Ozonolyses of 4,4-dimethyl-2-cyclohexen-1-yl acetate and 4,4-dimethyl-2-cyclopenten-1-yl acetate. Competition between the steric effects of the allylic methyl groups and the electronic effects of the acetoxy group on the direction of cleavage of the primary ozonides

Article abstract of DOI:10.1021/jo960219p

In order to understand the relative directing effects of the substituent steric and electronic effects on the cleavage of the primary ozonides, ozonolyses of a series of cyclohexene and cyclopentene derivatives were conducted in methanol or in ether in the presence of trifluoroacetophenone. The ozonolysis of 4,4-dimethyl-2-cyclohexen-1-yl acetate (1k) in methanol provided exclusively the α-methoxyalkyl hydroperoxide 7k derived from capture of 5-acetoxy-5-formyl-2,2-dimethylpentanal oxide by the solvent, while in the case of the relevant 4,4-dimethyl-2-cyclopenten-1-yl acetate (11) the solvent-captured product 61 derived from trapping of 2-acetoxy-5-formyl-5-methylpentanal oxide was the major product. The remarkable difference in the regiochemistry of the fragmentation between the primary ozonides, 2k and 2l, is rationalized in terms of the significant difference in the steric congestion.

Full text of DOI:10.1021/jo960219p

J . Org. Chem. 1996, 61, 5953-5958
5953
Ozon olyses of 4,4-Dim eth yl-2-cycloh exen -1-yl Aceta te a n d
4,4-Dim eth yl-2-cyclop en ten -1-yl Aceta te. Com p etition betw een th e
Ster ic Effects of th e Allylic Meth yl Gr ou p s a n d th e Electr on ic
Effects of th e Acetoxy Gr ou p on th e Dir ection of Clea va ge of th e
P r im a r y Ozon id es
Shin-ichi Kawamura, Hideyuki Yamakoshi, and Masatomo Nojima*
Department of Material Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565, J apan
Received February 2, 1996X
In order to understand the relative directing effects of the substituent steric and electronic effects
on the cleavage of the primary ozonides, ozonolyses of a series of cyclohexene and cyclopentene
derivatives were conducted in methanol or in ether in the presence of trifluoroacetophenone. The
ozonolysis of 4,4-dimethyl-2-cyclohexen-1-yl acetate (1k ) in methanol provided exclusively the
R-methoxyalkyl hydroperoxide 7k derived from capture of 5-acetoxy-5-formyl-2,2-dimethylpentanal
oxide by the solvent, while in the case of the relevant 4,4-dimethyl-2-cyclopenten-1-yl acetate (1l)
the solvent-captured product 6l derived from trapping of 2-acetoxy-5-formyl-5-methylpentanal oxide
was the major product. The remarkable difference in the regiochemistry of the fragmentation
between the primary ozonides, 2k and 2l, is rationalized in terms of the significant difference in
the steric congestion.
Ta ble 1. Ozon olysis of Cycloa lk en es 1a -n
The basic mechanism that describes the ozonolysis of
an alkene to produce a 1,2,4-trioxolane (secondary ozo-
nide) evolved during the 1950’s and is known as the
Criegee mechanism.1 It consists of three steps. The first
step is a [3 + 2] cycloaddition reaction of ozone with the
alkene leading to formation of a primary ozonide (PO,
1,2,3-trioxolane). The second is a cycloreversion process
of PO to provide the transient carbonyl oxide and a stable
carbonyl compound, which may proceed in two different
ways in the case of unsymmetrically substituted alkenes.
Finally, recombination of the carbonyl oxide and the
carbonyl compound gives the 1,2,4-trioxolane. Much of
the current interest in this process centers on the factors
affecting the direction of cleavage of the unsymmetrically
substituted PO.2 Three factors have been found to play
an important role in determining the regiochemistry of
PO cleavage, i.e., the electronic effect of the substituent
attached to the C-C double bond,3 the electronic effect
of the heteroatom substituent at the allylic position,4 and
the steric effect of the allylic dialkyl substituents.5 To
predict the regiochemistry in cleavage of the PO from the
given alkene, it would be required to understand the
relative directive effects of these three factors. For this
purpose, we have conducted ozonolyses of a series of
properly-substituted cycloalkenes in the presence of
trifluoroacetophenone in ether or in methanol and have
determined in each case the ratios of two possible cross-
products
ratio of
substr
solvent
additive
(% yield)a
path a:bb
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
ether
ether
ether
ether
PhCOCF3
PhCOCF3
PhCOCF3
PhCOCF3
8a (67)
5b (65)
8c (71)
8d (6)
0:100
100:0
0:100
0:100
5:95c
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
ether
6e (4), 7e (84)
6f (64)
10g (72)
6h (28), 7h (56)
6i (1.5), 7i (72)
6j (15), 7j (63)
10k (68)
12 (58), 13 (6)
5m (88)
100:0d
0:100
33:67e
2:98f
19:81f
0:100
90:10
100:0
0:100
PhCOCF3
PhCOCF3
ether
8n (79)
a
In some cases the ozonolysis product was transformed into
b
the more stable, easily assignable compound. See Schemes 1, 3,
and 4 for each substrate. c Taken from the data in ref 3b. Taken
d
from the data in ref 5c. e Determined by the 1H NMR spectra of
the crude product mixture. f Taken from the data in ref 4a.
ozonides or the composition of the solvent-derived prod-
ucts, respectively.
