September 1966
KOTES
783
tional activities with the same activities of the corresponding 7-demethyl homologs. The ketones I1 (R = H ; R1 = H and C2H5; R 2 = CH3jwere made through the cuprous chloride catalyzed addition of methylmagnesium bromide to the respective gonadienones I (R = COCH3; R 1 = H and CzH5) (cf. ref 2 and 3 ) , which were obtained from the corresponding gon-4-en-3-ones by Zderic and eo-workers' general method.5 The a configuration is assigned to the 7-methyl group by analogy with the formation of 17pacetoxy-7a-methylestr-4-en-3-one from 17P-acetoxyestra-4,6-dien-3-one by the same procedure. The ketone 11, (R = R' = H ; R 2 = CH3) was obtained directly from the Grignard addition reaction with I (R = COCH,; R1 = H), presumably because of ester hydrolysis under the acid work-up. A similar treatment of I (R = COCH3; R' = C2HJ, however, gave the acetate I1 (R = COCH,; R' = C2Hs; R 2 = CH3j, from which the corresponding 17/3-01 was obtained by reduction with lithium aluminum hydride in ether, followed by manganese dioxide oxidation in chloroform. Application of an analogous sequence to the preparation of the ketone I1 (R = H ; R1 = C=CH; R2 = CH3) was less efficient, and this compound was best obtained from the ketone I1 (R = R1= H ; RZ = CH3) by conversion to the 3-ethylene ketal, oxidation of the 17-hydroxyl to a 17-carbonyl group, interaction with lithium acetylide, and acid hydrolysis of the resulting ethynyl alcohol.
( 3 g) was refluxed in acetic anhydride-acetyl chloride-pyridine (45:24:2.4 ml) for 3 hr. The solvents were evaporated under reduced pressure and the residue was partitioned between water and benzeneether. The organic solution was washed, dried, and evaporated, and the residue was triturated with hot ether to give crude (f)-3,17p-diacetoxy-l3p-ethylgona-3,5-diene (3.125 g), 238 mp ( e 19,500). N-Bromosuccinimide mp 148-156', A,, (0.5 g) was added to the foregoing diacetate (1 g) in acetonewater-acetic acid (106: 27.2: 2.72 ml) containing pyridine (0.6 ml) and sodium acetate (2.72 g) a t 0", and the mixture was stirred for 3 hr at -5 to +5", added to ice-cold brine (800 ml), and extracted with ether. The ether solution was washed, dried, and concentrated below 15". Calcium carbonate (3 g) and dimethylformamide (70 ml) were added, the remaining ether wah distilled, and the suspenqion refluxed for 1 hr. The mixture wai filtered, the residue was washed with ether, the filtrate and washings were combined and added to brine, and the mixture was extracted with ether. Recrystallization of the product from ethvl acetate-hexane gave the dienone (0.475 -a ) , mp - 163-166', Am&; 283 mp (e 24,370): Anal. Calcd for C21H2803: C, 76.8: H,8.6. Found: C,76.5; H. 8.6. ( f)-13p-Ethyl-17p-hydroxy-7a-methylgon-4-en-3-one (11, R = R1 = H ; R2 = CHI).-The foregoing gonadienone (2 g) in tetrahydrofuran ( T H F ) (20 ml) was added to ethereal methylmagnesium bromide (3 M)-THF (16:20 ml) containing cuprous chloride (0.3 g ) a t 0". The mixture was stirred for 20 min and poured into ice-cold brine containing HC1. The product was collected with ether, chromatographed on neut,ral alumina, and recryst,allized from et,hyl acetate-hexane to give the gonenone 242 mp (E 16,730). (0.56 g), mp 152-154", A,, Anal. Calcd for C20H3002: C, 79.4; H, 10.0. Found: C, 79.1; €I, 9.9. 3,17p-Diacetoxy-13p,l7~-diethylgona-3,5-diene.