Synthesis of 1,2,4-trioxanes and 1,2,4-trioxepanes by N-halogenosuccinimide-mediated cyclisations of unsaturated hydroperoxyacetals

Article abstract of DOI:10.1039/a605616d

Ozonolyses of vinyl ethers 1a-c in CH₂Cl₂ in the presence of allylic and homoallylic alcohols 3a-c give in each case the corresponding unsaturated hydroperoxy acetals 4a-h, derived from capture of the carbonyl oxides 2a-c by the unsaturated alcohols. N-Halogenosuccinimide-mediated cyclisations of the hydroperoxides give the corresponding 1,2,4-trioxanes and/or 1,2,4-trioxepanes, depending on the structure of the hydroperoxides and the identity of the N-halogenosuccinimides.

Full text of DOI:10.1039/a605616d

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Synthesis of 1,2,4-trioxanes and 1,2,4-trioxepanes by N-
halogenosuccinimide-mediated cyclisations of unsaturated
hydroperoxyacetals
Yoshihiro Ushigoe, Yoshihiro Kano and Masatomo Nojima *
Department of Material Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565, Japan
Ozonolyses of vinyl ethers 1a–c in CH 2Cl2 in the presence of allylic and homoallylic alcohols 3a–c
give in each case the corresponding unsaturated hydroperoxy acetals 4a–h, derived from capture of the
carbonyl oxides 2a–c by the unsaturated alcohols. N-H alogenosuccinimide-mediated cyclisations of the
hydroperoxides give the corresponding 1,2,4-trioxanes and/or 1,2,4-trioxepanes, depending on the
structure of the hydroperoxides and the identity of the N-halogenosuccinimides.
The discovery of pharmacologically active six- and seven-
O3
R1R2C=CHOMe
R1R2COO
membered ring peroxides has given rise to renewed interest in
the development of new syntheses of such structures.1
Although several methods have been developed for the syn-
thesis of 1,2,4-trioxanes,2 in the case of 1,2,4-trioxepanes only
one reliable method is known. Adam and Duran 3 reported that
the acid-catalysed cyclocondensation of 3-hydroxypropyl
hydroperoxides and ketones provides the corresponding 1,2,4-
trioxepanes. As a new synthetic method for 1,2,4-trioxanes and
1,2,4-trioxepanes, we considered that electrophilic cyclisation
of unsaturated hydroperoxy acetals might be promising,4 an
expectation which has been independently confirmed recently
by Dussault and Davies.5 In their work they used an I2 /base
system to initiate the cyclisation of unsaturated hydroperoxy
acetals, in which the peroxy anion plays a key role. We report
herein our own results for the N-halogenosuccinimide-mediated
synthesis of 1,2,4-trioxanes and 1,2,4-trioxepanes.
1a-c
2
R3
R4
OH
R4
3a,b
R3
R1
OOH
R4
O
R4
R2
4a-f
R1
R2
R3
R4
4, % yield
a
Ph
H
H
Me
Me
Me
H
H
H
47
72
64
C7H15
b
c
-(CH2)5-
Results and discussion
d
e
Ph
H
H
H
H
Me
Me
59
62
C7H15
Preparation of unsaturated hydroperoxy acetals
-(CH2)5-
Ozonolysis of 1-phenyl-2-methoxyethene 1a in CH2Cl2 in the
presence of 2-methylprop-2-en-1-ol 3a (10 equiv.) at Ϫ70 ЊC,
followed by column chromatography on silica gel, gave the
expected unsaturated hydroperoxy acetal 4a (47%). This implies
that electron-deficient ozone reacts selectively with the electron-
rich vinyl ether 1a to afford benzaldehyde oxide 2a which, in
turn, is efficiently captured by the allylic alcohol 3a.6 Also,
ozonolyses of the vinyl ethers 1a–c in the presence of 2-
methylprop-2-en-1-ol 3a or 3-methylbut-2-en-1-ol 3b gave, in
each case, the corresponding unsaturated hydroperoxy acetals
4b–f in moderate yields (Scheme 1). From the ozonolyses of the
vinyl ethers 1a,c in the presence of 3-methylbut-3-en-1-ol 3c,
were obtained the 1-(3-methylbut-3-enyloxy)alkyl hydroperox-
ides 4g,h (Scheme 1). Thus, treatment of a mixture of a vinyl
ether and an unsaturated alcohol with ozone seems to be an
efficient method for the preparation of the unsaturated
f
H
Me
65
R1
OOH
O
O3
R1R2C=CHOMe
OH
R2
1
4g,h
3c
R1
Ph
-(CH2)5-
R2
4, % yield
g
h
H
58
45
1
hydroperoxy acetals. The H and 13C NMR spectra, together
Scheme1
with the elemental analyses, supported the structure. As add-
itional confirmation, treatment of the unsaturated hydroper-
oxide 4d with PhNCO in the presence of a catalytic amount
of pyridine gave the expected ester 5d [eqn. (1)].
Ph
O
Ph
OOH
Me
O
Me
O
Synthesis of 1,2,4-trioxanes and 1,2,4-trioxepanes
PhNCO
pyridine
(1)
With the unsaturated hydroperoxy acetals 4a–h to hand, we
then conducted N-halogenosuccinimide-mediated cyclisations.
Treatment of the hydroperoxide 4a with N-bromosuccinimide
Me
Me
5d
4d
J. Chem. Soc., Perkin Trans. 1, 1997
5

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(NBS) in CH2Cl2 gave the corresponding 1,2,4-trioxane 6a,
together with a complex mixture of unidentified, highly polar
products. The physical properties of the unidentified products
imply that oligomerisation of the hydroperoxide 4a and/or
dehydration may compete with the desired cyclisation process.
There was no evidence for the formation of the corresponding
1,2,4-trioxepane. In attempting to optimise the conditions for
this reaction, we repeated it under a variety of conditions and
found that the reaction with 2 equiv. of NBS in CH2Cl2 in the
presence of NaHCO3 for 15 h is most satisfactory (Scheme 2).
