549-1
K. \I
~ U T , I H. ,
[CONTRIBUTION FROM THE
J. R r ~ c , o r , n~
N D CART,DJERASSI
RESEARCH LABORATORIES OF SYNTEX
VOI.
82
s. A., MEXICO,D. F., h l E X . 1
Steroids. CXLV.' 2-Methylandrostane Derivatives. Demonstration of Boat Form in the Bromination of 2 a-Methyl-androstan-17p-ol-3-one BY R . MAULI,H. J. RINGOLD AND CARLDJERASSI RECEIVEDFEBRUARY 18, 1960 Sodium borohydride reduction of 2a-1nethylandrostan-17p-ol-8-one ( I a ) led t o a mixture of the 3p,17p-diol I1 and the 3a,l7&diol I11 while lithium aluminum hydride reduction of I and of 2 a , 17a-dimethylandrostan-l7~-ol-3-one ( I b ) gave exclusively the 3/3,17@-diols The 1-dehydro derivatives ISTof I a and I b were prepared by bromination-dehydrobromination and the 1 ,-t-bis-dehydro derivative V of I b was prepared by selenium dioxide dehydrogenation or by dibromination-dehydrobromination. Kinetically controlled bromination of I a or of its enol acetate V I yielded 2a-bromo-2~-methylandrostan-l7@ol-3-one acetate ( V I I b ) in which ring A is in the bout conformation ( X I I I ) while acid-catalyzed equilibration of V I I b afacetate ( V I I I ) and the rearrangement forded the thermodynamically more stable 2p-bromo-2a-methplandrostan-l7~-ol-3-one product 4a-bromo-2a-methylandrostan-17~-ol-3-one acetate ( I X ) . These results demonstrate t h a t in the 2-methyl series kinetic bromination of the ketone and enol acetate follow the same stereochemical course and indicate t h a t the kinetic bromination proceeds in a n equatorial manner followed by conformational inversion to a boat ( X I I I ) while the thermodynamic product is the 2P-bromo axial compound.
The marked anti-tumor activity2s3of 2a-methyl- torial. I n the case of androstane-3, lTP-diol, androstan-17P-ol-3-one4~~ (Ia) and of 2a,17a-di- acetylation of the 38,176-diol leads to a -50 @D methylandrostan-176-01-3-0ne~~~ (Ib) promoted our shift while acetylation of the 3a,lTP-diol leads to interest in the synthesis of structural modifications a f 7 @D shift. I n the case of 2a-methylcholestanof these molecules. In this paper we describe the 36-01'~ where the 36-hydroxy configuration has preparation of the corresponding 3,17-diols of I a been proved the 3-acetate exhibits a A@D of - 179 and of Ib, the 2-methyl-Al-3-keto compounds and compared to the free compound. It is evident the 2-meth~l-Al.~-3-keto dienone derived from from Table I that I I a with an @D shift after Ib,6these compounds being of interest for biological acetylation of -164 is the 36-isomer. When the evaluation. In the course of bromination-dehy- reduction of I a was carried out with lithium drobromination experiments carried out with 2a- aluminum hydride instead of sodium borohydride methylandrostan-17P-ol-3-onecertain anomalies only the XP-equatorial isomer was obtained." were noted that invoked the necessity of assigning Similarly, 2 a ,17a-dimethylandrostan-17p-ol-3-one a boat conformation (XIII) to 2a-bromo-26- (Ib) was reduced with lithium aluminum hydride methylandrostan-lT~-ol-3-oneacetate (VIIb). exclusively to 2a,17a-dimethylandrostan-3/3,17flThis result was in accord with that found in the diol (IIb). 2a-methylcholestanone series which is discussed in the preceding paper7 and a more intensive study of TABLE I the bromination of I paralleled the study of the MOLECULAR ROTATION DIFFEREKCES bromination of 2a-methylcholestanone. The pertinent bromination experiments are discussed in the A.[41D Compound [+ID. (acetate-free) latter portion of this paper while the mechanism of bromination is considered in detail in the third Xndrostane-3p, 17p-diol diacetate 12b paper8 of this series. - 38b - 50 2a-Methylandrostane-3,17-diols.--Reduction of Androstane-3a,l7p-diol diacetate + 386 2a-methylandrostan-l7&01-3-one(Ia) with sodium +49 + 7 borohydride in methanol gave about six parts of 2a-Methylcholestane-3p-01 + 321° - 147'0 - 179 2a-niethylandrostane-3/3,17,8-diol (IIa) to one part acetate of 2a-methylandrostane-3a,l7&diol (IIIa). Al- 2a-Methylandrostane-3/3,17p-diol 31 - 133 - 164 though neither compound formed a precipitate diacetate with alcoholic digitonin solution, nor was it possible 2a-Methylandrostane-3a,17p-diol 67 after acetylation to differentiate by infrared diacetate +148 81 meansg the equatorial 3a-acetate from the axial [&I = molecular rotation (see footnote 21 in ref. 8.) Wacetate, comparison of molecular rotation data Determined in these laboratories. (Table I) definitely established, as anticipated, that the more prevalent isomer was the WequaA1-2-Methylandrosten-17P-ol-3-ones .-Bromina(1) Paper CXLIV. J. S. Slills, 0. Candiani a n d C. Djerassi, J . Org. tion of 2a-methylandrostan-17P-ol-3-one (Ia) with Chc,itz., 26, 1056 (1960). one equivalent of bromine in acetic acid and in the ( 2 ) C. Huggins a n d K. hlainzer, J . E x a l l . >\fed., 106,485 (19.57). presence of an equivalent amount of sodium acetate 13) C . 11. Blackburn and D. S. Childs, J r . , Puoc. S t a 8 3 f e e l . , ,Lfayo gave a bromo-ketone which, without purification, Cliwic, 3 4 , 113 (1939). (4) H . J Ringold a n d G. Rosenkranz, J . Oug. Chcm., 21,1333 (1956). was dehydrobrominated with collidine yielding (.?) H. J. Ringold, E . Batres, 0.Halpern and E. Necoechea, T X I S i11-2-methylandrosten-17/?-ol-3-one (I'F'a), Amax 241 JOCRSAL, 81,427 (1939). mk, log E 3.99. Compound IVa lacked the charif;) 2 - 1 \ l e t h y l - ~ ~ ~ ~ - a n d r o s t a d i e n - 1 7 ~ - 0 1 - has 3 - o n ebeen previoiisly acteristic'O infrared carbon-carbon stretch band of described; J. Iriarte a n d H . J. Ringold, Teluahedrorz, 3, 28 (1958). ( 7 ) C. Djerassi, S . Finch, R . C. Cookson a n d C. W. Bird, T H I S A4-3-ketones found a t about 1620 cm.-' and was
+
+ +
82, 5488 (1960). (8) R . Villotti, H. J , R i n g o l d a n d C . Djerassi, ibid., 82, Nov. 5 (1960). (9) R . S . Jones, P. Humphries, F. Herling a n d K. Dobriner, i b i d . , 73, 3213 (1951).
