Synthesis and some transformations of (-)-carveol

Article abstract of DOI:10.1134/S1070428009060025

Reduction of the oxo group in (-)-carvone with LiAlH4, NaBH4, and (i-Bu)2AlH was performed. It was found that the reduction with the system CeCl₃ ? 7 H2O-NaBH4 in methanol at 20°C is the most practical procedure for the synthesis of (-)-carveol. Solvolysis of (-)-carvyl methanesulfonate gave products of SN2 and SN2' replacement of the methylsulfonyloxy group, the latter slightly prevailing. Overman rearrangement of (-)-carveol resulted in the formation of the corresponding trichloroacetamide derivative, and intramolecular iodoetherification of the title compound afforded 6-iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene. Pleiades Publishing, Ltd., 2009.

Full text of DOI:10.1134/S1070428009060025

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 810–814. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © R.F. Valeev, N.S. Vostrikov, M.S. Miftakhov, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 6, pp. 828–831.
Synthesis and Some Transformations of (–)-Carveol
R. F. Valeev, N. S. Vostrikov, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received March 17, 2008
Abstract—Reduction of the oxo group in (–)-carvone with LiAlH4, NaBH4, and (i-Bu)2AlH was performed. It
was found that the reduction with the system CeCl3 ·7H2O–NaBH4 in methanol at 20°C is the most practical
procedure for the synthesis of (–)-carveol. Solvolysis of (–)-carvyl methanesulfonate gave products of SN2 and
SN2′ replacement of the methylsulfonyloxy group, the latter slightly prevailing. Overman rearrangement of
(–)-carveol resulted in the formation of the corresponding trichloroacetamide derivative, and intramolecular
iodoetherification of the title compound afforded 6-iodomethyl-2,6-dimethyl-7-oxabicyclo[3.2.1]oct-2-ene.
DOI: 10.1134/S1070428009060025
Commercially available and cheap monoterpene
(R)-(–)-carvone (I) is widely used in organic synthesis
as chiral template [1–5]. In the present work we
examined some aspects of selective transformations of
(–)-carvone into building blocks that are more suitable
for subsequent target-oriented syntheses. Initially, we
planned to obtain (–)-carveol (II) by reduction of I
with lithium tetrahydridoaluminate in diethyl ether at
–78°C [6]. According to the GLC data, the purity of
compound II synthesized in this way was 95%, and the
concentration of minor (–)-carveol (III) reached 5%.
The best results (from the viewpoint of stereoselec-
tivity) were obtained using Luche’s reagent (NaBH4–
CeCl3 · 7 H2O) [7]. In this case, the reduction of
(–)-carvone (I) in methanol at room temperature gave
(–)-carveol (II) in 90% yield, and its purity was 98%
(after chromatographic purification on silica gel; cf.
[8–10]) (Scheme 1). In the reduction of I with Luche’s
reagent in THF the yield of (–)-II was 96%, and the
reduction with (i-Bu)2AlH in CH2Cl2 at –78°C gave
80% of (–)-II. From the preparative viewpoint, it is
convenient to perform reduction of (–)-I in methanol
with subsequent purification of the product by vacuum
distillation, although in this case the yield of (–)-II is
somewhat lower (~80%).
We made an attempt to convert (–)-carveol (II) into
its enantiomer. The known procedure for the trans-
formation of (–)-II into (+)-II includes initial prepara-
tion of epoxy derivative, mesylation, and reductive
fragmentation of methanesulfonate IV with “dissolved
metal” (Scheme 2). The yield of (+)-carveol (+)-II in
the latter step was moderate (57%) [11]. We tried
a shorter way of converting carveol enantiomers into
each other via solvolysis of allylic methanesulfonates,
which follows SN2′ mechanism. For this purpose,
(–)-carveol (II) was treated with methanesulfonyl
chloride in the presence of triethylamine, and methane-
sulfonate V thus obtained was heated for 1 h at 60°C in
a mixture of DMSO and 10% aqueous sodium hydrox-
ide (1:1 by volume). The subsequent chromatographic
purification on silica gel gave pure (according to the
GLC data) carveol (III, [α]D20 = +17o).
