2315
ERXEST~T-ENKERT
ASD
Compound IV and Acetyl Derivative.--.% mixture of 0.4 g. of the product from alkaline formaldehyde treatment of
11, 1.0 g. of IO$& palladium-charcoal catalyst, and 50 ml. of glacial acetic acid was shaken under hydrogen (40 lb ) a t SOo for 1 5 hours. Filtration of the catalyst and evaporation of the solvent gave glassy material which crystallized partly in t h e presence of methanol. Trituration with this solvent afforded 0.2 g. of colorless crystals, m.p. 227-230'. Recrystallization from methanol- ether gave pure material, 1n.n.230-232". A n d . Calcd. for Cn?Ha20s:C , 63.76; H, 5 . 3 5 . Found: C. 63.98; H , 5.40. dcetylation with refluxing acetic anhydride (2 hours), evaporation of excess reagent, and recrystallization from methanol gave colorless crystals, m , p . 17.5-17?1.5~. After
[COSTRIRUTIOS FROM
THE
TR.AVIS E. STEVESS
Ynl. 7 s
drying the material a t 80°, a hemihydrate was obtained. A n d . Calcd. for C24H?409.1/?H.'O:C, 61.93; H , 5.41. Found: C, 61.83; H , 5.39. After further drying a t 10llo, a weight loss of 1.45; (calcd.: 1 .9370) \vas detected, and anhydrous material was I Ihtained. Anal. Calcd. for CZ4H2,O9:C , 63.15; H , 5 3 0 . Found, C , 63.44; H, 5 . 2 5 . T h e infrared spectrum (chf.) had a n intense peak a t S.6.5-5.68 M . The ultraviolet spectrum (ethanol) had A,, 294 mp (log e 3 . 5 8 ) with a n inflection at 235 mG (log e 4.30' and a valley a t 281 mp (log E 3.56). and was in all respects very similar to the spectrum of compound RETIIESD.1
14,>ID.
DEPARTMENT O F CHEMISTRY, I O W A
STATE
COLLEGE]
Addition Reactions of 1-Methyl-2-naphthol with Unsaturated Ketones1 BY ERNESTI
T
v AND~ TRAL-IS ~ E. ~ STEVENS? ~ ~ ~
RECEIVEDSOVEMBER 17, 1955 The base- and acid-catalyzed addition reactions of methyl vinyl, methyl p-chlorovinyl a n d methyl ethynyl ketones with 1-methyl-2-naphthol are described. The structure and stereochemistry of the products are elucidated. A new synthetic route t o hydrophenanthrones is presented
X s part of their later total synthesis of the steroid nucle~is,~ Cornforth and Robinson introduced in 1 R 4 j 4 a simple, attractive method for the conversion of a naphthol derivative into a hydrophenanthrone. Formally this process involved a reduction followed by two alkylations I
side chain into 1-methyl-2-naphthol ( I ) came under consideration. L'arious cases of ortho-alkylation of phenols zsia their /3-addition to a,&unsaturated ketones are already on record. The acid-catalyzed version of this reaction is the usual synthetic route to benzopyrrylium salts, e.g., by the use of methyl O-chlorovinyli and methyl ethynyl ketones8
TYhile the introduction of only one alkyl group a t a time into the intermediate tetralone had caused some difiiculty a t first, this obstacle has been overcome by the utilization of a heterogeneous reaction processi and perhaps more interestingly by the prior transformation of the tetralone into its ene-aniine.fi In connection with a contemphted terpene and il or steroid synthesis it was of interest to ascertain whether the above reaction sequence could be reversed, i.e., the alkylations to precede the reduction. For this purpose the introduction of a butanone Base-catalyzed addition reactions, llichael reactions, have been reported also, e.g.9,10 ( I ) P a r t of this wurk was presented a t the Symposium on the Chemistry of S a t u r a l Products, Technion, Haifa, Israel June 28 -29, 1R.i.i. # , 2 ) Sational Science Foundation Predoctoral Fellon,, I9:,3 -1955 (3) H. h l . E. Cardwell, J . R' Cornforth, S . K. Duff, H . Holtermann
and R Robinson, J C h e m Sol-., 3(il (1933). '4) J . 11'. Cornforth a n d K Robinson, i b i d . , 1670 ( 1 9 4 f i ) . ( 5 ) C. A Grob and W.Jundt, IIPIB.Chin7 A c t a , 31, 1091 (1948,. (6) G. Stork, R. Terrell and J Szmuszkovicz, THISJ O U R N A L , 7 6 , 3024 ( I D % ) ; and private communicaton from Professor Stork.
