834
E.M.F. Billaud et al. / European Journal of Medicinal Chemistry 92 (2015) 818e838
(
2
sext., 6H, J ¼ 7.4 Hz, 3xCH
xCH CH
N), 1.51 (quint., 6H, J ¼ 8.1 Hz, 3xCH
CH
N), 3.41 (t, 2H, J ¼ 5.4 Hz, CH
H, J ¼ 5.4 Hz, CH NH), 7.03 (dd, 1H, J ¼ 8.4, 6.0 Hz, H-5), 8.04 (m,
H, H-6, H-2), 8.32 (m, 1H, NH); C NMR (50 MHz, CDCl
3
CH
2
CH
2
), 1.44 (t, 6H, J ¼ 7.3 Hz,
CH CH ), 3.25 (q, 4H,
CH NH), 3.91 (q,
10, v/v) to give 68 (36.3 mg, 61
(SiO , dichloromethane/ethanol, 9/1, v/v) 0.14; IR (KBr)
1318, 1399, 1457, 1540, 1652, 2825, 2917, 2960, 3075,
m
mol) as a yellow oil. Yield 30%; R
f
3
2
3
2
2
2
n
1262,
J ¼ 7.3 Hz, 2xCH
3
2
2
2
ꢀ
1
1
2
2
2
3200e3400 cm
;
H NMR (200 MHz, CDCl
CH CH ), 1.24 (m, 18H, 3xCH
N), 1.51 (m, 6H, 3xCH CH CH
), 2.80 (q, 4H, J ¼ 7.0 Hz,
N), 2.88 (t, 2H, J ¼ 5.5 Hz, CH CH NH), 3.69 (q, 2H,
NH), 7.53 (d, 1H, J ¼ 5.7 Hz, H-4), 7.94 (brs, 1H, NH),
3
)
d
0.86 (t, 9H,
13
3
)
d
9.1
Sn), 13.8
CH ), 29.0
NH), 49.2
NH), 114.4 (d, JC-F ¼ 30 Hz, C-5), 128.5
J
¼
7.0 Hz, 3xCH
3
2
2
2
CH CH Sn,
2
2
1
117119
(
(
(
(
(
2CH
3
CH
2
N), 10.1 ( JC- Sn/Sn
¼
352 Hz, 3xCH
Sn ¼ 57 Hz, 3xCH CH
20 Hz, 3xCH CH Sn), 35.9 (CH
N), 53.6 (CH CH
2
2xCH
2xCH
3
CH
CH
2
3
2
2
3
11 11
Sn/
3xCH
3
CH
2
CH
2
), 27.3 ( JC-
7
9
3
2
2
3
2
2
2
2
J
C-117Sn/119Sn
¼
2
2
2
J ¼ 5.5 Hz, CH
8.33 (m, 2H, H-3, H-6), 8.77 (s, 1H, H-8); C NMR (50 MHz, CDCl
10.7 (3xCH Sn), 11.1 (2CH CH N), 13.7 (3xCH CH CH ), 27.3
( JC- Sn/Sn ¼ 59 Hz, 3xCH CH CH ), 29.1 (3xCH CH Sn), 36.9
(CH NH), 47.5 (2xCH CH N), 51.9 (CH CH NH), 122.9 (C-4), 125.8
C-8), 126.6 (C-8a), 133.4 (C-7), 138.2 (C-6), 142.7 (C-3), 144.8 (C-5,
2
2
13
2xCH
3
CH
2
2
2
3
)
3
3
C-3, C-1), 130.3 (d, JC-F ¼ 9 Hz, C-6), 137.7 (d, JC-F ¼ 17 Hz, C-2),
d
2
3
2
3
2
2
1
19
3 117119
1
68.5 (CO), 169.9 (d, JC-F ¼ 242 Hz, C-4); F NMR (470 MHz, CDCl
3
)
3
2
2
2
2
þ
d
ꢀ89.4; ESI-MS m/z 529.33 [MþH] .
