), 33.4 (t, CH2), 33.7 (t, CH2), 33.8 (t, CH2), 34.0
(t, CH2), 37.6 (t, CH2), 73.0 (d, OCH), 87.9 (d, OOCH), 105.0 (s,
OCOO), 117.2 (t, CH2=), 140.4 (s, C=CH2).
Photooxygenation Using Polymer-Bound Porphyrin Dyes as
Sensitizers as well as Reaction Media; Solvent-Free Photooxy-
genation Conditions
a. Using Commercial PS-DVB Copolymer
MS (EI, 70 eV): m/z (%) = 290 (M+, <1), 220 (M+ – C4H6O, 1), 150
The polymer particles (ca. 2–3 g) were distributed in a petri dish (19
cm diameter) and were swollen with CH2Cl2 (20 mL). The substrate
(ca. 10 mmol) and the nonpolar sensitizer (TPP or TTP, ca. 3–6 mg)
in EtOAc (20 mL) were subsequently added and the excess solvent
was evaporated by leaving the petri dish in a well ventilated hood.
The petri dish was covered with a glass plate and the sandy solid
was irradiated with halogen lamp or sodium street lamp. The poly-
mer beads were subsequently rinsed with EtOH (3 × 30 mL) and fil-
tered (the beads were kept for regeneration and reuse). The solvent
was evaporated under reduced pressure (Caution! water bath tem-
perature should not exceed 30 °C) and the composition of the prod-
uct was determined by 1H as well as 13C NMR spectroscopy.
+
+
(C10H14O+, 57), 108 (C8H12+, 47), 93 (C7H9 , 57), 81 (C6H9 , 37), 80
+
+
+
(C6H8 , 97), 79 (C6H7 , 100), 67 (C5H7 , 32), 55 (C3H3O+, 27).
Anal. Calcd for C18H26O3 (290.40): C, 74.45; H, 9.02. Found: C,
73.61; H, 8.94.
(3RS,5RS,6RS)-5-Cyclopropyl-3-(naphth-2-yl)-6-(prop-1-en-2-
yl)-1,2,4-trioxane (26d)
A solution of 25 (1.25 g, 7.91 mmol) and b-naphthaldehyde (1.23 g,
7.88 mmol) in CH2Cl2 were treated with catalytic amounts of
BF3·OEt2 (0.2 mL). Usual work-up and further purification of the
crude product by preparative thick-layer chromatography (SiO2,
EtOAc–n-hexane, 1:10, Rf 0.67) afforded the pure 1,2,4-trioxane
26d as a yellow oil which crystallized upon standing (0.72 g, 31%).
b. Using Synthesized PP-S-DVB Copolymers
The dye-cross-linked polymer beads (TSP-S-DVB or PP-S-DVB,
ca. 0.60 g) in a petri dish (14 cm in diameter) were swollen with
CH2Cl2 (20 mL), then the substrate (ca. 5 mmol) in EtOAc (20 mL)
was added. Subsequent treatment as described before afforded the
product.
IR (film): 3088, 3011, 2968, 2934, 1647, 1603, 1126, 1071, 904,
859, 814 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.39–0.64 (m, 4 H, CH2CH2), 0.98
[m, 1 H, CH(CH2)2], 1.87 (m, 3 H, CH3C=), 3.44 (dd, 1 H, J = 7.4,
9.1 Hz, OCH), 4.68 (d, 1 H, J = 9.1 Hz, OOCH), 5.14 (m, 2 H,
CH2=), 6.31 (s, 1 H, OCHOO), 7.46–7.98 (m, 7 Harom).
13C NMR (75.5 MHz, CDCl3): d = 2.0 (t, CH2), 2.8 (t, CH2), 11.6 [d,
CH(CH2)2], 20.7 (q, CH3C=), 81.0 (d, OCH), 87.8 (d, OOCH),
104.0 (d, OCHOO), 117.5 (t, CH2=), 124.2 (d, CHarom), 126.2 (d,
CHarom), 126.7 (d, CHarom), 127.0 (d, CHarom), 127.7 (d, CHarom),
128.2 (d, CHarom), 128.5 (d, CHarom), 131.8 (s, Carom), 132.9
(s, Carom), 134.1 (s, Carom), 139.9 (s, C=CH2).