CH2I
O
O
Ph
CH3
Hb
O
Hc
Ha
8%
12%
Fig. 1 The NOE in the 1,2,4-trioxane 6c
major isomer was isolated in a pure state by repeated column
chromatography on silica gel and/or recrystallisation. To con-
firm the structure of the major isomer of the trioxane 6c, NOE
measurements were undertaken. As shown in Fig. 1, the 3-
phenyl group and the 6-iodomethyl group were confirmed as
having a cis relationship. In this connection, Dussault and
Davies5 have reported that the I2 /base-mediated cyclisations of
α-(prop-2-enyloxy)octyl hydroperoxide gives 3-heptyl-6-
iodomethyl-1,2,4-trioxane (ca. 20%) as a mixture of two stereo-
isomers, the base-dependent ratio of which is 4:1–10:1. Inter-
estingly, the cis isomer is the major product.
O
O
O
Ph
NBS
O
Ph
20 °C
Br
OOH
6a
4a
6a
% yield
Reaction
time/h
NBS
ratio
Entry
Additive
Solvent
2
4
6
8a
1
2
3
4
5
6
7
1
CH2Cl2
CH2Cl2
From the reaction of the hydroperoxide 4g with NBS was
obtained the 1,2,4-trioxepane 7a as a ca. 3:2 mixture of two
stereoisomers (18% yield) (Scheme 4). The reaction of the
25
2
2
4
CH2Cl2
CH2Cl2
31
23
31
36
O
O
4
R1
R1
R2
O
NBS
X
NaHCO3
NaHCO3
CH2Cl2
CH2Cl2
or NIS
6
2
2
2
OOH
R2
O
15
7a-c
4g,h
NaHCO3 ClCH2CH2Cl
30
6
a
Unchanged 4a was recovered in 40%.
R1
Ph
R2
H
X
7, % yield
a
b
c
Scheme 2
Br
Br
I
18
18
32
-(CH2)5-
-(CH2)5-
O
O
R1
R1
R2
NBS
O
R2
or NIS
X
O
OOH
Scheme 4
4a,b
6a-d
hydroperoxide 4h with NBS gave the trioxepane 7b (one iso-
mer). Iodo trioxepane 7c was also obtained from the reaction
of the hydroperoxide 4h with NIS (32%). In contrast, the
hydroperoxide 4g reacted with NIS to give a complex mixture
of unidentified products. In this connection, Dussault and
Davies5 have reported that the expected trioxepane, 7-iodo-
methyl-3-heptyl-1,2,4-trioxepane, cannot be isolated from
the reaction of α-(but-3-enyloxy)octyl hydroperoxide with I2 /
ButOK in the presence of 18-crown-6, although the hydro-
peroxy acetal is consumed under the reaction conditions.
Treatment of the hydroperoxides 4d,e with NBS gave mix-
tures of the two isomeric cyclic peroxides, 9a,b and 10a,b, the
structures of which were determined on the basis of their
DEPT spectra (see Experimental section).7 The relatively large
difference in the chemical shifts between the two geminal
methyl groups in the trioxepane 10 was also characteristic.
Judged from the 1H and 13C NMR spectra of the crude reaction
mixture, only one isomer was produced for each of the cyclic
peroxides. From the reaction of the hydroperoxide 4f, only the
1,2,4-trioxepane 10c was obtained (34%) (Scheme 5). In con-
trast, NIS seems to favour the production of the 1,2,4-trioxane.
Thus, the reaction of the hydroperoxides 4d,e gave exclusively
the corresponding 1,2,4-trioxanes 9d,e, while a mixture of the
two isomeric peroxides, 9f and 10f, was obtained from the
hydroperoxide 4f.
R1
Ph
R2
H
6, % yield
X
a
b
c
Br
Br
I
36
25
18
C7H15
Ph
H
H
15
I
H
C7H15
d
Scheme 3
The results from the peroxyhalogenation of the unsaturated
hydroperoxy acetals 4a,b are summarised in Scheme 3. The
reaction with NBS gave 6-bromomethyl-6-methyl-1,2,4-
trioxanes 6a,b in isolated yields of 25–36%. From the reactions
of 4a,b with N-iodosuccinimide (NIS), the iodo-1,2,4-trioxanes
6c,d were obtained, albeit in poorer yields (15–18%). It should
be noticed that for the synthesis of 1,2,4-trioxanes, this method
has a complementary relationship with the halogenocyclisation
of the hemiperacetals derived from 2,3-dimethylbut-3-en-2-yl
hydroperoxide and aliphatic aldehydes reported by Bloodworth
and Shah.4b
Reaction of the hydroperoxide 4c with NBS or NIS was
found to be sluggish and gave (1H NMR) only the correspond-
ing trioxanes. However, column chromatography on silica gel
results in peroxide decomposition, the reason for which is
obscure.
A plausible mechanism for the described reaction is illus-
trated in Scheme 5. The first step may involve formation of the
halogenium ion intermediate 8, which is followed by attack of
the hydroperoxy group on the electron-deficient carbon to yield
For the trioxanes 6a–d, two stereoisomers are possible and
these were obtained as ca. 4:1 mixtures. However, only the
6
J. Chem. Soc., Perkin Trans. 1, 1997

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R1
R2
R1
R2
O
O
R1
R2
O
a
OOH
O
OOH
4d-f
O
b
4d-f
11
NBS
or NIS
a
b
+X
O
O
R1
R2
O
O
R1
R2
R1
R2
O
a
O
O
O
O
12
NIS
b
13
H
8
NIS
a
b
O
O
O
O
R1
R2
O
R1
R2
O
O
O
R1
R2
O
O
R1
R2
I
X
O
O
I
X
9d-f
10d-f
9a-f
10a-f
Scheme 6
% yield
R1
R2
X
participation of the free-radical chain mechanism, the N-
halogenosuccinimide-mediated cyclisation of the hydroper-
oxide 4i, derived from capture of the carbonyl oxide 2c with
E-but-2-en-1-ol 3d, was undertaken.
