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Synlett 2010(10): 1505-1510  
DOI: 10.1055/s-0029-1219940
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Selective and Facile Palladium-Catalyzed Amination of 2-Fluoro-4-iodopyridine in the 4-Position under Microwave Conditions

Moumita Koley, Michael Schnürch, Marko D. Mihovilovic*
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax: +43(1)5880115499; e-Mail: mmihovil@pop.tuwien.ac.at;
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Publication History

Received 30 November 2009
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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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).