5322
CORIRlUNICRTIONS TO THE
EDITOR
Xrol. SO
eliminate this explanation. These measurements were a t approximately the same chloride and amine concentrations as the first seven experiments of Table I T T and, since a plot of the first-order rate 2,A-Di* constants os. the sodium nitrate concentrations is nitro1 x 104 linear, me can use these data to estimate kl(Bo) chloro7z-ButplSodium kd X 104. 1.2 benzene, amine, hydroxide, fi X 101, 1.2 mole-2 mole-' k a ( B ~ at ) ~ any particular sodium hydroxide conmole,'I. sec. - 1 sec. - 1 sec. -1 mole,& mole,'l. centration. This assumes that sodium hydroxide (1.01326 0.09816 O.O6O:3 2.62 0 1.7 and sodium nitrate will have equivalent salt effects ,01312 ,09909 ,0741 2.67 Seg Seg. on kl and ka. 13.ctually, sodium hydroxide might ,01293 ,09903 ,1207 3.21 15.9 12.(l be expected t o be less dissociated in 509; dioxane,01312 .OS856 ,1481 3.X2 8.9 7.5 507&water than sodium nitrate, since the hydroxide ,01275 .09916 ,1810 3.63 13.3 10.6 ion is smaller, and its charge is less distributed. ,01317 ,0986; ,2322 3.85 8.7 -i.9 By using these values for k,(Bo) k3(Bo)2, the k4's ,111333 ,09933 ,2413 4 00 8.5 i3 shown in the last column of Table I V were cal,01248 .0485,5 ,2500 2.83 10.5 culated. At the two lowest sodium hydroxide con6.4 X 1. mole-1 see.-' for kl, ka arid k 5 , respec- centrations the k4 values are in one case small and in the other negative. The remaining values are tively. Except for the two measurements a t the lowest not appreciably lower than those given in the fifth sodium hydroxide concentrations, where one k4 is column of Table IT. These positive values for kd negative and the other zero, the values obtained are cannot, therefore, be attributed to a salt effect on appreciable and of the same order of magnitude kl and k l . These results, taken a t their face value, suggest as k3. However, even in those cases where the k J ' s (Cc)term is significant and that the are positive, the contribution of the k4(B,)(CO) that the kd(Bo) term to the total rate, k , is small and varies from reaction of 2,klinitrochlorobenzene with n-butyl3.9 to 6.1yG. This makes the zero and negative amine is subject to catalysis by hydroxide ion. values at the lowest sodium hydroxide concentra- They are not, however, sufficient to constitute clear tions understandable, since in these experiments proof of these contentions. TVe are not prepared the contribution from the k ; term probably is less to claim that we have demonstrated the fact of catalysis by hydroxide ion, but we would insist than the experimental uncertainties involveci. This, of course, brings into question the relia- that, on the basis of the available evidence, the asbility of even those experiments for which k4 is sertion that the reaction of 2,4-dinitrochlorohenzene positive, for, even under the most favorable condi- with primary and secondary amines is not subject tions, we are still trying to determine a small rlif- to hydroxide ion catalysis is unjustified. Acknowledgment.-I am indebted to Dr It. C. ference between relatively large quantities. There is the possibility that the positive k4 that we have Petersen of these laboratories for itiaii!- helpful ;m(l obtained is really the result of a positive salt effect stimulating discussions. on k l and krr. The data o f Table TI can be used to SORTK .\DAMS, M A ~ s .
,.
+
+
T O T H E EDI T OR BISMETHYLENEDIOXY STEROIDS. 11. SYNTHESIS OF 9a-METHYLHYDROCORTISONE AND 9m-METHYLPREDNISOLONE' Sir:
Replacement of the hydrogen atom a t C-9 in adrenocortical steroids by various substituents produces a pronounced effect on biological activity.' We felt that knowledge of the bioactivity of 9methyl corticoids would advance the theory of how these effects are mediated. , This communication outlines a synthesis of these difficultly accessible steroids. Jones, AIeakins and Stephenson3 have reported the preparation of a 9a-methyl-A7-11-ketosteroid (1) Paper I in this series: R. E. Beyler, R. R I . lIoriarty, Frances Hoffman and L. H. Sarett, THISJOUREAL, 80, 1517 (1958) ( 2 ) J. Fried, Ann. 5.Y . A c a d . Sci., 61, 573 (1955). ( 8 ) E. R. H. Jane-, 0. D. Rleakins and J , S. Stephenson, .I. Chciii. S c c , 2156 (1958).
