in absoliik EtOH using I T 4 Rariey nickel" ratalyst. The catalyst was removed by filtration and the EtOH was evaporated at reduced pressure. The residue was recrystallized from petroleum ether (60-70') affording 0.5 g (427;) o f desired amino alcohol 3: mp 149-151": ir (CEICl,), 2.78, 2.96, 3.33, 8.41, 3.30, 6.25, 6.3.>, 6.70, 6.92, 7.40, '3.85, 10.66 p ; nmr (CDCl,), 6 7.70 (multiplet, aromatic ortho protons), 7.34 iriniltiplet, aromatic ireeta arid para protons), 3.00 (WI;~ = I9 cps. axial methine proton ~ OH, ) x. a t c-3). r h d . ( C I B H ? ~ c, 2(a)-Phenyl-trans-decalin-2(e),3( e)-diol 3-Tosylate (12).- T o 9 (1.05 g, 0.0043 mole), dissolved in 20 ml of a n h y d r o i ~pyridine, was added p-tol~~eiiesiilfoiiyl chloride (2.0 g, 0.0 1 mole) and the solution was allou-ed to jtarid at room temperature for 48 hr. I t 0 w:w added and the reaiilting oil was scratrhed with a glaw rod to pr(~iriolecrystallization. The solid was removed by filtrat ion aiid recrystallized from petroleiim et,her (60-70°) affording 1.0 g (.i8F;) of t,osylate 12: mp '39-100°; ir (C€IC13), 2.78, 3.42, : 3 . X , 6.27, 6.70, 6.92, 7.40, 8.,X, 9.13, 0.74, 10.33, 10.82, 11.25, 1 1.W, 11.98 p ; nnir (CCl,), 8 7.2-8.0 (multiplet, aromatic protoris), 4.80 jqiiartet, ./$):, = 11 cps, ./:$,, = 6 i'p, axial rnethinr pr(itc~iiat (X),2.43 (singlet, ArCI13). .171ai. (('L3112SS04) C, I i . 3(a)-Amino-2(a)-phenyl-trans-2(e)-decaIoi(2).--Conipoiind 12 (1.0 g, 0.0023 mole) was placed iti a steel bomb arid the bomb was c~)olctlin 1)ry Ice-.\le2C0, TI) the bomb was added cn.
I00 nil of liqiiid XI&. The bomb w a s miled atid 1ie;ried at 120 for 24 hr. The presslire was released and the residue was disd v e d in CNCI,. The CHCl3 solution w a filtered ~ and t,hesolvent was evaporated. The residue was rec~ystallizedfrom petroleiim of amino alr~ohol2: in ether (60--iOo) affording 0.80 g (30 116--1I f " : ir (C1ICYj'),2 . W j 2.9'7, 4, 3.42, S.,j1, 6.2.7, 6." 6.71, 6.92, 7.40, 9.8>, 10.01, 10.28, I 7 p ; iinir (C'I)Cl:!), 6 7 multiplet, arcrrnatic proi.ons), :1.8:2 i 11.1 ' ? = f i cps, cqii:it(~~,ial inethineproton a t ('-3 I. . i n n / . ((>l611&()) (1, I I , S . 3( e)-Amino-2(e)-phenyl-trans-2(a)-decalol (4 I.--- ('~JInp~Jlill(i 15 ((1.0g 0.004 mole) w a s dissolved it1 100 i d o f xbsoliite EfOfl satiirateti with S I I . , arid material war hydrogenated ritider T i l kg/cm2 of HBusing It.4 Raney Xi c*atalyst.17 Ttic c~ntalystw:i* removed by filtraiiciri and the solvent FWS evaporated at i.cdrlcwl preasure. The iwidiir wah chromatographed 011 si1ic:i gcl i.\Ierck 0.03--0.20 nirn) eluting with cyc.lohexaiie-l':tO.~(. [ I : 1 i affording O..? g i3O';j of h i r e d amino alrohcll 4 : nip 146- 148'; it, iCHClZ), 2.78, ?. H >> CH&H > C,O?Et, H,N >>> C02H, C'OSC'H,C'H,. . \ l e s s + ,Br. Tivo ni:i,jor conclusions can he drawn from these (lata. Ic'irst, act'ivity c n ~ ihe ret'airied or enhanced in hubntituted compounds. This would not be expectetl on steric grounds if a-face adsorption were involved, t)(it is in harmony with adsorption on the p face of the st croitl. Srt:otitily, x t i v i t y of :I givwi :ui:thg is ( I t + w i r i t i ( v I 11) ucturc of thc substitueiit' 011 t,he cycloprop:m(, villa. Thorefore, it, is now est'ablished t h a t in principle such ;t series of arialogs could shed light on the elcc-
tronic reyuirenieiits in the A ring, :is outliiicd pix'viously. Howver, the sniall number of act i1.c. coiiipounds niakes the present series inntlequ:itc: for 1 t i is purpose, and a further discussion must aw\.nitsthr coiiiplet.iori of another series of compounds, ciirretit1)being carried out in our laboratory.
