Ozonolytic decyclization of (R)-4-menthen-3-one

Article abstract of DOI:10.1023/A:1020853629281

Ozonolytic decyclization of (R)-4-menthen-3-one is accompanied by fragmentation of the isobutyl group, leading to ω-functionalized 3-methylpentanoic acid derivatives.

Full text of DOI:10.1023/A:1020853629281

Russian Journal of Organic Chemistry, Vol. 38, No. 7, 2002, pp. 1005 1008. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 7, 2002,
pp. 1047 1050.
Original Russian Text Copyright
2002 by Kharisov, Gazetdinov, Botsman, Muslukhov, Ishmuratov, Tolstikov.
,
Ozonolytic Decyclization of (R)-4-Menthen-3-one* **
R. Ya. Kharisov, R. R. Gazetdinov, O. V. Botsman, R. R. Muslukhov,
G. Yu. Ishmuratov, and G. A. Tolstikov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: kharis@anrb.ru
Received October 5, 2001
Abstract Ozonolytic decyclization of (R)-4-menthen-3-one is accompanied by fragmentation of the isobutyl
group, leading to -functionalized 3-methylpentanoic acid derivatives.
Monoterpenoids constitute a class of compounds
which are widely used in the synthesis of optically
active substances. One of such substrates is (R)-pule-
gone (enantiomeric purity 100%) which is isolated
from Mentha pulegium. Numerous examples have
been reported on the use of (R)-pulegone for the
synthesis of chiral building blocks [2]. However,
(L)-( )-menthol (I), a relatively readily accessible
monoterpenoid, has been reported mainly as a chiral
auxiliary [3], whereas its application for the synthesis
of chirons seems to be poorly explored. With the goal
of further extending synthetic potential of (L)-( )-
menthol (I), in the present work we examined ozono-
lytic decyclization of (R)-4-menthen-3-one (II) which
was obtained previously [4] from compound I via
bromination debromination of the corresponding enol
acetate. Analysis of published data [5, 6] led us to
presume that ozonolysis of the conjugated enone
system in molecule II involves formation of zwitter-
ionic intermediate IV through decomposition of
ozonide III. If the ozonolysis is carried out in an inert
medium, the subsequent rearrangement of inter-
mediate IV (like the Baeyer Villiger reaction [7, 8])
should give isobutyric (3R)-3-methyl-5-oxopentanoic
anhydride (V). Acid methanolysis of mixed anhydride
V should result in formation of the corresponding
esters VI and VII (Scheme 1).
According to published data [7, 8], cleavage of the
deactivated double bond in a conjugated enone system
requires excess ozone. Therefore, we used 3.5 equiv
of O3 per mole of enone II. The reaction was carried
out in methylene chloride at 65 C. The mixture was
Scheme 1.
____________
*
For preliminary communication, see [1].
**
This study was financially supported by the Integratsiya
Federal Special-Purpose Program of the Russian Federation
(project no. 485).
1070-4280/02/3807-1005$27.00 2002 MAIK Nauka/Interperiodica

