5866 Journal of Medicinal Chemistry, 2004, Vol. 47, No. 24
Rosen et al.
(1); IR (NaCl) ν 3099 (w), 3034 (w), 2983 (m), 2927 (m), 2874
(w), 1737 (s), 1616 (w), 1520 (w), 1438 (s), 1399 (s), 1384 (s),
1306 (s), 1268 (m), 1239 (m), 1181 (s), 1107 (m), 1071 (w), 1045
(w), 1002 (m), 974 (w), 903 (w), 883 (w), 860 (w), 846 (w), 815
(s), 789 (w), 721 (w); Anal. (C13H15FO2) C, H.
H. The structure of 10b was confirmed by X-ray structural
analysis (cf. Supporting Information).
trans-(()-2-(4-Chlorophenyl)-2-fluorocyclopropane-
carboxylic Acid (9c). Using the same procedure, hydrolysis
of 7c (145 mg, 0.6 mmol) gave, after recrystallization from CH2-
Cl2/pentane, 9c as a colorless, crystalline solid (Yield: 80 mg,
Data for 8d: (Yield: 420 mg, 19%) 1H NMR (CDCl3) δ 1.03
(3 H, q, J ) 7.2 Hz, CH2CH3), 1.77 (1 H, ddd, J ) 7.2 Hz, J )
10.3 Hz, J ) 19.1 Hz, CHAHB), 1.93 (1 H, ddd, J ) 7.2 Hz, J
) 7.4 Hz, J ) 12.2 Hz, CHAHB), 2.34 (3 H, d, J ) 1.9 Hz, Car-
CH3), 2.53 (1 H, ddd, J ) 7.4 Hz, J ) 10.3 Hz, J ) 17.9 Hz,
CHX), 3.93 (t, J ) 7.2 Hz, 2 H, CH2CH3), 7.14-7.17 (2 H, m,
aromatic), 7.33-7.37 (2 H, m, aromatic); 13C NMR (CDCl3) δ
13.9 (q, CH2CH3), 16.5 (dt, J ) 10.2 Hz, CHAHB), 21.2 (q, Car-
CH3), 27.7 (dd, J ) 16.5 Hz, CHX), 60.6 (t, CH2CH3), 83.0 (ds,
J ) 220.0 Hz, CF), 128.5 (dd, J ) 2.5 Hz, aromatic), 128.9 (d,
aromatic), 130.2 (ds, J ) 20.3 Hz, aromatic), 139.2 (ds, J )
2.5 Hz, aromatic), 169.0 (s, CdO); 19F NMR (CDCl3) δ -152.52
(dm, J ) 19.1 Hz); MS m/z (%) 222 (63), 207 (6), 193 (20), 177
(13), 174 (15), 172 (15), 166 (36), 164 (30), 149 (100), 147 (28),
139 (60), 133 (31), 129 (33), 119 (14), 115 (8), 109 (10), 101 (4),
91 (7), 77 (5), 65 (2), 55 (3), 39 (2); IR (NaCl) ν 3104 (w), 3061
(w), 2984 (s), 2930 (m), 2877 (w), 1731 (s), 1617 (w), 1522 (m),
1466 (m), 1439 (s), 1397 (s), 1380 (s), 1362 (m), 1342 (s), 1267
(m), 1220 (s), 1163 (s), 1101 (m), 1076 (w), 1039 (m), 1001 (w),
961 (m), 887 (s), 866 (m), 823 (s), 800 (w), 760 (m), 721 (w);
Anal. (C13H15FO2) C, H.
1
62%). Data for 9c: Mp 138 °C; H NMR (CDCl3, 400 MHz) δ
1.69 (1 H, ddd, J ) 7.4 Hz, J ) 9.3 Hz, J ) 10.6 Hz, CHAHB),
2.18 (1 H, ddd, J ) 2.5 Hz, J ) 7.6 Hz, J ) 9.3 Hz, CHX), 2.33
(1 H, ddd, J ) 7.4 Hz, J ) 7.6 Hz, J ) 20.3 Hz, CHAHB), 7.25-
7.39 (4 H, m, aromatic); 13C NMR (CDCl3) δ 19.1 (dt, J ) 12.6
Hz, CHAHB), 28.6 (dd, J ) 11.4 Hz, CHX), 80.6 (ds, J ) 228.9
Hz, CF), 126.2 (dd, J ) 6.4 Hz, aromatic), 128.8 (d, aromatic),
134.4 (s, aromatic), 135.9 (ds, J ) 22.8 Hz, aromatic), 170.7
(ds, J ) 2.5 Hz, CdO); 19F NMR (CDCl3, 188.30 MHz) δ
-186.84 (m); MS as trimethylsilyl ester m/z (%) 288/286 (2/6),
273/271 (3/11), 251 (1), 235 (4), 233/231 (6/16), 207 (5), 198/
196 (7/21), 160 (22), 151/149 (4/13), 141/139 (7/24), 133 (21),
115 (12), 107 (2), 77 (23), 73 (100), 45 (7); IR (KBr) ν 3558 (m),
3478 (br), 3418 (br), 3236 (w), 3093 (w), 2928 (w), 2860 (w),
2637 (w), 1702 (s), 1641 (m), 1620 (m), 1497 (w), 1451 (m),
1431 (m), 1404 (w), 1369 (w), 1314 (m), 1243 (m), 1223 (m),
1107 (m), 1096 (w), 1060 (w), 1021 (m), 972 (w), 935 (m), 895
(w), 869 (w), 817 (m), 782 (w), 737 (w), 660 (m). Anal. (C10H8-
ClFO2) C, H.
