A sample of 2,3,5-trimethyl-~-arabonamide prepared according t o Humphrey's, Pryde and Waters13 melted at 137.5138' and had [ ( Y ] ~ ~+16.9' D (c 2.0 in water). A mixture of equal amounts of the D- and L-forms melted at 149-150'. 3,4,6-Trimethyl-N-methyl-~-g1ucosaminic Acid (VI). -2,3,5-trimethyl-~-arahinose (IV) (3.7 g . ) was subjected to a cyanhydrin synthesis as descrihed above for 2,ci-dimethylo-arabinose. The final product of the reaction, 3,4,F-trimethyl-N-methyl-D-glucosmiinic acid (1'1) ( 1 . : I 9 g. ) crystallized readily from absolute alcohol, m . p . 200-206.5°. [m]% 1 9 . 5 " (initial) - + 4-S.2" ( f i i i : r l :ifter 20 Iioiirs), ( c 2.1
in water).
Three recrystallizations of the acid did not alter its melting point and specific rotation. ..lltnl. Calcd. for C,aHllOsN: C, 47.79; H, 8.42; N , 5.57. OCH ;3;,01. ~ ~ c, 47.87; ~ H ~ , 8.35; ~ 3 ,5.48; d : o&, 37.5:'
Acknowledgment.-The authors are indebted to Mr. J. F. .Alicino and his associates for the microana$,ses reported in this paper. i 3 ~ r - s s ; n . rS~.~J..
Sfi\v
~ C ~ S T R I B T I T I O FROM X TlIR ClfEMIC.41. I..&HOR 91'ORY OF T I A R V A R D VNIVI?RSIT\'
1
Reductive Methylation of Steroid Ketones BY JorrN
c. B ~ n c o c r i ,' \ N D h J I S F.F r E s E R RECEIVED JULY 10, 1952
A dehydro derivative of methyl ilg~ll)-iithocholen:tetentatively regarded by Fieser and Rajagopalan as a 3,g-oxide is xctually the normal 3-ketone ( I ) , and a product derived from it by hydrogenation in methanol-hydrobromic acid and c h x acterized by the presence of an inert oxygen function is the 38-methyl ether 11. Comparable reductive methylations have been demonstrated with a satiiratetl bile acid :? 1 I ' l i l
f4
I
irrlrri!,
i n d I H r i < h i l t i n l l r l d T h i n & 4 r I o , 2 6 , 510 ( l N 7 )
Nov. 5 , 1952
REDUCTIVE METHYLATION OF STEROID KETONES
5473
under the conditions of formation of the 3P-hydroxy ester froin I (and in attempted isomerization of VIa with palladium-charcoa12)). is in keeping with other observations that such a bond is hydrogenable only with difficulty.4 The apparently novel formation of a methyl ether on hydrogenation of a ketone in methanol-hydrobromic acid is describable as a process of reductive methylation, comparable to the reductive alkylation of an amine through a Schiff base. The conversion of methyl dehydrolithocholate (VII) to the 3p-methoxy derivative (111) already cited is a second example t h a t demonstrates lack of any dependence on a 9,ll-double bond. Coprostanone on reductive methylation afforded in good yield a new methyl ether (configuration not established, probably p). Hydrogenation of cholestanone in methanol-hydrobromic acid gave the known cholestanyl methyl ether,jq6 identical with a sample prepared by niethanolysis of cholesteryl tosylate and hydrogenationa6 The formation of the Pmethoxy derivative in the acid-catalyzed reaction represents a steric course the opposite of that in the hydrogenation of cholestanone to epicholestanol in ether-hydrogen bromide.
n
Experimental
a
3
Q
z
0
;q
ag %O
bb!
+
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I
U
potassium acetate in acetic anhydride. That the 0,ll-double bond evidently escaped reduction
Methyl 3-Ket0-A~(~~)-cholenate (I, Previously Called2 "Methyl 3a ,8~0xido-A~(~~)-cholenate ' ').-A simpler method of preparation consisted in adding a solution of 330 mg. of sodium dichromate dihydrate in 3 cc. of acetic acid dropwise over 1 hr. to a cooled solution of 1 g. of methyl As(ll)-lithocholenatein 10 cc. of acetic acid. After 8 hr. at 25" dilution with water caused separation of shiny flakes; 0.92 g., m.p. 109-110'. Repeated crystallization from dilute methanol or dilute acetone effected only slow purification, but a single crystallization from 60-90' ligroin gave 0.75 g. of I , m.p. and mixed m.p. with Rajagopalan's 5.79, 5.83 f i , k:$x 5.75, 5.82 f i . sample,? 117-119'; :,",A: Oxidation was also conducted by refluxing for 3 hr. a solution of 265 mg. of methyl AR(l1)-1ithocholenatein 8 cc. of benzene with 6 cc. of cyclohexanone and 585 mg. of aluminum isopropoxide. The mixture was diluted, acidified, steam distilled, and the product collected in ether and chromatographed. Benzene-petroleum ether mixtures eluted 99 mg. of I , m.p. 116.5-117.5' (no depression in m.p. when mixed with above sample), CY*~D+35 i 1' Chf. The semicarbazone was obtained by refluxing 89 mg. of I in 10 cc. of methanol with 89 mg. of semicarbazide hydrochloride and 150 mg. of sodium acetate in 1 cc. of water for 3 hr., concentrating the solution t o half volume and diluting vithwater. Thecrpstallizateamounted t o 127mg.,m.p.189" dec. Recrystallization did not raise the m.p.; 2.82, 3.0, 5.80, 5.92, 6.35 p . Anal. Calcd. for C26H4103N3 (443.60): C, 70.39; H , 9.32. Found: C , 70.68; H, 9.32. The 2,4-dinitrophenylhydrazonewas prepared by warming 90 mg. each of I and 2,4-dinitrophenylhydrazinein 6 cc. of methanol for 1 miri. The flocculent yellow precipitate was crystallized from chloroform-methanol, m.p. 203.5206', 367.5 nifi (22,400). Anal. Calcd. for C31H4206SI (566.68): C, 65.70; H , 7.47. Found: C, 65.71; H, 7.72. Methyl 3P-Metho~y-A~(~~)-cholenate (11, Formerly2 "Methyl 3a,8a-Oxidocholanate").-As in the early work,2 a mixture of 450 mg. of I and 45 mg. of platinum oxide i t 1 methanol merely absorbed hydrogen sufficient to saturate the catalyst until 5 drops of 48% hydrobromic acid were added, when 0.9 mole of gas was taken up rapidly. A first (5) T. Wagner-Jauregg and I
