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DOI: 10.1055/s-0029-1219940
Selective and Facile Palladium-Catalyzed Amination of 2-Fluoro-4-iodopyridine in the 4-Position under Microwave Conditions
Publication History
Publication Date:
12 May 2010 (online)
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Abstract
The selective C-N cross-coupling of 2-fluoro-4-iodopyridine with aromatic amines is reported. In contrast to conventional substitutions where C-N bond formation takes place at the 2-position (e.g., 2,4-dichloropyridine), the Buchwald-Hartwig cross-coupling was found to be complementary and exclusive for the 4-position. Reactions were carried out under microwave irradiation typically within 30 minutes. These conditions also allowed a decrease in the amount of base required to 3.5 equivalents compared to 20 equivalents in established protocols. Additionally, use of potassium carbonate as a mild base was sufficient, and good yields of the coupling products were obtained in all cases with the simple system Pd(OAc)2/BINAP.
Key words
cross-coupling - heterocycles - catalysis - amines - regioselectivity
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References and Notes
General Procedure:
2-Fluoro-4-iodopyridine (4; 1 equiv), aryl/alkyl
amine (1.2 equiv), K2CO3 (3.5 equiv), Pd(OAc)2 (2
mol%), and BINAP (2 mol%) were charged into a microwave
vial and anhydrous toluene (2 mL) was added. The vial was then sealed,
evacuated and flushed with argon. Then the reaction mixture was
irradiated at 180 ˚C in a CEM Explorer™ microwave
unit for 30 min with stirring. After cooling to r.t., the solid
material was removed by filtration and washed with CH2Cl2 (10 mL).
The solvent was evaporated and the resulting crude product was purified
by flash column chromatography.
2-Fluoro-
N
-phenylpyridin-4-amine
(5a): Yellow solid; mp 148-150 ˚C;
GC-MS: m/z (%) = 188
(100) [M]+, 187 (65), 167
(20); ¹H NMR (CDCl3, 200 MHz): δ = 6.45
(d, J = 1.7 Hz,
1 H), 6.67-6.78 (m, 2 H), 7.23 (d, J = 6.8 Hz, 3 H),
7.44 (t, J = 7.1 Hz,
2 H), 7.86 (d, J = 7.8 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 92.5 (q, J
C-F = 44.1 Hz),
108.2 (q, J
C-F = 3.1 Hz),
122.4 (d), 129.7 (d), 138.9 (s), 147.8 (d), 138.9 (s), 147.8 (q, J
C-F = 16.6 Hz),
154.5 (d, J
C-F = 3.1 Hz), 165.5
(d, J
C-F = 221.5 Hz).
2-Fluoro-
N
-(4-methoxyphenyl)pyridin-4-amine (5b): Yellow
crystals; mp 150 ˚C; GC-MS: m/z (%) = 218 (79)[M]+,
203 (100), 155 (13); ¹H NMR (CDCl3,
200 MHz): δ = 3.83 (s, 3 H),
6.20 (d, J = 1.7 Hz,
1 H), 6.31 (s, 1 H), 6.51 (td, J
1 = 5.9 Hz, J
2 = 1.9 Hz,
1 H), 6.95 (d, J = 8.9 Hz,
2 H), 7.14 (d, J = 8.8 Hz,
2 H), 7.81 (d, J = 8.8 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 55.5 (t), 91.6 (q, J
C-F = 42.4 Hz), 107.5
(q, J
C-F = 2.8 Hz),
114.9 (d), 125.8 (d), 131.4 (s), 147.4 (q, J
C-F = 18.7 Hz),
156.5 (d, J
C-F = 11.6 Hz),
157.6 (s), 165.5 (d, J
C-F = 232.7 Hz).
2-Fluoro-
N
-(2-methoxyphenyl)pyridin-4-amine (5c): Brown
oil; GC-MS: m/z (%) = 218 (100)[M]+,
203 (83), 175 (33); ¹H NMR (CDCl3,
200 MHz): δ = 3.85 (s, 3 H),
6.45 (d, J = 1.9 Hz,
1 H), 6.56 (s, 1 H), 6.70 (d, J = 5.8 Hz,
1 H), 6.96 (t, J = 6.9 Hz,
1 H), 7.04-7.17 (m, 1 H), 7.35 (d, J = 7.4 Hz,
1 H), 7.87 (d, J = 5.8 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 55.6 (t), 92.8 (q, J
C-F = 42.4),
108.7 (q, J
C-F = 2.5 Hz),
111.2 (d), 120.7 (d), 120.8 (d), 124.4 (d), 128.5 (s), 147.6 (q, J
C-F = 18.4 Hz),
150.7 (s), 154.6 (d,
J
C-F = 10.2 Hz),
165.5 (d, J
C-F = 232.1 Hz).