+
JOURNAL,
(10) Y .Mazur a n d F. Sondheimer, i b i d . . 80, 5220 11958). (11) T h e course of hydride reduction was similar with Per-methylcholestanone; see refs. 7 a n d 10.
549.5
~-METHYL-ANDROSTANE DERIVATIVES
&-I /-OR‘
CH,-0
I
IIIa, R ’ = H, b, R’=CH,CO
IIa, R = H , R ’ = H b, R=CH3, R’=H
Ia, R = H , R ‘ = H b, R=CH3, R ’ = H C , R = H, R’ = CH,CO
CH3 i
i
-
V
IVa, R = H , R ‘ = H b, R=CH3, R ‘ = H C, R = H , R’=CH3C0
I
Cg&c 0
Br:&0 ’+
AcO CH3&+
VIIa, R’= H b, R’=CH3CO
VI
I
CH,3
VI11
+
CH& ;
I
Br
I
IX
YAc
O&gH*& 0-
0
,,
,
I
H
Br
-H +c 0
XIV
XI11
shown by direct comparison to be different from the methylformamide to A1~4-2,17a-dimethylandrostaknown4s5 2a-methyltestosterone. Similar bro- dien-17B-ol-3-one (V), Xmax 248 mp, a product also mination of 2a,l7a-dimethylandrostan-17B-ol-3-obtained by dehydrogenation of I b with selenium one followed by calcium carbonate-dimethyldioxide in boiling t-butyl alcoh01.l~ acetamide dehydrobromination12 yielded A1-2,17aIt was later found that A’-2-methylandrostendimethylandrosten-17p-ol-3-one (IVb) . Treat- 17P-ol-3-one could best be prepared, as the 17ment of Ib with two equivalents of bromine gave acetate IVc, by conversion of l a to its enol acetate the intermediate 2,4-dibromo compound which was (13) Ch. Meystre, H. Frey, W. Voser and A. Wettstein, Helu. Chim. dehydrobrominated with calcium carbonate-diActa, 39, 734 (1956); S. A. Szpilfogel, T. A. P. Posthumus, M. S. (12) Private communication f r o m Glaxo Laboratories Ltd.
D e Winter a n d D. A. Van D M ~ Rec. , trav. chiin., 75, 475 (1956).
5496
R. MAULI,H. J. RINGOLD AND CARLDJERASSI
17-acetate VI, bromination in the presence of pyridine or of sodium acetate and dehydrobromination of the intermediate 2a-bromo-2P-methyl-3ketone VIIb with boiling collidine. Configuration of Bromo Ketones.-As stated above, kinetically controlled bromination of the enol acetate VI in the presence of pyridine14 or of sodium acetate7 gave a monobromo ketone VIIb, m.p. 112-115', [alp --Bo, whose bromine atom location was established a t C-2 by collidine dehydrobromination to A1-2-methylandrosten-17Po1-3-one acetate (IVc) or by dinitrophenylhydrazine elimination to the corresponding phenylhydrazone. Both the infrared16 and ultraviolet16 spectrum of IVc were characteristic of a n axial halo ketone and in accord with the anticipated'' 26bromo-2a-methyl configuration. However, the rotatory dispersion curve of VIIb exhibited a negative Cotton effect with trough a t 337.5 mp while according to the axial halo ketone rule18 a 2P-bromo-3-keto-5a-steroid should exhibit a strongly positive Cotton effect. Thus, on the basis of these measurements and following the argument developed in the preceding paper7 for the 2-bromocholestanone case, VIIb can only possess the 2a-bromo(axial)-2/?-methyl ring A boat configuration (XIII) for which a negative Cotton effect would be p r e d i ~ t e d . ~ Since ~ ' ~ under identical non-equilibrating bromination conditions cholestanone enol acetate gave 20-bromocholestanonel (bromine equatorial, ring A chair), and androstan-17P-ol-3-one enol acetate 17-acetate also gave 2a-bromoandrostan-l7~-ol-3-one acetate8 we believe that the kinetically controlled product in the bromination of these enol acetutes i s the 2a-equatorial bromo compound which remains as such in the absence of a 2P-methyl group but undergoes a "flip" to the ring A boat conformation in the presence of a 2P-methyl group. This did not establish, however, that bromination of a 3-ketone would follow the same stereochemical course as bromination of the corresponding enol acetate. To establish this point, Ba-methylandrostan17P-ol-3-one (Ia) and its 17-acetate IC were brominated in acetic acid in the presence of one equivalent of sodium acetate. The sodium acetate was dissolved in the bromine solution which was added dropwise to the steroid dissolved in acetic acid after the bromination had been initiated by the addition of a trace of hydrogen bromide. Thus, it was usually possible by this procedure to brominate while keeping the concentration of hydrogen bromide a t a minimum and to effect bromination of the %ketone under apparent nonequilibrating conditions providing that bromine addition was a t just the proper rate. When the bromine solution (14) E. R. H. Jones and D. J. Wluka, J . Chem. Sac., 911 (1959). (15) R. N. Jones, D. A. Ramsay, F. Herling and K. Dobriner, THIS JOURNAL, 74, 2828 (1952). (IS) R. C.Cookson, J . Cltcpn. SOC.,282 (1954). (17) This structure would be predicted on the basis of the assumption that kinetically controlled bromination of a cyclohexanone a5ords 76, the axially oriented bromo-ketone, E. J. Corey, THISJOURNAL, 175 (1954). Furthermore the tacit assumption is made (see ref. 10) that the chair form of the enol is involved; for further discussion on this point see ref. 8. (18) C. Djerassi, "Optical Rotatory Dispersion. Applications to Organic Chemistry," McGraw-Hill Book Co., Inc., New York, N. Y., 1960, Chapter 9.