17) A . N . Nesmeyanov, h ' . Kochetkov and M. Rybinskaya, Isvest. A k a d . Y a i r k . S.S S R , Otdel Khim. S a i c k . , 479 (1953) [C. A . , 48, in015 (1954)l; ~ ~ k A ki n i i ~. Y d~ K~ s..c ~ . R , 93, 71 (1953) IC. A , 4 9 , 3033 (19.55)]. ( 8 ) A. W Johnson and Itilled methq-1vinyl ketone in 35 ml. of anhydrous ether w a s :ttlded olution o: 1.9 g. of boron triether. Aftcr a n ll-lir. i)eri()(l ture \xis poured into a n iceure, the solution made d k a lutioii, iieutrali7ed with x c r acid and extracted with ether. The organic e s t r x t mashed with sodium bicarbonate qolution a r ~ dwater, d over magnesium sulfate and evanorated to a d:irk o i l . 'I'he lritter was e x t r x t e d six time? with XO-ml. portion; of reflusiiig petroleum etlier and the cooled, combinetl chromatographed on a Celite-silicic acid column. with petroleum ether-ether f l 9 : l ) gave 2.21 g . ( itartitig nanhthol, m , p . 110-111". From thc~7 : 1.33 g. 123qc) of the ketone I T I b , m.p. 102~-103",co?~ltibe obtained. Since further elution gave o d y oily m:rterial, it was taken up in 9: 1 netroleurn ether~-etherand c1irom:itogr:\phed on another Celite-Tilicic acid columTi. "lie 2: 1 eltiate yielded 60 mg. of ketone T-Ila, m.1).107-10X3, aftc.r recrystallization from petroleum ether. Rechrom itogy of the residneq on yet :inother column i~roclucctl0.1:4 . 2 ( c total yield) of :!dtlitio*l:rl k e t m e I.II.,, rn . I ) . 107 '
10X0.
With fi-Toluenesulfonic Arid Catalvst.-l-l~ctliyl-2naphthol (J.0 g . , 31.6 mmcile,) and methyl viil! 1 ketixic
-1Iay -30,1936
-1DDITION REACTIONS O F l-lfETHYL-2-N.%PHTHOL WITH
KETOXES
2323
(7.0 g., 0.10 mole) were added t o a solution of 5.5 g. of p - ether gave long white needles, m.p. 70-71O; spectra: infrared: C=O 1680 cm.-' (5); ultraviolet: A,,,. 215 m p (e toluenesulfonic acid hydrate in 80 ml. of glacial acetic acid. 21,600); A m i n . 240 mp (e 23,900). After shaking vigorously, the sohition was allowed to stand a t room temperature for 11 hr. The reaction mixture then A n a l . Cnlccl. for C,sI-rlr02: C, i9.62; €-I,6.24. Found: was poured into 500 ml. of water, partially neutralized with C, 79.47; H , fj.26. l o yo sodium bicarbonate solution and dried over magneIn Aqueous Methanol.-l-,l.etliyl-2-uaphthol (1 .O 9.1 sium sulfate, the chloroform was evaporated leaving a dark and 0.80 ml. of methyl 0-chlorovinyl ketone were added to oil. The latter was extracted with eight 100-ml. portions a cooled solution of 1.0 g. of sodium hydroxide in 15 ml. of of hot petroleum ether and the cooled, combined extracts water and 5 mi. of methanol. After 18 hr. a t room temperachromatographed on a Celite-silicic acid column. The 19: 1 ture the reaction was worked up in the same fashion a5 the petroleum ether-ether eluate gave 2.36 g. (47.270) of startt-butoxide run. However, a 967, recovery of only starting ing material, m.p. 110-11lo. The 9 : l fraction gave a naphthol could be made. yellow oil which solidified after trituration with petroleum In Dioxane.-Sodium 1-methyl-2-naphthoxide was preether, thus yielding 1.21 g. (18.3y0) of 4a-methyl-4,4a-dipared by dissolving a known amount of sodium hydroxide hydro-:! (3H)-phenanthrone (11) as hard yellow clusters in methanol and adding a n equimolar quantity of l-rnethylmelting a t 93-97'. Recrystallization from petroleum ether 2-naphthol to the methanolic solution. The salt, obtained produced pale yellow needles, m.p. 97-98'; spectra: infraby evaporation of the solvent under reduced pressure, was red: C=O 1655 cm.