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MedChemComm
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DOI: 10.1039/C6MD00277C
Journal Name
ARTICLE
MHz) δ 1.60 (s, 6H), 4.82 (s, 2H), 6.99 (d, J = 2.4 Hz, 1H), 7.19 (dd, J = 123.1 (q, J = 287 Hz), 126.7, 127.1, 128.2, 129.7, 130.2, 136.0, 139.3,
9.0, 2.5 Hz, 1H), 7.29 (s, 1H), 7.79 (d, J = 9.1 Hz, 1H), 7.99 (s, 1H); 19
NMR (CDCl3, 376 MHz) δ -78.33; 13C NMR (Acetone-d6, 100 MHz) δ 474.1135, found 474.1138.
27.0, 65.4, 76.6-77.8 (m), 102.9, 106.6, 111.0, 114.6, 119.5, 123.2 Amide 7f. Prepared from 4 (150.0 mg, 0.41 mmol) in the same
F
153.9, 157.1, 167.6; HRMS (ESI) calcd for C22H18F6NO4 ([M+H]+)
+
1
(q, J = 286 Hz), 126.0, 128.4, 131.5, 137.6, 150.2, 159.0, 170.0; manner as described for 7a (200 mg, 99% yield). H NMR (Acetone-
+
HRMS (ESI) calcd for C18H15F6O5 ([M+H]+) 425.0818, found d6, 400 MHz) δ 4.50 (d, J = 5.9 Hz, 2H), 4.72 (d, J = 2.0 Hz, 2H), 6.98-
425.0798.
7.07 (m, 2H), 7.13 (dd, J = 9.0, 2.5 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H),
Amide 7a. Potassium carbonate (170.0 mg, 1.23 mmol) was 7.30-7.38 (m, 2H), 7.42 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 8.09 (s, 1H);
added to a solution of 4 (150.0 mg, 0.41 mmol) and 6a (111.6 mg, 19F NMR (Acetone-d6, 376 MHz) δ -117.73, -76.14; 13C NMR (DMSO-
0.62 mmol) in acetone (5 mL), then the result suspension was d6, 100 MHz) δ 41.1, 67.0, 78.0-79.2 (m), 104.8, 110.2, 114.8, 115.0,
heated at reflux until 4 was consumed as indicated by TLC. After 116.7, 122.6, 123.1 (q, J = 287 Hz), 129.0, 129.1, 129.7, 130.2, 135.5,
removal of the solvent under reduced pressure, the residue was 136.0, 153.9, 157.1, 159.9, 162.3, 167.6; HRMS (ESI) calcd for
dissolved in EtOAc (25 mL), washed with 2N HCl (30 mL) and brine C22H17F7NO4+ ([M+H]+) 492.1040, found 492.1041.
(30 mL x 2). The organic layer was dried over anhydrous Na2SO4,
Amide 7g. Prepared from 4 (150.0 mg, 0.41 mmol) in the same
1
concentrated under vacuum and used without purification. The manner as described for 7a (170 mg, 78% yield). H NMR (Acetone-
residue was dissolved in TFA/H2O (9/1, 11.3 mL), then anisole (45 d6, 400 MHz) δ 3.65 (s, 3H), 3.74 (s, 3H), 4.43 (d, J = 6.2 Hz, 2H), 4.70
μL) was added and the resulting mixture was stirred overnight. The (s, 2H), 6.81 (d, J = 1.0 Hz, 2H), 6.89 (s, 1H), 7.08-7.26 (m, 2H), 7.39
reaction mixture was concentrated under vacuum and then diluted (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 8.09 (s, 2H); 19F NMR (Acetone-d6,
with EtOAc (25 mL), washed with brine (30 mL x 2), the organic 376 MHz) δ -76.03; 13C NMR (Acetone-d6, 100 MHz) δ 42.7, 55.4,
layer was dried over anhydrous Na2SO4, concentrated under 55.6, 67.5, 79.8-80.4 (m), 105.6, 112.0, 112.1, 115.0, 118.0, 120.2,
vacuum and purified by flash chromatography on silica gel (20-80% 123.8 (q, J = 286 Hz), 124.2, 129.7, 131.0, 131.8, 136.7, 149.1, 149.8,
+
EtOAc/petroleum ether) to give 7a as clear oil (131 mg, 77% yield). 154.4, 158.0, 168.8; HRMS (ESI) calcd for C24H22F6NO6 ([M+H]+)
1H NMR (Acetone-d6, 400 MHz) δ 0.88 (t, J = 7.4 Hz, 3H), 1.41-1.66 534.1346, found 534.1369.