(1RS,2RS)-1-Cyclopropyl-2-hydroperoxy-3-methylbut-3-en-1-
ol (threo-22)
Photooxygenation of 21 (1.0 g, 7.94 mmol) for 60 h afforded a dia-
stereomeric mixture (dr: syn:anti, 62:38) of b-hydroxy allylic hy-
droperoxides 22 (1.0 g, 80%) as a colorless oil.
threo-22, Major Isomer
1H NMR (300 MHz, CDCl3): d = 0.20–0.52 (m, 4 H, CH2CH2),
0.78–0.99 (m, 1 H, CH), 1.75 (m, 3 H, CH3C=), 3.07 (dd, 1 H,
J = 8.0, 8.0 Hz, CHOH), 4.29 (d, 1 H, J = 9.3 Hz, CHOOH), 5.05
(m, 2 H, CH2=C).
HRMS (EI, 70 eV): C19H20O3: calcd: M = 296.141 g/mol; found:
M = 296.141 0.005 g/mol.
Anal. Calcd for C19H20O3 (296.37): C, 77.00; H, 6.80. Found: C,
76.47; H, 6.83.
13C NMR (75.5 MHz, CDCl3): d = 1.8 (t, CH2CH2), 3.2 (t,
CH2CH2), 14.0 (d, CH), 18.9 (q, CH3C=), 75.0 (d, CHOH), 93.3 (d,
CHOOH), 115.5 (t, CH2=C), 141.6 (s, C=CH2).
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

FEATURE ARTICLE
1,2,4-Trioxanes by Photooxygenation of Allylic Alcohols
2441
Lewis Acid Catalyzed Cleavage of b-Hydroxy Hydroperoxides
and Subsequent Cross-Peroxyacetalization Reaction; General
Procedure
CHCH2), 24.7 (t, CH2), 30.7 (t, CH2), 39.6 (t, CH2CH), 88.1 (d,
OOCH), 102.3 (s, OCOO), 139.0 (s, C=CH2).
To a stirred solution of appropriate b-hydroxy hydroperoxide in an-
hydrous CH2Cl2 (100 mL) was added at r.t. catalytic amounts of
BF3·OEt2 (ca. 0.2 mL) and the mixture was further stirred for 12 h
at r.t. The mixture was partitioned between CH2Cl2 and aq sat.
NaHCO3 solution and the phases were separated. The aqueous
phase was extracted with CH2Cl2 (3 × 30 mL) and the combined or-
ganic phases were washed with brine, H2O, and dried (Na2SO4).
Solvent evaporation (water bath temperature should not exceed
30 °C) followed by chromatographic purification afforded the pure
1,2,4-trioxanes.
(3RS,4RS,12RS,13RS)-4,13-Dibutyl-3,12-diisopropenyl-
1,2,5,10,11,14-hexaoxadispiro[5.2.5.2]hexadecane (tst-29b) and
(3RS,4RS,12SR,13SR)-4,13-Dibutyl-3,12-diisopropenyl-
1,2,5,10,11,14-hexaoxadispiro[5.2.5.2]hexadecane (tat-29b)
A solution of 25 (R = n-Bu) (1.45 g, 8.33 mmol) and cyclohex-1,4-
dione (0.46 g, 4.11 mmol) in CH2Cl2 were treated with catalytic
amounts of BF3·OEt2 (0.2 mL). Usual work-up followed by prepar-
ative thick-layer chromatography (SiO2, EtOAc–n-hexane, 1:10,
Rf 0.53) afforded a diastereomeric mixture of the pure 1,2,4-triox-
anes 29b in a ratio 1:1 (0.07 g, 4%) as an oil which crystallized on
standing.
(3RS,5RS,6RS)-3,5-Dicyclopropyl-6-(prop-1-en-2-yl)-1,2,4-tri-
oxane (27)
First Diastereomer (tst-29b)
Following the above procedure, from 1-cyclopropyl-2-hydroper-
oxy-3-methylbut-3-en-1-ol (22; 1.50 g, 9.5 mmol) was obtained af-
ter usual work-up, the crude 1,2,4-trioxanes 27 and 28 as a mixture
in a ratio of 61:39 (0.66 g, 33%). The yellow oil was then purified
by preparative thick-layer chromatography (SiO2, EtOAc–n-hex-
ane, 1:10, Rf 0.81) to give the 1,2,4-trioxane 27 (0.23 g, 12%).
1H NMR (300 MHz, CDCl3): d = 0.24–0.59 (m, 8 H, 4 CH2), 0.74–
0.95 (m, 2 H, 2 CH), 1.77 (s, 3 H, CH3C=), 3.06 (dd, 1 H, J = 7.9,
8.7 Hz, OCH), 4.45 (d, 1 H, J = 9. 2 Hz, OOCH), 4.73 (d, 1 H,
J = 6.2 Hz, OCHOO), 5.04 (br s, 2 H, CH2=C).
