LEONGOODMAN, S. WINSTEIXAND K.BOSCHAK
4312
1701. 80
[ C \ O S T K I H I : . T I U N F K O X THD D U P A K I ' X E S T ) 5 . W i n s t p i n . I. Goodman and R . Boschnn 1) i3li d . ' l t , s t r a c l i . S I l i i i I n t e r n a t i n n a i Congrc,s of Pure and hpplird Cliririis( r ? , New Y o r k , S Y . . S e p t . , 1951
' I!i.iO).
1
dilute base or silver nitrate in titration. 'Toward both of these reagents, the oxazolinium bromide I1 displayed satisfactory equivalent weights. The ilxazolinium bromide was converted easily to the iree oxazoline IV and the oxazolinium picrate, both of which were obtained as analytically pure materials. As suniniarized i i i 'l'able I , a iiiuch superior routc t o the oxazoliniuni bromide I1 involved the use of N H S a s the psitii-e bromine donor atid the l t ~ 'I'.\H1.l.: SLlM11.4KI
OF?
~'R(Oi)L'Ct'5 O F
I .\DDl'll(-j>
&AC7'1 I I E ~ E (XI EI Yield., (
)XALO~~JI?
nr oxazoI2ra.riil
hol\etit
lin~.HRr
Hr2
lle01-T
I!
SHS
f 1 0 Iromidr. ,7., .>-
Rromit rthpf-
_.,
.I.>
s ,-
7hilic :icetic i i c ~ i t l as ~ u l \ : e n t . ~I'ielris t i ! ' I of oxazoliniuni lxoinide I I easily wwc achieved from trcatnietlt of 3-benzaiilidocycli)hexeiie with KBS in glacial acetic acid followed 1)isolation of the oxazoline IV as the hydrobrornide 11. The reaction between 3-benzamidocyclohexene a~id NBS also was carried out in aqueous dioxane, the free oxazoline I V being isolated as a distillable liquid. Structure, Configuration and Transformations of the 0xazoline.-In a reaction analogous to the regeneration of olefins frniii vicinal dihalides, haloethers, etc., the oxazolinium salt I1 readily was
BENZAMIDO GROUPI N
=lug. 20, 105s
c
c
AI 3s
N
I
I1
. A4cOH Zll,
H
C
s
111
J CHaCOaII CBIf5
C6Hj
I c=o
I
c-=o
I1
I-I
\ /
‘{
s
oJ--(
I
SaOH
oxazoline to a cis-benzamido-alcohol, The anticipated trans relationship of the bromine and oxygen atoms in the bromohydrin VII, and therefore the bromo-oxazoline IV, was confirmed by the rapid, quantitative conversion with dilute aqueous base5 to the epoxide VIII, identical with material prepared from 3-benzamidocyclohexene (I) with peracetic acid.6 An equivalent weight fairly close to theoretical could be obtained by determination of base consumption by bromohydrin VII, but a slow, continuing consumption of base, probably resulting from amide hydrolysis, reduced the accuracy of the determination. Summarizing the stereochemical relationships among the three adjacent groups in the benzamidobromohydrin I T I , the benzamido group is cis to hydroxyl, while the bromine atom is trans. I t may be instructive to regard formation of the benzamido-bromohydrin VI1 as only one example of possible stereospecific syntheses of trisubstituted alicyclic derivatives which depend on participation of complex neighboring groups in electrophilic olefin addition reactions. Some of the general possibilities may be better appreciated from the generalized scheme R R R
011
I ’ =
I
C
Br
A ~-
--
ye‘\
E% - + A -
I
B
zs
I
reconverted in high yield to 3-benzamidocyclohexene with zinc in acetic acid. The same reaction proceeds less smoothly with the free oxazoline IV. The presence of an oxazoline rather than an oxazine ring in the heterocyclic product from bromine addition to benzamidocyclohexene was confirmed by hydrogenolysis over a palladium catalyst. This gave rise to 2-phenyl-cis-cyclohexoxazolinc-8,D (V), the picrate of which proved to be identical with t h a t of authentic materia1 prei’ared from fmns-2-benzamidocyclohexa~iol (VI) and thionyl chloride.a The cis configuration of the oxazoline rather than trans is, of course, the one predicted from the mechanism of formation of the oxazolinium salt during halogen addition to benzainidocyclohexene (see IX). CGH;
I
I
\-,
I3 I 1 _____
1
l
E
the complex neighboring group3 being represented as -A-C(R)=B and the electrophilic reagent’ as EZ. Two features of the preparation of epoxide VI11 from 3-benzamidocyclohexene (I) deserve coniment. It is interesting that the reaction of I with peracetic acid, another example of an electrophilic olefin addition, proceeds without neighboring benzainido group participation. From such participation, an hydrovyoxazoline would be expected. Howex-er, donation of positive hydroxyl to the olcfinic group apparently occurs without back-side benzamido group inter\-ention, followed by protoii loss froin the epoxide conjugate acid X.
