Concise synthesis of 2-methoxyestradiol through C(sp2)-H methoxylation.
Steroids
; 162: 108697, 2020 10.
Article
em En
| MEDLINE
| ID: mdl-32682814
ABSTRACT
An efficient and concise synthesis of 2-methoxyestradiol (4) from 17ß-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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Carbono
/
Estradiol
Idioma:
En
Revista:
Steroids
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China