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The Journal of Organic Chemistry
d, J = 0.8 Hz), 7.93 (1H, d, J = 0.8 Hz) ; 13C NMR (100 MHz,
suspension was cooled to
0
°C.
A
Nꢀ(2,2,6,6ꢀ
1
2
3
4
5
6
7
8
CDCl3): δ 55.3, 78.9, 111.4, 111.6, 118.2, 121.5, 127.8, 127.9,
129.3, 129.8, 130.2, 134.0, 137.3, 143.1, 160.0 ; HRMS (ESIꢀ
TOF) m/z: [M+Na]+ calcd for C29H24N2NaO 439,1786 ; found
439,1768.
tetramethylpiperidinꢀ4ꢀyl)formamide (3.8 g, 20.6 mmol) was
added in portion over 10 min (CAUTION: hydrogen gas evoꢀ
lution!). The cooling bath was replaced with an oil bath and
the colorless solution was heated at 65 °C for 24h under a slow
stream of argon. The resulting white suspension was cooled to
0 °C and then carefully quenched by dropwise addition of
water (10 mL; CAUTION: violently exothermic reaction,
evolution of hydrogen gas!) followed by a 20% aq NaOH
solution (20 mL). The resulting suspension was stirred at room
temperature for 15 min. MeOH (40 mL) was added then the
mixture was filtered on celite. The filtrate was concentrated
and then the residue was dissolved with EtOAc (50 mL). The
organic layer was washed with water, brine, dried over anhyꢀ
drous MgSO4, filtered and concentrated to give diamine 18
(3.25 g, 93%) as a yellow liquid which was used without furꢀ
ther purification ; 1H NMR (400 MHz, (CD3)2SO): δ 0.72 (2H,
t, J = 11.8 Hz), 1.00 (6H, s), 1.09 (6H, s), 1.68 (2H, dd, J =
3.4, 12.3 Hz), 2.26 (3H, s), 2.6 (1H, tdd, J = 3.5, 11.5, 11.5
Hz) ; 13C NMR (100 MHz, (CD3)2SO): δ 28.5, 32.5, 34.3,
44.5, 49.7, 50.6 ; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C10H23N2 171.1856 ; found 171.1853.
3ꢀ[2ꢀ(Benzyloxy)ꢀ4ꢀbromophenyl]ꢀ6ꢀfluoropyridazine (15)
To a stirred solution of chloropyridazine 7 (750 mg, 1.99
mmol) in dry DMF (12 mL), anhydrous NMe4F (375 mg, 3.98
mmol) was added at room temperature under argon atmosꢀ
phere. The resulting reaction mixture was stirred at the same
temperature for 24h before it was diluted with DCM (70 mL).
The organic layer was washed with water (3 × 120 mL), brine
(1 × 100 mL), dried over anhydrous MgSO4, filtered and conꢀ
centrated to give fluoropyridazine 15 (700 mg, 98%) as a
white solid which was used without further purification ; mp =
167ꢀ170 °C ; 1H NMR (400 MHz, CDCl3): δ 5.12 (2H, s), 7.13
(1H, dd, J =1.5, 9.2 Hz), 7.27ꢀ7.40 (7H, m), 7.8 (1H, d, J = 8.2
Hz), 8.12 (1H, dd, J = 7.5, 8.2 Hz) ; 13C NMR (100 MHz,
CDCl3): δ 71.3, 114.7 (d, J = 33 Hz), 116.5, 124.2, 125.1,
125.2, 127.5, 128.6, 128.9, 132.5, 133.7 (d, J = 7 Hz), 135.6,
156.7, 157.6 (d, J = 2.7 Hz), 165.7 (d, J = 245 Hz) ; 19F NMR
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
decoupled H (376 MHz, CDCl3): ꢀ81.27 (1F, s) ; 19F NMR
6ꢀ[2ꢀ(Benzyloxy)ꢀ4ꢀ(1ꢀtritylꢀ1Hꢀpyrazolꢀ4ꢀyl)phenyl]ꢀNꢀ
methylꢀNꢀ(2,2,6,6ꢀtetramethylpiperidinꢀ4ꢀyl)pyridazinꢀ3ꢀ
amine (19)
1
coupled H (376 MHz, CDCl3): ꢀ81.27 (1F, d, J = 7.5 Hz) ;
HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for C17H13BrFN2O
359.0190 ; found 359.0192.