N
-(4-Chlorophenyl)-2-fluoropyridin-4-amine
(5d): Colorless solid; mp 175-178 ˚C;
GC-MS: m/z (%) = 222 (100)[M]+,
224 (47), 186 (31); ¹H NMR (CDCl3,
200 MHz): δ = 6.31 (s, 1 H),
6.35 (d, J = 1.9 Hz,
1 H), 6.63 (d, J = 5.8 Hz,
1 H), 7.14 (d, J = 8.8 Hz,
2 H), 7.35 (d, J = 8.6 Hz,
2 H), 7.9 (d, J = 5.8 Hz,
1 H). ¹³C NMR (CDCl3, 50 MHz): δ = 92.9
(q, J
C-F = 42.7 Hz),
108.2 (q, J
C-F = 3.5 Hz),
123.8 (d), 129.9 (d), 130.3 (s), 137.5 (s), 148.1 (q, J
C-F = 17.6 Hz),
154.8 (d, J
C-F = 14.7 Hz),
165.5 (d,
J
C-F = 235.2 Hz).
Ethyl 4-(2-fluoropyridin-4-ylamino)benzoate
(5e): Light-yellow solid; mp 170 ˚C; GC-MS: m/z (%) = 260
(67)[M]+, 232 (25), 215 (100); ¹H
NMR (CDCl3, 200 MHz): δ = 1.40 (t, J = 7.1 Hz,
3 H), 4.39 (q, J = 7.2 Hz,
2 H), 6.56 (d, J = 1.7 Hz,
1 H), 6.72 (s, 1 H), 6.79 (d, J = 5.6 Hz,
1 H), 7.19-7.26 (m, 2 H), 7.97 (d, J = 5.8 Hz,
1 H), 8.06 (d, J = 8.8 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 14.4 (q), 60.9 (t), 94.2
(q, J
C-F = 41.3 Hz),
109.2 (q, J
C-F = 3.5 Hz), 119.5
(d), 125.7 (s), 131.4 (d), 143.5 (s), 148.2 (q,
J
C-F = 19.2 Hz),
153.4 (d, J
C-F = 11.3 Hz),
165.9 (d,
J
C-F = 234.3 Hz).
4-(2-Fluoropyridin-4-ylamino)benzonitrile(5f): Yellow solid;
mp 195-197 ˚C; GC-MS: m/z (%) = 213 (100)[M]+, 212
(45), 192 (16); ¹H NMR (CD3OD, 200 MHz): δ = 6.68 (d, J = 1.7 Hz,
1 H), 6.98 (d, J = 5.8 Hz,
1 H), 7.35 (d, J = 8.6 Hz,
2 H), 7.70 (d, J = 8.6 Hz,
2 H), 7.92 (d, J = 6.6 Hz,
1 H). ¹³C NMR (CD3OD,
50 MHz): δ = 97.6 (q, J
C-F = 39.9 Hz),
108.8 (d), 113.2 (q, J
C-F = 3.2 Hz),
122.16 (s), 123.1 (d), 137.4 (d), 148.67 (d), 151.1 (q, J
C-F = 15.8 Hz),
158.0 (d, J
C-F = 11.6 Hz),
169.2 (d, J
C-F = 234.1 Hz).
2-Fluoro-
N
-(4-phenoxyphenyl)pyridin-4-amine (5g): Brown
crystals; mp 149 ˚C; GC-MS: m/z (%) = 280 (100)[M]+,
203 (63), 77 (41); ¹H NMR (CDCl3,
200 MHz): δ = 6.51 (d, J = 1.9 Hz,
1 H), 6.61 (s, 1 H), 6.81 (d, J = 5.8 Hz,
1 H), 7.23 (d, J = 2.1 Hz,
2 H), 7.37 (m, 3 H), 7.48 (s, 1 H), 7.57
(t, J = 7.9 Hz,
3 H), 8.80 (d, J = 5.8 Hz, 1 H). ¹³C
NMR (CDCl3, 50 MHz): δ = 92.0
(q, J
C-F = 39.5 Hz),
107.8 (q, J
C-F = 3.2 Hz),
118.9 (d), 119.9 (d), 123.5 (d), 125.0 (d), 129.9 (d), 133.9 (s),
147.9 (q, J
C-F = 22.9 Hz),
154.8 (s), 155.8 (d, J
C-F = 11.9 Hz),
157.0 (s), 165.6 (d, J
C-F = 233.0 Hz).
