Fluoro-Olefins as Inhibitors
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 6 1775
upon standing. For the preparation of 9.6c (R ) phenyl), acid
9.4 was activated as the corresponding acid chloride. Acid 9.4
(1 mmol) was dissolved in dry dichloromethane (15 mL) under
nitrogen together with a catalytic amount of dimethylforma-
mide. Oxalyl chloride (0.14 g, 1.1 mmol), dissolved in 1 mL of
dry dichloromethane, was added dropwise via a syringe and
stirring was continued for 10 min. Aniline (0.1 g, 1.1 mmol),
dissolved in 1 mL of dry dichloromethane, was added to the
appropriate acid chloride and stirring was continued for 16 h
at room temperature. The target product was isolated after
flash chromatography (hexanes/EtOAc 9:1). Compounds 9.5,
9.6, 10.5, and 10.6 were only charaterized by mass spectrom-
etry.
adamantyl-), 43.63 (s, CH), 51.76 (s, adamantyl-), 64.65 (s,
CH2O), 136.48 (d, 2JC-F ) 14.1 Hz (CH2)2Cd), 144.41 (d, 1JC-F
) 252.3 Hz, CH2C(F)d), 159.55 (d, 2JC-F ) 28.8 Hz, C(O)). MS
(ES+) m/z: 422.7 (M + H)+, 444.5(M + Na)+.
(2Z)-2-[(2R,S)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-
cyclopentylidene]-2-fluoro-N-(4-fluorobenzyl)ethanam-
1
ide (11.3/1c) (R ) 4-Fluorobenzyl-). Yield: 88%. H NMR
CDCl3 (400 MHz): δ 0.07 (s, 6H, Si(CH3)2), 0.85 (s, 9H,
C(CH3)3), 1.62-1.87 (m, 4H, CH2CH2CH), 2.68-2.92 (m, 2H,
CH2CH2CH2CH), 3.02-3.12 (m, 1H, CHCH2O), 3.46-3.52 (t,
2JH-H ) 3JH-H )9.6 Hz 1H, CHCH2O), 3.66-3.72 (dd, 2JH-H
)
3
9.4 Hz, JH-H ) 4.8 Hz 1H, CHCH2O), 4.48-4.52 (m, 2H,
ArCH2), 6.38-6.54 (br s, 1H, NHC(O)), 6.98-7.08 (m, 2H, Ar),
7.22-7.36 (m, 2H, Ar). 13C NMR CDCl3 (400 MHz): δ -5.18
(s, Si(CH3)2), 14.30 (s, C(CH3)3), 18.5 (s, CH2CH2CH), 24.97
(s, CH2CH2CH), 26.1 (s, C(CH3)3), 30.81 (s, CH2CH2CH2CH),
42.43 (s, CHCH2O), 46.13 (s,CHCH2O), 63.44 (s, ArCH2),
115.72 (d,2JC-F ) 21.4 Hz, Ar), 129.7 (d,3JC-F ) 8 Hz, Ar),
(2Z)-2-[(2R,S)-2-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-
cyclopentylidene]-2-fluoro-N-(2-phenylethyl)ethanam-
ide (11.3/1a) (R ) 2-Phenylethyl-). Yield: 84%. 1H NMR
CDCl3 (400 MHz): δ 0.03 (s, 6H, Si(CH3)2), 0.89 (s, 9H,
C(CH3)3), 1.67-1.96 (m, 4H, CH2CH2CH), 2.62-2.93 (m, 3H,
CH2CH2CH2CH + CH2Ar), 2.91-3.18 (m, 2H, CH2CH2CH2CH
+ CHCH2O), 3.47 (t, 3JH-H ) 2JH-H ) 8.4 Hz, 1H, CH2O), 3.52-
2
134.04 (d,4JC-F ) 3.2 Hz, Ar), 137.04 (d, JC-F ) 12.2 Hz
1
(CH2)2Cd), 144.26 (d, JC-F ) 250.1 Hz, CH2C(F)d), 161.17
2
(d,2JC-F ) 31.1 Hz, C(O)), 162.46 (d, JC-F ) 244.3 Hz, Ar).
3
3.56 (m, 2H, ArCH2CH2N), 3.69-3.73 (dd, JH-H ) 8.6 Hz,
MS(ES+) m/z: 396.4 (M + H)+, 419.7 (M + Na)+.