1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3 H, J = 7.1 Hz, CH3CH2),
1.05–1.72 (m, 8 H, CH2), 1.60 (m, 3 H, CH3C=), 2.20 (m, 2 H, CH2),
3.86 (m, 1 H, OCH), 4.25 (d, 1 H, J = 9.6 Hz, OOCH), 5.04 (s, 2 H,
CH2=).
13C NMR (75.5 MHz, CDCl3): d = 13.9 (q, CH3CH2), 19.7 (q,
CH3C=), 22.5 (t, CH2CH3), 25.2 (t, CH2), 27.0 (t, CH2CH2), 30.4 (t,
CH2CH2), 30.8 (t, CH2), 69.8 (d, OCH), 87.7 (d, OOCH), 102.4 (s,
OCOO), 118.1 (t, CH2=C), 139.2 (s, C=CH2).
Second Diastereomer (tat-29b)
IR (film): 3083, 2957, 2873, 1648, 1455, 1373, 1258, 1105, 1007,
13C NMR (75.5 MHz, CDCl3): d = 1.4 (t, CH2CH), 1.7 (t, CH2CH),
1.9 (t, CH2CH), 2.8 (t, CH2CH), 11.5 [d, CH(CH2)2], 12.0 [d,
CH(CH2)2], 20.6 (q, CH3C=), 80.8 (d, OCH), 87.4 (d, OOCH),
106.4 (d, OCHOO), 117.1 (t, CH2=C), 139.4 (s, C=CH2).
928, 911 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.86 (t, 3 H, J = 7.1 Hz, CH3CH2),
1.05–1.72 (m, 8 H, CH2), 1.60 (m, 3 H, CH3C=), 2.20 (m, 2 H, CH2),
3.86 (m, 1 H, OCH), 4.25 (d, 1 H, J = 9.6 Hz, OOCH), 5.04 (s, 2 H,
CH2=).
13C NMR (75.5 MHz, CDCl3): d = 13.9 (q, CH3CH2), 19.8 (q,
CH3C=), 22.5 (t, CH2CH3), 24.9 (t, CH2), 27.1 (t, CH2CH2), 30.5 (t,
CH2CH2), 31.2 (t, CH2), 69.8 (d, OCH), 87.7 (d, OOCH), 102.3 (s,
OCOO), 118.1 (t, CH2=C), 139.1 (s, C=CH2).
(3RS,5RS,6RS)-5-Cyclopropyl-3,6-di(prop-1-en-2-yl)-1,2,4-tri-
oxane (28)
1H NMR (300 MHz, CDCl3): d = 0.17–0.52 (m, 4 H, CH2CH2),
0.67–1.24 [m, 1 H, CH(CH2)2], 1.69 (m, 3 H, CH3C=), 1.74 (t, 3 H,
J = 1.2 Hz, CH3C=), 3.21 (dd, 1 H, J = 7.1, 9.0 Hz, OCH), 4.43 (d,
1 H, J = 9.1 Hz, OOCH), 4.98–5.04 (m, 3 H, CH2=C), 5.18 (br s, 1
H, CH2=C), 5.45 (s, 1 H, OOCHO).
Anal. Calcd for C24H40O6 (424.57): C, 67.89, H, 9.50. Found: C,
67.43; H, 9.37.
13C NMR (75.5 MHz, CDCl3): d = 1.5 (t, CH2), 2.3 (t, CH2), 11.3 [d,
CH(CH2)2], 17.5 (q, CH3C=), 20.4 (q, CH3C=), 79.8 (d, OCH), 87.5
(d, OOCH), 104.5 (d, OOCHO), 116.5 (t, CH2=C), 117.2 (t,
CH2=C), 138.7 (s, C=CH2), 139.2 (s, C=CH2).
Lewis Acid Catalyzed Transperoxyacetalization;
(3RS,5RS,6RS)-5-Cyclopropyl-3-ethyl-6-(prop-1-en-2-yl)-1,2,4-
trioxane (24b); Typical Procedure (Method B)
A solution of 22 (1.20 g, 7.59 mmol) and propionaldehyde diethyl
acetal (1.0 g, 7.58 mmol) in CH2Cl2 were treated with catalytic
amounts of BF3·OEt2 (0.2 mL). Usual work-up and further purifica-
tion of the crude product (0.67 g, 45%) by preparative thick-layer
chromatography (SiO2, EtOAc–n-hexane, 1:10, Rf 0.76) afforded a
colorless oil composed of a diastereomeric mixture of the pure
1,2,4-trioxane 24b as the major product, and 27, 28 as minor prod-
ucts (315 mg, 21%).
