Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halides using Pd-PEPPSI-IPent

Reaction Scheme


Over the past two decades, considerable attention has been given to the development of new ligands for the palladium-catalyzed arylation of amines and related NH-containing substrates (i.e. Buchwald-Hartwig amination). The generation of structurally diverse ligands, by research groups in both academia and industry, has facilitated the accommodation of sterically and electronically divergent substrates including ammonia, hydrazine, amines, amides, and NH heterocycles. Despite these achievements, problems with catalyst generality persist and access to multiple ligands is necessary to accommodate all of these NH-containing sub- strates. In our quest to address this significant limitation we identified the BippyPhos/[Pd (cinnamyl)Cl]2 catalyst system as being capable of catalyzing the amination of a variety of functionalized (hetero)aryl chlorides, as well as bromides and tosylates, at moderate to low catalyst loadings. The successful transformations described herein include primary and secondary amines, NH heterocycles, amides, ammonia and hydrazine, thus demonstrating the largest scope in the NH-containing coupling partner reported for a single Pd/ligand catalyst system. We also established BippyPhos/[Pd (cinnamyl)Cl] 2 as exhibiting the broadest demonstrated substrate scope for metal-catalyzed cross-coupling of (hetero)aryl chlorides with NH indoles. Furthermore, the remarkable ability of BippyPhos/[Pd(cinnamyl)Cl]2 to catalyze both the selective monoarylation of ammonia and the N-arylation of indoles was exploited in the development of a new one-pot, two-step synthesis of N-aryl heterocycles from ammonia, ortho-alkynylhalo (hetero)arenes and (hetero)aryl halides through tandem N-arylation/hydroamination reactions. Although the scope in the NH-containing coupling partner is broad, BippyPhos/[Pd(cinnamyl)Cl]2 also displays a marked selectivity profile that was exploited in the chemoselective monoarylation of substrates featuring two chemically distinct NH-containing moieties.



To an oven dried screw-capped vial was added a stir bar, [Pd(cinnamyl)Cl]2 (2.6 mg , 0.005 mmol, 1 mol%), BippyPhos (10.1 mg, 0.02 mmol, 4 mol%), and 1 mL (0.5 M [ArX]) of toluene. The resulting mixture was then stirred for approximately 2 minutes at which point NaOtBu (67.3 mg, 0.7 mmol, 1.4 equiv) was added. The mixture was then stirred briefly followed by the addition of the aryl (pseudo)halide (0.5 mmol) and then the amine (0.53 mmol, 1.05 equiv). The vial was sealed with a cap containing a PTFE septum, removed from the glovebox and placed in a temperature-controlled aluminum heating block set at 110 �C and stirred vigorously. Reaction S5 progress was monitored by use of TLC or GC methods and after complete consumption of the aryl halide (8-18 h), the reaction mixture was cooled and filtered through a short plug of silica on Celite and washed with 15 mL of methylene chloride. After concentrating the so-formed mixture under reduced pressure, the crude product was purified by column chromatography.



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