A. L. W E D S AND CARL DJERASSI
1712 [CoVTRIBUTION
FROM THE
LABORATORY OF ORGANIC CHEMISTRY OF
Vol. 68 UNIVERSITY OF WISCONSIX]
THE
The Preparation and Partial Aromatization of 1,4-Cholestadienone-3by the DienonePhenol Rearrangementi BY
L. \LrILDS
AND CARL nJER.\SSI's3
Inhoffen and ~ o - w o r k e r s reported ~,~ that the unsaturated ketone l14-cholestadienoiie-:S ( I ) underwent re;irrangenient to an isomeric phenol, with niigratioii of the angular iiiethpl group a t C10, when tre:,ittd with sulfuric acid and acetic aiihyclride at roo'!iiteiiipcrature. 'lliey assigned to this product thc structure IIa, by a t ialogy to the rtsarraiigeincnt of smtoiiin io tlesniotrol)osaiitoiiiii.i~ In coniic~ctioiiwith siniilar rructioiis i i i the ;IIIdrostaiie series,5s7js wc have I i a t l occasiori t o rc.l)eat and confirin this work. Sul)stantial iiiiprovcbments in the experinieiital I)rocetlures were tleveloprd for preparing the dieiione I froin cholestanone via the 2,4-dibroiiio derivative 111, :uid for its tra~isfonnatio~i into the isoiiieric phenol I I a . In the dehydrobroriiiiiatioii of 111 by nieaiis of collidine, the dieiione I ww accompanied by a crystalline by-product. This was shown to be a 1:1 molecular compound of l,l-cholestadienone-3 ( I) and ~,~i-c_holestadienone-3 from the ultraviolet absorption spectrum aiid by comparison with material prepared from the two pure dienones. The pure 4,li-cholestadienone-3 could be prepared in 415% yield by applying to cholesterol the unusual inodijication of the Oppenauer oxidation
IIa R = H IIb R = CHI
discovered by n ' e t t ~ t e i n ,employing ~ quinone and aluininuiii f-butoxide."' Oxidation of the methyl ether IIb with nitric wit1 was carried out with the hope of obtaining ;,-tiieth(~xyherizi.ti~,1,",:(-tricarboxylic. acid, or a iiitro tlerivative, frotii ring *,I. Instead benzeneI ,?,:{! &tetr:icarl)osylic acid (IV) was isolated (as the tetrariiethylester) arising frorii ring I{ which TWS aroiriatized i i i thr prc I I 'I'reatineiit of 1111 with boiling rilkalirie 11 riganate, a procedure which \ w s successhi for preparing the desired iiiethosy acid from ~-rnetho\cy-~,(i-tliiiiethyll~enzaltlehytle,I" gave almost no reaction with IIb. The isolation of the tetracarboxylic acid V would appear to eliiriitiate from coiisideration a possible (though less probable) structure for the phenol having a seven-membered ring B, and supports formula ITa. The extension of the dienone-phenol rearrangement to a somewhat analogous chrysene tferivative, where the structures of both the dienone and the rearrangement product were established by synthesis, affords further support for the course of the rearrangement. This is reported in an accompanying cornmunication.13
Experimentall 4 Cholestanol-3 and Cnolestanone-3. - I~~~!!owiiig tlie procalul-e of I)urlaiitl,16:](I g. of cholestcrol (purified by refluxing iii alcohol for tiveiity-four hour.; with Kancy nickel catalyst atid recrystallizing), 75 cc. of aiihvilrous ether and 8 g. of a special Raiiey iiickcl catalyst'6 270-cc. botiib at 100' and a hydrogen pr 11). per sq. iii. for about fifteen hours. Th tcst portions of which gave only a faiiit LieiiermannI~iirchartltest,'7 were combined, cetitrifugctl t o rvniove the c:italyst, coiiceiitratetl and crystallized from alcohol. -1total of i 2 g. (SO';) of cholestanol \vas obtaiiietl, iii. p. 142-113 (reported's 152-143 "). Using the method described by Bruce,1g the cholestanol was oxidized to cholcstanone in 82yo yield, m . p. 129129.,5 2,4-Dibromocholestanone-3 (111).2G-A sinal1 amount I I ~ - % cr.) of a solution of 26.4 g. of bromine in 165 cc. of O
@ .
