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Organic & Biomolecular Chemistry
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HRMS (ESI): m/z calcd for C26H23N4O2F [M + H]+ 443.1878, found
H]+ 507.0826, found 507.0835; C25H20N4O2F80.9163Br [M + H]+
509.0806, found 509.0817.
443.1879.
DOI: 10.1039/C9OB01350D
(S)‐3‐((S)‐4‐((2‐Bromophenyl)amino)‐3‐methyl‐5‐oxo‐1‐phenyl‐4,5‐
dihydro‐1H‐pyrazol‐4‐yl)‐3‐fluoro‐1‐methylindolin‐2‐one (3p). 3p
was obtained as a white solid (97.3 mg, 96% yield), m.p. 163–165 C.
HPLC (Daicel Chiralpak ADH, n‐hexane/2‐propanol = 95:5, flow rate
1.0 mL/min, detection at 254 nm): major diastereoisomer, tR = 20.4
min (minor), tR = 25.3 min (major); minor diastereoisomer, tR = 41.0
(S)‐3‐Fluoro‐1‐methyl‐3‐((S)‐3‐methyl‐5‐oxo‐1‐phenyl‐4‐(m‐tolyl‐
amino)‐4,5‐dihydro‐1H‐pyrazol‐4‐yl) indolin‐2‐one (3m). 3m was
obtained as a white solid (83.9 mg, 95% yield), m.p. 136‐138 °C. HPLC
(Daicel Chiralpak IA, n‐hexane/2‐propanol = 80:20, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 6.0 min
(minor), tR = 10.5 min (major); 99% ee for the major diastereoisomer.
[]D20 = ‒7.1 (c 4.01, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.37 (d, J =
7.6 Hz, 1H, ArH), 7.33–7.29 (m, 3H, ArH), 7.25–7.21 (m, 2H, ArH), 7.10
(tt, J1 = 7.4 Hz, J2 = 1.2 Hz, 1H, ArH), 7.01–6.94 (m, 2H, ArH), 6.78 (d,
J = 7.6 Hz, 1H, ArH), 6.73 (s, 1H, NH), 6.56 (d, J = 7.6 Hz, 1H, ArH), 6.43
(s, 1H, ArH), 6.26 (dd, J1 = 8.2 Hz, J2 = 2.6 Hz, 1H, ArH), 3.21 (s, 3H,
CH3), 2.46 (d, J = 1.2 Hz, 3H, CH3), 2.18 (s, 3H, CH3) ppm; 13C NMR (176
MHz, CDCl3): δ 169.5 (d, 2JC‐F =19.4 Hz), 168.8 (d, 3JC‐F =5.1 Hz), 158.4,
144.6, 144.3 (d, 3JC‐F = 5.5 Hz), 139.2, 136.7, 132.8, 129.4, 128.7, 125.9,
20
min; 98% ee for the major diastereoisomer. []D = –82.4 (c 2.88,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, J1 = 7.8 Hz, J2 = 1.4 Hz,
1H, ArH), 7.42–7.30 (m, 5H, ArH), 7.27–7.23 (m, 2H, ArH), 7.15–7.10
(m, 1H, ArH), 7.01–6.95 (m, 2H, NH+ArH), 6.80 (d, J = 8.0 Hz, 1H, ArH),
6.60 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1H, ArH), 6.05 (dd, J1 = 8.2 Hz, J2 = 1.4
Hz, 1H, ArH), 3.23 (s, 3H, CH3), 2.38 (d, J = 1.6 Hz, 3H, CH3) ppm; 13
C
NMR (176 MHz, CDCl3): δ 169.1 (d, 2JC‐F = 22.0 Hz), 168.0 (d, 3JC‐F = 5.3
Hz), 157.7, 144.5 (d, 3JC‐F = 5.1 Hz), 141.5, 136.7, 133.2, 133.0, 128.7,
128.7, 126.0, 124.9, 123.0, 120.0, 119.44, 119.36 (d, 2JC‐F = 18.7 Hz),
111.2, 110.5, 109.3, 89.7 (d, 1JC‐F = 209.4 Hz), 73.4 (d, 2JC‐F = 23.4 Hz),
26.4, 15.9 (d, 4JC‐F = 4.0 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ –170.1
ppm. HRMS (ESI): m/z calcd for C25H20N4O2F78.9183Br [M + H]+
507.0826, found 507.0825; C25H20N4O2F80.9163Br [M + H]+ 509.0806,
found 509.0808.
