\'()I.
5220 [CONTRIBUTION FROM
THE
DANIELSIEPF RESEARCHIIUSTITUTE,
TIIE l%rEIZ31ANN
so
INSTITUTE OF SCICXCE]
Synthesis and Reactions of Ring A Methylated Saturated Steroids1 BY I'EHUDA *VAZUR AND
FR-4NZ
SONDHEIMER
RECEIVED MARCH31, 1958 Methylation of cholestan-3-one (I) gives niainly 2a-tnethylcholestan-3-one (11) or 2,2-dimethylcholestan-3-one (1111, depending on conditions. 2a-Methylcholestan-3-one (11) also can be obtained from I through conversion to the ethoxyoxalate IV, methylation and base treatment. The same sequence with A4-cholesten-3-one (V) produces 2a-methyl-A'cholesten-3-one (VII), which on reduction with lithium in ammonia is converted to a mixture of 2~-methylcholestan-3-one (11) and 2a-methylcholestan-38-01 (VIIIa). Catalytic hydrogenation of VI1 leads to a mixture of 2a-methylcholestan-3one (11) and 28-methylcoprostan-3-one (X). Lithium aluminum hydride reduction of the ketones 11,411 and X yields 2amethylcholestan-P8-o1 (VIIIa), 2,2-diinetli~-lcholestan-3~-ol(IXal and 2~-methylcoprostan-3a-ol(XIa), respectively. Bromination of 2a-methylcholestan-3-one (11) gives 2a-inethyl-2,8-bromocholestan-3-one (XIIL) which can be dehydrobrominated t o 2-methyl-AI-cholestan-3-one (XIV). Catalytic hydrogenation of the latter yields 2,9-methyl-cholestan-3one (XV), isomerized t o the Za-isomer I1 with acids. Bromination of 2~-methylcoprostan-3-one(X, appears t o take place at. C-2 as well as at C-4 and after dehydrobroinination a mixture of 2-niethyl-A1-coprosten-3-one (XVIII) and Za-methylA4-cholesten-3-one (VII) is obtained in which the former predominates. Reduction of 4-methyl-A'-cholesten-3-one (XIX) with lithium in ammonia produces 4a-meth~lcholestai1-3-one (XX). Catalytic hydrogenation of X I X leads to a mixture of 48-methylcholestan-3-one ( X X I ) (epitnerized to X X with acids), 4a-methylcholestan-3-one (XX) and 40-methylcoprostan-3-one ( X X I I ) . Reduction of the ketones XX, XXVII and X X I I yields 4a-methylcholestan-3~-ol (XXVIa), 4,4-dimethylcholestan-33-ol (XXVIIIa) and 48-methytcoprostan-3a-01 ( X X X I I I a ) , respectYvely. Enol acetylation of 4a-methylcholestan-3-one (XX) leads t o the acetate X X I X , wnich on bromination is converted to 2a-brorno-4a-metliylcholestan-3-one ( X X X ) and then by dehydrobrvmination t o 4a-methyl-A1-cholesten-3-one ( x x x r j . Coprostan-3-one ( X X X I I ) on methylation furnishes maiilly 49-methylcoprostan-3-one ( X X I I ) which on successive bromination and dehydrobrornination yields 4-methyl-A4-cholesten-3-one (XIX). T h e infrared spectra and molecular rotations of some of the methylated steroids are tabulated and various aspects of the data are discussed.
