Es tra-l,3,5(10), 15-tetraenes.
1.
Birch Keduc tioii
The :ttlditioii ( i f org;iiiolit hiiiin rcicgeiilh t,ii :brneilici~yes~ i.tt-I,:j,:i( Io), I ~ ~ - t ~ ~ ~ i ~ ~ i 1 , t3I~> ii t~s l -i l l( d~ :I - i*orit,< ~i~t 1i-suhstit~tt,edAis deiivat,ives (6). Birch reduction of 6a and 6b at -7s" 1t:d t o ruliiciioii of iiilg .4 \viihout, r!hduction of the A15 double bond. Oppenaiier oaidatinri at, room lenipertttiirc of Ihc iiitermedittt e :I-rnet,hoxyesf ra2,5(10),15-trien-l7~-nl (10) afforded the ketone 11 which was coiiverted to a scricn of wtive progt\tirrs. 'rhc hypoeholesteremic and estrogenic activities of the intermediate nrnmatir steroid. arc i q o r t e d . .A himpic prcic~rt11ir.c for ethynylatinn of base-sensitive ketoiies is described.
As part of a synthetic program leading t o modified steroidal estrogens arid their derivatives, some re:ictions of estra-1,3,5(10),15-tet~raenes,in part'icular 3methoxycstra-l,3,3(lo),15-tetraen-17-one (3), were es:tmincd.' The A15-17-~~ne 3 had previously been prepared i i i five steps from estroiie methyl et'her (1) b!. Johnson :uid Johns. We used essentially the same procedui,e, but reduced the number of st'eps to four by direct bromination of estrone methyl ether with CuBrZ3 (Scheme I). 111 :in effort to reduce the number of steps even further, t'he direct, dehydrobromination of bromo Icetolie 2 w:ts reesamined. I n a related series, Pappo, et ( I ) E. \ \ , Cantrail. R. Littell, and W. Bernatein, .I. Org. Ciiem.. 29, 6 1 l!t6.i]. liar e iiwd 3 to prepare a series of 16-s11I~tituted derivative,, ( 2 ) \\., 5 . .lolinron a n d \\-, F. Joli V I . C ' / ~ w i .Sor.. 79, 20005 ( 1 9 > i t . ( ; $ I L. it. (ila,,ier, .I. O r g . Ciiern.. , I ) I ? . I'ai,pu. H 11. 1ilo01~1a n d \\. P. ~ l o l ~ n s o r.I. i , . l n i . C'//ctti. li31J 1 I!J561. !
~
September 1908
h T R . 4 - 1 ,fJ
,s(10 )
SCHEME
CH30
925
+TETRAEXES
1
CH,O
I
LiAIH, or RLi
10
6a,R=H b, R = CH3 c, R = C d X 3 d, R = C=CCH20H
&
e, R=C=CH
OH
3"
0 9a, R=CH, b.R = C=CH c, R
CECCI 7a, R CH, b,R=H
PnOH
&
1. LiAIH(O.t-Bu),
2. Ac10
0
12a, R = CH3 b, R = C=CH c, R
13a, R = CH3 b, R = C=CH
CrCCl
Reduction of the unsaturated ketone 3 with LiAIH, at 0 to -5" afforded a 78% yield of the Al5-17P-ol 6a. At higher temperatures considerable amounts of the saturated alcohol and the saturated ketone 1 were obtained (as demonstrated by tlc) .* RIeerwein-Pondorff reduction using aluminum isopropoxide and iPrOH in refluxing C6H6 gave the unsaturated alcohol in 72% yield. Interaction of the unsaturated ketone 3 with Grignard reagents led to mixtures of compounds. With organolithium reagents, essentially pure products were
obtained. Use of 1IeLi in THF afforded the alcohol 6b. Reaction with lithium chloroacetylide gave the chloroethynyl derivative 6c. The reaction with the lithium derivative of 2-(2-propynyloxy) tetrahydropyrang yielded an intermediate which, after acid hydrolysis, gave the hydroxypropynyl derivative 6d. Direct ethynylation of 3 with lithium acetylide-ethylenediamine complex in T H F or DMSO or with sodium acetylide in DRlSO'O afforded unpromising mixtures. When lithium acetylide in T H F (prepared by addition
(8) J , Fajkos, Collertzon CtPrh. Chrm Cornmiin , 23, 2 1 5 5 (1958), reported t h a t aodnlm Imroh&iirlcie rediirtlon oE an analogoun AlLli-one g a l e the saturated alcoilol e \ c I u s I \ P I T .
