Convenient and practical synthesis of (R)-(+)-4-methyl-2-cyclohexen-1-one

Full text of DOI:10.1021/jo9517656

2
542
J . Org. Chem. 1996, 61, 2542-2543
Sch em e Ia
Con ven ien t a n d P r a ctica l Syn th esis of
R)-(+)-4-Meth yl-2-cycloh exen -1-on e
(
Hyo Won Lee,*,† Sung Kee J i, Ihl-Young Choi Lee, and
‡
J ae Hyun Lee‡
Department of Chemistry, Chungbuk National University,
Cheongju 360-763, Korea and Korea Research Institute of
Chemical Technology, Daejeon 305-606, Korea
Received September 26, 1995
In our efforts toward the synthesis of the cyclohexane
unit 1 of tetronasin, optically pure (R)-(+)-4-methyl-2-
cyclohexen-1-one (2) was required as a starting material.
Optically active 4-methyl-2-cyclohexen-1-one is useful as
a chiral building block.1
-4
In case of (S)-(-)-4-methyl-
a
Reagents: (a) NaBH , MeOH, 0 °C; (b) O , CH Cl :MeOH 1:1,
4
3
2
2
2
(
-cyclohexen-1-one, this compound is available from
Sudan Red; CH3SCH3; (c) HOCH2CH2OH, CH3C(OCH2CH2O)-
CH2CH3, CSA, rt; (d) (CF3SO2)2, Py, CH2Cl2, -23 °C; (e) DBU, 50
C; (f) aqueous THF, H2SO4.
1
4
S)-(+)-carvone or 4-methylcyclohexanone. (R)-(+)-4-
°
methyl-2-cyclohexen-1-one has been prepared by various
methods2 reported in the literature utilizing starting
materials such as (R)-(+)-3-methylcyclohexanone and (R)-
,3
6
9
2
2% yield by transketalization using ethylene glycol and
-ethyl-2-methyl-1,3-dioxolane in the presence of catalytic
amount of camphorsulfonic acid at room temperature for
.5 h. It is advisable that compounds 4 and 5 be used
immediately after preparation because of their unstabil-
ity. Mosher’s method using 2-methoxy-2-phenyl-2-(tri-
fluoromethyl)acetic acid (MTPA) esters was used to
confirm the configuration of the hydoxyl group as R.
Spectral data of H NMR indicates that only one enan-
(+)-pulegone (3). However, these methods are not suit-
able for the preparation of optically active (R)-(+)-4-
methyl-2-cyclohexen-1-one in large scale. Herein we
would like to report the convenient and practical prepa-
ration of (R)-(+)-4-methyl-2-cyclohexen-1-one from (R)-
1
7
(+)-pulegone.
1
tiomer of compound 6 was obtained. The resulting
hydroxyl group of 6 was converted to trifluoromethane-
sulfonate ester 7 in 95% yield by treating with trifluo-
romethanesulfonic anhydride and pyridine in CH
23 °C. The consequent elimination of trifluoromethane-
sulfonate group of compound 7 with 1,8-diazabicyclo-
5.4.0]undec-7-ene (DBU) at 50 °C in 1 h and hydrolysis
under acidic condition in 10 min furnished the desired
R)-(+)-4-methyl-2-cyclohexen-1-one (2) in 68% yield (two
2 2
Cl at
-
The previously reported method3 utilizing (R)-(+)-
[
pulegone seems to give good optical rotation for (R)-(+)-
4
-methyl-2-cyclohexen-1-one. However, it is rather un-
(
suitable for large scale because it employs the inconvenient
Shapiro reaction for the introduction of the double bond
and suffers from low yield as a result of selective
ozonolysis between endo and exo double bonds of an
intermediate compound. In contrast, we could prepare
steps). Thus, the overall yield from crude pulegone
became 45%.
Exp er im en ta l Section
Gen er a l. 1H and 13C NMR spectra were recorded at 500 MHz
and 125 MHz, respectively, on a commercially available spec-
trometer. Unless otherwise indicated in a specific experiment,
all of the chemicals used were reagent grade and no additional
purification has been done. Technical grade (R)-(+)-pulegone
was purchased from Aldrich Chemical Co. and used without
further purification.