(m, 2H), 3.24-3.31 (m, 2H), 4.64 (s, 2H), 7.09-7.25 (m, 2H), 7.42 (s,
Amide 7h. Prepared from 4 (150.0 mg, 0.41 mmol) in the same
1
1H), 7.91 (d, J = 9.0 Hz, 1H), 8.09 (s, 1H); 19F NMR (Acetone-d6, 376 manner as described for 7a (210 mg, 95% yield). H NMR (Acetone-
MHz) δ -76.08; 13C NMR (Acetone-d6, 100 MHz) δ 11.1, 23.0, 41.0, d6, 400 MHz) δ 2.98 (t, J = 7.0 Hz, 2H), 3.59 (dd, J = 13.2, 6.8 Hz, 2H),
67.4, 79.7-80.3 (m), 105.4, 111.9, 114.8, 117.8, 123.6 (q, J = 286 Hz), 4.65 (s, 2H), 7.03-7.21 (m, 3H), 7.26 (d, J = 8.2 Hz, 1H), 7.35-7.47 (m,
124.1, 129.5, 130.8, 136.6, 154.4, 157.8, 168.6; HRMS (ESI) calcd for 2H), 7.91 (d, J = 9.0 Hz, 2H); 19F NMR (Acetone-d6, 376 MHz) δ -
C18H18F6NO4+ ([M+H]+) 426.1135, found 426.1118.
75.99; 13C NMR (Acetone-d6, 100 MHz) δ 33.2, 39.0, 67.7, 80.0-80.6
Amide 7b. Prepared from 4 (110.0 mg, 0.30 mmol) in the same (m), 105.7, 112.2, 115.1, 118.2, 123.9 (q, J = 287 Hz), 124.5, 127.7,
1
manner as described for 7a (100 mg, 78% yield). H NMR (Acetone- 129.4, 129.9, 131.2, 132.9, 133.0, 135.2, 136.4, 137.9, 154.5, 158.1,
+
d6, 400 MHz) δ 0.48-0.64 (m, 2H), 0.66-0.80 (m, 2H), 2.06 (dt, J = 168.9; HRMS (ESI) calcd for C23H18Cl2F6NO4 ([M+H]+) 556.0512,
4.4, 2.2 Hz, 1H), 4.61 (s, 2H), 7.08-7.23 (m, 2H), 7.42 (s, 1H), 7.90 (d, found 556.0510.
J = 9.0 Hz, 1H), 8.08 (s, 1H); 19F NMR (Acetone-d6, 376 MHz) δ -
Amide 7i. Prepared from 4 (115.1 mg, 0.31 mmol) in the same
76.06; 13C NMR (Acetone-d6, 100 MHz) δ 5.9, 22.8, 67.6, 79.9-80.5 manner as described for 7a (28 mg, 16% yield). 1H NMR (Acetone-
(m), 105.5, 112.1, 114.9, 117.9, 123.8 (q, J = 286 Hz), 124.2, 129.7, d6, 400 MHz) δ 4.84 (s, 2H), 6.26 (s, 1H), 7.05 (dd, J = 9.0, 2.5 Hz,
+
131.0, 136.7, 154.5, 158.0; HRMS (ESI) calcd for C18H16F6NO4
([M+H]+) 424.0978, found 424.0976.
1H), 7.21-7.32 (m, 3H), 7.36-7.43 (m, 3H), 7.51 (d, J = 7.5 Hz, 2H),
7.81 (t, J = 8.4 Hz, 3H), 8.04 (s, 1H); 19F NMR (Acetone-d6, 376 MHz)
Amide 7c. Prepared from 4 (150.0 mg, 0.41 mmol) in the same δ -76.08; 13C NMR (DMSO-d6, 100 MHz) δ 54.3, 67.3, 78.8-79.4 (m),
manner as described for 7a (130 mg, 72% yield). H NMR (Acetone- 105.1, 110.6, 117.1, 120.6, 123.0, 123.7 (q, J = 288 Hz), 125.2, 128.0,
1
d6, 400 MHz) δ 1.12 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 8.0 Hz, 3H), 3.42 128.9, 130.1, 130.7, 136.5, 140.6, 144.9, 154.9, 157.7, 169.0; HRMS
(q, J = 7.0 Hz, 2H), 3.51 (q, J = 7.1 Hz, 2H), 4.95 (s, 2H), 7.02-7.18 (m, (ESI) calcd for C28H20F6NO4+ ([M+H]+) 548.1291, found 548.1284.
