Phosphorus(III)-assisted regioselective C-H silylation of heteroarenes

Abstract

Heteroarenes containing carbon-silicon (C-Si) bonds are important building blocks that play an important role in the construction of natural products, pharmaceuticals, and organic materials. In this context, the C-H silylation of heteroarenes is a topic of intense interest. Indole C-H silylation can preferentially occur at the nucleophilic C3 and C2 position (pyrrole core), while accessing the C4-C7 positions (benzene core) of the indole remains highly challenging. Here, we show a general strategy for the regioselective C7-H silylation of indole derivatives. Mainly, the regioselectivity is determined by strong coordination of the palladium catalyst with phosphorus (III) directing group. Using this expedient synthetic strategy, the diverse C7-silylated indoles are synthesized effectively which exhibits the broad functional group compatibility. Moreover, this protocol also been extended to other heteroarenes such as carbazoles. The obtained silylated indoles have been employed in various transformations to enable the corresponding differently functionalized indole derivatives. Significantly, a cyclopalladated intermediate is successfully synthesized to test the hypothesis about the P(III)-directed C-H metalation event. A series of mechanistic experiments and density functional theory (M06-2X) calculations has shown the preferred pathway of this directed C-H silylation process.

Fig. 1. Development of a protocol to access C7-selective C–H silylation of indoles.

a C–H Silylation of indoles at C2-position. b C–H Silylation of indoles at C2-position. c C–H Borylation of indoles at C7-position. d C–H Silylation of indoles at C7-position.

Fig. 2. Substrate Scope.

Reaction conditions: 1 (0.20 mmol), I (1.0 mmol), Pd(OAc)₂ (10 mol%), DMBQ (0.7 mmol) in toluene (0.5 mL), 72 h, 120 °C, under Ar. All reported yields are isolated yields.

Fig. 3. Further investigations.

a C–H Functionalization of complex molecules. b Downstream transformations. c C–H Silylation of carbazoles. d C–H Germylation of indole 1a. Reagents and conditions: (a) 1a (5.0 mmol, 1.0 equiv.), I (30 mmol, 6.0 equiv.), Pd(OAc)₂ (10 mol%), DMBQ (20 mmol, 4.0 equiv.) in toluene (10 mL), 4.5 days, 120 °C, under Ar; (b) 2a (0.20 mmol), H₂O₂ (2.0 mL), KF (0.8 mmol), KHCO₃ (0.8 mmol) in THF (1.0 mL), 72 h, 40 °C; c 2a (0.20 mmol), H₂O₂ (1.0 mL) in THF (0.5 mL), 72 h, rt; d 2a (0.20 mmol), BCl₃ (0.24 mmol, 1 M in DCM) in DCM (1.0 mL), 6 h, rt, under Ar; then solvent was removed and RBr 14 (0.24 mmol), Pd(PPh₃)₄ (5 mol%), DME (2 mL) and 2 M Na₂CO₃ aqueous solution (0.5 mL), 24 h, reflux, under Ar. e 15c (0.2 mmol), TBAF (1 M in THF, 0.4 mL) in THF (2.0 mL), 100 °C, 24 h. f 4 (0.20 mmol), BBr₃ (0.24 mmol, 1 M in DCM) in DCM (1.0 mL), 2 h, 0 °C to rt, under Ar; then solvent was removed and pinacol (0.4 mmol) and NEt₃ (1.0 mmol) in DCM (1.0 mL) were added, 1 h, rt; g 4 (0.20 mmol), iPr₂AlH (8.0 equiv.) in THF (1.0 mL), 12 h, 100 °C, under Ar; h 18 (0.20 mmol), [Ir(OMe)(cod)]₂ (5 mol% mmol), dtbpy (10 mol%), HSiMe(OTMS)₂ (0.60 mmol), NBE (0.6 mmol) in THF (1.0 mL), 24 h, 80 °C, under Ar.

Fig. 4. Mechanistic experiments.

a Cyclopalladation of indole 1a to a bimetallic Pd(II) complex 23. b Kinetic profiles of Pd-catalysed C–Hsilylation between substrates 1a and I. c KIE experiments of 1a and d-1a. d Investigation of the byproducts from DMBQ.

Fig. 5. Free energy profiles for C2 (red) or C7 (black) selective C–H silylation of indole 1a.

DFT method: M06/6-311 ++G(d,p), SDD for Pd, SMD(toluene)// B3LYP-D3/6-31 G(d), lanl2dz for Pd, with Grimme correction for entropy and Head-Gordon correction for enthalpy in 120°C. All energies are in kcal/mol.