(
R)-(+)-4-methyl-2-cyclohexen-1-one practically in large
scale by employing a new and simple reaction pathway
from (R)-(+)-pulegone. Furthermore, in our method there
is only one double bond in the intermediate so that there
is no need to pay attention to the selective ozonolysis of
double bonds. And the subsequent elimination of hy-
droxy group provides the double bond of enone. The
other manipulations are the simple protection and depro-
tection of the carbonyl group in the reaction pathway (see
Scheme 1).
(2R,4R)-(-)-Isop r op ylid en e-4-m eth yl-2-cycloh exa n ol (4).
To a solution of (R)-(+)-pulegone (20.0 g, 131 mmol) in MeOH
4
(100 mL) was added NaBH (6.46 g, 170 mmol) at 0 °C. After
stirring for 1 h at room temperature, the resulting solution was
treated with water and extracted with ether (2 × 100 mL). The
Commercially available (R)-(+)-pulegone of technical
4
extracts were dried over anhydrous MgSO , and evaporation of
grade with 85% purity was reduced with NaBH
4
to yield
solvent provided the crude syrup, which was used for the next
step. However, the crude product was purified by column
5
alcohol 4 in 87% yield and subsequent ozonolysis at -78
C in CH Cl and methanol provided the hydroxy ketone
in 81% yield. The presence of methanol was found to
be critical. The use of CH Cl alone gave unfavorable
chromatography (SiO
of pure alcohol as a colorless solid: mp 30-31 °C; [R]
c 6.00, CHCl ).
2R,4R)-2-Hyd r oxy-4-m eth ylcycloh exa n on e (5). To a so-
2
, hexane:ether ) 4:1) to give 17.6 g (87%)
°
5
2
2
20
D
) -99.6°
(
3
2
2
(
side products. Compound 5 was converted to ketal 6 in
lution of 4 (16.6 g, 108 mmol) in methylene chloride and
methanol (1:1, 100 mL) was added 0.10% Sudan Red 7B in
solution of dichloromethane (3.5 mL). The red solution was
cooled to -78 °C and ozonized until the red color began to
†
Chungbuk National University.
Korea Research Institute of Chemical Technology.
‡
(
(
(
(
(
1) Hua, D. H.; Venkataraman, S. J . Org. Chem. 1988, 53, 1095.
2) Barieux, J .-J .; Gore, J . Bull. Soc. Chim. Fr. 1971, 3978.
3) Silvestri, M. G., J . Org. Chem. 1983, 48, 2419.
4) Hiroi, K.; Sato, S. Synthesis 1985, 635.
5) Luche, J . L.; Rodriguez-Hahn, L.; Crabbe, P. J . Chem. Soc.,
(6) Hagiwara, H.; Uda, H. J . Org. Chem. 1988, 53, 2308.
(7) (a) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.
(b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J Am. Chem.
Soc. 1991, 113, 4092.
Chem. Commun. 1978, 601.
0
022-3263/96/1961-2542$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 7, 1996 2543
lighten. The solution was rapidly purged with N
2
for 30 min.
crude triflate. For the characterization, a small amount of the
triflate was purified through column chromatography.
The solution was treated with dimethyl sulfide (10 equiv) and
allowed to warm to room temperature overnight. The solvent
was removed in vacuo to give crude syrup, which was purified
by column chromatography (silica gel, hexane:ethyl acetate )
1
H NMR (CDCl ) δ 0.97 (d, J ) 6.3 Hz, 3H), 1.24 (m, 1H),
3
1.51 (td, J ) 13.7, 4.0 Hz, 1H), 1.57-1.65 (m, 2H) 1.69 (q, J )
11.9 Hz, 1H), 1.79 (ddd, J ) 2.7, 3.7, 13.2 Hz, 1H), 2.02 (m, 1H),
3.91-4.03 (m, 3H), 4.08 (m, 1H), 4.77 (dd J ) 4.9, 11.9 Hz, 1H);
4
:1) to provide 11.2 g (81%) of pure hydroxy ketone as a colorless
1
13
oil: H NMR (CDCl
3
) δ 1.04 (d, J ) 6.4 Hz, 3H), 1.29 (q, J )
C NMR δ 118.11, 106.94, 88.65, 66.00, 65.53, 37.95, 34.40,
1
2
2
1
2.3 Hz, 1H), 1.39 (m, 1H), 2.05 (m, 2H), 2.38-2.48 (m, 2H),
30.91, 30.71, 21.09.