-l3~, 17a-Diethyl-17p-hydroxygon-4-en-3-one4(3 g) was refluxed for 2 hr in acetic anhydride-acetyl chloride-pyridine (48:24:2.4 ml). The solvents were removed under reduced pressure and the residue OR nR was partitioned between benzene-ether and water. The product from the organic layer was triturated with et,her and washed with hexane to give the diacetate (3.5 g), mp 122-125", A,, 238 mp (e 18,200). Anal. Calcd for C2:H3804: C, 75.0; H, 9.1. Found: C, 74.6; H, 9.1. ( =k)-17p-Acetoxy-13p,l7~-diethylgona-4,6-dien-3-one (I, R = COCHa; R1 = CzH6).-N-Bromosuccinimide (3.4 g) was added I I1 with stirring to the foregoing diacetate (3.4 g) in acetone-water (130: 16 ml) containing sodium acetate (2.4 g) a t 0". The mixture Biological Activities.-Androgenic and anabolic acwas stirred a t 0" for 3 hr, poured into ice-cold brine, and extivities werc estimated by the Hershberger test,6 arid tracted with ether. The et,her solution was concentrated below progestational activities by the Clauberg test.' 20". Calcium carbonate (10 g) and dimethylformamide (235 ml) were added, the ether was distilled, and the remaining suspension TABLEI refluxed for 1 hr. The product was chromatographed on neut,ral alumina and recrystallized from ether to give the gonadienone BIOLOGICAL !xCTIVITIES OF 282 mp (e 28,700). (1.6 g), mp 151-153", A,, ( ~ ) - ~ ~ ~ ~ - ~ T H Y I . - ~ ~ ~ - H Y U R o X Y G O N(11, - ~ - E= N -I~I )- 0 ~ ~ ~ Anal. Calcd for C23H3203: C, 77.5; H, 9.05. Found: C, 77.1; nl R2 Anah'" Andh ProgC H, 9.05. CH, 300 60 7 H ( & )-17p-Acetoxy-13p,l7~-diethyl-7~-methylgon-4-en-3-one (11, R = COCH,; R1 = C2H6; R2 = CHI).-The foregoing dienone 70 50 C H, 48 CzHs (1 g) in T H F (10 ml) was added under nitrogen with stirring to 26 20 CH, 27 C=CH ethereal methylmagnesium bromide (3 M)-THF (8: 10 ml) H H 54 27 3 containing cuprous chloride (0.2 g ) a t 0". The mixture was 17 300 H 350 CzH6 stirred for 1 hr, poured into brine containing HCl, and extracted H 70 8 915 C-CH with ether. The product, was chromatographed on neutral Anabolic potency expressed in terms of testost,erone propioalumina and recrystallized from ether-hexane to give the gonenone iiat,e ( = 100). Androgenic pot,ency expressed i n t,ermsof t,estos(0.25 g), mp 142-144', Amax 242 mp ( e 18,250). Progestat,ional potency expressed terone propionate ( = 100). Anal. Calcd for C24H3.$03: C, 77.4; H, 9.7. Found: C, 7 . 4 : in tmermsof progest,erone ( = 100). H, 9.7. ( i)-13p,17~-Diethyl-17p-hydroxy-7a-methylgon-4-en-3-one (11, R = H; R1 = C2H6; R2 = CHs).-The foregoing acetate Experimental Section8 (0.49 g ) was refluxed with LiA1H4 (0.4 g) in ether (60 ml) for 1.5 hr. Saturated aqueous tartaric acid (40 ml) was added to the ( =k)-17p-Acetoxy-l3p-ethylgona-4,6-dien-3-one (I, R = COCH3 ; R1 = H).-( f)-13p-Ethyl-17p-hydroxygon-4-en-3-one4 cooled solution. The product in chloroform (50 ml) was stirred at room temperature with MnOz (2.5 g) for 3 hr. Recrystalliza( 5 ) J. A. Zderic. A. Bowers, H . Carpio, and C. Djerassi, J . Am. Chem. tion of the product from ether gave the keto1 (0.11 g), mp 130Soc., 80, 2596 (1958). 132', Amax 244 mp (e 16,500). (6) L. G . Hershberger, h;. (;, Stuvlry, iiiid H . l i , h l v h e r , I ' m c . S W . E l p t f . d r ~ u I . Calcd for C,,H,,O,.: (', 79.95; H , 10.4. Foiitid: (:, H i d . .Mr,/., 83, 175 ( I Y . 5 3 ) . 7 ! ) . S ; 11, 10.2. (TI R. L. Elton and R. A. Edgren, E n d o c r i n o l o g y , 63,464 (1958). ( 8 ) Melting points were determined in capillary tubes (Thomas-Hoover apparatus) and are uncorrected. Ultraviolet absorption spectra were recorded in 9570 ethanol.
( =k )-13p-Ethyl-17a-ethynyl-l7p-hydroxy-7~-methylgon-4-en-
%-one (11, R = H ; R' I1 ( R = R 1 = H; R2
= =
C r C H ; R2 = CHs).-The gonenone CH3) (1.35 g) was refluxed for 6 hr ill
