SYNTHESIS OF STEROIDAL METI-IYLESE COMPOUNDS BY THE WITTIGREACTION 5029
Sept. 20, 1957
TABLE1'
R MERCAPTO-ACIDS, HSCH2CH2CH(CH2),,COOH B.P.
Yield,
R
iz
yo
"C.
hfm.
n2O~
4 4 4 4 4 2 3 5 6
81.3 75.3 54.6 74.4 60.5 52.2 74.6 54.8 37.2
116 133 140 141 173 107 148 142
0.14 .09 .08
1.4802 1.4813 1 ,4809 1.4810 1.4810 1.4839 1.4842 1.4823 1.4812
145
.1 1.0 0.05 .85 .05 .04
d20
Formula
1.016 1.013 0 995 988 987 1.044 1.031 1.004 0.993
acidified and extracted with ether. After drying and removal of the ether, the residue was distilled a t low pressure. Properties and analytical data are given in Table V.
Acknowledgments.-We are indebted to Mr. L. Rrancone a n d staff for microanalytical determina-
[COSTRIBUTIOSFROM
THE
Carbon, % Calcd. Found
56.80 58.78 60.50 62.02 62.02 54.51 56.80 60.50 62.02
57.16 58.98 60.62 62.22 62.40 54.78 57.00 60.20 61.64
Hydrogen, % Calcd. Found
Sulfur, % Calcd. Found
9.53 9.87 10.16 10.41 10,41 9.15 9.53 10.16 10.41
16.85 15.70 14.69 13.80 13.80 18.19 16.85 14.69 13.80
9.83 10.21 10.10 10.13 10.44 9.05 9.53 10.02 10.09
16.92 15.89 14.68 14.10 13.34 17.66 17.22 14.81 14.05
tions, to hfr. W. Fulmar and staff for infrared studies and to M ~J.. sanjurjo for assistance in the high pressure operations. PEARL RIVER,NEW YORK
DAXIELSIEFF RESEARCH ISSTITUTE, THE\ v E I Z M A N N ISSTITUTE
OF SCIENCE]
Synthesis of Steroidal Methylene Compounds by the Wittig Reaction' BY FRANZ SONDHEIMER AND RAPHAEL MECHOULAM RECEIVED MARCH22, 1957 Different types of saturated and a,@-unsaturatedsteroidal ketones have been converted to the corresponding methylene compounds through reaction with triphenylphosphine-methylene. Such methylene compounds thereby became readily available. Steroidal hydroxy-ketones may be subjected t o the reaction either directly or after protection of the hydroxyl group. Several methylene steroids described previously are shown t o have been impure.
The recently discovered reaction between triphenylphosphine-alkylidenes of type I11 (obtained from the bromides I by the sequence shown) and carbonyl compounds to produce the corresponding ethylenes IV, the so-called Wittig reaction, has become one of wide scope and utility in synthetic chemistry.2 We first became interested in the application of this reaction in the steroid field in R* R?
I
R--CHBr I
[ ?* ]
PPliS
---+
R'CHPPh3 Br I1
R2 R 3
I
I
R'- C=C-R4 I 1-
-BuLi
R3 t-O=&--R'
1
R'C=PPha IIIa
if
Y + R'---C-PPh, e @
IIIb
connection with a study we undertook to find new methods for constructing compounds containing sterol side chains from 17-keto and 20-keto steroids. This study led us to investigate the interaction between a variety of steroidal ketones with different triphenylphosphine-alkylidenes. It was found that the reaction proceeded most smoothly when triphenylphosphine-methylene (111, R1 = R 2 = H) was employed and the present paper records the use of this reagent for the synthesis of (1) Presented in part before t h e Organic Chemistry Dirision a t t h e 1 3 1 s t Meeting of t h e Americn Chemical Society, Miami, Fla., April,
1957. (2) Cf.G. Wittig, E r p e r i e n l i a , 1 2 , 41 (1956); A n g e u . C h e m . , 68, 505 ( 1 9 5 G ) , and earlier references cited there.