Vol. 82
was added too rapidly the excess sodium acetate which was concomitantly added quenched the reaction which could then be re-initiated only by the addition of excess hydrogen bromide leading in general to partial equilibration. When 2a-methylandrostan-17P-ol-3-one (Ia) was brominated by this procedure (i.e., without stoppage) and the reaction mixture immediately precipitated in water, a single bromo ketone (VIIa) was obtained. Compound VIIa exhibited a negative Cotton effect curve (trough a t 335 mp), its ultraviolet and infrared spectra were characteristic of an axial halo ketone and on dehydrobromination by collidine or by dinitrophenylhydrazine gave A1-2-methylandrosten-17P-ol-3-one (IVa) and its dinitrophenylhydrazone, respectively. Acetylation of VIIa a t room temperature with acetic anhydride-pyridine gave the 17-acetate identical with VIIb obtained by bromination of the enol acetate. Thus VIIa must be assigned the structure 2a-bromo-2~-methylandrostan-l7~-0~-3-one (ring A boat) (XIII) and in this case kinetically controlled bromination of the ketone follows the suine slereochemical course as bromination of the enol acetate. Having established the product of kinetically controlled bromination i t now became of interest to determine if the 2a-bromo compound VI1 was also the thermodynamically stable isomer. For this purpose, a preliminary experiment was carried out in which VIIb was allowed to stand a t room temperature in a solution of acetic acid containing hydrogen bromide and aliquots were withdrawn at intervals of 5 minutes to 20 hours. The specific rotation, the ultraviolet maximum and the first rotatory dispersion extremum of each aliquot were determined (Table 11). TABLE I1 HBr CATALYZED EQUILIBRATION OF 2a-BROMO-2P-METIKYLANDROSTAN-17P-OL-3-ONE ACETATE (VIIb) Equilihrm. ..I_tion time, min.
0 5 20 80 320 1200
[a]D
-
6'
4- 5
4- 7 +24 $38 +42
E2" (u.v.)
Rotatory dispersion Cutve, Trough or mr peak
309(2.09) 308(2.10) 308(1.98) 303(1.86) 302(1.80) 301(1.81)
338 338 335 327.5 327.5 325
( - 470') ( - 340) ( - 198) ( + 712) ( + 900)
(+lo451
It may be seen from Table I1 that VIIb appeared to undergo isomerization under these conditions and that equilibrium was reached a t a period between 4 hours and 20 hours with [a]D,Xmax and rotatory dispersion curve peaks essentially constant. The intensity (f1045') of the rotatory dispersion curve peak after 20 hours equilibration was indicative of the formation of another axial a-halo ketone. The drop in the ultraviolet maximum to 301 mp and the drop in intensity to log e 1.81 indicated the formation of some equatorial a-halo ketone, and further the position of the rotatory dispersion curve peak a t 325 mp was intermediate between an axial and a n equatorial a-halo ketone.ls (19) C. Djerassi, J. Osiecki, R. Riniker and B. Riniker, THISJOUR80, 1216 (1958).
NAL,
Oct. 20, 1960
2-METHYL-ANDROSTANE
DERIVATIVES
5497
TABLE111 CONSTANTS OF BROMO-2-METHYLANDROSTAN-17~-OL-3-ONE ACETATEISOMERS Compound, androstan17B-ol-3-one acetate
2a-Bromo-2p-methyl- (VIIb) 28-Bromo-2a-methyl- (VIII) 4a-Bromo-2a-methyl- (IX)
M.P.,
oc.
1 12-1 15 135-140 147-150
[ab
-
6"
4-100
- 28
A%?.
A!%
(u.v)
(i.r)
309(2.09) 307 (2.06) None
5.79,5.86 5.8L5.86 5.80
Rotatory dispersion curve peak
337.5 (-494') 330 ( -1-2480)" 302.5 ($222)
a The amplitude of the Cotton effect curve of the corresponding 19-nor-bromo ketone (ref. 8 ) is somewhat greater but such increase appears to be characteristic of 19-nor-3-keto steroids in general; C. Djerassi, 0. Halpern, V. Halpern and B. Riniker, THISJOURNAL, 80,4001 (1958).
A preparative 20-hour equilibration of VIIb ther discussion. When the pure 4a-bromo comwas then run under the same conditions and the pound I X was dehydrobrominated by heating toreaction product fractionally crystallized yielding gether a mixture of the compound and 2,4-dinitrotwo new bromo ketones VI11 and IX, isomeric phenylhydrazine in acetic acid the hydrazone dewith the starting material. The former, m.p. rivative of 2a-methyltestosterone acetate was the 135-140', [ a ] +looo, ~ whose bromine atom was sole reaction product. However, when 2,4-diniaxial by ultraviolet and infrared spectra, exhibited trophenylhydrazine was added to a solution of I X a strongly positive Cotton effect rotatory disper- in hot acetic acid a mixture of A1-and A4-2-methyl sion curve (+2500° a t 330 mp) a s would be antic- dinitrophenylhydrazones was obtained. To deteripated18 for a 2-axial bromo-3-keto-5a-hydrogen mine the course of this rearrangement I X was ring A chair steroid, and was dehydrobrominated heated for a few minutes in boiling acetic acid but by collidine or by the dinitrophenylhydrazine in the absence of dinitrophenylhydrazine. Hydromethod to A1-2-methylandrosten-17P-ol-3-one 17- gen bromide was liberated almost immediately acetate (IVc) and its dinitrophenylhydrazone. and chromatographic separation of the mixture led The bromo ketone VI11 can thus be assigned the to the isolation of both 2a-methyltestosterone ace2/3-brom0-2a-methylandrostan-17~-01-3-one acetate tate and 2-methyl-A1-androsten-17~-ol-3-one acering A chair structure XIV. tate, the latter probably having been formed The third isomeric bromo ketone I X exhibited by some hydrogen bromide-catalyzed isomerizam.p. 147-150', [ a ] D -28'. Its infrared and tion of the 4-bromo to the 2P-bromo compound ultraviolet absorption spectra were indicative of VIII, both bromo compounds then undergoing an equatorial bromo ketone while the rotatory thermal dehydrohalogenation. dispersion curve exhibited a low intensity positive When pure 2a-bromo-2P-methyl compound VIIb Cotton effect with a peak a t 302.5 mp, con- was dehydrobrominated with lithium carbonatesistenti8,19 with a n equatorial a-halo ketone. lithium bromide-dimethylformamide, a by-product When I X was dehydrobrominated with collidine (XI) was isolated a s well as the expected A'-2and with 2,4-dinitrophenylhydrazineyielding 2cu- methyl compound IVc. Compound X I did not methyltestosterone acetate (X) and its dinitro- exhibit selective absorption in the ultraviolet and phenylhydrazone, it became obvious that I X is 4a- on the basis of elemental analysis and its high bromo-2a-methylandrostan-l7~-ol-3-oneacetate melting point we suspected that X I was the dimer ring A chair (XV), a product arising from acid- derived from the exocyclic 2-methyleneandrostancatalyzed bromine migration. 17/3-01-3-one acetate,22a possible dehydrobrominaFurther confirmation of the nature of the equilib- tion product. This was readily confirmed when riumpr oducts was obtained when a 23-hour isom- we subjected 2-dimethylamirioinethylandrostanerization experiment was worked up yielding 17j3-01-3-one (XII), prepared by the Mannich condensation of androstan-17P-ol-3-one with dia mixture of bromo compounds ( [ a ] D $36') which was dehydrobrominated with lithium car- methylamine hydrochloride, to slow passage bonate-lithium bromidez0 in boiling dimethyl- over an alkaline alumina column. Under these formamide. The dehydrobromination product conditions we could not isolate the intermediate was chromatographically separated yielding almost 2-methylene compound but only dimeric material equal amounts of 2a-methyltestosterone acetate which on acetylation was identical with XI. (X) and of 2-methyl-A1-androsten-176-ol-3-one BiologicalActivity.z3-By the oral route IVb and V acetate (IVc). These experiments establish con- exhibited high myotrophic and low androgenic activclusively that kinetically controlled bromination of ity in the castrate male rat (7-day assay) when Pa-methylandrostun-17P-ol-3-one, its 17ucetate and compared with 17a-methyltestosterone. its enol acetate 17ucetate, yield the Pa-bromo com- controlled bottom side (equatorial) bromination with conformational poundz1 VII while the thermodynamically more change t o the boat form (XIII) of ring A occurring after bromination. stable isomer is the Z6-bromo (axiul) derivative roth, (22)R.I tResin has been and H. shown, Zetzsch, K. DimBer., K * C & L V
VIII.