Citrostadienol, a substance isolated from citrus oil in these laboratories, showed properties which indicated i t to be a ring A methyl-3B-hydroxy steroid.2 It was mainly in this connection that we became interested in preparing and studying the properties of ring A methylated steroids. We have already reported on the synthesis of 4-methylA4-3-keto steroids.3 In the present paper we describe the preparation of the various 2- and 4methylated saturated 3-keto and 3-hydroxy steroids of the cholestane and coprostane series. A study also has been made of certain reactioiis of these compounds in order to determine whether the extra alkyl substituents change the normal course of such reactions. When our work was started nearly three years ago, no hydroaroniatic steroid with additional alkyl groups a t C-2 or a t C-4 had been described, excepting for the 4,4-dimethyl steroids; the numerous naturally occurring tetracyclic triterpenes (4,4,li-trimethyl steroids) are to be included in this class and 4,4-dimethyl steroids lacking the 14-methyl group had been prepared in connection with the synthesis of lanosterol. LVhile the work described in this paper was in progress, a number of other research groups reported on the synthesis of various 2- and 4-methylated steroids as will be int1ic:ttetl later where relevant to our own work. The direct methylation of cholestan-3-one (1) with methyl iodide and 1.4 molar equivalents of potassium t-butoxide in boiling t-butyl alcohol after 3 minutes yielded mainly 2a-methylcholestan-3-one (11), m.p. 120". The structural assigi-
ment rests on the independent methods by which the same substance was prepared subsequently, on its behavior on bromination (see below) and on its stability toward both acids and bases. The reaction also produced smaller amounts of 2,2-dimethylcholestan-3-one (III), m.p. 113", which proved to be the major product when the alkylation was carried out for a longer time with a large excess of potassium t-butoxide and methyl i ~ d i d e . ~ The structure I11 follows from the analogous dimethylation of other 3-keto-5a-steroids as described recentlyS6 The monomethylation a t C-2 of cholestan-3-one (I) could alternatively be brought about by the sodium hydride catalyzed condensation of I with ethyl oxalate to give the 2-ethoxyoxalate IV, which on being methylated with methyl iodide over potassium carbonate in boiling acetone and then treated with sodium ethoxide in boiling ethanol, yielded the same 2a-methylcholestan-3one (11) as had been obtained directly. The corresponding reaction in the androstane series has been reported.6 The direct monomethylation of A4-cholesten-3one (V) a t C-4 previously has been described by US.^ hlethylatiori a t C-2 could be brought about by subjecting V to the sequence involving ethoxyoxalation (to give VI), and then methylation and treatment with sodium ethoxide.6 The analogous reactioii has been carried out with other A'-% ketone^.^,^ This method of methylation was found to proceed rather better in the unsaturated than in the saturated series. The resulting 2a-methylA4-cholesten-3-one (VII), m.p. 127", showed es-
(1) Presented in part (a) a t the 1'3th Meeting of t h e Cliemical Society of Israel, Rehovoth, June, 1956 ( B u l f . Resmrch Coz6?fcI'lIsrael, SA, 283 (1956)) and (b) a t the 16th International Congress o f Pure and Applied Chemistry, Paris, July, 1957 (Congress Eandbook, Division of Organic Chemistry, p. 263). (2) Cf. Y.Mazur, A. Weizmann and F. Sondheimer, THISJ O U R N A L , 80, 1007 (1958). (3) F. Sondheimer and Y .Mazur ibid., 79, 2906 (1957). (1) Cf. R. B. \\'oodward. A . A. Patchett, D. 13. R . Barton. D A . J. [ y e s arhl R. B. Keliy,ibid. 76, 2 8 5 2 (1934); J . Chei,:. Cnc , 1 Ii31 (165;).
( Z ) While this manuscript was in preparation, M. Moiisseron, .'1 Winteruitz and A C. de Paulet (Cornfit. rend., 246, 1859 (1957)) in :L preliminary cominunicatiou independently reported on t h e direct methylation of uholestan-3-one ( I ) to give I1 and 111. These workers also described the conversion of A'-cholesten-3-one ( I r )wiu t h e ethoxyoxalate V I t o t h e 2a-methyl compound VII. (fl) H. J. Ringold and G. Rosenkranz, J. O Y X . C h c ~ n . ,2 1 , 13A3 ( 1956).
(7)
I.