IIOOC
COOIi I COOH
(!I)
\Yetistein, l i d ; , C
iiiiii.A c t a .
23, 388 (1940).
( I l l ) 'l'his affurds a simpler method of preparation t h a n th;il of
Br -
111
Dane, \Yang and Schulte, Z . p h y s t o l . Chem., 249, 87 (1!>37). (11) 'The theoretical possibility of this acid arising from ring C seems improbable t o u a . (12) '1'0 lie reported in i i icpar:ite cominnnicatioii. , I:$) \\.ilds :$nil l)]erd\\i ' T I I I S J O I I K N A I . . 68, 1716 il!l I(',). 1 I I) :Ill rncltirr; p o i n t 5 a r t currrcteil. I l . > j 1 . 1.: Durl;tii i ii,i the 5trricturc 5 . c ~Ht>tc-i:an of the calculated quantity. The excess collidine r a s removed by distillation under reduced pressure, the residue was extracted with ether, washed with water, dilute hydrochloric acid, dilute potassium hydroxide and dried over sodium sulfate. iifter removal of t h e ether t h e rc:sidual oil, which showed little tendency t o crystallize, nas digest::d thoroughly with boiling methanol and the la.tter decanted from 0.73 g. of a black, insoluble oil, which still contained stinie bromine. The methanol-soluble fraction (111g.1 \\.as dissolved in petroleum ether (b. p. 411-60"J antl adsorbed on a column of 150-200 g. of alumina.22 Th: material was then fractionally eluted using the free-flox method (no suction) with 100-cc. portions of petroleum ether, petroleum ether-benzene (in the ratios 5 , 50 GO, 25,'75), benzene, benzene-ether (75/25, 0, 25:73'i, ether and finally acetone. A given solvent isture was used as long as a n appreciable amount of niaterial was found to be removed. Crystalline material was usually obtained from all fractions up t o benzeneel her (30/50). T h e melting point varied from 84-10Oo for the first fractions 1.0 as high as 103-111' for the later ones; the total amount of crystalline material was 7.7-8.0 g. (73-765 ). Recrystallization from methanol (Sorit) -,53';) of material satisfactory for subthe i n . 1). varied in different runs from -111 '. Concentration of the filtrate c i ) , in. 1). 68-87" and about 0.85 g. m . p . i ? - . f i Y ', n.hich is shown below t o contain 4,6cliolestadici~oiie-~~ as well as the l,.l-isonier. B y aromatizatioii with sulfuric acid in acetic anhydride this material tratcs ivcre found t o contain a n additional 1,4-isi)nier, iiiclicating thc total yield t o be nl satiiple was obtained t y recrystallization from methanol as colorless stout prisms, m . p . 110-112", jcuj?4.% ,3l .* 1.3" (10.2 mg. in 1.3 cc. of chloroform), Inhoffe11~~ I-eportcrl in. p. 111.5-112.5", [ a r I 2 a 28.1' (chloroform 1 , xrhila- 13utenandtz1reported m. p. 108-110 O,
+
+
DIENONE-PHENOL REARRANGEMENT
1713
[ C Y ] ~ ~f D 31 '. T h e absorption spectrum,24measured in absolute alcohol solution, exhibited a single maximum at 245 mp (log E = 4.15). This is in agreement with t h a t reported by DannenbergZ5a for Inhoffen's sample (236 mp, log E = 4.20 in ether) since it has been found, in general, t h a t the maximum of a,O-unsaturated ketoiies is shifted by about G mp t o higher wave lengths in going from ether toalcohol solutions.2s d n a l . Calcd. for CrrHa?O: C, 84.8; H , 11.1. Found: C,81.8; 85.0; H, 11.0; 11.2. Variations in the above procedure, especially in the time and temperature, gave yields which were poorer or uiichanged. \Vheri the amount of collidine was increased to 1 ,?i cc. per gram of dibromo ketone, rathcr than 4 cc. per gi-am, t h c tcntleiicy for rearrangement to the 4,ti-cholestatliciioiie-3 was increased, anti t h c yield of the pure 1,4isomer wasreduced t o l(ic;. Identification of the By-product from the Dehydrobromination.