In our case, the initial (–)-carveol (II) had [α]D20
=
20
–25.4° {published data: [α]D = –25.8 [6], –23.9 [12],
–23.0 (c = 5.6, EtOH, ee 100%) [11]}; (–)-III: [α]D20
=
Scheme 1.
Me
Me
Me
–213.8 [12]. Obviously, the observed optical rotation
of solvolysis product III results from the presence of
a small excess of enantiomeric (+)-carveol (III) which
is formed according to the SN2′ mechanism. Taking
into account that racemization is hardly probable under
the above conditions (alkaline medium), (–)-carveol
(III) is likely to be formed via SN2 substitution of the
O
HO
HO
+
Me
CH2
Me
CH2
Me
CH2
I
II
III
810

SYNTHESIS AND SOME TRANSFORMATIONS OF (–)-CARVEOL
811
Scheme 2.
Me
Me
O
MsO
OH
Me
IV
CH2
Me
CH2
(+)-II
MeSO2Cl, Et3N
(–)-II
Me
Me
Me
MsO
OH
HO
OH–
+
>98%
Me
CH2
Me
CH2
(+)-III
Me
(–)-III
CH2
V
Thus we proposed a highly stereoselective and
practical procedure for the reduction of (–)-carvone to
(–)-carveol using the system NaBH4–CeCl3·7H2O and
studied solvolysis of the corresponding methanesul-
fonate. (–)-Carveol (II) was converted into N-carvyl-
trichloroacetamide via Overman rearrangement, and
intramolecular iodoetherification of (–)-II gave iodo-
methyl-substituted bicyclic ether.
methylsulfonyloxy group in (–)-(V) by hydroxy group.
We can conclude that the solvolysis of methanesulfo-
nate V is not regioselective and that it follows both
possible paths, SN2 and SN2′, though each of these
paths is stereoselective [only (+)- or (–)-carveol (III) is
formed].
With a view to obtain nitrogen-containing chiral
building blocks, (–)-carveol (II) was subjected to
Overman rearrangement [13]. Treatment of (–)-II with
trichloroacetonitrile in methylene chloride in the pres-
ence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at
0°C gave trichloroacetimidate VI which was converted
into trichloroacetamide VII by heating in boiling
xylene (Scheme 3). It is known that this [3,3]-sigma-
tropic rearrangement is suprafacial and stereospecific.
EXPERIMENTAL
The IR spectra were recorded on a UR-20 spec-
1
trometer from samples prepared as thin films. The H
and 13C NMR spectra were measured on a Bruker AM-
300 instrument at 300 and 75.47 MHz, respectively,
using CDCl3 as solvent and tetramethylsilane as in-
ternal reference. Thin-layer chromatography was per-
formed on Silufol plates. The optical rotations were
measured on a Perkin–Elmer 241 MS polarimeter. The
purity of the initial compounds was checked by GLC
on a Chrom 5 chromatograph.
(–)-Carveol (II) was then subjected to intramolec-
ular iodoetherification. cis Arrangement of the isopro-
penyl and hydroxy groups in its molecule favored
iodine-initiated intramolecular cyclization with prefer-
ential formation of sterically less hindered bicyclic
product VIII (Scheme 4). Minor stereoisomer IX was
formed in trace amounts (3–5%) and was detected by
downfield signals from the C6Me group in the 13C
NMR spectrum.
Reduction of (R)-(–)-carvone with LiAlH4. A so-
lution of 5 g (33 mmol) of (R)-(–)-carvone in 10 ml
of diethyl ether was added dropwise to a suspension of
Scheme 3.
Me
Me
H
Cl3C
O
N
CCl3
Cl3CCN, DBU
CH2Cl2, 0°C
Xylene, Δ
NH
O
(–)-II
Me
VI
CH2
Me
CH2
VII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

VALEEV et al.
812
Scheme 4.
