Concise synthesis of 2-methoxyestradiol from 17β-estradiol through the C(sp2)-H hydroxylation
Meng-Yu Ba1, Li-Wen Xia1, Hong-Liang Li1
1School of Pharmaceutical Science, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of New of New Drug Research and Safety Evaluation, Zhengzhou 450001, China.
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).
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