2JH-H ) 4.4 Hz 1H, CH2O), 6.18-6.41 (br s, 1H, NHC(O)),
7.12-7.28 (m, 3H, Ar), 7.24-7.38 (m, 2H, Ar). 13C NMR CDCl3
(400 MHz): δ -5.1 (s, Si(CH3)2), 14.07 (s, C(CH3)3), 18.05 (s,
CH2CH2CH), 26.11 (s, C(CH3)3), 27.54 (s, CH2CH2CH), 30.75
(s,CH2CH2CH2CH),36.26(s,ArCH2CH2N),40.37(s,ArCH2CH2N),
46.06 (s,CHCH2O), 65.14 (s, CH2O), 126.18 (s, Ar), 128.94 (s,
Ar), 136.77 (d, 2JC-F ) 12.4 Hz (CH2)2Cd), 138.95 (s, Ar), 144.4
(2E)-2-[(2R,S)-2-({[tert-Butyl(dimethyl)silyl]oxy}meth-
yl)cyclopentylidene]-2-fluoro-N-(4-fluorobenzyl)ethan-
amide (11.3/2c) (R ) 4-Fluorobenzyl-). Yield: 89%. 1H NMR
CDCl3 (400 MHz): δ 0.09 (s, 6H, Si(CH3)2), 0.87 (s, 9H,
C(CH3)3), 1.62-1.82 (m, 3H, CH2CH2CH), 1.96-2.02 (m, 1H,
CH2CH2CH), 2.43-2.64 (m, 2H, CH2CH2CH2CH), 3.52-3.58
1
2
2
(m, 1H, CHCH2O), 3.61-3.68 (t, JH-H )3JH-H ) 9.2 Hz 1H,
(d, JC-F ) 249.4 Hz, CH2C(F)d), 161.28 (d, JC-F ) 30.9 Hz,
C(O)). MS (ES+) m/z: 392.2 (M + H)+, 314 (M + Na)+.
CHCH2O), 3.71-3.77 (dd, 2JH-H ) 9.4 Hz, 3JH-H ) 4.8 Hz, 1H,
CHCH2O), 4.42-4.58 (m, 2H, ArCH2), 6.62-6.78 (br s, 1H,
NHC(O)), 6.98-7.08 (m, 2H, Ar), 7.22-7.36 (m, 2H, Ar). 13C
NMR CDCl3 (400 MHz): δ -5.2 (s, Si(CH3)2), 14.30 (s,
C(CH3)3), 18.5 (s, CH2CH2CH), 23.05 (s, CH2CH2CH), 26.15
(s, C(CH3)3), 30.12 (s, CH2CH2CH2CH), 42.45 (s, CHCH2O),
44.68 (s,CHCH2O), 64.68 (s, ArCH2), 115.7 (d,2JC-F ) 21.4 Hz,
Ar), 129.7 (d,3JC-F ) 8.1 Hz, Ar)), 134.14 (d,4JC-F ) 3.3 Hz,
(2E)-2-[(2R,S)-2-({[tert-Butyl(dimethyl)silyl]oxy}-
methyl)cyclopentylidene]-2-fluoro-N-(2-phenylethyl)-
ethanamide (11.3/2a) (R ) 2-Phenylethyl-). Yield: 87%.
1H NMR CDCl3 (400 MHz): δ 0.03 (s, 6H, Si(CH3)2), 0.89 (s,
9H, C(CH3)3), 1.57-1.82 (m, 3H, CH2CH2CH2CH), 1.92-2.01
(m, 1H, CH2CH2CH2CH), 2.41-2.63 (m, 2H, CH2CH2CH2CH),
2.81-2.96 (m, 2H, CH2Ar), 3.41-3.48 (m, 1H, CH2O), 3.51-
2
1
3.68 (m, 3H, ArCH2CH2N+CHCH2O), 3.67-3.78 (dd, 2JH-H
)
Ar), 137.94 (d, JC-F ) 13.6 Hz (CH2)2Cd), 144.46 (d, JC-F
)
249.4 Hz, CH2C(F)d), 160.68 (d,2JC-F ) 34.5 Hz, C(O)), 162.45
9.6 Hz, 3JH-H ) 4.8 Hz 1H, CH2O), 6.31-6.51 (br s, 1H, NHC-
(O)), 7.08-7.22 (m, 3H, Ar), 7.24-7.38 (m, 2H, Ar). 13C NMR
CDCl3 (400 MHz): δ -5.1 (s, Si(CH3)2), 14.03 (s, C(CH3)3),
18.19 (s, CH2CH2CH2CH), 26.06 (s, C(CH3)3), 29.37 (s, CH2-
CH2CH2CH), 29.98 (s, CH2CH2CH2CH), 35.96 (s, ArCH2CH2N),
40.65 (s, ArCH2CH2N), 44.04 (s,CHCH2O), 66.18 (s, CH2O),
126.8 (s, Ar) 128.91 (s, Ar), 137.18 (d, 2JC-F ) 13.8 Hz (CH2)2Cd
(d, JC-F ) 244.3 Hz, Ar). MS(ES+) m/z: 396.4 (M + H)+.
2
General Procedure for Reduction of r-Fluoro-r,â-
unsaturated Amides (9.7, 9.8, 11.4) and r,â-Unsaturated
Amides (10.7, 10.8). To an intensely stirred solution of POCl3
(5.2 mmol, 0.79 g) in dry dichloromethane (10 mL), cooled to
0 °C under nitrogen, was dropped a solution of the amide (1.28
mmol) in dry dichloromethane (2 mL). After addition, the ice
bath was removed and stirring was continued for 1 h, followed
by the thorough evaporation of the solvent and excess POCl3.
