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Synthesis of bipyridine derivatives through Negishi coupling reaction
- Dec 31, 2017 -

Advances in Bipyridine Synthesis via Negishi Coupling

  Negishi reactions require aryl zinc halides and suitable coupling partners (Figure 1). The pyridyl zinc halides can be achieved by transmetallation with pyridyl lithium or direct reaction between pyridyl halides and active zinc (Zn*). For nearly quantitative yields, (trifluoromethane-sulfonyl)oxypyridine reagents are an excellent choice for coupling partners. Many recent reports, however, employ pyridyl halides, which are more accessible. Chloro, bromo and iodo substituted compounds are good coupling agents in Negishi reactions; whereas, fluoro reagents are typically inert.

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Figure 1: General example of preparation of bipyridines by Negishi coupling between pyridyl zinc reagents and pyridyl halides or triflates, and illustration of selectivity in zinc reagent preparation and halide coupling.

     Generally, aromatic iodides are more reactive than bromides and chlorides, however bromides are most commonly employed. Halides at the 3-position can also participate in the coupling reactions to provide 2,3’-bipyridines, but their reactivity is less than that of 2-halopyridines. This allows for selective coupling at the 2-halo site in the presence of dihalosubstituted pyridines (Figure 2). Generally, aromatic iodides are more reactive than bromides and chlorides, however bromides are most commonly employed. Halides at the 3-position can also participate in the coupling reactions to provide 2,3’-bipyridines, but their reactivity is less than that of 2-halopyridines. This allows for selective coupling at the 2-halo site in the presence of dihalosubstituted pyridines (Figure 2).

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Figure 2: Chemoselectivity and regioselectivity in Negishi coupling in the preparation of bipyridine complexes.

  Negishi coupling shows impressive tolerance of various functional groups, including alkyne, CN, COOR, NO2, NR2, OR, OH, and TMS. This enables further functionalization of 2,2’-bipyridines (Figure 3).

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Figure 3: Functional group tolerance in Negishi cross coupling.

Bipyridines Prepared by Stille and Suzuki Coupling

  Other palladium catalyzed coupling reactions can also be used to prepare 2,2’-bipyridine derivatives (Figure 4). Stille coupling can provide various bipyridine compounds with moderate to good yields. The challenge with this method is that coupling reactions usually have to be carried out in toluene under refluxing conditions for a couple days. Heat sensitive compounds may not be tolerant of this method. Additionally, toxicity is a concern for tin reagents. Due to the difficulty of obtaining stable 2-pyridylboron coupling precursors, Suzuki coupling was not used in making 2,2-bipyridine compounds until recent years. The relatively high catalyst loadings could also limit its applications in organic synthesis.

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Figure 4: Preparation of 2,2􀀁-bipyridine by Stille and Suzuki coupling.