Several anomalies transpired during various dehydrobromination experiments and require fur(20) R. Joly and J. Warnant, Bull. soc. chim. France, 367 (1958). (21) In the succeeding paper (ref. 8) of this series arguments are developed which suggest strongly that t h i s invokes kinetically
I S B , 1399 (1940), that 2-methylenecyclohexanone rapidly forms a dimer 0 0 to which the structure i has been assigned. i (23) Bioassays by Dr. R . I. Uorfman, The Worcester Foundation for Experimental Biology.
A
R.~ ~ A U L H. I , J. RINGOLD AND
5498
Vol. 82
DJERASSI
pure I I b , m . p . 125-128', [ a ]-~26". No 3a-isomer could be detected. (Ic).--%aAnal. Calcd. for C21b~360?.1/zC3H60:c, 77.31; H,11.24; hlethylandrostan-17B-ol-3-one"." (1,a) (280 mg.) was aceO , l l . 4 4 . Found: C,77.22; H, 11.19; 0, 11.40. tylated for 2 days a t 0' with acetic anhydride (2 ml.) and pyridine (4 ml.). Removal of the solvent zn zacuo and c r j stal2,17~~-Dimethyl-~~-anclrosten-17p-ol-3-one (IVb) .--A solulization of the residue from methanol containing a few drops tion of 2.5 g. of anhydrous sodium acetate and 5 . 5 g. of of water afforded 230 mg. of acetate IC, 1n.p. 160-163", bromine (1.1 equiv.) in 100 ml. of glacial acetic acid was [a]D 29". prepared and then added dropwise over a 40-minute period Anal. Calcd. for C22Ha403:C, 76.26; H, 9.89; 0, 13.83. t o 10 g. of I b in 100 ml. of acetic acid care being taken t h a t the rate of bromine addition did not exceed the rate of upFound: C,76.02; H, 10.00: 0, 13.89. take. The solution was poured with stirring into ice-water, 2a-Methylandrostane-3$,17p-diol(IIa) and 2 ~ M e t h y l - the crude bromo compound filtered, washed, dried in tlacuo androstane-3a,l7p-diol (IIIa) by Sodium Borohydride Re- and then dissolved in IO0 ml. of dimethylacetamide. Finely duction of 1a.-Sodium borohydride (0.38 g.) was added divided calcium carbonate12 ( 5 9 . ) was added and the stirred in portions t o a stirred solution of 0.91 g. of %-methylsuspension boiled for 30 minutes, cooled, filtered and the :~ndroftan-I7p-01-3-one~.~ (Ia) in 50 ml. of methanol. After solutioti concentrated in z'acz~ot o a small volume. IYater standing for 3 hours a t room temperature the solution was was added and the product isolated by ethyl acetate exconcentrated in vacuo t o ca. 13 ml. and 30 ml. of lyLhy- traction as a n oil. Chromatography on 300 g. of alkaline drochloric acid was added. The precipitate, 0.72 g.. m.p. alumina gave in the hexane-benzene (1:4) fractions after 165-215', was collected and the mother liquors on extrac- acetone-hexane recrystallization, 2.3 g. of IVb, m.p. tion with chloroform yielded an additional 0.14 g. of crude 146-151°, [ a ] ~ 29",, , ,A 241 mp, log E 4.00, infrared reduction product, m.p. 160-312". The combined pre- ; : :A 5.99 p . cipitates were chromatographed on 27 g. of ethyl acetateA n a l . Calcd. for C21H3202: C, 79.96; H , 10.19; 0, washed alumina. T h e benzene-chloroform eluates (19: 1; 10.11. Found: C , 79.95; H, 10.11; 0 , 1 0 2 3 . 9: 1 and 4 : 1) after crystallization from aqueous methanol yielded 0.30 g. of pure 2a-methylandrostane-3P,1TP-diol 2 , 17~-Dimethyl-~1~a-androstadien-17~-ol-3-one (V). (a) (IIa), m.p. 175-177", [ a ] D lo", and a second fraction By Dibromination-Dehydrobromination.--4 solution of 1 of 0.26 g., m.p. 170-174'. g. of 2a,li~-dimethylandrostan-lip-ol-3-one ( I b ) in 10 ml. Anal. Calcd. for C Z O H ~ ~ O ~ . ~ /C, Z H76.14; ~ O : H, 11.18; of anhydrous dioxane was treated dropx-ise over a 30-minute period with a solution of 1.1 g. of bromine in 15 nil. of 0, 12.68. Found: C, 76.04; H , 11.24; 0, 12.54. dioxane. The straw-colored solution was poured into water, 2~~-Methylandrostane-3p,17P-diol diacetate (IIc), prepared the gummy precipitate filtered, washed with water and by pyridine-acetic anhydride treatment of IIa and crystalcr)-stallized from aqueous methanol yielding 1.25 g. of lized from methanol, exhibited m . p . 148-153' with re- intermediate 2,4-dibromo compound which without further solidification a n d m . p . 