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Synlett 2009(5): 808-812  
DOI: 10.1055/s-0028-1087951
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Palladium-Catalyzed Direct C-3 Arylations of Indoles with an Air-Stable HASPO

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

Publication History

Received 11 December 2008
Publication Date:
24 February 2009 (online)

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Abstract

Efficient direct arylations of indoles occurred highly ­regioselectively at position C-3 with an in situ generated palladium complex derived from an air-stable HASPO, which enabled syntheses of diversely functionalized indoles, also with sterically hindered substrates.

Key words

C-H bond functionalization - heteroarenes - indoles - ­regioselectivity - palladium

    References and Notes

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31

Representative Procedure - Synthesis of 3a (Table 1, Entry 10)
A suspension of Pd(OAc)2 (5.6 mg, 0.025 mmol, 5.0 mol%) and 4h (28.4 mg, 0.05 mmol, 10 mol%) in dry dioxane (1 mL) was stirred for 30 min under N2 at ambient temperature. K2CO3 (207.0 mg, 1.50 mmol), indole (1a, 59.0 mg, 0.50 mmol), and 4-bromotoluene (2a, 106.0 mg, 0.62 mmol) were added, and the suspension was stirred at 95 ˚C for 20 h. After the reaction mixture was cooled to ambient temperature, Et2O (50 mL) and brine (50 mL) were added. The aqueous phase was extracted with Et2O (2 × 50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The remaining residue was purified by column chromatography on SiO2 (n-hexane-EtOAc, 10:1) to yield 3a (97.0 mg, 94%) as a pale yellow solid; mp 107.4-108.3 ˚C). ¹H NMR (300 MHz, DMSO-d 6): δ = 11.27 (br s, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 7.64-7.56 (m, 3 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 7.19-7.07 (m, 2 H), 2.34 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d 6): δ = 136.8 (Cq), 134.1 (Cq), 132.9 (Cq), 129.2 (CH), 126.3 (CH), 125.0 (Cq), 122.8 (CH), 121.2 (CH), 119.4 (CH), 118.9 (CH), 115.6 (Cq), 111.8 (CH), 20.6 (CH3). IR (KBr): 3387, 2361, 2337, 1653, 1617, 1116, 802, 747 cm-¹. MS (EI): m/z (%) = 207 (100) [M+], 206 (37), 117 (12), 90 (8). ESI-HRMS: m/z calcd for C15H14N 208.1121: found: 208.1121. The spectral data are in accordance with those reported in the literature. [¹9]

32

Analytical Data Indole 3i: mp 80.3-82.2 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 8.19 (br s, 1 H), 7.62 (t, J = 1.8 Hz, 1 H), 7.53 (dt, J = 7.7, 1.6 Hz, 1 H), 7.39-7.23 (m, 5 H), 6.93 (dd, J = 8.8, 2.4 Hz, 1 H), 3.88 (s, 3 H). ¹³C NMR (126 MHz, CDCl3): δ = 154.9 (Cq), 137.5 (Cq), 134.6 (Cq), 131.7 (Cq), 130.0 (CH), 127.1 (CH), 125.9 (Cq), 125.8 (CH), 125.3 (CH), 123.0 (CH), 116.8 (Cq), 112.7 (CH), 112.2 (CH), 101.5 (CH), 56.0 (CH3). IR (KBr): 3391, 1620, 1594, 1485, 1440, 1271, 1214, 791 cm-¹. MS (EI): m/z (%) = 257 (100) [M+], 242 (26), 215 (33), 178 (13), 152 (15) 128 (11). ESI-HRMS: m/z calcd for C15H13ClNO: 258.0680; found: 258.0682.
Indole 3k: mp 134.1-135.8 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 8.07 (br s, 1 H), 7.84 (d, J = 7.9 Hz, 1 H), 7.53-7.50 (m, 2 H), 7.40-7.32 (m, 2 H), 7.18-7.07 (m, 3 H), 2.52 (s, 3 H), 2.46 (s, 3 H). ¹³C NMR (126 MHz, CDCl3): δ = 138.2 (Cq), 136.1 (Cq), 135.5 (Cq), 128.6 (CH), 128.1 (CH), 126.7 (CH), 125.2 (Cq), 124.5 (CH), 122.8 (CH), 121.4 (CH), 120.4 (Cq), 120.4 (CH), 118.8 (Cq), 117.6 (CH), 21.7 (CH3), 16.6 (CH3). IR (KBr): 3411, 1653, 1635, 1540, 1457, 1113, 789, 751 cm-¹. MS (EI): m/z (%) = 221 (100) [M+], 204 (10), 178 (10), 110 (6), 102 (7). ESI-HRMS: m/z calcd for C16H16N: 222.1277; found: 222.1277.
Indole 3l: mp 113.0-115.2 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.92 (br s, 1 H), 7.65 (d, J = 7.4 Hz, 1 H), 7.38-7.28 (m, 4 H), 7.18-7.07 (m, 3 H), 2.50 (s, 3 H), 2.42 (s, 3 H). ¹³C NMR (126 MHz, CDCl3): δ = 137.9 (Cq), 135.2 (Cq), 135.1 (Cq) 131.2 (Cq), 130.0 (CH), 128.3 (CH), 127.8 (Cq), 126.5 (CH), 126.4 (CH), 121.4 (CH), 119.8 (CH), 118.8 (CH), 114.5 (Cq), 110.2 (CH), 21.7 (CH3), 12.7 (CH3). IR (KBr): 3392, 1682, 1653, 1559, 1457, 1306, 792, 746 cm-¹. MS (EI): m/z (%) = 221 (100) [M+], 204 (20), 178 (9), 130 (15), 102 (15). ESI-HRMS: m/z calcd for C16H16N: 222.1277; found: 222.1272.