<i>Anti</i>-selective Cyclopropanation of Nonconjugated Alkenes with Diverse Pronucleophiles via Directed Nucleopalladation
A facile approach to obtaining densely functionalized cyclopropanes is described. The reaction proceeds under mild conditions via the directed nucleopalladation of nonconjugated alkenes with readily available pronucleophiles and gives excellent yields and good <i>anti</i>-selectivity using I<sub>2</sub> and TBHP as oxidants. Pronucleophiles bearing a diverse collection of electron-withdrawing groups, including -CN, -CO<sub>2</sub>R, -COR, -SO<sub>2</sub>Ph, -CONHR, and -NO<sub>2</sub>, are well tolerated. Internal alkenes, which are generally challenging substrates in other cyclopropanation methods, provide excellent yields and good diastereoselectivity in this methodology, allowing for controlled access to cyclopropanes substituted at all three C atoms. DFT calculations and mechanistic experiments reveal that the major mechanistic pathway involves the initial α-iodination of the nucleophile, followed by <i>anti</i>-carbopalladation and intramolecular C(sp<sup>3</sup>)-I oxidative addition. Strain-release-promoted C(sp<sup>3</sup>)-C(sp<sup>3</sup>) reductive elimination then furnishes the cyclopropanated product.
Authors
- Davin G. Piercey (ORCID: https://orcid.org/0000-0003-3732-9371)
- Turki M. Alturaifi (ORCID: https://orcid.org/0000-0002-6379-1669)
- Peng Liu (ORCID: https://orcid.org/0000-0002-8188-632X)
- Shouliang Yang (ORCID: https://orcid.org/0009-0005-0871-7457)
- Keary M. Engle (ORCID: https://orcid.org/0000-0003-2767-6556)
- Nicholas F. Scherschel (ORCID: https://orcid.org/0009-0006-8652-0649)
- Warabhorn Rodphon (ORCID: https://orcid.org/0000-0002-5655-119X)
- Indrawan McAlpine (ORCID: https://orcid.org/0000-0002-4230-4892)
- Hui‐Qi Ni (ORCID: https://orcid.org/0009-0006-4848-638X)
- Fen Wang (ORCID: https://orcid.org/0000-0003-1035-2205)
Institutions
- Scripps Research Institute (US)
- University of Pittsburgh (US)
- Pfizer (United States) (US)
- Purdue University West Lafayette (US)
- Genesis HealthCare (US)
- Energetics (United States) (US)
- Université Bourgogne Franche-Comté (FR)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2024-08-22
- DOI
- https://doi.org/10.1021/jacs.4c07039
- Citations
- 14
- Primary Topic
- Cyclopropane Reaction Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 3.50
Funders
- National Science Foundation
- Pfizer
- University of Pittsburgh
- National Research Council of Thailand
- National Institutes of Health
- University of California, San Diego
- Center for Research Computing, University of Pittsburgh
- Office of Naval Research
- National Institute of General Medical Sciences
- Office of Advanced Cyberinfrastructure