Resu lts a n d Discu ssion
Ozon olysis of Alk yl-Su b st it u t ed Cycloh exen es.
Ozonolysis of 1-methylcyclohexene (1a ) in the presence
of trifluoroacetophenone in ether gave exclusively the
crossed-ozonide 8a (67% yield) derived from the cycload-
dition of the carbonyl oxide intermediate 4a with the
additive, suggesting that the carbonyl oxide intermediate
can be efficiently captured by trifluoroacetophenone, an
electron-deficient ketone, and moreover, the directive
effect of the electron-donating methyl group is important
(Table 1 and Scheme 1). Also, the steric effect of the
dialkyl groups at the allylic position was found to play
an important role in determining the direction of cleavage
of PO from 1,2,3,3-tetramethylcyclohexene (1b). Treat-
ment of 1b with ozone in the presence of trifluoroac-
etophenone resulted in exclusive formation of the crossed-
ozonide 5b (65%) derived from the reaction of the
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Criegee, R. Angew. Chem., Int. Ed. Engl. 1975, 11, 745.
(2) (a) Bailey, P. S. Ozonation in Organic Chemistry; Academic
Press: New York, 1978; Vol. 1; 1982, Vol. 2. (b) Bunnelle, W. H. Chem.
Rev. 1991, 91, 335. (c) McCullough, K. J .; Nojima, M. In Organic
Peroxides; Ando, W., Ed.; Wiley: New York, 1992. (d) Lin, C.-C.; Wu,
H.-J . Tetrahedron Lett. 1995, 36, 9353.
(3) (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.
(4) (a) Bunnelle, W. H.; Isbell, T. A. J . Org. Chem. 1992, 57, 729.
(b) Hayes, H.; Wallace, T. W. Tetrahedron Lett., 1990, 31, 3355.
(5) (a) Criegee, R. Chem. Ber. 1975, 108, 743. (b) Griesbaum, K.;
Volpp, W. Chem. Ber. 1988, 121, 1795. (c) Mayr, H.; Baran, J .; Will,
E.; Yamakoshi, H.; Teshima, K.; Nojima, M. J . Org. Chem. 1994, 59,
5055; (d) Teshima, K.; Kawamura, S.; Ushigoe, Y.; Nojima, M.;
McCullough, K. J . J . Org. Chem. 1995, 60, 4755.
S0022-3263(96)00219-8 CCC: $12.00 © 1996 American Chemical Society

5954 J . Org. Chem., Vol. 61, No. 17, 1996
Kawamura et al.
Sch em e 1
sterically less-congested carbonyl oxide 3b and the
additive.
To obtain information for the relative directive effect
between the substituent electronic and steric effects, we
then conducted the ozonolyses of 6,6-dialkyl-substituted
1-methylcyclohexenes 1c,d . In each case the sole product
was the crossed-ozonide 8, derived from capture of the
sterically more-congested carbonyl oxide 4 by the additive
(Scheme 1 and Table 1), suggesting that in both sub-
strates 1c,d the directive effect of the electron-donating
methyl substituent at C-1 is more important. This was
in marked contrast to the fact that in the case of 1,5,5-
trimethylcyclopentene (1f) the steric effect of the dim-
ethyl groups is decisive, thereby providing exclusively the
sterically less-congested carbonyl oxide intermediate 3f
(Table 1).5c
To understand the notable difference in behavior
between two substrates, 1c and 1f, semiempirical calcu-
lations on the structures of POs, 2c and 2f, were
undertaken by the PM3 method.6 The optimized struc-
tures suggest that there exists a notable difference in the
structure between 2c and 2f (Figure 1). In the PO 2f
the central oxygen of the 1,2,4-trioxolane ring is placed
in close proximity to one of the adjacent methyl groups.
In the cycloreversion process leading to the ketone oxide
intermediate 4f (path b in Scheme 1), the oxygen atom
and the methyl group are likely to be brought more
closely together (steric congestion), while in the alterna-
tive pathway a leading to the aldehyde oxide intermedi-
ate 3f, the oxygen may move to come apart from the
methyl substituent (strain relief).3c Exclusive formation
of the crossed ozonide 5f from 1f would then imply that
in path b the retarding steric effect of the allylic dimethyl
groups overcomes the accelerating electronic effect of the
methyl substituent at C-1, and as a result, the alternative
pathway a begins to contribute predominantly. In the
cycloreversion of the more extended PO 2c, however, the
steric interaction between the allylic dimethyl groups and
the central oxygen of the trioxolane ring would not be
important (Figure 1), and therefore, the direction of
F igu r e 1. Structures of PO 2c,f,k ,l calculated by the PM3
method.
cleavage of the PO 2c is likely to be controlled by the
electronic effect of the methyl substituent at C-1. As will
be seen later, a similar ring size effect has been observed
between 4,4-dimethyl-2-cyclohexen-1-yl acetate (1k ) and
4,4-dimethyl-2-cyclopenten-1-yl acetate (1l).
