."'
C-19-Functional Steroids. 1.1
l'estostcrone 1)erivativch '
Xovember, 1963
C-~~-FUNCTIONAL STEROIDS.VI
727
AP
AcO
I R = OAc I1 R = Cat!i7 XX R = CH3CO
c1OAc V
111 R = OAc IV R = C8Hi7 X X I R = CH3CO
&-
COCH3
AcOH @ R
R S'I R = OAc VII R = cS~ili X X I I R = CHjCO
XXIII R XXIV R
HO XI1 R XI11 R
= =
= =
OAc OH
0 CY XIV R = CHzOH CHO
XV RI = 0, Rz XVI RI = OH, Rz XVII Ri = 0. Rv
I11 with zinc in acetic acid at 90-95' for 30 min. to afford VI. Higher temperatures resulted in partial acetylation and subsequent dehydrat'ion of the 19oxime to give a mixture of products. This trans elimination of hypochlorous acid, taken together with the previously discussed infrared data, constitutes convincing evidence that no epimerization of the 6P-hydroxy group takes place during the photolysis, in contrast to the reported'? photolytic epimerization of another nit'rite. The oxime VI was readily dehydrated with acetic anhydride t o afford the nitrile VI11 on a preparative scale. Hydrolysis of VI11 gave the diol IXI3 and oxidation to the 3-oxo-A4 system was then undertaken. Although Oppenauer oxidation is often used for this conversion, in the present case it was found that oxidation of IX gave a resinous mixture which was difficult to separate by chromatography. Oxidation with chromic acid in acetoneI4 was more successful. Thus, selective (5 min.) oxidation of IX with 8 N chromic acid in acetone formed the hydroxyketone X,I3 which was later employed for the synthesis of the 17a-methyl compound. Longer oxidat'ion gave the As-diketone XI, which has no selective ultraviolet absorption. Although isomerization of 3-oxo-A5 steroids to the conjugated A4 derivatives has been accomplished with mineral acid, alkali,14,11" and oxalic acid,I6 only gummy mixtures or starting material were obtained when these (12) A. Nickon, J. R. Mahaian, a n d F. J. McGuire. J . O r g . Chem., 26, 3617 (1961). (13) Alternate syntheses of I X and X have been recorded in ref. 2. Compounds VIII and I X also have been obtained by a different segnence involving the Barton reaction by R. Gardi a n d C. Pedrali. Gazz. chim. ital., 91, 1420 (1961). (14) C.f. C. Djerassi, R . Engle, and A. Bowers. J . Org. Chem., 2 1 , 1547 (19.56). (15) A. Butenandt and $1.Schmidt-Thorn&, Ber., 69, 882 (1936). (IC;) L. F. Fieser, J. A m . Chem. Soc., 75, 5421 (1953).
= =
0 OH OH
XVIII R = C N XIX R = CH20H
procedures were applied to XI, possiby owing to the influence of the electronegative 19-nitrile function. It was found, however, that simple chromatography of XI on basic alumina produced XV; neutral alumina gave lower yields of XV, whereas acid alumina was ineffective. In agreement with findings on related c o m p ~ u n d s the , ~ ~presence of the 19-nitrile function in XV causes a hypsochromic shift of 10 mp in the ultra231 mp). Selective reduction of violet spectrum (A,, androstenedione to testosterone with tri-t-butoxy lithium aluminum hydride has been reported,I8 but under similar conditions XV did not give the expected XVII. Instead, equal amounts of the A4-diol XVI and what appeared to be impure 3~-hydroxy-17-oxoandrost-4-ene19-nitrile were isolated by chromatography. The reversed reactivity of the keto groups at C-3 and C-17 may be due to the inductive or steric effect of the C-19 nitrile. Success was achieved in the preparation of XVII by complete reduction of XV with tri-t-butoxy lithium aluminum hydride to the allylic diol XVI, followed by selective oxidation with manganese dioxide. The progesterone derivatives XX1g-XXV were obtained by similar methods. The 17a-methyl compounds were obtained by treatment of X with methylmagnesium bromide to furnish XII. Reduction of XI1 with lithium aluminum hydride stopped at the imine stage2 and gave XI11 after hydrolysis. Further reduction of XI11 with sodium borohydride gave the triol XIV. Oxidation of XI1 and XIV gave, refipectively, the methyl testosterone analogs XVIII and X I X . (17) E. P. Oliveto. L. Weber, AI. AI. Pechet, and E. B. Hershberg, ibid., 81, 2833 (1959). (18) J. Fajkos, Collection Czech. Chem. Commun., 24, 2284 (1959). (19) After our initial disclosure of compound XX in ref. 30, its preparation was also recorded in ref. 8c.