Me
Me
I2, NaHCO3
MeCN, 0°C
O
O
Me
CH2I
CH2I
+
(–)-II
Me
VIII
IX
0.32 g (8.3 mmol) of LiAlH4 in 30 ml of diethyl ether
under stirring at –78°C in a stream of argon. The mix-
ture was stirred for ~1.5 h until the initial ketone
disappeared (TLC). Excess LiAlH4 was decomposed
by carefully adding 10% sulfuric acid at 0°C to pH ~7.
The organic phase was separated, the aqueous phase
was extracted with ethyl acetate (3×15 ml), and the
extracts were combined with the organic phase,
washed with a solution of sodium chloride, dried over
MgSO4, and evaporated. The residue was purified by
column chromatography on silica gel using ethyl
acetate–petroleum ether (1:3) as eluent. We isolated
4.8 g (95%) of a mixture of stereoisomers (–)-II and
(–)-III at a ratio of 95:5 (according to the GLC data).
Light yellow oily liquid, [α]D20 = –25.4° (c = 2.1,
EtOH); published data [6]: [α]D20 = –25.8° (ee 97%).
stirring to a solution of 0.1 g (0.67 mmol) of (–)-I
in 20 ml of anhydrous methylene chloride, cooled to
–70°C. The mixture was stirred for 1 h at that tem-
perature, 0.17 ml of water was slowly added dropwise,
the mixture was allowed to warm up to 25°C, the sol-
vent was distilled off under reduced pressure, and the
powder-like residue was extracted with hot methanol
(3×10 ml). The extract was evaporated, and the resi-
due was dried with benzene (azeotropic distillation).
We thus isolated 0.08 g (80%) of a mixture of stereo-
isomers (–)-II and (–)-III at a ratio of 4:1 (according
to the 1H NMR data).
5-Isopropenyl-2-methylcyclohex-2-en-1-ol (III).
Carvyl methanesulfonate (IV), 0.7 g (4.6 mmol), was
added under stirring to 40 ml of a 1 :1 mixture of
DMSO with 5% aqueous sodium hydroxide. The mix-
ture was stirred for 5 h at room temperature (until the
initial compound disappeared according to the TLC
data), neutralized with 5% hydrochloric acid, and
extracted with methylene chloride (3 ×20 ml). The
extracts were combined, dried over MgSO4, and evap-
orated. After removal of DMSO under reduced pres-
sure, the residue was subjected to column chromatog-
raphy on silica gel using ethyl acetate–petroleum ether
(1:3) as eluent to isolate 0.45 g (99%) of compound
III as a mixture of enantiomers, [α]D20 = +17.2° (c =
0.85, EtOH). IR spectrum, ν, cm–1: 3334 (OH), 3082,
(1R,5R)-5-Isopropenyl-2-methylcyclohex-2-en-1-
ol (II). IR spectrum, ν, cm–1: 3331 (OH), 3082 (=C–H),
1
1645 (C=C). H NMR spectrum, δ, ppm: 1.47–1.52 m
(1H, 6-H), 1.72 s (3H, CH3), 1.74 d (3H, CH3, J =
2 Hz), 1.85–2.30 m (5H, 4-H, 5-H, 6-H, OH), 4.17 br.s
(1H, 1-H), 4.71 s (2H, =CH2), 5.44 m (1H, 3-H).
Reduction of (–)-carvone (I) with NaBH4–CeCl3·
7 H2O. a. Sodium tetrahydridoborate, 0.025 g
(0.67 mmol), was added at 20°C to a solution of 0.1 g
(0.67 mmol) of (–)-carvone (I) and 0.25 g (0.67 mmol)
of CeCl3·7H2O in 10 ml of methanol. The mixture was
stirred for 5 min, 20 ml of diethyl ether and 20 ml of
water were added, the organic layer was separated, and
the aqueous layer was extracted with diethyl ether
(3 ×10 ml). The extracts were combined with the
organic phase, dried over Na2SO4, and filtered. The
filtrate was concentrated under reduced pressure, and
the residue was subjected to column chromatography
on silica gel using ethyl acetate–petroleum ether (1:5)
to isolate 0.09 g (90%) of (–)-carveol (II).