(1950). (10) C . H Rol)lnqon, N F. Bruce, and E. P. Oliveto, 975 (1963).
(9) H B TTenhest, E R. 13. Tones, and I. M. S. Walls J Chem Soc , 1646
J. O r g . Chrm., as,
September 1968
ESTR.k-1,3,5(10), 15-TETRAESES
contrast to the norethynodrel (17-hydroxy-19-nor-17stpregn-z( IO)-en-20-yn-3-one) to norethindrone shift. Compounds 6b, 6c, and 6e were somewhat more active than estrone methyl ether in lowering cholesterol levels in male rats (Table 11). The methyl deT ~ B L I1 E OR.\LHYPOCHOLESTEREMIC .\ND UTEROTROPHIC ACTIVITIES Hypocholestereniic
EDlS," Colllpd
Estrogenic
nig, kg
lIDa,'
day X 4
nig 'kgiday X 3
Ratio
Estrone methyl ethei, 1.6< < O . -7 >3 63, 9 1. 3 6 6a acetate 5.4 -1 . % ; i d -4.3 6b 0.7 -.50e -0.018 6C 0.8 2.8 0.03 6d f >250# ... Ge 0. I 0.25 0.4 Minimum dose required to reduce serum cholest,erol33% over control. b 3linimum dose required to increase uterine weight 50 mg over control. A. arnold, G. 0.Potts, J. Ylchuliff, R . G. Christiansen, and T. C. Aliller, Proc. Soc. Exptl. Biol. d f e d . , 121, 122 (1966). d Significant stimulation a t 0.25 mg/kg. e SignifiSigcant stimulation at 0.1 mg.'kg. f Inactive at 16 mglkg. iiificant stimulation. Q
rivative 6b had a better hypocholesteremic to uterotrophic activity ratio than estrone methyl ether had. However, it showed significant uterotrophic activity at as low a dose as 0.1 mg/kg/day X 3, suggesting that it is an impeded estrogen.27 Compound 6e mas 16 times as hypocholesteremic as estrone methyl ether was, but was equally as estrogenic. Compound 6d, with a hydroxyproppnyl group st (2-17, gave no evidence of hypocholesteremic activity a t 16 mg/kg/day x 4 and was not tested further. Minimal estrogenic activity was rioted at 2.50 mg/kg'day x 3.
Experimental Section Unless otherwise noted, the organic extracts from the reactions were washed ( H 2 0 and satnrated aqueons NaCl), dried (KanSO1j, and concentrated under reduced pressure. All melting points are corrected. The ir spectra were recorded on a Perkin-Elmer infrared spectrophotometer Model 21, uv spectra on a Cary spectrophotometer Model 15, and nmr spectra on a 1-arian A-60 spectrometer using precalibrated paper. Solutions ( 10-207c) were used wit,h (CH3)&i as int,ernal standard. Silica gel G (Brinkmann Instruments) was used for tlc. Spectra were run under the supervision of Dr. R. K. Kullnig, who assisted in the interpretation of the nmr spectra. Xicroanalyses were carried out under t,he supervision of Mr. K . D. Fleischer. 16-Bromo-3-methoxyestra-1,3,5(lO)-trien-l7-one (2).2-CuBr23 (500 g) was added to a warm solution of 250 g of estrone methyl ether (1) in 2 1. of C6H6and 2 1. of MeOH. The mixture was stirred a t reflux for 1 hr and filtered while still hot. The filtrate was concentrated under reduced pressure to about 1 1. and then diluted with 3 1. of CsH6 and 1 1. of H20. The mixture was shaken well, then filtered while still m r m . The aqueous layer was extracted with 1: 1 EtnO-CsHs. The combined organic extracts were washed (XaCl), dried, concentrated to about 800 ml, and cooled. Filtration afforded 220.9 g (69%) of light yellow crystals, nip 175-178" (vac); second crop, 30.2 g (9';c), mp 173176" (vac). 3-Methoxyestra-l,3,5(10),15-tetraen-l7-one(3).-The bromo ketone 2 was converted to the unsaturated ketone in 47-53T0 yield by the procedure of Johnson and Johns.2 (26) J. H. Fried, T. 9. Bry, -1.E. Oberster, R . E. Beyler, T. B. Windholz, .1. Hannah, L. H. Sarett. and S. L. Steelman, J. A m . Chem. Soc., 83, 4663 (11161). (2i) C. Hnggins and E. V. Jensen, J . Ezptl. .Wed., 10% 347 (1955).