-' (s); ultraviolet: A, 242 mp ( E dried at 80" (1 mm.) for 2 hr. 16,800), 354 mp ( E 14,900). Methyl 8-chlorovinyl ketone (0.85 g., 8.1 mmoles) was Anal. Calcd. for CljH140: C, 86.68; H, 6.72. Found: added to 25 ml. of purified dioxane containing 1.20 g. (6.67 C, 85.67; H , 6.58. mmoles) of sodium 1-methyl-2-naphthoxide. After 10 hr. a t room temperature the red-colored reaction mixture was I t s purple, crystalline 2,4-dinitrophenylhydrazone was poured into 200 ml. of water, neutralized with acetic acid recrystallized from ethanol-ethyl acetate, m.p. 213-215" and extracted with chloroform. After being washed with dec. Anal. Calcd. for C21H1R04S4: C, 64.61; H , 4.6Fi; R', sodium bicarbonate solution and water, the organic extract was dried over magnesium sulfate and concentrated t o an 14.35. Found: C , 64.30; H, 5.06; N, 14.7. oily residue. A petroleum ether solution of the oil was chroThe 2 : l eluate yielded 0.19 g. of ketone VIIa, m.p. 107matographed on a Celite-silicic acid column. Elution with 108". The non-crystalline fractions were recombined in petroleum ether-ether (19: 1) gave 0.17 g. (1670) of starting petroleum ether and rechromatographed on Celite-silicic acid. However, the infrared spectra of the various eluates naphthol, while the 9: 1 eluate led to 0.84 g. (567c) of the still indicated incomplete separation. As a consequence butenone X, m.p. 68-70". The 5 : l eluate yielded a small amount of substance, m.p. 205-208' dec., which was not chromatography on alumina of a petroleum ether-benzene (1:l) solution of the again recombined fractions was at- investigated further. In Acetonitrile.-llethyl 8-chlorovinyl ketone (0.85 g., tempted. Elution with benzene and benzene-ether (1: 1) 8.1 mmoles) was added a t 40" t o a stirred mixture of 1.20 followed by fractional crystallization from petroleum ether g. (6.67 mmoles) of sodium 1-methyl-2-naphthoxide in 30 led t o an additional 0.48 g. (7.370) of ketone 11, m.p. 96ml. of acetonitrile. After warming for one hour, the solu9 i 0 , 0.13 g. of ketone VIIa, m.p. 105-106°, and 20 mg. of tion was heated to 70" for ten minutes. After a n additional ketone VIIb, m.p. 98-100' 9 hr. a t room temperature the reaction mixture was worked With Hydrochloric Acid Catalyst.-When a reaction beUP in the same manner as in the dioxane run; 0.16 g. (15%) tween methyl vinyl ketone and l-methyl-2-naphthol was of starting naphthol, 0.82 g. (5470) of X , m.p. 68-70', and carried out in absolute ethanol solution saturated with dry a trace of the 205-208' dec. substance ( c j . dioxane run) were hydrogen chloride gas under the same conditions as in the pisolated. toluenesulfonic acid run, 89.4y0 of starting naphthol was 4-(l-Methyl-2-naphthoxy)-2-butanone(XI) .-A mixture recovered and 6.57,of 4a-methyl-4,4a-dihydro-2(3H)-phen(XI of 500 mg. of 4-(l-methyl-2-naphthoxy)-3-buten-2-one anthrone (11) was produced. and 150 mg. of 5% palladium-on-charcoal catalyst in 25 ml. Base-catalyzed Equilibration of Ketones VIIa and VI1b.of ethyl acetate was hydrogenated a t atmospheric pressure Ketone VIIb (0.50 g., 2.2 mmoles) was added t o 20 ml. of and room temperature. Hydrogenation ceased spontaneabsolute ethanol, containing 2.2 mmoles of sodium ethoxide and the solution left standing a t loom temperature for 10 ously after the uptake of one mole of hydrogen a t the end of 3 hr. Filtration and evaporation of the solution gave a pale hr. The pale yellow mixture was poured into 100 ml. of yellow oil which on crystallization from