1
1645. H NMR spectrum, δ, ppm: 1.58–1.62 m (1H,
6-H), 1.76 s (3H, CH3), 1.82 s (3H, CH3), 1.92–1.97 m
(3H, 4-H, 6-H), 2.13–2.34 m (2H, 5-H, OH), 4.04 m
(1H, 1-H), 4.74–4.76 m (2H, =CH2), 5.59–5.61 m
(1H, 3-H). 13C NMR spectrum, δC, ppm: 20.85 (CH3),
20.91 (CH3), 30.99 (C4), 35.23 (C5), 36.71 (C6),
68.64 (C1), 109.06 (=CH2), 125.47 (C3), 134.22 (C2),
149.15 (C=CH2).
(1R,5R)-5-Isopropenyl-2-methylcyclohex-2-en-1-
yl methanesulfonate (V). Triethylamine, 1.3 g
(13 mmol), was added under stirring in a stream of
argon to a solution of 1.0 g (6.6 mmol) of (–)-carveol
(II) prepared as described above (method a) in 20 ml
of methylene chloride. The mixture was stirred for
15 min, a solution of 1.5 g (13 mmol) of methanesul-
fonyl chloride in 15 ml of methylene chloride was
b. Likewise, the reduction of (–)-I with CeCl3·
7H2O–NaBH4 in THF at 0°C gave 90% of (–)-II with
a purity of 98% (according to the GLC data).
Reduction of (–)-carvone (I) with (i-Bu)2AlH.
A solution of 2.7 mmol of (i-Bu)2AlH in 5 ml of an-
hydrous methylene chloride was added dropwise under
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

SYNTHESIS AND SOME TRANSFORMATIONS OF (–)-CARVEOL
813
slowly added dropwise, and the mixture was stirred for
4 h at 40°C, cooled, and neutralized to pH ~7 with 3%
hydrochloric acid. The organic phase was separated,
and the aqueous phase was extracted with methylene
chloride (3×10 ml). The extracts were combined with
the organic phase, dried over MgSO4, and evaporated,
and the residue was purified by chromatography on
silica gel using ethyl acetate–petroleum ether (1:5) as
eluent. Yield 0.9 g (60%), light yellow oily liquid,
[α]D20 = –57.5° (c = 1.7, EtOH). IR spectrum, ν, cm–1:
3082, 1645, 1440 (SO2), 1379 (S–CH3). 1H NMR spec-
trum, δ, ppm: 1.56 m (1H, 6-H), 1.76 s (3H, CH3),
1.83 s (3H, CH3), 1.94–2.25 m (4H, 4-H, 5-H, 6-H),
2.15 s (3H, SO2CH3), 4.74 br.s (3H, =CH2, 1-H), 5.52–
5.54 m (1H, 3-H). 13C NMR spectrum, δC, ppm: 20.93
(CH3), 21.07 (CH3), 30.76 (C4), 34.86 (C5 and
SO2CH3), 37.14 (C6), 60.67 (C1), 109.26 (=CH2),
126.53 (C3), 133.15 (C2), 148.45 (C=CH2).
moved under reduced pressure, and the residue was
purified by column chromatography on silica gel using
ethyl acetate–petroleum ether (1:10) as eluent. Yield
0.6 g (60%), colorless crystals, mp 90–90.5°C, [α]D20
=
–38.8° (c = 4.3, MeOH). IR spectrum, ν, cm–1: 3298
1
(NH), 1692. H NMR spectrum, δ, ppm: 1.60–1.65 m
(1H, 6-H), 1.69 s (3H, CH3), 1.76 s (3H, CH3), 2.04 m
(1H, 6-H), 2.13–2.33 m (3H, 4-H, 5-H), 4.52 m (1H,
1-H), 4.76 s (1H, =CH2), 4.79 s (1H, =CH2), 5.64–
5.68 m (1H, 3-H), 6.68 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 19.64 (CH3), 21.14 (CH3), 30.13 (C4),
34.02 (C6), 39.25 (C5), 51.34 (C1), 92.88 (CCl3),
109.87 (=CH2), 125.96 (C3), 132.03 (C2), 148.42
(C=CH2), 161.49 (C=O).
