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

doi:10.1055/s-0029-1219940

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Synlett 2010(10): 1505-1510
DOI: 10.1055/s-0029-1219940

LETTER

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)

Abstract
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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

References and Notes

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17

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).