Reversing conventional site-selectivity in C(sp3)-H bond activation

Nat Chem. 2019 Jun;11(6):571-577. doi: 10.1038/s41557-019-0245-6. Epub 2019 Apr 15.

Abstract

One of the core barriers to developing C-H activation reactions is the ability to distinguish between multiple C-H bonds that are nearly identical in terms of electronic properties and bond strengths. Through recognition of distance and molecular geometry, remote C(sp2)-H bonds have been selectively activated in the presence of proximate ones. Yet achieving such unconventional site selectivity with C(sp3)-H bonds remains a paramount challenge. Here we report a combination of a simple pyruvic acid-derived directing group and a 2-pyridone ligand that enables the preferential activation of the distal γ-C(sp3)-H bond over the proximate β-C(sp3)-H bonds for a wide range of alcohol-derived substrates. A competition experiment between the five- and six-membered cyclopalladation step, as well as kinetic experiments, demonstrate the feasibility of using geometric strain to reverse the conventional site selectivity in C(sp3)-H activation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alcohols / chemical synthesis
  • Alcohols / chemistry*
  • Benzene Derivatives / chemical synthesis
  • Carbon / chemistry*
  • Chemistry Techniques, Synthetic / methods*
  • Cyclization
  • Hydrogen / chemistry*
  • Molecular Structure
  • Organometallic Compounds / chemical synthesis
  • Palladium / chemistry
  • Pyridones / chemistry
  • Pyruvates / chemistry

Substances

  • Alcohols
  • Benzene Derivatives
  • Organometallic Compounds
  • Pyridones
  • Pyruvates
  • Palladium
  • Carbon
  • Hydrogen