2H), 7.30 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H); 19F NMR
Amide 7j. Prepared from 4 (150.0 mg, 0.41 mmol) in the same
(Acetone-d6, 376 MHz) δ -76.04; 13C NMR (Acetone-d6, 100 MHz) δ manner as described for 7a (88 mg, 95% yield). 1H NMR (Acetone-
12.8, 14.1, 40.6, 66.0, 78.0-79.2 (m), 104.7, 110.0, 116.5, 122.4, d6, 400 MHz) δ 4.81 (s, 2H), 7.11 (t, J = 7.4 Hz, 1H), 7.20-7.39 (m,
123.1 (q, J = 288 Hz), 129.6, 130.2, 136.0, 153.9, 157.6, 166.0; HRMS 4H), 7.42 (s, 1H), 7.72-7.83 (m, 2H), 7.95 (d, J = 9.0 Hz, 1H), 8.12 (s,
(ESI) calcd for C19H20F6NO4+ ([M+H]+) 440.1291, found 440.1298.
1H); 19F NMR (Acetone-d6, 376 MHz) δ -76.04; 13C NMR (Acetone-d6,
Amide 7d. Prepared from 4 (150.0 mg, 0.41 mmol) in the same 100 MHz) δ 67.7, 79.7-80.3 (m), 105.6, 111.9, 114.8, 117.9, 120.5,
1
manner as described for 7a (90 mg, 42% yield). H NMR (DMSO-d6, 123.6 (q, J = 286 Hz), 124.2, 124.5, 129.0, 129.6, 130.9, 136.6, 138.6,
+
400 MHz) δ 1.62 (s, 6H), 2.00 (d, J = 10.7 Hz, 10H), 4.53 (s, 2H), 7.06 154.2, 157.9, 166.8; HRMS (ESI) calcd for C21H16F6NO4 ([M+H]+)
(d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 7.44 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H); 460.0978, found 460.0982.
19F NMR (DMSO-d6, 376 MHz) δ -76.01; 13C NMR (DMSO-d6, 100
Amide 7k. Prepared from 4 (150.0 mg, 0.41 mmol) in the same
1
MHz) δ 28.7, 35.9, 40.9, 51.0, 67.0, 78.0-79.1 (m), 104.6, 110.1, manner as described for 7a (130 mg, 63% yield). H NMR (Acetone-
116.6, 122.5, 123.1 (q, J = 288 Hz), 129.6, 130.2, 136.0, 153.9, 157.3, d6, 400 MHz) δ 1.20 (d, J = 6.9 Hz, 6H), 2.71-2.98 (m, 1H), 4.81 (s,
166.4; HRMS (ESI) calcd for C25H26F6NO4+ ([M+H]+) 518.1761, found 2H), 7.12-7.33 (m, 4H), 7.42 (s, 1H), 7.60-7.73 (m, 2H), 7.93 (d, J =
518.1766.
9.0 Hz, 1H), 8.12 (s, 1H); 19F NMR (Acetone-d6, 376 MHz) δ -76.11;
Amide 7e. Prepared from 4 (100.0 mg, 0.27 mmol) in the same 13C NMR (Acetone-d6, 100 MHz) δ 23.9, 33.8, 67.9, 79.8-80.4 (m),
manner as described for 7a (91 mg, 71% yield). 1H NMR (Acetone- 105.7, 112.1, 114.9, 118.0, 120.8, 123.7 (q, J = 287 Hz), 124.3, 127.0,
d6, 400 MHz) δ 4.51 (d, J = 8.0 Hz, 2H), 4.71 (s, 2H), 7.10-7.16 (m, 129.7, 131.0, 136.3, 136.7, 145.2, 154.3, 158.0, 166.7; HRMS (ESI)
1H), 7.17-7.33 (m, 6H), 7.40 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 8.08 (s, calcd for C24H22F6NO4+ ([M+H]+) 502.1448, found 502.1424.
1H); 19F NMR (Acetone-d6, 376 MHz) δ -76.03; 13C NMR (DMSO-d6,
Amide 7l. Prepared from 4 (120.0 mg, 0.33 mmol) in the same
100 MHz) δ 41.8, 67.0, 78.0-78.9 (m), 104.8, 110.1, 116.7, 122.6, manner as described for 7a (47 mg, 27% yield). 1H NMR (Acetone-
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