Nov-Dec 2002
Syntheses and the Structural Characterization of Menthopyrazole Analogues
1239
7 and trans-7. The product mixture was purified by Kugelrohr
distillation, and was identical with the reported NMR data [20].
[3]. The subsequent mixture was separated by silica gel column
chromatography with benzene-hexane mixture (v/v 1:1), respec-
tively. All products were obtained as colorless oils, and cis-6
crystallized upon standing for a few days.
General Procedure for Formylation and the Pyrazole Ring
Formation.
(4R,7S)-2-Acetyl-4-methyl-7-isopropyl-4,5,6,7-tetrahydro-2H-
indazole (trans-6).
Method A.
To a suspension of NaH (1.9 g, 48 mmol, 60 % in oil) in Et2O
(40 ml), l-menthone or the mixture of cis-7 and trans-7 (42
mmol) in Et2O (40 ml) was added, followed by ethyl formate (6.3
g, 85 mmol) in Et2O (40 ml). After stirring for 18 hours under
argon atmosphere, the mixture was dissolved in H2O. The
organic layer was extracted with 1 M NaOH. The combined
aqueous layers were acidified with hydrochloric acid, and
extracted with Et2O. The Et2O layers were washed with satu-
rated NaCl, and dried over anhydrous MgSO4. After removal of
the solvent, the residual oil (6.7 g) was comprised of a 13:1 ratio
of (3R,6R)- (cis-5) and (3R,6S)-2-hydroxymethylene-6-iso-
propyl-3-methylcyclohexanones (trans-5). In the case of 7, the
residual oil (2.4 g) was comprised of a 3:2 ratio of (3R,6R)- (cis-
8) and (3S,6R)-2-hydroxymethylene-6-isopropyl-3-methylcyclo-
hexanones (trans-8). The mixture was refluxed with hydrazine
monohydrate (1.1 g, 22 mmol) and hydrazine hydrochloride (135
mg, 2.0 mmol) in methanol (30 ml) for 3 hours. The reaction
mixture was quenched with H2O and extracted with Et2O. The
Et2O layer was washed with water and saturated NaCl, dried over
anhydrous MgSO4 and concentrated. The product (6.1 g) was
found to be cis-2 and trans-2 mixture with the ratio of 13:1 after
Kugelrohr distillation under reduced pressure. Otherwise, cis-3
and trans-3 mixture (2.2 g) was isolated with the ratio of 3:2 by
Kugelrohr distillation under reduced pressure.
Trans-6 showed bp 200 °C/4 mmHg; 1H NMR (270 MHz,
CDCl3): d 0.88 (3H, d, J= 6.9 Hz), 1.03 (3H, d, J= 6.9 Hz), 1.18
(1H, q, J= 12.2 Hz), 1.21 (3H, d, J= 6.6 Hz), 1.46 (1H, q, J= 12.2
Hz), 1.90-1.98 (2H, m), 2.38-2.45 (1H, m), 2.59-2.71 (2H, m),
2.64 (3H, s), 7.95 (1H, d, J= 1.3Hz); 13C NMR (270 MHz,
CDCl3): d 18.1 (CH3), 19.9 (CH3), 20.9 (CH3), 21.5 (CH2), 23.7
(CH3), 28.1 (CH), 30.1 (CH), 32.2 (CH2), 41.0 (CH), 123.7
(CH), 128.4 (C), 157.6 (C), 169.5 (C).
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.48; H, 9.17; N, 12.46.
(4R,7R)-2-Acetyl-4-methyl-7-isopropyl-4,5,6,7-tetrahydro-2H-
indazole (cis-6).
Cis-6 showed bp 200 °C/4mmHg; 1H NMR (270 MHz,
CDCl3): d 0.92 (3H, d, J= 6.9 Hz), 1.06 (3H, d, J= 6.9 Hz), 1.19
(3H, d, J= 6.9 Hz), 1.43-1.59 (1H, m), 1.65-1.88 (3H, m), 2.13-
2.28 (1H, m), 2.53-2.67 (1H, m), 2.64 (3H, s), 2.78-2.88 (1H, m),
7.94 (1H, d, J= 1.3Hz); 13C NMR (270 MHz, CDCl3): d 19.0
(CH3), 20.6 (CH3), 21.51 (CH3), 21.58 (CH2), 22.1 (CH3), 26.3
(CH), 29.2 (CH2), 30.6 (CH), 40.0 (CH), 124.0 (CH), 127.6 (C),
157.5 (C), 169.6 (C).
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.30; H, 9.14; N, 12.70.