petroleum ether was water, neutralized with acetic acid and extracted with transformed into white crystals, m.p. 45-47'. Chromatogchloroform. The extract was washed with water, dried raphy of a petroleum ether solution of the substance on a over magnesium sulfate and evaporated leaving a colorless Celite-silicic acid column produced 20 mg. of l-methyl-2oil. Chromatography of a petroleum ether solution of the naphthol, m.p. l l O - l l l o , from petroleum ether-ether oil on a Celite-silicic acid column led t o 195 mg. of starting (19: 1) elution and 4-( l-methyl-2-naphthoxy)-2-butanone ketone (L'IIb), m.p. 103-104", 011 elution with 4 : l petro( X I ) , m.p. 50-51°, from the 9 : l eluate. Two recrystallileum ether-ether and 290 mg. of its isomer VIIa, m.p. 107zations from petroleum ether yielded an analytical sample, logo, from further fractions. m.p. 31-52'; spectra: infrared: C=O 1710 cm.-' (s); When 0.50 g. of VIIa was treated in like manner, it was ultraviolet: A, 230 mM (e 69,000), 282 mp (e 52001, 322 converted t o a mixture of 185 mg. of VIIb, m.p. 103-104", mp (c 17001, 335 mp ( E 1700). and 290 mg. of starting material, m.p. 107-108'. Anal. Calcd. for ClsHlo02: C, 78.82; H , 7.07. Found: Reactions of Methyl P-Chlorovinyl Ketone and I-MethylC, 78.90; H , 7.07. 2-naphthol. In t-Butyl Alcohol.-l-Methyl-2-naphthol (5.00 g., 01.6 mmoles) and methyl /3-chlorovinyl ketone (3.50 g., Base-catalyzed Reactions of XI. A . With Methanolic 35.0 mmoles) were added t o 75 ml. of a cooled t-butyl alcohol Hydroxide.-Five hundred milligrams of the naphthoxysolution wherein 1.50 g. (38.4 mmoles) of potassium had butanone X I was added to a mixture of 0.75 g. of sodium been dissolved and the red solution left a t room temperature hydroxide in 5 mi. of water and 50 ml. of methanol. The for 8 hr. It then was poured into 300 ml. of water, neusolution was refluxed in a nitrogen atmosphere for 2 hr., tralized with acetic acid and extracted with chloroform. cooled, poured into 200 ml. of w,iter and the aqueous solution The extract was washed with sodium bicarbonate solution neutralized with acetic acid and extracted with chloroform. and water, dried over magnesium sulfate and evaporated The organic extract was washed with sodium bicarbonate under reduced pressure leaving a dark oil. After extraction solution and water and evaporated to dryness. A benzene of the oil by five 80-ml. portions of hot petroleum ether, the solution of the residue yielded 0.34 g. (987,) of l-methyl-2combined, cooled extract was chromatographed on a Celitenaphthol, m.p. 109-11Oo, after filtration through a short silicic acid column. Elution with petroleum ether-ether alumina column and usual work-up. ( 3 2 : l ) gave 2.16 g. (437,) of starting material, m . p . 110B. With Potassium t-Butoxide.-One milliliter of t111'. Further elution ( 1 9 : l ) yielded 2.49 g. (34.8%) of 4butyl alcohol in which 8.6 mg. of potassium had been dis(l-methyl-2-naphthoxy)-3-buten-2-one(X), m.p. 68-70". solved was added to a solution of 500 mg. of XI in 10 ml. of On rechromatography and similar elution of several of the t-butyl alcohol. The pale yellow mixture was left standing oily fractions a n additional 0.19 g. (3.8%) of starting napha t room temperature with occasional shaking for 15 hr., thol and 0.58 g. (8.17c)of the ketone X, m.p. 68-70', were after which time i t was poured into 100 ml. of water, neuobtained. Recrystallization of the product from petroleum tralized with acetic acid and extracted with chloroform.
