The First Applications of Carbene Ligands in Cross-Couplings of Alkyl Electrophiles: Sonogashira Reactions of Unactivated Alkyl Bromides and Iodides

Reaction Scheme

Abstract

The synthesis of ?,?-alkynyl esters and amides using air-stable potassium alkynyltrifluoroborates as nucleophilic partners in a mild Suzuki-Miyaura cross-coupling reaction has been achieved. Propargyl esters and amides were obtained in high yields using a low catalyst loading, and the substrate scope of the reaction has been significantly improved over previous methods.

Substrates

Procedure

To a Biotage 10 mL microwave vial equipped with a magnetic stirbar were added the appropriate alkynyltrifluoroborate (1.1 mmol, 1.10 equiv), K3PO4 (3.0 mmol, 3 equiv), XPhos (10 �mol, 4.7 mg, 1 mol %) and the XPhos-Pd-G2 (10 �mol, 7.86 mg, 1 mol %). The vial was sealed with a cap lined with a Teflon septum and was evacuated and filled with Ar three times. Degassed toluene (2.4 mL) and H2O (0.8 mL) were added, followed by the 2-chloroacetate or 2-chloroacetamide (1.0 mmol) under Ar. In cases where the electrophile was a solid, it was added along with the solid materials before sealing the vial. The reaction mixture was stirred at 80 �C for 18 h. The cooled reaction mixture was extracted with EtOAc (3 x 3 mL) and dried (Na2SO4). The crude product was purified by flash column chromatography (elution with hexanes/EtOAc = 9:1 for esters, hexanes/EtOAc = 4:1 to 1:4 for amides) to afford the expected product.

Products

Materials

     
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