July 5 , 1959
SODIUAI BOROHYDRIDE REDUCTIONS IN DIXETHYLFORMAMIDE
g., 1.6%) of hexaphenyldisiloxane, m.p. 226-228' (mixed m.p.) could be isolated as one of the products from this run.
Acknowledgment.-This research was supported by the United States Air Force under Contract A F 33(616)-3510 rnonitorpd by Materials Laboratory, Directorate of Laboratories, Wright Air Development Center, Wright Patterson AFB,
[CONTRIBUTION FROM
THE
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Ohio. Infrared analyses were obtained through the courtesyof the Institute for Atomic Research, Iowa State College, and special acknowledgment is made to Dr. V. A. Fassel and Mr. R. Kniseley for the spectra. AMES,IOWA
MERCKSHARP& DOHMERESEARCH LABORATORIES, M E R C K& Co., Ixc.]
Selective Sodium Borohydride Reductions in Aqueous Dimethylformamide Solution. Neighboring Group Effects in the Cortical Side Chain1 BY D. TAUB, R . D. HOFFSOMMER AND N. L. WENDLER RECEIVED DECEMBER 20, 1958 Sodium borohydride reduction of corticosterone 21-acetate ( I ) in aqueous dimethylformamide proceeded largely with acetyl migration to give the 2Op-acetate 21-01 I11 as well as the 20/3-ol-Zl-acetate 11. The Zl.-mesylate-ZOp-acetate VIIIa on demesylation gave mixtures of I1 and I11 in which I1 predominated. Similar sodium borohydride reductions of hydrocortisone 21-acetate ( X I ) and cortisone 21-acetate ( X I I I ) led directly to Reichstein's Substances E and U 21-acetates, respectively.
The present work originated in an attempt to modify the procedure of Norymberski and Woods2 for the preferential reduction of the 20-keto group of cortical steroids in the presence of the A4-3-keto and/or 11-keto groupings, such t h a t concomitant loss of easily hydrolyzable ester functions elsewhere in the molecule would not occur. Under the conditions employed by Norymberski and Woods (1.5 mols of sodium borohydride per mol of steroid in methanol a t 0' for one hour) the 21acetate function of 21-acetoxy-20-keto steroids readily undergoes methanolysis and the principal products, produced in moderate yields, are 20P21-diols3 or, following mild acetylation, the corresponding diacetates. In preliminary studies we found t h a t reduction of 20-ketoacetoxy systems in aqueous dimethylformamide proceeds more slowly than in methanol ~ but without loss of acetate f u n ~ t i o n a l i t y . ~These conditions were applied in detail to the reduction of corticosterone acetate (I) in the interest of obtaining the corresponding 21-monoacetate II.4 When compound I was treated with sodium borohydride in 50% aqueous dimethylformamide, a new substance, m.p. 234-240°, which partly, precipitated during the reduction, was formed in 75-8070 yield. Its analysis, infrared and ultra(1) Presented in p a r t a t t h e 132nd Meeting of t h e American Chemical Society, September 1957, h'ew York, N. Y.(Abstracts, p. 23P). (2) J. K. Norymberski a n d C. F. Woods, 1.Chem. SOL.,3426 (1955). (3) (a) See for example: C. M. Southcott, H. E. Bandy, S. E. Newsom a n d M. Darrach, Can. J. Biochem. Physiol., 34 913 (1956). (b) I t should be noted t h a t t h e 170-acetoxy function in CIg-steroids is stable t o sodium borohydride in aqueous methanol (E. Elisberg, H. Vanderhaeghe and 1.. F. Gallagher, THISJ O U R N A L , 74, 2814 (1952). (3c) N. L. Wendler, R. P. Graber a n d G. G . Hazen, Tetvahedvon, 3 , 144 ( 1 9 3 ) . (4) 21-Monoacetates m a y be obtained from t h e corresponding 20.21diols of 3-keto-44-pregnenes in low yield b y partial acetylation a n d chromatography [e.!., L. H. S a r e t t , THISJ O U R N A L . 68, 2478 (1946) ] a n d similarly from 17a,20,2l-triols [e.g., Huang-Minlon a n d R . H. Pettebone, ibid., 7 4 , 1662 (1952)l. Catalytic reduction of t h e 20-carbonyl group, which proceeds in good yield to t h e corresponding ZOp-hydroxy compound without loss of t h e 21-acetate function [L. H. Sarett, ibid.. 7 1 , 1169 (1949) 1, is n o t applicable to A4-3-keto systems since reduction o f A-ring functionality would occur also.