(3RS,4RS,12RS,13RS)-4,13-Diisobutyl-3,12-diisopropenyl-
1,2,5,10,11,14-hexaoxadispiro[5.2.5.2]hexadecane (tst-29a) and
(3RS,4RS,12SR,13SR)-4,13-diisobutyl-3,12-diisopropenyl-
1,2,5,10,11,14-hexaoxadispiro[5.2.5.2]hexadecane (tat-29a)
A solution of 25 (R = i-Bu) (1.32 g, 7.59 mmol) and cyclohexan-
1,4-dione (0.42 g, 3.75 mmol) in CH2Cl2 were treated with a cata-
.
lytic amount of BF3 Et2O (0.2 mL). Usual work-up followed by
preparative thick-layer chromatography (SiO2, EtOAc/n-hexane,
1:10, Rf 0.71) afforded a diastereomeric mixture of the 1,2,4-triox-
anes 29a in a ratio of 1:1 (0.23 g, 15%) as an oil which crystallizes
on standing.
1H NMR: (300 MHz, CDCl3, both diastereomers) d = 0.81–0.94 (m,
6 H, (CH3)2CH), 1.06 (m, 1 H, CH2CH), 1.33 (m, 1 H, CH2CH),
1.59–1.89 (m, 3 H, CH2 and CHCH2), 1.72 (m, 3 H, CH3C=), 2.10–
2.35 (m, 2 H, CH2), 3.97 (m, 1 H, OCH), 4.24 (d, 1 H, J = 9.54 Hz,
OOCH), 5.05 (m, 2 H, CH2=C).
IR (film): 3085, 3009, 2973, 2927, 2881, 1653, 1648, 1116, 1088,
1047, 943, 904 cm–1.
1H NMR (300 MHz, CDCl3): d (major product a) = 0.31–0.62 (m, 4
H, CH2CH2), 0.79 [m, 1 H, CH(CH2)2], 0.90 (t, 3 H, J = 7.5 Hz,
CH3CH2), 1.56 (dq, 2 H, J = 5.3, 7.5 Hz, CH2CH3), 1.75 (m, 3 H,
CH3C=), 3.08 (dd, 1 H, J = 7.7, 9.1 Hz, OCH), 4.41 (d, 1 H, J = 9.1
Hz, OOCH), 5.01 (m, 2 H, CH2=), 5.08 (t, 1 H, J = 5.4 Hz,
OCHOO).
13C NMR (75.5 MHz, CDCl3): d (major product a) = 1.6 (t, CH2),
2.6 (t, CH2), 8.1 (q, CH3CH2), 11.4 [d, CH(CH2)2], 20.4 (q, CH3C=),
25.3 (t, CH2CH3), 80.3 (d, OCH), 87.6 (d, OOCH), 105.1 (d,
OCHOO), 117.0 (t, CH2=C), 139.3 (s, C=CH2).
13C NMR: (75.5 MHz, CDCl3, 1st diastereomer) d = 19.7 (q,
CH3C=), 21.3 (q, CH3CH), 23.5 (d, CHCH2), 23.7 (q, CH3CH), 25.2
(t, CH2), 31.2 (t, CH2), 39.6 (t, CH2CH), 67.8 (d, OCH), 88.1 (d,
OOCH), 102.3 (s, OCOO), 118.2 (t, CH2=C), 139.0 (s, C=CH2);
Additional signals of 2nd diastereomer: d = 19.6 (q, CH3C=), 23.5 (d,
Anal. Calcd for C11H18O3 (198.26): C, 66.64; H, 9.15. Found: C,
66.55; H, 9.15.
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

2442
A. Bartoschek et al.
FEATURE ARTICLE
(3RS,5RS,6RS)-5-Butyl-3-phenyl-6-(prop-1-en-2-yl)-1,2,4-tri-
oxane (30a) (Method B)
IR (film): 2912, 1648, 1222, 1109, 1090, 1023, 999, 926 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.07 (d, 3 H, J = 6.2 Hz, CH3CH),
1.52–2.11 (m, 13 H, CH and CH2), 1.73 (m, 3 H, CH3C=), 2.90 (br
d, 1 H, CH), 4.04 (dq, 1 H, J = 6.2, 9.6 Hz, OCH), 4.17 (d, 1 H,
J = 9.6 Hz, OOCH), 5.04 (m, 2 H, CH2=).
