Concise synthesis of 2-methoxyestradiol from 17β-estradiol through the C(sp2)-H hydroxylation

Steroids. 2019 Jun:146:99-103. doi: 10.1016/j.steroids.2019.03.013. Epub 2019 Apr 2.

Abstract

A four-step route for the synthesis of 2-methoxyestradiol (5) starting from 17β-estradiol (1) has been achieved with a 51% overall yield. The key step was the ruthenium-catalyzed ortho-C(sp2)-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl2(p-cymene)]2 as the catalyst, PhI(OAc)2 as the oxidant and trifluoroacetate/trifluoroacetic anhydride (1:1) as the co-solvent, the hydroxyl group could be singly installed at the 2-position of 3-dimethylcarbamoyloxyestradiol (2) with 65% yield. Subsequent methylation of hydroxy and removal of dimethyl carbamate afforded 2-methoxyestradiol (5).

Keywords: 17β-Estradiol; 2-Methoxyestradiol; CH hydroxylation; Ru-catalyst.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Methoxyestradiol / chemical synthesis*
  • 2-Methoxyestradiol / chemistry*
  • Carbon / chemistry*
  • Chemistry Techniques, Synthetic
  • Estradiol / chemistry*
  • Hydrogen / chemistry*
  • Hydroxylation

Substances

  • Estradiol
  • 2-Methoxyestradiol
  • Carbon
  • Hydrogen