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.

中文翻译：

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通过C（sp2）-H甲氧基化反应合成2-甲氧基雌二醇。

在三个合成步骤中，由17β-雌二醇（1）有效合成了2-甲氧基雌二醇（4），总产率为63.3％。关键步骤是2-芳氧基吡啶的钯催化直接C（sp2）-H甲氧基化。以2-吡啶氧基为导向基团，Pd（OAc）2为催化剂，PhI（OAc）2为氧化剂，甲醇为甲氧基化试剂和溶剂，甲氧基可方便地安装在3的2-位-（2-吡啶氧基）雌二醇（2）。随后，在间氯过氧苯甲酸被氧化为吡啶基N-氧化物后，可以通过用甲氧基阴离子进行亲核取代而轻易地除去吡啶基，以定量收率得到目标产物2-甲氧基雌二醇（4）。相反，如文献报道，当通过TfOMe-NaOMe / MeOH系统除去吡啶基导向基团时，TfOMe不可避免地使2-甲氧基-3-（2-吡啶氧基）雌二醇的17-OH甲基化（3）。实际上，我们幸运地发现了一种新的裂解吡啶基直接基团的方法，该方法非常适用于带有羟基的底物。