Unexpected C2-Arylation of 1-(Pyridin-2-yl)indole-3-carboxaldehyde Mediated by Copper

Abstract

The C2-arylation of 1-(pyridin-2-yl)indole-3-carboxalde­hyde with aryl iodides was carried out in the presence of Cu₂O in basic medium. This simple and efficient method led to the preparation of 1,2-diarylindole derivatives.

Key words

indole - arylation - copper - pyridine

References and Notes

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12

Analytical Data of 1-(Pyridin-2-yl)-1 H -indole-3-carboxaldehyde (2a) Mp 114-115 ˚C (MeOH). IR (KBr): 3101, 3050, 2821, 1667, 1649, 1593, 1579, 1539, 1471, 1455, 1444, 1224, 1128, 1083, 739 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.33-7.43 (m, 3 H, H-5, H-5′, H-6), 7.64 (d, 1 H, J = 8.3 Hz, H-3′), 7.95 (td, 1 H, J = 1.9, 7.7 Hz, H-4′), 8.02-8.05 (m, 1 H, H-4 or H-7), 8.38 (s, 1 H, H-2), 8.38-8.41 (m, 1 H, H-4 or H-7), 8.64 (dd, 1 H, J = 1.3, 4.7 Hz, H-6′), 10.16 (s, 1 H, CHO). ^¹³C NMR (75 MHz, CDCl₃): δ = 112.8 (CH), 115.7 (CH), 120.5 (C), 122.2 (CH), 122.3 (CH), 123.8 (CH), 125.1 (CH), 126.3 (C), 136.2 (C), 137.0 (CH), 139.0 (CH), 149.4 (CH), 150.9 (C), 185.4 (CO). ESI-MS: m/z = 223 [M + H]⁺. Anal. Calcd for C₁₄H₁₀N₂O: C, 75.66; H, 4.54; N, 12.60. Found: C, 75.99; H, 4.32; N, 12.55.

13

Analytical Data of 1,2-Di(pyridin-2-yl)-1 H -indole-3-carboxaldehyde (3a)
Mp 127-128 ˚C (EtOAc-PE). IR (KBr): 3051, 3012, 2831, 1648, 1443, 1387, 1050, 754, 741 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.19 (d, 1 H, J = 7.9 Hz, H-3′ or H-3′′), 7.27-7.44 (m, 5 H, H-3′ or H-3′′, H-5, H-5′, H-5′′, H-6), 7.54 (d,
1 H, J = 7,4 Hz, H-4 or H-7), 7.67-7.79 (m, 2 H, H-4′, H-4′′), 8.53-8.60 (m, 3 H, H-4 or H-7, H-6′, H-6′′), 10.18 (s, 1 H, CHO). ^¹³C NMR (75 MHz, CDCl₃): δ = 111.4 (CH), 117.7 (C), 122.1 (CH), 122.7 (CH), 123.1 (CH), 123.6 (CH), 124.0 (CH), 125.3 (CH), 125.4 (C), 126.8 (CH), 136.3 (CH), 137.4 (C), 138.4 (CH), 147.3 (C), 148.8 (C), 149.6 (CH), 149.9 (CH), 150.4 (C), 187.8 (CO). ESI-MS: m/z = 300 [M + H]⁺. Anal. Calcd for C₁₉H₁₃N₃O: C, 76.24; H, 4.38; N, 14.04. Found: C, 76.34; H, 4.43; N, 13.96.

15

Typical Procedure
In a sealed tube, a solution of 2a (100 mg, 0.45 mmol, 1 equiv), Cu₂O (6.5 mg, 0.045 mmol, 0.1 equiv), 2-iodo-pyridine (101 µL, 0.90 mmol, 2 equiv), and K₂CO₃ (124 mg, 0.90 mmol, 2 equiv) in anhyd DMF (0.9 mL) was stirred at 153 ˚C for 3 d. The reaction was cooled to r.t., filtered through Celite, and the filtrate was concentrated in vacuo. The residue was diluted in EtOAc (20 mL). The organic layer was washed with a solution of 2.5% aq NH₄OH (2 × 20 mL) and brine (20 mL). The organic phase was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (PE-EtOAc, 2:8 to 1:1) to provide 3a (110 mg, 84%).

19

Analytical Data of 2-Phenyl-1-(pyridin-2-yl)-1 H -indole-3-carboxaldehyde (3b) ^²6 Mp 171-172 ˚C (EtOAc-PE). IR (KBr): 3065, 3043, 2836, 1652, 1466, 1454, 1384, 1225, 1082, 756 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 6.94 (d, 1 H, J = 7.9 Hz, H-3′), 7.30-7.43 (m, 8 H, H-5, H-5′, H-6, H_arom), 7.51 (d, 1 H, J = 7.5 Hz, H-4 or H-7), 7.68 (td, 1 H, J = 1.9, 8.0 Hz, H-4′), 8.50 (br d, 1 H, J = 6.9 Hz, H-4 or H-7), 8.65 (dd, 1 H, J = 1.3, 4.9 Hz, H-6′), 9.97 (s, 1 H, CHO). ^¹³C NMR (75 MHz, CDCl₃): δ = 111.6 (CH), 116.9 (C), 122.2 (CH), 122.4 (CH), 123.2 (CH), 123.9 (CH), 124.8 (CH), 125.5 (C), 128.5 (2 CH), 128.8 (C), 129.5 (CH), 131.1 (2 CH), 137.5 (C), 138.3 (CH), 149.6 (CH), 149.9 (C), 150.2 (C), 187.6 (CO). ESI-MS: m/z = 299 [M + H]⁺. Anal. Calcd for C₂₀H₁₄N₂O: C 80.52; H, 4.73; N, 9.39. Found: C, 80.83; H, 4.85; N, 9.27.