A . Hogg F. 13. l.mco111, I, R = Ac
* I J
I
I XXI
XXVII
J XSIX
XIX
5223
XXXIIIa, R = H b, R = 4 c
\ T I XXII
T 13r..& .,
xxx
XXXI
XXXII
drogen from the P-side) exactly parallels the hydrogenation results obtained with the analogous tricyclic unsaturated ketone XXIV1s and with santonin (XXV).l9 The failure to obtain the isomer X X I I I probably is due t o the fact that the steric crowding of the axial 4a-methyl group in a 5P-compound such as X X I I I is so severe as to preo.\c vent the formation or isolation without epimerii .o.\c zation of this substance.1° P\ / \.' The lithium aluminum hydride reduction of 4amethylcholestan-3-one (XX) proceeded normally and yielded mainly 4~~-methylcholestan-3P-ol (XXVIa), m.p. 164", precipitated by digitonin. Similarly, the previously described 4,4-dimethylcholestan-3-one (XXVII)17 produced mainly the corresponding 30-01 XXVIIIa,21 m.p. 1 5 8 O , also (see below). Further elution of the column pro- precipitated with digitonin. The enol acetylation of 4cu-methylcholestan-3duced a mixture of 4a- and 4p-methylcholestan-3one, which could not be resolved into its compo- one (XX) also proceeded as in the unmethylated nents but was converted on acid treatment smoothly series. Thus, isopropenyl acetate and sulfuric acid to the pure 4a-methyl isomer XX. The axial 4p- yielded an enol acetate, m.p. 104', which on treatmethyl isomer X X I was found to be stable under ment with bromine in acetic acid and pyridine12 the chromatography conditions used and the 4a- produced a bromo ketone, m.p. l l O o , dehydrobromethylcholestan-3-one (XX) must therefore have minated by lithium chloride-dirnethylf~rmamide~~ been formed directly in the hydrogenation. The to an unsaturated ketone, m.p. 83". The latter catalytic hydrogenation of 4-methyl-A*-cholesten- differed from 4-methyl-A4-cholestene-3-one (XIX), 3-one (XIX) to give all of the possible isomers with and the observed ultraviolet maximum a t 230 mp the exception of 4a-methylcoprostan-3-one (XXIII) (log E 3.98) showed it to be 4a-methyl-A'-cholesten(to be expected formally from cis addition of hy- %one (XXXI). The enol acetate is therefore
methylcholestan-3-one (XX) by means of sulfuric acid in ethan01.l~ Chromatography of the hydrogenation product after removal of the crystalline X X I yielded 10% of 4P-methylcoprostan-3-one (XXII), m.p. 5 7 O , the structure of which rests on its identity with X X I I prepared from coprostan-3-one
,'
(17) After completion of these syntheses of t h e 4-methylated ketones XX and XXI (4.footnote l a ) , J. L. Beton, T.G. Halsall, E. R . H. Jones and P. C. Phillips ( J . Chem. Soc., 763 (19571) reported independent preparations by different methods of the same substances with physical properties in excellent agreement with ours. Moreover G. D. hfeakins and 0. R . Rodig (;bid., 4679 (1956)) described t h e lithium-ammonia reduction of 4-methyl-A4-cholesten-3-one (XIX) to 4u-methylcholestan-3-one (XX), the same saturated ketone also being obtained in poor yield by t h e catalytic hydrogenation of XIX over platinum i n acetic a c i d and sultseqnent chromic acid oxidation.
(18) R . B . Woodward, F. Sondheimer, D. T a u b , K. Heusler and W. M. McLamore, THISJOURNAL, 7 4 , 4223 (1952). (19) J. C. Banerji, D. X. R. Barton and R. C. Cookson, J. Chcm. Soc., 5041 (1957), and reference cited there. (20) It is of interest t h a t in t h e santonin series the isomer corresponding to X X I I I has now been obtained (footnote 19), though not by hydrogenation of santonin. (211 H. J. Ringold and G . Rosenkranz ( J . Org. Chcm., 2 2 , 602 (19571) have carried out the analogous reduction (with sodium borohydride) in the androstane series.
