ether iiiixtures, followed by gave 3.1'7 g of the tetrah The malyticsl sampl .t n a l . C:tlcd for Foriiid: C:, 6S.63; H 6~,9~-Difluoro-3~,1l~-dihydroxy-l6a,l7-isopropy~idenedioxypregn-4-en-20-one 36-t-butylacetate ( V , R = ( CH3),CCH,CO) ww prepared from the correspoiiding :3p-alc.ohol Y ( R = ll'i ;tiid t-butylacetyl (ahloride iii pyridiiic.: nip 24-2-tS" tlrc,, [e] 2 : b +74.4". .Innl. C:ilctI for CaoH,,Fd),: C', iiti.b9: H. F, 7.0,j. Fouiid: C, 6ti.64; H, qS.19; F, 7.K;.
Derivatives of 3,4-Diphenylchromanes as Estrogens and Implantation Inhibitors
A iiurnber uf sithstit,iited 3,4-diplieii~l~~Iiromslies have been prepared from isoflavaiiones. spectral, and biological propert,ies, i.e., estrogenic and aiitifertility activity, are discussed.
Several years ago Gaunt and co-workersl emphasized the necessity of the extension of classical endocrinology into broad endocrine pharmacology. While classical endocrinology is priniarily concerried with the isolation, synthesis, and improvement of natural hormones, endocrine 1)harniacology would imply the study of nonhormonal compounds to elucidate hormonal arid enzymic mechanisms and by this route to detect substances which would be able to restore deranged eridocrine homeostasis. Diverse nonsteroidal coml)ounds such as uiiiphenones, 1)yridyl ketones, aniinoindenes,? 2,3-dil)henyliridenes,3 1,2-diaryldihytlro- and 1,2-diaryltetraliydronnl,hthalC I I ~ ' , ~isoflavones,' 2,~-dialkyl-~3-isofla~eiis,fi diary1l)ro1)ionitriles,73,.2-diphe1iylcoumariiis.b and 2.3-diphenylk~etizofurans~have shown specific iriteractions with endocrines. lloreover, u recent coniriiunicatioii from our laboratories outliries thc qyiitliesik arid biological ~irol)ertiesof sonie rielv cis arid trans isomers of 1.2,3,4tetrahydro-l,2-cliaryliial~hthalenc derivatives.d l I t was shown that sonie of these compounds cxhibitetl ninrked estrogenic activity as well as potent antifertility activity i n thr fernnle rat. I t hay hccn noted also that 31iyl.idyl-l-chronioiie tlerivntivc.< l i u w .pccific effect. ( 1 ) 1%. (;ai;nl, .I. ,T. ('liart, a n d .L .L Iten*), ,Sci?we', 133, 0l:i ( l ! l t j l ) . ( 2 ) (a) I!.' L. Bencze a n d 1 J . .Illen, .I. 3 1 e d . i'hnrm. C'hern., 1, 3Ri hepparil, ibid.. 1, 407 (19%): (r) I\.. I,. Ihncxe and L. I. Barsky. i b i d . , 6 , 1298 (1962): ( d ) R. hlowles, a n d S . Ilouie, I?'ndorrinolog~/,71, 4 i 8 (1962). ( 3 ) (a) 1). Lednicer, .J. C. Babcock, S.C . Lyster. ,J. C. Stricki, and (i. I \ . I)iini.an, Chem. I n d . (London), 2098 (1961); ( l i ) 11, Lednicer, J. C. Babcork. 1'. Iliioiiv by ziiic dust -acetic acid Ho~evct., iiicc 1)otli of thcsc methods (lo iiot lend themselves to :I convcnicnt ~~rep:mitionof :i-l)henTrlchroniaIlotic~, ~ l i cinethotl of D:tRe :itid Ycdicchi was used in the uiur-e of our si tidy.1 These investigators found that t lie conden~ntionof iormaldehyde with an o-hydroxy1)liriiylbenzyl ketone derivative in bask medium yield? the desired isoflavaiioiie directly. T h u , o-liydroxy~)Iie~i~.l p-chlorobenzyl ketone arid 1)araformaldrhytle wore allowed to react in aqueous sodium hydroxide solution :it 55' to afford 3-p-chloro~~lien~l-4-cliroiii:rriorlc(I) jn yield (see Scheme I). This ~ u h t : i n c c\vi+then treated with the p-methoxy1
517
3,4-DIPHENYLCHRO;\IANESAS ESTROGENS
July 1966
SCHEME I
OCH,
OCH3 I
I
111
I
I
OH
I
OH
&cl IV
VI
1
1
OH
ACI
VI1
phenylmagnesium bromide, and the resulting tertiary alcohol was dehydrated to give 11. Under similar conditions, the condensation of p-(Zdiethylaminoeth0xy)phenylmagnesium bromide with I yielded V. Catalytic hydrogenation of I1 in ethyl acetate a t atmospheric pressure formed in 70% yield cis-3-p-chlorophenyl-4-p-methoxyphenylchromane (111). The stereochemical assignment was made on the basis of its mode of formation, Le., cis addition of hydrogen by catalytic reduction of an olefin. IIoreover, nmr studies supported this assignment (vide infra). Compound I11 then was converted to the phenol VI by heating with pyridine hydrochloride. Alkylation of VI with 2-diethylaminoethyl chloride resulted in a 46% yield of cis-3-p-chlorophenyl-4- [p-(Zdieth ylaminoethoxy)phenyl]chromane (IX) . The synthesis of the corresponding trans isomer was achieved by an alternate route. Sodium borohydride reduction of I gave a cis-trans mixture of secondary alcohol IV which in our hands resisted separation. Therefore, the mixture was carried through the next reaction step. Friedel-Crafts alkylation of phenol with 3-p-chlorophenyl-4-chromanol resulted in the formation of a mixture of phenolic products from which the trans isomer VI1 was isolated. This compound was distinctly different in physical and spectral properties from the cis phenol (VI). The trans basic ether VI11 was accordingly prepared by the previously described method. The other members of this series, i e . , the chromenes of Table I and the cis and trans chromane isomers outlined in Tables I1 and 111, respectively, were synthesized according to the sequences described above.
IX
VI11
Though it is difficult to determine the preferred conformation of flavansl6 as well as isoflavans, a number of interesting conclusions can be drawn from the pmr spectra. I n both the cis and trans derivatives the C-3 hydrogen is a broad multiplet a t approximately 3.6 and 3.3 ppm, respectively. For the cis compounds the width of the proton multiplet is approximately 15-20 cps and for the tyans isomers it is 25-30 cps. If one assumes that the preferred cis conformations a and b are as shown, Le., to obtain a proton spread
a
b
of 15-20 cps for the C-3 proton in the cis compounds, this proton must be axial interacting with the axial C-2 proton. The greater width of this area for the trans compounds must involve another pseudo-axial interaction from C-4. Thus, the substituents of the trans compounds must be pseudo-diequatorial and for the cis compounds the C-3 substituent is equatorial and C-4 is pseudo-axial. This relationship would also provide an explanation for the more shielded position of the C-3 hydrogen in the trans compounds since in these examples the C-3 proton and the aromatic ring (16) J. V-.Clark-L-uis, L. R.I. Jackman, and T. H. Spotswood. -4ustraZian .I. Chem., 17, 632 (1964).
$18
N