Experimental Sectioni9 The i i i e ~ 1 1 ~ L j eriiploj lb ed iri itie androgeiiic-riiy0l rol~liic a. has been discusbed previously.? 2[,3E-Methan0-5a-estran-l7,9-01 (Isomer A ) (3j.- .A s t i r n d m i l ture of 8.5 g (0.10 mol?) of Zn--Cu couple, 30 g of C H ~ 1 2:rritl , IiO iirg of I ? irr 200 n i l OF :tilliyrlroirs Et20W:IS h e a t 1 4 i i r i t l i b i , reflu\ for. '1'1i(~ii :3,0 g 10,00!1iiiiiI(~)i i L 1 2 ciissolvcd iii : i i i l ~ j . d r ( ~ 1,:12() ii~ a t l t l c ~ l . Tlic, iiiistiirc: \vas heated under reffils for !!O Iir :IIIII them filtered tliroiigli :iliiiiiiti:i, ivashed with diliitc IICI sciliitioii :iiid I120, :iiid clricd (S:i.>S04 1. Aftrr rvaporation of the. wIv(-tit I lir.
\\:t$
July 1968
MYOTROPHIC-ANDROGENIC 2aj3a-J1ETHANO-5a-ANDROSTANES
the residue q a s dissolved in 100 ml of 570 methanolic KOH solution. It was refluxed for 0.5 hr and the product was obtained by evaporation of the MeOH and addition of HzO. It was recrystallized from RIeOH to afford 1.2 g of material, mp 105-110". Further recrystallization gave the analytical sample, ~ ( c 1, CHCl3). Anal. ( C I & ~ O Oc, ) mp 114-115', [ a I 2 *+77"
H. From the mother liquid there was obtained 0.4 g of isomer B (4), mp 96-102". Recrystallization from aqueous MeOH gave the analytical sample, mp 104-105", [a]28D +62" (c 1, CHC13). Snal. (C19H300) C, H. 2a,3a-(p-Carboxymethan0)-5a-androstan-17p-o1(5).-A solution of 1.0 g (0.0025 mole) of 7 in 100 ml of 5% methanolic KOH was refluxed for 30 min, concentrated in vacuo, and poured into 300 ml of ice-water. Upon acidification t o p H 1 with 2070 HC1 crystalline product precipitated. It was filtered and dried t o afford 0.8 g (96%) of 5, mp 258-260'. Several recrystallizations from N e O H furnished the analytical sample, mp 265-266", [ a l Z o+14O ~ ( c 0.4, dioxane). Anal. (CzlH3203) c, H. 2a,3a- (pCarboxymethano)-5a-androstan-17-one (6).-A solution of 1.20 g of 5 in 200 ml of acetone wa8 allowed t o react wit'h 2 ml (excess) of 8 S CrOs solution a t 27". After 20 min, the excess reagent \vas destroyed with i-PrOH and the mixture was filtered. After the addition of a small quantity of Hz0, the mixture was evaporated under reduced pressure to give 0.98 g (82Yc) of product, mp 280-281'. Several recrystallizations from N e C N furnished the analytical sample, mp 282-283", [ a ]2 0 ~ f 7 6 " (c 1, CHClr), nmr 0.851 ppm (19-H). Anal. (CSIHIOOH) C, H. 2a,3a- (p-Carbethoxymethano)-5a-androtan-17p-o1 Acetate (7). -A mixture of 4.0 g (0.0126 mole) of 25 and 0.4 g of anhydrous CuSO4 was heated to 120" and 7.0 g (0.06 mole) of ethyl diazoacetate was added dropwise. The mixture was kept a t 120" for 15 min under stirring and 10 ml of 10% H0.4~ was added to decompose the excess reagent. The resulting mixture was cooled and extracted with Et20 and the extracts were combined, lyashed with 5 5 SaHC08 solution, and dried (XanSO4). The EtrO solution was evaporated in vacuo and the oily residue was treated with 2 ml of cold MeOH to afford, after filtration, 2.3 g (46%) of the crude product, mp 120-125". Several recrystallizat,ions from MeOH gave the analytical sample, m p 148-EO", [ a I z o ~-15' ( c 1, CHC13), nmr 0.778 ppm (19-H). Anal. (Cz~Has04)C, H. Ethylcarbonic 2a,3a-(p-Carboxymethano)-5a-androstan-l7one'Anhydride @).