1
2
A. Hoshi et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
(
d, JCOCCCF = 1.7 Hz), 44.4, 43.7, 28.2, 27.5, 26.8, 15.5, 14.5; EIMS
119.8, 119.8, 115.6, 63.0 (d,
JCONCF = 2.2 Hz), 61.6, 61.0 (d,
+
m/z (rel intensity) 511 (M , 5.2), 460 (15), 347 (100), 100 (38), 56
J
COCCCF = 2.2 Hz), 44.4, 43.7, 32.6, 27.4, 26.8, 16.1, 14.1; EIMS m/z
+
+
(
38); HRMS (EI) for C27
3
H30FN O
6
calcd 511.2118 (M ), found
(rel intensity) 511 (M , 17), 460 (23), 429 (39), 380 (33), 373
5
11.2113.
(58), 342 (71), 316 (29), 100 (100), 56 (76); HRMS (EI) for
+
C
27
H
30FN
3
O
6
calcd 511.2119 (M ), found 511.2104.
5
.1.26. N,2-Dimethoxy-5-[(1Z)-1-(3-methoxy-7-methyl-1,2-
benzoxazol-5-yl)-5-(5-methyl-1,3,4-oxadiazol-2-yl)pent-1-en-
5.1.29. 5-[(1Z)-1-(3-Cyanophenyl)-5-(5-methyl-1,3,4-oxadiazol-
2-yl)pent-1-en-1-yl]-N,2-dimethoxy-3-methylbenzenecarboxi-
midoyl Fluoride (10)
1
-yl]-3-methylbenzenecarboximidoyl Fluoride (7)
The general Stille coupling procedure was followed using aryl
iodide 39 (107 mg, 0.370 mmol), organostannane 51 (235 mg,
The general Stille coupling procedure was followed using
3-iodobenzonitrile 40 (90 mg, 0.39 mmol), organostannane 51
0
.370 mmol), CsF (168 mg, 1.11 mmol), Pd(PPh
3
)
4
(42 mg,
0
.037 mmol) and CuI (77 mg, 0.44 mmol) in dry DMF (15 mL).
3 4
(250 mg, 0.393 mmol), CsF (179 mg, 1.18 mmol), Pd(PPh )
The reaction mixture was stirred for 18 h and the product was
purified by column chromatography on silica gel using 20% ethyl
(45 mg, 0.039 mmol) and CuI (90 mg, 0.472 mmol) in dry DMF
(10 mL). The reaction mixture was stirred for 17 h and purified
by column chromatography on silica gel using 50% ethyl acetate–
acetate–hexanes to give the product 7 (165 mg, 87.8%) as a clear
1
hexanes to give the product 10 (141 mg, 80.3%) as a clear oil: 1
H
oil: H NMR (270 MHz, CDCl
3
) d 7.39 (s, 1H), 7.27 (s, 1H), 7.17 (d,
J = 1.8 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.01 (t, J = 7.4 Hz, 1H), 3.96
s, 3H), 3.87 (s, 3H), 3.67 (s, 3H), 2.81 (t, J = 7.4 Hz, 2H), 2.48 (s,
H), 2.36 (s, 3H), 2.31 (s, 3H), 2.27–2.19 (m, 2H), 1.93 (quint,
3
NMR (270 MHz, CDCl ) d 7.52 (dd, J = 5.7, 1.8 Hz, 1H), 7.46–7.35
(
3
(m, 3H), 7.17 (d, J = 1.9 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.10 (t,
J = 7.4 Hz, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 2.81 (t, J = 7.4 Hz, 2H),
2.48 (s, 3H), 2.33 (s, 3H), 2.28–2.20 (m, 2H), 1.94 (quint,
1
3
J = 7.4 Hz, 2H); C NMR (68 MHz, CDCl
57.9, 149.2 (d, JCF = 324.0 Hz), 140.4, 138.1, 135.1, 134.8, 132.7
d, JCCCF = 6.7 Hz), 129.0, 128.5, 128.4, 120.1 (d, JCCF = 27.9 Hz),
3
) d 166.4, 163.4, 162.8,
1
3
1
(
3
J = 7.4 Hz, 2H); C NMR (68 MHz, CDCl ) d 166.2, 163.3, 156.3,
149.0 (d, JCF = 324.5 Hz), 142.8, 139.5, 135.0, 133.8, 132.9, 131.0,
130.8, 130.4, 130.3, 128.8, 128.3 (d, JCCCF = 4.5 Hz), 120.2 (d,
1
3
19.8, 119.8, 115.7, 63.0 (d, JCONCF = 1.8 Hz), 60.9 (d, JCOCCCF = 1.8 Hz),
2.6, 29.0, 26.4, 24.8, 16.2, 14.2, 10.9; EIMS m/z (rel intensity) 508
JCCF = 27.4 Hz), 118.5, 112.1, 63.0 (d, JCONCF = 2.0 Hz), 60.9 (d,
+
(
M , 21), 457 (52), 426 (100), 380 (41), 348 (21), 98 (37); HRMS (EI)
J
COCCCF = 2.0 Hz), 29.0, 26.2, 24.7, 16.1, 10.8; EIMS m/z (rel inten-
+
+
for C27
4
H29FN O
5
calcd 508.2122 (M ), found 508.2105.