20

Analytical Data of 1-(Pyridin-2-yl)-2-(4-methylphenyl)-1 H -indole-3-carboxaldehyde (3f)
Mp 206-207 ˚C (EtOAc-PE). IR (KBr): 3048, 2916, 2836, 1642, 1435, 1081, 747, 737 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.37 (s, 3 H, CH₃), 6.92 (d, 1 H, J = 6.9 Hz,
H-3′), 7.15 (d, 2 H, J = 8.0 Hz, H_arom), 7.26 (d, 2 H, J = 8.0 Hz, H_arom), 7.29-7.41 (m, 3 H, H-5, H-5′, H-6), 7.50 (dd, 1 H, J = 0.9, 7.4 Hz, H-4 or H-7), 7.68 (td, 1 H, J = 1.9, 7.7 Hz, H-4′), 8.48 (dd, 1 H, J = 1.1, 7.3 Hz, H-4 or H-7), 8.65 (dd, 1 H, J = 1.1, 4.9 Hz, H-6′), 9.95 (s, 1 H, CHO). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.4 (CH₃), 111.5 (CH), 116.7 (C), 122.1 (CH), 122.5 (CH), 123.1 (CH), 123.8 (CH), 124.7 (CH), 125.5 (C), 125.8 (C), 129.2 (2 CH), 131.0 (2 CH), 137.5 (C), 138.3 (CH), 139.7 (C), 149.6 (CH), 150.2 (C), 150.3 (C), 187.6 (CO). ESI-MS: m/z = 313 [M + H]⁺. Anal. Calcd for C₂₁H₁₆N₂O: C, 80.75, H, 5.16; N, 8.97. Found: C, 8.48; H, 4.97; N, 9.03.

23

Analytical Data of 1-(Pyridin-2-yl)-1 H -indole-3-carbonitrile (11e)
Mp 150-151 ˚C (MeOH). IR (KBr): 3135, 3050, 2222, 1592, 1540, 1473, 1455, 1434, 1229, 1095, 735 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.32-7.45 (m, 3 H, H-5, H-5′, H-6), 7.56 (d, 1 H, J = 8.1 Hz, H-3′), 7.83 (br d, 1 H, J = 7.5 Hz, H-4 or H-7), 7.93 (td, 1 H, J = 1.9, 7.5 Hz, H-4′), 8.10 (br d, 1 H, J = 7.1 Hz, H-4 or H-7), 8.23 (s, 1 H, H-2), 8.63 (dd, 1 H, J = 1.1, 4.9 Hz, H-6′). ^¹³C NMR (75 MHz, CDCl₃): δ = 89.8 (C), 113.4 (CH), 115.3 (C), 115.6 (CH), 120.0 (CH), 122.3 (CH), 123.4 (CH), 125.2 (CH), 128.7 (C), 133.3 (CH), 134.4 (C), 139.1 (CH), 149.5 (CH), 150.7 (C). ESI-MS: m/z = 220 [M + H]⁺. Anal. Calcd for C₁₄H₉N₃: C, 76.70, H, 4.14, N, 19.17. Found: C, 76.72; H, 4.08; N, 19.25.

24

Analytical Data of 1,2-Di(pyridin-2-yl)-1 H -indole-3-carbonitrile (11d)
Mp 128-129 ˚C (CH₂Cl₂-PE). IR (KBr): 3065, 2213, 1589, 1569, 1467, 1448, 1435, 1393, 1225, 738 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.24-7.41 (m, 5 H, H-3′ or H-3′′,
H-5, H-5′, H-5′′, H-6), 7.50-7.53 (m, 1 H, H-4 or H-7), 7.82-7.89 (m, 4 H, H-3′ or H-3′′, H-4 or H-7, H-4′, H-4′′), 8.44 (br d, 1 H, J = 4.1 Hz, H-6′or H-6′′), 8.51 (dd, 1 H, J = 1.1, 4.7, H-6′ or H-6′′). ^¹³C NMR (75 MHz, CDCl₃): δ = 89.3 (C), 112.1 (CH), 116.1 (C), 120.0 (CH), 122.0 (CH), 123.1 (CH), 123.4 (CH), 123.5 (CH), 124.9 (CH), 125.5 (CH), 127.6 (C), 136.8 (CH), 137.2 (C), 138.4 (CH), 144.8 (C), 148.2 (C), 149.5 (CH), 149.6 (CH), 150.7 (C). ESI-MS: m/z = 297 [M + H]⁺. Anal. Calcd for C₁₉H₁₂N₄: C, 77.01, H, 4.08, N, 18.91. Found: C, 76.88; H, 4.27; N, 19.01.

25

Typical Procedure
In a microwave vial with a magnetic stir bar was introduced indole-3-carboxaldehyde (100 mg, 0.68 mmol, 1 equiv), Cu₂O (10 mg, 0.07 mmol, 0.1 equiv), and K₂CO₃ (189 mg, 1.36 mmol, 2 equiv) in anhyd DMF (1.4 mL). After a purge with argon, 2-iodopyridine (153 µL, 1.36 mmol, 2 equiv) was added. The vial was sealed and heated at 240 ˚C under microwave irradiation (Biotage Initiator) for 1 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was diluted in EtOAc (20 mL). The organic layer was washed with a solution of 2.5% aq NH₄OH (2 × 20 mL) and brine (20 mL). The organic phase was dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (PE-EtOAc, 2:8 to 1:1) to provide 2a (88 mg, 58%) and 3a (73 mg, 36%).