Thieme Chemistry Journal Awardees - Where Are They Now? Palladium-Catalyzed N-Arylation-Hydroamination Sequence for the Synthesis of Indoles with Sterically Demanding N-Substituents

Abstract

A palladium-catalyzed sequence consisting of an N-aryl-ation and an intramolecular hydroamination sets the stage for a modular synthesis of indoles bearing sterically hindered N-substituents.

Key words

amination - heteroarenes - hydroamination - indoles - palladium

References and Notes

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Representative Procedure - Synthesis of 3a (Table 1, Entry 11)
To a suspension of 2a (91.0 mg, 0.60 mmol), Pd(OAc)₂ (5.6 mg, 0.025 mmol, 5.0 mol%), 10 (10.6 mg, 0.025 mmol, 5.0 mol%), and KOt-Bu (168.0 mg, 1.50 mmol) in dry toluene (1.5 mL) was added 1a (96.0 mg, 0.50 mmol), and the mixture was stirred for 12 h at 105 ˚C. After the reaction mixture was cooled to ambient temperature, H₂O (25 mL) was added. The aqueous layer was extracted with Et₂O (3 × 30 mL), and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The remaining residue was purified by column chromatography on SiO₂
(n-hexane) to yield 3a (95.0 mg, 62%) as a white solid (mp 143-145 ˚C). ^¹H NMR (300 MHz, CDCl₃): δ = 7.77 (d, J = 8.1 Hz, 1 H), 7.51-7.48 (m, 1 H), 7.08-6.98 (m, 2 H), 6.29 (s, 1 H), 3.01 (t, J = 7.2 Hz, 2 H), 2.59 (d, J = 3.0 Hz,
6 H), 2.27 (s, 3 H), 1.81-1.68 (m, 8 H), 1.49-1.39 (m, 2 H), 0.98 (t, J = 7.2 Hz, 3 H). ^¹³C NMR (125 MHz, APT, CDCl₃): δ = 142.8 (C_q), 136.4 (C_q), 129.2 (C_q), 119.8 (CH), 119.3 (CH), 118.4 (CH), 115.2 (CH), 103.0 (CH), 61.0 (C_q), 42.3 (CH₂), 36.4 (CH₂), 33.2 (CH₂), 32.0 (CH₂), 30.3 (CH), 22.9 (CH₂), 14.2 (CH₃). IR (KBr): 3429, 2918, 2855, 2361, 2337, 1653, 1457, 777, 746, 731 cm^-¹. MS (EI): m/z (%) = 307 (22) [M⁺], 265 (6), 135 (100), 107 (5). ESI-HRMS: m/z calcd for C₂₂H₃₀N: 308.2373; found: 308.2374.

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Analytical Data
Indole 3j: mp 136 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 7.54-7.34 (m, 7 H), 6.98-6.95 (m, 1 H), 6.27 (s, 1 H), 2.54 (s, 3 H), 1.61 (s, 9 H). ^¹³C NMR (75 MHz, APT, CDCl₃): δ = 141.2 (C_q), 138.3 (C_q), 137.7 (C_q), 130.1 (2 × CH), 127.3 (CH), 126.8 (2 × C_q), 121.0 (CH), 120.1 (CH), 115.1 (CH), 106.0 (CH), 58.7 (C_q), 32.0 (CH₃), 22.3 (CH₃). IR (KBr): 3421, 3003, 2968, 2918, 2356, 1653, 1540, 1443, 1332, 1206, 1104, 1028, 814, 705, 607 cm^-¹ _. MS (EI): m/z (%) = 263 (22) [M⁺], 235 (4), 220 (4), 207 (100), 178 (5), 152 (2). ESI-HRMS: m/z calcd for C₁₉H₂₁NNa: 286.1566; found: 286.1567.
Indole 3l: ^¹H NMR (300 MHz, CDCl₃): δ = 7.67-7.61 (m, 1 H), 7.50-7.46 (m, 1 H), 7.04-6.99 (m, 2 H), 6.38-6.28 (m, 2 H), 5.16-5.10 (m, 2 H), 2.90 (t, J = 7.2 Hz, 2 H), 1.87-1.68 (m, 8 H), 1.49-1.39 (m, 2 H), 0.97 (t, J = 7.5 Hz, 3H). ^¹³C NMR (75 MHz, APT, CDCl₃): δ = 147.4 (CH₂), 143.2 (C_q), 137.3 (C_q), 128.9 (C_q), 119.8 (CH), 119.5 (CH), 118.8 (CH), 114.5 (CH), 111.4 (CH), 102.4 (CH), 62.0 (C_q), 32.2 (CH₂), 30.8 (CH₂), 29.5 (CH₃), 22.8 (CH₂), 14.0 (CH₃). IR (KBr): 3048, 2959, 2932, 2872, 1456, 1379, 1291, 1265, 1184, 918, 778, 738, 704 cm^-¹. MS (EI): m/z (%) = 241 (60) [M⁺], 190 (9), 173 (29), 131 (100), 115 (2). ESI-HRMS: m/z calcd for C₁₇H₂₄N: 242.1903; found: 242.1906.