2324
ERNEST WENKERTAND TRAVIS E. STEVENS
Vol. 78
4a-Methyl-4,4a,9,lO-tetrahydro-Z (3H)-phenanthrone (XV).-The ketol XIV (200 mg.) was added t o 25 nil. ?f dry benzeiie containing 100 mg. of p-toluenewlfoIlic acid hydrate and 200 mg. of calcium chloride. Tlie solution was heated at 50" for 30 minutes and then allowed t o cool and stand a t room temperature with occa,>ionalshaking for an additional hour. The mixture was washed with sodium bicarbonate solution and water, dried over maguesium sulfate and evaporated t o dryness. A petroleum ether-benzene ( 1 : l ) solution of the residue was filtered through a short alumina column to give 170 mg. of white crystals, m.p. 88-90", which on two recrystallizations from petroleum ether turned into white prisms, m.p. 89-90'; spectm: infrared: C=O 1665 ern.-' (s); ultraviolet: Xmsx 239 m p (e 18,000). Anal. Calcd. for ClbH160: C, 81.86; H , 7.60. Found: C, 84.56; H, 7.42. I t s bright red, plate-like 2,4-dinitrophenylhydrazone, m.p. 203-204', did not depress the m.p. of the same derivative of ketol XI\'. trans-4a-Methyl-3,4,4a,9,10,10a-hexahydro-2 (1H)-phenanthrone IXVI).-A solution of 200 mg. of ketone XV in 20 ml. of dry ether was added t o a solition of 100 mg. of lithium in 100 ml. of liquid ammonia. After thirty minutes 2.0 g. of ammonium chloride was added and the ammonia nllmed t o evaporate. The residue was taken up in chloroform-water and the aqueous layer washed with chloroform. The combined organic extrncts were washed with dilute hydrochloric acid, sodium bicarbonate solution and watcr and the chloroform removed by evaporation. A benzenepetroleum ether (3:2) solution of the solid residue was chromatographed on alumina. Elution of the column with the same solvent pair gave 140 mg. of trans-4a-methyl-3,4,4a,9,10,10a-hexahydro-2(lH)-phenanthrone(XVI), m.p. 104- 106'. Recrptallization from petroleum ether yielded plites, m.p. 107-108'; spectra: infrared: C=O 1710 ern.-' (s) ; ultraviolet: , , ,A, 265 m p ( e 400) ; Amin. 240 mp (e 200). Anal. C d c d . for CI6Hl80: C, 84.06; H , 8.46. Found: C, 84.05; H , 8.58. I t s sernicarbazone crystallized from aqueous ethanol :IS white platelets, m.p. 220-221' dec. Anal. Calcd. for Cl&2101V3: C, 70.81; H , 7.80; N, 15.49. Found: C, 70.72; H, 7.76; N,15.5. The orange p-nitrophenylhydrazone was recrystallized from ethanol, m.p. 178-180' dec. Anal. Calcd. for C2,Hz3O2Na:C, 72.18; H , 6.63; N, 12.03. Found: C, 71.97; H , 6.34; X, 11.9. Catalytic Hydrogenations of Enones 11, XI1 and XV. A . Reduction of 11.-A mixture of 800 mg. of ketone 11 and 200 mg. of 553 palladium-on-charcoal in 40 ml. of 95!a ethanol was hydrogenated at 740 mm. and 25'. Hydrogen absorption ceased after 8 hr. and a n uptake of two moles of Hz. After removal of the catalyst by filtration and evaporation of the filtrate, a petroleum ether solution of the oily residue was chromatographed on alumina. Elution with petroleum ether-benzene (3: 1) gave a clear oil, while continued elution with increasing quantities of benzene gave a solid fraction, which on recrystallization from petroleum Admixture ether yielded 90 mg. of crystals, m.p. 104-106'. of this compound with trans-ketone XVI (m.p. 107-108') gave m.p. 108-107', and its infrared spectrum proved to he superimposable on t h a t of XVI. 4a-Methyl-lOa-hydroxy-3,4,4a,9,lO,l0a-hexahydro-2T h e oil, from the first and major fractions of the chiomato(1H)-phenanthrone (XIV).-A mixture of 200 mg. of kegram, was rechromatographed on alumina again yielding tone X I I I , 50 mg. of 5y0 palladium-on-charcoal catalyst an oil, whose infrared spectrum had the same carbonyl b:md in 20 ml. of 95% ethanol was hydrogenated a t atmospheric as XVI but was otherwise distinctly different from X V I . pressure and room temperature. The hydrogen abcorption This substance, consequently cis-4a-methyl-3,4,4a,9,1~,10awas complete a t the end of 1 hr. and a two-mole uptake. hexahydra-2(1H)-phenanthrone (XVII), could not be inThe solution was filtered and the ethanol evaporated under duced to crystallize at room temperature although it bccame reduced pressure, leaving a white residue, m.p. 153-157". Two recrystallizations from petroleum ether-benzene gave crystalline a t - 10'. Its semicarbazone crystallized from aqueous ethanol as white prisms, m.p. 157-158'; spectra: infrared: OH 3380 cm.