cis-2-(4-Chlorophenyl)-2-fluorocyclopropanecarbox-
ylic Acid (10c). Using the same procedure, hydrolysis of 8c
(231 mg, 0.95 mmol) gave, after recrystallization from CH2-
Cl2/pentane, 10c as a colorless, crystalline solid (Yield: 188
mg, 92%). Data for 10c: Mp 103 °C; 1H NMR (CDCl3, 400
MHz) δ 1.83-2.04 (2 H, m, CHAHB), 2.52 (ddd, J ) 7.6 Hz, J
) 10.1 Hz, J ) 17.6 Hz, 1 H, CHX), 7.32-7.39 (4 H, m,
aromatic); 13C NMR (CDCl3, 100 MHz) δ 17.3 (dt, J ) 10.4
Hz, CHAHB), 27.6 (dd, J ) 17.3 Hz, CHX), 82.8 (ds, J ) 222.0
Hz, CF), 128.6 (d, aromatic), 129.7 (dd, J ) 4.4 Hz, aromatic),
131.1 (ds, J ) 20.5 Hz, aromatic), 135.4 (ds, J ) 3.2 Hz,
aromatic), 174.1 (s, CdO); 19F NMR (CDCl3, 188.30 MHz) δ
-153.56 (m); MS as trimethylsilyl ester m/z (%) 288/286 (7/
15), 273/271 (20/53), 251 (2), 235 (27), 233/231 (22/60), 207 (14),
198/196 (22/69), 171/169 (1/3), 161 (52), 151/149 (12/37), 141/
139 (14/57), 133 (56), 115 (24), 107 (6), 101 (3), 77 (26), 73 (100),
63 (2), 45 (8); IR (KBr) ν 3112 (w), 3064 (w), 2922 (w), 2762
(w), 2663 (w), 2572 (w), 1700 (s), 1603 (w), 1500 (m), 1456 (m),
1427 (m), 1385 (w), 1359 (w), 1336 (m), 1254 (s), 1185 (s), 1097
(s), 1017 (m), 966 (w), 888 (s), 834 (s), 765 (w), 734 (w), 660
(m), 572 (w), 528 (m); Anal. (C10H8ClFO2) C, H. The structure
of 10c was confirmed by X-ray structural analysis (cf. Sup-
porting Information).
trans-(()-2-Fluoro-2-(4-methylphenyl)cyclopropane-
carboxylic Acid (9d). Hydrolysis as described above of 7d
(524 mg, 2.32 mmol) gave, after recrystallization from CH2-
Cl2/pentane (1:4), 9d as a white, amorphous solid (Yield: 335
mg, 75%). Data for 9d: Mp 112 °C (CH2Cl2/pentane); 1H NMR
(CDCl3) δ 1.66 (1 H, ddd, J ) 6.9 Hz, J ) 9.1 Hz, J ) 10.5 Hz,
CHX), 2.16 (1 H, ddd, J ) 7.6 Hz, J ) 9.1 Hz, J ) 10.3 Hz,
CHAHB), 2.29 (1 H, ddd, J ) 6.9 Hz, J ) 7.6 Hz, J ) 20.0 Hz,
CHAHB), 2.36 (s, CH3), 7.17-7.25 (4 H, m, aromatic), 11.29 (1
H, br, CO2H); 13C NMR (CDCl3) δ 19.2 (dt, J ) 12.7 Hz,
CHAHB), 21.1 (q, CH3), 28.4 (dd, J ) 11.4 Hz, CHX), 81.6 (ds,
J ) 230.2 Hz, CF), 125.2 (dd, J ) 5.1 Hz, aromatic), 129.3 (d,
aromatic), 134.0 (ds, J ) 21.6 Hz, aromatic), 138.7 (s, aro-
matic), 174.4 (s, CdO); 19F NMR (CDCl3) δ -184.66 (ddd, J )
10.3 Hz, J ) 10.5 Hz, J ) 20.0 Hz); MS as trimethylsilyl ester
m/z (%) 266 (12), 251 (31), 235 (6), 223 (6), 211 (25), 207 (10),
176 (71), 149 (13), 147 (13), 133 (21), 129 (48), 119 (41), 115
(23), 109 (3), 91 (2), 77 (28), 73 (100), 51 (1), 45 (6); IR (KBr)
ν 3113 (br), 3055 (br), 2999 (br), 2926 (br), 2866 (br), 1691 (s),
1523 (w), 1451 (s), 1427 (s), 1388 (w), 1297 (s), 1245 (m), 1207
(s), 1131 (w), 1106 (m), 1053 (w), 1022 (w), 1010 (m), 965 (w),
897 (m), 866 (w), 834 (w), 811 (s), 789 (m), 769 (w), 714 (w),
658 (w), 642 (w), 569 (m), 491 (w); Anal. (C11H11FO2) C, H.