13C NMR (75.5 MHz, CDCl3): d = 17.0 (q, CH3CH), 19.8 (q,
CH3C=), 27.1 (d, CH), 27.2 (d, CH), 29.8 (d, CH), 36.5 (d, CH),
33.1 (t, CH2), 33.3 (t, CH2), 33.4 (t, CH2), 33.5 (t, CH2), 37.2 (t,
CH2), 65.0 (d, OCH), 88.7 (d, OOCH), 104.8 (s, OCOO), 117.6 (t,
CH2=), 139.3 (s, C=CH2).
A solution of 25 (R = n-Bu) (1.32 g, 7.59 mmol) and benzaldehyde
dimethyl acetal (1.15 g, 7.57 mmol) in CH2Cl2 were treated with
catalytic amounts of BF3·OEt2 (0.2 mL). Usual work-up and further
purification of the crude product by preparative thick-layer chroma-
tography (SiO2, EtOAc–n-hexane, 1:10, Rf 0.76) afforded the pure
1,2,4-trioxane 30a (0.96 g, 48%) as an oil.
1H NMR (300 MHz, CDCl3): d = 0.91 (t, 3 H, J = 7.2 Hz, CH3CH2),
1.23–1.61 (m, 6 H, CH2), 1.80 (m, 3 H, CH3C=), 3.92 (m, 1 H,
OCH), 4.54 (d, 1 H, J = 9.3 Hz, OOCH), 5.13 (m, 1 H, CH2=), 5.16
(s, 1 H, CH2=), 6.22 (s, 1 H, OCHOO), 7.37–7.54 (m, 5 Harom).
13C NMR (75.5 MHz, CDCl3): d = 13.9 (q, CH3CH2), 19.7 (q,
CH3C=), 22.6 (t, CH2CH3), 27.0 (t, CH2CH2), 30.1 (t, CH2CH2),
77.3 (d, OCH), 87.6 (d, OOCH), 104.0 (d, OCHOO), 118.5 (t,
CH2=C), 126.9 (d, CHarom), 128.3 (d, CHarom), 129.7 (d, CHarom),
134.6 (s, Carom), 138.8 (s, C=CH2).
MS (EI, 70 eV): m/z (%) = 264 (M+, 4), 220 (M+ – C2H4O, 55), 150
+
+
(C10H14O+, 34), 82 (C6H10+, 100), 81 (C6H9 , 53), 80 (C6H8 , 82), 79
(C6H7 , 97), 67 (C5H7 , 67), 55 (C3H3O+, 42).
+
+
Anal. Calcd for C16H24O3 (264.36): C, 72.69; H, 9.15. Found: C,
72.69; H, 9.05.
(5RS,6RS)-5-Isobutyl-6-(prop-1-en-2yl)spiro[1,2,4-trioxacyclo-
hexane-3,2¢-adamantane] (30d) (Method A)
MS (EI, 70 eV): m/z (%) = 262 (M+, not observed), 124 (C9H16
,
+
+
13), 106 (C7H6O+, 32), 105 (C7H5O+, 100), 77 (C6H5 , 33), 51
A solution of 25 (R = i-Bu) (1.70 g, 9.77 mmol) and adamantanone
(2.10 g, 13.5 mmol) in CH2Cl2 was treated with catalytic amounts
of BF3·OEt2 (0.2 mL). Usual work-up and further purification of the
crude product by preparative thick-layer chromatography (SiO2,
EtOAc–n-hexane, 1:10, Rf 0.80) afforded the 1,2,4-trioxane 30d
(0.28 g, 10%) as an oil which crystallized on standing to a white sol-
+
(C4H3 , 13).
Anal. Calcd for C16H22O3 (262.34): C, 73.25; H, 8.45. Found: C,
73.11; H, 8.46.
