Synthesis of hydroxy(or hydroperoxy)-substituted 1,2,4- trioxacycloalkanes by the ozonolysis of unsaturated hydroperoxy acetals

Article abstract of DOI:10.1021/jo970555l

Ozonolyses of unsaturated hydroperoxy acetals 4a-k gave in each case the mixtures of products containing the corresponding trioxanes 8a-f and 12e,f, trioxepanes 12g-i, trioxocane 12j, and trioxonane 12k. By choosing the proper conditions of the ozonolysis, the desired cyclic peroxide was selectively obtained in moderate to good yield. Alternatively, acid-catalyzed cyclization of the methanol-derived ozonolysis products 13h and 13j provided the corresponding trioxepane 12h and trioxocane 12j, respectively.

Full text of DOI:10.1021/jo970555l

J . Org. Chem. 1997, 62, 4949-4954
4949
Syn th esis of Hyd r oxy(or Hyd r op er oxy)-Su bstitu ted
1,2,4-Tr ioxa cycloa lk a n es by th e Ozon olysis of Un sa tu r a ted
Hyd r op er oxy Aceta ls
Yoshihiro Ushigoe, Yuko Torao, Araki Masuyama, and Masatomo Nojima*
Department of Materials Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565, J apan
Received March 25, 1997X
Ozonolyses of unsaturated hydroperoxy acetals 4a -k gave in each case the mixtures of products
containing the corresponding trioxanes 8a -f and 12e,f, trioxepanes 12g-i, trioxocane 12j, and
trioxonane 12k . By choosing the proper conditions of the ozonolysis, the desired cyclic peroxide
was selectively obtained in moderate to good yield. Alternatively, acid-catalyzed cyclization of the
methanol-derived ozonolysis products 13h and 13j provided the corresponding trioxepane 12h
and trioxocane 12j, respectively.
Sch em e 1
The discovery of pharmacologically active six- and
seven-membered-ring peroxides has given a renewed
interest in the development of new synthetic methods of
such structures.1 Because of the potential ease of modi-
fication, functionalized trioxanes and trioxepanes would
be very attractive.2 In this respect, Dussault3 and our
group4 independently discovered that electrophilic cy-
clization of unsaturated hydroperoxy acetals, derived
from capture of carbonyl oxide with unsaturated alcohol,
would be promising. Thus, a variety of halo-substituted
1,2,4-trioxanes and 1,2,4-trioxepanes have been prepared
by I2- or N-halosuccinimide-mediated cyclization. During
our continuing search for efficient transformation of
unsaturated hydroperoxy acetals to cyclic peroxides, we
have found that the ozonolysis is convenient for the
synthesis of not only 1,2,4-trioxanes and 1,2,4-triox-
epanes but also novel 1,2,4-trioxocanes and 1,2,4-trioxo-
nanes in which a hydroxy or hydroperoxy group is
directly attached to the ring.
Resu lts a n d Discu ssion
P r ep a r a tion of Un sa tu r a ted Hyd r op er oxy Ac-
eta ls. We previously reported that trapping of carbonyl
oxides with primary unsaturated allylic or homoallylic
alcohols proceeds well to give the corresponding unsatur-
ated hydroperoxy acetals 4d -h in good yields.4 To obtain
an information for the structural effect of allylic alcohols
on the efficiency, we conducted ozonolyses of â-methoxy-
styrene (1a ) in the presence of a series of allylic alcohols
X Abstract published in Advance ACS Abstracts, J uly 15, 1997.
(1) (a) Casteel, D. A. Nat. Prod. Rep. 1992, 289. (b) Posner, G. H.;
Cumming, J . N. Ploypradith, P.; Chang, H. O. J . Am. Chem. Soc. 1995,
117, 5885. (c) Posner, G. H.; Tao, X.; Cumming, J . N.; Klinedinst, D.;
Shapiro, T. A. Tetrahedron Lett. 1996, 37, 722.
3a -c (3 equiv) in CH2Cl2 at -70 °C (Scheme 1). The
yields of hydroperoxides decreased in the order 4a (51%)
> 4b (43%) > 4c (13%), suggesting that the steric bulk
of the alcohols affects remarkably the efficiency. As
potent precursors of medium-sized cyclic peroxides, hy-
droperoxides 4i-k were also prepared in moderate yields
(Scheme 1).
(2) (a) J efford, C. W.; McGoran, E. C.; Boukouvalas, J .; Richardson,
G.; Robinson, B.; Peters, W. Helv. Chim. Acta 1988, 71, 1805. (b)
Bloodworth, A. J .; J ohnson, K. A.Tetrahedron Lett. 1994, 35, 8057. (c)
Bloodworth, A. J .; Hagen, T.; J ohnson, K. A.; LeNoir, I.; Mousay, C.
Tetrahedron Lett. 1997, 38, 635. For the synthesis of 1,2,4-trioxanes,
see: (a) Bunnelle, W. H.; Isbell, T. A.; Barnes, C. L.; Qualls, S. J . Am.
Chem. Soc. 1991, 113, 8168. (b) Bloodworh, A. J .; Tallant, N. A. J .
Chem. Soc., Chem. Commun. 1992, 428. (c) Fujisaka, T.; Miura, M.;
Nojima, M.; Kusabayashi, S. J . Chem. Soc., Perkin Trans. 1 1989, 1031.
(d) Zhou, W.-S.; Xu, X.-X. Acc. Chem. Res. 1994, 27, 211 and the
references therein. For the synthesis of trioxepane, see: (a) Adam,
W.; Duran, N. J . Chem. Soc., Chem. Commun. 1972, 798.
(3) (a) Dussault, P. H.; Davies, D. R. Tetrahedron Lett. 1996, 37,
463. (b) Dussault, P. H.; Lee, H.-J .; Niu, Q. J . J . Org. Chem. 1995,
60, 784.