Ozon olysis of 2-Cycloh exen -1-yl Acet a t e a n d
2-Meth yl-2-cycloh exen -1-yl Aceta te. To investigate
the electronic effect of the allylic heteroatom substituent
on the regiochemistry of PO cleavage,4 we conducted
ozonolyses of 2-cyclohexen-1-yl acetate (1g) and 2-methyl-
2-cyclohexen-1-yl acetate (1h ) in methanol. Treatment
of 1g with ozone gave the methoxyalkyl hydroperoxide
7g derived from capture of the carbonyl oxide intermedi-
ate 4g by the solvent (Scheme 2 and Table 1). Since the
(6) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209, 221.

Ozonolysis of 4,4-Dimethyl-2-cyclohexen-1-yl Acetate
J . Org. Chem., Vol. 61, No. 17, 1996 5955
Sch em e 2
structures, the methoxyalkyl hydroperoxide 6h was
converted into the keto acetal 11, while the alternative
solvent-derived product 7h was transformed into the
ester 9h (Scheme 3). This implies that the presence of
the methyl-substituent at C-2 leads to a larger fraction
of the highly-substituted carbonyl oxide 3h compared to
ozonolysis of 1g. Thus, while the directive effect of the
heteroatom substituent still dominates in the ozonolysis
of 1h , it is partly compensated by the methyl substituent
at C-2. Bunnelle and Isbell4a have found a similar
difference in the mode of cleavage of PO between two
cyclopentene derivatives, 1i and 1j (Scheme 2 and Table
1).
Ozon olysis of 4,4-Dim eth yl-2-cycloh exen -1-yl Ac-
eta te a n d 4,4-Dim eth yl-2-cyclop en ten -1-yl Aceta te.
From the ozonolyses of cycloalkenes 1a -j, it is evident
that both the steric effect of the allylic dialkyl substitu-
ents and the electronic effect of the allylic heteroatom
substituent play important roles in determining the
direction of cleavage of PO. To know the relative
strength of these two factors, we have conducted the
ozonolyses of 4,4-dimethyl-2-cyclohexen-1-yl acetate (1k )
and 4,4-dimethyl-2-cyclopenten-1-yl acetate (1l) (Scheme
4 and Table 1).
Treatment of 1k with ozone in methanol gave exclu-
sively the R-methoxyalkyl hydroperoxide 7k , which was
transformed into the ester 10k . This clearly demon-
strates that of the two directive factors the electronic
effect of the allylic acetoxy group is decisive. From the
reaction of 1l with ozone in methanol, however, was
obtained a 9:1 mixture of two methoxyalkyl hydroperox-
ides, 6l and 7l. The structures of two solvent-derived
products, 6l and 7l, were confirmed by transformation
into the corresponding esters, 12 and 13, respectively
(reference the sequence illustrated in Scheme 3). Thus,
in the cycloreversion of PO 2l the directive effect of the
allylic methyl groups plays a more important role,
thereby providing predominantly the carbonyl oxide 3l
with the geminal methyl groups most remote from the
carbonyl oxide fragment. It should be noticed that this
apparent difference in behavior between 2k and 2l is very
similar to that observed between 2c and 2f from 1,6,6-
trimethylcyclohexene (1c) and 1,5,5-trimethylcyclopen-
tene (1f), respectively.
Sch em e 3
Since the directive effect of the allylic heteroatom
substituent does not seem likely to be influenced signifi-
cantly by the ring size of substrates, the notable differ-
ence in behavior between 2k and 2l would be due to the
difference in the steric congestion. The structures of PO
2k and PO 2l calculated by PM 3 method seems to
suggest that the difference in steric congestion between
these two POs is significant (Figure 1), which in turn
should reflect the difference in steric crowding between
the corresponding transition states leading to the steri-
cally-congested carbonyl oxide intermediates, 4k and 4l,
respectively. As a result, the carbonyl oxide intermediate
4k is predominantly produced from 2k , while the con-
tribution of the carbonyl oxide 3l predominates in the
case of 2l.