-' (m); C=O 1705 ern.-' (s); ultraviolet: Aman 265 sparkling white platelets, m.p. 195-187' dec., mixed m.p. with the derivative of XVI 199-201' dec. with preliminary m p ( e 400). Anal. Calcd. for ClSH1802: C, 78.22; €1, 7.88. Found: darkening. Anal. Calcd. for CleH210N3:C, 70.81; H , 7.80; N, C, 77.97; H, 7.71. 15.49. Found: C, 70.86; H, 7.90; N, 15.4. It yielded a bright red 2,4-dinitrophenylhydrazonewhich I t s yellow p-nitrophenylhydrazone was recrystallized from crystallized as plates from ethanol-ethyl acetate, m.p. 204aqueous ethanol, m . p . 148-150' dec. 205' dec . Anal. Calcd. for C2,HZ302K'3:C, 72.18; H, 6.63; N, Anal. Calcd. for C ~ I H ? O O ~ N C,~ :64.27; H , 5.14; K, 12.03. Found: C, 71.78; H, 6.73; X, 12.3. 14.28. Found: C, 64.16; H , 5.10; N, 14.4.
After a bicarbonate and water washing and drying over magnesium sulfate, the organic extract was evaporated to an oil which on petroleum ether extraction left a small gummy residue. 011crystallizatioii from 95>6 ethanol, the latter yielded 20 mg. of white cry\tals, m.p. 236-238", whose mixed m.p. with VI11 (n1.p. 2-14-243') was 241-242', and whose iufrarcd spectrum characterized it as V I I I . The petroleum ether extract was chromatographed on Celitesilicic acid column and eluted with petroleum ether-ether. The 1 9 : l eluate gave 160 mg. of 1-methyl-2-naphtho1, m.p. 110-11l0, the 9 : l eluate gave 85 mg. of diketone of VIIb, m.p. 102-103", and the 4 : l fraction 135 mg. of diketone VIIa, m.p. 106-107". The Reaction of Methyl Ethynyl Ketone and 1-Methyl2-naphthol.-l-Methyl-2-naphthol (5.00 g., 31.6 mmoles) was added t o 60 ml. of t-butyl alcohol in which 0.13 g. ( 3 . 3 mmoles) of potassium had been dissolved. After cooling the solution t o 15", 2.40 g. (35.4 mmoles) of 3-butyn-%one was added under a nitrogen atmosphere and the mixture allowed t o stand, with occasional shaking, for 24 hr. a t room temperature; 250 ml. of water then was added, the aqueous mixture neutralized with acetic acid arid extracted with chloroform. The extract was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated, leaving a dark, tarry residue. Extraction of the t a r with five 80-ml. portions of petroleum ether left a dark, solid residue. The extracts were chromatographed on Celite-silicic acid and eluted with petroleum etherether. T h e 3 2 : l eluate contaitAed 1.27 g. (25.47,) of starting naphthol, m.p. 110-111 the 1 9 : l fraction had 1.80 g. (25.4%) of ketone X, m.p. 68-70", the 4 : l eluate gave a yellow oil and the 2 : 1 fraction produced 1.67 g. of 4a-methyl-lOa-hydroxy-4a, lOa-dihydro-2( lH)-phenanthrone ( X I I I ) , m.p. 131-133'. Recrystallization of this substance from petroleum ether-benzene gave white crystals, m.p. 132-134'; spectra: infrared: O H 3340 cm.-' (w), C=O 1675 cm.-l (s); ultraviolet: A,, 222 m p (c 28,000), 264 m p ( E 7500). Anal. Calcd. for C16HI4O2:C, 79.62; H , 6.24. Found: C, 79.99; H, 6.26. Its deep purple 2,4-dinitrophenylhydrazonewas recry.;tallized from ethanol-ethyl acetate, m.p. 202-203" dec. Anal. Calcd. for CuHlsOaS4: C, 64.94; H, 4.313; S , 14.43. Found: (2,6492; H,4.13; S , 14.7. % \he'n a n ethanol solution of the dark reuidue from the initial petroleum ether extraction was put on a short charcoal-Celite column and eluted with ethanol-ethyl acetate, an additional 0.21 g. (2,5.6yc total yield) of X I I I , m.p. 131133', was obtained. A petroleum ether-benzene solution of the yellow oil from the silicic acid chromatogram was chromatograplied on alumina. Elution with benzene yielded 300 mg. of a pale yellow oil which even on rechromatography on alumina did not change its physical characteriqtics. It would crystallize on standing overnight a t - loo, but would revert t o an oil on warming t o 5 " . It gave a deep purple 2,4-dinitrophenylhydrazone, m.o. 194-196' dec., mixed m.p. with the derivative (m.p. 202-203" dec.) of XI11 194-196" dec. The oil, thus 4a-methyl-2(4aH)-phenanthrone(XII), may have been contaminated with some other wbstance in view of the formation of a smnll amount of orange crystals along with the purple hydrazone. ~