Syn th esis of 1,2,4-Tr ioxa n es. With unsaturated
hydroperoxy acetals 4a -f in hand, we then conducted
the ozonolyses under several conditions. Treatment of
4a with ozone in MeOH-ether at -78 °C gave the
expected 6-hydroxy-1,2,4-trioxane 8a almost quantita-
tively (Scheme 2). Moreover, it was obtained as a single
isomer.
(4) Ushigoe, Y.; Kano, Y.; Nojima, M. J . Chem. Soc., Perkin Trans.
1 1997, 5.
S0022-3263(97)00555-0 CCC: $14.00 © 1997 American Chemical Society

4950 J . Org. Chem., Vol. 62, No. 15, 1997
Ushigoe et al.
Sch em e 2
Sch em e 3
of the exo-anomeric effect. The same trend holds for
3-methoxy-6-hydroxy-1,2-dioxane.6a Trioxane 8a was,
however, labile on silica gel, and during column chroma-
tography equilibration between two stereoisomers oc-
curred very easily. Thus, although no indication of
decomposition of 8a was observed, elution of trans-8a
with CH2Cl2 gave a 3:1 mixture of cis- and trans-8a . In
marked contrast, elution of the 3:1 mixture of cis- and
trans-8a with ether resulted in the isolation of a 1:2
mixture of cis- and trans-8a . This may imply that the
relative stability is very similar between trans- and cis-
8a and, moreover, the ratio in equilibrium is solvent
dependent. Exactly the same trends were observed for
the ozonolysis of 4c and the behavior of the derived
product 8c. The 1H NMR spectrum of trioxane 8b
showed that it exists as a mixture of three isomer. In
connection with facile production of 8a -c from 4a -c,
DeNinno7 has found that ozonolyses of cyclic allylic
alcohols give labile bicyclic peroxides containing a 6-hy-
droxy-substituted 1,2,4-trioxane structure.
A plausible mechanism for the formation of trioxane
8a is illustrated in Scheme 2. Reflecting the directive
effect of alkoxymethyl group,8 cleavage of primary ozo-
nide 5a is highly selective, yielding exclusively formal-
dehyde oxide 7 and ω-oxo hydroperoxide 6a . In methanol
7 is transformed into water-soluble hydroperoxide 9.
Thus, after workup with water, only trioxane 8a is left
in the organic layer. Efficient production of 8a implies
that intramolecular hemiperacetalization of ω-oxo hy-
droperoxide 6a leading to trioxane 8a is a rapid process.6
Reaction of 4d with ozone in MeOH-ether gave
trioxane 8d in the isolated yield of 81%. When the same
reaction was repeated in CH2Cl2, the corresponding
ozonide 10d was obtained in 18% yield, together with 8d
(56%) (Scheme 3), suggesting that the intramolecular
cyclization of keto hydroperoxide 6d is significantly faster
than the intermolecular cycloaddition with acetone O-
oxide.
F igu r e 1. NOE of 6-hydroxy-1,2,4-trioxanes 8a ,c,e.
To confirm the structure, the NOE was measured
(Figure 1). The data clearly demonstrated that the
isolated trioxane was trans-8a with the hydroxy group
Treatment of hydroperoxy acetal 4f with ozone in
CH2Cl2 gave a mixture of 6-hydroxy-1,2,4-trioxane 8f
(38%) and 6-hydroperoxy-1,2,4-trioxane 12f (24%) (Scheme
4). In the reaction in ether, however, the corresponding
1
occupying an equatorial position. The H coupling con-
stants also supported the assigned stereochemistry of 8a .
This is in marked contrast to the fact that, in the case of
trans-3,6-dimethoxy-1,2,4,5-tetroxane,5 both of the meth-
oxy groups have been found to occupy the axial positions;
this novel stereochemistry has been rationalized in terms
(6) (a) Pierrot, M.; El Idrissi, M.; Santelli, M. Tetrahedron Lett. 1989,
30, 461. (b) Voss. T.; Prinzbach, H. Tetrahedron Lett. 1994, 35, 1535.
(7) DeNinno, M. P. J . Am. Chem. Soc. 1995, 117, 9927.
(8) (a) Bunnelle, W. H.; Isbell, T. A. J . Org. Chem. 1992, 57, 729.
(b) Hayes, H.; Wallace, T. W. Tetrahedron Lett. 1990, 31, 3355. (c)
Arjona, O.; Martin-Domenech, A.; Plumet, J . J . Org. Chem. 1993, 58,
7929. (d) Kawamura, S.; Yamakoshi, H.; Nojima, M. J . Org. Chem.
1996, 61, 5953.
(5) Chiang, C.-Y.; Butler, W.; Kuczkowski, R. L. J . Chem. Soc.,
Chem. Commun. 1988, 465.

Synthesis of OOH-Substituted Trioxacycloalkanes
J . Org. Chem., Vol. 62, No. 15, 1997 4951
Sch em e 4
Sch em e 5
lecular cyclization of carbonyl oxide intermediate 11h or
not, we then conducted ozonolysis of hydroperoxide 4h
in CH2Cl2. The product was a mixture of the expected
7-hydroperoxy-substituted 1,2,4-trioxepane 12h (28%)
and ozonide 10h (6%). When the same reaction was
repeated in ether, a significant increase in the yield of
peroxidic products was certainly observed. However, the
major product was ozonide 10h (46%), which could not
be separated from the contaminated 12h by column
chromatography on silica gel. Ozonolysis of 4h in
MeOH-ether did not give trioxepane 12h but instead
afforded R-alkoxyalkyl hydroperoxide 13h in high yield
(Scheme 5). This implies that, because of the substituent
electronic effect,9 only the carbonyl oxide intermediate
11h is produced from 4h . Moreover, in aprotic solvent
intermolecular cycloaddition with formaldehyde leading
to ozonide 10h competes well with intramolecular cy-
clization leading to trioxepane 12h . As an alternative
route for the synthesis of 12h , we conducted acidolysis
of the easily obtainable 13h . Certainly, treatment with
1 equiv of trifluoroacetic acid (TFA) in CH2Cl2 gave 12h
albeit in a low yield of 24% (Scheme 5).
