4183

COX~IUNICATIONS
TO THE EDITOR

:lug. 3, 1935

TABLE
I
PRODUCTS
OF REACTION
OF ALLYLIC
ALCOHOLS
WITH THIONYL
CHLORIDE
Alcohol

Reaction conditions

CHKHClCH=CHz

SOCl2,no solvent

CHaCH=CHCHzOH

SOC12, no solvent

CHaCH=CHCHzOH
CHaCHOHCH=CHz
( )transCHsCH=CHCHOHCHa
CsHsCH=CHCHzOH
CsHbCH=CHCH*OH

SOC12 in Et20
SOClz in Et20

Product composition

33% CHaCHClCH=CHs
6770 CH&H=CHCHICl
71% CHoCHClCH=CH*
29 7 0 CH,CH=CCH CHzCl
99% CHsCHClCH=CHt
100% CHsCH=CHCHzCl
100% (-1 tramCHsCH=CHCHClCHs
100% CeHsCHClCH=CHz
60% CsHrCHClCH=CHz
40% CeHsCH=CHCHzCl

SOCl, in EtzO
0.1 M R O H
0.1 MSOCl, in Et20
1 1.l ROH
1 M SOCL in Et20

+
+

show a-phenylallyl chloride is the product. This

thermodynamically less stable secondary chloride is
rearranged only very slowly in the reaction solution.
Our present evidence is still insufficient to decide
whether the SNi' mechanismZinvolves a one-stage
concerted process or ionization to an intimate,
rigidly oriented carbonium chlorosulfinate ion pairI6
followed by internal returne of the chloride component of the chlorosulfinate anion to give rearranged chloride. It is very clear that the SNi'
mechanisms does not involve a carbonium chloride
ion pair of the type employed by Cram' in his
preferred mechanism for the action of thionyl
chloride on the 3-phenyl-2-butanols. A carbonium
chloride ion pair in the a,y-dimethylallyl system
would lead to a trans-chloride which is 100%
racemic instead of the inverted chloride actually
observed. Further, a carbonium chloride ion pair
would not lead to the specific structural results
obtained with the butenols and cinnamyl alcohol.
The dominant role of the SNi' reaction is soinetimes difficult to preserve. I n the case of cinnamyl
alcohol, even the use of 1 M concentrations of
reactants changes the polarity of the medium and results in the product ion of a mixture of 60% cinnamyl
chloride and 40% a-phenylallyl chloride from the
reaction itself since a-phenylallyl chloride is stable
under the conditions used.
(5) E. Kosower, Ph.D. Thesis, U.C.L.A., 1952, page 97.
(6) W. G. Young, S. Winstein a n d H. L. Goering, THISJ O U R N A L ,
73, 1958 (1951).
(7) D. J. Cram, ibid., 75, 332 (1953).

FREDERICK
F. CASERIO
GERALDE. DENNIS
DEPARTMENT
OF CHEMISTRY
OF CALIFORNIA
UNIVERSITY
ROBERTH. DEWOLFE
Los ANGELES,CALIFORNIA
WILLIAMG. YOUNG
RECEIVED
APRIL28, 1955

(111),one of the products of addition of bromine to

bicycloheptadiene (IV), followed by zinc debromination of the resulting bromohydrin.

IV
7-Norborneol, m.p. 150-151, was obtained by
catalytic hydrogenation of anfi-7-norbornenol (I).
The first order rate constants (kl)for acetolysis of
the corresponding p-toluenesulfonates in acetic acid
(0.1 M in potassium acetate, containing 1% Ac20),
and other pertinent data, are
I11

,OTs

m.p. 60.5-61.0"

v
ki(205')

23.3 & 0.3 kcal./mole

5.7 & 2.0 e.u.
0.04 X
sec.-l

AH*

AS*
K1(25')

VI
m.p. 54.7-55.7'
8.40 X
sec.-l
35.7 & 0.6 kcal./mole
-3.5 & 1.7 e.u.
6.36 X 10-'6 sec.-l

The striking situation brought to light by the

new measurements is emphasized by the following
reactivities a t 25'
~TOLUENESULFON
ATE
anli-7-Norbornenyl
104
103
exo-5-Norbornenyl2
Cyclohexyl*
1
endo-5-Norbornenylz
10-1
10-7
7-Norborny13

