Cross-Electrophile Coupling of <i>N</i> -Hydroxyphthalimide Esters with Aryl Bromides Using an Inner-Sphere Homogeneous Reductant

Cross-electrophile coupling of aryl bromides and iodides with <i>N</i>-hydroxyphthalimide (NHP) esters offers a valuable strategy for forming C(sp²)-C(sp³) bonds that has recently seen increasing use in organic synthesis. However, developing a broadly applicable method remains challenging, particularly with electron-rich aryl bromides, often requiring electrochemical tools or electron-rich NHP derivatives to succeed. Here, we report new conditions that help overcome key limitations in solving this challenge and provide a broad scope of reactivity without the need for specialized hardware. Key to success is the identification of a new general class of homogeneous reductants for XEC: 1,4-bis(trialkylsilyl)dihydropiperazines (Si-DHP). These reductants reduce nickel(II) to nickel(0) faster than other common reductants and can be tuned by modifying the silicon substituents and the substitution pattern on the dihydropiperazine ring. We found that 1,4-bis(trimethylsilyl)dihydropiperazine (TMS-DHP) and 1,4-bis(trimethylsilyl)-2,3,5,6-tetramethyldihydropiperazine (TMS-Me₄DHP) are the most useful. The improved scope is demonstrated with a broad set of NHP esters and aryl bromides relevant to medicinal chemistry, including drug-like aryl bromide informers and comparisons to existing methodologies. Finally, these homogeneous reductants work well in a variety of solvents, addressing several long-standing issues for small- and large-scale applications.