From the view of selective synthesis of trioxepane 12h ,
it was, therefore, important to suppress the formation of
10h . As an approach to overcoming this problem, we
considered that ozonolysis in trifluoroethanol would be
promising, since this protic solvent with a lower nucleo-
philicity may not capture carbonyl oxide and, neverthe-
less, it may solvate strongly formaldehyde.10 Consistent
with this expectation, ozonolysis of hydroperoxide 4h in
trifluoroethanol-ether resulted in exclusive isolation of
trioxepane 12h in 65% yield. From ozonolysis of 4i under
ozonide 10f was the major product (46%). To obtain an
information for the identity of the ozonolysis intermedi-
ate, reaction of 4f was conducted in MeOH-ether. From
the reaction mixture, R-alkoxyalkyl hydroperoxide 13f
was isolated in 59% yield, together with 9% of 8f. This
clearly suggests that the direction of cleavage of primary
ozonide (PO) 5f is selective; pathway b (Scheme 4)
providing carbonyl oxide intermediate 11f predominates.
Probably, the directive effect of the electron-donating
methyl group is much stronger than the opposite direc-
tive effect of the electron-withdrawing alkoxymethyl
substituent.9 Then, formation of a significant amount of
8f in CH2Cl2 (38%) implies that in this solvent loss of an
oxygen atom from 11f may occur very easily (Scheme 4).
From the ozonolysis of 4e in CH2Cl2, 8e and 12e were
isolated in moderate yields (Scheme 4). The NOE of
hydroxy-substituted 1,2,4-trioxane 8e suggested that the
trioxane ring adopts a chair conformation with the
hydoxy substituent occupying the axial position (Figure
1).
Syn th esis of 1,2,4-Tr ioxep a n es. To see if seven-
membered-ring peroxide could be produced by intramo-
(9) (a) Fliszar, S.; Belzecki, C.; Chylinska, J . B. Can. J . Chem. 1967,
45, 221. (b) Griesbaum, K.; Kiesel, G. Chem. Ber. 1989, 122, 145. (c)
Bunnelle, W. H.; Lee, S.-G. J . Am. Chem. Soc. 1992, 114, 7577.

4952 J . Org. Chem., Vol. 62, No. 15, 1997
Ushigoe et al.
Sch em e 6
Sch em e 7
Sch em e 8
the same conditions, trioxepane 12i was obtained as a
sole isolable product (28%) (Scheme 6).
Treatment of unsaturated hydroperoxy acetal 4i with
ozone in CF3CH2OH-ether resulted in the production of
a 9:1 mixture of trioxepane 12i and ozonide 10i, which
could not be separated by column chromatography on
silica gel. However, dehydration of 12i occurred very
easily. Thus, treatment of the mixture with acetic
anhydride-triethylamine,11 followed by column chroma-
tography, gave pure peroxy lactone 14i in 41% yield.
Syn th esis of 1,2,4-Tr ioxoca n e a n d 1,2,4-Tr ioxo-
n a n e. Particularly interesting was to see if the entropi-
cally-disfavored12 eight-membered cyclic peroxide, tri-
oxocane derivative 12j, could be produced by intra-
molecular cyclization of the ozonolysis intermediate
from hydroperoxide 4j. Treatment of 4j with ozone in
CF3CH2OH-ether resulted in the formation of a complex
mixture of unidentified products. When the ozonolysis
of 4j was conducted in acetic acid-methylene chloride,
however, the expected trioxocane derivative 12j was
produced in 33% yield, suggesting that the more acidic
protic solvent, acetic acid, facilitates the intramolecular
cyclization of the corresponding carbonyl oxide interme-
diate. Treatment of R-alkoxyalkyl hydroperoxide 13j,
obtained from the ozonolysis of 4j in MeOH, with trif-
luoroacetic acid also provided the desired trioxocane 4j
in 38% yield (Scheme 7).
selective production of desired cyclic peroxides. Particu-
larly interesting is the fact that by the ozonolysis of
hydroperoxide 4j in acetic acid or the acidolysis of solvent-
derived ozonolysis product 13j, novel eight-membered
cyclic peroxide 12j is produced. Also, 1,2,4-trioxonane
derivative 12k is obtained from the ozonolysis of 4k in
acetic acid. These results clearly demonstrate the wide
scope of this methodology for the synthesis of 6-9-
membered cyclic peroxides.
Exp er im en ta l Section
Gen er a l P r oced u r e. 1H (270 MHz) and 13C NMR (67.5
MHz) spectra were obtained in CDCl3 with SiMe4 as standard.
The method of ozonolysis was previously described.13 â-Meth-
oxystyrene (1a ) and (methoxymethylene)cyclohexane (1b) were
prepared by the reported method.14
Ca u tion . Since organic peroxides are potentially hazardous
compounds, they must be handled with due care; avoid
exposure to strong heat or light, mechanical shock, oxidizable
organic materials, or transition metal ions. No particular
difficulties were experienced in handling any of the new
peroxides synthesized in this work using the reaction scales
and procedures described below together with the safeguard
mentioned above.
In light of these results, we next attempted the
synthesis of the 1,2,4-trioxonane derivative. Although
the yield was very low (19%), ozonolysis of hydroperoxide
4k in acetic acid-methylene chloride gave certainly the
trioxonane derivative 12k , together with ω-oxo hydrop-
eroxide 6k (28%) (Scheme 8).
Ozon olysis of Vin yl Eth er s 1a ,b in th e P r esen ce of th e
Un sa tu r a ted Alcoh ols 3a -c,i,j. Ozonolysis of â-methoxy-
styrene (1a ) in the presence of allyl alcohol (3a ) is representa-
tive. To a CH2Cl2 solution (15 mL) of vinyl ether 1a (330 mg,
2.94 mmol) and allyl alcohol (3a ) (330 mg, 3 equiv) was passed
a slow stream of ozone (1 equiv; flow for 8.8 min13) at -70 °C.