9
10
a
b
c
Ph
H
H
Br
Br
Br
27
31
14
16
34
C7H15
-(CH2)5-
Stereochemistry of the cyclisation
Ozonolysis of methoxymethylenecyclohexane 1c in CH2Cl2 in
the presence of E-but-2-en-1-ol 3d gave the unsaturated
hydroperoxy acetal 4i (45%). Treatment with NBS then gave a
mixture of the trioxane 14a and the trioxepane 15a, only one
isomer being obtained for each product (Scheme 7). When the
d
e
Ph
C7H15
-(CH2)5-
H
H
I
I
27
38
f
I
28
10
Scheme 5
OOH
O3
OH
OMe
O
either the 1,2,4-trioxane 9 (path a) or the 1,2,4-trioxepane 10
(path b). The former pathway is favoured in terms of the
entropy of the cyclisation, while the latter may provide signifi-
cant contribution, if the stability of the carbocation controls
the regiochemistry of the cyclisation. The observed com-
position of the two cyclic peroxides, 9 and 10, suggests that
several factors including the structure of the unsaturated
hydroperoxy acetals 4 and the identity of the N-halo-
genosuccinimides affect the mode of the cyclisation in a com-
plicated fashion. It is noted, however, that selective formation
of the 1,2,4-trioxanes 6a–d from the hydroperoxides 4a,b and
of the 1,2,4-trioxepanes 7a–c from the hydroperoxides 4g,h
would be understandable in the framework of a mechanism
involving the corresponding halogenium ion intermediates.
Alternatively, the cyclisation may proceed by a free-radical
chain mechanism with the propagation steps in Scheme 6.
Initiation, which probably involves electron transfer from the
hydroperoxide 4 to N-halogenosuccinimide,4a provides the per-
oxyl radical 11 which is known to cyclise to an alkyl radical. On
the basis of non-stereospecificity in the cyclisation of E- and
Z-hex-3-enyl hydroperoxides, Bloodworth and Curtis4a have
proposed the significance of a similar free-radical mechanism
particularly in the N-iodosuccinimide-mediated reaction. If
consideration is given to (i) the more favourable disposition of
the 6-exo over the 7-endo mode of cyclisation in the unsatur-
ated alkyl and peroxy radicals8 and (ii) the relative stability
between two peroxy radical intermediates, 12 and 13, the
1,2,4-trioxepane 10f from the hydroperoxide 4f does not seem
likely to be produced by the radical chain mechanism.
1c
3d
4i (45%)
O
O
Me
Br
Me
O
O
O
NBS
H
+
O
Br
H
14a (13%)
15a (15%)
4i
O
O
Me
Me
O
O
O
NIS
H
+
I
O
H
I
15b (10%)
14b (10%)
NIS
H
H
O
H
H
O
O
O
O
Me
O
Me
+
X
H
NIS
16, a; X = Br, b; X = I
17
Scheme 7
same reaction was repeated with NIS, however, the trioxane 14b
was obtained as a ca. 2:1 mixture of two stereoisomers, where-
as the trioxepane 15b was isolated as a single isomer.
The stereoselectively in the NBS-mediated cyclisation sug-
gests that the reaction proceeds via the bromonium ion inter-
The question is then, whether the radical chain mechanism is
operative or not in the reactions of the hydroperoxides 4d,e
with NIS, since in these cases the 1,2,4-trioxanes 9d,e were the
sole isolable cyclic peroxides. To confirm the possibility of the
J. Chem. Soc., Perkin Trans. 1, 1997
7

View Article Online
mediate 16a and thereby leads to stereospecific cyclisation
(trans addition); this probably yields the erythro isomer for the
trioxane 14a and the trans isomer for the trioxepane 15a.4a In
the case of iodocyclisation, the stereochemistry implies that the
stereospecific trans-addition via the iodonium ion 16b competes
with the free-radical chain process via the peroxyl-radical
intermediate 17, the former predominating for the formation of
the trioxepane 15b, while the latter would be important for the
formation of the trioxane derivative 14b.
δC 19.28, 72.47, 105.63, 112.44, 126.77, 128.07, 128.91, 135.51
and 141.38.
1-(2-Methylprop-2-enyloxy)octyl hydroperoxide 4b. Oil
(Found: C, 66.0; H, 11.2. C12H24O3 requires C, 66.6; H, 11.2%);
δH 0.88 (3 H, t, J 6.4), 1.2–1.7 (12 H, m), 1.76 (3 H, s), 4.08 (1 H,
d, J 12.9), 4.24 (1 H, d, J 12.9), 4.85 (1 H, t, J 5.8), 4.91 (1 H, s),
5.02 (1 H, s) and 9.02 (1 H, s); δC 13.91, 19.37, 22.48, 24.55,
29.02, 29.20, 31.63, 72.44, 106.99, 112.22 and 141.83.
1-(2-Methylprop-2-enyloxy)cyclohexyl hydroperoxide 4c. Oil
(Found: C, 64.4; H, 9.8. C10H18O3 requires C, 64.5; H, 9.7%); δH
1.3–1.8 (10 H, m), 1.78 (3 H, s), 3.96 (2 H, s), 4.87 (1 H, s ), 5.07
(1 H, s) and 8.33 (1 H, s); δC 19.37, 22.39, 25.16, 31.29, 63.85,
105.23, 110.62 and 142.73.