159-160°, [ a ] D -34". purification was dehydrobrominated by boiling for 1 hour Anal. Calcd. for C24Hz1O4: C, i3.80; H , 9.81; 0, 16.39. with 1 g. of finely divided calcium carbonate in 10 nil. of dimethylformamide. The hot mixture was filtered, the Found: C,73.66; H,9.61; 0, 16.97. solutiun concentrated to dryness in t " x o , water added and Elution of the alumina coluinn rvith bexizeiie~~chli~rofortiithe precipitate collected. Crystallization from acetone(1: 1) and crystallization from xnethaiiul gave 0.09 g. o f ether gave 0.31 g. of V, m.p. 1i8-183", A,,ox 248 mp, log 2a-methylandrostane-3a,l7~-diol t IIIa), 111.p. 21ri-2418", E 1.19. The analytical specimen from the same solvent [a]D 22". pair melted a t 18i-191°, [ a ] ~ IO", Amax 248 inp, log E 5.98, 6.10 1. Anal. Calcd. for CsoHaa02:C, 78.88; H , 11.18; 0 , 4.21; infrared ;:A: 10.44. Found: C,78.28; H, 11.24; 0, 10.59. . I n d . Calcd. for C21H300,:C , 80.17: H, 9.61. Found: Za-Methylandrostane-3a,17P-dioldiacetate t IIIb) pre- c. 7!).7ti: H , 9.44. pared from acetic anhydride-pyridine xcetylatiori and ( b 1 By Selenium Dioxide Dehydrogenation.'z---X mixture crystallized from methanol melted a t 191-198°, [a10 i i f 2 n , 17oi-diniethS.landrostan-liB-ol-3-one (0.5 g.), selenium 38O. diositir (0.65 g , ) , pyridine (0.1 ml.) and t-butyl alcohol (30 .inel. Calcd. for ClrHa,04: C, 78.80: H . 9.81; 0, 16.:19. 1111.) TWS hniled, with stirring, for 96 hours under a nitrogen Found: C , 73.83; H, 9. atmosphere. The cooled solution was filtered through Celite, evapurated to dryness and water was added. The crude Reduction of Pa-Methylandrostan- 17 !-01-3-one (Ia) with product after crystallizatior~from acetone (carbon) gave 0.18 Lithium Aluminum Hydride.--;\ solutio11 of 0.11 g. of g. of dienone \., m.p. 181--189',A,, 248 mp, log E 4.19. lithium aluminum lij-c!ri;li. i i i .iO nil. o f tetrahydrofuran which gave no melting point depression with the product \vas added dropwise ,:\-et- ~i :30-niinutr period to a stirred solution of 0.91 g . (.if 1;i in :30 i d . of tetrahydrofurati. obtained in ( a ) aiid whose infrared spectrum was identical. 2-Methyl-A1-androsten-17~-ol-3-one (IVa) without IsoStirring was continued fiir i i i i additional 2 hours wheii 10 lation of the Bromo Intermediate.-A solution of 2.8 g . of ml. of ethyl acetate followed by 100 ml. of 207; sulfuric acid were cautiously added (nitrogen atmosphere). Tlie 9a-methylandrost3n-lTp-ol-3-i~ne (Ia) in 20 ml. of acetic mixture was extracted several times with chliiroforiii, the acid was treated with a drop of hydrogen bromide-acetic acid and then a solution of 1.62 g. of bromine and 0.83 g. extract washed with water, dried a n d evaporated leaving sodium acetate in 30 mi. of acetic acid was added dropwise a solid residue, m.p. 163-171". rimxitography on alu- of over a 30-iriinutc period with stirring. Ice-water (200 ml.) mina, as described above. gave 0 . g . o f 2wniethylandrui r a s a d d e d , the crude _"-bromocompound filtered, washed stane-3,9,17,8-diol (IIa), identicd h the sodium borohydried in cuctio, and the product was dehydrobrorninated dride reduction product, but no: of the .?a-isoiner TITa aiid by heating in 40 ml. of boiling collidine for one hour. The could be detecteci. coded cllidinemixture was filtered free of collidine hydro2a, 17a-Dimethylandrostane-3p, 17p-diol (IIb) bromide and the filtrate concentrated in C ~ C U Ot o ca. 10 nil. ture of 2a,17a-dimethylandrostan-li~-ol-3-oiie poured into 250 nil. of cold dilute sulfuric acid solution. g.), lithium aluminuni hydride (1 9 . ) and tetrahydrofuran atid The gummy precipitate \vas filtered, dried and then chroma(200 ml.) was boiled for 4 hours under iiitrogeri and then tographed on 100 g. of alkaline alumina. The hexanecooled. Acetone (20 ml.') was cautiously added, then ice- benzene (1: 3 ) fractions were pooled and recrystallized front cold dilute sulfuric acid and the reduction product was acetone-hexane yielding 0.475 g . of 2-r11eth~.l-A~-anclrost~nisolated by ethyl acetate ext.raction. Chromatography 178-ol-3-one (ITa), m.p. 155-158", [ a ] D 52", Amas over 100 g. of alkaline alumina gave, in the benzene eluates, 211 mp. log E 3.90, infrared Ai:; 5.99 p ; mixture melting the 3,9,lip-diol (1.7 g., m.p. 120-124') which ~ r a recrystals point 135-150" with 2 a x n e t h q l t e s t o ~ t c r o n c of ~ ~ ~melting lized several times from acetone-hexane yielding 1.0 g. of point 154-155".
Experimental24
2a-Methylandrostan-17p-ol-3-one Acetate
+
+
+
+
+
+
(24) 31elting points are uncorrected. Rotations in chloroform axid ultraviolet absorption spectra ;elution Infrared spectra were determined with model 21 spectrophotometer. W e a r e grateful to for determination of rotntions a n d spectral d a t a .
were determined in 95%- ethanol a Perkin-Elmel r)r. J. M a t t h e w .
.4naZ. Calcd. for CzoHaoOt:C, 79.42; H. 10.00: 0 . 10.58. Found: C. 79.06: H , 9.77: 0 , 11.00
2-Methyl-A~-androsten-17p-ol-3-one Acetate ( IVc) .- Acet.