After addition of ether (70 mL), the organic layer was washed
with ice-cold potassium dihydrogen phosphate and saturated
brine and dried over anhydrous MgSO4. After evaporation of
the solvent under vacuum, the residue was separated by
Con clu sion . As a new and convenient synthetic
method of hydroxy(or hydroperoxy)-substituted 1,2,4-
trioxacycloalkanes, we have found that ozonolysis of
unsaturated hydroperoxy acetals is quite promising.
Proper choice of ozonolysis conditions is essential for the
(10) Ozonolysis of â-methoxystyrene in trifluoroethanol-ether gives
a complex mixture of products including 3,6-diphenyl-1,2,4,5-tetraox-
ane and benzaldehyde; no evidence is obtained for the formation of
the products derived from capture of benzaldehyde oxide by trifluo-
roethanol. Ushigoe, Y.; Nojima, M. Unpublished result.
(11) Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetrahedron Lett. 1982,
23, 3867.
(13) McCullough, K. J .; Nakamura, N.; Fujisaka, T.; Nojima, M.;
Kusabayashi, S. J . Am. Chem. Soc. 1991, 113, 1786.
(12) Thebtaranonth, C.; Thebtaranonth, Y. Cyclization Reactions;
CRC Press: Boca Raton, FL, 1994.
(14) Griesbaum, K.; Kim, W.-S.; Nakamura, N.; Mori, M.; Nojima,
M.; Kusabayashi, S. J . Org. Chem. 1990, 55, 6153.

Synthesis of OOH-Substituted Trioxacycloalkanes
J . Org. Chem., Vol. 62, No. 15, 1997 4953
column chromatography on silica gel. Elution with ether-
hexane (1:9) gave hydroperoxide 4a (220 mg, 51%).
r-P r op en oxyben zyl h yd r op er oxid e (4a ): oil; H NMR
6-Hyd r oxy-3-p h en yl-1,2,4-tr ioxa n e (tr a n s-8a ): oil (crude
product); 1H NMR δ 3.64 (dd, J ) 11.2 and 8.6 Hz, 1 H), 4.15
(dd, J ) 11.2 and 2.3 Hz, 1 H), 4.97 (s, 1 H; H-D exchange in
D2O), 5.48 (dd, J ) 8.6 and 2.3 Hz, 1 H), 5.99 (s, 1 H), 7.3-7.5
(m, 5 H); 13C NMR δ 68.4, 93.7, 103.1, 127.0, 128.4, 130.0,
132.9.
1
δ 4.29 (dd, J ) 5.6 and 1.3 Hz, 1 H), 4.37 (dd, J ) 5.6 and 1.3
Hz, 1 H), 5.23 (dd, J ) 11.5 and 1.3 Hz, 1 H), 5.36 (dd, J )
15.7 and 1.7 Hz, 1 H), 5.87 (s, 1 H), 5.9-6.1 (m, 1 H), 7.3-7.5
(m, 5 H), 8.56 (s, 1 H); 13C NMR δ 69.7, 105.9, 117.6, 126.9,
127.9, 128.3, 128.9, 129.2, 133.9, 135.5. Anal. Calcd for
C10H12O3: C, 66.65; H, 6.71. Found: C, 66.64; H, 6.85.
r-(1-Meth ylp r op en oxy)ben zyl h yd r op er oxid e (4b): oil
(a 2:1 mixture of two isomers); 1H NMR δ 1.32 (d, J ) 6.6 Hz,
1 H), 1.42 (d, J ) 6.6 Hz, 2 H), 4.24 (quintet, J ) 6.6 Hz, 0.34
H), 4.56 (quintet, J ) 6.6 Hz, 0.66 H), 5.1-5.3 (m, 2 H), 5.7-
5.8 (m, 0.66 H), 5.90 (s, 1 H), 5.9-6.1 (m, 0.34 H), 7.3-7.6 (m,
5 H), 8.6-8.7 (br s, 0.66 H), 8.0-8.1 (br s, 0.34 H); 13C NMR
δ 21.0, 21.4, 75.5, 76.0, 103.9, 105.1, 115.9, 116.9, 126.9, 127.1,
128.1, 128.3, 128.9, 129.2, 135.7, 136.2, 139.1, 139.8. Anal.
Calcd for C11H14O3: C, 68.02; H, 7.27. Found: C, 68.45; H,
7.40.
6-Hyd r oxy-5-m eth yl-3-p h en yl-1,2,4-tr ioxa n e (8b): oil (a
1
mixture of three isomers); H NMR δ 1.32 (d, J ) 6.9 Hz) +
1.34 (d, J ) 6.3 Hz) + 1.46 (d, J ) 6.9 Hz) (3 H), 3.4-4.2 (m,
1 H), 4.6-5.3 (m, 1 H), 6.01 (s) + 6.28 (s) + 6.41 (s) (1 H),
7.3-7.5 (m, 5 H); 13C NMR δ 12.5, 15.0, 15.6, 96.3, 97.2, 97.8,
98.7, 98.9, 103.6, 126.9, 128.1, 128.3, 129.3, 129.9, 133.2, 134.1,
134.4. Anal. Calcd for C10H12O4: C, 61.22; H, 6.17. Found:
C, 61.11; H, 6.35.
5,5-Dim eth yl-6-h yd r oxy-3-p h en yl-1,2,4-tr ioxa n e (tr a n s-
8c): oil (crude product); 1H NMR δ 1.38 (s, 3 H), 1.42 (s, 3 H),
3.41 (s, 1 H), 5.30 (s, 1 H), 6.29 (s, 1 H), 7.3-7.5 (m, 5 H); 13C
NMR δ 15.4, 24.7, 75.0, 98.7, 100.1, 127.2, 128.4, 30.0, 133.6.