c
rI
/’
s
IS \N’
//-----\y I“
A
E
\
I
c
Ir
+
t
1-11
1’111
Ir
\
\a
‘c
,’
0
-\
\. - /
IJr--S
Wheii an aqueous solution of the oxazoliiiiuiii bromide I1 was heated a t 100’ and then neutralized, the benzamido-broniohydrin VI1 was formed. A !runs relationship of the bromine atom and hydroxyl group of the bromohydrin VI1 can be anticipated from the expected trans nature of the addition to the double bond of benzamidocyclohexene (I) as portrayed in formula IX and the known retention of c o n f i g ~ r a t i o nin~ ~the ~ hydrolysis of a cis1 3 ) S. Winstein and R. Boschan, THISJ U U R N A L , 72, 4669 (1950). ( 4 ) G. E. h I c C a s l a n d , H . I S . C a r t e r a n d R . K Clark, J r . , i 6 i d ,71, 637 1949).
I
C
/ NB
t-
4313
3-BENZAMIDOCYCLOHEXENE
c
II \
0
/
S
The second feature of the preparation of epoxide VIII from 3-benzamidocyclohexene (I) and peraceP D Bartlett % b i d ,67, 321 (1935) (6) D Swern, cbid , 69, 1692 (1947) (7) S Winstein and L Goodman, t b i d , 76, Sd68 (1954) (3)
LEONGOODMAS, S. J ~ I I ~ S TAENIDXK. B o s c r ~ a s
4314
tic acid which deserves comment is that the cisepoxide VI11 was the only one observed. Henbest and Wilson* have reported recently that epoxidation of cyclic allylic alcohols occurs on the side of the ring cis t o the hydroxyl group and it is apparent that the benzamido group exerts a similar cisdirecting effect in the epoxidation leading to VIII. The Dibromides and their Transformations.Developing bromide ion competes with neighboring group intervention in addition of bromine to a substituted ~ l e f i n . ~This . ~ is responsible for the formation of dibromide 111 from treatment of 3benzamidocyclohexene (I) with bromine in methanol. Dibromide formation was made dominant by the addition of bromine t o benzamidocyclohexene in acetic acid containing a large quantity of lithium bromide. Under these conditions, the oxazolinium bromide I1 constituted only ca. 67, of the product. The dibromide fraction contained a high-melting isomer (A) and a low-melting one (€3) in approximate 30:iO proportions, and these could be obtained by fractional crystallization as analytically pure materials containing no ionic halogen. Both dibromides A and B regenerated 3-benzamidocyclohexene (I) smoothly on treatnicnt with zinc in ethanol. The behavior of the dibroinides in solvolysis was of potential interest because of the possibilities for anchimeric effects due to neighboring bromine or benzamido. HOWever, the solvolytic behavior of dibromides A and F3 was examined only briefly, and the work was interrupted before matters were fully clarified. When either of the dibromides A or B was heated in refluxing glacial acetic acid, there was formed a mixture of il and B accompanied by a new basic nitrogen coinpound X I isomeric with oxazoline 117. 1Vhen silver acetate was included in the refluxiiig acetic acid, good yields of the new basic nitrogen compound were obtained and none of the
\-01. b(J
The hydrolytic stability of the broino-base X I rules out a trans-oxazoline structure. B.ln Chi treatment with zinc in acetic acid, the hydrochloride of XI gave an excellent yield of 3-beiiznriiidocl;clohexene (I), and this rules out any deep-seated rearrangements in the formation of S I . Thus, tho facts point to a bromo-oxazine structure XI for the bromo-base from the dibromides A and I?. ?'hc parent oxazine XI1 recently has been reported by Burford, Hewgill and Jefferies" as a. crystallinc material, m.p. lo?", in agreemelit nit11 that oi the product of hydrogenolysis of the bromo-base XI. The most straightforward tentative assuniption regarding the dibromides A antl I-: is that they xrc the two trans-dibromidcs from ilOr17lal trans addition of bromine to 3-benzaniidocyclohexene ( I ) . With this assumption, and the additional one that oxazine ring closure iiix-ulves 0-(j i y participation of the benzamido group i n the rate-cletcriniiiiri~ step, one can interpret furt.her the behavior of thi: dibromides X and 13. T>ibroinide A w-ciultl ix: (lisposed toward oxazoline ioriiiatioil only 3 s ;t \.el-\unfavorable conformation (11.)) with cis-axial bromine and benzainitio groups. Dibroiriide B, in ;t not so unfavorable ccinforii~ation (I