vlatinn of 1 g. of IVc by haating for
nne
hour
Rt
90' with
Oct. 20, 1960
2-METHYL-ANDROSTANE
10 ml. of acetic anhydride-pyridine ( 1 : l ) gave, after the usual work-up and crystallization from acetone-hexane 0.83 g. of IVc, m.p. 145-14S0, [ a ] ~ 32", Amax 241 mp, log €4.03; infrared; : :A 5.78,6.00 p . Anal. Calcd. for C22H3203: C, 76.70; H , 9.36; 0, 13.93. Found: C, 76.69; H , 9.30; 0,13.68. Z-Methyl-A1-androsten-17~-ol-3-one 2,4-Dinitrophenylhydrazone. Procedure for Dinitrophenylhydrazone Formati0n.~5-2-Methyl-A~-androsten-17@-01-3-one (IS'a) (300 mg.) and 2,4-dinitrophenylhydrazine(200 mg.) were added t o 10 ml. of glacial acetic acid a t room temperature. A current of nitrogen was passed over the surface of the solution while the mixture was rapidly brought t o the boiling point by heating on a hot-plate. T h e acetic acid was allowed t o evaporate in the nitrogen stream for about 5 minutes until incipient crystallization occurred. T h e cooled solution was filtered and the dinitrophenylhydrazone of IVa recrystallized from chloroform-ethanol, m.p. 266-268'; 3861np~loge4.47. Anal. Calcd. for C26H34N406: C, 64.71; H , 7.10; N, 11.61; 0, 16.58. Found: C, 64.90; H , 7.21; N, 11.77; 0, 16.66. Z-Methyl-~1-androsten-17P-ol-3-one acetate 2,4-dinitrophenylhydrazone was prepared from 2-methy1-A1-androsten17P-ol-3-one acetate (IVc) as described above and crystallized from methylene dichloride-ethanol, m.p. 263-265", A% ,a': 385 mq, log E 4.42. Anal. Calcd. for C ~ S H ~ ~ NC, ~O 64.10; ~: H, 6.92; Tu', 10.68; 0, 18.30. Found: C, 64.02; H, 6.98; X, 10.58; 0, 18.30. 20-Methyltestosterone Acetate (X).-2a-Methyltestosterone4,jwas acetylated in the usual manner and crystallized from acetone, yielding the 17-acetate X, m.p. 184-186', [LY]Df lolo, A,, 240 mp, log B 4.22; infrared A:", 5.80, 6.03,6.19(m)p. Anal. Calcd. for C22H3203: C , 76.70; H , 9.36; 0, 13.93. Found: C, 76.55; H,9.19; 0,14.38. 2a-Methyltestosterone Acetate 2,4-Dinitrophenylhydrazone.-Treatment of X as described above gave the 2,4dinitrophenylhydrazone, m.p. 272-275', 385 m P , log~4.44. -4nal. Calcd. for C28H36N406: C, 64.10; H , 6.92; N, 10.68; 0 , 18.30. Found: C, 64.16; H , 6.90; N, 10.72; 0,18.21. 2-Methyl-A2-androstene-3,17P-diolDiacetate (VI).-A solution of 5.0 g. of 2~u-methylandrostan-17@-01-3-one (Ia) and 0.5 ml. of concentrated sulfuric acidZe in 400 ml. of freshly distilled isopropenyl acetate was boiled under reflux for 4 hours. Benzene (100 ml.) was added and 450 ml. of solvent was removed by distillation. The residue was diluted with 200 ml. of benzene, the solution washed three times with 50-ml. portions of water, dried over sodium sulfate and evaporated to dryness. The product was recrystallized twice from methanol yielding 4.15 g. of enol acetate VI, m.p. 171-173", [ a ] ~ 45'; infrared : : :A 5.75,5.80 and 8.15-8.27 (broad) p . Anal. Calcd. for C24H3804: C, 74.19; H , 9.34; 0, 16.47. Found: C, 74.19; H , 8.96; 0,16.97. Bromination of 2-Methyl-A2-androstene-3, K'p-diol Diacetate (VI). Preparation of 2a-Bromo-2P-methylandrostan-17p-ol-3-one 17-Acetate (VIIb). ( a ) Bromination in the Presence of Pyridine.-A solution of 1 g. of enol acetate VI in 45 nil. of acetic acid and 5 ml. of pyridine was treated with a solution of 0.53 g . of bromine in 5 ml. of acetic acid and allowed t o stand overnight a t room temperature before precipitating in 1 1. of ice-water. The precipitate of VIIb was filtered azd without purijication exhibited m.p. 110-112°. [ a ] ~ 9 ,,, ,A 3 0 2 3 1 2 mq, log E 2.0;; R . D . in methanol (c,0.0575): [ 0 ] 4 0 0 +113", [ a ] 3 3 2 . 5 -473 , [ a ] ? +1468". ~, Recrystallization from hexane gave 0.51 g. (46% i of 20-bromo-26-methylandrostan176-01-3 -one acetate (VIIbJ, m.p. 112-115" dec., [ a ] -Bo, ~ A, 309 m p , log E 2.0,; infrared A:", 5.79, 5.86 p ; negative Cotton effect (c,0.0575 in methanol) with trough at -494' (for curve see ref. 18, p . 127).
+
+
(2.5) U . V. K. blattox and E. C. Kendall, THISJOURNAL, 70, 882 (1948); C. Djerassi, i b i d . , 11, 1003 (1949).
126) Somewhat better yields are obtained by the substitution of p toluenesulfonic acid for sulfuric acid. Private communication from Dr. J . C . Orr.
DERIVATIVES
5499
.Anal. Calcd. for C22H33BrO3: C, 62.11; H, 7.82; Br, 18.78; 0, 11.28. Found: C, 62.34; H , 7.52; Br, 19.03; 0,11.42. ( b j Bromination in the Presence of Sodium Acetate.*'The solvent' used in this experiment was prepared by mixing 160 ml. of glacial acetic acid, 40 ml. of carbon tetrachloride and 2.0 g. of anhydrous sodium acetate. 2-MethylA2-androstene-3,17@-diol diacetate ( V I ) (2.0 8.) was dissolved in 156 ml. of the above solvent and 18.8 mi. of bromine solution (0.75 ml. of bromine in 50 ml. of the solvent) was added dropwise with stirring over a 30-minute period. After an additional 20 minutes stirring the reaction mixtuie was diluted with water and the product extracted into hexane. The extract was washed t o neutrality with bicarbonate and with water and then evaporated to dryness yielding a crystalline mass which recrystallized from methanol as colorless needles of VIIb, m.p. 113-115" (1.27 g . ) . This product was identical with VIIb obtained in part ( a ) above by ultraviolet, infrared, rotatory dispersion curve and mixture melting point determination. Dehydrobromination of 2~-Bromo-2~-methylandrostan-17~3-01-3-one Acetate (VIIb). ( a ) With Col1idine.-Bromo ketone VIIb (1.0 g.) was heated for 30 minutes in 10 ml. of boiling collidine. The cooled mixture was diluted with 50 ml. of ethyl acetate and washed with dilute sulfuric acid and then water. Evaporation of the dried (sodium sulfate) extract gave a semi-crystalline residue which was chromatographed on 50 g. of ethyl acetate-washed alumina. The hexane-benzene (19: 1) fractions yielded, after recrystallization from acetone-hexane, 0.52 g. of 2-methyl-A'androsten-17P-ol-3-one acetate (1LTc), m.p. 144-146", A,,,241mp,log~4.01. ( b ) With Dinitrophenylhydrazine .