-A solution of 0.40 g (0.0012 mole) of 6 in 60 ml of Me2C0 and 6 ml of HzO was cooled to 0" and 0.15 g (0.0014 mole) of Eta?; in 2 ml of Me2CO was added. While maintaining the temperature at O", a solution of 0.144 g (0.0013 mole) of ethyl chloroformate in 2 ml of Me&O was added slowly. The mixture was stirred at 0" for 1 hr and the solvent was evaporakd giving 0.33 g (69%) of crude product, mp 143-144". Several recrystallizations from MeCN furnished the analyt,ical sample, mp 14,5-147', [ C Y ] ~ O D +173' (c 1, CHCl,), nmr 0.820 ppm (19-H). Anal. (C24H340j)H ; C: calcd, 71.61; found; 71.20. 201,301-[ p-Carbo(l-aziridyl)methano]-5~-androstan-17-one (9). -To a stirred mixture of 0.10 g (0.0024 mole) of ethylenimine and 0.125 g (0.0012 mole) of MeSHz in 5 ml of CeHBwas added 0.46 g (0.0012 mole) of 8 in 3 ml of CeHe during 1 hr a t 0" and the reaction was stirred for an additional 1 hr a t 0". The solvent was evaporated in vacuo and the gummy residue was treated with a small amount of cold hexane. The precipitated product (0.23 g) (52%) was recrystallized from hexane to furnish the analytical sample, mp 142-144', [a]'OD +91" (c 1, CHC13). Anal. (C23H33NO,) C, H, X. 2a,3a- [ p-Carbo( 1-aziridyl)methano]-5a-androstan-17p-o (19) Melting points were determined with a Thomas-Hoover apparatus equipped with a corrected thermometer. I r spectra were obtained with a Beckman IR-8or Perkin-Elmer 337 instrument. Microanalyses were performed hy the Microanalytical Department, University of California, Berkeley, Calif. Nmr spectra were obtained a t a field strength of 60 M H z on samples in C D C k solutions on a Varian A-80h instrument, using TMS as internal standard. When only small amounts of sample were available, a Varian C-1024 computer was used for time averaging. Optical rotations were obtained in a 0.5-dm tube with a Rudolph photoelectric polarimeter. Glpc was carried o u t using a Barber-Coleman Model 5000 system employing 1.83-m U-tuhe columns of 2%; SE-30 on Gas Chrom Q or Z, H e carrier, Nn flame detection, column temperatures of 220-240°, "on column" injection a t 290°, and deteotor temperatures of 250'. Where analyses are indicated only by symbol of the elements or functions, analytical results obtained for those elements or functions were within 3~0.4% of the theoretical values.
S67
(IO).-A solution of 0.100 g of 9 and 0.2 g of LiAlH (t-BuO)a in 10 ml of anhydrous T H F was kept a t 0" for 1 hr. The product was isolated by Et20 extraction and recrystallized from MeCK to give the analytical sample, mp 175-176", [aIzon -16' ( c 1, CHC13), nmr 0.788 ppm (19-H). Anal. (C23H3jN02) C, H, N. 2~,3a-(@-Aminomethano)-5~-androstan-l7@-ol Hydrochloride (ll).-The crystalline free amine derived from 1.50 g (0.0044 mole) of 12 was dissolved in RleOH and reduced with 0.6 g of NaBH4. The excess NaBH4 was decomposed by addition of 5% HCl and the mixture was concentrated in vacuo and poured into ice water. The aqueous solution was made alkaline and extracted with EtnO. The product was rather insoluble inEtzOand partially precipitated. The 0.85 g (637,) of crude amine obtained was dissolved in anhydrous Et20 and acidified with saturated ethereal HC1 solution. The precipitated salt was filtered and recrystallized from EtOH-Et20 to give the analytical sample, mp 279+22" ~ ( c 0.5, CH30H). Anal. (CzoH34C1NO)C, H, 280°, [ a l Z o
x.
