Overcoming Scope Limitations in Cross-Coupling of Diazo Nucleophiles by Manipulating Catalyst Speciation and Using Flow Diazo Generation

The accessible scope of palladium-catalyzed diazo cross-coupling reactions has been expanded to include aryl chlorides by controlled diazo slow addition. The success of this strategy is based on manipulating speciation within the catalytic cycle through starvation of the diazo reagent to make the Pd(II) oxidative intermediate the resting state. The strategy is also applicable to cross-coupling reactions with aryl bromides and, in combination with safe, on-demand flow generation of nonstabilized diazo reagents, has been used to greatly expand the scope of applicable diazo compounds for this chemistry as well. Lastly, DFT calculations have provided insight into the mechanism and support for the proposed explanation for success of the slow addition strategy.