1006
KHARISOV et al.
then kept for 24 h at room temperature and treated
with acidified methanol (method a) to isolate acetal
VI and dimethyl 3-methylglutarate (VIII) (Scheme 2).
in this case the aldehyde group is protected via
acetalization.
Scheme 3.
Scheme 2.
Taking into account that diester VIII could be
formed by oxidation of the aldehyde group in IV
during ozonolysis, the amount of ozone was reduced
to 1 equiv. In this case, the conversion of enone II
was also complete, but treatment of the reaction mix-
ture according to procedure a gave a considerable
amount of diester VIII (up to 10% with respect to
VI). We succeeded in obtaining anhydride V by
raising the reaction temperature to 20 C and using
carbon tetrachloride as solvent instead of methylene
chloride. The formation of compound V was con-
firmed by spectral data (which were obtained at room
temperature). In the IR spectrum we observed absorp-
The oxidation of II with 1 equiv of ozone in carbon
tetrachloride at 20 C in the presence of 2 equiv of
methanol and the subsequent methylation (method c)
led to formation of acetal VI. The same result was
obtained on raising the temperature to 5 C. At that
temperature the reaction may be performed in cyclo-
hexane in the presence of methanol with the same
amount of ozone (Scheme 4). It should be noted that
in the ozonolysis in carbon tetrachloride and cyclo-
hexane in the presence of methanol the reaction
mixture divided into layers.
1
tion bands at 1720 and 2728 cm , which are typical
of aldehyde group, and anhydride carbonyl bands at
1
1808 and 1840 cm . The aldehyde group in V gives
Scheme 4.
1
rise to a multiplet at
spectrum and a doublet at
9.77 ppm in the H NMR
200.77 ppm in the 13C
NMR spectrum. The anhydriCde carbonyl carbon atoms
appear as singlets at
signals typical of ozonides were observed in the
region 103 105 ppm.
168.17 and 172.30 ppm. No
C
C
When ozonolysis of enones is performed at 65 C
in methylene chloride [7] in the presence of methanol,
zwitterionic intermediates are stabilized through
transformation into -methoxy hydroperoxides. Pre-
sumably, in our case (3R)-6-hydroperoxy-6-methoxy-
3,7-dimethyl-5-oxooctanal (IX) is obtained. When
the reaction mixture warms up to room temperature,
compound IX decomposes with strong heat evolution,
and the decomposition is complete in 48 h (accord-
ing to the iodine starch test). Methylation of the reac-
tion mixture (method b) should give rise to acetal VI
and volatile ester VII (Scheme 3). However, even
with 0.85 equiv of ozone per mole of enone II, the
reaction mixture contained diester VIII together with
compound VI (according to the GLC data; see table).
Probably, the aldehyde group in IX is oxidized by
the hydroperoxide moiety either intra- or intermole-
cularly. When the reaction mixture was treated with
methanol immediately after ozonolysis (method c),
only traces of diester VIII were formed. Obviously,
GLC analysis of the methylation products obtained
according to method c (0.85 mol of O3, 1 mol of
enone II, methanol) showed the presence of a con-
siderable amount of diester VIII in addition to initial
enone II and acetal VI. This may be due to better
solubility of hydroperoxide IX in methanol than in
nonpolar solvents, so that the aldehyde moiety in IX
can be oxidized to carboxy group with an ozone
oxygen mixture.
Our experimental data indicate enhanced reactivity
of the double bond in enone II in the ozonolysis.
Presumably, positive inductive effect of the isopropyl
group partially compensates negative mesomeric
effect of the carbonyl group in menthenone II, which
favors delocalization of the double bond intrinsic to
common enone systems. For example, the ozonolysis
of 1-methylcyclohexene in methanol at 40 C is
complete on passing 1 equiv of ozone [9], whereas
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 7 2002