4a-methyl-Az-cholesten-3-ol acetate (XXIX) and TABLE I the bromo ketone is 2a-bromo-4a-methylcholestan- CARBONYL STRETCHING FREQUENCIES OF SATURATED 2- A N D 3-one (XXX). The equatorial nature of the bromo 4-METHYL-3-KETO-STEROIDS(IN CSt SOLUTION) substituent in the latter is indicated by the position Frequency, cm. -' Compound of the infrared carbonyl band a t 1733 Cholestan-3-one (I) 1715 which further confirms that bromination had oc- 2a-Methylcholestan-3-one (11) 1711 curred a t C-2 and not a t C-4. 2~-Methylcholestan-3-onc (XV) 1711 Treatment of coprostan-3-one (XXXII) with 4a-Methylcholestan-3-one (XX) 1709 methyl iodide and potassium t-butoxide in t- 4~-Methylcliolestan-3-one( X X I ) 1708 butyl alcohol resulted mainly in methylation a t 2 2-Dimethylcholestan-3-one (111) 1702 C-4. Chromatographic purification gave 40% of 4,4-Dirnrthylcholestan-3-onc(XXVII) 1703 a non-crystalline product consisting largely of 43- Lanostan-3-one 170425b methylcoprostan-3-one (XXII). The pure ketone, 2,2,4,4-Tetramethy1cholestan-3-one 169825b m p. 59", could be oblained through conversion to Coprostan-3-one ( X X X I I ) 1713 the seinicarbazone, m.p. 205", and regeneration 2P-Methylcoprostan-3-one (X) 1709 with pyruvic acid.22 Alternatively the non-crys- 4 , ~ - h ~ e r h ~ ~ ~ c o p r o s l a n -(3X- oXnIeI ) 1709 talline ketone X X I I was reduced with lithium uluminum hydride to give mainly 46-methylcopro- equatorial one causes a considerable increase in the stan-3a-ol (XXXIIIa), the extra methyl group a t carbonyl frequency.I3 Our observations are in . , ~ ~ C-3. not affecting the normal course of reduction. agreement with the report by Lukes, et C Z ~ that The small 3p-01 fraction was renioved as the in- introduction of an equatorial methyl substituent soluble digitonide and acetylation then yielded pure a t C-2 in the ketone XXXIV causes a ca. 8 cm.-' 4B-methylcoprostan-3a-01 acetate (XXXIIIb) , decrease in the carbonyl frequency, but not with the m.p. 89". Saponification regenerated the alcohol XXXIIIa, m.p. 1 5 7 O , which on chromic acid ouidation produced the crystalline ketone XXII. The latter could not be epimerized and the methyl group is therefore assigned the equatorial B-configuration. That monomethylation has occurred a t C-4 follows from the fact that X X I I had been obtained as a minor product from the hydrogenation of 4-methyl-A4-cholesten-3-one (XIX). More- fact that introduction of an axial methyl group a t over the reverse process could be brought about. C-2 results in a ca. 14 cm.-l increase. No generThus, direct bromination of 4/?-methylcoprostan-3- alizations can therefore be based on the latter one (XXII) with bromine in acetic acid yielded an phenomenon which must be due to special factors. Introduction of a gem-dimethyl group a t C-2 or amorphous 4-bromo-ketone which on treatment with lithium chloride in boiling dimethylformam- a t C-4 of cholestan-3-one causes a carbonyl freideI5 produced the same 4-methyl-A4-cholesten-3- quency decrease of cu. I2 cin.-l as is also observed (lanostanone (XIX) as described p r e ~ i o u s l y . ~Alternatively with 4,4,14a-trimethylcholestan-3-one 3-one) and the pentacyclic triterpene ketones conthe unsaturated ketone X I X could be obtained by converting 4P-methylcoprostan-3-one (XXII) to taining the 4,4-dimethyl-3-one systern.?ja This its enol acetate, brominating the latter with bromine effect caused by dimethylation a t C-4 has been in pyridine and acetic acid12 and finally dehydro- discussed recently by Curnmins and Pagezbbwho brominating the resulting bromo ketone as before. further reported that the carbonyl frequency of the This incidentally completes a third route3 to 4- hitherto undescribed fully methylated 2,2,4,4methyl-A4-3-ketones,the starting material being the tetramethylcholestan-%one is lowered by cu. 17 corresponding saturated 3-ketone of the 53-con- crn.