(4S,7R)-2-Acetyl-4-isopropyl-7-methyl-4,5,6,7-tetrahydro-2H-
indazole (trans-9).
Method B.
1
To THF solution (40 ml) of LDA which was prepared in situ
from diisopropylamine (9 ml) and butyllithium solution (40 ml,
1.59 M in hexane), l-menthone or the mixture of cis-7 and trans-7
(60 mmol) in THF (10 ml) was added at –5 °C. After standing for
15 minutes at –5 °C, ethyl formate (6.0 g, 81 mmol) in THF (30
ml) was added to the mixture and stirred for 1.5 hours. The mix-
ture was quenched with H2O and the organic layer was extracted 1
M NaOH. The combined aqueous layers were acidified with
hydrochloric acid, and extracted with Et2O. The Et2O layer was
washed with saturated NaCl, and dried over anhydrous MgSO4.
After removal of the solvent, the residual oil (5.1 g) was com-
prised of a 1:3 ratio of cis-5 and trans-5. In the case of 7, the
residual oil (4.3 g) was comprised of a 1:2 ratio of cis-7 and trans-
7. The mixture was refluxed with hydrazine monohydrate (1.5 g,
30 mmol) and hydrazine hydrochloride (170 mg, 2.5 mmol) in
methanol for 3 hours. The reaction mixture was extracted with
Et2O, and the organic layer was washed with water and saturated
NaCl, dried over anhydrous MgSO4 and concentrated. The prod-
uct (5.6 g) was found to be cis-2 and trans-2 mixture with the ratio
of 1:3 after Kugelrohr distillation under reduced pressure.
Otherwise, cis-3 and trans-3 mixture (1.6 g) was isolated with the
ratio of 1:2 by Kugelrohr distillation under reduced pressure.
Trans-9 showed H NMR (270 MHz, CDCl3): d 0.84 (3H, d,
J=6.9 Hz), 0.99 (3H, d, J=6.9 Hz), 1.22-1.43 (2H, m), 1.34 (3H,
d, J=6.9 Hz), 1.78-1.94 (1H, m), 1.97-2.10 (2H, m), 2.56-2.77
(2H, m), 2.65 (3H, s), 2.78-2.88 (1H, m), 7.95 (1H, d, J= 1.6Hz);
13C NMR (270 MHz, CDCl3): d 19.0 (CH3), 20.6 (CH3), 21.51
(CH3), 21.58 (CH2), 22.1 (CH3), 26.3 (CH), 29.2 (CH2), 30.6
(CH), 40.0 (CH), 124.0 (CH), 127.6 (C), 157.5 (C), 169.6 (C).
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.65; H, 9.15; N, 12.77.
(4S,7S)-2-Acetyl-4-isopropyl-7-methyl-4,5,6,7-tetrahydro-2H-
indazole (cis-9).
1
Cis-9 showed H NMR (270 MHz, CDCl3): d 0.89 (3H, d,
J=6.9 Hz), 1.00 (3H, d, J=6.9 Hz), 1.29 (3H, d, J=6.6 Hz), 1.61-
1.72 (3H, m), 1.76-1.97 (2H, m), 2.46-2.54 (1H, m), 2.65 (3H, s),
2.85-2.96 (1H, m), 7.94 (1H, d, J= 1.0Hz); 13C NMR (270 MHz,
CDCl3): d 18.6 (CH3), 20.5 (CH3), 20.6 (CH3), 20.9 (CH2), 21.6
(CH3), 28.4 (CH), 29.3 (CH2), 31.2 (CH), 38.5 (CH), 124.1 (C),
124.4 (CH), 160.1 (C), 169.5 (C).
Anal. Calcd for C13H20N2O: C, 70.87; H, 9.15; N, 12.72.
Found: C, 70.69; H, 9.31; N, 12.68.
Deacetylation of N-Acetyl Derivatives.
Acetylation of cis-2, trans-2, cis-3 and trans-3.
All 2-acetyl derivatives (5.3 mmol), cis-6, trans-6, cis-9 and
trans-9, were refluxed with NaOH (1.1 mmol) in MeOH (15 ml),
respectively. The resulting mixture was quenched with dil.
hydrochloric acid, and extracted with Et2O. The organic layer
was washed with saturated NaCl, dried over anhydrous MgSO4,
A mixture (5 mmol) of cis-2 and trans-2 or a mixture (5 mmol)
of cis-3 and trans-3, prepared as above, was acetylated by acetyl
chloride (8.8 mmol) in toluene (20 ml) in the presence of triethyl-
amine (15 mmol), according to the formerly described method