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Modified Norbornene for Selective Meta-C–H Alkylation and Arylation

Introduction

For direct meta-C–H activation, Professor Jin-Quan Yu and co-workers developed an approach that bridges Pd(II)-catalyzed ortho-C–H activation with norbornene-mediated Pd(II)/Pd(IV) catalysis.1 However, β-hydrogen-containing alkyl iodides and aryl iodides void of ortho-coordinating groups were not compatible for the alkylation and arylation and amides. To improve access to synthetically significant meta-C–H activation, the Yu lab has advanced this ligand-enabled catalytic system to comprise a modified norbornene mediator, 2-carbomethoxynorbornene (ALD00510), and a quinoline-based ligand (ALD00004)2 now offered through Sigma-Aldrich. This advanced system boasts a superior scope and improved efficiency for Pd(II)-catalyzed meta-C(sp2)–H alkylation and arylation of amides with alkyl and aryl iodides.2

Advantages

  • Modified norbornene extends meta-C–H alkylation compatibility to previously problematic alkyl and aryl iodides
  • Suitable quinoline ligand provides superior reactivity not obtained with other phosphine or carbine ligands
  • Improved substrate scope and efficiency

Representative Applications

After determining the quinoline-based ligand ALD00004 afforded optimal reactivity for norbornene-mediated meta-C–H activation, Yu and co-workers systematically modified the norbornene mediator to discover that 2-carbomethoxynorbornene (ALD00510) resulted in the greatest product yields, with reasonable yields even at catalytic amounts (97% yield with 1.5 equiv; 72% yield at 0.5 equiv).2

Using optimized conditions, selective meta-alkylation of amides was achieved with a broad scope of alkyl iodides and aryl iodides. Alkyl iodides included Cl, OBn, NPhth, CN, CF3, CO2Me, and ketal groups; and amide substrates included substituted phenylacetamides. Notably, a diverse panel of aryl iodides void of ortho-coordinating groups also yielded meta-arylation products in high yields, which was a major limitation in previous meta-arylation protocols. A sampling of these reactions are shown below.2

 

Materials

     
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