various methylene-steroids (IV, R' = R 2 = H) from both saturated and a,p-unsaturated steroidal monoketones. We were not certain how successful the reaction would be with ketones containing other functions (hydroxy and acetoxy groups) which may react with triphenylphosphine-methylene, but in fact i t was found that reasonably satisfactory results were obtained also with these polyfunctional substances. The methylene compounds thus obtained are often prepared only with dit%culty and in some cases in impure form by other methods. On the other hand, the present route produces the methylene steroids simply and in a high state of purity. The triphenylphosphine-methylene reagent was prepared in ether solution in the usual way2 by treatment of methyltriphenylphosphoniumbromide with butyllithium, and the reactions with the ketones were b&t carried out in refluxing tetrahydrofuran. The various steroidal ketones investigated are listed in Table I, together with the yields and properties of the products. The structures of the resulting methylene-steroids were confirmed by the elemental analyses, infrared spectra (disappearance of the carbonyl band and appearance of the terminal methylene bands a t ca. 890 and 1650 ~ m . - ' )and ~ in some cases by comparison of the properties with those reported for the previously described compounds. Cholestan-3-one (no. l), a simple monofunctional compound containing the system Val produced 3(3) Cf.N. Sheppard and D. hI. Slmpson, @ t r o u t . Revs. (Lolidoif),6, 1 ( 1 0 5 2 ) , Table 7.
5030
FRANZ SONDHEIMER AND RAPHAEL MECHOULAM
Vol. 79
methylene-cholestane (Vb) in nearly YOYO yield found to give a somewhat poorer yield (27%) than on treatment with 3 molar equivalents of the re- did the ketol (36%)) whereas the ether (after acid agent. T h a t a hydroxyl group may be present was treatment) gave a rather better yield (44%). shown by submitting androstan-17p-ol-3-0ne (no. Since, however, the formation of the tetrahydro2 ) to the reaction under the same conditions, when pyranyl ether of steroidal keto-alcohols is usually 3-methylene-androstan-17,B-ol was formed. The not quantitative, i t is recommended that the free yield, however, was reduced to about 40y0. Heco- ketol be used in general in the Wittig reaction, esgenin acetate (110. 3), containing the 12-ketone sys- pecially in view of the finding with free androstantem VIa, yielded 12-methylene-tigogenin (VIb) 3P-ol-17-one (VII) that the employment of a great after saponificatioii of the reaction mixture and this excess of reagent materially increases the yield. example shows that an acetoxy grouping may be The 20-ketone, A5-pregnen-3P-ol-20-one (XIIIa) present. Androstan-3P-ol-17-one (VII) (no. 4)) a (no. O), reacted normally to give 20-methylene17-ketone, produced 17-methylene-androstan-3P-01As-pregnen-3P-ol-20-one(XIIIb). (VIIIa). The yield of the latter was 32y0 when Three different types of steroidal a,,B-unsaturated 3 molar equivalents of reagent was used, but was ketones were subjected to the reaction with triimproved to 523% by employment of 5 molar phenylphosphine-methylene. A4-Cholesten-3-one equivalents (no. 5 ) . This result, which was found (XIVa) (no. 10) produced 3-methylene-A4-cholestoward the end of the investigation, indicates that tene (XVIa), n1.p. 73", [ a ] D +140°, 12pne 23!) with polyfunctional compounds the use of a very nip, in SO% yield. This substance has been reconsiderable excess of reagent is to be recoinmended ported to be formed by dehydration of 3-methylfor satisfactory yields. As can be seen from Table A4-cholesten-3-01 (XV) (from A4-cholesten-3-one I, the 17-methyIene-androstan-3/3-01 (VIIIa) pro- and methylmagnesium iodide) by nieans of p duced did not agree well either in m . ~ or . rotation toluenesulfonyl chloride and pyridine and to exwith that obtained from 17a-methyl-androstan- hibit m.p. 64") [a]D+50.5" (benzene), Xzi:hexane 17P-ol-3-one (IX) by