It is clear that the geometry of the norbornyl

system is uniquely unfavorable for stabilization of a
7-NORBORNENYL AND 7-NORBORNYL CATIONS cationic center a t (2.7.
Sir:
We attribute the high reactivity of the unti-7We wish to record the synthesis of anti-7-nor- norbornenyl derivatives to powerful anchimeric
bornenol (I) and 7-norborneol (11), and a ratio of assistance to ionization at C.7, involving the 2,3
10" in the solvolytic reactivities of the corresponding *-electron cloud (VI arrow). It will be noted that
a homoallylic system4is present, which is geometritoluenesulfonates.
unti-7-Norborneno1, m.p. 117-118, was ob- cally unique in that a vacant orbital on C.7 can
tained: (i) as its acetate by reaction of ethylene overlap the p orbital systems of the double bond
with acetoxycyclopentadiene, generated in situ
(2) S. Winstein, H. M. Walborsky and K. Schreiber. THIS
JOURNAL,
from acetoxydicyclopentadiene, a t looo, and (ii) 72, 5795 (1950); H. L. Schmid a n d K . Schreiber, unpublished work.
Qualitative mention of low reactivity for 7-norbornyl chloride
by selective hydrolysis of the unsaturated dibromide and(3)syn-7-norbornenyl
chloride has been made by J. D. Roberts, P. 0.
(1) Dissertations (Harvard):
(1950), C J. Norton (1955).

P Wilder, Jr. (l950), R. E. Vanelli

Johnson and R. A. Carbon, ibid., 76, 5fiR5 (1954).

(4) hl. Simonctta and S. Winstein, ibrd , 76, 18 (19.51).

4184

C O M h l U N I C A T I O N S TO T H E

symmetrically. The 7-norbornenyl cation may be

represented by (VI). It reacts with solvent

EDITOR

Vol. 77

AI'4-pregnadiene-2l-ol-3,20-dione 2 1-acetate (VII)6

(m.p. 202-204', [ a ] " ~ 143' (chloroform), 152'

