Ionic Method Aromatizes Steroid's A, B Rings Refluxing nonaromatic intermediates in DMF or pyridine is simple way to aromatize the two rings under relatively mild conditions Reaction Is Easy Way to Equilenin Steroids ο CI
9« f 11/3-Dichloroandrostal,4-diene-3,17-dione
6 Equilenin
The mechanism probably involves /%> attack on C-19 methyl group
This reaction is made easier by ,ΓΓ Ç^Q ' protonation of the oxygen at C-3 •* X=CI
, Br
R=CI, OH
IONIC. Robert H. Lenhard, Dr. Milton Heller, and Dr. Seymour Bernstein (left to right), chemists at Lederle Laboratories, believe that ionic method provides an easy route to equilenin-type steroids having a variety of ring substituents 42
C&EN
JUNE
15,
1964
Steroids with aromatic A and Β rings have been made from nonaromatic steroid intermediates via an ionic method which eliminates the C-19 methyl group (C&EN, June 8, page 41). Refluxing intermediates of the 9a,ll/2-dichloiO-A 1,4 -3-one type in dimethylformamide for a half hour, or in pyridine for at least six hours, gives compounds containing both A and Β aromatic rings [/. Am. Chem. Soc, 86,2309 (1964)]. According to Dr. Seymour Bern stein, Dr. Milton Heller, and Robert H. Lenhard of Lederle Laboratories, Pearl River, N.Y. (a division of Ameri can Cyanamid ), the ionic method pro vides a potentially easy way to pre pare equilenin-type steroids with a variety of ring and C-17 substituents. Equilenin, a steroid found in mare's urine, is one of the steroids having aromatic A and Β rings synthesized by the Lederle group. Ring AB aromatic steroids have been made by other methods. One is by total synthesis; another is by dehydrogenation of ring A or Β aromatic precursors. Acid elimination of an allylic hydroxyl group in a ring A aro matic compound with subsequent re arrangement of double bonds can be used to form AB-ring aromatic ster oids. Pyrolysis of a A 1 ' 4 » 6 -triene-3one followed by selenium dioxide de ny drogenation can also be used. The Lederle group has found an ionic method to aromatize the two rings. The method is simple and in volves relatively mild conditions. Ionic methods have been used by others to aromatize a single ring in steroid compounds. At the University of Tokyo, for instance, Dr. K. Tsuda and his co-workers have used zinc in pyridine to eliminate the C-19 methyl group from nonaromatic precursors to form compounds in which ring A is aromatic. At G. D. Searle & Co., Dr. H. L. Dryden, Jr., G. M. Webber, and J. J. Wieczorek have used lithium to elimi nate the C-19 methyl group of ster oidal dienones as methyllithium, thus forming aromatic ring A. The Lederle scientists believe that the mechanism of the aromatization
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reaction involves attack by a halide ion. When a compound of the type 9a ? ll/?-dichloiO-A 1,4 -3-one is refluxed in dimethylformamide or pyridine, the halide ion generated (eliminated from the 9 a position) probably attacks the C-19 methyl group. This attack is made easier by protonation of the C-3 oxygen, the Lederle group believes. Gas chromatography shows that methyl chloride forms during the aromatization of a 9a,ll/3-dichloro-l,4diene-3-one. Methyl bromide was obtained from a similar 9,11-bromohydrin compound, which also aromatizes under the same conditions. An allylic shift, elimination of halogen or an R group, and isomerization provide the double bonds necessary for the aromatization of ring B. The aromatization reaction has been applied to a number of compounds. Refluxing 21-acetoxy-9a,ll/?-dichloro17a-hydroxypregna-l,4-diene-3,20-dione with dimethylformamide or pyridine gave two major products, each in about 25% yield. For one of the products, the Lederle chemists assign the structure 21-acetoxy-17a-hydroxypregna-l,4,8(14),9(ll)-tetraene-13, 20-dione. The other product is 2 1 acetoxy - 3,17a - dihydroxy - 19-norpregna - 1,3,5(10),6,8 - pentaen - 20 - one. Equilenin was synthesized by refluxing 9a,ll/?-dichloiOandrosta-l,4-diene3,17-dione in dimethylforamide. The method for aromatizing the two rings was discovered during studies of possible routes to new corticoid structures.
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