Reimer-Tiemann formylations of oestradiol and oestrone were investigated and, whilst substitution was effected under certain conditions to give mixtures of 2- and 4-formyloestrogens, yields were very low and the method was unsuitable for preparative purposes. Regioselective methods were developed and 2-formyloestradiol was conveniently prepared from oestradiol by formylation of the lithio derivative of the bis(methoxymethyl) ether and removal of the rotecting groups with hydrochloric acid. 4-Formyloestradiol was prepared by a sequence of reactions starting with the methoxyethyl ether of 4-bromooestradiol, then metal-halogen interconversion, formylation with N-methylformanilide, and removal of the protecting group. A number of related derivatives, including 2-formyloestriol, were prepared.

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.

A simple route to 2-alkyloestradiols is demonstrated by the conversion of oestradiol into its 2-isopropyl derivative.2-Alkyl-substituted oestradiols are known, and some of their biological activities have beenThe routes to these compounds, however, are limited. Thus 2-dialkylaminomethyloestradiols can be prepared by the Mannich reaction on oestradiol,' and nucleophilic substitution reactions at the benzylic position can lead to simple a n a 1 0~u e s .~~~ Meanwhile 2-allyloestradiol can be obtained from the Claisen rearrangement of the 3-ally1 ether4 or Cope rearrangement of a 19-alkenyl 1,4-dienone.~ None of these reactions easily lead to branched-alkyl 2-substituted oestradiols.We required 2-isopropyloestradiol (1) for other studies, and found that this compound could be made readily from the known 2-acetyloestradiol (2).6 Thus treatment of oestradiol with aluminium chloride/acetyl chloride afforded 2acetyloestradiol in 50-55% yield; no trace of 4-acetyloestradiol was detected. Reaction of 2-acetyloestradiol (2) with 2-chloroethyl methyl ether in the presence of potassium carbonate in dimethylformamide afforded 2-acetylestra-1,3,5(10)-triene-3,17P-diol 3methoxyethyl ether (3) in 80% yield. This protected oestradiol was then treated with methylmagnesium iodide at room temperature, and the benzylic alcohol (4) produced was treated with hydrogen in the presence of palladium/charcoal. The 2-isopropyl derivative (5) finally gave 2-isopropylestra-1,3,5(10)-triene-3,17~-diol(1) on treatment with boron tribromide. The overall yield of the diol (1) from the methoxyethyl ether (3) was 10%. Kaneko, H., Hashimoto, M., and Kobayashi, A., Chem. Pharm. Bull., 1964, 12, 196. Kaneko, H., Hashimoto, M., and Kawase, M., Japan. 982('67) (Chem. Abstr., l967,67,22086t).

2,4-Dibromoestra-1,3,S(10)-triene-3,17 β- diol 3-(2'-hydroxyethyl) ether (8) undergoes reaction with copper(11) chloride/sodium methoxide to afford a 4-bromo [2,3]- dioxan derivative (9) as the major product together with a minor amount of a 2-bromo [3,4]- dioxan derivative (10). These compounds were used to prepare a number of 2,4-disubstituted oestradiol derivatives. � Alternative routes to other 2,4-disubstituted oestradiols are described.

In an attempt to achieve selective functionalization at C‐2 and C‐4, the easily accessible dibromide (I) is subjected to etherification followed by ring closure giving the major product (IV), which is further converted to the 4‐formyl derivative (VII).