Tr ea tm en t of Tr ioxa n es tr a n s-8a ,c w ith Silica Gel in
CH2Cl2. Reaction of trans-8c is representative. A mixture of
trans-8c (40 mg, 0.20 mmol) and silica gel (5 g) in CH2Cl2 (10
mL) was stirred at rt for 10 h. Column chromatography on
silica gel (elution with CH2Cl2) gave a 3:1 mixture of cis- and
trans-8a (39 mg, 94%). The structure of the major isomer was
confirmed as cis-8a by the NOE measurement.
r-(1,1-Dim et h ylp r op en oxy)b en zyl
h yd r op er oxid e
1
(4c): oil; H NMR δ 1.38 (s, 3H), 1.49 (s, 3H), 5.15 (dd, J )
10.5 and 1.0 Hz, 1 H), 5.22 (dd, J ) 17.5 and 1.0 Hz, 1 H),
5.94 (s, 1 H), 5.97 (dd, J ) 17.5 and 10.5 Hz, 1 H), 7.2-7.6 (m,
5 H), 8.14 (s, 1 H); 13C NMR δ 26.42 (Me), 27.1, 77.6, 101.5,
114.7, 127.0, 128.2, 128.8, 137.5, 143.1. Anal. Calcd for
C12H16O3: C, 69.21; H, 7.74. Found: C, 69.11; H, 7.43.
1-(3-Bu ten oxy)cycloh exyl h yd r op er oxid e (4i): oil; 1H
NMR δ 1.4-1.8 (m, 10 H), 2.36 (q, J ) 6.6 Hz, 2 H), 3.58 (t, J
) 6.6 Hz, 2 H), 5.14 (dq, J ) 19.8 and 1.0 Hz, 1 H), 5.19 (dq,
J ) 11.7 and 1.0 Hz, 1 H), 5.8-6.0 (m, 1 H), 7.85 (br s, 1 H);
13C NMR δ 22.6, 25.4, 31.4, 34.2, 59.8, 105.5, 117.4, 136.2.
Anal. Calcd for C10H18O3: C, 64.49; H, 9.74. Found: C, 64.59;
H, 9.52.
6-Hyd r oxy-3-p h en yl-1,2,4-tr ioxa n e (cis-8a ): oil (in ad-
1
mixture with 25% of trans-8a ); H NMR δ 4.09 (dd, J ) 11.2
and 10.7 Hz, 1 H), 4.19 (dd, J ) 11.2 and 2.0 Hz, 1 H), 4.97 (s,
1 H), 5.20 (dd, J ) 10.2 and 2.0 Hz, 1 H), 6.22 (s, 1 H), 7.3-
7.5 (m, 5 H). 13C NMR δ 68.0, 93.8, 104.1, 126.7, 128.4, 130.2,
133.6. Anal. Calcd for C9H10O4: C, 59.34; H, 5.53. Found:
C, 59.28; H, 5.81.
5,5-Dim et h yl-6-h yd r oxy-3-p h en yl-1,2,4-t r ioxa n e (cis-
1
8c): oil (in admixture with 50% of trans-8c); H NMR δ 1.56
1-(4-Meth yl-4-pen ten oxy)cycloh exyl h ydr oper oxide (4j):
oil; 1H NMR δ 1.3-1.7 (m, 12 H), 1.72 (s, 3 H), 2.10 (t, J ) 7.6
Hz, 2 H), 3.48 (t, J ) 6.6 Hz, 2 H), 4.71 (br s, 2 H), 7.79 (s, 1
H); 13C NMR δ 22.3, 22.7, 25.4, 27.6, 30.9, 31.5, 34.4, 59.7,
105.3, 110.1, 145.8. Anal. Calcd for C12H22O3: C, 67.26; H,
10.35. Found: C, 66.92; H, 10.25.
1-(5-Meth yl-5-h exen oxy)cycloh exyl h ydr oper oxide (4k):
oil; 1H NMR δ 1.3-1.7 (m, 14 H), 1.71 (s, 3 H), 2.10 (t, J ) 7.6
Hz, 2 H), 3.51 (t, J ) 6.3 Hz, 2 H), 4.68 (s, 1 H), 4.71 (s, 1 H),
7.36 (s, 1 H); 13C NMR δ 22.3, 22.7, 24.2, 25.4, 29.5, 31.5, 37.4,
60.3, 105.4, 110.0, 145.7. Anal. Calcd for C13H24O3: C, 68.38;
H, 10.60. Found: C, 68.58; H, 10.49.
Ozon olysis of Un sa tu r a ted Hyd r op er oxy Aceta ls 4a -
d ,f,h ,j in MeOH-Eth er . The reaction of hydroperoxide 4f
is representative. A solution of unsaturated hydroperoxy
acetal 4f (290 mg, 1.57 mmol) in methanol (15 mL) and ether
(15 mL) was cooled to -78 °C, and ozone (1.0 equiv) was
bubbled through it at -78 °C. Aqueous KH2PO4 was added,
and the mixture was extracted with ether (70 mL), washed
with saturated brine, and dried over anhydrous MgSO4. After
evaporation of the solvent, the crude products were separated
by column chromatography on silica gel. Elution with diethyl
ether-hexane (25:75) gave 13f (220 mg, 59%).
(s, 3 H), 1.57 (s, 3 H), 3.80 (d, J ) 11.3 Hz, 1 H), 4.79 (d, J )
11.3 Hz, 1 H), 6.43 (s, 1 H), 7.3-7.6 (m, 5 H). Anal. Calcd for
C11H14O4: C, 62.85; H, 6.71. Found: C, 62.59; H, 6.77.