2
3
2
2
2
(
þ
4
.2.23.2. N-[2-(diethylamino)ethyl]-2-fluoro-5-(tributylstannyl)ben-
C-4a), 153.5 (C-1), 167.0 (CO); ESI-MS m/z 596.30 [MþH] .
zamide (12). Starting from N-[2-(diethylamino)ethyl]-2-fluoro-5-
iodobenzamide (9) (38.0 mg, 104 mol); reaction time at reflux:
h; chromatography: (dichloromethane/ethanol, 100/0 / 95/5, v/
m
4.2.23.5. N-[2-(diethylamino)ethyl]-1-fluoro-5-(tributylstannyl)iso-
quinoline-7-carboxamide (69). Starting from 5-bromo-N-[2-
3
v) to give 12 (24.8 mg, 47
dichloromethane/ethanol, 9/1, v/v) 0.32; IR (NaCl plates)
m
mol) as a yellow gum. Yield 46% R
f
(SiO
1072,
261, 1376, 1464, 1521, 1596, 1657, 2853, 2872, 2925, 2957,
2
,
(diethylamino)ethyl]-1-fluoroisoquinoline-7-carboxamide
(26.0 mg, 71 mol); reaction time at reflux: 5 h; chromatography:
(dichloromethane/ethanol, 98/2 / 90/10, v/v) to give 69 (9.9 mg,
17 mol) as a brown oil. Yield 24%; R (SiO , dichloromethane/
ethanol, 9/1, v/v) 0.28; IR (KBr) 1072, 1256, 1318, 1379, 1418, 1548,
1633, 2818, 2927, 2970, 3073, 3200e3400 cm
(200 MHz, CDCl CH CH
0.85 (t, 9H, J ¼ 7.2 Hz, 3xCH
J ¼ 7.2 Hz, 2xCH CH N), 1.27 (m, 6H, 3xCH Sn), 1.40 (m, 12H,
3xCH CH CH CH N), 2.95 (t, 2H,
), 2.83 (q, 4H, J ¼ 7.2 Hz, 2xCH
J ¼ 5.6 Hz, CH CH NH), 3.70 (q, 2H, J ¼ 5.6 Hz, CH NH), 7.44 (d, 1H,
J ¼ 5.9 Hz, H-4), 8.10 (d, 1H, J ¼ 5.9 Hz, H-3), 8.13 (m, 1H, NH), 8.33
(67)
n
m
1
3
ꢀ
1
1
200e3400 cm
;
H NMR (500 MHz, CDCl
CH
), 1.08 (t, 6H, J ¼ 8.1 Hz, 3xCH
), 1.50 (m, 12H, 3xCH CH CH , 2xCH
CH
N), 3.42 (t, 2H, J ¼ 6.3 Hz, CH
.04 (q, 2H, J ¼ 6.1 Hz, CH NH), 7.12 (dd, 1H, J ¼ 8.1 Hz,
3
)
d
0.88 (t, 9H,
Sn), 1.32 (m,
CH N), 3.27
CH NH),
m
f
2
J ¼ 7.4 Hz, 3xCH
3
CH
2
2
2
n
ꢀ
1
1
6
H, 3xCH CH CH
3
2
2
3
2
2
3
2
;
H
NMR
),1.20 (t, 6H,
(
4
q, 4H, J ¼ 7.3 Hz, 2xCH
3
2
2
2
3
)
d
3
2
2
3
2
J
H-
3
2
2
4
F
¼ 12.2 Hz, H-3), 7.57 (ddd, 1H, J ¼ 8.1, 1.4 Hz, JH-F ¼ 5.9 Hz, H-4),
3
2
2
3
2
7
.66 (m, 1H, NH), 8.03 (dd, 1H, J ¼ 1.4 Hz, 4JH-F ¼ 8.7 Hz,
2
2
2
3
13
J
H-117Sn/119Sn ¼ 38.2 Hz, H-6); C NMR (50 MHz, CDCl
3
)
d
9.0
Sn), 13.8
CH ), 29.1
NH), 48.6 (2xCH CH N),
NH), 116.0 (d, JC-F ¼ 22 Hz, C-3), 119.7 (d, JC-F ¼ 10 Hz,
1
3 117119
13
(
(
(
2CH
3
CH
2
N), 9.9 ( JC-117Sn/119Sn
¼
345 Hz, 3xCH
2
(d, 1H, J ¼ 1.8 Hz,
NMR (50 MHz, CDCl
3xCH Sn), 10.7 (2CH
J
H- Sn/Sn ¼ 42.4 Hz, H-6), 8.62 (s, 1H, H-8);
C
3
1 117119
1 1 119
3xCH
3
CH
2
CH
2
), 27.4 ( JC-117Sn/119Sn ¼ 61 Hz, 3xCH
3
