Ozonolysis of verbenone in methanol

Article abstract of DOI:10.1134/S1070428012070044

The conditions of ozonolysis of verbenone in methanol strongly affect the mechanism of formation of the major product, (1R,3S)-3-acetyl-2,2- dimethylcyclobutane-1-carboxylic acid.

Full text of DOI:10.1134/S1070428012070044

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 7, pp. 914–917. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © O.S. Kukovinets, T.I. Zvereva, V.G. Kasradze, L.R. Khalitova, N.N. Kabal’nova, E.V. Salimova, M.I. Abdullin, 2012, published
in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 7, pp. 919–922.
Ozonolysis of Verbenone in Methanol
O. S. Kukovinetsa, b, T. I. Zverevaa, V. G. Kasradzeb, L. R. Khalitovab, N. N. Kabal’novab,
E. V. Salimovab, and M. I. Abdullina
a Bashkir State University, Ufa, Bashkortostan, Russia
b Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: salimovaev@mail.ru
Received July 18, 2010
Abstract—The conditions of ozonolysis of verbenone in methanol strongly affect the mechanism of formation
of the major product, (1R,3S)-3-acetyl-2,2-dimethylcyclobutane-1-carboxylic acid.
DOI: 10.1134/S1070428012070044
Ozone is a potent and simultaneously selective oxi-
dant, which is widely used in target-oriented syntheses
of biologically active substances with a broad spec-
trum of action [1]. Proper consideration of the effect of
substrate structure on the composition and behavior of
peroxides formed in the course of ozonolysis makes it
possible to plan the use of ozone in the design of
complex molecules [2, 3].
With a view to reveal general relations holding in
the reaction of ozone with α,β-unsaturated ketones
and optimize the procedure for the preparation of
(1R,3S)-3-acetyl-2,2-dimethylcyclobutane-1-carbox-
ylic acid (I), which is the key intermediate product in
the synthesis of the citrus mealybug (Planococcus citri
Risso) pheromone and other cyclobutane-containing
biologically active substances, we examined ozonol-
ysis of verbenone (II). We previously reported on the
ozonolysis of verbenone (II) in acetonitrile and meth-
ylene chloride [4]. In continuation of these studies, the
ozonolysis of II was performed in methanol; the
results are collected in table. It is seen that the amount
of ozone consumed for the oxidation process at –40 to
–60°C does not depend on the solvent nature and is
1.1–1.2 mol of ozone per mole of the substrate. Excess
0.1–0.3 mol of the oxidant is likely to be consumed for
reaction with the solvent or further oxidation of the
ozonolysis products. The major ozonolysis product of
verbenone (II) in methanol, as well as in acetonitrile,
is keto acid I; in addition, its methyl ester III is formed
(Scheme 1).
The reaction stoichiometry was determined accord-
ing to [5]. Figure shows that in the initial period the
amount of ozone absorbed at the inlet (curve 3) rapidly
increases and reaches some constant value, i.e., ozone
enters the reactor at a constant concentration. After
30 min at –60°C, the optical density of the reaction
mixture at the outlet sharply increases (curve 2),
indicating complete consumption of a compound react-
ing with ozone. The time corresponding to termination
of O3/O2 supply is marked with an arrow. Under these
conditions, ~1–1.2 mol of ozone per mole of verbe-
none (II) was absorbed during the ozonolysis process.
Raising the temperature to 0°C (curve 1) leads to
increased consumption of ozone (2 mol of O3 per mole
of II) due to its reaction with the solvent.
According to the NMR data, peroxides IVa–IVc
generated by ozonolysis of II in methanol are stabi-
lized via reaction with the solvent to produce methoxy
Scheme 1.
Me
(1) O3–MeOH, –60°C
(2) –60 to 20°C
O
O
O
O
4
2
3
1
+
Me
OH
Me
OMe
Me
Me
Me Me
Me Me
O
II
(1R,3S)-I, 63%
(1R,3S)-III, 21%
914

