4978 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24
Tønder et al.
were crystallized with oxalic acid in acetone (1.2 equiv) in
acetone to give the oxalate salts.
for 90 h, then quenched with 1 N HCl (50 mL), rinsed three
times with diethyl ether, made alkaline (K2CO3), and extracted
with dichloromethane (5 × 50 mL). The solvent was removed
after drying (MgSO4), and the crude compound was crystallized
as the hydrochloride salt from ethanol and then recrystallized
from ethanol to give (Z)-3-acetonylidene-1-azabicyclo[2.2.2]-
octane (22) hydrochloride in 21% yield. Mp: 189-190 °C.
MS: m/z 165 (M+). 1H NMR (300 MHz, DMSO): δ 6.38 (s, 1H,
CHd), 4.31 (s, 2H, NCH2Cd), 3.35-3.19 (m, 4H, NCH2), 2.75-
2.66 (m, 1H, CH), 2.20 (s, 3H, CH3), 2.18-1.97 (m, 2H, CH2),
1.85-1.75 (m, 2H, CH2). Anal. (C10H15NO, HCl, CH3CH2OH)
C, H, N.
(Z)-13. Mp: 174-176 °C. MS: m/z 190 (M+). GC: >99% Z.
1H NMR (300 MHz, DMSO): δ 6.62 (s, 1 H, CHd), 6.32 (s, 1
H, Ar-H), 4.26 (d, 1 H, J ) 17 Hz, NCH2Cd), 4.16 (d, 1 H, J )
17 Hz, NCH2Cd), 3.55 (d, 1 H, J ) 5 Hz, CH), 3.44-3.33 (m,
1 H, NCH2), 3.31-3.19 (m, 3 H, NCH2), 2.27-2.18 (m, 1 H,
CH2), 2.22 (s, 3 H, Ar-CH3),1.69-1.62 (m, 1 H, CH2). Anal.
1
(C11H14N2O, C2H2O4, /4H2O) C, H, N.
(E)-13. Mp: 168-170 °C. MS: m/z 190 (M+). GC: >99% E.
1H NMR (300 MHz, DMSO): δ 6.42 (s, 1 H, Ar-H), 6.37 (s, 1
H, CHd), 4.09 (d, 1 H, J ) 17 Hz, NCH2Cd), 3.96 (d, 1 H, J
) 5 Hz, CH), 3.90 (d, 1 H, J ) 17 Hz, NCH2Cd), 3.41 (t, 1 H,
J ) 15 Hz, NCH2), 3.22 (m, 3 H, NCH2), 2.31-2.23 (m, 1 H,
CH2), 2.23 (s, 3 H, Ar-CH3), 1.65-1.58 (m, 1 H, CH2). Anal.
(C11H14N2O, C2H2O4) C, H, N.
Compounds 21 and 23 were prepared according to method
E.
Meth od F . (Z)-3-(5-Isoxa zolyl)m eth ylen e-1-a za bicyclo-
[2.2.2]octa n e (25). (Z)-3-Acetonylidene-1-azabicyclo[2.2.2]-
octane (22) (0.36 g, 2.2 mmol) was dissolved in dimethyl
formamide-dimethyl acetal (DMF-DMA) (3 mL), and the
solution was stirred overnight at 90 °C under N2. The mixture
was evaporated to dryness, and the residue was dissolved in
glacial acetic acid (10 mL). Upon addition of hydroxylammo-
nium chloride (0.50 g, 7.2 mmol), the solution was stirred at
90 °C for 60 min. The brownish mixture was evaporated to
dryness, whereupon the residue was dissolved in water, made
alkaline with K2CO3, and extracted with diethyl ether (2 ×
50 mL). The combined organic layers were dried and concen-
trated in vacuo to a brown oil. Column chromatography
(dichloromethane/methanol/ammonium hydroxide, 25% in wa-
ter: 80:20:0.5) gave 150 mg (37%) of the desired product as a
yellow oil. Crystallization with oxalic acid in acetone/diethyl
ether gave 180 mg of (Z)-3-(5-isoxazolyl)methylene-azabicyclo-
[2.2.2]octane ((Z)-25) oxalate as white crystals. Mp: 122-124
°C. MS: m/z 190 (M+). GC: 87% Z. 1H NMR (300 MHz,
DMSO): δ 8.60 (s, 1 H, Ar-3-H), 6.60 (s, 1 H, CHd), 6.45 (s, 1
H, Ar-4-H), 4.37 (s, 2 H, NCH2Cd), 3.42-3.22 (m, 4 H, NCH2),
2.86 (s, 1 H, CH), 2.11-1.80 (m, 4 H, CH2). Anal. (C11H14N2O,
Compounds 14, 15, and 17 were prepared according to
method C.
