3,3-Difluorocyclobutane Carboxylic Acid
661
1H NMR (400 MHz; CDCl3) d 2.98 (5H, m, ring protons). 13C NMR
1
(100 MHz, CDCl3) d 120.4 (t, JCF ¼ 271 Hz, CF2), 115.2 (s, CN), 40.6
2
3
(t, 2C, JCF ¼ 25 Hz, 2 ꢀ CH2), 11.9 (dd, JCF ¼ 16, 7 Hz, CHCN). 19F
21
NMR (376 MHz, CDCl3) d 284.0 (1F, d, J ¼ 190 Hz), 298.0 (1F, d,
;;
J ¼ 190 Hz). IR (neat) ymax 2976 (C-H), 2247 (C N) cm
.
3,3-Difluorocyclobutanecarboxylic Acid, 1 and 3,3-
Difluorocyclobutanecarboxamide, 10
To a solution of 9 (30 g, 256 mmol) in methanol (260 mL) sodium hydroxide
pellets (12.5 g, 1.2 eq., 312 mmol) followed by water (120 mL) were added
and the resulting mixture was stirred at room temperature for 72 h. The
mixture was then warmed to 608C and stirred for a further 3 hours. The
reaction mixture was cooled to room temperature and the solvent was evapor-
ated under reduced pressure. The residue was taken up in water (30 mL) and
washed with ethyl acetate (2 ꢀ 30 mL). The combined ethyl acetate extracts
were concentrated under reduced pressure to give the amide 10, as an
1
off-white solid (3.5 g, 10%). H NMR (400 MHz, CDCl3) d 2.83 (5H, m,
ring protons), 5.45 (2H, bs, NH). 13C NMR (100 MHz, CDCl3) d 174.5
1
(s, C55O), 118.9 (dd, JCF ¼ 268, 268 Hz (rounded to nearest 1 Hz), CF2),
2
3
38.9 (t, JCF ¼ 24 Hz, 2C, 2 ꢀ CH2), 27.65 (dd, JCF ¼ 14.5, 5 Hz,
CHCONH2). m/z (APCIþ) 136 (M þ Hþ, 100%), (APCI2) 135 (M, 100%).
IR (neat) ymax. 3351, 3175 (NH), 1628 (C55O) cm21. The aqueous phase
was then acidified to pHꢀ1 with 2M hydrochloric acid and extracted with
dichloromethane (3 ꢀ 50 mL) and diethyl ether (2 ꢀ 50 mL). The combined
organic extracts were dried (MgSO4) and the solvent concentrated in vacuo.
The brown residue was dissolved in a mixture of diethyl ether:pentane (2:1)
and passed through a pad of silica gel (40–63 m). The filtrate was concentrated
under reduced pressure to afford an off-white solid. Recrystallization from
diethyl ether/pentane afforded 1 (27.6 g, 80%), m.p. 48.6–49.58C; [lit. m.p.
48–508C].[3] 1H NMR (400 MHz, CDCl3) d 2.81 (4H, m, 2 ꢀ CH2), 3.05
(1H, m, CH-CO2H), 11.4 (1H, bs, CO2H). 13C NMR (100 MHz, CDCl3) d
1
180.1 (s, C55O), 118.6 (dd, JCF ¼ 269, and 270 Hz, CF2), 38.8
2
3
(t, JCF ¼ 25 Hz, 2 ꢀ CH2), 26.7 (dd, JCF ¼ 14 and 8 Hz, CHCO2H). 19F
NMR (376 MHz, CDCl3) d 284.0 (1F, d, J ¼ 190 Hz), 298 (1F, d,
J ¼ 190 Hz). m/z (ES2) 135 (M-Hþ, 80%), 271 (M2-Hþ, 100%). IR (neat)
y
max. 3350 (OH), 2968, 1704 (C55O) cm21. Found: C, 43.86; H, 4.43;
C5H6F2O2 requires C, 44.13; H, 4.44%.
REFERENCES
1. (a) Reiss, J. G. New J. Chem. 1995, 19, 891–909; (b) Elliott, A. J. Fluorinated phar-
maceuticals. ACS Monograph (1995), 187 (Chemistry of Organic Fluorine