Synthesis and Stabilities of 3-Borylated Indoles

Abstract

We report herein that 3-pinacol boronic esters undergo facile protodeborylation in the presence of palladium catalysts and base, and this contributes significantly to the generation of nonborylated indole byproducts in the B₂Pin₂-mediated palladium-catalysed borylative cyclization of 2-alkynylanilides. Suginome’s reagent provides an alternative method to access 3-borylated indoles as these compounds are less susceptible to protodeborylation.

Key words

palladium - cyclisation - indoles - boronic ester - protodeborylation

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• 13 Representative Procedure for the Borylation of N-Tosyl 3-Iodo Indoles – Synthesis of Indole 19 2-Cyclopropyl-3-iodo-1-tosyl-1H-indole (11, 200 mg, 0.455 mmol), Pd₂(dba)₃ (21 mg, 0.023 mmol), Cs₂CO₃ (297 mg, 0.910 mmol), PinB-Bdan (268 mg, 0.910 mmol) in MeOH (1 mL) was stirred at reflux under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool to r.t., and EtOAc (10 mL) was added. The organic extract was washed with H₂O (2 × 5 mL) and brine (5 mL), dried over MgSO₄, and the solvents removed under reduced pressure to provide the crude product. Purification of the residue by flash chromatography on silica gel using a solvent gradient of PE–EtOAc (95:5), increasing in polarity to EtOAc gave the target compound 19 as a colorless solid (151 mg, 70%), mp 240–241 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.25 (d, J = 8.5 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 2 H), 7.57 (d, J = 7.5 Hz, 1 H, ArH), 7.34–7.29 (m, 1 H, ArH), 7.25–7.20 (m, 3 H, ArH), 7.14 (dd, J = 8.0, 7.5 Hz, 2 H), 7.07 (dd, J = 8.5, 1.0 Hz, 2 H), 6.35 (dd, J = 7.0, 1.0 Hz, 2 H), 5.87 (s, 2 H), 2.39 (s, 3 H), 2.33 (tt, J = 8.5, 5.5 Hz, 1 H), 0.96 (dt, J = 8.5, 3.0 Hz, 2 H), 0.66–0.59 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 146.4, 144.6, 140.8, 137.6, 137.0, 136.3, 132.2, 129.7, 127.6, 126.6, 124.3, 123.3, 120.7, 119.8, 117.9, 114.5, 105.9, 21.6, 10.3, 8.9. ¹¹B NMR (128 MHz, CDCl₃): δ = 30.9. FTIR: ν_max = 3404, 3042, 2963, 2884, 1625, 1600 cm^–1. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₈H₂₄BN₃O₂S: 500.1580; found: 500.1561.