sity) 448 (M , 13), 397 (100), 351 (29), 299 (26), 98 (61); HRMS
(
+
4 3
EI) for C25H25FN O calcd 448.1911 (M ), found 448.1894.
5
.1.27. N,2-Dimethoxy-5-[(1Z)-1-(3-methoxy-7-methyl-1,2-
benzoxazol-5-yl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pent-1-en-
5.1.30. 5-[(1Z)-1-(3-Cyanophenyl)-5-(3-methyl-1,2,4-oxadiazol-
5-yl)pent-1-en-1-yl]-N,2-dimethoxy-3-methylbenzenecarboxi-
midoyl Fluoride (11)
1
-yl]-3-methylbenzenecarboximidoyl Fluoride (8)
The general Stille coupling procedure was followed using aryl
iodide 39 (78 mg, 0.27 mmol), organostannane 52 (207 mg,
The general Stille coupling procedure was followed using
3-iodobenzonitrile 40 (69 mg, 0.30 mmol), organostannane 52
0
.324 mmol), CsF (123 mg, 0.810 mmol), Pd(PPh
3
)
4
(31 mg,
0
.027 mmol) and CuI (6 mg, 0.027 mmol) in dry DMF (8 mL). The
3 4
(242 mg, 0.362 mmol), CsF (137 mg, 0.903 mmol), Pd(PPh )
reaction mixture was stirred for 16 h and was purified by column
(34 mg, 0.030 mmol), and CuI (7 mg, 0.03 mmol) in dry DMF
(8 mL). The reaction mixture was stirred for 16 h and was purified
by column chromatography on silica gel using 20% ethyl acetate–
hexanes to give the product 11 (72 mg, 54%) as a oil: 1H NMR
chromatography on silica gel using 50% ethyl acetate–hexanes to
1
give the product 8 (48 mg, 35%) as a oil: H NMR (270 MHz, CDCl
3
)
d 7.38 (d, J = 1.2 Hz, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 1.8 Hz,
H), 7.02 (d, J = 1.8 Hz, 1H), 6.00 (t, J = 7.4 Hz, 1H), 3.96 (s, 3H), 3.87
s, 3H), 3.67 (s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.35 (s, 3H), 2.35 (s, 3H),
1
3
(270 MHz, CDCl ) d 7.54–7.40 (m, 4H), 7.17 (d, J = 1.8 Hz, 1H),
(
7.02 (d, J = 1.8 Hz, 1H), 6.09 (t, J = 7.4 Hz, 1H), 3.97 (s, 3H), 3.88
(s, 3H), 2.85 (t, J = 7.4 Hz, 2H), 2.35 (s, 3H), 2.33 (s, 3H), 2.29–
1
3
2
.31 (s, 3H), 2.27–2.19 (m, 2H), 1.96 (quint, J = 7.4 Hz, 2H);
) d 178.9, 166.8, 162.8, 158.0, 156.2, 149.3 (d,
CF = 324.4 Hz), 140.6, 138.1, 135.1, 134.8, 132.8, 132.8, 128.9,
C
1
3
NMR (8 MHz, CDCl
3
3
2.23 (m, 2H), 1.97 (quint, J = 7.4 Hz, 2H); C NMR (68 MHz, CDCl )
J
d 178.7, 166.8, 156.4, 149.2 (d, JCF = 324.2 Hz), 142.8, 139.8, 135.0,
134.2, 133.8, 133.0, 131.1, 130.7, 130.6, 128.5 (d, JCCCF = 4.5 Hz),
1
28.6, 128.5, 119.9, 119.8, 115.8, 63.1 (d, JCONCF = 2.2 Hz), 61.0 (d,
J
(
(
COCCCF = 2.2 Hz), 32.7, 29.0, 26.5, 25.9, 16.2, 14.2, 11.6; EIMS m/z
128.0, 120.4 (d, JCCF = 27.4 Hz), 118.6, 112.2, 63.1 (d, JCONCF =
+
rel intensity) 508 (M , 4.3), 457 (60), 426 (100), 380 (41), 348
2.0 Hz), 61.0 (d, JCOCCCF = 2.0 Hz), 29.0, 26.3, 25.9, 16.2, 11.5; EIMS
+
+
20); HRMS (EI) for C27
H
29FN
4
O
5
calcd 508.2122 (M ), found
m/z (rel intensity) 448 (M , 9.7), 397 (100), 299 (42), 262 (69),
5
08.2145.