dehydration a t C-17 through 233 and 239 mp.1° The structural assignment distillation over copper sulfate to 17-methylene- rested upon the formation of formaldehyde in 6yo androstan-3-one (VIIIb),6 followed by Xeerwein- yield on ozonolysis and on its isomerization with Ponndorf reduction a t C-3.j Oxidation of our 1'3- acids to 3-niethyl-A3~5-cholestadiene (XVIIa), m.p. methylene-androstan-3/3-01 (VIIIa) with the pyri- '79.30, [a]D - 1290, XcYflohexane max 231 and 239 mp. dine-chromium .trioxide complex6 yielded 17methylene-androstan-3-one (VIIIb), which though This same isomerization product with very similar now agreeing reasonably well in m.p. with that re- properties was obtaiued by ourselves in almost ported by the Swiss worker^,^ still showed a consid- quantitative yield by treating 3-methylene-A4erably lower rotation. That the explanation for cholestene (XIVa) from the Wittig reaction with this discrepancy is to be ascribed to the impure acid, the rearrangement being accompanied by the nature of the products VIIIa and VIIIb as obtained disappearance of the methylene bands a t 882 and by the copper sulfate dehydration method5 is in- 1G34 cm.-' in the infrared. I t appeared that Jlusdicated by the molecular rotation data (see below) grave's dehydration product was a mixture of the and by carrying out the Wittig reaction with tri- dienes XVIa and XVIIa, and this was confirmed phenylphosphine-methylene with the As-compound, when we repeated his experiment and compared A5-androsten-3/3-ol-17-one (Xa) (no. 6). In this the infrared spectrum of the diene thus obtained case the product, 17-methylene-A5-androsten-3@-olwith the spectra of the pure dienes XVIa and 3-Jlethylene-i14-cholestene (XVIa) is (XI), agreed very well in properties with those re- XI'IIa. rather unstable due to its ready isomerization ; ported7 for the substance obtained by the decar1-oic acid both the t1i.p and the rotation of an analytical boxylation of A5,17(20)-pregnadien-3/3-ol-2 sample were considerably lowered after being (XII) and direct comparison confirmed identity. In order to determine the effect of protecting the stored in the dark for some weeks. The Wittig reaction of a A4-3-ketonemay also be hydroxyl group, the yields given by As-androsten3P-ol-17-one (Xa) (no. 6), its acetate (Xb) (no. 7) carried out in the presence of a hydroxyl group, as and its tetrahydropyranyl ether (Xc) (no. S)8 with evidenced by the conversion of testosterone (XIVb) 3 molar equivalents of the reagent were c o ~ n p a r e d . ~to 3-methylene-A4-androsten-l7@-ol(XVIb) (no. The ester (after saponification of the product) was 11). As in the cholesterol series, this substance is rather unstable and on treatment with acids is (4) D. H. R. Barton, A . S . Campos-Xeves a n d R. C . Cookson readily rearranged to 3-methyl-A3p6-androstadien( J . Ckem. Sac., 3500 (1956)) have n o w described the obtention of t h e 17/3-01 (XVIIb). The P-T-ketone, 7-ketocholessame compound b y this method. ( 5 ) L. Ruzicka, P. ?Keister and V . Prelog, Helo. Chiin. A c l o , 3 0 , 867 teryl acetate (XVIIIa) (no. 12), on treatment with (1947). (6) G. I. Poos, G. E. Arth, R. E. Beyler and L. H. Sarett, THIS J O U R N A L , 1 6 , 422 (1953). ( 7 ) F. Sondheimer, 0. Mancera, h f . Urquiza and G . Rosenkranz, i b i d . . 1 7 , 4145 (1955). (8) C. W. Greenhalgh, H. B. Henbest and E. R.H. Jnnes, J . C h r m . Sac., 1190 (1951); A . C. Ott. h :. '3. blurray and R.L . Pederson, HIS J O U R N A L , 1 4 , 1239 (1952). (9) H . H . Inhoffen, e l a l . , have now reported the reaction nf triphenylphosphine-methylene u-ith a keto-alcohol in t h e vitamin D series in which the alcohol function was protected as the tetrahydropyranyl ether (13. 13. Inhoffen, J. F. K a t h and K. Rrurkner, Aii,qe;is. ('iirm , 6 1 , 276 (1955)) or as the acetate (11. I I . InholTen, C;. Qiiilihvrt UKI I f . 1. Ires-, S i i f i r r ~ i s s r i ! . s , . h a i l r , t ,44, 1 I (1957)).