Thus, in the ozonolyses of cycloalkene derivatives three
factors, e.g., the electronic effect of the alkyl substituent
attached to the C-C double bond, the electronic effect of
the allylic heteroatom substituent, and the steric effect
of the allylic dialkyl substituents, affect the direction of
cleavage of PO in a complicated fashion. J udged from
the product contributions observed for the ozonolyses of
1b,c,h ,k , the order of the directive effects of these three
1H NMR spectrum of the crude product mixture sug-
gested that the hydroperoxide 7g exists as a mixture
with the corresponding hemiperacetal (a mixture of
stereoisomers),4a the crude ozonolyzate was transformed
into the corresponding ester by the reaction sequence
illustrated in Scheme 3. From the reaction mixture, ester
10g was isolated in a high yield of 72%. Selective
contribution of the carbonyl oxide intermediate 4g is
consistent with earlier studies that electron-withdrawing
substituents can have a strong directive effect on the
generation of carbonyl oxide from PO to favor the
fragmentation mode, which generates the carbonyl oxide
at the alkene carbon most remote to the substituent.3a
A somewhat different pattern of PO fragmentation was
found for the methyl-substituted cyclohexene 1h . Ozo-
nolysis of 1h in methanol gave a 1:2 mixture of two
solvent-derived products, 6h and 7h . To confirm the

5956 J . Org. Chem., Vol. 61, No. 17, 1996
Kawamura et al.
Sch em e 4
P r ep a r a tion of Acetoxy-Su bstitu ted Cycloa lk en es.
The acetoxy-substituted cycloalkenes 1k -n were prepared
from the acetylation of the corresponding 2-cycloalken-1-ols
(prepared by LAH reduction of the corresponding ketones14).
The synthesis of 1k is representative. Acetic anhydride (4.0
g, 39.2 mmol) was added to a solution of 4,4-dimethyl-2-
cyclohexen-1-ol (1.0 g, 7.9 mmol) in pyridine (8 mL), and the
mixture was allowed to stir at rt. After 20 h, the solution was
poured into 50 mL of ether, washed successively with 5% H2-
SO4 and saturated NaHCO3, dried over MgSO4, and concen-
trated. The residue was purified by flash column chromatog-
raphy on silica gel (ether-hexane, 1:9) to yield 1.0 g (75%) of
1k .
factors for the cyclohexene derivatives seems to follow
the sequence: the electronic effect of the allylic heteroa-
tom substituent > the electronic effect of the alkyl
substituent attached to the C-C double bond > the steric
effect of the allylic dialkyl substituents. In the case of
cyclopentene derivatives (see results from 1f,j,l), however,
the directive effect of the allylic dimethyl groups is
apparently the most important. The second is the
electronic effect of the allylic heteroatom substituent, and
the smallest one is the electronic effect of the alkyl
substituent attached to the C-C double bond.
In the case of POs from the highly-substituted cyclo-
hexenes 1m ,n , three directive effects mentioned above
may compete to each other. In reality, the ozonolyses
were found to be highly selective (Scheme 4 and Table
1). From the reaction of 2,4,4-trimethyl-2-cyclohexen-1-
yl acetate (1m ) with ozone in the presence of trifluoro-
acetophenone was obtained exclusively the crossed-
ozonide 5m , demonstrating that the sum of the directive
effects of the allylic dimethyls at C-4 and the methyl
substituent at C-2 exceeds the directive effect of the
acetoxy substituent at C-1. Also, ozonolysis of 3,4,4-
trimethyl-2-cyclohexen-1-yl acetate (1n ) in the presence
of trifluoroacetophenone gave exclusively the crossed-
ozonide 8n , derived from capture of the carbonyl oxide
intermediate 4n by the additive.
4,4-Dim eth yl-2-cycloh exen -1-yl a ceta te (1k ): oil; 1H
NMR δ 0.98 (s, 3 H), 1.03 (s, 3 H), 1.4-2.0 (m, 4 H), 2.05 (s, 3
H), 5.1-5.2 (m, 1 H), 5.54 (dd, J ) 3 × 10 Hz, 1 H), 5.64 (d, J
) 10 Hz, 1 H); IR 2950, 1740 cm-1
.
Anal. Calcd for
C10H16O2: C, 71.39; H, 9.59. Found: C, 71.01; H, 10.10.
4,4-Dim eth yl-2-cyclop en ten -1-yl a ceta te (1l): oil; 1H
NMR δ 1.09 (s, 3 H), 1.16 (s, 3 H), 1.62 (d, J ) 4 Hz, 1 H), 1.67
(d, J ) 4 Hz, 1 H), 2.04 (s, 3 H), 5.6-5.7 (m, 2 H), 5.87 (d, J )
5 Hz, 1 H); IR 2950, 1740 cm-1. Anal. Calcd for C9H14O2: C,
70.10; H, 9.15. Found: C, 69.77; H, 9.59.
2,4,4-Tr im eth yl-2-cycloh exen -1-yl a ceta te (1m ): oil; 1H
NMR (CCl4) δ 0.95 (s, 3 H), 1.02 (s, 3 H), 1.3-1.8 (m, 4 H),
1.63 (s, 3 H), 2.01 (s, 3 H), 5.17 (t, J ) 6 Hz, 1 H), 5.37 (s, 1
H); IR 2950, 1740 cm-1. Anal. Calcd for C11H18O2: C, 72.49;
H, 9.95. Found: C, 72.29. H, 10.14.