4 3
224 (34), 183 (40); HRMS (EI) for C25H25FN O calcd 448.1911
+
(
M ), found 448.1910.
5
.1.28. N,2-Dimethoxy-5-[(1Z)-1-(3-methoxy-7-methyl-1,2-
benzoxazol-5-yl)-5-(2-oxo-1,3-oxazolidin-3-yl)pent-1-en-1-yl]-
5.1.31. 5-[(1Z)-1-(3-Cyanophenyl)-5-(2-oxo-1,3-oxazolidin-3-yl)pent-
1-en-1-yl]-N,2-dimethoxy-3-methylbenzenecarboximidoyl
Fluoride (12)
3
-methylbenzenecarboximidoyl Fluoride (9)
The general Stille coupling procedure was followed using aryl
iodide 39 (135 mg, 0.469 mmol), organostannane 53 (300 mg,
The general Stille coupling procedure was followed using
3-iodobenzonitrile 40 (107 mg, 0.469 mmol), organostannane 53
0
.469 mmol), CsF (214 mg, 1.41 mmol), Pd(PPh
3
)
4
(54 mg,
0
.047 mmol) and CuI (107 mg, 0.563 mmol) in dry DMF (10 mL).
3 4
(300 mg, 0.469 mmol), CsF (214 mg, 1.41 mmol), Pd(PPh )
The reaction mixture was stirred for 16 h and purified by column
chromatography on silica gel using 75% ethyl acetate–hexanes to
give the product 9 (202 mg, 82.2%) as a clear oil: H NMR
(54 mg, 0.047 mmol) and CuI (107 mg, 0.563 mmol) in dry DMF
(10 mL). The reaction mixture was stirred for 16 h and purified
by column chromatography on silica gel using 60% ethyl acetate–
1
(
3
270 MHz, CDCl ) d 7.31 (s, 1H), 7.24 (s, 1H), 7.12 (s, 1H), 7.00 (s,
hexanes to give the product 12 (166 mg, 78.6%) as a clear oil: 1
H
1
3
2
H), 5.97 (t, J = 7.5 Hz, 1H), 4.20 (t, J = 8.0 Hz, 2H), 3.89 (s, 3H),
.82 (s, 3H), 3.60 (s, 3H), 3.43 (t, J = 8.0 Hz, 2H), 3.20 (t, J = 7.5 Hz,
3
NMR (270 MHz, CDCl ) d 7.53–7.36 (m, 4H), 7.18 (d, J = 2.2 Hz,
1H), 7.05 (d, J = 2.2 Hz, 1H), 6.13 (t, J = 7.4 Hz, 1H), 4.27 (t,
J = 8.0 Hz, 2H), 3.97 (s, 3H), 3.88 (s, 3H), 3.49 (t, J = 8.0 Hz, 2H),
3.27 (t, J = 7.4 Hz, 2H), 2.34 (s, 3H), 2.20–2.12 (m, 2H), 1.71 (quint,
H), 2.29 (s, 3H), 2.26 (s, 3H), 2.12–2.04 (m, 2H), 1.63 (quint,
1
3
J = 7.5 Hz, 2H); C NMR (68 MHz, CDCl
1
1
3
) d 162.8, 158.2, 157.9,
56.1, 149.2 (d, JCF = 324.5 Hz), 140.1, 138.1, 135.2, 134.9, 132.8,
32.8, 129.1, 128.4 (d, JCCCF = 4.5 Hz), 120.0 (d, JCCF = 27.4 Hz),
1
3
J = 7.7 Hz, 2H); C NMR (68 MHz, CDCl
3
) d 158.1, 156.3, 149.0 (d,
JCF = 324.5 Hz), 142.8, 139.2, 135.0, 133.9, 133.0, 131.1, 130.9,