17,21- D I B R O M O P R E G N A N - ~( p )-OL-%ONE
Feb., 1942
ment with Norit, was crystallized from methanol to give thick white needles, m. p. 141-142', yield 0.6 g. This gave no depression with the acetate of 16-pregnen-3(@)-01-20one, m. p. 142-144". A n d . Calcd. for C2aHarOa: C, 77.0; H, 9.6. Found: Pyridine on 17-Bromopregnan-3( @)-ol-ZO-one.-A solution of 1 g. of 17-bromopregnan-3(@)-ol-20-onein 50 cc. of dry distilled pyr-idine was refluxed for four hours. A white solid had separated a t the end of this time. The reaction mixture was worked up in the usual manner to give compact white crystals from acetone, 111. p. 169-172", yield 0.6 g. This gave no depression when mixed with 16-pregnen3(@)-01-20-one,m. p. 170-171 ". Anal. Calcd. for CslH&: C, 79.7; H, 10.2. Found: C , 79.6; H, 10.4. Treatment with boiling acetic anhydride gave the acetate, m. p. 143-146', which gave no depression with the acetate of 16-pregnen-3(p)-ol-20-one. A n d . Calcd. for C2,H,10a: C, 77.0; H, 9.6. Found: C, 77.4; H, 9.3. 16-Pregnene-3,ZO-dionefrom 17-Bromopregnan-3!p 1-01ZO-one.-To a solution of 2 g. of 17-brornopregnan-3((3)-ol20-one in $0 cc. of acetic acid a t room temperature was added a solution of 1 g. of chromic anhydride in PO cc. of 90% acetic acid. After standing for forty-five minutes at room temperature, water was added and the product was extracted with ether, and washed free from acid with 5% sodium bicarbonate solution and watcr. N o definite crystalline product was isolated. The entire product was dissolved in 15 cc. of dry distilled pyridine and refluxed for six hours. At the end of this time a solid had precipitatcd. The reaction mixture was poured into water and extracted with ether. The ethereal extract was washed free of pyridine with 10% hydrochloric acid and then washed with 5% sodium bicarbonate and water. After treatment with Norit, t h e ether was evaporated. The residuc was crystal-
213
lized from acetone to give white plates, m. p. 198-200°, yield 0.3 g. This did not depress the melting point of an authentic sample of 16-pregncne-3,20-dione. .4nal. Calcd. for CplHaoO?: C, 80.1; H, 9.6. Found: C, 80.0; H, 9.3. Pregnane-3,PO-dione from 17-Bromopregnan-3(@)-01-20one.--The non-crystalline product from the oxidation of 1 g. of li-bromopregnan-3(@)-ol-20-oneas described above was dissolved in 75 cc. of methanol. The solution was shaken with 2 g. of palladium-barium sulfate catalyst, 3 cc. of pyridine and hydrogen a t 3 atm. and room temperature for three hours. The reaction mixture was filtered and the filtrate was poured into water. The precipitated solid was extracted with ether and the ether extract was washed with 10 per cent. hydrochloric acid and water. The ether was evaporated and the residue was crystallized from ethanol to give white crystals, m. p. 117-119', yield 0.5 g. This gave no depression with an authentic sample of pregnane-3,20-dione, m. p. 118-120". Anal. Calcd. for CzlHszOz: C, 79.7; H, 10.2. Found: C, 79.6; H, 9.9. Zinc-Acetic Acid Reduction of 16-Pregnene-3,20diene.-A mixture of 500 mg. of 16-pregnene-3,20-dione, 20 cc. of acetic acid and 1 g. of zinc dust was heated on a steam-bath for one hour. The reaction mixture was worked up in the usual manner and the product was crystallized from aqueous methanol, m. p. 118-120". This did not depress the melting point of an authentic yample of pregnane-3,2O-dione. AnaZ. Calcd. for CZ1H8202: C, 79.7; H, 10.2. Found: C, 80.0; H, 10.3.
Summary 1 i-Bromopregnan-3(p)-ol-20-oneand its acetate have been prepared and some of their debromination reactions studied. STATE
COLLEGE, PENX'A.
RECEIVED DECEMBER 26, 1941
~...
[CONTRIBUTION FROM
Sterols.
THE
Scnooi.
OF
CHEMISTRY MD PHYSICS OF
THE
PENNSYLVANIA STATE COLLEGE j
CXXVIII. 17,Z1-Dibromopregnan-2(")-ol-20-one and its Conversion to Pregnanol-3 (p) ,2 l-diol-20-one* BY RUSSELLE. MARKER,HARRY R l . CROOKS,JR.,
AND
R. B. WAGNER
The ease of mono-bromination1 of pregnan-3(/3)- of 60% or more of 17,21-dibromide with or with01-20-one opened up the possibility that if a di- out the intermediate separation of the monobromide could be as easily obtained i t would offer bromide. That the formation of the dibromide a likely method of obtaining 21-hydroxy-20-keto- was not attended by any rearrangement was sterols closely related to desoxycorticosterone. shown by its ready reduction to the starting mateWe have now prepared 17,21-dibromopregnan- rial by zinc or iron and acetic acid. The position of the second bromine atom was 3(8)-01-20-one and studied some of its conversion proved as follows. Treatment of the dibromide products. with potassium acetate in acetic acid under mild Pregnan-3(,3)-01-20-one or the acetate on direct conditions removed the less stable 17-bromine as dibromination in acetic acid solution gave a yield hydrogen bromide to form 21-bromo-16-pregnen* Original manuscript received April 29, 1941. 3(@)-01-20-one. The conjugation of the carbonyl (1) Marker, Crooks and Wagner, THISJOURNAL, 64, 210 (1942).
