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Cross-Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Bromides Using an Inner-Sphere Homogeneous
Kasturi Ganguli1, Alexandro R Cruz1, Justin B Diccianni2
1Department of Chemistry, UW-Madison, Madison, Wisconsin 53706, United States.
Journal of the American Chemical Society
|January 8, 2026
Summary
New homogeneous reductants, 1,4-bis(trialkylsilyl)dihydropiperazines (Si-DHP), enable efficient cross-electrophile coupling for C(sp2)-C(sp3) bond formation. This advances organic synthesis, particularly for challenging aryl bromides, without specialized equipment.
Area of Science:
- Organic Synthesis
- Catalysis
- Medicinal Chemistry
Background:
- Cross-electrophile coupling (XEC) of aryl halides with N-hydroxyphthalimide (NHP) esters is crucial for C(sp2)-C(sp3) bond formation.
- Existing methods face challenges with electron-rich aryl bromides, often requiring electrochemistry or specialized NHP derivatives.
- A broadly applicable XEC method is needed to overcome these limitations in organic synthesis.
Purpose of the Study:
- To develop new, broadly applicable conditions for cross-electrophile coupling (XEC) of aryl bromides and iodides with NHP esters.
- To identify novel homogeneous reductants that facilitate XEC without specialized hardware.
- To expand the scope of XEC reactions, particularly for electron-rich aryl bromides relevant to medicinal chemistry.
Main Methods:
- Introduction of a new class of homogeneous reductants: 1,4-bis(trialkylsilyl)dihydropiperazines (Si-DHP).
- Evaluation of Si-DHP reductants, specifically 1,4-bis(trimethylsilyl)dihydropiperazine (TMS-DHP) and 1,4-bis(trimethylsilyl)-2,3,5,6-tetramethyldihydropiperazine (TMS-Me4DHP).
- Testing the developed conditions with diverse NHP esters and aryl bromides, including drug-like fragments.
Main Results:
- Si-DHP reductants demonstrate faster reduction of nickel(II) to nickel(0) compared to common reductants.
- The new conditions provide a broad scope of reactivity, successfully coupling various NHP esters and aryl bromides.
- The developed method functions effectively in diverse solvents, addressing scalability issues for small- and large-scale synthesis.
Conclusions:
- 1,4-bis(trialkylsilyl)dihydropiperazines represent a general and effective class of homogeneous reductants for XEC reactions.
- The developed methodology overcomes limitations of previous XEC approaches, offering a versatile tool for C(sp2)-C(sp3) bond formation.
- This work provides a valuable advancement for synthetic organic chemistry and medicinal chemistry applications.
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