-l as compared with the urimethylated compound. figuration. In the A4-3-ketone series, the introduction of a In Table I the inhared carbonyl stretching fremethyl group a t C-2 or a t C-4 also results in a lowerquencies are recorded for the various saturated 2and 4-methylated &ketosteroids described in this ing of the carbonyl frequency. Thus the values paper. I n the cholestane series it can be seen that (measured in carbon tetrachloride) for A4-cholesintroduction of one methyl group in the 2- or the ten-3-one (V), 2cu-methyl-A4-cholesten-3-one (VII) 4cr-rnethyl-A4-cholesten-3-one (XIX) are 1675, 4-position causes a decrease of about 5 an.-', ir- and 1671 and 1669 em.-', respectively. Of interest also respective of whether the methyl group is in the axial or in the equatorial configuration. Similarly in the infrared spectra of the a,p-unsaturated kein the coprostane series, introduction of an equa- tones is the fact that whereas the comparatively torial methyl group a t C-2 or a t C-4 lowers the small double bond band in the 1620 cm.-' regionz6 in the A4-3-ketones V, VI1 and X I X is well-defined, carbonyl frequency, the decrease being ca. 4 cm.-'. it is so weak and badly-defined in the A1-3-ketones An analogous effect has been observed by CherrierZ3for a-alkylcyclohexanones. The influence of XIV, XVIII and XXXI when measured under our 0-monomethylation on the infrared spectrum of conditions31as to be hardly recognizable. ( 2 4 ) R. M. Lukes, G. I. Pow, R,E. Beyler. W. F. Johns and I-. H. saturated ketones is in contrast to a-halogenation i b i d . , 75, 1707 (1953). where an axial substituent has little effect while an Sarett, ( 2 6 ) (a) Cf. A . R. H. Cole and D. W. Thornton, J . Chcm. SOC., r
( 2 2 ) Cf.E B Hershberg. J . Org. Chem , 13, 542 (1948). (23) C Cherrier, Com,hl i , p n d , 225, 1063 (1917), see a!so IT Con ' 5 orid R A Firrstonc ' r m J O L Y A A L , '18, 2290 (1956)
1007 (1956); (b) E. G. Cummins and J . E. Page, i b i d . , 3847 (1967). ( 2 6 ) Cf.R. N. Jones, P. Humphries, E. Packard and K . Dobriner, J O U R N A L , 78, SG (1050).
TIIIS
RINGA METHYLATED SATURATED STEROIDS
Oct. 5, 19rjS
In Table I1 the molecular rotations of the various saturated 2- and 4-methylated derivatives of cholestan-3P-01 and coprostan-3a-01 are recorded TABLE I1 MOLECULARROTATION DATA
SATURATED 2-
OF
4-METHYL-3-HYnROXY-STEROIDS AND (IN
Compound
THEIR ACETATES
[i?f]DoAo
+
AI
AAia
Cholestan-38-01 8gZQb 6OZQb - 29 0 2a-Methylcholestan38-01 (VIIIa) 32 -147 -179 -150 2,2-Dimethylcholestan38-01 (IXa) +129 87 - 42 13 .la-Methy lcholestan38-01 (XXVIa) +lo9 +I82 73 +lo2 4,4-Dimethylcholestan38-01 (XXVILIa) 87 f 41 70 46 4,4,14a-Trimethylcholestan-38-01‘ +151’ +194b 43 72 Coprostan-30-01 +12429b +20629b 82 0 28-Met hylcoprostan3a-01(Xla) 4-100 4-346 +246 +164 48-Methylcoprostan3a-01 (XXXIIIa) 60 27 - 33 -115 A& refers to the difference in AI between the inethylated and the unmethylated compound. * \V. Voser, M . Montavoii, H. H. Giinthard, 0. Jeger and L . Ruzicka, Helu. China. Acta, 33, 1893 (1950). Lanostan-3P-01.