728
I I s zt 2 1
2!I.7 i I ii
1 i . . i i 2.1 1 1 7 i 0 ti 1 2 . 0 f 0.*-1 15 1 f I . ! I
:$!,;i i 2.0 2.i 0 i :i2
2t7.!l f 2 I -1
:io. h f 2
Pharmacological Methods?" Androgenic-Myotrophic assay.?'--'l'hc test ma tcirids (total dobe 3.0 mg rat) in c~r-Lrt)o.iymet!iylcellulosc, (I. Sinchez. and H. J. Ringold, J . A m . Chem. Soc.. 81, 3702 (1939). (29) A . Bowers, L. C. Ibafiez, and H. J. Ringold, ibid., 81, 5991 (1959).
ment, Uniwrsity of California, Berkeley, California. Optical rotations were obtained in a 0.5 dm. tube with a Rudolph photoelectric polarimeter. N.m.r. spectra were obtained a t a field strength of 60 Mc./sec. on samples in deuteriochloroform solution on a Varian .&-BO instrument using tetramethylsilane as internal standard. Resonance positicns are reported in 6 (p.p.m.1 values where possible; unresolved humps are described in c.p.s. units (60 Mc./sec.). It is a pleasure t o thank M r . H. Roleivioz for large-scale preparation of intermediates.
Xovember, 1963
C-~~-FUSCTIOXAL STEROIDS.T'I
73 1
crystallized from acetone-hexane, had m.p. 193-194"; [ai:% ire and was acidified nith 2 0 q hydrochloric acid to pH 1. It $145' (c 1% in CHCL); : :A: 2.95,4.50, 6.00, and 6.16 p ; A,, was extracted with 3 portions of tetrahydrofuran-ether ( 2 :lo), 232 mp ( E 15,500). and the combined extract was washed with water until the washAnal. Calcd. for C Z O H ~ ~ ~ YC,O ~76.64; : H, 8.68. Found: ings were neutral. After drying over sodium sulfate the solvent C, i6.43; H, 8.58. was evaporated to afford 3.9 g. of residue. Recrystallization 3-Oxo-17~-methylandrost-4-ene-l7p,lS-diol (XIX).-A mixfrom acetone-hexane furnished 2.8 g. (677,) of XI1 as fine needles, ture of 10 ml. of cyclohexanone and 15 ml. of toluene u as heated m.p. 211-215". The analytical sample had m.p. 214-216"; to boiling and 4 ml. of distillate was collected and discarded. [ a I z 5-171' ~ (c l'lCin MeOHj; : :A: 2.83 (sharp), 3.06 (broad), Then 0.35 g. (0,0011 mole) of XIV was quickly dissolved in the and 4.50 p . hot anhydrous solution and 1.0 g. of powdered redistilled aluAnal. Calcd. for C r o H d O ? : C, 76.15; H, 9.27. Found: minum isopropoxide was added. The mixture quickly was C, 76.37; H , 9.31. 17~~-Methyl-19-oxoandrost-5-ene-3p,l7~-diol (XIII).-A brought to reflux and maintained there for 10 min. The mixed solvent was removed zn vacuo a t 70-75', and the residue was stirred suspension of 1 35 g. (0.00428 mole) of XI1 and 0.8 g. of taken up in 200 ml. of chloroform xhich was washed with '$' powdered lithium aluminum hydride in 300 ml. of anhydrous sulfuric acid (100 ml.) and lvater, and dried over sodium sulfate tetrahydrofuran ITas heated under reflux for 120 hr. The excess Evaporation of the chloroform left a sirupy residue containing hydride m.s decomposed I? ith ethyl acetate under ice-bath coolsome cyclohexanone. The residue was chromatographed on ing. This mixture n a s acidified with 20% hydrochloric acid to pH < 1, and wis stirred for 8 hr. until a clear solution resulted (if 10.0 g. of neutral alumina; the following eluents were used: four 5-ml. portions of ether; four 5-ml. portions of niethanolnot, more acid is needed to acidify the solution). The mixture ether (1%); four 5-ml. portions of methanol-ether ( 2 % ) ; four was extracted with several portions of ether and the ether extract 5-ml. portions of methanol-ether (4%); four 5-ml. portions of \vas washed with water until the washings were neutral. After methanol-ether ( 8 % ) ; four 5-ml. portions of methanol-ether drying over sodium sulfate, the solvent was evaporated under (617,); and four 5-ml. portions of methanol-ether (32%). There reduced pressure to afford 0.8 g. (5970) of the crudeproduct, m.p. was obtained (from fractions of 8% methanol-ether) 0.15 g 195-203". The analytical sample, recrystallized from acetone(43%) of XIX, m.p. 190-192', and (from 16% methanol-ether) hexane, had m.p. 202-207"; [ a I z 7 D -253'; : :A: 3.02 (broad), a trace of the starting material (identified by m.m.p.). The 3.74 (weak), and 5.75 p (no C S band). analytical sample of XIX, recrystallized from acetone-hexane, Anal. Calcd. for C20H1003: C, 75.43; H, 9.50. Found: C, 2.08, had m.p. 195-196"; [ a ] " ~+66" ( e 0.5% in CHCL); : :A: i5.21; H, 9.28. 6.02, and 6.15 (shoulder)p ; 17CX-Methvlandrost-5-ene-3B,17B,19-triol (XIV).-A solution 243 mp ( e 14,100). Anal. Calcd. for C20H3003: C, 75.43; H, 9.50. Found: < I f 0.5 g. (0.00157 mole) of XI11 and 0.5 g. of sodium borohydride C, 75.64; H, 9.15. in 50 ml. of methanol was maintained a t 25" for 2 hr. The mix5a-Chloro-3p,6p-dihydroxypregnan-20-one 3-Acetate (XX).ture wts acidified with 5% hydrochloric acid and extracted with This compound was obtained from 24.0 g. of pregnenolone areether. The ether extract was washed with water until neutral tate by a procedure similar to that used for the preparation of I. and dried (sodium sulfate). Evaporation of the solvent afforded Crystallization of the crude product from aqueous ethanol gave 0.45 g. ( 9 0 8 ) of the crude product, m.p. 230-233". Recrystal10.8 g. (39Y0) of colorless crystals, m.p. 203-206'. Further lization from acetone-hexane gave the analytical sample, m.p. recrystalhation gave the analytical sample, m.p. 206-207" ~ (c0.5%in MeOH);: : A: 3.00p, no C=o 232-233"; [ a l Z 5-61" (inserted a t 200"); [01]25D +26" ( e 1% in CHCL); : :A: 2.98 band. 5.78, 5.88, and 8.13 p ; lit.19m.p. 196-197", [ a ] C H C 25.5". '3~ Anal. Calcd. for C40H3203: C, 74.96; H, 10.06. Found: Anal. Calcd. for C23H3,ClOa: C, 67.20; H, 8.58. Found: C, 74.70; H, 10.14. C, 66.91; H, 8.54. 3,17-Dioxoandrost-4-ene-19-nitrile(XV).-Crude X I (1.5 19-Oximino-5a-chloro-3p,6p-dihydroxypregnan-2O-one g.) u as chromatographed on alkaline alumina whereupon it 3-Acetate (XXI).-A solution of 7.0 g. (0.0159 mole) of the nitrite isomerized to the A4 diketone. From the 47, methanol in ether derived from YX in 200 nil. of toluene was irradiated for 2.0 hr. fractions there was obtained 0.9 g. (60%) of the product, m.p. a t 0". The fine precipitate of the insoluble 19-nitroso com182-184". Recrystallization from acetone-hexane gave the pound which formed during the photolysis was filtered and washed analytical sample, m.p. 184-185'; [ a ]25D $251' ( e lyOin CHC13); n i t h petroleum ether to afford 4.0 g. (577,) of nitroso compound. ~ ~ ~ : 4 . 5 0 , 5 , 7 5 , 5 . 9 5 , a n d 6 . 1 A",',9;"231p(~16,000). 4p; No exact melting point was observed owing to gradual isomerizaAnal. Calcd. for CI~HSXOL:C, 76.73; H, 7.80. Found: tion to the high melting oxime on heating. C, 76.94; H , 7.74. The crude nitroso compound was refluxed in 300 ml. of 2-pro3o.17~-Dihvdroxrandrost-4-ene-lS-nitrile (XVI).-A solution panol for 1 hr. The residue obtained from evaporation of the of 0.7 g. (0.00235 mole) of XV and 2.5 g. (0.0091 mole) of IiA1solvent was recrystallized from acetonitrile to furnish 3.1 g. ( ~ - B U O ) ~inH 50 ml. of tetrahydrofuran was maintained a t 0" for 45 min. After the addition of 100 ml. of 5% acetic acid, the (44%) of product, m.p. 223-226" (inserted a t 220'). Further recrystallization gave the analytical sample, m.p. 230-231 O ; product was extracted with ether, and the ether extract was [ a ]2 5 $16' ~ ( e 1% in CHCh); A":, 2.91,5.86, and 8.09 p . washed with 5% sodium bicarbonate solution and water and Anal. Calcd. for C23H34ClNOj: C, 62.77; H, 7.78; N,3.18. dried over sodium sulfate. Evaporation of the solvent gave 0.6 g. (SS',;) of colorless crystals, m.p. 24i-249". RecrystallizaFound: C, 62.83; H, 7.91; N, 3.58. 