á-(3-Methylbut-2-enyloxy)benzyl hydroperoxide 4d. Oil
(Found: C, 68.8; H, 7.8. C12H16O3 requires C, 69.2; H, 7.7%); δH
1.68 (3 H, s), 1.75 (3 H, s), 4.2–4.3 (2 H, m), 5.42 (1 H, t, J 6.3),
5.84 (1 H, s), 7.3–7.5 (5 H, m) and 8.87 (s, 1 H); δC 18.10, 25.80,
65.16, 105.27, 120.09, 127.01, 128.30, 129.09, 135.90 and
138.36. One drop of pyridine was added to a benzene solution
(15 cm3 ) of the hydroperoxide 4d (312 mg, 1.50 mmol) and
phenyl isocyanate (357 mg, 3.00 mmol) and the mixture was
stirred at room temp. for 15 h. The reaction mixture was
then poured into water and extracted with diethyl ether. After
the extract had been dried and concentrated, the products were
separated by column chromatography on silica gel. Elution
with diethyl ether–hexane (1:9) gave 3-methylbut-3-enyl ben-
zoate 5d, an oil (Found: C, 75.5; H, 7.5. C12H14O2 requires C,
75.8; H, 7.4%); δH 1.76 (3 H, s), 1.78 (3 H, s), 4.81 (2 H, d, J 6.3),
5.47 (1 H, t, J 6.3), 7.3–7.5 (3 H, m) and 8.04 (2 H, d, J 16.5); δC
18.10, 25.80, 61.85, 118.69, 128.28, 129.58, 130.46, 132.79,
139.12 and 166.63.
Perhaps in accordance with this, I2/KOBut-mediated cyclis-
ation, which is most likely to proceed via the iodonium ion
intermediate 8e,5 gave mainly two stereoisomeric 1,2,4-
trioxepanes 10e,eЈ (36%) together with two isomeric trioxanes
9e,eЈ (13%) (Scheme 8). It should be noticed that the reaction
O
O
O
NIS
C7H15
I
9e
O
C7H15
OOH
4e
O
O
O
C7H15
+
9e,e'
I2/KOBut
I
10e,e'
Scheme 8
with NIS resulted in exclusive formation of the 1,2,4-trioxane
9e, suggesting that a minor change in the reaction conditions
may affect significantly the reaction course, and thus lead to a
change in the product composition.
1-(3-Methylbut-2-enyloxy)octyl hydroperoxide 4e. Oil (Found:
C, 67.7; H, 11.3. C13H26O3 requires C, 67.8; H, 11.4%); δH 0.88
(3 H, t, J 6.3), 1.2–1.6 (12 H, m), 1.69 (3 H, s), 1.76 (3 H, s), 4.1–
4.3 (2 H, m), 4.84 (1 H, t, J 5.8), 5.37 (1 H, t, J 6.4) and 9.17 (1
H, s); δC 17.74, 22.43, 24.51, 25.52, 28.97, 29.13, 31.57, 31.60,
65.02, 106.54, 120.40 and 137.38.
1-(3-Methylbut-2-enyloxy)cyclohexyl hydroperoxide 4f. Oil
(Found: C, 65.2; H, 10.0. C11H20O3 requires C, 65.9; H, 10.1%);
δH 1.2–1.6 (10 H, m), 1.61 (3 H, s), 1.66 (3 H, s), 3.99 (2 H, d, J
5.8), 5.31 (1 H, t, J 5.8) and 8.77 (s, 1 H); δC 17.27, 22.19, 24.97,
25.14, 56.79, 104.70, 121.10 and 135.57.
Experimental
General
1H (270 MHz) and 13C NMR (67.5 MHz) spectra were obtained
in CDCl3 with SiMe4 as standard; J values are given in Hz. The
method of ozonolysis has been described earlier.9 1-Phenyl-2-
methoxyethene 1a, 1-methoxynon-1-ene 1b, and methoxymeth-
ylenecyclohexane 1c were prepared by a reported method.10
á-(3-Methylbut-3-enyloxy)benzyl hydroperoxide 4g. Oil
(Found: C, 69.4; H, 7.8. C12H16O3 requires C, 69.2; H, 7.7%); δH
1.79 (3 H, s), 2.42 (2 H, t, J 6.6), 3.7–3.8 (1 H, m), 3.9–4.0 (1 H,
m), 4.86 (2 H, t, J 6.9), 5.83 (1 H, s), 7.2–7.5 (5 H, m) and 8.59 (1
H, s); δC 22.59, 37.81, 66.87, 106.42, 112.13, 126.90, 128.28,
129.11, 135.62 and 143.00.
1-(3-Methylbut-3-enyloxy)cyclohexyl hydroperoxide 4h. Oil
(Found: C, 66.4; H, 10.3. C11H20O3 requires C, 66.0; H, 10.1%);
δH 1.3–1.8 (10 H, m), 1.81 (3 H, s), 2.31 (2 H, t, J 6.4), 3.63 (2 H,
t, J 6.4), 4.85 (2 H, s) and 8.20 (1 H, s); δC 22.55, 22.73, 25.29,
31.36, 37.86, 58.76, 105.34, 111.90 and 144.26.
1-(But-2-enyloxy)cyclohexyl hydroperoxide 4i. Oil (Found: C,
64.5; H, 9.6. C10H18O3 requires C, 64.5; H, 9.7%); δH 1.2–2.0 (10
H, m), 1.72 (3 H, d, J 6.1), 4.00 (2 H, d, J 6.3), 5.6–5.9 (2 H, m)
and 8.80 (1 H, s); δC 17.68, 22.57, 25.30, 31.50, 61.35, 105.54,
127.75 and 129.18.
Caution
Since organic peroxides are potentially hazardous compounds,
they must be handled with due care; avoid exposure to strong
heat or light, or mechanical shock, or oxidizable organic
materials, or transition metal ions. No particular difficulties
were experienced in handling any of the new peroxides syn-
thesised in this work using the reaction scales and procedures
described below together with the safeguards mentioned above.
Ozonolysis of a vinyl ether in the presence of an unsaturated
alcohol
Ozonolysis of 1-phenyl-2-methoxyethene 1a in the presence of
2-methylprop-2-en-1-ol 3a is representative. A slow stream of
ozone (3.20 mmol) was passed through a CH2Cl2 solution (15
cm3 ) of the vinyl ether 1a (430 mg, 3.20 mmol) and 2-
methylprop-2-en-1-ol 3a (2 cm3, 30 mmol) at Ϫ70 ЊC. After
adding diethyl ether (70 cm3 ) to the reaction mixture, the
organic layer was separated, washed with ice-cold aqueous
potassium dihydrogen phosphate and saturated brine, dried
(MgSO4 ) and the solvent was evaporated under reduced pres-
sure. The residue was separated by column chromatography on
silica gel. Elution with diethyl ether–hexane (1:4) gave the
hydroperoxide 4a (293 mg, 47%).