by alkylation of a A7-ll-ketonewith methyl iodidepotassium t-butoxide. The initial compound in our synthesis, 9,llPoxido-4-pregnene-17a-21-diol-3,20-dione4 (I), was combined with formaldehyde-hydrobromic acid to give Sa-bromohydrocortisone-BMD (IIa): m.p. 170-190° (dec.); found C, 57.35; H , 6.84; A:$?" 243 mp) E 15,500; A",!$ 2.7, 5.9S, 6.1. S.9-9.3 (BhID)p. Oxidation of IIa with chromic acid in tetrahydrofuran-acetic acid or pyridine gave 9abromocortisone-BMD (IIb) : m.p. 205-210' (dec.) ; found C, 57.48; H, 5.97; A,";:" 238 mp, E 15,800; A?': 530, 5.91, 6.1, 9.0-9.". Reaction of I I b with ethylene glycol-P-toluenesulfonic acid yielded Ra-bromocortisone-B1\ID-3-dioxolane (IIIa) : m.p. 190-195°, 215-220' (dec.); found C, 57.48; H , 6.04; A:"', 3.S7, 8.9-9.311. (1)
I
1 ried a n d R
r
53ho THISJ O W R N A I , 7 9 , 1130 f l 9 j i )
COMMUNICATIONS TO THE EDITOR
Oct. 5, 1955
This key intermediate (IIIa) was allowed to react with methylmagnesium iodide and excess methyl iodide in refluxing ether-tetrahydrofuran. The product was chromatographically separated into Sa-methylcortisone-BMD-3-dioxolane (IIIb) [m.p. 222-228'; found c, 67.85; H, 7.51; [ a I z 3 D -86 f 2' (CHCl,); n.m.r. showed three tertzary C-CHI groups; A%?' 5.86, 8.8-9.3~; rotatory dispersion curve similar to IIIc] and cortisone-BMD3-dioxolane (IIIc). Reduction of IIIb with lithium aluminum hydride afforded 9a-methylhydrocortisone-BMD-3dioxolane (IIId): m.p. 230-233'; found C, 67.61; H, 7.94; A%:,' 2.7, 8.8-9.2~. The dioxolane grouping was removed using acetone-p-toluenesulfonic acid to give 9a-methylhydrocortisoneBMD (IIc); m.p. 295-305'; found C, 68.40; H , 8.15; A"=,: 244 mp, E 14,800; Azzp' 2.7-2.9, 5.99, 6.13, 8.8-9.4~; Ri,ca. 1.3 X hydrocortisoneBMD. Reversal of the BMD function with 50% acetic acid yielded 9a-methylhydrocortisone (IVa) : m.p. 220-230'; found C, 70.42; H, 8.73; A,":,"" 244 r n p , E 14,300; A%:' 2.8, 5.80, 6.0, 6.15 p ; 21-acetate (IVb) : m.p. 235-238'; found C, 69.16; H , 8.15; A,":,"" 243 mp, E , 16,500; 2.9, 5.75, sh. 5.80, 6.04, 6.26, 8.2 p . Reaction of 1Vb with selenium dioxide in tbutanol-acetic acid produced Sa-methylprednisolone 21-acetate (IT'c): m.p. 220-225'; found C, 245 mp, E 14,000; A?': 69.02; H , 7.91; AZ::" 3.0, sh. 5.75, 5.80, 6.05, 6.18, 8 . 0 5 ~ . R*
R2
5323
A NEW SYNTHESIS OF CYCLOPROPANES FROM OLEFINS
Sir:
Although the addition of a divalent carbon intermediate to carbon-carbon unsaturation would be a direct method of forming three-membered carbocyclic rings, no completely satisfactory method for the formal addition of an unsubstituted methylene group to an olefin has been recorded. We now wish to report a versatile, stereospecific synthesis of cyclopropanes of the type I by the reaction of unsaturated compounds with methylene iodide and a zinc-copper couple.
\
c/
C-
/ \
/
\
+
ZIlI2
+ (CU)
\
CH:!
I Thus, cyclohexene (0.30 mole), methylene iodide (0.15 mole), and zinc-copper couple1 (0.22 mole of zinc) were stirred a t reflux in anhydrous ethyl ether for 45 hours. Simple distillation. gave a 48y0 yield of pure bicyclo[4.1.0]heptane (b.p. 116.5', nz5D 1.4546),2 whose infrared spectrum was identical to that of the authentic h y d r o ~ a r b o n . ~Many functionally substituted olefins have given the corresponding cyclopropanes. Yields ranged from 10-70%, depending greatly on the kind of couple employed, and in no cases were isomeric or rearranged products encountered. Thus, ethylene, cyclopentene, bicyclo[2.2.l]hept-2-ene,3-phenylpropene, styrene and 1-(o-methoxyphenyl)-propene gave cyclopropane (29y0), bicyclo [3.1.0]hexane (2776), tricyclo [3.2.1.02.4]octane (47YG), benzylcyclopropane (49%), phenylcyclopropane (32%) and l-(o-methoxyphenyl)-2-methylcyclopropane (70%), respectively. Similarly, methyl crotonate and vinyl acetate afforded methyl 2-methylcyclopropanecarboxylate and cyclopropyl acetate in yields of 9 and 31%, respectively. Conditions for optimum yields have not yet been completely determined. Ethereal solutions obtained from the reaction of zinc-copper couple and methylene iodide are known to contain iodomethylzinc i ~ d i d e . It ~ is reasonable to assume that such an intermediate would undergo displacement by the n-bond of the olefin to give a cyclopropane and. zinc iodide. An alternative mechanism may involve the spontaneous elimina.tion of zinc iodide to give a low energy methylene similar in reactivity to the dihalomethylenes described by Doer:ing and Hoff mann.2 Either hypothesis requires stereospecificityj and discrimination2,6in the formation of a cyclopropane. This indeed was found to be the case, for when the reaction was applied to pure ~
IIa, R1 = Br, R Z = ,OH