3,4,4-Tr im eth yl-2-cycloh exen -1-yl a ceta te (1n ): oil; 1H
NMR δ 1.00 (s, 3 H), 1.10 (s, 3 H), 1.4-2.0 (m, 4 H), 1.69 (s, 3
H), 2.04 (s, 3 H), 5.1-5.3 (m, 1 H), 5.33 (d, J ) 2 Hz, 1 H); IR
Con clu sion . We have conducted ozonolyses of a series
of cycloalkene derivatives in methanol or in ether in the
presence of trifluoroacetophenone. On the basis of these
trapping experiments of the carbonyl oxide intermedi-
ates, the factors affecting the direction of cleavage of PO
and their relative importance have been elucidated. The
information obtained in this study should be useful to
predict the branching ratio of the given PO.
(7) McCullough, K. J .; Nakamura, N.; Fujisaka, T.; Nojima, M.;
Kusabayashi, S. J . Am. Chem. Soc. 1991, 113, 1786.
(8) Neget, W. A.; Feldan, J .; Calabrese, J . C. J . Am. Chem. Soc. 1995,
117, 8992.
(9) Hamilton, R.; Mitchell, T. R. B.; Rooney, J . J .; J ohn, J .; McK-
ervey, M. A. J . Chem. Soc., Chem. Commun. 1979, 731.
(10) Fadel, A.; Salaun, J . Tetrahedron Lett. 1985, 41, 1267.
(11) Henri, C.; Robrt, V. Bull. Soc. Chim. Fr. 1968, 4, 1398.
(12) Pearson, A. J .; Hsu, S. Y. J . Org. Chem. 1986, 51, 2505.
(13) Gassman, P. G.; Bottorff, K. J . Tetrahedron Lett. 1987, 28, 5449.
(14) (a) 2-Methyl-2-cyclohexen-1-one: Warnhoff, E. W.; Martin, D.
G.; J ohnson, W. S. Organic Syntheses; Collect. Vol. VI, Wiley: New
York, 1963; p 162. (b) 4,4-Dimethyl-2-cyclopenten-1-one: David, P.;
Frank, A.; Tomas, H. Org. Synth. 1989, 67, 121. (c) 2,4,4-Trimethyl-
2-cyclohexen-1-one and 3,4,4-trimethyl-2-cyclohexen-1-one: David, I.
S.; J ampani, M. R. J . Org. Chem. 1981, 46, 1515.
Exp er im en ta l Section
Gen er a l P r oced u r es. 1H and 13C NMR spectra were
obtained in CDCl3 (unless otherwise noted) with SiMe4 as
standard. The method of ozonolysis was previously described.7
The cycloalkenes 1a ,8 1b,9 1c,10 1d ,11 1g,12 and 1h 13 were
prepared by the reported methods.

Ozonolysis of 4,4-Dimethyl-2-cyclohexen-1-yl Acetate
J . Org. Chem., Vol. 61, No. 17, 1996 5957
2950, 1740, 1450, 1380, 1250 cm-1
2950, 1740, 1240 cm-1. Anal. Calcd for C11H18O2: C, 72.49;
H, 9.95. Found: C, 72.19; H, 10.09.
.
Anal. Calcd for
C10H16O5: C, 55.54; H, 7.46. Found: C, 55.59; H 7.61.
The hydroperoxide 6h was transformed into the ketone 11
as follows. A 1:2 mixture of 6h and 7h (197 mg) was dissolved
in 2,2-dimethoxypropane (2 mL), treated with a few crystals
of p-toluenesulfonic acid, and stirred at rt. After 2 h, the
reaction mixture was diluted with ether (50 mL). The solution
was washed with saturated NaHCO3 and saturated brine,
Ca u tion : Since organic ozonides 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 organic ozonides synthesized in this work using the
reaction scales and procedures described below together with
the safeguard mentioned here.
Ozon olysis of Cycloa lk en e Der iva tives 1a -d in th e
P r esen ce of Tr iflu or oa cetop h en on e. Ozonolysis of 1-me-
thylcyclohexene (1a ) is representative. After a solution of 1a
(198 mg, 2.0 mmol) and trifluoroacetophenone (348 mg, 2.0
mmol) in ether (15 mL) was treated with ozone (O3/O2 stream)
(1.5 equiv) at -70 °C, the crude products were separated by
column chromatography on silica gel. Elution with ether-
hexane (1:9) gave the crossed-ozonide 8a (426 mg, 67%).