CH
2
2
3
)
d
10.6 ( JC- Sn/Sn ¼ 330 Hz, JC-17Sn/Sn ¼ 345 Hz,
2
1
119
C-17Sn/Sn ¼ 21 Hz, 3xCH
J
2
CH
2
Sn), 35.9 (CH
2
3
2
2
3
CH
2
N), 13.7 (3xCH
3
CH
2
CH
2
), 27.3
), 29.1 ( JC- Sn/Sn ¼ 20 Hz,
CH N), 51.8 (CH CH NH),
2
2
3
2 117119
51.8 (CH
2
CH
2
( JC-117Sn/119Sn ¼ 62 Hz, 3xCH
3 2 2
CH CH
NH), 47.4 (2xCH
4
3
C-1), 138.6 (d, JC-F ¼ 5 Hz, C-5), 138.9 (C-6), 142.0 (d, JC-F ¼ 8 Hz, C-
3xCH
2
CH
2
Sn), 36.7 (CH
2
3
2
2
2
1
3
19
2
4
4
), 161.3 (d, JC-F ¼ 251 Hz, C-2), 165.6 (d, JC-F ¼ 3 Hz, CO); F NMR
117.1 (d, JC-F ¼ 30 Hz, C-8a), 121.4 (d, JC-F ¼ 5 Hz, C-4), 122.5 (C-8),
þ
3
(
470 MHz, CDCl
3
)
d
ꢀ114.2; ESI-MS m/z 529.33 [MþH] .
132.7 (C-7), 138.5 (C-6), 140.6 (d,
J
C-F ¼ 17 Hz, C-3), 143.6 (C-5),
3
1
1
46.9 (d, JC-F ¼ 5 Hz, C-4a), 161.3 (d, JC-F ¼ 249 Hz, C-1), 167.0 (CO);
19
þ
4.2.23.3. N-[2-(diethylamino)ethyl]-6-fluoro-5-(tributylstannyl)nico-
F NMR (470 MHz, CDCl
3
) ꢀ70.7; ESI-MS m/z 580.32 [MþH] .
tinamide (25). Starting from N-[2-(diethylamino)ethyl]-6-fluoro-5-
iodonicotinamide (17) (30.0 mg, 82 mol); the reaction was stirred
under reflux for 4.5 h, then bis(triphenylphosphine)palladium(II)
dichloride (2.9 mg, 4 mol) was added and the mixture was
maintained at reflux for an additional 2.5 h; chromatography:
dichloromethane/ethanol, 98/2 / 90/10, v/v), to give 25 (30.1 mg,
mol) as a yellow oil. Yield 69%; R (dichloromethane/ethanol, 8/
, v/v) 0.48; IR (NaCl plates) 1065, 1244, 1376, 1410, 1458, 1541,
645, 2853, 2872, 2926, 2957, 3250e3350 cm
200 MHz, CDCl CH
0.87 (t, 9H, J ¼ 7.1 Hz, 3xCH
2H, 2xCH CH N, 3xCH Sn), 1.33 (sext., 6H,
CH ), 1.49 (m, 6H, 3xCH CH CH
N), 2.80 (t, 2H, J ¼ 5.7 Hz, CH
m
4.2.24. General procedure for the synthesis of stannanes 38, 44, 51
and 59
m
To
(1.14 mmol) in anhydrous toluene (25 mL), beforehand degassed
under argon, were successively added, hexabutylditin (783 L,
1.55 mmol) and freshly prepared tetrakis(triphenylphosphine)
palladium(0) [47] (33 mg, 28.6 mol). The resulting solution was
a solution of the appropriate iodinated compound
(
5
2
1
(
1
3
2
m
7
m
f
n
m
ꢀ
1
1
;
H
NMR
), 1.16 (m,
7.1 Hz,
refluxed for 2e14 h under argon. After cooling to room tempera-
ture, the mixture was filtered over Celite 545, which was washed
with toluene (3 ꢂ 10 mL) and the combined filtrates were evapo-
rated under vacuum. The obtained residue was purified by column
chromatography on alumina.
