Concise synthesis of 2-methoxyestradiol through C(sp²)-H methoxylation

An efficient and concise synthesis of 2-methoxyestradiol (4) from 17β-estradiol (1) has been achieved in three synthetic steps with a 63.3% overall yield. The key step was the palladium-catalyzed direct C(sp²)-H methoxylation of 2-aryloxypyridines. Using 2-pyridyloxyl as the directing group, Pd(OAc)₂ as the catalyst, PhI(OAc)₂ as the oxidant and methanol as both the methoxylation reagent and solvent, the methoxy group could be handily installed at the 2-position of 3-(2-pyridoxy) estradiol (2). Subsequently, the pyridyl group could be easily removed by nucleophilic substitution with a methoxy anion after being oxidized to a pyridyl N-oxide by m-chloroperoxybenzoic acid, delivering the target product 2-methoxyestradiol (4) in quantitative yield. In contrast, when the pyridyl directing group was removed by the TfOMe-NaOMe/MeOH system as reported in the literature, TfOMe inevitably methylated the 17-OH of 2-methoxy-3-(2-pyridoxy) estradiol (3). In effect, we have fortuitously found a new method to cleave the pyridyl directing group, which is highly suitable for substrates bearing hydroxy groups.