-The low melting fractions from several runs (in. p. 68-87")were combined and recrystallized from dilute acetone, yic!dirig clusters of needles with the in. p . (j!--fi8" anti [ a ] % 3%' (10.1 mg. iii 2 cc. of chloroforni). Atiwrptioii of 90 nig. of this material on aluniiiia2* and e!utioii gave the following fractions: Fraction .I (petroleum ether-benzene, 50/50), 30 rug., n i . p. (X-68': after one recrystallization from dilute methaiiol this yielded 23 mg. of crystals of m. p. 68.5-70", [ ~ z I * ? D f 31 * 0.3" (11.8mg. in 2 c c . of chloroform). The ahsorption spectrum, taken in absolute alcohol solution arid shown iii Fig. 1, exhibited a maximum at 383 mp (log E = 4.15) and a long plateau a t 212-258 mi*. The spectrum resembled t h a t of a synthetic sample of the 1 : l molecular compound of 1,4-cholestadienone-3 arid 4,Ocholestadienone-3. A mixed n1.p. of the synthetic sample (m.p. 68.5-70") with t h a t isolated above showed no depression. The material retained solvent rather tenaciously and was dried at 45' (0.2 mm.) for twenty hours before analysis. Anal. Calcd. for C27H120: C, 84.8; H, 11.1. Found: C,85.0; H,11.1. Fraction B (petroleum ether-benzene, 30 7 0 t o 10,'90) weighed 25 mg. and after recrystallization yielded 10 mg. m . p. 77-92', T h e absorption spectrum (Fig. 1 ) indicated i t to be richer in the 1,4-isomer than the rnolecular coinpound from Fraction A . Fraction C (benzene and benzciie-ether, 80/20) weighed 13 mg. and gave 5 mg. of thc iiearly pure 1,4-isoiner. m. p . 103-107 ' (see Fig. 1). 4,6-Cholestadienone-3.-The following procedure is based on t h a t of Wettsteiu for preparing 6-dehydrotestosterone b e n ~ o a t e . ~A solution of 2 g. of cholesterol and 12 g. of quinone in 120 cc. of dry toluene was conceiitrated under reduced pressure t o 100 cc., 2 g. of aluminum t-butoxide Tyas added and the mixture refluxed for fortyfive minutes. T h e solution was then cooled, diluted with water and steam distilled (1.5 1. of distillate). The black residual mixture was cooled in ice, 100 cc. of 1 S sulfuric acid addcd and the niisturc was extracted thoroughly with ether. The ethcr was waqhed six times with tiilutc, w l furic acid and six times with water. Then 5yh potassiuin hydroxide was added without shakiitg (to avoid a troublesome emulsion) and the black aqueous layer was separated. This treatment with alkali was repeated until the ether layer was light red, and then it was washed thoroughly b y shaking with alkali until no more color was rcruoved from the solution (now yellow). After washing w i t h n a t e r and drying over sodium sulfate the ether was removed. The residual reddish oil, which did not crystallize, was adsorbed from petroleum ether (b. p. 40-6OC) on 40 g. of
+
(24) T h e absorption spectra measurements were made using a
(31) I3utrninil1, LI:iinoli, I)anncnl)rrg, RIasch a n d Paland, B e y . , 73, 1617 ( I Y B O ) . (22) .4luminum C i t m j i a n y of America, grade F-20, minus 80tuesh. i S 3 i InholTcu aud IIuang-Alioluu, U c v . , 71, IT20 (1938); 72, 1680 (1'13CJ).
Beckman quartz photoelectric spectrophotometer; E =
1 C
log
Io
-
I
for a 1-cm. cell, where c is t h e concentration in mules per liter (2.5) (a) Dannenberg, A b h a n d l . pvezzAc. A k a d . TZ'iis.. .kfatlz,.voL. Klmre, no. 21 (11130); (1,) hVoodward, THIS J C J U R N I I . , 63, 1123 ( 1 V-ll).