(3RS,5RS,6RS)-5-Isobutyl-3-(naphthalen-2-yl)-6-(prop-1-en-2-
yl)-1,2,4-trioxane (30b) (Method A)
1
id. H NMR (300 MHz, CDCl3): d = 0.87 (d, 3 H, J = 6.6 Hz,
A solution of 25 (R = i-Bu) (1.21 g, 6.95 mmol) and b-naphthalde-
hyde (1.09 g, 6.99 mmol) in CH2Cl2 was treated with catalytic
amounts of BF3·OEt2 (0.2 mL). Usual work-up and further purifica-
tion of the crude product by preparative thick-layer chromatography
(SiO2, EtOAc–n-hexane, 1:10, Rf 0.71) afforded the 1,2,4-trioxane
30b (0.46 g, 21%) as an oil which crystallized on standing to a white
solid; mp 60–62 °C.
CH3CH), 0.90 (d, 3 H, J = 6.8 Hz, CH3CH), 1.01–1.10 (m, 1 H,
CH2CH), 1.34 (m, 1 H, CH2CH), 1.50–2.09 [m, 14 H, CH, CH2 and
CH(CH3)2], 1.72 (t, 3 H, J = 1.2 Hz, CH3C=), 2.91 (br d, 1 H, CH),
3.99 (ddd, 1 H, J = 3.0, 9.5, 9.5 Hz, OCH), 4.20 (d, 1 H, J = 9.5 Hz,
OOCH), 5.03 (m, 2 H, CH2=C).
13C NMR (75.5 MHz, CDCl3): d = 19.7 (q, CH3C=), 21.4 (q,
CH3CH), 23.5 (d, CHCH2), 23.8 (q, CH3CH), 27.2 (2 d, CH), 29.9
(d, CH), 33.1 (t, CH2), 33.3 (2 t, CH2), 33.5 (t, CH2), 36.6 (d, CH),
37.2 (t, CH2), 39.9 (t, CH2CH), 66.6 (d, OCH), 87.8 (d, OOCH),
104.7 (s, OCOO), 118.0 (t, CH2=C), 139.3 (s, C=CH2).
IR (CsI): 3095, 2956, 2934, 1605, 1347, 1098, 1080, 997, 863, 817
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.01 (d, 3 H, J = 6.6 Hz, CH3CH),
1.04 (d, 3 H, J = 6.8 Hz, CH3CH), 1.33 (m, 1 H, CH2CH), 1.70 (m,
1 H, CH2CH), 1.87 (s, 3 H, CH3C=), 2.08 (m, 1 H, CHCH2), 4.12
(ddd, 1 H, J = 2.3, 9.1, 10.3 Hz, OCH), 4.65 (d, 1 H, J = 9.1 Hz,
OOCH), 5.19 (m, 1 H, CH2=), 5.24 (m, 1 H, CH2=), 6.45 (s, 1 H,
OCHOO), 7.49–8.07 (m, 5 Harom).
13C NMR (75.5 MHz, CDCl3): d = 19.6 (q, CH3C=), 21.5 (q,
CH3CH), 23.6 (d, CHCH2), 23.7 (q, CH3CH), 39.2 (t, CH2CH), 75.6
(d, OCH), 88.0 (d, OOCH), 104.0 (d, OCHOO), 118.7 (t, CH2=),
124.0 (d, CHarom), 126.1 (d, CHarom), 126.6 (d, CHarom), 126.7 (d,
CHarom), 127.6 (d, CHarom), 128.0 (d, CHarom), 128.3 (d, CHarom),
131.9 (s, Carom), 132.8 (s, Carom), 133.9 (s, Carom), 138.6 (s, C=CH2).
MS (EI, 20 eV): m/z (%) = 150 (C10H14O+, 100), 124 (C9H16+, 27).
HRMS (EI, 70 eV): C19H30O3 calcd: M = 306.2195 g/mol; found:
M = 306.219 0.005 g/mol.
Anal. Calcd for C19H30O3 (306.44): C, 74.47; H, 9.87. Found: C,
74.06; H, 9.78.
(3RS,5RS,6RS)-3-(Furan-2-yl)-5-methyl-6-(prop-1-en-2-yl)-
1,2,4-trioxane (30e) (Method A)
A solution of 14 (0.71 g, 5.38 mmol) and furan-2-carboxaldehyde
(0.65 g, 6.77 mmol) in CH2Cl2 was treated with catalytic amounts
of BF3·OEt2 (0.2 mL). Usual work-up and further purification of the
crude product by preparative thick-layer chromatography (SiO2,
EtOAc–n-hexane, 1:10) afforded the pure 1,2,4-trioxane 30e as a
viscous colorless oil (0.38 g, 34%).
MS (EI, 70 eV): m/z (%) = 312 (M+, 3), 226 (M+ – C5H10O, 2), 156
(C11H8O+, 100), 155 (C11H7O+, 100), 128 (C10H8 , 30), 127 (C10H7 ,
100), 124 (C9H16+, 27), 109 (C8H13+, 17).