(ethanol) Xzi:hanol243 mp ( E = 15,800, Xzzp' 2.93 p

(OH), 5.72 and 5.&0 p (20-carbonyl, 21-acetate
interaction), 6.01, 6.16 and 6.23 p (A1s4-diene-3-one)
'
S.06 p (C-0-C of acetate), found: C, 74.46; H,
A
8.241, and 9a-fluoro-A's4-pregnadiene-1
I(?, 17a,21VI
triol-3,20-dione (IX) [m.p. 265-269' dec., [ c ~ ] * ~ D
stereospecifically; complete retention of con- +111" (ethanolj, X~~:'lano1 -39
3
inp ( E = 14,800),
figuration was observed in the hydrolysis of the found: C, 64.22; H, '7.31. Calcd. for C21H2iOjF.dibromide (111)to the alcohol, and in the acetolysis
CH,O: C, (j4.37; H, 7.611.
of 7-norbornenyl toluenesulfonate (V).
In addition to the recently noted, enhanced
DEPARTMENT
OF CHEMISTRY
glucocorticoid activity of the 21-acetate of IX'
USIVERSITYOF CALIFORNIA
S WINSTEIN
we wish to report that IX and its 21-acetate
Los AXGELES24, CALIFORNIA
I\l SHATAVSKY
possess intense mineralocorticoid action,8 oi the
COSVERSE
MEMORIAL
LABORATORY
C SORTON
order of the parent fluorinated steroid, 9a-fluoro-4HARVARD
U~IVERSITY
R. B \\'OODWARD
pregnene-1 1B,17a,%l-triol-3,20-dione."
CAMBRIDGE, hlASSACHUSE rTS
In subsequent reports we will describe in greater
RECEIVED
J U L Y 13, 1955
detail the chemistry and microbiology of these and
related transformations, and the biochemical studies
MICROBIOLOGICAL TRANSFORMATION OF STER- of the previously undescribed A'-unsaturated
OIDS. I. A'~"DIENE-3-KETOSTEROIDS
derivatives of the known natural and synthetic
Sit,:
steroid hormones.
I t has become a problem of
to
(6) Ci.R. L. Clarke, K. Dobriner, .4. Slooradian and C . ?if. Martini,
devise efficient techniques for the introduction of i b i d . , 77, 661 (1955).
AI-unsaturation in cortisone (Ij3 and cortisol (11)
(7) R . F. Hirschmann, R . Miller, K . E . R e y l e r , L. H . Sarett and
since it has been shown that A',4-pregnadiene- 11. Tishler, ibid., 77, 3166 (185n).
11, R . Cook, Jr., and F. Elmadjian, J . diii. P h o i ~ i i i .As.roC..
17a,21-diol-3,11,20-trione
(111) and A1m4-pregna- Sci.(8)Ed.;
X L I I , 329 (1953).
diene-1lp, 17a,21-triol-3,20-dione (IV) are consider(9) J. Fried and E. F Saho, THISJ O U R N A L , 76, 1455 (1954).
ably more potent anti-inflammatory agents than
A . SOBILE
the natural corticosteroids. We wish to report BIOLOGICAL
RESEARCH
LABORATORIES
IV, CHARNEY
that I may be converted to 111 and I1 may be con- SCHERING
CORPORATION
P. L. PERLMAX
H . L. HERZOG
verted to I V by the action of Corynebacterium
RESEARCH
LABORATORIES
C. C. PAYNE
simplex (X.T.C.C. (5946). Either I or 11, dissolved CHEMICAL
CORPORATION
11.E. TULLY
in methanol, was added to shake flasks containing SCHERING
31.A . JEVNIK
X. J.
a 24-hour culture of C . simplex in a nutrient medium BLOOMFIELD,
E . R.HERSHBERC
of 0.155 Difco yeast extract buffered a t PH 7.
RECEIVED
JLrL'i 11, 1955
The mixture was shaken a t 28' for ;3-24 hours.
Extraction of the resultant broth with chloroform,
followed by evaporation to a residue and crys- ISOLATION FROM URINE AND SYNTHESIS OF
TETRAHYDROCORTISONE GLUCURONOSIDE
tallization from acetone, afforded excellent yields
of I11 or IV, respectively. Compounds I11 and S i r :
IV, obtained in this way, were identical in every
It is generally agreed that 3a,l7cr,2l-trihydroiyrespect with samples prepared by purely chemical pregnane-11,20-dione (tetrahydrocortisone) is the
means. By similar microbiological procedures most abundant adrenocortical steroid metabolite
we have also prepared A1,~-pregnadiene-l'7cr,21- excreted by man, and that it is present in urine
diol-3,20-dione (17) [m.p. 246-249' dec., [ a I z 5 D
largely as a glucuronoside. Because of the general
76' (CHC13),hz::ht*hanol244 mp (t = 15,900),'?:A:
interest in this conjugate and the recent evidence
3.03 p (OH), 3.80 p (20-carboiiyl), 6.0, ( i . l f i and that its synthesis can be accomplished in vitro' we
6.22 p (~14,-dietie-:3-orie),"
found: C, 7:l..j(j; H, wish to report its recovery froin urine in a relativelj.
8.401, A1*-'-pregnadiene-l
l$,2l -diol-3,20-dione (VI) pure state and the synthesis and characterization
i m p . 2%7.%230.3 dec., [CYI'l'D +173O (methanol), of its tetraacetyl methyl ester.
Eight 230-mg. doses of free tetrahydrocortisone
2-13 mp ( E = 1-1,300),?':A:
2.88 and 2.9i
in aqueous alcohol were given orally to a man a t half
p (OH), 535 p (?O-carbonyl), 6.07, 6.20 and 0.25 p
(A1,4-diene-3-one),found: C, 73.49; H, S.12], hourly intervals. The urine which was collected
during this period and the twelve-hour interval
(I)
J. J . Bunim, bl. SI.Pechet and A . J. Bollet, J . .4nz. .bled . ~ S S O L . ,
that followed was acidified and extracted with
1 6 7 , 311 (1955).
butanol. The butanol extract was washed with
(2) H . L. Herzog, A . Xohile, S. Tolksdorf, XY. Charney, E . BI
Hershberg, P. L. Perlman and hf. M. Pechet, Science, 121, 176 (1955).
water, neutralized with aqueous sodium carbonate
( 3 ) E. Vischer, C. hleystre and A . Wettstein, HeZu. Chim. Acta,
and concentrated in vacuo. The crude product
38. 855 (1955), have reported t h e preparation of 111 and V by t h e
action of Fusarium solani on cortisone and Reichstein's Compound S, which separated weighed 2.92 g. and contained
1.45 g. of the desired sodium glucuronosidate as
respectively, and the preparation of VI and VI1 by t h e action of
Caloneclria decora on corticosterone and desoxycorticosterone (followed
determined by analysis based on the method of
by acetylation in t h e latter case).
Porter and Silber.' Four hundred milligrams of
(4) H. L. Herzog. C. C Payne. hl. A . Jevnik. D Gould, E. I..
~

d'--

Shapiro, E. P. Oliveto and E. B. Hershherg, THISJ O U R N A I , i n press

, . IV, Thnmn and A R l i n g s h e r p . > h i d ,7 5 , 5 7 G i '1
( i j .J. I i r i ~ dR

(1) kl. 1. Isselhacher and 1. Axelrod, Tins J O U R N A L , 7 7 , 1070 flRbd)

I ? ) C' c' P , l r f P r i n 4 li 7 . ? l l h r r I Erai C l w n : , 185. 201 1'130)
f