To a stirred solution of 16 (230 mg, 0.39 mmol) in butanꢀ1ꢀol
(4 ml), diamine 18 (133 mg, 0.78 mmol) was added at room
temperature under argon atmosphere. The mixture was heated
at 120 °C for 48h. After cooling to room temperature, butanꢀ1ꢀ
ol was removed using rotary evaporator, then the residue was
diluted with DCM (50 mL). The organic layer was washed
with water, dried over anhydrous MgSO4, filtered, concentratꢀ
ed and purified by flash chromatography on silica gel using
DCM / MeOH (10/0 to 8/2) as eluent to give 19 (160 mg,
3ꢀ[2ꢀ(Benzyloxy)ꢀ4ꢀ(1ꢀtritylꢀ1Hꢀpyrazolꢀ4ꢀyl)phenyl]ꢀ6ꢀ
fluoropyridazine (16)
The title compound was prepared similarly to the synthesis of
chloropyridazine 12 starting from fluoropyridazine 15 (200
mg, 0.55 mmol), boronate 11 (364 mg, 0.83 mmol), sodium
carbonate (117 mg, 1.1 mmol), Pd(PPh3)4 (129 mg, 0.11
mmol) and PhMe (5 ml) / EtOH (0.5 ml) / H2O (0.5 ml). The
crude product was purified by chromatography on silica gel
using pentane / Et2O (8/2 to 5/5) as eluent to give fluoroꢀ
pyridazine 16 (172 mg, 53%) as a white solid ; mp = 203ꢀ206
°C ; 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 7.13 (1H, dd,
J = 1.5, 9.2 Hz), 7.18 (7H, d, J = 1.5 Hz), 7.22 (1H, d, J = 8.3
Hz), 7.24ꢀ7.3 (6H, m), 7.32ꢀ7.43 (14H, m), 7.73 (1H, s), 7.99
(1H, dd, J = 1.4, 8.2 Hz), 8.00 (1H, s), 8.21 (1H, dd, J = 7.5,
8.3 Hz) ; 13C NMR (100 MHz, CDCl3): δ 71.1, 79.1, 110.2,
114.5 (d, J = 33 Hz), 119.1, 121.0, 123.1, 127.4, 127.9, 128.0,
128.3, 128.7, 129.5, 130.2, 131.8, 133.6 (d, J = 6.8 Hz), 136.1,
132.3, 137.5, 143.0, 156.6, 158.1 (d, J = 2.5 Hz), 165 (d, J =
244 Hz) ; 19F NMR decoupled 1H (376 MHz, CDCl3): ꢀ81.99 ;
1
56%) as a yellow solid ; mp = 105ꢀ108 °C ; H NMR (400
MHz, CDCl3): δ 1.18 (6H, s), 1.35 (6H, s), 1.38 (2H, m), 1.70
(2H, dd, J = 2.1, 12 Hz), 2.96 (3H, s), 5.13 (2H, s), 5.15 (1H,
m), 6.72 (1H, d, J = 9.7 Hz), 7.07 (1H, d, J =1.3 Hz), 7.14
(1H, dd, J = 1.3, 8 Hz), 7.17ꢀ7.25 (6H, m), 7.28ꢀ7.4 (14H, m),
7.63 (1H, s), 7.84 (1H, d, J = 9.5 Hz), 7.92 (1H,s), 7.98 (1H, d,
J = 8 Hz) ; 13C NMR (100 MHz, CDCl3): δ 28.8, 29.2, 35.3,
41.9, 47.5, 51.5, 71.0, 79.0, 110.4, 119.0, 121.4, 125.3, 127.3,
127.8, 127.9, 128.6, 129.2, 129.4, 130.2, 130.9, 134.1, 137.0,
137.4, 143.1, 149.1, 156.3, 158.2 ; HRMS (ESIꢀTOF) m/z:
[M+H]+ calcd for C49H51N6O 739.4119 ; found 739.4138.
1
19F NMR coupled H (376 MHz, CDCl3): ꢀ81.99 (dd, J = 1.4,
2ꢀ[6ꢀ[Methyl(2,2,6,6ꢀtetramethylpiperidinꢀ4ꢀ
yl)amino]pyridazinꢀ3ꢀyl]ꢀ5ꢀ(1ꢀtritylꢀ1Hꢀpyrazolꢀ4ꢀ
yl)phenol (20)
7.5 Hz) ; HRMS (ESIꢀTOF) m/z: [M+H]+ calcd for
C39H29FN4O 589.2398 ; found 589.2395.
N,2,2,6,6ꢀpentamethylpiperidinꢀ4ꢀamine (18)
To a stirred solution of 19 (110 mg, 0.15 mmol) in MeOH (7
ml), catalytic amount of 10% palladium on carbon was added
under H2 atmosphere. The mixture was stirred for 48h at room
temperature and then filtered on celite. The filtrate was conꢀ
centrated and purified by flash chromatography on silica gel
using DCM / MeOH (10/0 to 8/2) as eluent to give phenol 20
A solution of 17 (4.4 mL, 0.026 mmol) in ethyl formate (6.5
mL, 0.078 mmol) was heated at 65 °C for 4ꢀ5 h. The resulting
thick, white suspension was cooled to room temperature and
filtered. After the filter cake was washed with EtOAc (20 mL),
the solid was dried under vacuum to give 3.8 g (79 % yield) of
Nꢀ(2,2,6,6ꢀtetramethylpiperidinꢀ4ꢀyl)formamide, which was
used directly in the next step. A 250 mL round bottom flask
equipped with a large Teflonꢀcoated stir bar was charged with
LiAlH4 (1.17 g, 31 mmol), fitted with a reflux condenser, and
purged with argon. THF (40 mL) was added and the resulting
1
(90 mg, 94%) as a yellow solid ; mp = 132ꢀ135 °C ; H NMR
(400 MHz, CDCl3): δ 1.18 (6H, s), 1.35 (6H, s), 1.40 (2H, t, J
= 12.3 Hz), 1.69 (2H, dd, J = 2, 12 Hz), 3.00 (3H, s), 4.88 (1H,
m), 6.98 (1H, d, J = 9.8 Hz), 7.01 (1H, d, J = 8.1 Hz), 7.11
(1H, s), 7.16ꢀ7.23 (6H, m), 7.29ꢀ7.37 (9H, m), 7.52 (1H, d, J =
8.3 Hz), 7.66 (1H, s), 7.92 (1H, s), 7.79 (1H, d, J = 9.8 Hz),
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