1
dried over MgSO4, and concentrated. The H NMR spectrum
of the residue suggested that 6h was converted into the
corresponding dimethoxy-substituted ketone, while the hy-
droperoxide 7h was remained intact. The crude products were
separated by column chromatography on silica gel. The
fraction containing the corresponding dimethoxy-substituted
ketone (elution by ether-hexane, 1:5), after concentration (180
mg), was dissolved in benzene (5 mL) and treated with
triphenylphosphine (262 mg, 1.00 mmol) for 20 h. After
evaporation of the solvent, the crude products were separated
by column chromatography on silica gel. Elution with ether-
hexane (1:1) gave 3-acetoxy-7,7-dimethoxyheptan-2-one (11)
(3-Meth yl-5-p h en yl-5-tr iflu or om eth yl-1,2,4-tr ioxola n -
3-yl)p en ta n a l (8a ): oil; 1H NMR (CCl4) δ 1.30 (s, 3 H), 1.3-
2.6 (m, 8 H), 7.2-7.6 (m, 5 H), 9.63 (t, J ) 1.5 Hz, 1 H); 13C
NMR δ 21.86, 22.39, 23.34, 35.07, 43.46, 103.40 (q, J ) 34
Hz), 113.55, 121.53 (q, J ) 289 Hz), 126.54, 128.24, 128.27,
130.22, 202.02; IR 1735, 1460, 1390, 1310, 1200, 1100, 960,
1
(48 mg, 21%): oil; H NMR δ 1.4-1.8 (m, 6 H), 2.15 (s, 3 H),
2.16 (s, 3 H), 3.32 (s, 6 H), 4.35 (t, J ) 6 Hz, 1 H), 4.99 (dd, J
) 8 × 5, Hz, 1 H); 13C NMR δ 20.40, 20.66, 26.11, 30.01, 32.08,
52.83, 52.90, 78.54, 104.19, 170.56, 205.21; IR 2950, 1740,
1380, 1240 cm-1. Anal. Calcd for C11H20O5: C, 56.88; H, 8.68.
Found: C, 57.08; H, 8.77.
720 cm-1
Found: C, 56.59; H, 5.56.
. Anal. Calcd for C15H17F3O4: C, 56.59; H, 5.39.
Meth yl 5-a cetoxy-6,6-d im eth oxyh exa n oa te (10g): oil;
1H NMR (CCl4) δ 1.4-1.8 (m, 4 H), 2.08 (s, 3 H), 3.38 (s, 3 H),
3.42 (s, 3 H), 3.68 (s, 3 H), 4.30 (d, J ) 5 Hz, 1 H), 4.9-5.1 (m,
1 H); 13C NMR δ 20.66, 21.04, 28.55, 33.73, 51.54, 54.54, 55.44,
72.16, 104.42, 170.51, 173.71; IR 2950, 1740, 1440, 1370, 1240,
1
Cr ossed -ozon id e 5b: oil; H NMR δ 1.148 (s, 3 H), 1.154
(s, 3 H), 1.34 (s, 3 H), 1.35-1.44 (m, 2 H), 1.55-1.61 (m, 2 H),
1.87-1.94 (m, 2 H), 2.14 (s, 3 H), 7.38-7.49 (m, 3 H), 7.54-
7.56 (m, 2 H); 13C NMR δ 19.27, 22.43, 24.26, 24.33, 25.11,
35.91, 39.66, 47.66, 103.37 (q, J ) 32.9 Hz), 113.59, 121.50 (q,
J ) 289.3 Hz), 126.50, 128.27, 130.24, 131.97, 213.80; IR 2950,
1705, 1190, 1080, 955, 720 cm-1. Anal. calcd for C18H23F3O4:
C, 59.99; H, 6.43; F, 15.82. Found: C, 60.21; H, 6.35.
1080 cm-1
. Anal. Calcd for C11H20O6: C, 53.22; H, 8.12.
Found: C, 52.97; H, 8.23.
Ozon olysis of 4,4-Dim eth yl-2-cycloa lk en -1-yl Aceta tes
1k ,l in Meth a n ol. Ozonolysis of 1k is representative. 4,4-
Dimethyl-2-cyclohexen-1-yl acetate (1k ) (240 mg, 1.43 mmol)
was dissolved in MeOH-CH2Cl2 (15 mL, 1:5), and solid
NaHCO3 (0.5 g) was added. To the mixture cooled in a dry
ice-methanol bath (-70 °C), was passed a slow stream of
ozone (1.5 equiv). After the reaction, ether (30 mL) was added,
the solid NaHCO3 was removed by filtration, and the filtrate
was concentrated at aspirator pressure, taking care to keep
the reaction mixture below 40 °C. The residue was taken up
in CH2Cl2 (4 mL). Then, acetic anhydride (729 mg, 5 equiv)
and triethylamine (216 mg, 1.5 equiv) were added, and the
solution was stirred at rt for 20 h. This was treated with
methanol (1 mL) for 15 min. After concentration, the crude
products were separated by column chromatography on silica
gel. Elution with ether-hexane (1:1) gave methyl 2,2-dim-
ethyl-5-acetoxy-5-formylpentanoate (9k ) (243 mg, 74%): oil;
1H NMR δ 1.19 (s, 6 H), 1.4-1.8 (m, 4 H), 2.19 (s, 3 H), 3.68
(s, 3 H), 4.9-5.0 (m, 1 H), 9.51 (s, 1 H).
