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Regioselective bromination of the 16-hydroxymethyl-3-methoxyestra-1,3,5(10)-trien-17-ol isomers

E. Mernyák, Gy. Schneider and J. Wölfling

Department of Organic Chemistry, József Attila University, H-6720 Szeged, Dóm tér 8., Hungary

The cis isomers of 16-hydroxymethyl-3-methoxyestra-1,3,5(10)-trien-17-ol (1 and 2) transform into 16-bromomethyl-3-methoxyestra-1,3,5(10)-trien-17-acetates (3 and 4) on treatment with hydrogen bromide and acetic acid. The process is accompanied by the formation of some diacetates (5 and 6) and rearranged products (7 and 8). The trans isomers (9 and 10) yield, under similar experimental conditions, only diacetates (11 and 12).

Scheme 1

The mechanism of the formation of  3 and 4 can be interpreted by the front side neighbouring group participation. We assume that the first step of the transformation of 2 is the formation of the monoacetate 13. This compound is cyclised in acidic medium to the orthoester 14, which is converted by HBr to the ambident 1,3-dioxane-2-ylium ion (15) and stabilized in the form of 16b-bromomethyl-3-methoxyestra-1,3,5(10)-trien-17b-acetate (4). The same mechanism may be supposed for the reaction starting from 1 and resulting 3 Scheme 2

A reversed phase, isocratic HPLC method has been developed for separation of the reaction products. The structure of the isolated and purified compounds were established by NMR spectroscopy.


Financial support of this research by the National Research Foundation (Grants OTKA F016119 and T016122) is gratefully acknowledged.