violet absorption spectra were in conformity with those expected for structure I1 and it readily formed monomesylate and monotosylate derivatives. However, CrOs oxidation of the reduction product did not produce 11-dehydrocorticosterone acetate CH20.4~
CH2OH
COOH AcOCH
I
I
W
"
I ill
I 1
'
V
I11
I
n
, l i l CH20Ac
i
CHzOSOzR
CH2OR
I
I
ROCH
AcOCH HO
I
I1
I'
VIIIa, R=CHB VIIIb, R=CH,C,H,
VIa, R = H VIb, R = A c
I
1
CH~OAC
I
(IV) as would be expected from 11. The oxidation product was an acetoxy acid formulated as V on the basis of its properties and analysis. The substance, m.p. 234-240°, must therefore have a 20-acetate-21-01 part ~ t r u c t u r e . ~The 20P-acetate-21-01 formulation I11 was shown to be (5) Acetyl migration from Cle to C17 was recently observed during t h e sodium borohydride reduction o f d,l-ethylenedioxy-5-androstenellg,l8-diol-17-one 18-acetate by P. Wieland, K. Heusler a n d A. Wettstein, Hels. Chim. Acta, 41, 1657 (1958).
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R.D. HOFFSOMMER AND N. L. L ~ E N D L E R
Vol. 81
correct by hydrolysis to the corresponding diol have been a result of the slight solubility of 111 in \-Ia and acetylation to the diacetate VIb as well as the specific aqueous dimethylformamide solvent oxidation of the latter to the known L4-pregnene- system used-the precipitation of I11 from solution 20p, 21-diol-3,1l-dione-200p,2l-diacetate (VII) (Re- displacing the equilibrium in its favor. With these ichstein's Substance T-diacetate) .6 The A ~ J D considerations in mind a reduction was carried (diacetate 1% - diol VIa) value of +lSS" is in out under conditions (80%) aqueous chiethylagreement with that expected for the 2OP-config0 uration and extremely unlikely for the 20aII configuration for which a negative AJJD would be H9CCOCHZ 0 HOC", HO\ .,OCH* \\ I expected.: HOCH HJC/'\OCH H,CCO-CH It proved possible to rearrange the POP-acetate group of I11 to C-21 zliu the 20&acetate-21-mesylate VIIIa or tosylate VIIIb. The '21-mesylate in refluxing collidine was converted to a mixture I1 IX I11 separable b y chromatography into the 2OpI ? acetate-21-01 I1 (46%) and the 20P-01-21-acetate U.IHH, H,O t H20 / 111 plus mixed fractions.8 Displacement of sulfonate esters under solvolytic conditions with /O-CHZ 0 CHPOS02R CH~OAC participation of correctly oriented neighboring CHJ-C' 3 I 'I 1 CO FO-CH H,C-CO-CH acyl groups is a well known phenomenong but to our knowledge has not been reported previously to occur in refluxing collidine or similar weakly basic amines. The reaction generally has been run r X VI11 in acetic acid, and, in the presence of water the intermediate acetoxonium ion is cleaved with re- formamide) where all the reactants remained in tention of configuration.9 Demesylation of VIIIa solution. Under these conditions I1 and I11 were in refluxing aqueous acetic acid ( i O y c ) containing isolated in roughly equal amounts, indicating that potassium acetate gave as major products the 21- acetyl migration in this system does occur in solumonoacetate I1 (35%,'),the diacetate VIb (33%) and tion to a large extent. Finally, i t was of interest small amounts of impure 2OOp-monoacetate 111. to attempt the direct conversion of the 2Op-01 Under generally similar conditions Fukushima and 21-acetate I1 into the 20P-acetate-21-01 111. This co-workers converted a lTa-acetoxy,20P-tosyloxywas accomplished by dissolving I1 in 50% aqueous pregnane to the corresponding 20a-acetate.'O dimethylformamide containing 1% potassium biThe rearrangements herein described may be carbonate followed by cooling and seeding with 111. depicted as proceeding through an o r t h o a ~ e t a t e ( ~
