Transformations of peroxide ozonolysis products of (R)-Menth-4-en-3-one in the presence of nitrogen-containing organic compounds

Article abstract of DOI:10.1134/S1070428013010089

The results of ozonolysis of (R)-menth-4-en-3-one in methylene chloride, methanol, or their 1: 1 mixture in the presence of pyridine, triethylamine, or semicarbazide hydrochloride are reported. Probable schemes for the formation of ozonolysis products, in

Full text of DOI:10.1134/S1070428013010089

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 1, pp. 42–45. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © G.Yu. Ishmuratov, A.V. Bannova, E.R. Latypova, V.S. Tukhvatshin, O.S. Kukovinets, R.R. Muslukhov, G.A. Tolstikov, 2013,
published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 1, pp. 52–55.
Transformations of Peroxide Ozonolysis Products
of (R)-Menth-4-en-3-one in the Presence of Nitrogen-Containing
Organic Compounds
G. Yu. Ishmuratova, b, A. V. Bannovaa, b, E. R. Latypovab, V. S. Tukhvatshinb,
O. S. Kukovinetsa, b, R. R. Muslukhova, and G. A. Tolstikova
a Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: insect@anrb.ru
b Bashkir State University, Ufa, Bashkortostan, Russia
Received May 31, 2012
Abstract—The results of ozonolysis of (R)-menth-4-en-3-one in methylene chloride, methanol, or their 1:1
mixture in the presence of pyridine, triethylamine, or semicarbazide hydrochloride are reported. Probable
schemes for the formation of ozonolysis products, including minor ones, are proposed. Nitrogen-containing
organic compounds can act as reducing agents toward peroxides or catalyze their rearrangements.
DOI: 10.1134/S1070428013010089
We previously described [1] transformation paths of
(R)-menth-4-en-3-one (I) under ozonolysis conditions
in aprotic solvents (CH2Cl2 or CCl4) and their mixtures
with methanol. These transformations involved either
rearrangement of intermediate zwitterion II into mixed
(3R)-3-methyl-5-oxopentanoic isobutyric anhydride
(III) or stabilization of II as α-methoxy hydroperoxide
IV. Acid-catalyzed methanolysis of IV, as well as of
anhydride III, afforded ester V (Scheme 1).
The present article reports on the results of ozonol-
ysis of cyclic conjugated enone I in methylene chloride
or methanol and their mixture in the presence of nitro-
gen-containing organic compounds, such as pyridine,
triethylamine, and semicarbazide hydrochloride that
are known [2, 3] as peroxide oxygen acceptors.
The ozonolysis of I in methylene chloride in the
presence of 1 equiv of pyridine gave dioxo acid VI in
good yield (Scheme 2). When methylene chloride was
Scheme 1.
Me
O
Me
CH2Cl2 or CCl4
Me
O
Me
O
–O
O
Me
O
O
O3
II
Me
O
O
O
Me
Me
Me
CH2Cl2 or CCl4, MeOH
Me
Me
Me
O
–MeOH
I
III
OMe
O
HO
IV
OMe Me
O
MeOH, TsOH
MeO
OMe
V
42

