NOTES
Dec., 1949 TABLE I PHYSICALA N D ANALYTICALDATA BENZOICACIDS
4149
carbon of the pregnanes is quite complicated and FOR
involved leading to low yields. A new and very SUBSTITUTED
simple reaction has now been found in which this can be accomplished in high yield from naturally M. p., Yield Hydrogen occurring steroidal sapogenins containing ketonic R % ' Calcd. Found "C.O groups on C-12. As sapogenins occur widely disH120-121 9 4 . 0 4.90 4.88 9-Chloro237-238 9 3 . 9 3.19 3.41 tributed in nature, they now present a large pom-Chloro154-156 9 5 . 6 3.19 3.29 tential source of material for this synthesis. o-Chloro140-141 9 5 . 0 3.19 3.32 Treatment of the oxidation product of the dim-Nitro3.01 3.23 139-140 70.6 acetate of pseudobotogenin with a dilute metha173-174 7 2 . 2 m-Amino5.15 5.01 m-HydroxyCa. 200 7 9 . 2 4 . 0 3 3.81 nolic solution of potassium carbonate gives an 2-Chloro-5-nitro165-166 8 3 . 0 1.99 2.11 immediate precipitation of the acetate of 16-dehy1 . 9 9 2.17 3-Nitro-4-chloro180-182 8 7 . 3 dropregnen-5-01-3-dione-12,20 removing i t from All melting points are uncorrected. further action with the alkaline solution.2 A small Trifluoromethylary1s.-With the exception of m-hy- amount of a secondary product resulting from this droxybenzotrifluoride, all trifluoromethylaryls were ob- reaction was further studied. It has now been tained through the courtesy of the Hooker Electrochemical Company and were used without further purification. found that this new material is the major product The m-hydroxybenzotrifluoride was easily prepared by of the hydrolysis if alcoholic potassium hydroxide conversion of m-aminobenzotrifluoride through the di- is employed instead of dilute methanolic potasazonium transformation. sium carbonate. In this case the product does Hydrolysis of Benzotrifluoride.-A mixture of 36.5 g. (0.25 mole) of benzotrifluoride and 28 g. of 100% sulfuric not precipitate during the reaction. The same acid was heated cautiously until the evolution of hydrogen product was obtained when 16-dehydropregnenfluoride began as could be detected by its etching of the 5-01-3-dione-l2,20 acetate was treated with alcoglass walls of the reaction vessel. The heat source then holic potassium hydroxide. The new product was withdrawn and reapplied intermittently until the benzotrifluoride layer disappeared. After the evolution of analyzes for a pregnendioldione, containing two hydrogen fluoride had ceased, the reaction mixture was hydroxyl groups, only one of which acetylates poured, with stirring, into 1 1. of ice-water, the resultant with boiling acetic anhydride. It is recovered precipitate sucked dry, and finally washed thoroughly with unchanged when shaken with hydrogen and palcold water. The crude product was purified through its sodium salt using Norit, and the free acid was recrystallized ladium catalyst, showing that i t does not contain from hot water.? This procedure is typical for the series the conjugated double bond system. These reacinvestigated. tions indicate that the new hydroxyl group was Using 8070 sulfuric acid the starting material is recov- introduced in the 17-position as a tertiary carbiered unchanged after refluxing for several hours, while with 20-3070 fuming sulfuric acid small amounts of sulfones and nol. A secondary hydroxyl group on C-16 would sulfonic acids are formed. Prolonged or excessive heating readily form an acetate under the conditions emgives rise t o tars. Occasionally it is difficult to initiate ployed. Whether the formation of a 17-hydroxyl the reaction. In these cases, the addition of small amounts group in the conjugated ketone system by alkali of 20-3070 oleum portionwise is effective. m-Nitrobenzotrifluoride in particular is subject to this difficulty and with is characteristic only of pregnenes containing a it 15% oleum must be used for the reaction to take place. ketone group in the beta-position a t C-12 has not Since 65% fuming sulfuric acid is required to effect satis- been determined but present indications are that factory sulfonation of trifluoromethylaryls,* probably be- the addition of water to the 16-double bond is cause of the strong inductive effect of the meta-directing CFa- group, it is apparent that the rate of sulfonation is influenced by the presence of a C-12 ketone in the far slower than attack of the CF3- group. This competi- molecule. In the strong alkaline hydrolysis of tive situation accounts for the appearance of sulfur-con- the oxidation product, the first product formed taining by-products only a t the higher concentrations of is probably the expected 16-dehydropregnene sulfur trioxide. which then hydrates under the influence of alkali Acknowledgments.-The author expresses ap- to give the 17-hydroxy compound. preciation to Dr. K. M. Seymour and Mr. P. G. Because of the significance of this reaction in the Scheurer for their helpful suggestions. preparation of cortisone or its analogs from ste(7) Only traces of fluorine and no sulfur or chlorine could be deroidal sapogenins, it has been applied to kammotected by the usual qualitative tests. genin, another possible starting material for the (8) Zitscher, U. S. Patent 2,141,893 (Dec. 27, 1938). antiarthritic hormone. This sapogenin is now J. I. HOLCOMB RESEARCH LABORATORIES known to occur in many plants and new sources AND THE CHEMISTRY DEPARTMENT OF BUTLERUNIVERSITY for it and the other steroidal sapogenins will be reINDIANAPOLIS, INDIANA RECEIVED JUNE 6, 1949 ported a t a later date. Pseudokammogenin triacetate3 was oxidized as described for pseudobotogenin diacetate.2 Steroidal Sapogenins. 174. 17-Hydroxy-20Treatment of the oxidation product with alcoketopregnanes from Steroidal Sapogenins holic potassium hydroxide gave a diketopregnene BY RUSSELLE. MARKER' containing three hydroxyl groups, only two of I n the synthesis of cortisone and its analogs which are acetylatable. The product cannot be the introduction of a hydroxyl group on the C-17 (2) Marker, THISJOURNAL, 71, 2656 (1949). -Analyses, Carbon Calcd. Found 68.85 6 8 , 6 5 53.79 53.66 53.79 53.70 53.79 53.73 50.33 50.39 61.32 61.41 60.81 60.69 41.52 41.71 41.52 41.80
%--
(1) Present address: Hotel Genevr, Mexico City, Mexico.
(3) Marker and Lopez, dbid., 69, 9878. 9876 (1947).
4150
NOTES
Vol. 71
cal with the triketone produced from the oxidation product of pseudohecogenin folBotogenin' lowed by strong alkaline hy-0-c-c-c-c