1-Met h yl-3-(3-m et h yl-5-isoxa zolyl)m et h ylen ep yr r oli-
d in e (16). A solution of diisopropylamine (0.83 mL, 6.3 mmol)
in THF (15 mL) was cooled to 0 °C, and n-butyllithium (2.36
M in hexanes, 6.3 mmol) was added under N2. After the
mixture was stirred for 60 min at 0 °C, 3-methyl-5-trimeth-
ylsilanylmethylisoxazole39 (12) (0.98 g, 5.8 mmol) was added
dropwise. Stirring was continued for 15 min at 0 °C, followed
by 15 min at -78 °C, during which a dark orange color
appeared. 1-Methylpyrrolidinone40 (0.53 g, 5.3 mmol) was
dissolved in THF (2 mL) and added dropwise to the anion
solution at -78 °C. The reaction mixture was stirred at -78
°C for 1 h, upon which it was allowed to warm to 20 °C and
stirred at that temperature for 2 h. HCl (1 N, 50 mL) and ethyl
acetate (50 mL) were added, and the layers separated. Further
extraction with 1 N HCl (2 × 50 mL), basification (K2CO3) of
the aqueous layers, and extraction of these with dichlo-
romethane (4 × 50 mL) gave a solution, which upon drying
and evaporation yielded 0.63 g of a brown oil. Column
chromatography (eluent: ethyl acetate/methanol/ammonium
hydroxide, 25% in water: 75/25/0.5) followed by crystallization
with oxalic acid in acetone gave 16 mg (1.1%) of (Z)-1-methyl-
3-(3-methyl-5-isoxazolyl)methylenepyrrolidine ((Z)-16) oxalate
and 57 mg (4.0%) of (E)-1-methyl-3-(3-methyl-5-isoxazolyl)-
methylenepyrrolidine ((E)-16) oxalate.
(Z)-16. Mp: 177-179 °C. MS: m/z 178 (M+). GC: >99% Z.
1H NMR (300 MHz, CDCl3): δ 6.23 (s, 1 H, CHd), 5.84 (s, 1
H, Ar-H), 3.50 (s, 2 H, NCH2Cd), 2.69 (s, 4 H, CH2 CH2), 2.46
(s, 3 H, NCH3), 2.28 (s, 3 H, Ar-CH3). Anal. (C10H14N2O,
C2H2O4) C, H, N.
(E)-16. Mp: 170-173 °C. MS: m/z 178 (M+). GC: >99% E.
1H NMR (300 MHz, CDCl3): δ 6.28 (s, 1 H, CHd), 5.90 (s, 1
H, Ar-H), 3.30 (s, 2 H, NCH2Cd), 2.65 (s, 4 H, CH2 CH2), 2.42
(s, 3 H, NCH3), 2.28 (s, 3 H, Ar-CH3). Anal. (C10H14N2O,
C2H2O4) C, H, N.
Meth od D. 3-(3-Meth yl-5-isoxa zolyl)m eth ylen ea zeti-
d in e (18). The free base 1-benzhydryl-3-(3-methyl-5-isox-
azolyl)methyleneazetidine (15) (0.78 g, 2.5 mmol) was dissolved
in toluene (20 mL) and cooled to 0 °C. 1-Chloroethyl chloro-
formate (0.815 g, 5.7 mmol) was added, and the reaction
mixture was stirred for 20 min. The reaction mixture was
evaporated in vacuo, then redissolved in methanol (20 mL),
and heated at reflux for 1 h, and evaporated in vacuo. The
crude material was suspended in diethyl ether and the
precipitated crystals collected by filtration, giving the hydro-
chloride salt of the title compound in 370 mg yield (80%). Mp:
168-169 °C (dec). MS: m/z 150 (M+). 1H NMR (300 MHz,
DMSO): δ 9.88 (s, 2 H, NH2+), 6.56 (s, 1 H, CHd), 6.38 (s, 1
H, Ar-H), 4.87 (s, 2 H, NCH2), 4.76 (s, 2 H, NCH2), 2.23 (s, 3
H, Ar-CH3). Anal. (C8H10N2O, HCl) C, H, N.
