Rapid Protium–Deuterium Exchange of 4-Aminopyridines in Neutral D₂O under Microwave Irradiation

Abstract

4-Aminopyridines undergo surprisingly rapid and highly selective H/D exchange at C-2 and C-6 in neutral D₂O upon microwave irradiation at only 190 °C for two hours in a sealed vessel. This method contrasts and complements acid-mediated H/D exchange, requires no catalyst, and is appropriate for the synthesis of deuterium isotopologues of N- and C-substituted 4-aminopyridines and a benzofused (quinoline) analogue.

Key words

deuteration - heterocycles - microwave synthesis

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• 29 General Procedure for H/D Exchange of 4-Aminopyridines A solution of the substrate in D₂O (5 mL) was irradiated in a sealed Pyrex tube at 190 °C for 2 h (hold time) using a CEM Explorer microwave synthesizer (maximum pressure 150 psi) by moderation of the initial microwave power (300 W). The mixture was cooled in a stream of compressed air and extracted with CH₂Cl₂ (3 × 10 mL). The organic extracts were combined, dried (MgSO₄), filtered, and evaporated in vacuo.
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• 31 See Supporting Information for detailed experimental procedures and characterization data. 4-Aminopyridine-d ₂ (8a) Compd 8a was prepared as a colorless solid; mp 157 °C. IR (neat): 3433, 3144, 3036, 2967, 2262, 1686, 1616, 1583, 1519, 1368, 1299, 1279, 1005, 891, 756 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.95 (0.04 H, d, J = 5 Hz, 2,6-H), 6.55 (1 H, s, 3,5-H). ¹³C NMR (125 MHz, CD₃OD): δ = 155.3 (s, C-N), 148.4 (s, CH isotopologue), 148.1 (t_D, J = 26 Hz, CD), 108.9 (s, CH). MS (EI): m/z (%) = 96 (100) [M^•+], 69 (25), 41 (35). 4-(Methylamino)pyridine-d ₂ (10a) Compd 10a was prepared as a colorless solid; mp 125 °C. IR (neat): 3396, 3323, 3269, 3030, 2497, 2402, 2232, 1909, 1635, 1564, 1460, 1301, 1250, 1153, 1042, 914 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.99 (0.04 H, d, J = 7 Hz, 2,6-H), 6.51 (1.56 H, s, 3,5-H), 2.80 (3 H, s, Me). ¹³C NMR (125 MHz, CD₃OD): δ = 155.5 (s, CN), 147.9 (t_D, J = 27 Hz, CD), 106.7 (s, CH), 27.8 (s, Me). MS (EI): m/z (%) = 111 (52), 110 (100) [M^•+], 109 (69). 4-(Dimethylamino)pyridine-d ₂ (11a) Compd 11a (300 mg, 2.45 mmol) was prepared as a colorless solid; mp 113–114 °C. IR (neat): 3286, 3250, 3179, 3045, 2922, 2819, 2236, 1579, 1498, 1350,1308, 1225, 1068, 993, 750 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 8.06 (0.07 H, m, 2,6-H), 6.63 (1.88 H, s, 3,5-H), 3.03 (6 H, s, 2Me). ¹³C NMR (125 MHz, CD₃OD): δ = 155.0 (s, CN), 147.7 (t_D, J = 25 Hz, CD), 106.3 (s, CH), 37.7 (s, Me). MS (EI): m/z (%) = 124 (86) [M^•+], 123 (100), 107 (6), 96 (24), 80 (54), 52 (81), 42 (42). HRMS: m/z [M + H] calcd for C₇H₈D₂N₂: 125.1042; found: 125.1043. 4-Pyrrolidinopyridine-d ₂ (12a) Compd 12a (300 mg, 2.02 mmol) was prepared as a colorless solid; mp 59 °C. IR (neat): 3074, 2961, 2910, 2845, 2230, 1583, 1532, 1478, 1361, 1286, 1246, 1154, 997, 700 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.20 (0.10 H, d, J = 5 Hz, 2,6-H), 6.36 (1.82 H, s, 3,5-H), 3.29 (4 H, t, J = 6 Hz, 2′,5′-H), 2.02 (4 H, t, J = 6 Hz, 3′,4′-H). ¹³C NMR (125 MHz, CD₃OD): δ = 152.4 (s, CN), 147.5 (t_D, J = 27 Hz, CD), 106.7 (s, CH), 46.7 (s, CH₂), 24.8 (s, CH₂). MS (EI): m/z (%) = 150 (85) [M^•+], 149 (100), 121 (15). HRMS: m/z [M + H] calcd for C₉H₁₀D₂N₂: 151.1199; found: 151.1199. 