The First Negishi Cross-Coupling Reaction of Two Alkyl Centers Utilizing a Pd-N-Heterocyclic Carbene (NHC) Catalyst

Reaction Scheme

Abstract

The development of an NHC-based system capable of cross-coupling sp3-sp3 centers in high yield has been a long-standing challenge. This communication describes the use of a Pd-NHC catalytic system that achieves room-temperature Negishi cross-couplings of unactivated, primary bromides and alkyl organozinc reagents with a variety of functionality.

Substrates

Procedure

A vial equipped with a stirbar was charged with Pd2(dba)3 (9.2 mg, 0.010 mmol) and IPr�HCl (17 mg, 0.040 mmol) in a glove-box and the vial was capped with a septum. The vial was removed from the glove box and dry THF (0.3 mL) and dry NMP (0.8 mL) were added via syringe. After stirring for 5-10 min at rt, n-butylzinc bromide (0.12 mL of a 0.5 M THF solution, 0.06 mmol) was added and the reaction mixture was stirred for 1 h at rt, afterwhich alkylzinc reagent (1.3 mL of a 0.5 M THF solution, 0.65 mmol) and the alkyl bromide (0.50 mmol) were added. The septum was replaced with a Teflon�-line screw cap under an inert atmosphere and the solution stirred at rt for 24 h. The reaction mixture was then transferred to a separatory funnel with diethyl ether (10 mL) and the organic layer successively washed with 1 M Na3EDTA solution (prepared from EDTA and 3 eq. NaOH), water, and brine. After drying over anhydrous MgSO4, the solution was filtered and concentrated and the residue purified by flash chromatography

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Materials

     
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