THE20-EPIMER
May 20, 1956
OF THE
B. Reduction of XI1.-A mixture of 260 mg. of trienone XI1 and 100 mg. of 5y0 palladium-on-charcoal catalyst in 15 ml. of ethanol was hydrogenated at atmospheric pressure and room temperature. Hydrogen absorption corresponding to three moles was complete in 10 hr. After filtration and evaporation of the solution, a petroleum ether solution of the residue was chromatographed on alumina. Elution with petroleum ether-benzene (3:2) gave 120 mg. of an oil whose infrared spectrum was identical t o t h a t of ketone XVII. I t s semicarbazone melted a t 193-195' and did not depress the melting point of the same derivative of X V I I . Further elution of the column yielded oils whose infrared spectra indicated them to be mixtures of XVI and X V I I . C. Reduction of XV.-A mixture of 200 mg. of monoenone X V and 100 mg. of 5% palladium-on-charcoal catalyst ethanol was hydrogenated a t 740 mm. and in 25 ml. of 25 . Hydrogen absorption ceased after 1 hr. and an uptake corresponding to the reduction of one double bond. The solution was filtered and evaporated and a petroleum ether solution of the residual oil chromatographed on alumina. Ten fractions were eluted using 2 : 1 petroleum ether-benzene and 1 : 1 solvent pair. Their infrared spectra indicated the contents to be mainly XL7I mixed with about 10% XVI. A combination of the first two fractions was converted t o a semicarbazone, which after two recrystallizations from aqueous ethanol melted at 195-197' dec. S o depression was observed in the melting point on admixture with authentic semicarbazone of X V I I . &-4a-Methyl-3,4,4a, loa-tetrahydro-2 (1H)-phenanthrone (XX) .-A solution containing 1.50 g. of hydrophenanthrone XV and 3.5 ml. of ethylene glycol in 150 ml. of benzene was distilled until 120 ml. of solution remained. After the addition of 40 mg. of p-toluenesulfonic acid hydrate and the attachment of a water separator, the solution was refluxed and stirred for 4 hr. The cooled mixture was washed Kith sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated, leaving a thick oil. I t s infrared spectrum indicated the abyence of any ketone. As a consequence the oily ketal was used in the next reaction without further purification. I t s ultraviolet spectrum exhibited a maximum at 265 mp ( e 400). One gram of the ketal was added to 50 ml. of ethylene glycol containing 2.0 g. of potassium hydroxide and the solution heated under a nitrogen atmosphere at 190" for 5 hr. The cooled mixture then was poured into 250 ml. of water, neutralized with acetic acid, filtered and both residue and fil-
[CONTRIBUTION FROM
THE
C Z 2 - LFROM ~ ~TICOGENIN ~ ~ ~ ~
2326
trate extracted with chloroform. The organic extracts were washed with sodium bicarbonate and water, dried over magnesium sulfate and evaporated. T h e residue was dissolved in 60 ml. of 95yo ethanol containing 10 ml. of 10% sulfuric acid and refluxed on a steam-bath for 1 hr. The cooled reaction mixture was poured into 250 ml. of water and extracted with chloroform. The latter was washed with sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. A benzene-petroleum ether (3:2) solution of the organic residue was chromatographed on alumina and eluted by the same solvent pair. The infrared spectra of the first fractions showed the presence of a considerable amount of unhydrolyzed ketal, as a consequence of which they were recombined and again put into 10 ml. of 10% sulfuric acid and 40 ml. of 957, ethanol and refluxed on a steam-bath for 1 hr. The resulting hydrolysate, combined with the remaining eluates of the chromatogram, was rechromatographed on alumina and reeluted as a petroleum ether-benzene (1: 1) solution. A reaction product of 125 mg of 4a-methyl-3,4,4aI 1Oa-t et rahydro2(1H)-phenanthrone, m.p. 65-67', was obtained, which on two recrystallizations from petroleum ether gavc white plates, m.p. 68-69'; spectra: infrared: C=O 1710 em.