An Alternative Route to 2-Bromo-Estradiols and 2-Iodo-Estradiols From Estradiol

Abstract

Through careful choice of reaction conditions, alkylation of estradiol with chloromethyl methyl ether may yield either the 3,17β-bis(methoxymethy1) ether or the 3-methoxymethyl ether derivative. Treatment of either of these protected estradiols with s- butyllithium, then with trimethylsilyl chloride affords, regioselectively, the 2-trimethylsilyl derivatives which can conveniently be converted into 2-bromo-or 2-iodo-estradiol.

2-(Hydroxyalkyl)estradiols: Synthesis and Biological Evaluation

“…It is noteworthy that the formylated product was obtained as a single regioisomer, as evidenced by one aldehyde proton signal observed in the 1 H NMR spectrum of the crude product. It had previously demonstrated that 6 could be deprotected with aqueous acid to give 7 . After removal of the MOM ethers, 7 was reduced with lithium aluminum hydride to give the first estratriol 1 in 71% yield (Scheme ).…”

“…13 The protected estradiol 5 was formylated in the 2-position according to the procedure of Pert and Ridley. 14 Thus, the 2-position was lithiated by treatment of 5 with s-BuLi at low temperature, and the resulting anion was quenched with dimethylformamide to give the 2-formylated estradiol 6 in 86% yield as a single regioisomer. For this reaction to be successful, it was essential to distill the dimethylformamide from calcium hydride just prior to use, otherwise the reaction would fail.…”

“…It had previously demonstrated that 6 could be deprotected with aqueous acid to give 7. 14 After removal of the MOM ethers, 7 was reduced with lithium aluminum hydride to give the first estratriol 1 in 71% yield (Scheme 1).…”

“…A solution of 6 (2.00 g, 5.15 mmol), 6 M aqueous HCl (25 mL), and THF (25 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water and then extracted with EtOAc (4 × 50 mL). The combined organics were dried (MgSO 4 ), concentrated, and then chromatographed (1:3 increasing to 1:2) to afford the title compound (1.52 g, 98%) as a pale yellow, crystalline solid: mp 225−227 °C (lit . mp 231−233 °C); IR (KBr, cm -1 ) 3361, 3116, 3023, 2964, 2927, 2865, 1658, 1612, 1442, 1384, 1352, 1342, 1290, 1267, 1242, 1117, 1051, 1020, 870; 1 H NMR (DMSO) 10.41 (1H, brs), 10.12 (1H, s), 7.55 (1H, s), 6.66 (1H, s), 4.50 (1H, d, J = 4.7 Hz), 3.52 (1H, q, J = 8.2 Hz), 2.49 (2H, brm), 0.65 (3H, s); 13 C NMR (DMSO) 192.2, 158.2, 146.6, 131.9, 126.5, 120.0, 116.4, 79.9, 49.4, 42.9, 42.6, 38.1, 36.3, 29.8, 29.3, 26.3, 25.8, 22.6, 11.0; MS m/z (M + ) calcd 300.1725, obsd 300.1732.…”

Homologation of Estrone or Estradiol. Appending a Carbon Substituent Into the 3-hydroxyestra-1,3,5-triene Skeleton

“…Also other electrophiles may be used after transmetalation from lithium to copper, for example CuI and allyl bromide effect 2-allylation in 66% yield [18]. The original publication for this procedure was published by Pert and Ridley already in the late eighties [19]. A process relying on the presence of the free phenolic hydroxyl group of estradiol (21) was developed by Peters and coworkers [20] who used ethylmagnesium bromide, hexamethylphosphoric triamide and paraformaldehyde for C-2 formylation in 94% yield (Scheme 2.9).…”