Reaction of the hydroperoxides 4a–c with N-halogenosuccinimide
Reaction of the hydroperoxide 4a with NBS is representative.
To a CH2Cl2 solution (15 cm3 ) of the hydroperoxide 4a (380
mg, 2.0 mmol) was added NBS (697 mg, 4.0 mmol) and then
NaHCO3 (165 mg, 2.0 mmol). The mixture was stirred at room
temp. in a flask covered by aluminum foil for 15 h and then
diluted with hexane (30 cm3 ). The precipitated succinimide was
filtered off, washed with hexane (3 × 5 cm3 ) and the combined
filtrate and washings were concentrated by rotary evaporator to
leave an oily residue. This was separated by column chroma-
tography on silica gel. Elution with diethyl ether–hexane (95:5)
á-(2-Methylprop-2-enyloxy)benzyl hydroperoxide 4a. Oil
(Found: C, 68.4; H, 7.2. C11H14O3 requires C, 68.0; H, 7.3%); δH
1.94 (3 H, s), 4.37 (1 H, d, J 12.9), 4.49 (1 H, d, J 12.9), 5.12 (1 H,
s), 5.25 (1 H, s), 6.05 (1 H, s), 7.5–7.7 (5 H, m) and 9.46 (1 H, s);
8
J. Chem. Soc., Perkin Trans. 1, 1997

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gave the trioxane 6a (196 mg, 36%) whilst a subsequent elution
with diethyl ether–hexane (30:70) gave an unidentified polar
product as an oil (52 mg); δH 1.3–1.9 (m), 3.5–4.8 (m), 5.3–5.4
(m), 5.9–6.4 (m) and 7.3–7.7 (m), the ratio of the peak areas
being 4:6:2:1:10; δC 33.14, 68.57, 105.91, 117.59 and 126.9–
130.0; νmax/cmϪ1 3400, 3050, 2950, 1710, 1495, 1450, 1280, 1090,
755 and 700; m/z (CI) 339 (1%), 337 (4), 335 (2), 293 (2), 291 (8),
289 (7), 275 (10), 273 (11), 257 (80), 255 (80), 175 (95) and 105
(100). Elution with diethyl ether–hexane (40:60) then gave a
different unidentified product (67 mg) as an oil (Found: C, 48.5;
H, 4.7; Br, 29.3. C11H13BrO3 requires C, 48.4; H, 4.8; Br, 29.3%);
δH 1.46 (3 H, s), 3.58 (2 H, dd, J 10.6 and 15.2), 4.39 (2 H, dd,
11.6 and 15.5), 7.45 (1 H, br s), 7.5–7.7 (3 H, m) and 8.05 (2 H,
d, J 6.9); δC 23.13, 40.52, 68.90, 71.03, 128.52, 129.67, 133.39
and 166.31; νmax/cmϪ1 3470, 2950, 1720 and 1295; m/z (CI) 275
(37), 273 (37), 257 (100) and 255 (100).
6-Bromomethyl-6-methyl-3-phenyl-1,2,4-trioxane 6a. Mp 50–
52 ЊC (from ethyl acetate–hexane) (Found: C, 48.3; H, 4.8; Br,
29.1. C11H13BrO3 requires C, 48.4; H, 4.8; Br, 29.3%); δH 1.28 (3
H, s), 3.84 (1 H, d, J 10.2), 3.87 (1 H, d, J 11.4), 4.07 (1 H, d, J
10.2), 4.35 (1 H, d, J 11.4 Hz), 6.08 (1 H, s) and 7.3–7.5 (5 H,
m); δC 19.89, 34.61, 69.74, 78.49, 104.00, 126.92, 128.50, 130.15
and 133.69.
6-Bromomethyl-6-methyl-3-heptyl-1,2,4-trioxane 6b. Oil
(Found: C, 49.3; H, 8.0. C12H23BrO3 requires C, 48.8; H, 8.0%);
δH 0.8–1.8 (18 H, m), 3.65 (1 H, d, J 11.9), 3.77 (1 H, d, J 10.4),
3.91 (1 H, d, J 10.4), 4.11 (1 H, d, J 11.9) and 5.10 (1 H, t, J 5.4);
δC 14.04, 19.75, 22.55, 23.56, 28.99, 29.24, 31.63, 31.77, 34.72,
69.20, 78.17 and 104.57.
6-Iodomethyl-6-methyl-3-phenyl-1,2,4-trioxane 6c. Mp 84 ЊC
(from ethyl acetate–hexane) (Found: C, 41.3; H, 4.0; I, 39.7.
C11H13IO3 requires C, 41.3; H, 4.1; I, 39.6%); δH 1.29 (3 H, s),
3.84 (2 H, s), 3.95 (1 H, d, J 11.9), 4.35 (1 H, d, J 11.9), 6.05 (1
H, s) and 7.3–7.5 (5 H, m); δC 9.89, 21.64, 69.79, 77.68, 103.90,
126.86, 128.45, 130.10 and 133.59.
Reaction of the hydroperoxides 4d–f with N-halogenosuccinimide
Reaction of the hydroperoxide 4d with NBS is representative. A
mixture of the hydroperoxide 4d (610 mg, 2.93 mmol), NBS
(1044 mg, 5.86 mmol) and NaHCO3 (246 mg, 2.93 mmol) in
CH2Cl2 (20 cm3 ) was stirred at room temp. for 15 h. Work-up as
described above gave the crude products which were separated
by column chromatography on silica gel. Elution with benzene–
hexane (1:4) gave the trioxane 9a (115 mg, 14%). Subsequent
elution with benzene–hexane (3:7) gave the 1,2,4-trioxepane
10a (115 mg, 14%).