TRANSFORMATIONS OF PEROXIDE OZONOLYSIS PRODUCTS
43
Scheme 2.
low-molecular-weight insect bioregulators [9]
(Scheme 6).
O3, pyridine (1 equiv)
CH2Cl2, 0°C
O
Me
O
Me
I
HO
Me
Scheme 6.
O
(1) O3, MeOH–CH2Cl2 (1:1), 0°C
(2) H2NC(O)NHNH2·HCl
VI
I
V
replaced by methanol, other conditions being equal,
methyl hydrogen (3R)-3-methylglutarate (VII) was
obtained in high yield (Scheme 3). Ester VII is
an intermediate product in the synthesis of mitosenes
that show pharmacological activity against Escherichia
coli and leukemia in mice [4], verrucarin derivatives
possessing antitumor, fungicidal, cytotoxic, and anti-
bacterial activity [5, 6], and Windaus and Grund-
mann’s C19 ketone (for the preparation of vitamins D2
and D3) [7].
The formation of diketo acid VI from peroxide II
is likely to include the following transformations
(Scheme 7). In the first step, pyridine reduces carbonyl
oxide II to dioxo aldehyde X; in the second step, pyr-
idine with ozone forms a complex which effectively
oxidizes aldehydes to the corresponding acids [10].
Scheme 7.
Me
O
Me
C5H5N
–C5H5N
C5H5N·O3
II
VI
Me
O
→O
Scheme 3.
O
O3, pyridine (1 equiv)
MeOH, 0°C
X
O
Me
O
I
Formyl ester IX and 3-methylglutaric acid mono-
HO
OMe
ester VII are formed according to Scheme 8, where
pyridine (or triethylamine) catalyzes the transforma-
tion of hydroperoxide IV into anhydride III.
VII
The use of a 1:1 mixture of methylene chloride and
methanol in the ozonolysis of I reduced the yield of
VII to 63%; in addition, dioxo acid VI, keto ester
VIII, and formyl ester IX were detected as minor
products (Scheme 4). Compound VIII is known as
intermediate product in the synthesis of (S)-(+)-hydro-
prene [8]. Analogous results were obtained using
triethylamine instead of pyridine (Scheme 5).
Scheme 8.
Pyridine or Et3N
–MeOH
MeOH
IV
III
IX
C5H5N·O3 or Et3N·O3
VII
Presumably, keto ester VIII is the methanolysis
product of intermediate acyl cation XII arising from
rearrangement of sterically strained molozonide XI
(Scheme 9).
Scheme 4.
O3, pyridine (1 equiv)
MeOH–CH2Cl2 (1:1), 0°C
I
VI
+
VII
Me
O
Me
O
Me
O
O
Scheme 9.
+
+
Me
MeO
Me
H
OMe
VIII
IX
O3, pyridine or Et3N
MeOH–CH2Cl2, 0°C
VI:VII:VIII:IX = 1.7:18.9:2.8:1.0
I
O
O
Scheme 5.
Me
O
O
O3, Et3N (1 equiv)
MeOH–CH2Cl2 (1:1), 0°C
Me
XI
I
VI
+
VII
+
VIII
+
IX
VI:VII:VIII:IX = 2.3:19.2:1:1.2
Me
O
Me
MeOH
VIII
When the peroxide ozonolysis product generated
Me
–O2
O
from compound I in a 1 : 1 mixture of methylene
chloride with methanol was treated with semicarbazide
hydrochloride, we isolated in high yield acetal V, the
key building block for the synthesis of a number of
XII
Semicarbazide hydrochloride is likely to catalyze
the rearrangement of hydroperoxide IV, which is ac-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