(10) 0 . C . hfusgrave, J . Chctn. Sac., 3121 (1951). (11) N . F. Kucherova and LI. I. Ushakov (Zhur. Obshchei K h i m . , 2 3 ,
319 (1953); C . A . , 48, 2744 (1934)) have reported t h a t decomposition of t h e mixture obtained f r o m A+hulesten-3-one and methylmagnesium iodide with aqueous ammonium chloride solution a t room temperature resulted in n l & 8(i70 uf a substance, m.p. 08-69", ID -12' (CClr), t o which the .7-methyl-A*.r-cholestadiene structure (i) was assigned. Unfortilnately no ultraviolet d a t a were presented HdC. (which would have distinguished i from X V h and S V I I a , onrl this product is very probably also B mixture of tlie 3 . r i i ~ l ~ i ~ l ~ i l ~ - ~ ~ S ' V ~ ~I a~ arid ~ i i the ~ i ~5-uieIhsl~ ~ ~ i i rAI~ 6-diene l X V I 1.1.
/v. I/ 'j ,
Sept. 20, 1957
SYNTHESIS OF STEROIDAL METHYLENE COMPOUNDS BY THE WITTIGREACTION 5031
c3 (3 Ul 6 x
0"
xe
m
(3
I
a
cdr."
7
J c3
ca
2
c
2
U
m
9
t.
a r -
m
a
5032
FRANZ SONDHEIMER AKD RAPHAEL hfECHOVL.4M R
from the saturated ketones to the corresponding methylene derivatives involves a negative shift in the [MID in all the cases investigated, this shift being ca. - 70 in the case of the 3-ketones ca. - 130 with the 12-ketone, ca. -210 with the 17-ketones and ca. -2270 with the 20-ketone. The good agreement (-220, -203 and -206) of the A[M]Dvalues of the three 17-keto steroids is to be noted especially. It will be recalled that the rotations of our 17-methylene-androstan-30-01 (VIIIa) and 1i-nieth-
\
I /?J H Ya,R b,
R
= =
0
YIa, R = 0 b, R = CHz
CH2 0
1-01. 79
OH
CHz I1
I-IIIa, R = - OH b, R = =O
SIIIa, R = 0 b, R = CIJ-
IX COOH
/?:A I Sa,
R
= H
b, R = Ac
XI
R
(12) B. Bann, I. 11. Heilbron and F. S. Spring, J . Chem. SOL.,1274 (1936); S. Weinhouse a n d M. S. Kharasch, J. @ Y E . Chem., 1, 490 (1936).
I
SI1
R
triphenylphosphine-methylene produced 7-methylene-cholesterol (XVIIIb), agreeing well in properties with the previously described substance of this structure.12 I n this case i t was determined that the ester grouping had been completely saponified by the reagent during the course of the reaction. Finally the A16-20-ketone,As,l6-pregnadien-3P-ol-20one acetate (XIXa) (the degradation product of diosgenin), was subjected to the Wittig reaction (no. 13) and after acetylation yielded 20-methylene-Ab*16-pregnadien-3P-ol acetate (XIXb) . I n Table I1 the molecular rotations ( [ i w ] of ~) various ketones are compared with those ( [ M ] D ~ of the corresponding compounds in which the ketone group has been replaced by methylene, described in this paper. I t can be seen that passing
R
CH
= =
CsHi, 011
A \ III'i,
R
b, R
= IC, K' = 0
R ' = CH?