.51 (m, 1H), 3.58 (d, J ) 3.3 Hz, 1H), 4.16 (m, 1H); 13C NMR δ
11.62, 74.26, 44.54, 38.41, 35.46, 30.20, 20.93; IR (neat) 3485,
The crude triflate was dissolved in DBU (13 mL, 88.0 mmol)
and stirred for 1 h at 50 °C under the nitrogen atmosphere. Then
water (10 mL) was added to the reaction mixture. The reaction
mixture was extracted with ether (3 × 20 mL). The ethereal
-1
20
725 cm ; [R]
128.0344 (obsd).
6R,8R)-8-Meth yl-1,4-d ioxa sp ir o[4.5]d eca n -6-ol (6). To a
D
3
) +16.6° (c 2.20, CHCl ); HRMS 128.0837 calcd
7 12 2
for C H O
(
4
extracts were dried over anhydrous MgSO and concentrated
solution of hydroxy ketone 5 (9.20 g, 71.9 mmol) in 2-ethyl-2-
methyl-1,3-dioxolane (100 mL) and ethylene glycol (45 mL) was
added camphorsulfonic acid (1.40 g, 6.03 mmol) at room tem-
perature under nitrogen. The solution was stirred for 1 h at
room temperature. The resulting solution was poured into
in vacuo to give crude syrupy product of (R)-8-methyl-1,4-
dioxaspiro[4.5]decen-6-ene, which was used for hydrolysis with-
out any further purification. This crude ketal was dissolved in
a solution of 15% aqueous sulfuric acid (15 mL) and tetrahy-
drofuran (20 mL) and stirred at room temperature for 10 min.
The reaction mixture was extracted with dichloromethane (3 ×
aqueous NaHCO
with ether (3 × 100 mL). The combined extracts were washed
with water and brine and dried over anhydrous MgSO . Evapo-
ration of the solvent gave crude product, which was purified by
column chromatography (SiO , hexane:ethyl acetate ) 2:1) to
get pure 11.4 g (92%) of ketal as a colorless oil: bp 72-73 °C/
3
to neutralize, and the product was extracted
1
4
5 mL) and dried over anhydrous MgSO and concentrated in
4
vacuo to give crude product, which was distilled at 75-76 °C
(
20 mmHg) to furnish 4.15 g of pure product (65% for three
2
steps); [R]
CHCl )].
3
20
) +113° (c 1.41, CHCl
)[lit.3 [R]
22
+105° (c 9.2,
D
3
D
1
0
(
1
1
(
3
.1 mmHg: H NMR (CDCl ) δ 0.95 (d, J ) 6.4 Hz, 3H), 1.19
m, 1H), 1.22 (q, J ) 12.1 Hz, 1H), 1.41 (td, J ) 13.6, 4.1 Hz,
Ack n ow led gm en t. This work was supported by the
grant-in-aid from Korea Science and Engineering Foun-
dation (Grant 92-25-00-08).
H), 1.52-1.61 (m, 2H), 1.78 (ddd, J ) 2.8, 3.5, 13.5 Hz, 1H),
.92 (m, 1H), 2.03 (d, J ) 7.0 Hz, 1H), 3.63 (m, 1H), 3.96-4.09
1
3
m, 4H); C NMR δ 109.45, 72.66, 65.48, 65.18, 40.71, 32.33,
-
1
20
3
6
0.67, 29.94, 21.56; IR (neat) 3474, 2971 cm ; [R]
D
) +5.0° (c
.50, CHCl ): HRMS 172.1099 calcd for C
3
9
H
16
O
3
172.1099 (obsd).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
(
R)-4-Meth yl-2-cycloh exen -1-on e (1). To a solution of
NMR spectra for compounds 2, 5, 6, and 7 are provided (10
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
hydroxy ketal 6 (10.0 g, 58.7 mmol) in CH
2
Cl
2
(100 mL) were
added pyridine (9.50 mL, 117 mmol) and trifluoromethane-
sulfonic anhydride (10.4 mL, 61.6 mmol) at -23 °C under the
nitrogen atmosphere. After 30 min, water was added to the
solution and the separated dichloromethane layer was dried over
anhydrous MgSO
4
. The solvent was removed in vacuo to give
J O9517656