Estrone, chlorination

The effect of chlorinating estrone in aqneous solution has been examined. Three reactions involving chlorination of different rings emerged ... 

Bakke et al. (1982) have shown how montmorillonite catalyses chlorination and nitration of toluene nitration leads to 56 % para and 41 % ortho derivative compared to approximately 40 % para and 60 % ortho derivatives in the absence of the catalyst. Montmorillonite clays have an acidity comparable to nitric acid / sulphuric acid mixtures and the use of iron-exchanged material (Clayfen) gives a remarkable improvement in the para, ortho ratio in the nitration of phenols. The nitration of estrones, which is relevant in making various estrogenic drugs, can be improved in a remarkable way by using molecular engineered layer structures (MELS), while a reduction in the cost by a factor of six has been indicated. With a Clayfen type catalyst, it seems possible to manipulate the para, ortho ratio drastically for a variety of substrates and this should be useful in the manufacture of fine chemicals. In principle, such catalysts may approach biomimetic chemistry our ability to predict selectivity is very limited. 

As reviewed by Fereira et al. [104], the reaction of estrogens, that is estrone, estradiol, and ethinylestradiol, with free chlorine occurs mainly via an electrophilic substitution at the ortho and para positions, which results eventually in cleavage of the aromatic structure. Several authors have reported that dichlorinated derivatives present less estrogenic activity than monochlorinated derivatives, and in most cases, estrogen DBFs are less potent in terms of estrogenicity than the parent compounds. 

Nakamura H, Kuruto-Niwa R, Uchida M, Terao Y (2007) Formation of Chlorinated Estrones via Hypochlorous Disinfection of Wastewater Effluent Containing Estrone. Chemosphere 66 1441... 

Using iV-silylaldimines as electrophiles, aminoalcohols (41) are obtained as reaction products, which after chlorination followed by cyclization under basic conditions lead to the formation of tetrahydroisoquinolines (42) (Figure 1) (00JHC1061). When ketones derived from D-fructose, and D-glucose, as well as (9-ethoxymethyl-substituted estrone and (-)-menthone are used as electrophiles, diols (36f)-(36i)... 

This method is of limited appeal in steroid synthesis because the chlorination step precludes its application to unsaturated or to phenolic compounds (e.g. norequilenin [112]). A more satisfactory sequence, again due to Johnson [113a], is embodied in the hydrochrysene approach [113b] to all eight possible isomers of estrone [114, 115, 120] (FF 497-502), epiandro-sterone [116] (FF 536-7), testosterone [117, 118] (FF 537-8)... 

---