~ I X ' I I< , = 0 I,, R = CH:
ylene-androstan-%one (VIIIb) did not agree with the published figures'; the A [illJ D values of the three 1'7-ketones are -17'7, -143 and -2202 if the published figures are used for the calculations, and this consideration confirms the view that our compounds are pure. I n the case of the a,Bunsaturated ketones, passing from a A5-7-ketone and a Al6-20-ketonet o the corresponding methylene compounds also involves a negative shift in the molecular rotation (ca. -330 and ca. -140, respectively), whereas in the A4-3-ketone series a positive shift of ca. +180 is observed. It is of in~ ~ ) to note that the isomerization of a 3-methylterest ene-A4-compound to the corresponding 3-methylA3J-diene both in the cholesterol and in the testosterone series (XVIa + XVIIa and XVIb XVIIb) is accompanied by a very large negative shift in [MID,the A [ A ~ ] Dbeing -1039 and -971 in the two series.
-
Sept. 20, 1957
S Y N T H E S I S O F STEROIDAL
METHYLENE COMPOUNDS
Other aspects of the Wittig reaction in the steroid field are now being investigated and will be reported later. Acknowledgments.-We are indebted to Dr. G. Rosenkranz of Syntex S. A., Mexico City, for generously providing the various steroidal starting materials. Experimental13 Typical Procedure for the Reaction of Steroidal Ketones with Triphenylphosphine-methylene.-.\ 1 N ethereal solution of butyllithium (9 cc.) was added to a suspension of 3.57 g. (10 millimoles) of methyltriphenylphosphonium bromide (prepared from methyl bromide and triphenylp h ~ s p h i n e )in ' ~ 50 cc. of ether with swirling, under nitrogen. The mixture was shaken in nitrogen for 2 hr., the steroid dissolved in 50-100 cc. (or more if necessary) of ether was added, the mixture was shaken for a further 4 hr. and then allowed to stand overnight. Ether was distilled off at the same time as tetrahydrofuran was added until most of the ether had been replaced. The mixture was refluxed for 6 hr., cooled, diluted with water and extracted with ether. The organic extract was washed with water, dilute hydrochloric acid (the acid washing was omitted in experiments no. 10 and 11, where the acid-labile 3-methylene-A4-steroids are formed) and water, dried and evaporated. T h e residue was either crystallized directly or more commonly chromatographed on alumina. In addition t o the methylene compounds, t h e chromatograms yielded triphenylphosphine oxide and other phosphorus-containing compounds which were not further investigated. 17-Methylene-androstan-3-one(VIIIb) by Oxidation of 17-Methylene-androstan-3&01 (VIIIa) .-Chromium trioxide (0.1 g . ) was added carefully to 3 cc. of dry pyridine. .\ solution of 0.1 g. of 17-methylene-androstan-30-01 (from experiment no. 4) in 3 cc. of pyridine was added dropwise, and the mixture was allowed t o stand a t room temperature overnight. Water and then equal parts of benzene and ether were added, the mixture was filtered through Celite and the organic layer was washed with water, dried and evaporated. Crystallization from methanol furnished 17'methylene-androstan-3-one, m.p. 130-131.5", [ a ] +41:; ~ vmax 882, 1653 and 1706 cni.-l; reported5: m.p. 127-128 , [a]D +62O. Anal. Calcd. for CzoH300: C, 83.86; H , 10.56. Found: C, 83.64; H , 10.37. 3-Methyl-A3~5-cholestadiene(XVIIa) from 3-MethyleneA4-cholestene (XVIa).-Concentrated hydrochloric acid ( 1 cc.) was added t o 0.15 g. of 3-methylene-A4-cholestcne (from experiment no. 10) dissolved in 35 cc. of ethanol, and the solution was refluxed for 2 hr. Isolation with ether and crystallization from acetone-methanol yielded 0.13 g. of (13) Melting points are uncorrected. Rotations were determined a t L'0-25O in chloroform solution unless specified otherwise. Ultraviolet spectra were measured on a Unicam Model S . P . 500 spectrophotometer and infrared spectra (in chloroform solution) on a Perkin-Elmer model 12 C single beam spectrophotometer with sodium chloride prism. Analyses were carried o u t in our microanalytical department under the direction of M r . Erich Lleier. (11) G. Wittig and U. Schollkopf, Ber., 87, 1318 (1954).