-' (s); ultraviolet: A, 287 mp (e 9800); A m i n , 234 mp (e3000). Anal. Calcd. for C1&1160: C, 84.86; H , 7.60.' Found: C, 84.87, 84.36; H, 8.01, 7.61. Further elution of the column with benzene gave a trace of product whose infrared spectrum was identical with t h a t of starting ketone XV. Reduction of XX.-A mixture of 55 mrc. of ketone X X , 20 mg. of palladium-on-charcoal catalyst in-15 ml. of 95% ethanol was hydrogenated a t atmospheric pressure and room temperature. Hydrogen absorption ceased spontaneously a t the end of 45 minutes and a one-mole uptake. T h e solution was filtered and evaporated in a stream of nitrogen. The infrared spectrum of the residue was identical with that of XVII. A benzene solution of the residue was filtered through a short alumina column. The infrared spectrum of the benzene eluate was identical with t h a t of the crude residue. The oil was converted t o a semicarbazone, which melted at 191-193" dec. after one recrystallization from ethanol. I t s mixed melting point with an authentic semicarbazone of XVII was 192-194" dec. The infrared spectra of the two semicarbazones were identical. AYES, IOWA
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DEPARTMENTS OF MEDICINEA N D OF BIOCHEMISTRY, WESTERNRESERVEUNIVERSITY, AND LAKESIDEHOSPITAL]
THE
The 20-Epimer of the C,,-Lactone from Tigogenin' BY JOHN W. CORCORAN AND H. HIRSCHMANN RECEIVEDNOVEMBER 5, 1955
3~,16~-Dihydroxy-20-iso-bisnorallocholanic 22+16-lactone has been prepared. The parent acid lactonized upon acetylation a t room temperature. The resulting acetoxy lactone XI opened its lactone ring less readily than the 20-epimer which, however, has the energetically preferred structure. The results are interpreted in terms of steric repulsion of the (2-18 and C-21 methyl groups. This concept is useful for assigning configurations at C-20 provided the stability of both isomers can be compared.
Several years ago2in a study of the rates of methanolysis of some steroids carrying acetoxy groups in the 16- and 20-positions an anomaly was encountered which seemed explicable on the following assumption: the space adjacent to the angular methyl group a t C-13 is too restricted to readily accommodate bulky substituents of C-20 and, there( 1 ) T h e data in this paper have been taken from a thesis presented by John W. Corcoran to the Graduate School of Western Reserve University in partial fulfillment of the requirements for the degree of Doctor of Philosophy. T h e investigation was supported by a grant from the National Cancer Institute of the National Institutes of Health, U. S. Public Health Service. (2) H. Hirschmann and F. B. Hirschmann, J. B i d . Chem.. 184, 259 (1950).
fore, those conformations are preferred which place the hydrogen rather than the methyl group a t C-20 next to the methyl a t C-13. One would expect to observe the inff uence of such methyl-methyl interference on chemical behavior most readily if the rotation around the C-17 to C-20 bond is prevented by ring closure,' as the two stereoisomers a t C-20 might show differential stability. A good case for such a study would result if C-20 and C-16 were joined in a 5-membered ring on the &side of the molecule since this situation produces in the models of one of the stereoisomers (Ia) a very close approach of the two methyl groups, (2-18 and C-21. Several investigators have applied this concept of