Ozon olysis of Un sa tu r a ted Hyd r op er oxy Aceta l 4d in
CH2Cl2. A solution of unsaturated hydroperoxy acetal 4d (310
mg, 1.57 mmol) in CH2Cl2 (15 mL) was cooled to -78 °C, and
ozone (1.5 equiv) was bubbled through it at -78 °C. Aqueous
KH2PO4 was added, and the mixture was extracted with
diethyl ether, washed with saturated brine, and dried over
anhydrous MgSO4. After evaporation of the solvent, the crude
products were separated by column chromatography on silica
gel. Elution with diethyl ether-hexane (10:90) gave ozonide
10d (70 mg, 18%). Subsequent elution with diethyl ether-
hexane (20:80) gave trioxane 8d (150 mg, 56%).
3-Hyd r oxy-1,2,5-tr ioxa sp ir o[5.5]u n d eca n e (8d ): oil: 1H
NMR δ 1.3-1.7 (m, 10 H), 3.63 (dd, J ) 3.0 and 11.9 Hz, 1 H),
3.82 (d, J ) 9.6 Hz, 1 H; H-D exchange in D2O), 4.08 (dd, J )
3.0 and 11.9 Hz, 1 H), 5.15 (dt, J ) 9.6 and 3.0 Hz, 1 H); 13C
NMR δ 22.1, 22.5, 25.3, 61.3, 94.4, 103.5. Anal. Calcd for
C8H14O4: C, 55.16; H, 8.10. Found: C, 55.04; H, 8.41.
r-[(5,5-Dim et h yl-1,2,4-t r ioxola n -3-yl)m et h oxy]cyclo-
1
h exyl h yd r op er oxid e (10d ): oil; H NMR δ 1.3-1.9 (m, 10
H), 1.52 (s, 3 H), 1.57 (s, 3 H), 3.61 (dd, J ) 4.3 and 11.4 Hz,
1 H), 3.70 (dd, J ) 4.3 and 11.4 Hz, 1 H), 5.42 (t, J ) 4.3 Hz,
1 H), 8.99 (s, 1 H); 13C NMR δ 22.6, 23.8, 23.9, 25.3, 31.52,
58.8, 102.2, 106.0, 109.6. Anal. Calcd for C11H20O6: C, 53.22;
H, 8.12. Found: C, 53.34; H, 8.29.
2-((1-Hyd r op er oxycycloh exyl)oxy)-1-m eth oxy-1-m eth -
1
yleth yl h yd r op er oxid e (13f): oil; H NMR δ 1.40 (s, 3 H),
1.4-1.8 (m, 10 H), 3.42 (s, 3 H), 3.61 (d, J ) 10.4 Hz, 1 H),
3.80 (d, J )10.4 Hz, 1 H), 8.64 (s, 1 H), 9.36 (s, 1 H); 13C NMR
δ 16.8, 22.7, 25.4, 31.2, 32.0, 49.3, 62.4, 105.9, 106.1. Anal.
Calcd for C10H20O6: C, 50.84; H, 8.86. Found: C, 50.62; H,
8.86.
Ozon olysis of Un sa tu r a ted Hyd r op er oxy Aceta ls 4e,f
in CH2Cl2. Reaction of hydroperoxide 4e is representative.
A solution of unsaturated hydroperoxy acetal 4e (776 mg, 4.00
mmol) in CH2Cl2 (15 mL) was cooled to -78 °C, and ozone (1.5
equiv) was bubbled through it at -78 °C. Aqueous KH2PO4
was added, and the mixture was extracted with ether, washed
with saturated brine, and dried over anhydrous MgSO4. After
evaporation of the solvent under reduced pressure, the crude
products were separated by column chromatography on silica
gel. Elution with ether-hexane (15:85) gave 12e (196 mg,
23%). Subsequent elution with ether-hexane (20:80) gave 8e
(349 mg, 45%).
3-((1-Hyd r op er oxycycloh exyl)oxy)-1-m eth oxy-1-m eth -
ylp r op yl h yd r op er oxid e (13h ): oil; 1H NMR δ 1.42 (s, 3 H),
1.4-2.1 (m, 11 H), 2.3-2.4 (m, 1 H), 3.38 (s, 3 H), 3.6-3.9 (m,
2 H), 9.19 (s, 1 H), 9.77 (s, 1 H); 13C NMR δ 18.4, 22.6, 24.3,
25.4, 31.3, 31.5, 31.7, 48.9, 59.6, 105.3, 107.2. Anal. Calcd
for C11H22O6: C, 52.79; H, 8.86. Found: C, 53.52; H, 9.1
4-((1-Hyd r op er oxycycloh exyl)oxy)-1-m eth oxy-1-m eth -
1
ylbu tyl h yd r op er oxid e (13j): oil; H NMR δ 1.32 (s, 3 H),
1.3-2.0 (m, 14 H), 3.35 (s, 3 H), 3.5-3.6 (m, 2 H), 8.77 (s, 1
H), 9.06 (s, 1 H); 13C NMR δ 18.4, 22.6, 24.3, 25.4, 31.3, 31.5,
31.7, 48.9, 59.6, 105.3, 107.2. Anal. Calcd for C12H24O6: C,
54.53; H,9.15. Found: C, 54.95; H, 9.16.
1-Meth yl-4-ph en yl-2,3,5-tr ioxan yl h ydr oper oxide (12e):
oil; 1H NMR δ 1.61 (s, 3 H), 3.88 (d, J ) 11.5 Hz, 1 H), 3.98 (d,
J ) 11.5 Hz, 1 H), 6.12 (s, 1 H), 7.3-7.6 (m, 5 H), 8.40 (s, 1

4954 J . Org. Chem., Vol. 62, No. 15, 1997
Ushigoe et al.
H); 13C NMR δ 18.3, 65.0, 102.2, 105.9, 127.0, 128.2, 129.7,
134.1. Anal. Calcd for C10H12O5: C, 56.60; H, 5.70. Found:
C, 57.47; H, 6.04.
