Cross-Electrophile Coupling of NHP Esters With Aryl Bromides Using an Inner-Sphere, Homogeneous Reductant

Cross-electrophile coupling of aryl bromides and iodides with N-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 re-ductants and can be tuned by modifying the silicon substitutents 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 medic-inal 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-scale and large-scale applications.