OZONOLYTIC DECYCLIZATION OF (R)-4-MENTHEN-3-ONE
Ozonolysis of (R)-4-menthen-3-one
1007
Run
no.a
Amount of O3,
mol per mole of II
Solvent
Temperature,
C
Decomposition
methodb
Products
1
2
3
4
5
6
7
8
9
3.5
1
1
0.85
1
1
1
1
0.85
CH2Cl2
CH2Cl2
CCl4
CH2Cl2 MeOH
CH2Cl2 MeOH
CCl4 MeOH
CCl4 MeOH
cyclo-C6H12 MeOH
MeOH
65
65
20
65
65
20
5
a
a
VI, VIII
VI, VIII
V
II, VI, VIII
VI, VIII
VI
VI
VI
Without decomposition
b
c
c
c
c
c
5
5
II, VI, VIII
a
See Experimental.
b
Method a: methanolysis after 24 h; b: methanolysis after 48 h; c: methanolysis immediately after ozonolysis.
3 to 12 equiv of ozone is required to effect ozonolysis
of 2-cyclohexenone.
respect to II) was passed at 65 C through a solution
of 1.00 g (6.58 mmol) of enone II in 10 ml of
CH2Cl2. The mixture was then treated according to
method a: it was purged with argon and was left to
stand for 24 h at room temperature; a solution of
0.05 g of p-toluenesulfonic acid in 20 ml of methanol
was added, the mixture was stirred for 48 h, 0.50 g of
NaHCO3 was added, and the mixture was evaporated
under reduced pressure. The residue was treated with
50 ml of Et2O, and the extract was washed with
a saturated solution of NaCl (to pH 7), dried over
Na2SO4, and evaporated to obtain 1.12 g of an oily
substance which contained mainly (according to the
GLC data) compounds VI and VIII at a ratio of 7:3.
By chromatography on silica gel [gradient elution
with petroleum ether (bp 40 70 C) tert-butyl methyl
ether, 10:1 to 3:1] we isolated 0.21 g (16.8%) of
acetal VI and 0.43 g (37.8%) of diester VIII.
The stability of peroxy-containing ozonolysis prod-
ucts increases as the solvent polarity rises, i.e., in
going from carbon tetrachloride to methylene chloride
and then to methanol. Zwitterionic intermediate IV
is likely to form a relatively stable complex with
methylene chloride whose dipole moment is about
1.6 D, and peroxide products decompose within 24 h.
In carbon tetrachloride ( = 0), the rate of rearrange-
ment of analogous complex is considerably higher,
and the reaction yields anhydride V. As stated above,
stabilization of intermediate IV in methanol is
achieved via formation of even more stable -methoxy
hydroperoxide IX.
EXPERIMENTAL
Run no. 2. An ozone oxygen mixture (1 equiv of
O3) was passed at 65 C through a solution of 1.00 g
(6.58 mmol) of enone II in 10 ml of CH2Cl2. The
mixture was then treated according to procedure a
to obtain 1.21 g of an oily substance. The major com-
ponents of the product were compounds VI and VIII
at a ratio of 9:1 (GLC).
The IR spectra were recorded on a UR-20 spec-
trometer from samples prepared as thin films. The
1H and 13C NMR spectra were obtained on a Bruker
AMX-300 instrument (300.13 MHz for 1H and
75.47 MHz for 13C) using CDCl3 as solvent and
internal reference ( 7.27 ppm,
77.00 ppm). GLC
analysis was performed on a ChroCm-5 chromatograph;
1.2-m column packed with 5% of SE-30 on Chroma-
ton N-AW-DMCS (0.16 0.20 mm); oven temperature
50 300 C; carrier gas helium. The specific rotations
were measured on a Perkin Elmer 241-MC instru-
ment. The reactions were carried out in dry purified
solvents. The ozonizer efficiency was 40 mmol of O3
per hour. The presence of peroxide compounds was
checked by iodine starch test.
Run no. 3. An ozone oxygen mixture (1 equiv of
O3) was passed at 20 C through a solution of 0.20 g
(1.31 mmol) of enone II in 11 ml of CCl4. The
mixture was concentrated by purging with argon.
According to the spectral data, the residue contained
1
anhydride V. IR spectrum, , cm : 808, 936, 1080,
1168, 1232, 1288, 1412, 1456, 1504, 1520, 1680,
1
1704, 1720, 1740, 1808, 2728, 3050. H NMR spec-
trum, , ppm: 1.10 d (3H, 3-CH3, J = 8.9 Hz), 1.23 d
(6H, 2 -CH3, J = 7.0 Hz), 2.32 2.72 m (6H, CH2,
Ozonolysis of (R)-4-menthen-3-one. Run no. 1.
An ozone oxygen mixture (3.5 equiv of O3 with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 7 2002