OZONOLYSIS OF VERBENONE IN METHANOL
915
Ozonolysis of verbenone (II)
Amount of absorbed ozone,
Solvent
Temperature, °C
–60
Yield of acid I, %
mol per mole of verbenone
Methylene chloride
1.1–1.3
1.1–1.2
70
63
Methanol
–40
–00
Acetonitrile
1.1–1.3
1.1–1.3
~2
1.5–1.7
~2
83
71
70
57
45
Methylene chloride
Methanol
Acetonitrile
Methanol
Scheme 2.
O–
O
O
O
O
O
OH
O–
O
O3, –60°C
O–
II
+
Me
CHO
Me
O
Me
Me Me
Me Me
Me Me
IVa
IVb
IVc
HOO
O
O
O
O
OH
MeOH, –60°C
+
MeO
Me
CHO
Me
OOH
Me
OOH
Me Me
Me Me
Me Me
OMe
OMe
Va
Vb
Vc
hydroperoxides Va–Vc (Scheme 2). In the 13C NMR
spectrum recorded at –60°C immediately after ozona-
tion of II in CD3OD, signals from the double-bonded
carbon atoms in compound Vc appeared at δC 130.01
and 131.25 ppm, and the carbon atoms linked to two
oxygen atoms in Va and Vb resonated at δC 109.25 and
and by NMR. Methyl formate liberated during the
rearrangement was detected by GLC using a capillary
column. Traditional procedures for decomposition of
ozonides, e.g., by the action of dimethyl sulfide,
ensured considerably lower yield of acid I and ester III
(48 and 18%, respectively).
1
116.63 ppm, respectively. The H NMR spectrum of
Intermediate formation of compound Va is con-
firmed by the presence of a signal at δ 9.63 ppm typ-
that mixture contained three downfield signals at
δ 12.34, 12.70, and 13.41 ppm from the hydroperoxide
protons in Va–Vc; a weak signal was also observed at
δ 9.63 ppm. According to PM3 quantum-chemical cal-
culations, tautomeric transformation like Vb↔Vc is
possible. The total energies of tautomers Vb and Vc
are –294245.467 and –294133.274 J/mol, respectively,
i.e., the difference is as small as ~25 J/mol.
0.25
3
0.20
0.15
2
Rise in temperature leads to spontaneous decom-
position of peroxide ozonolysis products, which does
not require the presence of a reducing agent, and crys-
talline acid I gradually separates from the solution with
time. We presumed that increased temperature favors
shift of the equilibrium toward methoxy hydroperoxide
Vb which is converted into acid I and ester III via
intramolecular rearrangements (Scheme 3). Ester III
was separated from acid I by column chromatography
and was identified by GLC using an authentic sample
0.10
0.05
1
0.00
0
5
10
15
20
25
30
Time, min
Variation of ozone absorption in the ozonolysis of verbenone
(II) in methanol at (1) 0 and (2) –60°C; (3) reactor inlet.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 7 2012

KUKOVINETS et al.
916
Scheme 3.
HO
O
O
O
O
–60 to 20°C
O
I + III + HCOOMe
Me
OOH
Me
Me Me
Me Me
VI
OMe
OMe
Vb
Scheme 4.
O
O
–60 to 0°C
O3, –60°C, MeOH
II
Va–Vc
+ I + III
Me
CHO
Me Me
VII
O
O
NaBH(OAc)3
Silica gel
+
I
+
III
VIII, 30%
Me
OH
Me Me
VIII
Scheme 5.
O
O
CHO
O3/O2, 20°C
O3/O2
–O2
O3/O2, MeOH
–CO2, –O2
II
[IVa–IVc]
Vb
+
+
I III
Me
Me Me
VII
ical of an aldehyde proton in the 1H NMR spectrum of
the verbenone ozonolysis products in methanol. We
failed to isolate compound VII because of its instabil-
ity under conditions of chromatographic purification,
but treatment of the product mixture with sodium tri-
acetoxyhydridoborate gave the corresponding reduc-
tion product, alcohol VIII, which was isolated and
identified (Scheme 4). The IR spectrum of VIII con-
tained absorption bands due to stretching vibrations of
ketone (1705 and 1720 cm–1) and hydroxy groups
(3260 cm–1). Compound VIII displayed in the
1H NMR spectrum two singlets at δ 2.06 and 3.88 ppm
from protons in the acetyl and C(O)CH2 groups,
respectively. Protons on C1 and C3 in the cyclobutane
fragment resonated as doublets of doublets at δ 3.51
and 2.69 ppm, respectively, signals from magnetically
nonequivalent methylene protons on C4 were observed
at δ 1.82 and 2.76 ppm, and the OH signal was located
at δ 5.31 ppm.
EXPERIMENTAL
The H and 13C NMR spectra were recorded on
1
a Bruker AM-300 spectrometer at 300 and 75.46 MHz,
respectively, from solutions in CDCl3; the chemical
shifts are given relative to tetramethylsilane. The IR
spectra were measured from thin films on a Specord
M-80 spectrometer. The optical rotations were deter-
mined on a Perkin Elmer 241 MS polarimeter from
solutions in chloroform. GLC analysis was performed
using Chrom-5 (1200× 3-mm column packed with
5% SE-30 on Chromaton N-AW-DMCS; carrier gas
helium) and Shimadzu GC-2014 instruments (DB-
35MS capillary column, 25 m; flame ionization detec-
tor; carrier gas helium; oven temperature programming
from 50 to 300°C at a rate of 10 deg/min). Silica gel
(Macherey-Nagel, 0.063–0.2 mm) was used for pre-
parative column chromatography. The amount of ab-
sorbed ozone was determined by spectrophotometry by
measuring the optical density of ozone in the gas phase
at the inlet and outlet of the reactor (λ 300 nm, SF-46
spectrophotometer, cell path length 5.2 cm).
The ozonation of verbenone (II) in methanol at 0–
20°C required ~2 mol of O3 per mole of II. Excess
ozone oxidizes aldehyde and methoxy hydroperoxide
groups and partly the solvent (MeOH). In this case, the
reaction is likely to follow the scheme described in [6]
(Scheme 5).
(1R,3S)-3-Acetyl-2,2-dimethylcyclobutane-
1-carboxylic acid (I) and its methyl ester III.
a. An ozone–oxygen mixture was passed at –60°C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 7 2012