6-(1-Bromo-1-methylethyl)-3-phenyl-1,2,4-trioxane 9a. Oil
(Found: C, 50.2; H, 5.4. C12H15BrO3 requires C, 50.2; H, 5.3%);
δH 1.44 (3 H, s), 1.46 (3 H, s), 4.2–4.4 (3 H, m), 5.98 (1 H, s) and
7.2–7.5 (5 H, m); δC 25.07, 55.96, 69.49, 85.01, 105.64, 126.72,
128.32, 129.38 and 135.10.
6-Bromo-7,7-dimethyl-3-phenyl-1,2,4-trioxepane 10a. Oil
(Found: C, 49.9; H, 5.3. C12H15BrO3 requires C, 50.2; H, 5.3%);
δH 1.42 (3 H, s), 1.53 (3 H, s), 4.0–4.3 (3 H, m), 6.20 (1 H, s) and
7.2–7.5 (5 H, m); δC 21.10, 25.25, 56.53, 64.94, 84.44, 103.27,
126.45, 128.54, 129.29 and 134.99.
6-(1-Bromo-1-methylethyl)-3-heptyl-1,2,4-trioxane 9b. Oil
(Found: C, 50.2; H, 8.1; Br, 25.7. C13H25BrO3 requires C, 50.5;
H, 8.1; Br, 25.8%); δH 0.87 (3 H, t, J 6.6), 1.2–1.8 (12 H, m), 1.37
(3 H, s), 1.44 (3 H, s), 4.0–4.1 (3 H, m) and 4.97 (1 H, t, J 5.6); δC
14.07, 22.10, 22.59, 24.35, 25.03, 29.08, 29.27, 31.07, 32.11,
56.10, 69.15, 84.60 and 106.88.
6-Bromo-7,7-dimethyl-3-heptyl-1,2,4-trioxepane 10b. Oil
(Found: C, 50.5; H, 8.2; Br, 25.7. C13H25BrO3 requires C, 50.5;
H, 8.1; Br, 25.8%); δH 0.88 (3 H, t, J 6.4), 1.2–1.6 (12 H, m), 1.35
(3 H, s), 1.52 (3 H, s), 3.8–4.1 (3 H, m) and 5.17 (1 H, t, J 5.6); δC
14.07, 20.83, 22.59, 24.46, 25.23, 29.06, 29.26, 30.95, 31.68,
56.71, 63.76, 83.99 and 104.39.
9,9-Dimethyl-10-bromo-7,8,12-trioxaspiro[5.6]dodecane 10c.
Oil (Found: C, 47.65; H, 7.0. C11H19BrO3 requires C, 47.3; H,
6.9%); δH 1.2–1.7 (10 H, m), 1.33 (3 H, s), 1.52 (3 H, s) and 3.7–
4.0 (3 H, m); δC 19.66 (CH3 ), 22.54, 22.91, 25.20, 25.25 (CH3 ),
33.11, 33.61, 55.89 (CHBr), 63.51 (OCH2 ), 83.27 (COO) and
105.27 (OCOO).
6-(1-Iodo-1-methylethyl)-3-phenyl-1,2,4-trioxane 9d. Oil
(Found: C, 43.4; H, 4.5. C12H15IO3 requires C, 43.1; H, 4.5%);
δH 2.20 (3 H, s), 2.31 (3 H, s), 4.27 (1 H, d, J 4.5), 4.35 (1 H, dd,
J 11.9 and 4.5), 4.82 (1 H, d, J 11.9), 6.15 (1 H, s) and 7.3–7.5 (5
H, m); δC 35.55 (CH3 ), 36.08 (CH3 ), 52.08 (CHI), 64.04
(OCH2 ), 84.91 (OOCH), 103.81 (OCHOO), 127.03, 128.46,
129.94 and 134.21.
3-Heptyl-6-(1-iodo-1-methylethyl)-1,2,4-trioxane 9e. Oil
(Found: C, 44.0; H, 7.1; I, 35.0. C13H25IO3 requires C, 43.8; H,
7.1; I, 35.6%); δH 0.87 (3 H, t, J 6.4), 1.2–1.9 (12 H, m), 1.95 (3
H, s), 1.96 (3 H, s), 3.7–4.3 (3 H, m) and 5.18 (1 H, t, J 5.2); δC
14.07 (CH3 ), 22.61, 23.74, 29.02, 29.29, 31.65, 34.05 (CH3 ),
34.38 (CH3 ), 39.97 (CI), 68.38 (OCH2 ), 85.70 (OOCH) and
104.42 (OCHOO).
3-Heptyl-6-iodomethyl-6-methyl-1,2,4-trioxane
6d.
Oil
(Found: C, 42.2; H, 6.9. C12H23IO3 requires C, 42.1; H, 6.9%);
δH 0.87 (3 H, t, J 6.4), 1.19 (3 H, s), 1.2–1.8 (12 H, m), 3.68 (1 H,
d, J 10.1), 3.72 (1 H, d, J 11.9), 3.76 (1 H, d, J 10.1), 4.12 (1 H,
d, J 11.9) and 5.08 (1 H, t, J 5.1); δC 10.19, 14.05, 21.58, 22.55,
23.56, 29.00, 29.26, 31.65, 31.77, 69.31, 76.39 and 104.57.
Reaction of the hydroperoxides 4g,h with N-halogeno-
succinimide
Reaction of the hydroperoxide 4g with NBS is representative. A
mixture of the hydroperoxide 4g (447 mg, 2.15 mmol), NBS
(767 mg, 4.30 mmol) and NaHCO3 (181 mg, 2.15 mmol) in
CH2Cl2 (20 cm3 ) was stirred at room temp. for 15 h. Work-up as
described above gave the crude products which were separated
by column chromatography on silica gel. Elution with benzene–
hexane (3:7) gave the trioxepane 7a (109 mg, 18%).
7-Bromomethyl-7-methyl-3-phenyl-1,2,4-trioxepane 7a. Oil (a
3:2 mixture of two isomers) (Found: C, 50.5; H, 5.1.