1.51 (s) (3 H), 2.1-2.6 (m, 2 H), 3.9-4.2 (m, 2 H), 5.98 (s) +
6.13(s) (1 H), 7.3-7.6 (m, 5 H), 8.27 (s) + 8.41 (s) (1 H); 13C
NMR δ 20.3, 20.8, 39.6, 40.3, 62.7, 65.0, 105.7, 108.5, 110.7,
112.5, 126.7, 126.8, 128.2, 128.4, 129.1, 129.6, 134.6. Anal.
Calcd for C11H14O5: C, 58.40; H, 6.24. Found: C, 58.56; H,
6.47.
6-Hyd r oxy-6-m eth yl-3-p h en yl-1,2,4-tr ioxa n e (8e): mp
1
95-97 °C (from ethyl acetate-hexane); H NMR δ 1.39 (s, 3
H), 3.95 (d, J ) 11.5 Hz, 1 H), 4.02 (d, J ) 11.5 Hz, 1 H), 4.40
(s, 1 H), 6.12 (s, 1 H), 7.3-7.6 (m, 5 H); 13C NMR δ 15.1, 65.9,
97.4, 103.7, 126.7, 129.9, 130.2, 133.3. Anal. Calcd for
C10H12O4: C, 61.22; H, 6.17. Found: C, 61.01; H, 6.18.
3-Meth yl-1,2,5-tr ioxa sp ir o[5.5]u n d eca n -3-yl h yd r op er -
oxid e (12f): mp 85 °C (from ethyl acetate-hexane); 1H NMR
δ 1.44 (s, 3 H), 1.4-2.1 (m, 10 H), 3.67 (d, J ) 12.2 Hz, 1 H),
3.78 (d, J ) 12.2 Hz, 1 H), 8.31 (s, 1 H); 13C NMR δ 19.9, 22.3,
22.5, 25.3, 30.0, 32.7, 61.1, 103.1, 106.0. Anal. Calcd for
C9H16O5: C, 52.93; H, 7.90. Found: C, 52.95; H, 7.92.
3-Hydr oxy-3-m eth yl-1,2,5-tr ioxaspir o[5.5]u n decan e (8f):
9-Meth yl-7,8,12-tr ioxa sp ir o[5.6]d od eca n -9-yl h yd r op -
1
er oxid e (12h ): oil; H NMR δ 1.59 (s, 3 H), 1.5-1.8 (m, 10
H), 1.9-2.1 (m, 2 H), 3.6-3.7 (m, 1 H), 3.8-4.0 (m, 1 H), 8.07
(s, 1 H); 13C NMR δ 20.20 (Me), 22.3, 22.8, 25.3, 31.8, 32.6,
39.9, 58.1, 107.1, 110.4. Anal. Calcd for C10H18O5: C, 55.03;
H, 8.31. Found: C, 55.25; H, 8.57.
7,8,12-Tr ioxaspir o[5,6]dodecan -9-yl h ydr oper oxide (12i):
1
oil (in admixture with 10% of 10i); H NMR δ 1.2-1.8 (m, 10
H), 1.9-2.1 (m, 2 H), 3.7-3.8 (m, 2 H), 5.37 (t, J ) 4.8 Hz, 1
H), 9.42 (s, 1 H); 13C NMR δ 22.3, 22.8, 25.2, 31.2, 33.1, 34.1,
58.3, 107.0, 107.8.
1
oil; H NMR δ 1.31 (s, 3 H), 1.4-2.2 (m, 10 H), 3.55 (d, J )
11.6 Hz, 1 H), 3.91 (d, J ) 11.6 Hz, 1 H), 4.30 (s, 1 H); 13C
NMR δ 20.5, 22.1, 22.3, 25.4, 28.0, 34.2, 65.3, 97.3, 102.6. Anal.
Calcd for C9H16O4: C, 57.43; H, 8.57. Found: C, 57.72; H, 8.53.
Ozon olysis of Un sa tu r a ted Hyd r op er oxy Aceta ls 4e,f,h
in Eth er . The reaction of hydroperoxide 4h is representative.
A solution of unsaturated hydroperoxy acetal 4h (233 mg, 1.17
mmol) in ether (15 mL) was cooled to -78 °C, and ozone (1.5
equiv) was bubbled through it at -78 °C. Aqueous KH2PO4
was added, and the mixture was extracted with diethyl ether,
washed with saturated brine, and dried over anhydrous
MgSO4. After evaporation of the solvent, the crude products
were separated by column chromatography on silica gel.
Elution with diethyl ether-hexane (15:85) gave a 3:1 mixture
of 10h and 12h (177 mg, 63%). Two products could not be
separated by repeated column chromatography on silica gel.
r-[2-(3-Meth yl-1,2,4-tr ioxa n -3-yl)eth oxy]cycloh exyl h y-
9-Oxo-7,8,12-tr ioxaspir o[5.6]dodecan e (14i): oil; 1H NMR
δ 1.4-2.0 (m, 10 H), 2.6-2.7 (m, 1 H), 3.4-3.5 (m, 1 H), 3.8-
4.0 (m, 2 H); 13C NMR δ 22.2, 22.5, 25.1, 29.4, 33.0, 35.3, 54.9,
108.5, 176.0; IR 3000, 1750, 1200, 1080 cm-1
. Anal. Calcd
for C9H14O4: C, 58.05; H, 7.58. Found: C, 58.17; H, 7.40.
Ozon olysis of Un sa tu r a ted Hyd r op er oxy Aceta ls 4j,k
in CH3CO2H/CH2Cl2. The reaction of 4j is representative.
To a solution of 4j (166 mg, 0.78 mmol) in AcOH-CH2Cl2 (1:2,
30 mL) was passed a slow stream of ozone-O2 at 0 °C. After
the reaction, the mixture was poured into aqueous NaHCO3
and the products were extracted with ether. Then, the ether
layer was washed with saturated brine, dried over MgSO4.
After evaporation of the solvent, the residue was separated
by column chromatography on silica gel. Elution with ether-
hexane (15:85) gave 12j (60 mg, 33%).