927
Direct Dehydrobromination of Bromo Ketone (2).-A mixture of 47.3 g of the bromo ketone, 70 g of LiBr, and 60 g of Li2C03 in dimethylacetamide was refluxed for 3.5 hr. The red solution was cooled and poured into 1500 ml of 20y0 aqueous AcOH and the mixture was extracted with 1: 1 EtnO-CsH6. Work-up gave a red residue, which was chromatogaphed on silica gel. Elution with 1% E t 2 0 in C6H6 afforded, after recrystallization from EtOH, 14.5 g (39T0j of 3-methoxyestra-1,3,5(lOj,l4-tetraen17-one (4): mp 102-103.5" (lit.2 mp 103-104°); [ a I z 5 D +293' (lit.1 +293'); ir (KBr), 5.74 p ; nrnr (CDCls), 1.13 (CHI), 3.72 (OCHI j,. and 5.57 ppm (Ct,H, unresolved multiplet). lllixture melting point with an authentic sample prepared by the method of Johnson and Johiis2 was not depressed. Their ir spectra were siiperimposable. Elution with 2 . 5 7 , E t & i n C6H6 yielded, after recrystallization from EtOH, 13.9 g (38%) of 3-methoxy-14p-estra-1,3,5(10),15tetraen-17-one: mp 100-101.5" (lit.2mp 101-102°); [a]2 5 +485" ~ (lit.1 +477"); ir (KBr), .5.88 p ; nmr (CDCl,), 1.13 (CH,), 3.70 (OCHsj, 6.13 (CI,H qnartet, J = 6, 2.5 Hz), and 7.53 ppm (ClsH quartet, J = 6, 2.5 Hz). Mixtiire melting point with an authentic sample prepared by the method of Johnsons and Johns was not depressed. Their ir spectra were superimposable. The 14a-A15-1i-orie 3 (mp li9-183', lit.2 180-181", [ a ] 2 5 ~-54", 1it.l -90") had nmr peaks (CDC1,) a t 1.08 (CH,), 3.75 (OCH3), 6.08 (C16Hquartet, J = 6, 3 Hz), and 7.6%ppm (C16H quartet, J 6, 1.5-2 Hz). 3-Methoxyestra-1,3,5(lOj,15-tetraen-l7~-01 (6a).-Reduction of 8.47 g of 3 with LiillHc in E t d - c & ~ at 0 to -5' afforded 6.63 g (78%) of once recrystallized colorless crystals, mp 150-153' (vac) (C6Hs-i-PrOH). Additional recrystallization gave color~ (CHC13); ir (KBrj, less rods: mp 152-154' (vac); [ a I z 5+l.5' 2.92 p ; uv (95% EtOH), 221 sh mp ( e WOO), 279 (2050), and 288 (1900); nrnr (CDClI), 0.85 (CHI), 3.75 (OCHI), 4.38 (C17Hj, 5.70 (ClrH octet, J = 5.8, 3, 1.4 Hz), and 6.03 ppm (CI& poorly resolved multiplet, J = 5.8, 1.4 Hz). Anal. (C19H2r02)C, H. The acetate of 6a was obtained as colorless prisms: mp 136.5~ (CHCl,); ir (KBr), 5.78 p. Anal. 138" (vac): [ a I z 5-35.0" (CPIHBBOI) c, H. 3-Methoxy-17-methylestra-1,3,5(10),15-tetraen-l7~-01 (6b j.A solution of 10.0 g of 3 in 120 ml of T H F was added to a stirred