C12H15BrO3 requires C, 50.2; H, 5.2%); δH 1.30 (1.8 H, s), 1.46
(1.2 H, s), 2.0–2.5 (2 H, m), 3.41 (1.2 H, s), 3.52 (0.4 H, d, J
10.6), 3.65 (0.4 H, d, J 10.6), 4.0–4.2 (2 H, m), 6.04 (0.4 H, s),
6.08 (0.6 H, s) and 7.2–7.5 (5 H, m); δC 22.19, 24.71, 37.06,
39.37, 41.03, 41.39, 64.91, 65.05, 83.27, 83.92, 106.94, 107.71,
126.70, 128.23, 129.18, 129.36, 134.77 and 135.29.
9-Bromomethyl-9-methyl-7,8,12-trioxaspiro[5.6]dodecane 7b.
Oil (Found: C, 46.9; H, 6.7. C11H19BrO3 requires C, 47.3; H,
6.9%); δH 1.26 (3 H, s), 1.3–2.2 (12 H, m) and 3.6–4.0 (4 H, m);
δC 22.54, 22.93, 23.56 (CH3 ), 25.36, 32.24, 32.40, 37.61, 40.27,
58.40 (OCH2 ), 82.50 (OOC) and 106.54 (OCOO).
9-Iodomethyl-9-methyl-7,8,12-trioxaspiro[5.6]dodecane7c. Oil
(Found: C, 40.9; H, 6.0. C11H19IO3 requires C, 40.5; H, 5.9%);
δH 1.27 (3 H, s), 1.4–2.2 (12 H, m), 3.49 (1 H, d, J 10.2), 3.62 (1
H, d, J 10.2) and 3.7–3.9 (2 H, m); δC 13.46, 22.55, 22.95, 25.38,
25.47 (CH3 ), 32.24, 32.46, 40.52, 58.53 (OCH2 ), 81.71 (OOC)
and 106.47 (OCOO).
3-(1-Iodo-1-methylethyl)-1,2,5-trioxaspiro[5.5]undecane 9f.
Mp 63 ЊC (from ethyl acetate–hexane) (Found: C, 40.5; H, 5.8;
I, 38.8. C11H19IO3 requires C, 40.5; H, 5.9; I, 38.9%); δH 1.4–2.2
(10 H, m), 1.98 (3 H, s), 2.05 (3 H, s), 3.58 (1 H, dd, J 3.4 and
9.7), 3.97 (1 H, dd, J 11.6 and 3.4) and 4.07 (1 H, dd, J 11.6 and
9.7); δC 22.23, 25.39, 29.54, 34.05 (CH3 ), 34.27 (CH3 ), 41.48
(CI), 61.83 (OCH2 ), 85.32 (OOCH) and 102.50 (OCOO).
9,9-Dimethyl-10-iodo-7,8,12-trioxaspiro[5.6]dodecane 10f. Oil
(Found: C, 40.7; H, 5.7. C11H19IO3 requires C, 40.5; H, 5.9%);
δH 1.3–1.7 (10 H, m), 1.31 (3 H, s), 1.55 (3 H, s) and 3.8–4.0 (3
H, m); δC 21.89 (CH3 ), 22.57, 22.95, 25.21, 26.04 (CH3 ), 31.20,
33.77, 38.10 (CHI), 65.64 (OCH2 ), 83.36 (OOC) and 105.89
(OCOO).
Reaction of the hydroperoxide 4i with N-halogenosuccinimide
The reaction of the hydroperoxide 4i with NIS is representative.
A mixture of the hydroperoxide 4i (372 mg, 2.00 mmol), NIS
(900 mg, 4.00 mmol) and NaHCO3 (168 mg, 2.00 mmol) in
J. Chem. Soc., Perkin Trans. 1, 1997
9

View Article Online
CH2Cl2 (20 cm3 ) was stirred at room temp. for 15 h. Work-up as
described above gave the crude products which were separated
by column chromatography on silica gel. Elution with diethyl
ether–hexane (3:97) gave the trioxepane 15b (64 mg, 10%, sin-
gle isomer). The second fraction (elution with diethyl ether–
hexane, 1:9) gave the 1,2,4-trioxane 14b (63 mg, 10%, a mixture
of two stereoisomers). The structures of the trioxane 14a,b and
the trioxepane 15a,b were determined by comparison of the 1H
and 13C NMR spectra with those of the relevant trioxane 9f and
the trioxepane 10f; (i) in the 13C NMR spectra only three signals
were observed for the highly symmetrical cyclohexane ring of
the trioxane 14a,b, while in the case of the trioxepane 15a,b six
signals were observed, and (ii) in the 1H NMR spectra the
methyl signal of the trioxepane 15b responded at a relatively
higher field.
3-(1-Bromoethyl)-1,2,5-trioxaspiro[5.5]undecane 14a. Oil
(Found: C, 45.5; H, 6.4. C10H17BrO3 requires C, 45.3; H, 6.5%);
δH 1.2–1.9 (10 H, m), 1.91 (3 H, d, J 6.6), 3.91 (1 H, dd, J 10.9
and 3.3), 4.12 (1 H, dd, J 10.9 and 4.0), 4.31 (1 H, ddd, J 4.0,
3.3 and 9.0) and 4.55 (1 H, qd, J 6.6 and 9.0); δC 22.52, 25.30,
31.25, 31.34, 48.56, 58.44, 63.61 and 105.72.
10-Bromo-9-methyl-7,8,12-trioxaspiro[5.6]dodecane 15a. Oil
(Found: C, 45.8; H, 6.65); δH 1.2–1.8 (10 H, m), 1.35 (3 H, d, J
6.6), 3.63 (1 H, ddd, J 10.1, 10.6 and 4.0), 3.87 (1 H, dd, J 12.2
and 4.0), 4.01 (1 H, dd, J 10.6 and 12.2) and 4.22 (1 H, qd, J 6.6
and 9.9); δC 16.73, 22.54, 22.86, 25.18, 31.00, 33.44, 52.42,
64.87, 83.94 and 106.02.