3
)
d
3
2
CH
2
3
2
2
J
¼
xCH
xCH
3
CH
CH
2
2
2
3
2
2
), 2.71 (q, 4H, J ¼ 7.1 Hz,
3
2
CH NH), 3.58 (q, 2H,
2
4
J ¼ 5.7 Hz, CH NH), 7.56 (brs, 1H, NH), 8.31 (dd, 1H, J ¼ 2.5 Hz, JH-
2
3
F
¼ 6.2 Hz, JH-117Sn/119Sn ¼ 33.5 Hz, H-4), 8.59 (d, 1H, J ¼ 2.5 Hz, H-2);
4.2.24.1. N-[2-(diethylamino)ethyl]-4-fluoro-6-(tributylstannyl)quin-
oline-3-carboxamide (38). Starting from N-[2-(diethylamino)
ethyl]-4-fluoro-6-iodoquinoline-3-carboxamide (37) (475 mg,
1.14 mmol); reaction time at reflux: 4.5 h; elution chromatography:
cyclohexane/ethyl acetate, 4/6, v/v to give 38 (247 mg, 0.43 mmol)
1
3
1
C NMR (50 MHz, CDCl
3
)
d
10.1 ( JC-117Sn/119Sn ¼ 339 Hz, 3xCH
2
Sn),
3
1
3
(
1.3 (2CH
3
CH
CH
NH), 47.2 (2xCH
2
N), 13.7 (3xCH
2
CH
2
Sn), 27.3 ( JC-117Sn/119Sn ¼ 61 Hz,
2
1
1
xCH
3
CH
2
2
), 29.0 ( JC-17Sn/19Sn ¼ 20 Hz, 3xCH
3
CH
2 2
CH ), 36.8
2
CH
2
3
CH
2
N), 51.7 (CH
2
CH
2
NH), 121.7 (d,
J
C-
4
3
F
2
6
¼ 62 Hz, C-5), 128.3 (d, JC-F ¼ 5 Hz, C-3), 147.4 (d, JC-F ¼ 16 Hz, C-
as a yellow oil. Yield 37%; R
v/v) 0.62; IR (CCl
f
(Al
2
O
3
, cyclohexane/ethyl acetate, 4/6,
3
1
ꢀ1
),148.9 (d, JC-F ¼ 15 Hz, C-4),165.3 (CO),169.5 (d, JC-F ¼ 233 Hz, C-
4
)
n
1071, 1377, 1474, 1518, 1664, 2925, 2960 cm
H NMR (200 MHz, CDCl CH
0.92 (t, 9H, J ¼ 7.1 Hz, 3xCH
.09 (t, 6H, J ¼ 7.1 Hz, 2xCH CH N), 1.21 (m, 6H, 3xCH
6H, 3xCH CH CH ), 1.61 (m, 6H, 3xCH CH CH ), 2.61 (q, 4H,
J ¼ 7.1 Hz, 2xCH CH N), 2.70 (t, 2H, J ¼ 6.1 Hz, CH CH NH), 3.60 (q,
2H, J ¼ 5.3 Hz, CH NH), 7.61 (m,1H, NH), 7.94 (d,1H, J ¼ 8.3 Hz, H-8),
;
),
19
þ
1
); F NMR (470 MHz, CDCl
3
) ꢀ50.0; ESI-MS m/z 530.27 [MþH] .
3
)
d
3
2
CH
2
1
3
2
2
Sn), 1.38 (m,
4.2.23.4. 1-Chloro-N-[2-(diethylamino)ethyl]-5-(tributylstannyl)iso-
3
2
2
3
2
2
quinoline-7-carboxamide (68). Starting from 5-bromo-1-chloro-N-
2-(diethylamino)ethyl]isoquinoline-7-carboxamide (66) (80.0 mg,
08 mol) in anhydrous toluene (2.5 mL); reaction time: 6 h at
reflux; chromatography: (dichloromethane/ethanol, 98/02 / 90/
3
2
2
2
[
2
3
117119
2
m
8.09 (dd, 1H, J ¼ 1.7, 8.3 Hz, H-7), 8.26 (d, 1H, JH- Sn/Sn ¼ 40.3 Hz, H-
4
19
5), 9.44 (d, 1H,
J
H2-F ¼ 10.6 Hz, H-2); NMR F (470 MHz, CDCl
3
)