ice-cold solution of 75 ml of RleLi in Et20 (1.68 A', Foote Mineral Co.) under X2 during 7 min. After an additional 15 min of stirring, HzO was added and the mixture was extracted with EtaO. Kork-up gave 7.04 g (67%) of once recrystallized colorless flakes, mp 92-99' (C6H6-hleOH), plus a second crop, 2.67 g (25'3j, mp 90-95". Tlc showed these crops to be essentially pure (25% ether in CsH6,followed by HzSOa, heat). Bdditional recrystallization afforded colorless flakes: mp (softens a t 90-93') ~ (CHC13); ir (KBr), 2.76 and 2.99 p ; 104-105O (vac); [ a I z 5-65.3' nmr (CDCls), 0.92 (angular CHI), 1.20 ( C I ~ C H , )5.64 , (C15H quartet, J = 6, 3 Hz), and 5.90 ppm (C16H quartet, J = 6, 1 Hz). Anal. (CsoH26O2) C, H. 21-Chloro-3-rnethoxy-19-nor-l7a-pregna-l,3,5(10 jJ5-tetraen20-yn-17-01 (Gc).-In a manner similar to the preparation of 6b, 2.00 g of 3 was treated with lithium chloroacetylide [prepared by addition of 5 ml of cis-l,2-dichloroethylene in 25 ml of absolute Et20 to an ice-cold solution of 25 ml of MeLi in Et20 (1.68 M ) under N2]. Work-up afforded 1.62 g (67%) of pale yellow crystals, mp 159-160". Recrystallization from MeCN gave pale tan crystals: mp 160-162" (vac); [aIz6D -2.54.1' (CHC13); ir (KBr), 2.92 and 4.52-4.60 p w; nmr (CDCl,), 0.93 (CHI), 3.77 (OCHI), 5.73 (ClaH quartet, J = 6, 3-4 Hz), and 6.08 ppm (C16H doublet, J = 6 Ha). Anal. (C~IHZSCIO,) C, H, C1. 17- (3-Hydroxy-1 -propynyl)-3-methoxyestra-l,3,5 (10),15-tetraen-17p-01 (6dj.-In a manner similar to the preparation of 6b, 3.00 g of 3 was treated with the lithium salt of 2-(propynyloxy)tetrahydropyrang [prepared by reaction of the substituted acetylene, bp 87-88" ( 2 5 mmj, n-ith AIeLi in EtsO]. Work-up yielded 5.52 g of yellow oil. Hydrolysis of this oil with p-toluenesulfonic acid monohydrate in EtOH at reflux afforded 2.91 g (797c) of once recrystallized t,an crystals, mp 214-217' (EtOAc-MeOH). Additional recrystallization yielded light yellow crystals: mp 217-219" (vac); [ a ] Z 5 ~ -248.7" (pyridine); ir (KBr), 3.04 p ; nmr (DMSO-&), 0.89 (CHI),3.70 (OCH,), 4.16 (CHZO),5.iO ( C ~ I H quartet, J = 6 Hzj, and 6.03 ppm ( C d I doublet, J = 6 Hz). Anal. (C&2603) H. 3-Methoxy-19-nor-17~-pregna-1,3,5(10),15-tetraen-20-yn-17-o1 (6e).--A solution of 100 ml of BuLi in hexane (1.59 .If, Foote Llineral Co.) and 100 ml of T H F was added during 15 min to a
c,