2
124.7, 123.0, 120.6, 119.6 (d, JC‐F = 18.1 Hz), 119.6, 115.4, 110.3,
1
2
109.2, 89.6 (d, JC‐F = 209.1 Hz), 73.7 (d, JC‐F = 23.4 Hz), 26.4, 21.4,
15.9 (d, 4JC‐F = 4.0 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ ‒170.5 ppm.
HRMS (ESI): m/z calcd for C26H23N4O2F [M + H]+ 443.1878, found
443.1878.
(S)‐3‐Fluoro‐1,5‐dimethyl‐3‐((S)‐3‐methyl‐5‐oxo‐1‐phenyl‐4‐
(phenylamino)‐4,5‐dihydro‐1H‐pyrazol‐4‐yl) indolin‐2‐one (3q). 3q
was obtained as a white solid (71.6 mg, 81% yield), m.p. 180–182 C.
HPLC (Daicel Chiralpak IA, n‐hexane/2‐propanol = 85:15, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 9.3 min
(minor), tR = 13.4 min (major); minor diastereoisomer, tR = 28.8 min
(major), tR = 35.0 min (minor); 98% ee for the major diastereoisomer.
[]D20 = –35.7 (c 1.08, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.35 (d, J
= 8.0 Hz, 2H, ArH), 7.27–7.21 (m, 2H, ArH), 7.18 (s, 1H, ArH), 7.13–
7.09 (m, 4H, ArH), 6.85 (s, 1H, NH), 6.75 (t, J = 7.4 Hz, 1H, ArH), 6.67
(d, J = 8.0 Hz, 1H, ArH), 6.52 (d, J = 8.0 Hz, 2H, ArH), 3.21 (s, 3H, CH3),
2.46 (s, 3H, CH3), 2.25 (s, 3H, CH3) ppm; 13C NMR (176 MHz, CDCl3): δ
169.5 (d, 2JC‐F = 22.0 Hz), 168.7 (d, 3JC‐F = 5.3 Hz), 158.4, 144.6, 141.9
(S)‐3‐Fluoro‐1‐methyl‐3‐((S)‐3‐methyl‐4‐((3‐nitrophenyl)amino)‐5‐
oxo‐1‐phenyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl) indolin‐2‐one (3n). 3n
was obtained as a yellow solid (90.3 mg, 95% yield), m.p. 73–75 °C.
HPLC (Daicel Chiralpak IA, n‐hexane/2‐propanol = 80:20, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 13.3 min
(minor), tR = 17.3 min (major); 85% ee for the major diastereoisomer.
[]D20 = ‒15.6 (c 1.99, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.60 (dd,
J1 = 8.4 Hz, J2 = 1.2 Hz, 1H, ArH), 7.41–7.37 (m, 2H, ArH), 7.30–7.24
(m, 7H, ArH), 7.18–7.13 (m, 1H, ArH), 7.04 (t, J = 7.6 Hz, 1H, ArH),
6.88–6.84 (m, 2H, NH+ArH), 3.27 (s, 3H, CH3), 2.47 (d, J = 1.2 Hz, 3H,
2
CH3) ppm; 13C NMR (176 MHz, CDCl3): δ 169.4 (d, JC‐F = 22.0 Hz),
167.8 (d, 3JC‐F = 5.1 Hz), 157.1, 149.4, 145.5, 144.4 (d, 3JC‐F = 5.1 Hz),
136.3, 133.1, 130.3, 128.8, 126.5, 124.9, 123.5, 120.3, 120.1, 119.3
(d, 2JC‐F = 18.3 Hz), 114.3, 109.5, 107.4, 89.3 (d, 1JC‐F = 209.3 Hz), 73.2
3
(d, JC‐F = 5.3 Hz), 136.9, 133.0, 132.8, 129.5, 128.7, 125.7, 125.4,
2
1
119.7 (d, JC‐F = 18.1 Hz), 119.6, 119.3, 114.0, 109.1, 89.7 (d, JC‐F
=
209.3 Hz), 73.8 (d, 2JC‐F = 23.4 Hz), 26.5, 20.9, 16.0 (d, 4JC‐F = 3.9 Hz)
ppm; 19F NMR (376 MHz, CDCl3): δ –170.2 ppm. HRMS (ESI): m/z calcd
for C26H23N4O2F [M + H]+ 443.1878, found 443.1882.
2
4
(d, JC‐F = 23.2 Hz), 26.5, 15.9 (d, JC‐F = 4.0 Hz) ppm; 19F NMR (376
MHz, CDCl3): δ ‒170.0 ppm. HRMS (ESI): m/z calcd for C25H20N5O4F
[M + H]+ 474.1572, found 474.1578.