3~-Hydroxy-19-oximinopregn-5-ene-20-one 3-Acetate (XXII). tion from acetone-hexane gave the analytical sample, m.p. 248-A solution of 2.5 g. (0.00568 mole) of X S I in 50 rnl. of glacial 249'; [ a ] 2 5+106" ~ (c in methanol); : :A: 2.91, 3.02, and acetic acid (preheated to 85") n as treated with 5.0 g. of zinc dust 4.50 p. Anal. Calcd. for C1gH2iXO2: C, i5.71; H, 9.03. Found: in a manner similar to that described for the preparation of VI. There \Tas obtained 2.0 g. of crude product, n1.p. 153-158", C, i5.68; H , 9.15. nhich was recrystallized from aqueous methanol to yield 1.7 g. 17~-Hydroxy-3-oxoandrost-4-ene-lS-nitrile (XVII).-A solution of 0.3 g. (0,001 mole) of XV in 50 ml. of tetrahydrofuran mas (78%) of XXII, m.p. 160-165" (inserted a t 150"); [ C X ] ' ~ D-71' stirred with 1.5 g. of manganese dioxide a t 25" for 10 hr. The ( e 1% in CHCla);:!A: 3.04,5.78, and 5.90 p. manganese dioxide a as removed by filtration and washed with Anal. Calcd. for C23H18N04: C, 71.29; H, 8.58. Found: C, 71.19; H, 8.79. acetone. The residue from evaporation of the filtrate was crysPregn-5-en-3p-ol-20-one-lS-nitrile Acetate (XXIII).-A solutallized from aqueous ethanol to furnish 0.25 g. (837,) of crystals, m.p. 186-189'. Further recrystallization gave the analytical tion of 1.65 g. (0.00426 mole) of X X I I in 30 nil. of acetic anhydride was refluxed for 2 hr. and poured into 300 ml. of water. sample, m.p. 1S9-190°; [ a ] " D +178' (c 1% in CHCL); A":, The precipitate n a s filtered to aflord 1.5 g. (92%) of product, 3.06,4.50,5.9Siand 6.14 p ; A",;"." 232 mp ( E 14,500). Anal. Calcd. for C1gH&O2: C, 76.22; H, 8.42. Found: m.p. 140-1 42". Recrystallization from aqueous methanol gave C, 75.95; H , 8.58. ~ (c 17; in the analytical sample, m.p. 145-146'; [ a I z 5-92" CHC13); A":, 4.50, 5.80, and 7.98 p . 17~-Methyl-17~-hydroxy-3-oxoandrost-4-ene-lS-nitri~e (XVIIl).-A solution of 0.5 g. (0.00159 mole) of XI1 in 100 nil. of Anal. Calcd. for C23H81xo8: C, 74 76; H, 8.46. Found: acetone was treated with 0.75 ml. of 8 N chromic acid reagent as C, 74.61; H, 8.74. described in the preparation of 3,17-dioxoandrost-4-ene-19Pregn-5-en-3p-ol-20-one-19-nitrile (XXIV).-A solution of nitrile. The crude material was chromatographed on alkaline 1.3 g. (0.0398 mole) of X X I I I and 4.5 g. of potassium hydroxide alumina to give 0.28 g. ( 5 6 c , c )of S V I I I , m.p. 192-193" (from in SO ml. of methanol and 10 ml. of water was kept a t 27" for 81 frsctions of 2' , methanol-ether). The analytical smiple, rehr. The solvent wns concentrated nnd poured into nnter to
acid gax tlic esprcted ircrrt.diaxia1 9cu-Iiyvd1~1sy-11& chloro derivative (2f). TThcii a cliloroforin holutioii ol thiocyaiiic acid \\ :i+ added to tho 98,l lp-epoxide (1 1) ?, fractional cryhtallimtioii techniquez produced two addition products. ( ) i i tlic b a b i h ~ i spectral ' evidence oiie u a s assigiicd a\ tlict '3a-thiocyaiio-ll8-hydrosy derivative (2f), mid tlw otlier TI as tentatively azsigned as the ~~~-i~otliiocyaiio!)J,ll$-cposide (12). (1
I
o (
II
0 -
01
2
loa. X =Br
9
11
b, X - = F
OH
0H
&S&jfj& 14
i
6
::0
4
13 2a
F
NCS 12 +
18 n13
0 7
\
0
0
0
0
C1
Perbancoicp Acid 0
9
CLH50
succinimide
17