ISHMURATOV et al.
44
companied by elimination of methanol molecule, and
acid methanolysis of intermediate mixed anhydride III
with formation of acetal V (Scheme 10).
(petroleum ether–t-BuOMe, 3:1), [α]D21 = –2.0° (c =
0.78; CH2Cl2). IR spectrum (KBr), ν, cm–1: 3680–3039
(COOH), 1708 (C=O). H NMR spectrum, δ, ppm:
1
1.03 d (3H, 3-CH3, J = 6.6 Hz), 1.10 d (6H, 7-CH3,
C8H3, J = 7.0 Hz), 2.28–2.55 m (5H, 2-H, 3-H, 4-H),
3.50 sept (1H, 7-H, J = 7.0 Hz), 10.2 br.s (1H, OH).
13C NMR spectrum, δC, ppm: 17.40 q (7-CH3, C8),
20.01 q (3-CH3), 25.61 d (C3), 33.55 d (C7), 40.47 t
(C2), 42.75 t (C4), 178.52 s (C1), 199.16 s (C5),
202.92 s (C6). Mass spectrum, m/z (Irel, %): 201 (100)
[M + H]+, 199 (47) [M – H]+.
Scheme 10.
MeOH
H2NC(O)NHNH2·HCl
H2NC(O)NHNH2·HCl
IV
III
V
–MeOH
EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR
Prestige-21 spectrometer from thin films. The H and
b. An ozone–oxygen mixture (23.0 mmol of O3)
was passed at 0°C through a solution of 2.00 g
(13.2 mmol) of enone I and 1.1 ml (13.2 mmol) of pyr-
idine in 20 ml of anhydrous methanol until the initial
compound disappeared. The mixture was purged with
argon and stirred at room temperature until peroxide
compounds disappeared, methanol was distilled off
under reduced pressure, 100 ml of diethyl ether was
added to the residue, and the solution was washed with
brine (3 ×5 ml) to pH 7 and a saturated solution of
CuSO4 (3×5 ml), dried over MgSO4, and evaporated.
The residue was subjected to chromatography on silica
gel using petroleum ether–tert-butyl methyl ether
(10:1) as eluent to isolate 1.77 g (84%) of (3R)-3-
methyl-5-methoxy-5-oxopentanoic acid (VII). Rf 0.19
(petroleum ether–t-BuOMe, 3:1), [α]D21 = +1.6° (c =
0.32, CHCl3). The IR and 1H NMR spectra of the prod-
uct were identical to those reported in [6]. 13C NMR
spectrum, δC, ppm: 19.76 q (3-CH3), 27.13 d (C3),
40.44 t (C2), 40.65 t (C4), 51.50 q (OCH3), 172.76 s
(C5), 178.36 s (C1). Mass spectrum, m/z (Irel, %): 161
(100) [M + H]+, 159 (30) [M – H]+.
1
13C NMR spectra were measured on a Bruker AM-300
spectrometer at 300.13 and 75.47 MHz, respectively,
using CDCl3 as solvent and reference (δ 7.27,
δC 77.00 ppm). Chromatographic analyses were per-
formed on Chrom-5 [1.2-m column packed with
5% SE-30 + 3% OV-225 on Chromaton N-AW-DMCS
(0.16–0.20 mm), oven temperature 50–200°C] and
Shimadzu GC-9A instruments [25-m quartz capillary
column, stationary phase DB-1, film thickness
0.25 μm; oven temperature 80–280°C]; carrier gas
helium. The optical rotations were measured on
a Perkin Elmer 241-MC polarimeter. Silica gel L (60–
200 μm, Lancaster, UK) was used for column chroma-
tography; TLC was performed on Sorbfil plates
(Russia), The mass spectra (atmospheric pressure
chemical ionization, 20 eV; positive and negative ion
detection) were obtained on a Shimadzu LCMS 2010
EV instrument; nebulizer gas (nitrogen) flow rate
0.05 l/min; eluent aqueous methanol (1:1), flow rate
0.03 ml/min. Petroleum ether with bp 40–70°C was
used for chromatographic separations. The efficiency
of ozonizer was 35 mmol O3 per hour. The solvents
used were preliminarily dried according to standard
procedures.
c. An ozone–oxygen mixture (23.0 mmol of O3)
was passed at 0°C through a solution of 2.00 g
(13.2 mmol) of enone I and 1.1 ml (13.2 mmol) of
pyridine in a mixture of 10 ml of anhydrous methylene
chloride and 10 ml of anhydrous methanol until the
initial compound disappeared. The mixture was purged
with argon, stirred at room temperature, and evaporat-
ed under reduced pressure. The residue was treated
with 100 ml of diethyl ether, and the solution was
washed with brine (3×5 ml) until pH 7, dried over
MgSO4, and evaporated. According to the GLC data,
the residue contained compounds VI–IX at a ratio of
1.7:18.9:2.8:1.0. The product mixture (2.00 g) was
separated by chromatography on silica gel using petro-
leum ether to petroleum ether–tert-butyl methyl ether
(20:1) as eluent to isolate 0.11 g (4%) of VI, 1.32 g
(63%) of VII, 0.18 g (7%) of VIII, and 0.06 g (6%) of
Ozonolysis of (R)-menth-4(5)-en-3-one.
a. An ozone–oxygen mixture (23.0 mmol of O3) was
passed at 0°C through a solution of 2.00 g (13.2 mmol)
of enone I and 1.1 ml (13.2 mmol) of pyridine in 25 ml
of anhydrous methylene chloride until the initial com-
pound disappeared (TLC). The mixture was purged
with argon and stirred at room temperature until per-
oxide compounds disappeared (KI test), 100 ml of
diethyl ether was added, and the mixture was washed
with brine (3×5 ml) to pH 7, dried over MgSO4, and
evaporated. The residue was subjected to chromatog-
raphy on silica gel using petroleum ether–t-butyl
methyl ether (20:1) as eluent to isolate 2.00 g (76%) of
(3S)-3,7-dimethyl-5,6-dioxooctanoic acid (VI). Rf 0.44
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