OZONOLYSIS OF VERBENONE IN METHANOL
917
through a solution of 0.5 g (3.3 mmol) of verbenone
(II) in 5 ml of anhydrous methanol until initial com-
pound II disappeared completely (TLC, petroleum
ether–ethyl acetate, 3:2). The mixture was purged with
argon, left to stand for 48 h at 20°C, and evaporated
under reduced pressure, and the residue (0.52 g) was
recrystallized from CH2Cl2–petroleum ether (1.5:2.5)
to isolate acid I. Yield 0.34 g (63%), white crystals,
mp 98.5–100°C [7], [α]D20 = +28.5° (c = 0.62).
dried over MgSO4. The drying agent was filtered off,
the solvent was distilled off from the filtrate, 20 ml of
anhydrous petroleum ether was added to the residue
(1.02 g), crystals of acid I (0.37 g, 34.3%) were
filtered off, the mother liquor was evaporated, and the
residue was subjected to column chromatography
(petroleum ether–ethyl acetate, 9:1) to isolate 0.22 g
(16%) of ester III and 0.4 g (30%) of alcohol VIII as
a light yellow oily substance. IR spectrum, ν, cm–1:
1
1705 s, 1720 s (C=O); 3260 br.s (OH). H NMR spec-
The mother liquor was subjected to column chro-
matography (petroleum ether–ethyl acetate, 8.5:1.5) to
isolate 0.13 g (21%) of ester III as a colorless oily sub-
stance. The spectral parameters of III were identical to
those reported in [4]. IR spectrum, ν, cm–1: 1710
(C=O), 1735 (C=O, ester). 1H NMR spectrum, δ, ppm:
0.98 s and 1.40 s (3H each, 2-CH3), 2.03 s (3H,
trum, δ, ppm: 0.85 s and 1.59 s (3H each, 2-CH3),
2
1.82 d.d.d (1H, 4-Hcis, J4,1 = J4,3 = 8.0, J = 11.0 Hz),
2.06 s (3H, CH3CO), 2.76 d.d.d (1H, 4-Htrans, J4,1
=
2
J4,3 = J = 11.0 Hz), 2.96 d.d and 3.51 d.d (2H, 1-H,
3-H, J1,4-cis = J3,4-cis = 8.0, J1,4-trans = J3,4-trans = 11.0 Hz),
3.88 d (2H, CH2O), 5.31 br.s (1H, OH). 13C NMR
spectrum, δC, ppm: 17.82 q and 29.80 q (CH3), 18.23 t
(CH2), 30.18 q (CH3), 44.73 s (C2), 45.15 d (C1),
52.35 d (C3), 56.42 t (OCH2), 201.18 s and 207.33 s
(C=O). Found, %: C 65.23; H 8.70. C10H16O3. Cal-
culated, %: C 65.21; H 8.69.
2
CH3CO), 2.11 d.d.d (1H, 4-Hcis, J4,1 = J4,3 = 8.0, J =
2
11.0 Hz), 2.53 d.d.d (1H, 4-Htrans, J4, 1 = J4, 3 = J =
11.0 Hz), 2.66 d.d and 3.06 d.d (2H, 1-H, 3-H, J = 8.0,
8.0, 11.0 Hz), 3.63 s (3H, OCH3). Found, %: C 65.23;
H 8.70. C10H16O3. Calculated, %: C 65.22; H 8.70.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 09-03-00831).
b. The procedure was the same as in a, but the ozo-
nolysis was carried out at 0°C. As a result, 0.24 g
(45%) of acid I and 0.12 g (18%) of ester III were
isolated.
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c. The ozonation procedure was the same as in a.
After purging with argon, 0.36 ml of dimethyl sulfide
was added, and the mixture was stirred for 20 min at
–60°C, allowed to warm up to room temperature, left
to stand for 48 h, and evaporated under reduced pres-
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solution was washed with a saturated solution of sodi-
um chloride, dried over Na2SO4, filtered, and evaporat-
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a to isolate 0.26 g (48%) of I and 0.11 g (18%) of III.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 7 2012