A. L. WILDSAND CARLDJERASSI
1714
t
Vol. 68
hydride was cooled t o room temperature and a solution of 0.1-0.2 g. of concentrated sulfuric acid in 1 cc. of acetic anhydride was added dropwise. The dark green solution was allowed t o stand at room temperature for three hours, 0.1 g. of sulfuric acid in 0.5 cc. of acetic anhydride added and allowed to stand for another hour. The mixture was poured slowly with stirring into 20 cc. of ice-cold 45y0 aqueous potassium hydroxide solution, extracted with ether, and the oily residue left after evaporation of t h e ether was hydrolyzed b y refluxing for fifty minutes with 2 cc. of 45% potassium hydroxide and 15 cc. of methanol, Diiution with water and scratching gave 0.44 g. (88%) of the colorless phenol, m. p. 143-145". Recrystallization from petroleum ether (b. p. 40-60 ") raised the m. p. of t h e . colorless needles to 145.5-146", [ C X ] ~ ~ J D 161 * 1' (10.9 mg. in 1.2 cc. of chloroform). Inhoffen and Ziihlstiorff5 reported 145-146". T h e phenol could be chromatographed on alumina and eluted with benzene or benzeneether. With less pure cholestadienone (m. p. 98-107 ") the yield of the pure phenol was 7 4 4 3 % . Even when non-crystalline mixtures were used the crystalline phenol was readily isolated.
l
4.2
+
3.9 13
3.6
220
3-Methoxy-l-methyl-IO-norcholestatriene-l,3,!5 (IIb).
260
210
280
300
X, m p .
Fig. 1.-Ultraviolet absorption spectra (in- absolute alcohol): curve S, synthetic sample of molecular compound of 1,4-cholestadienone-3 and 4,6-chloestadienone-3; curve T, theoretical curve (1:l ratio) for the molecular compound; curve A , fraction A of chromatogram of the by-product frcmm the preparation of I; curve 13, fraction B of by-product;, curve C, fraction C of by-product. alumina.22 The first eluates, using 200 cc. of petroleum ether-benzene (70/30) and 200 CC. of a 50/50 mixture of these solvents, contained only 40 mg. of a n oil and were discarded. The product was then eluted with 500 cc. of petroleum ether-benzene (35/65), 300 cc. of benzene and finally benzene-ether (200 cc. of 80/20 and 100 cc. of 60/40). The total amount of material obtained by evaporation was 0.751 to 8.82 g. (36-41%), in. p. 78-80". Recrystallization from methanol gave needles with the m. p. 80.5-81.5", [ C Y ] ~ ~ D33" (10.8 mg. in 2 cc. of chloroform). The absorption spectrum in absolute alcohol showed a singli: maximum a t 284 rnp (log E = 4.42) arid a miiiimum a t 221 mp (log E = 3.33). The physical coristants reported previously are: m . p. 83",'0 80-81 O f @ . 79.5-81""; [ c x ] ~ ~+33.4,2@ D 35 =t2 O Z 7 (chloroform); max: 285 mp in alcohol (log E = 4.4) .26 The molecular compound, prepared by recrystallizing 100 mg each of the 4,6- and 1,4-isomers from methanol containing a few drops of water, crystallized as clusters of needles, in. p. 68.5-iOo, [ a ] * + D -t 33 * 0.2" (8.5 mg. in 2 cc. of chloroform); see Fig. 1 for the absorption spcctrum. Anal. Fourid: C, 8.4.3; H, 11.0. 3-Hydroxy-l-methyl-lO-norcholestatriene-l,3,5 (IIa) .When the procedure of Inhoffen, el a1.,5 was used, t h e product was oily, due t o incomplete hydrolysis of t h e intermediate acetate. The following procedure was found t o be more reliable. A solution of 0.5 g. of 1,4-cholestadienone (m. p. 106-110") in 12.5 cc. of warm acetic au-
+
(26) Bergstrom and Wintersteiner, J . Biol. Chcm., 143, 503 (1942); Winterstcinet and Ruigh. THISJOURNAL. 64, 2463 (1942). (27) Hwdegger, Ruzicka and Tagmann, Elelv. Chim. A d a , 26, 2217 (1943).