4-Aminoquinoline-d ₁ (13a) Compd 13a was prepared as an orange solid; mp 155 °C. IR (neat): 3443, 2968, 1683, 1528, 1475, 1339, 1316, 1245, 1009, 917, 751 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 8.25 (0.11 H, s, 2-H), 8.06 (0.91 H, d, J = 8 Hz, 5- or 8-H), 7.81 (0.91 H, d, J = 8 Hz, 5- or 8-H), 7.64 (1 H, t, J = 8 Hz, 6- or 7-H) 7.43 (1 H, t, J = 8 Hz, 6- or 7-H), 6.62 (0.77 H, s, 3-H). ¹³C NMR (125 MHz, CD₃OD): δ = 152.6 (s, CN), 149.2 (t_D, J = 26 Hz, CD), 147.9 (s, CN), 129.2 (s, CH), 127.4 (s, CH), 124.0 (s, CH), 121.4 (s, CH), 118.6 (s, C), 102.2 (s, CH). MS (EI): m/z (%) = 145 (100) [M^•+], 144 (15), 118 (13). HRMS: m/z [M + H] calcd for C₉H₇DN₂: 146.0823; found: 146.0824. 4-Amino-3-methylpyridine-d ₂ (14a) Compd 14a was prepared as a colorless solid; mp 106 °C. IR (neat): 3345, 3311, 3164, 2536, 2404, 2367, 2288, 2237, 2194, 1631, 1553, 1436, 1264, 1197, 1042, 877 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 7.87 (0.06 H, s, 2-H), 7.71 (0.07 H, d, J = 7 Hz, 6-H), 6.57 (0.92 H, s, 5-H), 2.08 (2.96 H, s, Me). ¹³C NMR (125 MHz, CD₃OD): δ = 153.5 (s, CN), 148.3 (s, CH isotopologue), 146.4 (s, CH isotopologue), 146.1 (t_D, J = 25 Hz, CD), 116.7 (s, CC), 108.3 (s, CH), 12.7 (s, Me). MS (EI): m/z (%) = 110 (100) [M^•+], 109 (33), 81 (29). 4-Amino-2-methylpyridine-d ₄ (15a) Compd 15a was prepared as a colorless solid; mp 98 °C. IR (neat): 3324, 3065, 2911, 2848, 2366, 1638, 1602, 1559, 1495, 1345, 1297, 1261, 985, 705 cm^–1. ¹H NMR (500 MHz; CD₃OD): δ = 7.84 (0.04 H, d, J = 6 Hz, 6-H), 6.43 (0.95 H, d, J = 2 Hz, 3-H), 6.39 (0.92 H, d, J = 2 Hz, 5-H), 2.27 (0.08 H, m, 1′-H). ¹³C NMR (125 MHz, CD₃OD): δ = 157.3 (s, CN), 155.7 (s, CC), 147.5 (t_D, J = 26 Hz, CD), 108.0 (s, CH), 106.6 (s, CH), 21.4 (sept_D, J = 19 Hz, CD₃). MS (EI): m/z = 112 (%) [M^•+], 111 (22), 110 (11), 83 (22), 69 (23), 41 (25). 4-Amino-3-bromopyridine-d ₁ (16a) Compd 16a was prepared as an orange solid; mp 70 °C. IR (neat): 3448, 3149, 2925, 2536, 2156, 1707, 1628, 1589, 1502, 1419, 1339, 1270, 1184, 1074, 1013, 823 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 8.20 (0.02 H, s, 2-H), 7.90 (0.66 H, d, J = 6 Hz, 6-H), 6.70 (0.83 H, d, J = 6 Hz, 5-H). ¹³C NMR (125 MHz, CD₃OD): δ = 152.3 (s, CN), 149.6 (t_D, J = 27 Hz, CD), 147.0 (s, CH), 109.5 (s, CH), 105.4 (s, C). MS (EI): m/z (%) = 174 (60) [M^•+], 94 (30), 67 (29). 4-Amino-3-iodopyridine-d ₂ (17a) Compd 17a was prepared as an orange oil; mp 99 °C. IR (neat): 3421, 3294, 3038, 1639, 1581, 1491, 1412, 1337, 1267, 1185, 820, 725 cm^–1. ¹H NMR (500 MHz, CD₃OD): δ = 8.38 (0.01 H, s, 2-H), 7.92 (0.25 H, d, J = 6 Hz, 6-H), 6.68 (0.75 H, s, 5-H). ¹³C NMR (125 MHz, CD₃OD): δ = 155.4 (t_D, J = 28 Hz, CD), 154.8 (s, CN), 147.7 (s, CH), 108.7 (s, CH), 79.8 (s, C). MS (EI): m/z (%) = 222 (100) [M^•+], 221 (30) 127 (15), 95 (23), 67 (22), 40 (20).
• 32 Di Giuseppe A, Castarlenas R, Oro LA. C. R. Chim. 2015; 18: 713