(1R,5R,6S)-6-Iodomethyl-2,6-dimethyl-7-oxabi-
cyclo[3.2.1]oct-2-ene (VIII). A solution of 0.5 g
(3.3 mmol) of (–)-carveol (II) in 20 ml of acetonitrile
was cooled to 0°C, 0.55 g (6.6 mmol) of NaHCO3 was
added in one portion under stirring, the mixture was
stirred for 15 min, and 0.84 g (3.3 mmol) of crystalline
iodine was added. The mixture was stirred for 2 h at
room temperature (until the initial compound disap-
peared according to the TLC data) and evaporated,
15 ml of a saturated solution of Na2S2O3 was added to
the residue, and the mixture was extracted with ethyl
acetate (3×10 ml). The extracts were combined, dried
over MgSO4, and evaporated, and the residue was
purified by column chromatography on silica gel using
ethyl acetate–petroleum ether (1:10) as eluent. Yield
0.66 g (73%), light yellow liquid, [α]D20 = –17.5° (c =
5.0, EtOH). IR spectrum: ν 1088 cm–1 (C–O–C).
1H NMR spectrum, δ, ppm: 1.45 s (3H, CH3), 1.50 m
(1H, 8-H), 1.70–1.72 m (3H, CH3), 1.91–1.95 m (1H,
8-H), 2.23–2.38 m (2H, 4-H, 5-H), 2.49–2.50 (1H,
4-H), 3.32 s (1H, CH2I), 3.36 s (1H, CH2I), 4.13–
4.15 m (1H, 1-H), 5.25–5.27 m (1H, 3-H). 13C NMR
spectrum, δC, ppm: 14.22 (CH2I), 21.41 (CH3), 27.94
(CH3), 29.76 (C4), 35.10 (C8), 40.77 (C5), 77.53 (C1),
84.03 (C6), 120.72 (C3), 139.80 (C2).
2,2,2-Trichloro-1-[(1R,5R)-5-isopropenyl-2-
methylcyclohexen-2-en-1-yloxy]ethan-1-imine (VI).
(–)-Carveol (II), 1 g (6.6 mmol), was dissolved in
20 ml of methylene chloride, 2 g (13 mmol) of DBU
was added under stirring, the mixture was stirred for
15 min, and a solution of 1.9 g (13 mmol) of trichloro-
acetonitrile in 10 ml of methylene chloride was care-
fully added dropwise. The mixture was stirred for 6 h
at room temperature until the initial compound disap-
peared (TLC), 10 ml of a saturated aqueous solution of
ammonium chloride was added, the organic phase was
separated, and the aqueous phase was extracted with
methylene chloride (3×15 ml). The extracts were com-
bined with the organic phase, washed with a solution
of sodium chloride, dried over MgSO4, and evaporat-
ed, and the residue was purified by column chromatog-
raphy on silica gel using ethyl acetate–petroleum ether
(1:5) as eluent. Yield 1.45 g (74%), light yellow
liquid, [α]D20 = –19.4° (c = 1.25, EtOH). IR spectrum, ν,
cm–1: 3323 (N–H), 3082, 1680 (C=N), 1645. 1H NMR
spectrum, δ, ppm: 1.26–1.43 m (1H, 6-H), 1.73 s (3H,
CH3), 1.76 s (3H, CH3), 1.81 m (1H, 6-H), 1.94–
2.40 m (3H, 4-H, 5-H), 4.74 s (2H, =CH2), 4.78 m
(1H, 1-H), 5.62–5.64 m (1H, 3-H), 8.28 s (1H, NH).
13C NMR spectrum (acetone-d6), δC, ppm: 20.58 (CH3),
20.78 (CH3), 29.41 (C4), 29.67 (C6), 35.97 (C5), 75.86
(C1), 108.67 (CCl3), 108.86 (=CH2), 123.98 (C3),
133.97 (C2), 150.03 (C=CH2), 162.50 (C=NH).
This study was performed under financial support
by the Federal Science and Innovation Agency and by
the Council for Grants at the President of the Russian
Federation (project no. NSh-1725.2008.3).
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