TRANSFORMATIONS OF PEROXIDE OZONOLYSIS PRODUCTS
45
IX. The IR and 1H and 13C NMR spectra of VI and VII
were identical to those described previously.
and the solution was washed with brine (3×5 ml) to
pH 7, dried over MgSO4, and evaporated. The residue
was subjected to chromatography on silica gel using
petroleum ether to petroleum ether–tert-butyl methyl
ether (20:1) as eluent to isolate 1.13 g (45%) of methyl
(3R)-3-methyl-5,5-dimethoxypentanoate (V). Rf 0.45
(petroleum ether–t-BuOMe, 3:1), [α]D21 +0.2° (c =
0.55, CH2Cl2) [12]. Mass spectrum, m/z (Irel, %): 175
(79) [M – Me], 159 (93) [M – OMe]. The IR and
1H and 13C NMR spectra of V were identical to those
reported in [12, 13].
Methyl (3S)-3,7-dimethyl-5-oxooctanoate (VIII).
Rf 0.51 (petroleum ether–t-BuOMe, 3:1), [α]D21 = +2.2°
1
(c = 0.5, CH2Cl2) [8]. The IR and H and 13C NMR
spectra of VIII were identical to those reported in [8].
Methyl (3R)-3-methyl-5-oxopentanoate (IX).
Rf 0.23 (petroleum ether–t-BuOMe, 3:1), [α]D21 = +0.6°
(c = 1.33, CH2Cl2). The IR spectrum of IX was
identical to that reported in [11]. 1H NMR spectrum, δ,
ppm: 0.95 d (3H, 3-CH3, J = 6.7 Hz), 2.21 d.d (1H,
2
3
4-H, J = 12.2, J = 5.7 Hz), 2.25–2.38 m (3H, 2-H,
3-H), 2.48 d.d (1H, 4-H, 2J = 12.2, 3J = 6.4 Hz), 3.61 s
(3H, OCH3), 9.70 s (1H, CHO). 13C NMR spectrum,
δC, ppm: 20.05 q (3-CH3), 24.94 d (C3), 40.45 t (C2),
40.52 t (C4), 49.94 q (OCH3), 178.26 s (C5), 201.62 d
(C1). Mass spectrum, m/z (Irel, %): 145 (79) [M + H]+,
143 (25) [M – H]+.
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triethylamine in a mixture of 10 ml of anhydrous
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1
VIII, and 0.08 g (4%) of IX. The IR and H and
13C NMR spectra of VI–IX were identical to those
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was passed at 0°C through a solution of 1.50 g
(9.9 mmol) of compound I in a mixture of 20 ml of
anhydrous methanol and 20 ml of anhydrous methy-
lene chloride until the initial compound disappeared.
The mixture was purged with argon, 3.40 g
(30.0 mmol) of semicarbazide hydrochloride was
added, and the mixture was stirred for 48 h at room
temperature and evaporated under reduced pressure.
The residue was treated with 100 ml of diethyl ether,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013