1008
KHARISOV et al.
CH), 9.77 d (1H, CHO, J = 0.005 Hz). 13C NMR
spectrum, C, ppm: 18.23 (C2 ), 19.79 (3-CH3), 24.64
(C3), 34.92 (2 -CH3), 41.42 (C2), 49.60 (C4), 168.17
(C1), 172.30 (C1 ), 200.77 (CHO).
(to pH 7), dried over Na2SO4, and evaporated to
obtain 5.44 g (87%) of acetal VI.
Run no. 8. An analogous experiment was carried
out in cyclohexane.
Run no. 4. An ozone oxygen mixture (0.85 equiv
of O3) was passed at 65 C through a solution of
1.00 g (6.58 mmol) of enone II in 10 ml of CH2Cl2
containing 0.54 ml (0.43 g, 13.4 mmol) of methanol.
The mixture was treated according to procedure b:
it was purged with argon and was left to stand for
48 h at room temperature. A solution of 0.05 g of
p-toluenesulfonic acid in 20 ml of methanol was
added, the mixture was stirred for 48 h, 0.50 g of
NaHCO3 was added, and the mixture was evaporated
under reduced pressure. The residue was treated with
50 ml of Et2O, and the extract was washed with
a saturated solution of NaCl (to pH 7), dried over
Na2SO4, and evaporated. The residue was 1.05 g of
an oily substance which contained mainly compounds
II, VI, and VIII at a ratio of 1:3:2 (GLC).
Run no. 5. An ozone oxygen mixture (1 equiv of
O3) was passed at 65 C through a solution of 1.00 g
(6.58 mmol) of enone II in 10 ml of CH2Cl2 contain-
ing 0.54 ml (0.43 g, 13.4 mmol) of methanol. The
mixture was treated according to procedure c: it was
purged with argon, a solution of 0.05 g of p-toluene-
sulfonic acid in 20 ml of methanol was added, the
mixture was stirred for 48 h, 0.50 g of NaHCO3 was
added, and the mixture was evaporated under reduced
pressure. The residue was treated with 50 ml of
Et2O, and the extract was washed with a saturated
solution of NaCl (to pH 7), dried over Na2SO4, and
evaporated under reduced pressure. The residue was
1.15 g of an oily substance, the major component of
which was acetal VI (GLC).
Run no. 9. An ozone oxygen mixture (0.85 1 equiv
of O3) was passed at 5 C through a solution of 1.00 g
(6.58 mmol) of enone II in 10 ml of methanol. The
mixture was then treated according to procedure c
to isolate 1.20 g of an oily substance. According to
the GLC data, the major components of the product
were compounds II, VI, and VIII at a ratio of 2:2:1.
Methyl (R)-5,5-dimethoxy-3-methylpentanoate
(VI). [ ]2D5 = 1.54 (c = 4.76, CHCl3) (cf. [10]). The
1
IR and H NMR parameters were almost identical to
those reported in [10]. 13C NMR spectrum, C, ppm:
19.48 q (3-CH3); 26.14 d (C3); 38.38 t (C4); 40.78 t
(C2); 50.56 q, 51.42 q, and 52.00 q (OCH3); 102.30 d
(C5), 172.35 s (C1).
Dimethyl 3-methylglutarate (VIII). The IR and
1H NMR spectral parameters were almost identical
to those reported in [11].
REFERENCES
1. Kharisov, R.Ya., Botsman, O.V., Gazetdinov, R.R.,
Ishmuratov, G.Yu., and Tolstikov, G.A., Izv. Ross.
Akad. Nauk, Ser. Khim., 2001, no. 6, p. 1067.
2. Ishmuratov, G.Yu., Yakovleva, M.P., Khari-
sov, R.Ya., and Tolstikov, G.A., Monoterpenoidy
v sinteze opticheski aktivnykh feromonov nasekomykh
(Monoterpenoids in the Synthesis of Optically Active
Insect Pheromones), Ufa: Gilem, 1999.
3. Weiping, C. and Jianliang, X., Tetrahedron Lett.,
2001, vol. 42, pp. 2897 2899.
4. Treibs, W. and Albrecht, H., J. Prakt. Chem., 1961,
vol. 13, nos. 5 6, pp. 291 305.
5. Fliszar, S. and Granger, M., J. Am. Chem. Soc.,
1969, vol. 91, no. 12, pp. 3330 3337.
6. Odinokov, V.N. and Tolstikov, G.A., Usp. Khim.,
Run no. 6. An ozone oxygen mixture (1 equiv of
O3) was passed at 20 C through a solution of 1.00 g
(6.58 mmol) of enone II in 7 ml of CCl4 containing
0.54 ml (0.43 g, 13.4 mmol) of methanol. The mixture
was then treated according to procedure c to obtain
1.06 g (85%) of acetal VI.
1981, vol. 50, no. 7, pp. 1207 1251.
7. Chorvat, R.J. and Pappo, R., J. Org. Chem., 1976,
Run no. 7. An ozone oxygen mixture (1 equiv of
O3) was bubbled at 5 C through a solution of 5.00 g
(32.9 mmol) of enone II in 35 ml of CCl4 containing
2.82 ml (65.9 mmol) of methanol. The mixture was
purged with argon, a solution of 0.25 g of p-toluene-
sulfonic acid in 50 ml of methanol was added, and
the mixture was left to stand for 2 days at room
temperature (until peroxide compounds disappeared
according to iodine starch test). Sodium hydrogen
carbonate, 2.50 g, was added, and the mixture was
evaporated under reduced pressure. The residue was
treated with 100 ml of Et2O, and the extract was
washed with a saturated solution of sodium chloride
vol. 41, no. 17, pp. 2864 2865.
8. US Patent no. 3109016, 1963; Chem. Abstr., 1964,
vol. 60, p. 3045f.
9. Galin, F.Z., Kukovinets, O.S., Zainullin, R.A., She-
reshovets, V.V., Kashina, Yu.A., Akhmetov, A.M.,
Kunakova, R.V., and Tolstikov, G.A., Russ. J. Org.
Chem., 2001, vol. 37, no. 2, pp. 238 242.
10. Mori, K. and Kuwahara, S., Tetrahedron, 1982,
vol. 38, no. 4, pp. 521 525.
11. Lam Lister, K.P., Hui Raimond, A.H.F., and
Jones, J.B., J. Org. Chem., 1986, vol. 11, no. 11,
pp. 2047 2050.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 7 2002