2a,3a- [ p-Aminomethano] -5a-androstan-17-one Hydrochloride 6 (2.50 g, 0.0076 mole) was converted t o 8 (l2).-Compound as described. To the resulting reaction mixture was added a solution of 0.815 g (0.012 mole) of N a y 2 in 6 ml of H20. The mixture was stirred for 1 hr and poured into 500 ml of ice water. The white precipitate was collected by filtration and dried to afford 2.42 g ( 7 3 7 , ) of the crude azide, mp 122" (evolution of N2). This azide (2.42 g) was dissolved in 12 ml of toluene and heated on a steam bath until no more nitrogen was evolved (1 hr). Removal of toluene in vacuo afforded a yellowish oil which was shown to be almost pure isocyanate by its infrared spectrum (vgfi 2230 cm-1). The isocyanate was suspended in 16 ml of 20% aqueous HC1 and the mixture was heated under reflux for 1 hr, during which time the amine HC1 precipitated. Recrystallization from lYc aqueous HC1 gave 2.00 g (78Yc)of colorless needles. Further recrystallization from CH30H-Et20 gave the analytical ~ (c 1, CH,OH). ilnal. (CZoHa2C1NO) C, H, sample [ a y l Z o+92"
N. 2a,3a-(p-Dimethylaminomethano)-5~-androstan-l7@-0~ methochloride (13) was obtained from 11 with Me1 and KzCOBin MeOH. A solution of 0.36 g of the methiodide in 5 ml of MeOH was passed through 10 g of IRA-400 resin which was washed with MeOH previously. The eluates were collected until neutral and evaporated to dryness. Several recrystallizations from EtOH-Et20 gave the analytical sample, mp 280-283' dec, [ a l Z o D -31" (C 1, CHaOH). A d . (CaoHaoClNO.H,O) C, H, N. 2a,3a-( @-Dimethylaminomethano)-5a-androstan-17-one methochloride (14) was obtained from 12 with Me1 and KOH in MeOH solution. The crude product was recrystallized from H2O t o give 0.43 g (60%) of the quaternary iodide, mp 272-276". One additional recrystallization from EtOH-Et20 raised the melting point t o 280-283'. A solution of the iodide in hIeOH was passed through IRA-400 resin previously washed with RleOH. Recrystallization from EtOH-Et20 gave the analytical sample, mp 274-275' dec, [ a l 2 0 ~+So (cO.5, CHIOH). Anal. ( C L ~ H ~ ~ C C, ~ NH, O N. ) 2a,3a-(~-Aldehydomethano)-5a-androstan-17~-01 (15).-Reduction of 0.68 g (0.0019 mole) of 10 in 180 ml of Et20 with 0.07 g (0.0019 mole) of LiA1H4 a t 0" for 1 hr, decomposition with 10 ml of cold 5 il; HzSO~,and work-up using preparative tlc on silica gel gave 16 (27y0) and 15 (55%). The product 15 had mp 158160°, [ a l Z o D +30° ( c 1, CHC1,). Anal. (C21H3202)C, H. 2a,3a-(~-Hydroxymethylmethano)-5a-androstan-17p-ol (16). -A solution of 0.100 g of 9 in 15 ml of EtOH was treated with 0.04 g of NaBH4. The crude product (98%) was crystallized from MeCY-RIeOH ( 7 : 3 )to give the analytical sample, mp 217218O, [aIzon 24' ( c 0.5, dioxane), nmr 0.762 ppm (19-H). Anal. (CZ1Hr402) C, H. 2a,3a-(~-Bromomethan0)-5a-androstan-l7@-01 Acetate (18).Compound 19 was reduced with L ~ A ~ H ( ~ - B UinOT) ~H F solution in the usual way. Acetylation of the resulting alcohol with Ac2O in pyridine solution gave 18. Ilic~atiun 340 f r o m tlie S J iiiex Inatitiite Sirmiid C'llciiiiatly. l o r b g : ~ i :t mixture of products from which tlie (io!,itiil,lication iW4 see 1'. I T . Nelson, J. \V. 1111 .i. Edwardr, a n d J . f l . 1;ried. .I. A m . C h e n . S O C . , in prrss. This I on is also part Y I of t h e ;cr-difluoron~ethyleiic adducts 2a, b were isolated aftcir (1
w r i w , l l r t l i j ienation of Unsaturated Ketones. P a r t V: G. Tarzia. S . H. l ) y w n , I. '1.liarrison. .J. .\, Edwards, an(1.J. 11. E'ried, Steroida, 9 , 387 (1967). -1 irurtion of this material was presented ai tile symposium on .\ntiinAammator>- .\genrs sponsored b y tlie lledicinal Chemistry Section a t tlie 134tli eetinv of t h e American Chemical Swiety, ('liicago, Ill., Sept 196;. lite of IIornione Bioloiiy, Ssntex Research. . d c o d . Sca.. 82, 802 (19.59). S a r r t t , A ? < I L.V.Y. , 1) 1,. I f . S a r r t t , '1. . i . Patcliett, a n d 9. 1.. Steelinan, I'royr. D r a y R e a . . 5 , 1 . i (l!)ti3). ( a ) J. Fried, "Alc~clianisin o i .Xction of Steroid Iformones," Tile Ala?Alillan %., New York, N. Y., 1961, p 2 3 2 . ( 0 ) I. E. Rush, I ' t i u r m a c o l . Rei,., 14, 447 11968). ( 7 ) T h e %ketone can be replaced b y a 2,3-fused heterocyclic ring v i t h a cmisiderat~leenhancement, of biological activitl-; rf. R . Hirschmann, N. G. Stt*intmx, t'. Buciiechachrr, .T. i f . Vrieci, ,~I