+
-
+
+
+
+
+
+
in methanol.** It is of interest to note that whereas there is no appreciable solvent effect with 2amethyl- and 4a-methylcholestan-3-onecontaining TABLE 111 SOLVENTEFFECT ON THE SPECIFICROTATIONS OF EQUATORIAL A N D AXIAL ~ - ~ / I E T H Y L KETONES Compound
CHCL)
[MIDOH
+ +
AND
+ +
+
and compared with those of the corresponding acetates. It has been observed previously that the shift in molecular rotation caused by acetylating the 3P-hydroxy group is generally negative with saturated steroids and positive with triterpenes and this fact has proved to be of value in distinguishing between the two classes of compounds.27 Klyne and Stokes27bhave attributed this reversal to the presence of the 4,4-dimethyl group in the triterpenes and have pointed out that the observed direction of the shift in the triterpenes (positive when a 38-01 is acetylated, negative when a 3ar-01 is acetylated) is as expected from their known absolute configuration. The direction of the shift in molecular rotation (AI) observed on acetylating the methylated alcohols in Table I1 likewise is in keeping with expectation. Thus in the case of the 30-hydroxy compounds, the AI values of the 2methyl and 2,2-dimethyl derivatives are more negative than that of the unmethylated 3p-01, while the AI values of the 4-methyl and 4,4-dimethyl derivatives are more positive. Conversely in the 3a-hydroxy series, the A1 value of the 2methyl compound is more positive than that of the unmethylated 3a-01 and the AI of the 4-methyl compound is more negative. The fact that the monomethyl alcohols exhibit larger A1 values than do the corresponding gem-dimethyl compounds is presumably ascribable to the presence of an extra asymmetric center adjacent to the alcohol group in the monomethyl compounds. In Table 111 the specific rotations of the four monomethylcholestan - 3 - ones in chloroform solution are compared with the values determined (27) Inter a!. (a) D. H. R. Barton, J . Chem. Soc., 813 (1945); (E) W. Klyne and W. hf. Stokes, ibid., 1979 (1954).
5225
[ct]CHCI:OD
[ct]M*OAOD
A[ct]D
2a-Methylcholestan-3-one (11) +32 +3lZ8 - 1 2p-Meth) lcholestan-3-one (XY) +X6 +67” -19 4a-iUethylcholestan-3-one $26 +2528 - 1 (XX) 48-Methylcholestan-3-one +36 +16** -20 (XXI) “a”-Tetrah\.drosanton in +28“ -t-27b - 1 (XXXVa) “ 7”-Tetrahydrosantonin +72“ 4-52’ -20 (XXXVb) 30-Nor-19a(H)-taraxastan-20+I5W 4-2038 5 one (XXXVIb) 30-hlortaraxastan-20-one +65“0 4-3928 -26 (XXXVIa) 17a~-hfethyl-D-hornoandrostan38-01-17-one (XXXVIIa) -54‘ -5p f 2 17aa-Methyl-D-homoandrostan3p-ol-17-one (XXXVIIb) -27’ -39**d - 12 Cocker and T. F. N. McMurry, J . Chenz. SOC., 5 W. 4549 (1956). C.‘Djerassi, R. Riniker and B. Riniker, THISJOURSAL,78, 6362 (1956). C F . Raniirez and S. Stafiej, zbid., 77, 134 (1955); 78, 644 (1956). Rotation measured in dioxane.
+
equatorial methyl groups, the [ a ] D values in methanol for the corresponding axial 2P- and 4pmethyl compounds are considerably lower than in chloroform. This shift, which is in the opposite direction t o that usually observed when passing from chloroform to methanol as a solvent,29occurs also with other axial a-methyl ketones. Thus ‘‘a’’tetrahydrosantonin (XXXVa) with the equatorial methyl group next to the ketone shows essentially
XXXVa, R = H, R’ = Me b, R = Me, R’ = €1
the same specific rotation in the two solvents, whereas “y”-tetrahydrosantonin (XXXVb) with the methyl group axially orientated again exhibits a considerably lower [ a ]value ~ in methanol than in chloroform. The same behavior is shown by the pair 30-nor-lSa(H)-taraxastan-2O-one(XXXVIb) and 30-nortaraxastan-20-011e (XXXVIa), except that in this case the shift occurs with the latter isomer which presumably is the equatorial methyl (28) The values in methanol were obtained by C. Djerassi, 0. Halpern, V. Halpern and R . Riniker (THIS JOURNAL, BO, 4001 (1958)) in the course of determining the rotatory dispersions. (29) Cf. (a) P. A. Plattner and H. Heusser, Helu. Chim. Acta, 27, 748 (1944); (b) D. H. R. Barton, J . Chctn. SOC., I l l 6 (1946); (c) L. F. Fieser and M. Fieser, “Natural Products Related t o Phenanthrene,” Reinhold Publishing Corp., New York, N. Y., 3rd edition, 1949, p. 205.
