C. Experimental Section
2. Typical Procedures (TP)
2.1 Typical Procedure for the metalation of heteroaromatics with hindered metal amide bases (TP1)
A dry and argon flushed 50-mL Schlenk-Tube, equipped with a magnetic stirring bar, was charged with a solution of the corresponding N-heteroarene (1.0 mmol) in dry THF (5 mL) and then cooled to the indicated temperature. A THF-solution of the indicated hindered metal amide base, titrated prior use, was added dropwise and the reaction mixture was stirred at the indicated temperature for the given time. Complete metalation was monitored by GC analysis of reaction aliquots, quenched with iodine in dry THF using decane as internal standard.
2.2 Typical Procedure for the BF3-triggered metalation of heteroaromatics with
hindered metal amide bases (TP2)
A dry and argon flushed 50-mL Schlenk-Tube, equipped with a magnetic stirring bar, was charged with a solution of the corresponding N-heteroarene (1.0 mmol) in dry THF (5 mL) and cooled to 0 °C. BF3·OEt2 (156 mg, 1.1 mmol) was added dropwise and stirred for 15 min at the same temperature. The reaction mixture was cooled to the given temperature followed by dropwise addition of a THF-solution of the indicated hindered metal amide base titrated prior use, and stirring the reaction mixture at the indicated temperature for the given time. Complete metalation was monitored by GC analysis of reaction aliquots, quenched with iodine in dry THF using decane as internal standard.
2.3 Typical Procedure for the metalation with “TMPBF3·MgCl·LiCl” (TP3)
A dry and argon flushed 50 mL Schlenk-Tube, equipped with a magnetic stirring bar, was charged with TMPMgCl·LiCl (11; 0.92 mL, 1.1 mmol, 1.2 M in THF) and cooled to -40 °C.
BF3·OEt2 (156 mg, 1.1 mmol) was added dropwise and the resulting mixture was stirred for 10 min before the corresponding N-heteroarene (1.0 mmol) dissolved in dry THF (5 mL) was added. The reaction mixture was stirred at -40 °C for the indicated time. Complete metalation was monitored by GC-analysis of reaction aliquots, quenched with iodine in dry THF using decane as internal standard.
C. Experimental Section 78
2.4 Typical Procedure for the BF3-triggered metalation of quinine (68) with
TMPMgCl·LiCl (TP4)
A dry and argon flushed 50-mL Schlenk-tube, equipped with a magnetic stirring bar, was charged with a solution of quinine (1.0 mmol) in dry THF (4 mL) and cooled to 0 °C. MeLi (0.61 mL 1.0 mmol, 1.63 M in Et2O) were added dropwise and stirred for 1 h at 25 °C. After
cooling to 0 °C BF3·OEt2 (312 mg, 2.2 mmol) was slowly added and stirred for 15 min at the same temperature. After dropwise addition of a THF-solution of the hindered metal amide base TMPMgCl·LiCl (1, 1.1 mmol), titrated prior use, the reaction mixture was stirred for further 40 min at 0 °C.
2.5 Typical Procedure for one pot Negishi cross-coupling for biaryl synthesis (TP5)
Anhydrous LiCl was placed in an argon-flushed flask and dried using a heat gun under high vacuum (1 mbar). Zinc dust (<10 micron, Aldrich, 98+%) was added under argon, and heterogeneous mixture of Zn and LiCl was dried again on high vacuum. The reaction flask was flushed with argon, and then THF was added. Zn was activated by BrCH2CH2Br (5 mol%, heating to ebullition for 15 s) and TMSCl (1 mol%, heating to ebullition for 15 s). The substrate was added at room temperature, and the resulting reaction mixture was stirred at temperature T1. The completion of the insertion reaction was checked by GC analysis of reaction aliquots quenched with sat. aqueous NH4Cl solution (more than 96% conversion). After completion of zinc insertion, an aryl halide was added at room temperature, followed by addition of Pd catalyst. The resulting reaction mixture was stirred at temperature T2. After the completion of the reaction (checked by GC analysis of reaction aliquots quenched with sat. aqueous NH4Cl solution), the reaction mixture was quenched with sat. aqueous NH4Cl solution (5 mL), followed by filtration. The aqueous phase was extracted with ether or EtOAc, and the combined organic phase was washed with brine and dried over MgSO4. After concentration of the solution in vacuo, the crude residue was purified by flash silica gel chromatography.
2.6 Typical Procedure for one pot Negishi cross-coupling reaction between an alkyl zinc intermediate and a haloaryl (TP6)
Anhydrous LiCl was placed in an argon-flushed flask and dried using a heat gun under high vacuum (1 mbar). Zinc dust (<10 micron, Aldrich, 98+%) was added under argon, and heterogeneous mixture of Zn and LiCl was dried again on high vacuum. The reaction flask
C. Experimental Section 79 was flushed with argon, and then THF was added. Zn was activated by BrCH2CH2Br (5 mol%), TMSCl (1 mol%), and I2 (a THF solution, 2 mol%). The substrate was added at room temperature, and the resulting reaction mixture was stirred at temperature T1. The completion of the insertion reaction was checked by GC analysis of reaction aliquots quenched with a solution of NH4Cl in water (more than 96% conversion). After completion of zinc insertion, an aryl halide was added at room temperature, followed by addition of PEPPSI and 1,3-dimethylimidazolidin-2-one (DMI). The resulting reaction mixture was stirred at temperature T2. After the completion of the reaction (checked by GC analysis of reaction aliquots quenched with sat. aqueous NH4Cl solution), the reaction mixture was quenched with sat. aqueous NH4Cl solution (5 mL), followed by filtration with cotton plug. The aqueous phase was extracted with Et2O or EtOAc, and the combined organic phase was washed with brine and dried over MgSO4. After concentration of the solution in vacuo, the crude residue was purified by flash silicagel chromatography.
C. Experimental Section 80