-2n-Bromo-2i3-methylandrostan-li&ol-3-one acetate (VIIb) was heated with 2,4dinitrophenylhydrazine in acetic acid and under nitrogen as described above. The product after crystallization from methylene dichloride-ethanol melted a t 263-265", 385 mp, log E 4.41, and was shown b y mixture melting point determination and by infrared comparison t o be identical with the 2,4-dinitrophenylhydrazone derived from 2methyl-Ai-androsten-17p-ol-3-0ne acetate. Bromination of 2a-Methylandrostan-17P-ol-3-0ne(Ia). Isolation of 2~-Bromo-2~-methylandrostan-17p-ol-3-one (VIIa) .-A solution of 3.04 g. of 2a-methylandrostan-l'iP-ol-3one in 50 ml. of glacial acetic acid was treated with one drop of hydrogen bromide-saturated acetic acid and then dropwise over a 45-minute period with a solution of 1.76 g. of bromine and 0.90 g. of anhydrous fused sodium acetate in 50 ml. of acetic acid. T h e addition rate was regulated so t h a t it did not exceed the bromine uptake rate. Water (150 ml.) was added with stirring and the resulting gun1 scratched until solidification occurred and it could be filtered. The product was washed, dried in Z I U C U O , and recrystallized twice from methanol yielding 2.17 g. (5670) of pure 2~~-bromo-2~-methylandrostan-l7~-ol-3-one (VIIa), m.p. 130-132" dec., [ a ] -5', ~ Amax 311 mp, log E 2.10, infrared A:," 5.83 p negative Cotton effect (c, 0.061 in dioxane) with trough a t CY]^^^ -662". Anal. Calcd. for C20H31Br02: C, 62.64; H , 8.15; Br, 20.87; 0, 8.35. Found: C, 62.65; H , 7.87; Br, 21.17; 0 8.42. Acetylation of 2~~-Bromo-2p-methylandrostan-l7/3-01-3one.-A solution of 0.26 g. of VIIa in 1 ml. of pyridine and 1 ml. of acetic anhydride was allowed t o stand for 16 hours a t room temperature. The solvent was removed i n ZIUCUO without heating and the residue crystallized from methanol yielding 0.18 g. of 2~~brom0-2p-methylandrostan-l7~-01-3one acetate (VIIb), m.p. 112-114'. [ ~ Y ] D - S o , identical with the sample prepared from the enol acetate'Sr1. Dehydrobromination of 2a-Bromo-2P-methylandrostan178-01-3-one (VIIa). ( a ) With Collidine.-Compound YIIa (1.1 9.) was dehydrobrominated with 30 ml. of boiling collidine as described in the preparation of IVa above. The crude dehydrobromination product was purified by chromatography on 30 g. of alkaline alumina. The hexane-benzene (1:3) fractions yielded, after recrystallization from acetone-hexane, 0.4 g. of b1-2-methylandrosten-l7~-01-3one (IVa), m.p. 155-157",, , ,A 241 mp, log E 4.00, identical with the sample reported above. (27) Experiment carried out by Dr. J. C.. Orr of these Inboratori?..
R. MAULI,H. J. RINGOLD AND CARLDJERASSI
5500
(b) With 2,4-Dinitrophenylhydrazine.-Treatment of VIIa with dinitrophenylhydrazine in boiling acetic acid for 5 minutes as described above gave the 2,4-dinitrophenylhydrazone of 2-methyl-A~-androsten-17fi-ol-3-one, m.p. 266-268", identical with the product prepared from IVa. Hydrogen Bromide-catalyzed Equilibration of &-Bromo2B-methylandrostan-17p-ol-3-one Acetate (VIIb). (a) Kinetic Run.-To VIIb, 1.2 g . , dissolved in 30 ml. of glacial acetic acid, three drops of saturated hydrogen bromideacetic acid solution was added with stirring. Stirring was discontinued and at given intervals aliquots of 5 ml. were withdrawn and added t o 50 ml. of stirred ice-cold water. The precipitates were filtered after standing for 3 t o 5 minutes, washed well with water and dried for 1 hour over potassium hydroxide in a vacuum desiccator and then dried for 1 hour in high vacuum. The constants, which were then determined, are recorded in Table I1 of the text. ( b ) Preparative Equilibration. Isolation of 4a-Bromo-Zamethylandrostan-l7~-01-3-one Acetate (IX) and Zp-Bromo2a-methylandrostan-17p-ol-3-oneAcetate (VIII) .-A solution of 1.0 g. of VIIb in 30 ml. of glacial acetic acid containing 3 drops of hydrogen bromidc-acetic acid mas allowed t o stand for 20 hours a t room temperature. The waterprecipitated and washed product was dried overnight in a vacuum desiccator and then suspended in 40 ml. of ether. T h e mixture was boiled for a few minutes and the insoluble portion (mainly I X ) filtered. This fraction, 4a-bromo-Zamethylandrostan-17~-01-3-oneacetate (IX), after three crystallizations from methylene dichloride-methanol melted constantly a t 147-160' dec. (0.12 g.), [ a ]-28", ~ no ultraviolet maximum between 270-320 inp, infrared 5.80 p , positive Cotton effect ( c , 0.108 in methanol) with peak a t [cu]302.5 4-222'(forcurveseeref. 18, p . 127). Anal. Calcd. for CZZH33Br03: C , 62.11; H , 7.85; Br, 18.78; 0, 11.28. Found: C, 62.21; H , 7.61; Hr, 18.96; 0,11.52. The ether solution was concentrated, depositing a inixture of IX and of VIII, and then was taken to dryness. Several recrystallizations of the residue from methylene dichloride-methanol gave 0.25 g. of pure 2p-bromo-Zamethylandrostan-17p-ol-3-oneacetate (VIII), r11.p. 135307 m p , log e 2.06; infrared 140' dec., [ a ] ~ loo",, , ,A A;:i 5.86, 5.81 p ; positive Cotton effect ( c , 0.090 in methanol) with p e a k a t CY]^^^ $2480'. Anal. Calcd. for CZ?Ha3Br03: C, 62.11; H, 7.85; Rr, 15.78. Found: C,62.03; H, 7.59; Br, 19.00. (c) Preparative Equilibration Followed by Dehydrobromination .-2a-Bromo-2P-metliylandrostan-lip-Ol-3-(JIlC :teetate (VIIb) (0.9 g.) was equilibrated with hydrogen bromide-acetic acid for 23 hours as described above. The crude product ( [ a ] ~ 36". Found: Br, 16.0) was dehydrobrominated by heating for 3 . 