1
Cr ossed -ozon id e 8c: oil; H NMR (CCl4) δ 1.10 (s, 3 H),
1.15 (s, 3 H), 1.23 (s, 3 H), 1.1-1.7 (m, 4 H), 2.38 (t, J ) 6 Hz,
2 H), 7.3-7.8 (m, 5 H), 9.77 (br s, 1 H); 13C NMR δ 16.89, 18.69,
22.16, 22.61, 37.75, 39.84, 44.27, 103.02 (q, J ) 34 Hz), 117.12,
121.48 (q, J ) 288 Hz), 126.45, 128.18, 130.04, 132.73, 202.07;
IR 3000-2900, 1730, 1450, 1380, 1310, 1200, 1080, 950, 720
cm-1. Anal Calcd for C17H21F3O4: C, 58.94; H, 6.12. Found:
C, 59.24; H, 6.33.
1
Cr ossed -ozon id e 8d : oil; H NMR (CCl4) δ 1.27 (s, 3 H),
1.3-2.5 (m, 14 H), 7.3-7.7 (m, 5 H), 9.73 (br s, 1 H); 13C NMR
δ 17.76, 20.24, 25.68, 25.98, 32.61, 34.43, 37.69, 44.38, 51.20,
102.75 (q, J ) 33 Hz), 117.64, 121.55 (q, J ) 289 Hz), 126.52,
128.22, 130.06, 132.88, 202.22; IR 1720, 1460, 1380, 1305,
1180, 1080, 950, 715 cm-1
.
Ozon olysis of 2-Cycloh exen -1-yl Acetates 1g,h in Meth a-
n ol. Ozonolysis of 1h is representative. To a solution of
2-methyl-2-cyclohexen-1-yl acetate (1h ) (154 mg, 1.00 mmol)
in MeOH-CH2Cl2 (15 mL, 1:5, v/v) was passed a slow stream
of ozone (1.5 equiv) at -70 °C. After evaporation of the solvent
under vacuum, the crude products were separated by column
chromatography on silica gel (elution with ether) to give a
mixture of two R-methoxyalkyl hydroperoxides, 6h and 7h (197
mg, 84%); the ratio was determined by the characteristic signal
The ester 9k was then dissolved in 2,2-dimethoxypropane
(2 mL), treated with a few crystals of p-toluenesulfonic acid,
and stirred at rt for 2 h. After conventional workup, the crude
products were separated by column chromatography on silica
gel. Elution with ether-hexane (1:1) gave 10k (269 mg, 68%).
Meth yl 2,2-dim eth yl-5-acetoxy-6,6-dim eth oxyh exan oate
1
1
for each product in H NMR spectrum [6h , δ 3.36 (s, 3 H, OMe);
(10k ): oil; H NMR (CCl4) δ 1.13 (s, 6 H), 1.4-1.7 (m, 4 H),
7h , δ 3.50 (s, 3 H, OMe)].
2.00 (s, 3 H), 3.27 (s, 3 H), 3.33, (s, 3 H), 3.62 (s, 3 H), 4.18 (d,
J ) 6 Hz, 1 H), 4.93 (td, J ) 6 × 3 Hz, 1 H); 13C NMR δ 20.81,
24.46, 24.78, 24.89, 35.69, 41.75, 51.50, 54.20, 55.11, 72.27,
To confirm the structure, the hydroperoxide 7h was trans-
formed into the ester 9h . After the ozonolysis as above, the
residue (a 1:2 mixture of 6h and 7h from 1.56 mmol of 1h )
was taken up in CH2Cl2 (4 mL) and cooled to 0 °C. Acetic
anhydride (795 mg, 5 equiv) and triethylamine (236 mg, 1.5
equiv) were added, and the solution was stirred at rt for 20 h.
This 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 (1:1) was obtained methyl 5-acetoxy-6-oxohep-
tanoate (9h ) (167 mg, 50%): oil; 1H NMR δ 1.6-1.9 (m, 4 H),
2.16 (s, 3 H), 2.17 (s, 3 H), 2.36 (t, J ) 7 Hz, 2 H), 3.68 (s, 3
H), 5.00 (dd, J ) 8 × 4 Hz, 1 H); 13C NMR δ 20.59, 20.66,
26.13, 29.47, 33.30, 51.66, 78.22, 170.55, 173.40, 204.99; IR
104.12, 170.24, 177.79; IR 2950, 1740, 1380, 1240, 1080 cm-1
.
Anal. Calcd for C13H24O6: C, 56.51; H, 8.75. Found: C, 57.04;
H, 8.62.