1
1.5 C2H2O4, /4C3H6O ) C, H, N.
Compounds 24 and 26 were prepared according to method
F.
(Z/E)-3-(1-Aza bicyclo[2.2.2]oct-3-ylid en e)-3-flu or o-p r o-
p ion ic Acid Eth yl Ester (27). Triethyl-2-fluoro-2-phospho-
noacetate (4.9 g, 20 mmol) was dissolved in dry DMF (20 mL)
at 0 °C under N2, whereupon potassium tert-butoxide (2.5 g,
22 mmol) was added over a period of 5 min. The reaction
mixture was stirred for 1.5 h at 0 °C, upon which 1-azabicyclo-
[2.2.2]octan-3-one (2.5 g, 20 mmol) dissolved in dry DMF (10
mL) was added dropwise. Stirring was continued for 30 min
at 0 °C, followed by 30 min at 20 °C. TLC (dichloromethane/
methanol/ammonium hydroxide, 25% in water: 80/20/0.5)
showed that no starting material was left. The alkaline
reaction mixture was neutralized with glacial acetic acid (1
mL) and concentrated in vacuo. The resulting oil was dissolved
in dichloromethane (100 mL) and washed with 10% NaHCO3
(3 × 100 mL) and water (100 mL). Drying (MgSO4) and
evaporation gave the crude product (4.6 g). Crystallization with
oxalic acid in acetone gave (Z/ E)-3-(1-azabicyclo[2.2.2]oct-3-
ylidene)-3-fluoro-propionic acid ethyl ester (27) as the oxalate
salt (4.8 g, 79%). The product was used without further
purification. 1H NMR (300 MHz, DMSO): δ 4.27 (quartet, 2H,
J ) 7 Hz, OCH2), 4.11 (d, 2H, J ) 3 Hz, NCH2Cd), 3.85-3.75
(m, 1H, CH), 3.38-3.17 (m, 4H, NCH2), 2.09-1.96 (m, 2H,
CH2), 1.90-1.78 (m, 2H, CH2), 1.28 (t, 3H, J ) 7 Hz, CH3).
(E)-3-(F lu or o-(3-m eth yl-5-isoxa zolyl)m eth ylen e)-1-a za -
bicyclo[2.2.2]octa n e (28). To a solution of acetone oxime (590
mg, 8.0 mmol) in dry THF (10 mL) was added n-butyllithium
(1.6 M in hexanes, 10 mL, 16 mmol) under N2 at 0 °C. The
viscous solution was stirred for 45 min at 0 °C, whereupon
(Z/ E)-3-(1-azabicyclo[2.2.2]oct-3-ylidene)-3-fluoro-propionic acid
ethyl ester (27) (1.1 g, 5.0 mmol) in THF (15 mL) was added
dropwise. The mixture was stirred at 0 °C for 5 min, and then
the temperature was kept at 5 °C overnight. The following day
stirring was continued at 50 °C for 3 h, upon which the
temperature was lowered to 0 °C and concentrated sulfuric
acid (6 mL) was added dropwise. After being stirred at 20 °C
Compounds 19 and 20 were prepared according to method
D.
Meth od E. (Z)-3-Aceton ylid en e-1-a za bicyclo[2.2.2]oct-
a n e (22). Dimethyl 2-oxopropylphosphonate (4.9 g, 30 mmol)
was added dropwise to a solution of 1-azabicyclo[2.2.2]octan-
3-one (2.0 g, 16 mmol) and KOH (1.93 g, 30 mmol) in water
(7.7 mL) at -5 °C. The reaction mixture was stirred at -5 °C