General Procedure for Hydrolysis with KOH. A solu-
tion of the cyclopropanecarboxylic ethyl ester (7 or 8) (1 mmol)
in methanol (2 mL) was added to KOH (0.56 g, 10 mmol) in
methanol (5 mL) at 0 °C. The reaction mixture was stirred
overnight at room temperature and then poured into water
and extracted with CH2Cl2 (25 mL). The organic layer was
discarded and the aqueous phase was acidified with concen-
trated HCl to pH 1 and extracted with CH2Cl2 (2 × 25 mL).
The organic phases were dried (Na2SO4) and all volatiles
removed under vacuum. The acids were isolated as white
powders and further purified by recrystallization.
trans-(()-2-Fluoro-2-(4-fluorophenyl)cyclopropane-
carboxylic Acid (9b). Using the same procedure as above,
hydrolysis of 7b (226 mg, 1.00 mmol) gave, after recrystalli-
zation from CH2Cl2/pentane at -20 °C, 9b as a colorless,
crystalline solid (Yield: 290 mg, 95%). Data for 9b: Mp 114
°C; 1H NMR (CDCl3) δ 1.67 (1 H, ddd, J ) 7.2 Hz, J ) 9.3 Hz,
J ) 10.6 Hz, CHX), 2.16 (1 H, ddd, J ) 7.6 Hz, J ) 9.3 Hz, J
) 11.8 Hz, CHAHB), 2.30 (1 H, ddd, J ) 7.2 Hz, J ) 7.6 Hz, J
) 19.9 Hz, CHAHB), 7.04-7.36 (4 H, m, aromatic), 11.30 (1 H,
br, COOH); 13C NMR (CDCl3) δ 19.1 (dt, J ) 12.7 Hz, CHAHB),
28.3 (dd, J ) 11.4 Hz, CHX), 81.2 (ds, J ) 228.9 Hz, CF), 115.7
(dd, J ) 21.7 Hz, aromatic), 127.3 (ddd, J ) 5.7 Hz, J ) 8.3
Hz, aromatic), 132.7 (dds, J ) 3.8 Hz, J ) 21.6 Hz, aromatic),
162.9 (dds, J ) 249.2 Hz, aromatic), 174.2 (s, CdO); 19F NMR
(CDCl3) δ -113.26 (1 F, m, aromatic), -183.47 (1 F, m,
aliphatic); MS as trimethylsilyl ester m/z (%) 270 (6), 255 (23),
225 (6), 215 (35), 180 (51), 151 (17), 133 (57), 123 (36), 115 (7),
107 (2), 77 (26), 73 (100), 47 (2), 45 (7); Anal. (C12H13FO2) C,
H. The structure of 9b was confirmed by X-ray structural
analysis (cf. Supporting Information).
cis-(()-2-Fluoro-2-(4-fluorophenyl)cyclopropanecar-
boxylic Acid (10b). Using the general procedure, hydrolysis
of 8b (204 mg, 0.90 mmol) with KOH gave, after recrystalli-
zation from CH2Cl2/pentane at -20 °C, 10b as a colorless,
crystalline solid (Yield: 167 mg, 93%) Data for 10b: Mp 98
1
°C (CH2Cl2/pentane); H NMR (CDCl3) δ 1.77-1.93 (2 H, m,
CHAHB), 2.48 (1 H, ddd, J ) 7.5 Hz, J ) 10.0 Hz, J ) 17.4 Hz,
CHX), 6.90-7.50 (4 H, m, aromatic), 11.06 (s1 H, COOH); 13
C
NMR (CDCl3) δ 17.4 (dt, J ) 10.2 Hz, CHAHB), 27.5 (dd, J )
17.8 Hz, CHX), 82.9 (ds, J ) 222.6 Hz, CF), 115.4 (dd, J )
21.7 Hz, aromatic), 128.5 (dds, J ) 3.2 Hz, J ) 20.8 Hz,
aromatic), 130.5 (ddd, J ) 3.2 Hz, J ) 8.2 Hz, aromatic), 163.3
(dds, J ) 3.2 Hz, J ) 248.6 Hz, aromatic), 175.2 (s, CdO); 19
F
NMR (CDCl3) δ -111.93 (1 F, m, aromatic), -151.26 (1 F, m,
aliphatic); MS as trimethylsilyl ester m/z (%) 270 (7), 255 (14),
225 (5), 215 (21), 180 (51), 152 (16), 133 (42), 123 (41), 115 (6),
107 (2), 77 (21), 73 (100), 47 (3), 45 (8); Anal. (C12H13FO2) C,
cis-(()-2-Fluoro-2-(4-methylphenyl)cyclopropanecar-
boxylic Acid (10d). Using the general procedure for hydroly-
sis with KOH, 10d was prepared from 333 mg (1.47 mmol) of