RVSSELLE. MARKER, HARRYM. CROOKS, JR.,
2 I4
AND
R. B. WAGXER
Vol. T i l
group with the double bond appeared greatly to acid was added dropwise. After standing for fifteen minincrease the resistance of the primary halogen to utes the mixture was poured into water. The precipitated ,solid was filtered and washed free of acid. The material replacement. Preplan-3(@)-ol-20-one could he crystallized from acetone; in. p. 190-191"; yield 5.0 g. r .btained from 2 1-bromo-16-pregnen-3(0) -01-20A m i . Calcd. for C2aHa10aBr2: C, -53.3; H, (j.t.i. (me either by reduction with zinc or iron and T'(JUnd; C, 52.n; 13, 6 . i . acetic acid or by hydrogen-palladium reduction Broriiination of pregnan-3(p)-ol-20-oneby the same proin pyridine. If the compound was reduced with cedure gave a product which crystallized from ether as thick hydrogen-palladium in the abserice of pyridine white nccdlcs, i n . p. 190--192', and depressed the melting the product was 21-bromoprcgnan-:3(P)-ol-_"o-ont.. point when mixed with dibromoprcgnan-3(/3)-ol-20-one aceiate: yield 10.0 g. from 10 g. of pregnan-3(/3)-01-20-one. Treatment of this latter compound with potasAmi. Calcd. for CriHR&Br2: C, 52.9; 14, fj.8. sium acetate in acetic acid2 gave 21-acetosy-preg- 1;ound: C, 5 2 , s ; 13, 6 . 7 . naii-3(@)-01-20-one ~l the same nieltiiig point as Reduction of 17,2l-Dibromopregnan-3(fi)-ol-20-one that obtained by Reichsteiii by treatment of 21- Acetate. (ai With Zinc and Acetic Acid.-To a solutioti uf 2 g of l'i,:!l-dibrornopregnan-3(8)-ol-I"O-one acetate in diazo-prcgnan-3!B~-ol-i'O-oiiewith acetic acid. . I ( I cc. of glacial acetic acid was added 4 g . of zinc dust. The conversion of 2 1 -l)romopregriali-.~~~)-ol'Tlie iiiisture 'was heated on a steam-ttath for thirty inin_ I ( L ~m e to the 2 1-acetoxy-compouiid was compliiiic\ The rraction iiiisture was filtered and the filtrate cated, and the yield correspondiiigly luwered, bj- poured into water. T h c precipitated solid was extractctl crith ether and ilic ether extract was washed with water, itic simultaneous ilxmatic ti o f 1 k i prcgncii-3($1 ,il-2O-orie. This by-product was ver? lihcly the 5:s: sodium bicarhonatc solution, and watcr. T h e ether r e 4 t of a rclatiwly bimple rearraiigemei~t~ - wab renioved and the residuc crystallized from inethanol to give 1 2 g. uf white plate>, i i l . p. 117-119"; no clepresicmoval of the hromiirc followed by an allylic. sirm in rnclting poini with prcgnati-3iS)-ol-2(~-~1:c acetate. sliiit of t l i ~ eiiol form o i tlie ketone to give a frag 111. p , Il7--119', cb) With Iron and Acetic Acid.-SuhstitutiotIiti~ii of merit coi~ vcrtiblc. to 1t,-pregiieii-:I;(Bj-ol-2C)-tme hy ~)owd:.rc.ci iron for thc zinc dust of reduction ( a j with tt\-pulsion of a protckii from C' 1 f i -
C":
CH,
hca.1ing ~~onti~itic.tl for a fotal of two hours gave a yield of , vc.liitc. plate?, from 2 g. of dibromidr; 110 iregnaii-3(13,1-ol-20-oncacetat c. .lu./i Calctl. for C ~ ; ~ ~ I - ~ : 4 t i fC, l L :7fj.t;; H. l i l I . Fcunti: c', ;ti.?, Fi, I O , ~ I 1,cj Similar treatnitat of I7,21-dibro1noprcgnan-3(~j-o12O-oni. with iron and acetic acid gave white crystals from nietlianol, 111. 1). 144-1 46' ; no depression with pregiian-
C--(JH
e-()
:li/3j..ol-"O-orlt,
i
-Br -
-+
--
--+
-
-- H /
--+ /
It is entirely possible that this same type of rearrangement complicates the 21-diazo conversion of Reictistein, necessitating chromatographing to obtain the pure 21-acetoxy or 21-halo compound. This is apparently a type of rearrangement riot previously recognized. We wish to thank Parke, DaT-is and Compaiq for their assistance.
Experimental Part Bromination of Pregnan-3( p)-ol-ZO-one and of its Acetate.-A solution of 5 g. of pregnan-3(p)-ol-20-om acetate from sarsasapogenin in 150 cc. of glacial acetic acid was warmed t o 40". Two drops of 48% hydrobromic acid was added and then 29 cc of 1 -11bromine in acetic ______
( 2 ) Reichstein, Heiu. Chim. A d a , 23, 655 (1940).
3) Cf.P. C. Whitmore and co-workers and W G Young dnd co wotkeT5, THISJOURNAL, 1932 to d a t e
\
21-Bromo-16-pregnen-3( rj)-ol-ZO-one Acetate from 17, 2 1-Dibromopregnan-3( B)-ol-20-one Acetate. ---.a solution o f 5 g. of 17,~l-dil~romopregnan-3(/3j-ol-20-one acetate and .i g. of fused potassium ac ate in 80U cc. of glacial acetic
acid waq refluxed for tiiiie minutes. The reaction mixt u r e waq concentrated t o 1 1 cc. in z)(mIo, and poured into walt,r. The prccipitatcd d i d was extracted with ether t11
