1
1
12.3, 65.7 (d, J = 5.9 Hz), 38.8, 37.6, 29.3 (t, J = 10.5 Hz), 23.3 (dd, J = 12.7, 10.7 Hz). 19F NMR (CDCl
3
, 376 MHz) δ –136.8 (dd, J =
+
+
59.2, 12.5 Hz), –138.3 (dd, J = 159.3, 14.2 Hz). MS (ESI): m/z = 267 ([M+H] ), 171 ([M–CH
3 2
SO –F] ), 151. Anal. Calcd. for
9 12 2 2 3
C H F N O
S: C, 40.60; H, 4.54; N, 10.52; S, 12.04. Found: C, 40.95; H, 4.74; N, 10.77; S, 11.74.
4
.7.3. (2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methyl methanesulfonate (19c).
1
Yield 1.4 g (99%). Reddish oil. H NMR (CDCl
3
, 400 MHz) δ 7.41 (s, 1H), 6.15 (s, 1H), 4.53 (dd, J = 11.0, 7.5 Hz, 1H), 4.43 – 4.36
(
m, 1H), 3.90 (s, 3H), 3.08 (s, 3H), 2.68 (dd, J = 13.4, 7.0 Hz, 1H), 2.30 (dq, J = 15.0, 7.6 Hz, 1H). 13C NMR (CDCl
3
, 101 MHz) δ
1
37.9, 133.2, 111.2 (t, J = 287.7 Hz), 104.9, 64.5 (d, J = 4.9 Hz), 37.4, 36.2, 28.5 (t, J = 10.3 Hz), 23.0 (dd, J = 13.2, 10.5 Hz). 19
F
+
NMR (CDCl
3
, 376 MHz) δ –135.0 (d, J = 160.3 Hz), –136.6 (d, J = 160.3 Hz). MS (ESI): m/z = 267 ([M+H] ). Anal. Calcd. for
S: C, 40.60; H, 4.54; N, 10.52; S, 12.04. Found: C, 40.92; H, 4.24; N, 10.53; S, 12.29.
.8. General procedure for the preparation of 20
9 12 2 2 3
C H F N O
4
Potassium phthalimide (0.65 g, 3.5 mmol) was added to a solution of mesylate 19 (0.61 g, 2.3 mmol) in DMF (10 mL) at rt. The
reaction mixture was stirred vigorously at 100 °C for 3 h. The completion of the reaction was controlled by the disappearance of the
mesylate in TLC. The resulting mixture was cooled to rt. The combined organic layers were washed with H O (350 mL), brine (230
mL), dried over anhydrous Na SO , filtered and concentrated under reduced pressure. A crude product was purified by column
chromatography (EtOAc –hexane (1:1) as eluent) afforded pure 20.
2
2
4
4
.8.1. 2-((2,2-Difluoro-3-(1-methyl-1H-pyrazol-3-yl)cyclopropyl)methyl)-isoindoline-1,3-dione (20a).
1
Yield 0.60 g (82%). White solid. H NMR (CDCl
3
, 400 MHz) δ 7.87 – 7.80 (m, 2H), 7.74 – 7.67 (m, 2H), 7.23 (d, J = 2.2 Hz, 1H),
6
.00 (d, J = 2.1 Hz, 1H), 4.01 (dd, J = 14.7, 7.0 Hz, 1H), 3.91 (ddt, J = 14.5, 8.1, 1.5 Hz, 1H), 3.80 (s, 3H), 2.78 (ddd, J = 11.8, 7.4, 2.6
Hz, 1H), 2.50 – 2.38 (m, 1H). 13C NMR (CDCl
, 101 MHz) δ 167.3, 144.1, 133.6, 131.5, 130.4, 123.0, 112.5 (t, J = 289.5 Hz), 103.7,
8.6, 34.7 (d, J = 4.9 Hz), 27.4 (t, J = 10.1 Hz), 26.7 (t, J = 11.4 Hz). 19F NMR (CDCl
, 376 MHz) δ –138.5 (dd, J = 157.6, 11.5 Hz), –
3
3
3
1
6
+
39.0 (dd, J = 157.6, 11.5 Hz). MS (ESI): m/z = 318 ([M+H] ). Anal. Calcd. for C16
H
13
F
2
N
3
O
2
: C, 60.57; H, 4.13; N, 13.24. Found: C,
0.78; H, 4.00; N, 13.18.
4
.8.2. 2-((2,2-Difluoro-3-(1-methyl-1H-pyrazol-4-yl)cyclopropyl)methyl)-isoindoline-1,3-dione (20b).
1
Yield 1.1 g (91%). White solid. H NMR (CDCl
3
, 400 MHz) δ 7.89 – 7.81 (m, 2H), 7.76 – 7.69 (m, 2H), 7.27 (s, 1H), 7.18 (s, 1H),
4
.04 (dd, J = 14.6, 6.1 Hz, 1H), 3.85 – 3.76 (m, 1H), 3.80 (s, 3H), 2.59 (dd, J = 14.1, 7.2 Hz, 1H), 2.09 – 1.97 (m, 1H). 13C NMR
, 101 MHz) δ 167.4, 137.9, 133.7, 131.4, 128.0, 123.0, 113.3, 113.1 (t, J = 289.5 Hz), 38.7, 34.9 (d, J = 5.5 Hz), 29.4 (t, J = 9.9
(CDCl
3
Hz), 23.7 (t, J = 11.6 Hz). 19F NMR (CDCl
, 376 MHz) δ –137.0 (dd, J = 157.9, 13.7 Hz), –138.6 (dd, J = 157.9, 14.1 Hz). MS (ESI):
: C, 60.57; H, 4.13; N, 13.24. Found: C, 60.37; H, 3.94; N, 12.95.
3
+
m/z = 318 ([M+H] ), 171. Anal. Calcd. for C16
H
13
F
2
N
3
O
2
4
.8.3. 2-((2,2-Difluoro-3-(1-methyl-1H-pyrazol-5-yl)cyclopropyl)methyl)-isoindoline-1,3-dione (20c).
1
Yield 1 g (85%). White solid. H NMR (CDCl
H), 5.96 (s, 1H), 4.09 (dd, J = 14.6, 5.6 Hz, 1H), 3.84 (dd, J = 14.5, 9.3 Hz, 1H), 3.76 (s, 3H), 2.66 (dd, J = 13.0, 7.2 Hz, 1H), 2.27 (td,
, 101 MHz) δ 168.0, 138.3, 134.8, 134.4, 131.8, 123.6, 112.2 (t, J = 291.6 Hz), 104.9, 36.5, 34.6
3
, 400 MHz) δ 7.84 (dd, J = 5.1, 3.1 Hz, 2H), 7.72 (dd, J = 5.2, 3.0 Hz, 2H), 7.30 (s,
1
J = 13.5, 6.9 Hz, 1H). 13C NMR (CDCl
3