5 liours, in a nitrogen atmosphere, with 2.0 g. of lithium carbonate and 1.5 g. of lithium bromide in 70 nil. of boiling dimethylformarnide. The cooled suspension was filtered and the filtrate Concentrated to dryness in vacuo. The residue was chromatographed on 50 g. of silica gel whence the first group of benzene eluates (259 mg.) were combined and crystallized from acetoiiehexane )-ielditig 80 mg. of A1-2-methylandrosten-17~-ol-3one acetate (IVc), 11i.p. 143-146". Continued elution with benzene yielded 264 ing. of product which after acetonehexane recrystallizatiou yielded 75 mg. of Za-methyltestosIZechroniatograpliy terone acetate (X), n1.p. 170-174'. of the mother liquors furnished :tn additional 83 mg. of IVc, n1.p. 145-148', and 64 nig. of X, n1.p. 175-180". Identity of these fractions was established by ultraviolet spectruin, by conversion to their 2,4-diriitrophenylliydrazones,by iriixture melting point determination and by infrared coinparison with authentic samples. Dehydrobromination of 2p-Bromo-2a-methylandrostan17fi-ol-3-one Acetate (VIII). ( a ) With Col1idine.-Compound VIII, 1.42 g., was dehydrobrominated with 10 ml. of boiling collidine as described above for the preparation of IVa and the crude reaction product chromatographed on 50 g. of neutral alumina. The hexane eluates were crystallized from acetone-hexane yielding 0.53 g. of 2-methyl-AIandrosten-17P-ol-3-one acetate (IVc), m .p. 143-145 O , [a]D$- 31", X,,,241 m p , log €4.01. Theinfrared spectrum was identical with an authentic specimen and the two samples gave no melting point depression on admixture. ( b ) With Dinitr0phenylhydrazine.-Dehydrobrorriination in hot acetic acid, effected as described above, gave the au-
+
+
Vol. 82
thentic 2,4-dinitrophenylhydrazone of 2-methyl-AI-androsten-17fi-ol-J-one acetate, m.p. 263-265'. Dehydrobromination of 4~-Bromo-Z~methylandrostan17p-ol-3-one Acetate (IX) . (a) With Col1idine.-Compound IX, 0.83 g., was dehydrobrominated with 10 ml. of boiling collidine as described for IVa. T h e residue was chromatographed on 15 g. of silica, hexane-benzene (1: 1) eluting material melting between 160-175' which was combined and recrystallized from methanol yielding 0.29 g. of 2amethyltestosterone acetate (X), m.p. 178-180', Amax 240 m p , log e 4.20 and 0.14 g. of X, m.p. 165-167', Amax 240 mp, log e 4.19. Neither sample gave a melting point depression with analytically pure X of m.p. 184-186" and the infrared spectra of the three samples were virtually superimposable. (b) With 2,4-Dinitrophenylhydrazine.-Dehydrobromination of IX with dinitroDhenvlhvdrazine in boiling acetic acid as described above ga;e 2cu:methyltestosterone acetate 2,4-dinitrophenylhydrazone,m.p. 271-273", A,%'* 385 m p , log E 4.43, identical with the product prepared from X. Thermal Dehydrobromination of 4~~-Bromo-Za-methylandrostan-17P-ol-3-one Acetate (IX).m-A solution of 4abromo-2a-methylandrostan-17p-ol-3-one(39 mg.) in acetic acid (1.0 ml.) was boiled on a hot-plate. Evolution of hydrogen bromide was rapid but had ceased after 3 minutes. After 6 minutes boiling, only about 0.2 ml. of solvent remained. Cooling and addition of methanol yielded 28 mg. of tan crystals which was chromatographed on 1.0 g. of ethyl acetate-washed alumina. The f i s t product eluted from the column (16 mg.) was shown t o be 2-methyl-A'androsten-17p-ol-3-one acetate (IVc). Recrystallization from methanol gave material of m.p. 139-141°, undepressed on admixture with authentic IVc. Identity was further established by infrared comparison and by conversion to the dinitrophenylhydrazone. The second substance eluted from the column, 2amethyltestosterone acetate (X) (11 mg.) was recrystallized from methanol to m.p. 178-18l0 undepressed wlth authentic X and was converted to the 2,4-dinitrophenylhydrazoneof X, m.p. 268-270', whose infrared spectrum in chloroform confirmed the assigned structure. 2-Dimethylaminomethylandrostan-17p-ol-3-one (XII) .il mixture of androstan-17fi-ol-3-one (6 g.), paraforinaldehyde ( 2 . 5 E . ) , dlmethylamine hydrochloride ( 5 g.) and 96% ethanol (75 ml.) was boiled for 3.5 hours and then concentrated t o about half the original volume. Water (200 mi.) wits added, then 5 ml. of concentrated hydrochlorlc acid and the insoluble residue filtered. The filtrate was basified with potassium carbonate solution and the Mannich base i s ) lated by ether extraction. Crystallization frnm acetonc gave 4.1 g. of 2-dinietliylaminonietli~landrostat~-l iBol-3-one, 1n.p. 167-170'. The analytical specimen frmn the same solvent melted a t 170-171" dec. ,4nal. Calcd. for C&,,XO2: C, 76.00; €1, 10.73; S, 4.03. Found: C,76.09; H, 10.70; NA.26. Dimer of 2-Methyleneandrostan-17p-ol-3-one Acetate (XI). ( a ) From 2-Dimethylaminoandrostan-17p-01-3-one (XII).-A solution o f 100 mg. of X I 1 it1 2 ml. of bcnzellc was adsorbed onto a column of 3 g. of alkaline alumina :mtl :tllowerl t o stand for 1.25 hours. The product, isdated by chloroform elution, was acetylated with 2 rill. of pyridiiir nnd 1.7 ml. of acetic anhydride a t room temperature for 16 hours. Isolation in the usual manner gave a residue inelting at 235-245". Crystallization from acetcine yielded the analytical specimen, m.p. 249-250°, [nlr, +47', n i ) sclcctive absorption in the ultraviolet; infr:xred A!% , 5.81 p . Anal. Calcd. for Ca4Hs40a:C, 76.7U; IS, 9.38; 0, lc'3.9:j. Found: C, 76.72; H,8.56; 0, 13.97. ( b ) From Z~u-Bromo-2p-methylandrostan-17~-ol-3-one Acetate (VIIb).--A mixture of VIIb (0.90 g.), lithium carbniiate (2.0 g.) arid lithium bromide (1.5 g.) was heated in boiling dimethylfomamide for 3.5 hours under a nitroge-1 atmosphere. The cooled suspension was filtered and the filtrate evaporated to dryness, in z~ucuu. The residue was chromatographed on 50 g. of silica gel yielding in the benzene-chloroform fractions, 0.26 g. of 2-methyl-A'-androsten-17p-ol-3-one acetate (IVc), m.p. 140-145°, while the chloroform eluate gave, after crystallization frnm methanol, 0.165 g. of dimer XI, m.p. 235-237'. Further recrystallization raised the melting point to 245-247', undepressed on admixture with the product obtained in (a). and the infrared spectra of the two samples were identical.