5221;
K
R'
light petroleurn-benzene (9:1 and 4:1) yielded 2.11 g; of unchanged cholestan-3-one (fraction D), m.p. 125-129 . Crystallization of fr:tction T3 from ethcr-~nicth:inol giivl' juirr 2n-iiirihylrh
li I), 2
i!,
XXX1.1
= 1 1 , R ' = XIc = Me, R' = H
XSS~II a, R = H, R ' = M e b, R = M e , R ' = H
compound.30 However, with this pair the usual stability relationship is reversed, the equatorial isomer being the less stable due to interference with the C-12 methylene group. The presently described solvent shift is therefore operative with the less stable isomer XXXS'Ia, as is also the abnormality of the rotatory dispersion. ?? The last pair in Table 111 shows that the effect is also observed when comparing rotations measured in chloroform and dioxane. Thus whereas the equatorial methyl compound XXXVIIa shows almost the same rotation in the two solvents, the axial isomer XXXVIIb in dioxane has a markedly lower rotation than in chloroform, the direction of the shift again being opposite to the usual ~ n e , ~ The ~ b ,magnitude ~ is however less than in the other cases where chloroform was compared with methanol. The observation that the. rotations of epimerizable 0-methyl ketoiies are considerably lower in methanol or dioxane than in chloroform seeins to be general. Acknowledgments.-If7e would like to thank Professor E. R. H. Jones, F.R.S., for giving us advance information prior to publication about the bromination of enol acetates and Professor C. Djerassi for sending us a manuscript of the paper mentioned in footnote 28 before publication. %'e are also indebted to Dr. S. Pinchas of this Institute for determining the infrared spectra. Experimental 3 1 Direct Methylation of Cholestan-3-one (I). (a) To Give Mainly Z~~-Methylcholestan-3-one(11).-.I solution of 700 ing. (18 millimoles) of potassium in 35 cc. of t-hutyl alcohol was added to a boiling solution of .i g. (13 millimoles) of cholestan-3-one (I) in 50 cc. of benzene and 25 cc. of t-butyl alcohol. Methyl iodide (5 cc.) in 5 cc. of benzene was then added and refluxing was continued for 3 minutes. T h e solution was cooled, ice ~ 1 -added a ~ and the product was isolated with ether. The crystalline residue was chromatographed in light petroleum solution on 300 g. of alumina. Elution with light petroleum yielded first 850 mg. of partially crystalline material (fraction i\) enriched in 2,Z-dimethylcholestan-3-one, then 1.01 g. of 2Q-methylcholestan%one (fraction B), 1n.p. 117-119', and then 482 mg. of material with m.p. 115-121' (fraction C) which by rechroinatography was shown to he a mixture of cholestan-3-one and 3cr-ineth~.lcholestan-.~-one.Lastly light petroleurri and (30) T. R. Ames, J. L. Beton, A . Bowers, T. G . Halsall and E. R. H. Jones, J . Chem. Soc., 1905 (1054). (31) Melting points are uncorrected. All chromatograms were carried o u t with Merck "acid-washed" alumina. Rotations were determined a t room temperature in chloroform solution. Ultraviolet spectra were measured in 95% ethanol solution on a Unicam Model S.P. 500 spectrophotometer. Infrared spectra were determined on a Perkin-Elmer model 12C single beam spectrophotometer with sodium chloride prism. Analyses were carried o u t in our microanalytical