(S)‐3,5‐Difluoro‐1‐methyl‐3‐((S)‐3‐methyl‐5‐oxo‐1‐phenyl‐4‐
(S)‐3‐Fluoro‐1‐methyl‐3‐((S)‐3‐methyl‐5‐oxo‐1‐phenyl‐4‐(o‐tolyl‐
amino)‐4,5‐dihydro‐1H‐pyrazol‐4‐yl) indolin‐2‐one (3o). 3o was
obtained as a white solid (84.7 mg, 96% yield), m.p. 168–170 °C. HPLC
(Daicel Chiralpak IA, n‐hexane/2‐propanol = 95:5, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 12.0 min
(minor), tR = 13.7 min (major); >99% ee for the major diastereoisomer.
[]D20 = ‒31.9 (c 2.08, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J
= 7.6 Hz, 1H, ArH), 7.35–7.29 (m, 3H, ArH), 7.26–7.21 (m, 2H, ArH),
7.13–7.07 (m, 2H, ArH), 7.00 (t, J = 7.6 Hz, 1H, ArH), 6.88 (td, J1 = 7.8
Hz, J2 = 1.6 Hz, 1H, ArH), 6.82 (s, 1H, NH), 6.78 (d, J = 8.0 Hz, 1H, ArH),
6.67 (td, J1 = 7.4 Hz, J2 = 1.2 Hz, 1H, ArH), 6.05 (d, J = 8.0 Hz, 1H, ArH),
3.22 (s, 3H, CH3), 2.44–2.43 (m, 6H, CH3) ppm; 13C NMR (176 MHz,
CDCl3): δ 169.6 (d, 2JC‐F = 22.0 Hz), 168.9 (d, 3JC‐F = 5.1 Hz), 158.4, 144.4
(phenylamino)‐4,5‐dihydro‐1H‐pyrazol‐4‐yl) indolin‐2‐one (3r). 3r
was obtained as a white solid (88.1 mg, 98% yield), m.p. 166–168 C.
HPLC (Daicel Chiralpak IA, n‐hexane/2‐propanol = 80:20, flow rate 1.0
mL/min, detection at 254 nm): major diastereoisomer, tR = 8.1 min
(minor), tR = 12.1 min (major); >99% ee for the major diastereoisomer.
[]D20 = +26.2 (c 4.12, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 7.39 (d, J
= 8.0 Hz, 2H, ArH), 7.25 (t, J = 8.0 Hz, 2H, ArH), 7.18–7.06 (m, 4H, ArH),
6.99 (t, J = 8.8 Hz, 1H, ArH), 6.77–6.73 (m, 2H, NH+ArH), 6.67 (dd, J1
= 8.0 Hz, J2 = 4.0 Hz, 1H, ArH), 6.51 (d, J = 8.0 Hz, 2H, ArH), 3.17 (s, 3H,
CH3), 2.44 (d, J = 1.6 Hz, 3H, CH3) ppm; 13C NMR (176 MHz, CDCl3): δ
169.1 (d, 2JC‐F = 21.3 Hz), 168.5 (d, 3JC‐F = 5.1 Hz), 158.7 (d, 1JC‐F = 241.8
Hz), 158.1, 144.3, 140.3 (d, 4JC‐F = 4.6 Hz), 136.7, 129.5, 128.8, 125.9,
120.9 (dd, 3JC‐F = 8.2, 2JC‐F = 18.0 Hz), 119.8, 119.2, 119.1, 114.0, 112.9
(d, 2JC‐F = 24.6 Hz), 110.1 (d, 3JC‐F = 7.7 Hz), 89.3 (d, 1JC‐F = 209.8 Hz),
3
(d, JC‐F = 5.3 Hz), 142.7, 136.8, 132.8, 130.7, 128.7, 127.2, 125.9,
2
124.8, 124.6, 123.1, 119.7 (d, JC‐F = 18.3 Hz), 119.5, 119.1, 109.5,
2
4
73.6 (d, JC‐F = 23.4 Hz), 26.5, 15.9 (d, JC‐F = 3.7 Hz) ppm; 19F NMR
(376 MHz, CDCl3): δ –118.4, –170.8 ppm. HRMS (ESI): m/z calcd for
C25H20N4O2F2 [M + H]+ 447.1627, found 447.1629.
1
2
109.3, 89.3 (d, JC‐F = 209.4 Hz), 73.8 (d, JC‐F = 23.4 Hz), 26.4, 17.6,
15.9 (d, 4JC‐F = 4.0 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ ‒170.4 ppm.
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