9-Meth yl-7,8,13-tr ioxa sp ir o[5.7]tr id eca n -9-yl h yd r op -
1
d r op er oxid e (10h ): oil (in admixture with 25% of 12h ); H
1
er oxid e (12j): mp 123 °C (from ether-hexane); H NMR δ
NMR δ 1.44 (s, 3 H), 1.4-1.8 (m, 10 H), 2.0-2.2 (m, 2 H), 3.6-
3.7 (m, 2 H), 5.15 (s, 1 H), 5.21 (s, 1 H), 8.73 (s, 1 H); 13C NMR
δ 20.5, 22.4, 22.9, 23.6, 31.1, 31.7, 36.9, 58.1, 94.0, 105.3, 109.3.
r-[(3-Meth yl-1,2,4-tr ioxa n -3-yl)m eth oxy]cycloh exyl h y-
d r op er oxid e (10f): oil (in admixture with 30% of 12f); 1H
NMR δ 1.57 (s, 3 H), 1.2-1.7 (m, 10 H), 3.56 (s, 1 H), 3.57 (s,
1 H), 5.12 (s, 1 H), 5.31 (s, 1 H), 8.03 (s, 1 H); 13C NMR δ 19.1,
22.6, 25.3, 31.4, 62.1, 94.3, 105.0, 108.8.
1.44 (s, 3 H), 1.3-1.9 (m, 14 H), 3.63 (ddd, J ) 12.9, 7.9 and
3.0 Hz, 1 H), 3.81 (ddd, J ) 12.9, 5.9 and 3.0 Hz, 1 H), 7.99 (s,
1 H); 13C NMR δ 18.7, 22.8, 25.2, 25.5, 30.0, 32.4, 33.3, 62.9,
104.5, 110.8. Anal. Calcd for C11H20O5: C, 56.88; H, 8.68.
Found: C, 56.89; H, 8.62.
9-Meth yl-7,8,14-tr ioxa sp ir o[5.8]tetr a d eca n -9-yl h yd r o-
1
p er oxid e (12k ): oil; H NMR δ 1.37 (s, 3 H), 1.3-2.0 (m, 16
H), 3.4-3.5 (m, 1 H), 3.84 (ddd, J ) 23.8, 10.9 and 3.6 Hz, 1
H), 8.44 (s, 1 H); 13C NMR δ 15.7, 18.8, 22.8, 22.9, 25.4, 26.6,
28.0, 31.1, 33.2, 56.3, 105.6, 114.5. Anal. Calcd for C12H22O5:
C, 58.52; H, 9.00. Found: C, 58.84; H, 9.09.
Ozon olysis of Un sa tu r a ted Hyd r op er oxy Aceta ls 4g-i
in CF 3CH2OH/E t h er . The reaction of hydroperoxide 4i is
representative. A solution of unsaturated hydroperoxy acetal
4i (293 mg, 1.58 mmol) in trifluoroethanol/ether (1:2 v/v; 15
mL) was cooled to 0 °C, and ozone (1.5 equiv) was bubbled
through it at -0 °C. Aqueous KH2PO4 was added, and the
mixture was extracted with diethyl ether, washed with
saturated brine, and dried over anhydrous MgSO4. After
evaporation of the solvent, the crude products were separated
by column chromatography on silica gel. Elution with diethyl
ether-hexane (2:8) gave a 9:1 mixture of 12i and 10i (174 mg,
53%), which could not be separated by column chromatography
on silica gel. Therefore, the mixture was treated with acetic
anhydride and triethylamine. After the ozonolysis as above,
the residue (an 8:1 mixture of 12i and 10i from 1.23 mmol of
4i) was taken up in CH2Cl2 (4 mL) and cooled to 0 °C. Acetic
anhydride (225 mg, 3 equiv) and triethylamine (112 mg, 1.5
equiv) were added, and the solution was stirred at rt for 20 h.
This mixture was treated with methanol (1 mL) for 15 min
and then diluted with ether (50 mL). The solution was washed
with 5% H2SO4 and saturated NaHCO3, dried over MgSO4,
and concentrated. The crude products were separated by
column chromatography on silica gel. From the fraction eluted
by ether-hexane (15:85) was obtained 1,2,4-trioxepane deriva-
tive 14i (57 mg, 41% based on 4i).
r-(5-Oxoh exoxy)cycloh exyl h yd r op er oxid e (6k ): oil; 1H
NMR δ 1.3-1.9 (m, 14 H), 2.16 (s, 3 H), 2.51 (t, J ) 6.9 Hz, 2
H), 3.51 (t, J ) 6.9 Hz, 2 H), 8.15 (s, 1 H); 13C NMR δ 20.4,
22.7, 25.4, 29.4, 30.0, 31.5, 43.3, 59.8, 105.3, 209.9; MASS (CI;
isobutane) 231 (M+ + 1), 215, 197, 171, 115, 99.
Acid olysis of r-Meth oxya lk yl Hyd r op er oxid es 13h ,j.
Acidolysis of 13h is representative. To a solution of 13h (210
mg, 0.85 mmol) in CH2Cl2 (10 mL) was added TFA (97 mg,
1.0 equiv) in CH2Cl2 (10 mL) at 0 °C. This solution was stirred
at rt for 2 h. Aqueous KH2PO4 was added, and the mixture
was extracted with ether, washed with saturated brine, and
dried over anhydrous MgSO4. After evaporation of the solvent,
the crude products were separated by column chromatography
on silica gel. Elution with diethyl ether-hexane (15:85) gave
12h (40 mg, 24%).
Ack n ow led gm en t. This work was supported in part
by a Grant-in Aid for Scientific Research on Priority
Areas (09270212) from the Ministry of Education,
Science, Culture and Sports of J apan. We thank British
Council (Tokyo) for the award of travel grant to M. N.
1-Met h yl-4-p h en yl-2,3,5-t r ioxep a n yl h yd r op er oxid e
(12g): oil (a 1:1 mixture of two isomers); 1H NMR δ 1.43 (s) +
J O970555L