3-(1-Iodoethyl)-1,2,5-trioxaspiro[5.5]undecane 14b. Oil (a ca.
2:1 mixture of two stereoisomers) (Found: C, 38.7; H, 5.6.
C10H17IO3 requires C, 38.5; H, 5.5%); δH 1.2–1.8 (10 H, m), 1.91
(0.9 H, d, J 6.3), 1.95 (2.1, H, d, J 6.3) and 3.8–4.2 (4 H, m); δC
17.39, 18.03, 22.21, 23.88, 24.23, 25.39, 29.92, 60.99, 67.80,
81.65, 81.92, 101.46 and 102.86.
10-Iodo-9-methyl-7,8,12-trioxaspiro[5.6]dodecane 15b. Mp
27–29 ЊC (Found: C, 38.6; H, 5.4); δH 1.3–1.8 (10 H, m), 1.42 (3
H, d, J 6.3), 3.79 (1 H, ddd, J 11.1, 10.6 and 3.9), 3.94 (1 H, dd,
J 12.2 and 3.9), 4.05 (1 H, dd, J 12.2 and 11.1) and 4.33 (1 H,
qd, J 6.3 and 10.6); δC 17.52, 22.52, 22.86, 25.20, 31.07, 33.61,
34.70, 66.74, 85.09 and 106.11.
and 10eЈ, by repeated column chromatography on silica gel
failed. Only the decomposition of a significant amount of the
peroxides was observed. A similar trend was observed for the
mixture of two peroxides, 9e and 10e.
7,7-Dimethyl-3-heptyl-6-iodo-1,2,4-trioxepane 10eЈ. This
compound was mixed with 30% of the trioxane 9eЈ. Oil (Found:
C, 43.4; H, 7.0. C13H25IO3 requires C, 43.8; H, 7.1%); δH 0.87 (3
H, t, J 6.9), 1.2–1.7 (12 H, m), 1.46 (3 H, s), 1.49 (3 H, s), 4.10 (1
H, dd, J 9.6 and 12.2), 4.18 (1 H, dd, J 2.3 and 12.2), 4.26 (1 H,
dd, J 2.3 and 9.6) and 4.96 (1 H, t, J 5.6); δC 14.07, (CH3 ), 22.61,
24.37, 25.14 (CH3 ), 25.30 (CH3 ), 29.09, 29.27, 31.70, 32.26,
36.84 (CHI), 71.38 (CH2O), 84.69 (COO) and 106.90 (OCOO).
3-Heptyl-6-(1-iodo-1-methylethyl)-1,2,4-trioxane 9eЈ. This
compound was mixted with 70% of 10eЈ; only the characteristic
signals in the NMR spectra are shown; δH 0.89 (3 H, t, J 6.3),
2.17 (3 H, s), 2.22 (3 H, s), 4.0–4.2 (2 H, m), 4.62 (1 H, dd, J 2.6
and 10.9) and 5.19 (1 H, t, J 5.3); δC 35.62 (CH3 ), 36.12 (CH3 ),
63.45 (CH2O), 84.91 (COO) and 103.95 (OCOO).
7,7-Dimethyl-3-heptyl-6-iodo-1,2,4-trioxepane 10e. This com-
pound was mixted with 20% of the trioxane 9e. Oil (Found: C,
43.5; H, 7.0); δH 0.88 (3 H, t, J 6.9), 1.2–1.6 (12 H, m), 1.39 (3 H,
s), 1.61 (3 H, s), 3.96 (1 H, dd, J 2.0 and 10.9), 4.0–4.1 (2 H, m)
and 5.19 (1 H, t, J 5.9); δC 14.07 (CH3 ), 22.57, 23.25 (CH3 ),
24.46, 25.77 (CH3 ), 29.04, 29.26, 30.98, 31.66, 38.60 (CHI),
65.70 (CH2O), 83.90 (COO) and 104.39 (OCOO).
References
1 D. A. Casteel, Nat. Prod. Rep., 1992, 289.
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and M. Nojima in Organic Peroxides, ed. W. Ando, Wiley, New
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7 E. Breitmaier and W. Voelter, Carbon-13 NMR Spectroscopy, VCH,
Weinheim, 1987.
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York, 1992, ch. 2; (b) C. Thebtaranonth and Y. Thebtaranonth,
Cyclization Reactions, CRC Press, Boca Raton, 1994.
9 K. J. McCullough, N. Nakamura, T. Fujisaka, M. Nojima and
S. Kusabayashi, J. Am. Chem. Soc., 1991, 113, 1786.
Reaction of the hydroperoxide 4e with I2/KOBut
To a benzene solution (20 cm3 ) of the hydroperoxide 4e (455
mg, 1.98 mmol), KOBut (222 mg, 1.98 mmol) and 18-crown-6
(523 mg, 1.98 mmol), was added I2 (1005 mg, 3.96 mmol) dur-
ing 5 min at 0 ЊC. The mixture was then stirred at room temp.
for 12 h after which it was diluted with diethyl ether (70 cm3).
The organic layer was separated, washed with aqueous
NaHSO3 and saturated brine, dried (MgSO4 ) and the solvent
was evaporated under reduced pressure. The residue was separ-
ated by column chromatography on silica gel. Elution with
benzene–hexane (15:85) gave a 7:3 mixture of the trioxepane
10eЈ and the trioxane 9eЈ (160 mg, 27%). Subsequent elution
with benzene–hexane (1:4) gave a mixture of the diastereo-
isomeric trioxepane 10e and trioxane 9e (153 mg, 22%,
10e:9e = 4:1). An attempt to separate the cyclic peroxides, 9eЈ
10 K. Griesbaum, W.-S. Kim, N. Nakamura, M. Mori, M. Nojima and
S. Kusabayashi, J. Org. Chem., 1990, 55, 6153.
Paper 6/05616D
Received 12th August 1996
Accepted 6th September 1996
10
J. Chem. Soc., Perkin Trans. 1, 1997