+
+
HRMS (EI, 70 eV): C20H24O3 calcd: M = 312.173 g/mol; found:
M = 312.173 0.005 g/mol.
IR (film): 3126, 3085, 2979, 2901, 1647, 1636, 1601, 1149, 1087,
1065, 1000, 984, 915 cm–1.
Anal. Calcd for C20H24O3 (312.40): C, 76.89; H, 7.74. Found: C,
76.61; H, 7.63
1H NMR (300 MHz, CDCl3): d = 1.22 (d, 3 H, J = 6.3 Hz, CH3CH),
1.74 (m, 3 H, CH3C=), 4.0 (dq, 1 H, J = 6.3, 9.1 Hz, OCH), 4.45 (d,
1 H, J = 9.1 Hz, OOCH), 5.09 (m, 2 H, CH2=), 6.25 (s, 1 H,
OCHOO), 6.34 (m, 1 H, CH), 6.53 (m, 1 H, CH), 7.39 (m, 1 H, CH).
13C NMR (75.5 MHz, CDCl3): d = 16.2 (q, CH3CH), 19.5 (q,
CH3C=), 74.1 (d, OCH), 88.7 (d, OOCH), 98.4 (d, OCHOO), 110.0
(d, CH=), 110.3 (d, CH=), 118.4 (t, CH2=C), 138.4 (s, C=CH2),
143.3 (d, OCH=), 147.3 (s, OCq=).
(5RS,6RS)-5-Methyl-6-(prop-1-en-2yl)spiro[1,2,4-trioxacyclo-
hexane-3,2¢-adamantane] (30c) (Method A)
A solution of 14 (2.0 g, 15.2 mmol) and adamantanone (2.28 g, 15.2
mmol) in CH2Cl2 were treated with catalytic amounts of BF3·OEt2
(0.2 mL). Usual work-up and further purification of the crude prod-
uct by preparative thick-layer chromatography (SiO2, EtOAc–n-
hexane, 1:10, Rf 0.89) afforded the pure 1,2,4-trioxane 30c as a col-
orless oil which crystallized on standing (0.47 g, 12%); mp 48–
49 °C.
Anal. Calcd for C11H14O4 (210.23): C, 62.85; H, 6.71. Found: C,
62.80; H, 6.70.
Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York

FEATURE ARTICLE
1,2,4-Trioxanes by Photooxygenation of Allylic Alcohols
2443
Table 1 Crystal Data for Compounds 23a, 26d and tat-29a
Product Formula
M [gmol–1]
Cell Dimensions a, b, g [°]
[Å]
V [Å3], Z
Crystal System
Space Group
Reflexes Measd/ R/RW
Reflexes Obsvd
23a
C18H26O3
a = 7.388(1)
b = 10.428(1)
c = 20.250(1)
a = 90
b = 94.19
g = 90
V = 1555.9(3)
Z = 4
monoclinic
P21/n
9215
1805
0.0586
0.1128
26d
C19H20O3
a = 12.8550(6)
b = 14.8204(5)
c = 8.3185(3)
a = 90
b = 94.95
g = 90
V = 1578.90(11) monoclinic
3443
1851
0.0507
0.1112
Z = 4
P21/c
tat-29a C24H36O6
a = 23.634(1)
b = 8.201(1)
c = 11.220(1)
a = 90
b = 90
g = 90
V = 2174.7(3)
Z = 4
orthorhombic
Pbcn
1441
321
0.0773
0.0682
(3RS,5RS,6RS)-3-(2-Chlorophenyl)-5-ethyl-6-(prop-1-en-2-yl)-
1,2,4-trioxane (30f) (Method A)
H, J = 9.7, 7.1 Hz, OCH), 3.71 (m, 2 H, CH2CH3), 5.58 (s, 1 H,
OCHOO).
A solution of 25 (R = Et) (1.50 g, 10.3 mmol) and 2-chlorobenzal-
dehyde (1.44 g, 10.2 mmol) in CH2Cl2 was treated with catalytic
amounts of BF3·OEt2 (0.2 mL). Usual work-up and further purifica-
tion of the crude product by preparative thick-layer chromatography
(SiO2, EtOAc–n-hexane, 1:10) afforded the 1,2,4-trioxane 30f (0.60
g, 22%) as an oil.
