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

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(sp ² )-H bond hydroxylation of aryl carbamates. Using dimethyl carbamate as the directing group, [RuCl ₂ (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).
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