2-Fluoro-
N
-(4-morpholinophenyl)pyridin-4-amine (5h): Colorless
crystals; mp 154 ˚C; GC-MS: m/z (%) = 273 (100)[M]+,
215 (80), 214 (21); ¹H NMR (CDCl3,
200 MHz): δ = 3.16 (s, 4 H),
3.88 (t, J = 4.8 Hz,
4 H), 6.21 (s, 1 H), 6.28 (s, 1 H), 6.50
(d, J = 5.6 Hz,
1 H), 6.93 (d, J = 6.9 Hz,
2 H), 7.10 (d, J = 8.6 Hz,
2 H), 7.81 (d, J = 6.3 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 49.4 (t), 66.8 (t), 91.7
(q, J
C-F = 43.7 Hz),
107.6 (q, J
C-F = 3.2 Hz),
116.6 (d), 125.2 (d), 130.9 (s), 147.4 (q, J
C-F = 17.3 Hz),
149.1 (s), 156.4 (d,
J
C-F = 13.7 Hz),
165.5 (d, J
C-F = 233.0 Hz).
N
-Benzyl-2-fluoropyridin-4-amine
(5i): Yellow oil; GC-MS: m/z (%) = 202 (42)[M]+,
91 (100), 65 (11); ¹H NMR (CDCl3,
200 MHz): δ = 4.36 (d, J = 4.4 Hz,
2 H), 5.03 (s, 1 H), 6.00 (d, J = 1.8 Hz,
1 H), 6.32-6.40 (m, 1 H), 7.27-7.38
(m, 5 H), 7.75 (d, J = 5.4 Hz,
1 H). ¹³C NMR (CDCl3, 50 MHz): δ = 45.2
(t), 88.5 (q, J
C-F = 51.2 Hz),
104.9 (q,
J
C-F = 2.4 Hz),
125.8 (d), 126.1 (d), 135.5 (s), 145.1 (q,
J
C-F = 19.1 Hz),
155.5 (d, J
C-F = 12.3 Hz),
161.3 (d), 165.8 (d, J
C-F = 232.2 Hz).
2-Fluoro-
N
-(4-methoxybenzyl)pyridin-4-amine (5j): Yellow
solid; mp 123-124 ˚C; GC-MS: m/z (%) = 121 (100),
122 (9), 232 (7)[M]+; ¹H
NMR (CDCl3, 200 MHz):
δ = 3.73
(s, 3 H), 4.20 (d, J = 5.3 Hz,
2 H), 4.75 (s, 1 H), 5.92 (d, J = 1.8 Hz,
1 H), 6.27 (td, J
1 = 5.9 Hz, J
2 = 1.8 Hz,
1 H), 6.82 (d, J = 8.8 Hz,
2 H), 7.16 (d, J = 8.8 Hz,
2 H), 7.69 (d, J = 5.5 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 46.7 (t), 55.3 (q), 90.4
(q, J
C-F = 42.7 Hz),
106.9 (q, J
C-F = 2.5 Hz), 114.3
(d), 128.8 (d), 129.2 (s), 147.2 (q, J
C-F = 18.7 Hz), 157.3
(d, J
C-F = 12.0 Hz),
159.2 (s), 165.5 (d, J
C-F = 232.1 Hz).
2-Fluoro-4-(piperidin-1-yl)pyridine
(5k): Yellow oil. GC-MS: m/z (%) = 180 (59)[M]+,
179 (100), 123 (22); ¹H NMR (CDCl3,
200 MHz): δ = 1.51-1.63 (m,
6 H), 3.22-3.31 (m, 4 H), 6.11 (s, 1 H),
6.54 (dt, J
1 = 6.1 Hz, J
2 = 1.9 Hz,
1 H), 7.83 (d, J = 6.1 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 24.2 (t), 25.0 (t), 91.3
(q, J
C-F = 42.0 Hz),
105.5 (s), 147.5 (q, J
C-F = 10.1 Hz),
158.8 (q, J
C-F = 11.7 Hz),
166.1 (d, J
C-F = 232.1 Hz).