The crude chloroimidate was dispersed in freshly dried diethyl
ether (10 mL), cooled under nitrogen to 0 °C, followed by the
addition of LiAlH4 (2.56 mmol, 94 mg) in one portion. Stirring
was continued for 10 min, and after removal of the ice bath
stirring was continued for another 3 h. Excess LiAlH4 was then
quenched with water (0.6 mL), and stirring was continued for
5 min to allow free water to be adsorbed onto the insoluble
salts. The suspension was filtered, and the filter cake was
washed with diethyl ether (3 × 15 mL). The combined ether
layers were then evaporated, yielding crude amine. For
compounds 11.4, the crude amine was used without further
purification in the next step (Boc protection). For compounds
9.7, 9.8, 10.7, 10.8 the crude amine was precipitated with a 1
M solution of hydrogen chloride in diethyl ether, the ether was
carefully decanted, and the final product was washed twice
with small portions of dry diethyl ether and then dried under
reduced pressure.
1
), 138.99 (s, Ar), 144.62 (d, JC-F ) 249.4 Hz, CH2C(F)d),
2
160.72 (d, JC-F ) 30.9 Hz, C(O)). MS(ES+) m/z: 392.2 (M +
H)+, 314 (M + Na)+.
(2Z)-N-(1-Adamantyl)-2-[(2R,S)-2-({[tert-butyl(dimethyl)-
silyl]oxy}methyl)cyclopentylidene]-2-fluoroethanam-
ide (11.3/1b) (R ) 1-Adamantyl-). Yield: 91%. 1H NMR
(CDCl3): δ 0.03 (s, 6H, SiCH3), 0.88 (s, 9H, CH3), 1.62-1.89
(m, 10H, CH2CH2CH, adamantyl-), 2.02-2.05 (s, 6H, adaman-
tyl-), 2.07-2.11 (s, 3H, adamantyl-), 2.72-2.49 (m, 2H, CH2-
CH2CH2CH), 3.01-3.13 (m, 1H, CH2CH2CH), 3.37-3.43 (m,
1H, CH2O), 3.63-3.77(m, 1H, CH2O), 5.83 (s, 1H, NH). 13C
NMR CDCl3 (400 MHz): δ -5.02 (s, SiCH3), 14.09 (s, C(CH3)3),
18.33 (s, CH2CH2CH), 24.71 (s, CH2CH2CH), 25.97 (s, CH3),
28.42 (s, CH2CH2CH2CH), 29.44 (s, adamantyl-), 36.34 (s,
adamantyl-), 41.60 (s, adamantyl-), 45.94 (s,CH), 51.83 (s,
2
adamantyl-), 63.11 (s, CH2O), 135.44 (d, JC-F ) 12.9 Hz,
1
(CH2)2Cd), 144.47 (d, JC-F ) 253.3 Hz, CH2C(F)d), 160.18
2
(d, JC-F ) 28.5 Hz, C(O)). MS(ES+) m/z: 422.7 (M + H)+.
(2E)-N-(1-Adamantyl)-2-[(2R,S)-2-({[tert-butyl(dimethyl)-
silyl]oxy}methyl)cyclopentylidene]-2-fluoroethanam-
ide (11.3/2b) (R ) 1-Adamantyl-). Yield: 85%. 1H NMR
CDCl3 (400 MHz): δ 0.02 (s, 6H, SiCH3), 0.86 (s, 9H, CH3),
1.58-1.87 (m, 9H, CH2CH2CH, adamantyl-), 1.91-2.14 (m,
10H, CH2CH2CH, adamantyl-), 2.42-2.49 (m, 2H, CH2CH2-
CH2CH), 3.42-3.53 (m, 1H, CH2CH2CH), 3.67 (d, 3JH-H ) 5.6
Hz, 2H, CH2O), 5.97 (s, 1H, NH). 13C NMR CDCl3 (400 MHz):
δ -5.44 (s, SiCH3), 14.09 (s, C(CH3)3), 18.28 (s, CH2CH2CH),
23.11 (s, CH2CH2CH), 25.91 (s, CH3), 29.39 (s, adamantyl-),
30.19 (s, CH2CH2CH2CH), 36.29 (s, adamantyl-), 41.52 (s,
N-(2-Cyclopentylidene-2-fluoroethyl)cyclohexan-
amine (9.7a). Yield: 92%. 1Η ΝΜR D2O (400 MHz): δ 0.88-
1.22 (m, 6H, CH2CH2CH2), 1.41-1.52 (m, 4H, CH2CH2), 1.58-
1.69 (m, 2H, CH2), 1.82-1.97 (m, 2H, CH2), 2.04-2.14 (m, 2H,
CH2), 2.16-2.25 (m, 2H, CH2), 2.81-3.03 (m, 1H, CH), 3.67
(d, 3JH-F ) 21.2 Hz, 2H, CH2N). ES+-MS m/z: 212.2 (M + H)+.
N-Benzyl-2-cyclopentylidene-2-fluoroethanamine (9.7b).
Yield: 86%. 1Η ΝΜR D2O (400 MHz) δ 1.53-1.60 (m, 4H, CH2-
CH2), 2.02-2.18 (m, 2H, CH2), 2.24-2.38 (m, 2H, CH2), 3.88