BY T H E W I T T I G
REACTION 5033
3-methyl-A3~s-cholestadiene, m.p6 75-77', whict on further purification showed m.p. 79-80 , [a]D -132 , 232 m p (log E 4.30) and 239 m,u (log E 4.32); reportedlo: m.p. 79-79.5", [a]D -129", Xg$hexane 231 m p (log E 4.33) and 239 m p (log E 4.36). Repetition of the dehydration of 3-methyl-A4-cholesten-301 (XV) with p-toluenesulfonyl chloride and pyridine acTABLE I1 MOLECULARROTATIONDATA OF METHYLENESTEROIDS' CHz [MID
[.MID
+ +
A [MID
Cholestan-3-one (Va) 4-15S6 92 - 66 Androstan-17P-ol-3-one 94 (EtOH)C 23 71 (\'a) 43d - 86 -129 Hecogenin (VIa) Androstan-3P-ol-17-one (VW +255e 35 -220 Androstane-3,17-dione +3206 +117 -203 A6-Androsten-3P-ol-17-one 16' - 189 -205 (Xa) A5-Pregnen-3&ol-20-one (XIIIa) 88 (EtOH)" - 185 -27'3 A'-Cholesten-3-one (XIVa) +342h +535 $193 +480 +166 Testosterone (XIVb) $314' 7-Ketocholesterol (XVIIIa) -416' -748 -332 As,16-Pregnadien-3p-ol-17one acetate ( X I X a ) - 125k -269 -144 a S e e footnote 13. 6 D . H. R. Barton, J . Chem. Soc., 813 (1945). A . Butenandt, K . Tscherning and G. Hanish, Ber., 68, 2097 (1935). M . E. Wall, M. M. Krider, E. S . Rothman and C . R . Eddy, J . Biol. Chem., 198, 533 (1952). a Determined in these Laboratories. f G. Rosenkranz, 0. Mancera, F. Sondheimer and C . Djerassi, J . Org. Chem., 21, 520 (1956). e.4. Butenandt and G. Fleischer, Ber., 70, 96 (1937). h L . F. Fieser, THIS JOURNAL,75, 437'7 (1953). < F . Sondheimer, S. Kaufmann, J. Romo, H . Martinez and G. Rosenkranz, ibid., 75, 4712 (1953). i s . Bergstrom and 0. Wintersteiner, J . BZoZ. Chem., 141, 597 M. E. Wall, H. E. Kenney and E. S . Rothman, (1941). THISJOURNAL, 77, 5665 (1955).
+
+
-
+
+ +
cording t o Musgrave'o gave a diene with 1n.p. 61-63', [ a ] +55"; ~ reportedlo: m.p. 63-64", [ a ]+so" ~ (bcnzene). The infrared spectrum of this material clearly showed it to be a mixture of the two isomers XVIa and XVIIa by comparison with the spectra of the pure isomers. 3-Methyl-A3~5-androstadien-17~-ol (XVIIb).-This substance was obtained in ca. 70% yield by boiling 3-methyleneA4-androsten-17p-ol (XVIb) (from experiment 11) with hydrochloric acid in ethanol, as described above in the cholesterol series. It crystallized from methanol and showed 1ll.p. 128-130", [a]D -175", XZ$'"' 233 m,u (log E 4.28) and 239 m p (log E 4.33). Anal. Calcd. for C Z O H O ~C, O :83.86; H, 10.56. F ( J U I I ~ : C, 83.56; H, 10.46. REHOVOTH, ISRAEL