13C NMR (75.5 MHz, CDCl3): d (minor diastereomer) = 14.7 (q,
CH3CH2), 16.1 (q, CH3CH), 19.5 (q, CH3C=), 61.6 (t, CH2CH3),
65.8 (d, OCH), 88.9 (d, OOCH), 110.0 (d, OCHOO), 118.2 (t,
CH2=C), 139.0 (s, C=CH2).
MS (EI, 70 eV): m/z (%) = 82 (C6H10+, 100), 70 (C4H6O+, 28), 69
+
(C4H5O+, 27), 67 (C5H7 , 68).
IR (film): 3079, 2971, 2925, 2879, 1647, 1597, 1576, 1445, 1086,
1053, 1003, 960, 916 cm–1.
Crystallographic Data (Table 1)
1H NMR (300 MHz, CDCl3): d = 0.97 (dd, 3 H, J = 7.4, 7.4 Hz,
CH3CH2), 1.43–1.62 (m, 2 H, CH2CH3), 1.73 (m, 3 H, CH3C=), 3.82
(ddd, 1 H, J = 3.5, 8.1, 9.2 Hz, OCH), 4.48 (d, 1 H, J = 9.2 Hz,
OOCH), 5.05 (m, 2 H, CH2=), 5.48 (s, 1 H, OCHOO), 7.21–7.65 (m,
4 Harom).
13C NMR (75.5 MHz, CDCl3): d = 9.3 (q, CH3CH2), 19.7 (q,
CH3C=), 23.6 (t, CH2CH3), 78.7 (d, OCH), 87.4 (d, OOCH), 101.0
(d, OCHOO), 118.5 (t, CH2=C), 126.8 (d, CHarom), 128.7 (d,
CHarom), 129.5 (d, CHarom), 130.9 (d, CHarom), 132.1 (s, Carom), 133.5
(s, Carom), 138.7 (s, C=CH2).
Data Collection: Nonius-Kappa-CCD diffractometer, room temper-
ature, Mo-Ka-radiation (l = 0.71073 Å), graphite monochromator,
j – w – scans, 2 Q limits [°]: 2–54.
Structure Analysis and Refinement: Solved by direct methods; full
matrix least-squares refinement with anisotropic thermal parame-
ters for C, N and O and isotropic parameters for H.
Programs Used: For structure determination SHELXS-97 and for
refinement SHELXL-97.
MS (EI, 70 eV): m/z (%) = 142 (C7H537Cl+, 13), 141 (C7H437Cl+,
Acknowledgment
42), 140 (C7H535Cl+, 39), 139 (C7H435Cl+, 100), 113 (C6H537Cl+, 7),
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG project GR 881/13-1) and by the University of
Cologne (setting up funding 2004/05). The SEM pictures were ta-
ken at the Max-Planck Institute for colloids and interfaces, Golm,
Germany, in the group of Prof. Markus Antonietti. Antimalarial-te-
sting was performed in Basel (Swiss Tropical Institute, Prof. R.
Brun) and Bonn (Medicinal Parasitology, Prof. A. Hörauf, Dr. M.
Saeftel). Tamer El-Idreesy thanks the Egyptian government for a
long-term Ph.D. grant and Anna Bartoschek thanks the University
of Cologne for a graduation grant.
111 (C6H535Cl+, 21), 96 (C7H12+, 30), 81 (C6H9 , 20).
+
Anal. Calcd for C14H17ClO3 (268.74): C, 62.57; H, 6.38. Found: C,
62.55; H, 6.36.
(3RS,5RS,6RS)-3-Ethoxy-5-methyl-6-(prop-1-en-2-yl)-1,2,4-tri-
oxane and (3RS,5SR,6SR)-3-Ethoxy-5-methyl-6-(prop-1-en-2-
yl)-1,2,4-trioxane (30g) (Method B)
A solution of 14 (0.75 g, 5.68 mmol) and triethyl orthoformate (5.0
g, 33.8 mmol) in CH2Cl2 was treated with catalytic amounts of
BF3·OEt2 (0.2 mL). Usual work-up followed by evaporation of ex-
cess orthoester afforded an oil composed of a diastereomeric mix-
ture of the 1,2,4-trioxanes 30g in the ratio of 72:28 (0.75 g, 70%).
References
1H NMR (300 MHz, CDCl3): d (major diastereomer) = 1.19 (d, 3 H,
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2444
A. Bartoschek et al.
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Synthesis 2005, No. 14, 2433–2444 © Thieme Stuttgart · New York