Met h yl
2-a cet oxy-4,4-d im et h yl-5,5-d im et h oxyp en -
ta n oa te (12): oil; 1H NMR δ 0.93 (s, 3 H), 0.96 (s, 3 H), 1.7-
1.8 (m, 2 H), 2.14 (s, 3 H), 3.51 (s, 6 H), 3.37 (s, 3 H), 3.85 (s,
1 H), 5.13 (dd, J ) 8 × 4 Hz, 1 H); 13C NMR δ 20.60, 21.78,
22.86, 37.54, 39.05, 52.08, 58.31, 58.38, 70.12, 113.23, 170.21,
171.27; IR 2950, 1750, 1380, 1240, 1080 cm-1. Anal. Calcd
for C12H22O6: C, 54.95; H, 8.45. Found: C, 54.91; H, 8.53.
Met h yl
2,2-d im et h yl-4-a cet oxy-5,5-d im et h oxylp en -
ta n oa te (13) (in admixture with 80% 12): oil; 1H NMR δ 1.18
(s, 3 H), 1.21 (s, 3 H), 1.7-1.8 (m, 2 H), 2.02 (s, 3 H), 3.39 (s,
3 H), 3.41 (s, 3 H), 3.66 (s, 3 H), 4.22 (d, J ) 5 Hz, 1 H), 5.0-

5958 J . Org. Chem., Vol. 61, No. 17, 1996
Kawamura et al.
5.1 (m, 1 H); 13C NMR δ 20.83, 23.72, 26.81, 38.55, 40.13, 51.56,
54.66, 55.49, 69.40, 104.69, 170.08, 177.75.
34 Hz), 104.48 (q, J ) 34 Hz), 112.42, 112.54, 121.01 (q, J )
287 Hz), 121.13 (q, J ) 288 Hz), 126.68, 126.77, 128.30, 128.41,
128.41, 128.59, 130.49, 131.95, 132.38, 169.95, 170.02, 205.55,
205.60; IR 2950, 1760, 1460, 1220, 1090, 760 cm-1. Anal. Calcd
for C19H23F3O6: C, 56.43; H, 5.73. Found: C, 56.66; H, 6.01.
2-(Acyloxy)-5-m et h yl-5-[3-m et h yl-5-p h en yl-5-(t r iflu o-
r om eth yl)-1,2,4-tr ioxola n -4-yl]h exa n a l (8n ): oil; 1H NMR
δ 1.11 (s, 3 H), 1.21 (s, 3 H), 1.26 (s, 3 H), 1.5-2.0 (m, 4 H),
2.20 (s, 3 H), 4.9-5.0 (m, 1 H), 7.3-7.6 (m, 5 H), 9.54 (s, 1 H);
13C NMR δ 18.86, 20.56, 23.22, 23.97, 31.63, 33.40, 39.48,
103.18 (q, J ) 34 Hz), 117.01, 121.44 (q, J ) 289 Hz), 126.57,
128.34, 130.24, 132.67, 170.64, 198.25; IR 3000, 1750, 1380,
1090, 960, 720 cm-1. Anal. Calcd for C19H23F3O6: C, 56.43;
H, 5.73. Found: C, 55.87; H, 6.00.
Ozon olysis of High ly-Su bstitu ted Cycloh exen -2-yl Ac-
eta tes 1m ,n in th e P r esen ce of Tr iflu or oa cetop h en on e.
Ozonolysis of 1m is representative. After treating a solution
of 2,4,4-trimethyl-2-cyclohexen-1-yl acetate (1m ) (192 mg, 1.05
mmol) and trifluoroacetophenone (184 mg, 1.05 mmol) in ether
(15 mL) with ozone (1.5 equiv) at -70 °C, the crude products
were separated by column chromatography on silica gel.
Elution with ether-hexane (1:4) gave the crossed-ozonide 5m
(373 mg, 88%).
2,2-Dim eth yl-5-a cetoxy-6-[3-m eth yl-5-p h en yl-5-(tr iflu -
or om eth yl)-1,2,4-tr ioxola n -3-yl]p en ta n a l (5m ): oil (a 1:1
1
mixture of two isomers); H NMR δ 1.08 (s, 3 H), 1.09 (s, 1.5
H), 1.10 (s, 1.5 H), 1.36 (s, 1.5 H), 1.5-1.7 (m, 4 H), 2.16 (s,
1.5 H), 2.11 (s, 3 H), 5.24 (t, J ) 6 Hz, 0.5 H), 5.29 (t, J ) 6
Ack n ow led gm en t. We thank the British Council
(Tokyo) for the award of travel grants to M.N.
Hz, 1 H), 7.4-7.6 (m, 5 H), 9.45 (s, 0.5 H), 9.46 (s, 0.5 H); 13
C
NMR δ 17.21, 19.08, 20.77, 20.81, 21.17, 21.24, 21.37, 21.40,
24.64, 25.00, 32.69, 33.06, 45.48, 72.40, 72.76, 104.10 (q, J )
J O960219P