N
-(2-Fluoropyridin-4-yl)pyridin-2-amine
(6a): Yellow solid; mp 143 ˚C;
GC-MS: m/z (%) = 188
(100), 189 (30)[M]+, 168 (8); ¹H
NMR (CDCl3, 200 MHz): δ = 6.80-6.90
(m, 2 H), 7.09 (d, J = 6.1 Hz,
1 H), 7.15 (s, 1 H), 7.32 (d, J = 1.8 Hz,
1 H), 7.64 (m, 1 H), 7.99 (d, J = 5.4 Hz,
1 H), 8.34 (d, J = 3.5 Hz,
1 H). ¹³C NMR (CDCl3,
50 MHz): δ = 95.9 (q, J
C-F = 43.2 Hz),
110.2 (q, J
C-F = 3.1 Hz),
11.7 (d), 117.5 (d), 138.1 (d), 147.7 (q, J
C-F = 17.3 Hz),
148.2 (d, J
C-F = 12.6 Hz),
151.8 (d), 153.5 (s), 165.2 (d, J
C-F = 233.4 Hz).
N
-(2-Fluoropyridin-4-yl)pyridin-3-amine
(6b): Colorless crystals; mp 152 ˚C; GC-MS: m/z (%) = 189
(100)[M]+, 188 (37), 168 (22); ¹H
NMR (CDCl3, 200 MHz): δ = 6.39
(d, J = 1.9 Hz,
1 H), 6.71 (d, J = 5.8 Hz,
1 H), 7.22-7.42 (m, 2 H), 7.61 (d, J = 8.8 Hz,
1 H), 7.91 (d, J = 5.9
Hz, 1 H), 8.40 (d, J = 4.1 Hz,
1 H), 8.51 (s, 1 H). ¹³C
NMR (CDCl3, 50 MHz): δ = 92.9
(q, J
C-F = 43.0 Hz),
108.3 (q, J
C-F = 3.1 Hz),
124.1 (d), 129.1 (d), 136.2 (s), 143.8 (d), 145.4 (d), 148.0 (q, J
C-F = 18.0 Hz),
154.6 (d, J
C-F = 12.0 Hz),
165.5 (d, J
C-F = 234.0 Hz).
N
-(2-Fluoropyridin-4-yl)-4-phenylthiazol-2-amine
(6c): Colorless crystals; mp 195 ˚C; GC-MS: m/z (%) = 271 (100)[M]+,
134 (49), 270 (39); ¹H NMR (CD3OD, 200 MHz): δ = 7.27
(s, 1 H), 7.39-7.49 (m, 4 H), 7.70 (d, J = 1.6 Hz,
1 H), 7.94 (d, J = 7.0 Hz,
2 H), 7.98 (d, J = 5.8 Hz,
1 H). ¹³C NMR (CD3OD,
50 MHz): δ = 95.9 (q, J
C-F = 49.4 Hz),
111.1 (q, J
C-F = 3.0 Hz),
127.0 (d), 128.9 (d), 143.8 (s), 148.0 (q, J
C-F = 19.4 Hz),
152.9 (d), 153.7 (d), 155.2 (q, J
C-F = 12.4 Hz),
165.2 (d, J
C-F = 239.3 Hz).
4-Iodo-2-(piperidin-1-yl)pyridine
(7): Yellow oil; GC-MS: m/z (%) = 288 (100)[M]+,
258 (63), 204 (34); ¹H NMR (CDCl3,
200 MHz): δ = 1.62 (s, 6 H),
3.50 (d, J = 5.5 Hz, 4 H),
6.89 (dd, J
1 = 5.1 Hz, J
2 = 1.2 Hz,
1 H), 6.99 (s, 1 H), 7.79 (d, J = 5.1 Hz,
1 H).¹³C NMR (CDCl3,
50 MHz): δ = 24.6 (t), 25.4 (t), 46.1
(t), 106.6 (s), 115.9 (d), 120.9 (d), 148.2 (d), 159.7 (s).