Synlett 2009(8): 1219-1222  
DOI: 10.1055/s-0029-1216727
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Lutz Ackermann*, René Sandmann, Mikhail V. Kondrashov
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Goettingen, Tammannstr. 2, 37077 Goettingen, Germany
Fax: +49(551)396777; e-Mail: Lutz.Ackermann@chemie.uni-goettingen.de;
Further Information

Publication History

Received 13 February 2009
Publication Date:
17 April 2009 (online)

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.

    References and Notes

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25

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 (Cq), 136.4 (Cq), 129.2 (Cq), 119.8 (CH), 119.3 (CH), 118.4 (CH), 115.2 (CH), 103.0 (CH), 61.0 (Cq), 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. 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.

26

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 (Cq), 138.3 (Cq), 137.7 (Cq), 130.1 (2 × CH), 127.3 (CH), 126.8 (2 × Cq), 121.0 (CH), 120.1 (CH), 115.1 (CH), 106.0 (CH), 58.7 (Cq), 32.0 (CH3), 22.3 (CH3). IR (KBr): 3421, 3003, 2968, 2918, 2356, 1653, 1540, 1443, 1332, 1206, 1104, 1028, 814, 705, 607 cm . 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 (Cq), 137.3 (Cq), 128.9 (Cq), 119.8 (CH), 119.5 (CH), 118.8 (CH), 114.5 (CH), 111.4 (CH), 102.4 (CH), 62.0 (Cq), 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. 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.