Copper-Free Sonogashira Coupling of Cyclopropyl Iodides with Terminal Alkynes

Reaction Scheme

Abstract

An efficient palladium-catalyzed cyanation of aryl chlorides is established. In the presence of a highly effective Pd/CM-phos catalyst, cyanation of aryl chlorides proceeds at 70 �C in general, which is the mildest reaction temperature achieved so far for this process. Common functional groups such as keto, aldehyde, ester, nitrile and -NH2, and heterocyclic coupling partners including N-H indoles are well tolerated. Moreover, a sterically hindered nonactivated, ortho, ortho-disubstituted electrophile is shown to be a feasible coupling partner in cyanation.

Substrates

Procedure

Pd(OAc)2 (4.5 mg, 2 mol%) and CM-phos (16.2 mg, 4 mol%) were added into a Schlenk tube with the presence of magnetic stir bar which is Teflon-coated. The tube was evacuated and then re-filled with nitrogen for 3 cycles. Pre-complexation of palladium precursor and ligand was initiated by injecting freshly distilled anhydrous dichloromethane (1.0 mL) and Et3N (0.1 mL) into the tube. The solution was stirred and warmed with hair drier till the solvent condensed on the tube wall. The solvent was removed under vacuum. Aryl chloride (1.0 mmol), Na2CO3 (0.125 mmol), and potassium hexacyanoferrate (II) trihydrate (0.5 mmol) were charged successively to the tube followed by another 3 evacuation-nitrogen refill cycles. Water (1.0 mL) and acetonitrile (1.0 mL) were used as a solvent mixtures. The tube was immersed into a preheated 70 �C oil bath for 18 hours. The reaction was quenched by cooling to ambient temperature and added with EtOAc and water. The organic supernatant was analyzed by GC. The organic layer was separated and the remained aqua medium was further extracted with EtOAc (10 mL � 3). The combined organic phases were concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (230-400 mesh). The pure fractions were collected, dried under vacuum, and followed by proton (1H) and carbon (13C) NMR characterization.

Products

Materials

     
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