(a) From the Phenol 1Ia.-A warm solution of 0.5 g. of the phenol (m. p. 143-145') in 17 cc. of alcohol was treated alternately with 1.8cc. of sodium hydroxide solution (6 g. in 10 cc. of water) and 2.5 cc. of dimethyl sulfate, and t h e process was repeated four times. After standing for fifteen minutes the solution was diluted, cooled in ice, filtered and the product dried; yield 0.48 g. (93%), m. p. 103.5-105 '. Recrystallization of a sample from alcohol ~ gave colorless prisms, m. p. 104.5-105", [ a I z 4 +165 =t 0.2" (9.7 mg. in 2 cc. of chloroform); reported5 m. p. 103-105".
(b) From 2,4-Dibromocholestanone-3 (111) without
Isolation of Intermediates.-A solution of 8 g. of the dibromo ketone I11 in 35 cc. of collidine was heated at reflux for eighty minutes and the mixture worked up as before. The methanol-soluble oil (4.8 g.) was not chromatographed b u t was aromatized directly by treating a solution iu 100 cc. of acetic anhydride with 2.3-2.5 g. of concentrated sulfuric acid in 14 cc. of acetic anhydride. After standing for four hours, the mixture was hydrolyzed with methanolic alkali and the crude phenol isolated as before (2.94 g . , or 527, yield, m . p. 13-1-138"). Methylation of this material in 100 cc. of warm alcohol with five portions each of 11 cc. of sodium hydroxide solution (36 g. in 60 cc. of water) and 15 CC. of dimethyl sulfate (cooling when the reaction became too vigorous), gave 2.37 g. (41% overall yield) of t h e methyl ether, ni. p. 101-103", with sintering a t 98". One recrystallization from alcohol (using Torit) gave 1.i4 g. (30%) of material of m . p. 104-105" and 0.26 g. (47,) of m.p. 97-100O. Although the over-all yield by method ( b ) was not quite as high for material of comparable purity as by the longer procedure of chromatographic separation and isolation of t h e unsaturated ketone I, the procedure was less time-consuming. Nitric Acid Oxidation of the Methyl Ether 1Ib.--A mixture of 400 mg. of the methyl ether (m. p. 104-105°), 3 cc. of concentrated nitric acid and 8 cc. of watcr was heated in a sealed tube at 190" for twenty-four hours. The clear yellow solution was evaporated to dryness, water was added and evaporated, and the process repeated with water and then methanol. The product was dried in a vacuum desiccator (weight 80 mg., melting point indefinite), treated with a n excess of ethercai diazomethane (from 1 g. of iiitrosomethj.lurea), alloved to stand for a day and t h e methylation repeated. T h e ether was evaporated and the product dissolved iii acetone, filtered and crystallized from petroleum ether (b. p. 60-ti8') containing a few drops of acetone t o give 71 rng. (t237c yield) of crystals melting at 118-126.5' (sint. a t 113'). Sublimation a t 120-140° and 0.15 min. and two recrystallizations gave 40 mg. (13%) of colorless needles, m. p. 129-130°, of t h e tetramethyl ester of benzene-1,2,3,4-tetracarboxylic acid. A mixed m. p. with a n authentic sample (in. p. 130-131'; kindly furnished by Dr. W. S. Johnson) prepared by oxi-
Sept., 103-G
3-HYDROXY-1-METHYLCHRYSENE
dation of l-ketotetrahydrophenanthrene2* showed no depression (rn.p. 129.5-130.5"). Anal. Calcd. for Cl4Hl4Os: C, 54.3; €1, 4.5. Found: C , 54.0; H, 4.9.
Summary
The synthesis of 1,4-cholestadienone-3 (I) and (2qj Johii56,n . ~ n d(::,ldman
[(:OVTRIBUTION
'l'iirs
J
