Spiro-pyrimidine synthesis

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sF iB o -rm H iD iire m w m m u

By F i l l s F r t l i r l t l Ehrioh

Ttioola

to th e F ooulty o f thm Gruduoto School of th o loto o roitjr of Morylood l a y o r t lo l f u l f i l l o o a t of thm ro

I

!

I

a a 13

4*

1*t4 ?

* m ¥*

i o *"«

f04

i f

i

ii.

m m m iA V s m

D ic y o lie str u c tu r e s such as

CH^v

co - m

'zc

0 ^ 1

|

CO

* in which

I

CO - IK

o&0 carbon atom i s common t o two rings* wore f i r s t d esign ated by iron Sawyer^* as *& pireoyelanes••

The term “spirem e* eras la t e r proposed

by £a& aieseu^* who worked o a t a system o f nom enclature f o r such compounds*

According to t h i s system* the substance rep resen ted hy

th e above formula would he named cyclop rop an e-?,t,6~ trik eto-h oxah yd r© ~ p y r la id in e -l,5 * “*p iran e.

The term “sp iren c* i s o b je c tio n a b le in th e

k% e a s e o f h eteroeye lee* in th a t th e ending im p lie s a hydrocarbon* •

Don and T od er^ recommend th a t th e two r in g s w ith t h e ir su b s titu e n t groups he named se p a r a te ly In th e euetonary way* and th e te n s •sp ire * (in i t a l i c s ) in s e r te d between them* preceded by numbers lo c a tin g th e p o s itio n o f th e c e n tr a l carbon w ith resp ect to each r in g in th e order named*

Thus, th e above compound would be named eyelep r© p aao*1.5-sp ire»

? , lw 6 - t rlk ©t o-he xehyd ro-py rlmld in e •

III.

D iscu ssion OF BRSULT6

Tli# work o f Dox and Toder*^ on tb # attem pt #4 sy n th e sis o f oy© lopropane-1 • 5 - s p i r o - ? , k • 6 - t rik o to -h e x a h y d ro -p y r i a i dine vac r e p e a te d . P e e u lta i d e n t i c e l w ith th # ir c war# o h ta iiia d .

L ikew ise, whoa ex tra s#

pro#eation# were taken to in s u re anhydrous c o n d itio n s th ro u g h o u t th e condensation o f th# e th y l cyclopropane d l#arb oxylet# and th# urea* an amorphous product was ob tain ed .

Further A ttem pts to prepare t h i s

oenpound by treatm ent o f th e d la a ld e o f cyclopropane d ic a r b o x y lie aeid w ith e th y l oarbonate, employing sod inn eth oxid e as eondems in g agen t, a ls o produced the amorphous produet p r e v io u sly rep orted .

The b a r b itu ric

so id was prepared by treatm ent o f th e diamide o f c y o lo p r o p a a e -l,1d le a r b o x y lle aold w ith o x a ly l ohloride*

The r e se tio n proceeds as

fo llo w s

c©fr%

c i oc

H.C' |

co - m

w ith th e lo s s o f hydrogen o h lo r id e and earbon monoxide. Attempt* were made t o prepare e th y l oyelopropazie d ie arboxy la te * which bad a lip h a tic or arom atic su b s titu e n ts on the cyclopropane rin g by the r e a c tio n o f th e appropriate d ih a lid e s w ith m aloalc e s t e r in th e presen ce o f sodium eth oxide as condensing agent*

These ex p o rlea n ts

were not s u c c e s s fu l due to th e d i f f i c u l t y experienced in condensing d lh a lld e s p o s se ss in g a primary and a secondary halogen, or two secondary h a logen s, w ith a s in g le m olecule o f m alonie e ste r *

In both o a s e s , th e

elem en ts o f hydrogen bromide were removed from th e d lh a lld e s to fo n t th e corresponding brom o-ethylonio compound. * fu rth er attem pt to s y n th e sise an e th y l cyclopropane d l

oarfeoxylate p o s s e s s in g an a ren a tlo su b s titu e n t on the cyclopropane rin g fey p y r o ly s is o f th e appropriate pyrasolim e, y ie ld e d th e corresponding s th y le n ie d e r iv a tiv e e x c lu s iv e ly . y C o o c 9n 9

h

C,H» - C |

I

CCOCjH, p y r o ly * .

/COOC.R, * C,K, - C * C \ | COOCaBs

k

340 )«

W elters and t l s e ^ b e lie v e th a t th e

decom position p oin t may have been m istaken fo r th e m eltin g p o in t by p reviou s I n v e s t ig a t o r s * ^

S o h itte n h ela and W ien er^ record th e m eltin g

p o in t o f oarbonvldlurea as ?33-?340 * Prepara t ion o f th e dlwalde o f

so ld

according t o th # method o f In gold , Sake and T horpe^ S e v e n ty -f1ve grams o f e th y l c y clo p ro p a n e-1 ,1 -d lea rb o x y la te was mixed w ith 375 grams o f concentrated aqueous ammonia and shaken o c c a s io n a lly fo r th ree days*

On th e fourth day th e d l sn id e which

separated was c o lle c t e d on a f i l t e r *

The f i l t r a t e was evaporated to

dryness in vacuo and th e combined s o l i d s were r e c r y s t a llis e d from hot e th y l a lc o h o l (m» p. 19P-4°}*

P reparation o f th e d lan ld o o f Cyolopropane-1® i-d io a r b o x y lle aold em ploylag liq u id ©anomie and ammonium c h lo r id e c a t a ly s t as suggested by Attdrieth and E loinbarf^9 Cm© hundred end f i r e great* o f e th y l oyo lo p ro p a n e-l,1 d ie a r b o x y la te / 4 greats o f ammonium o h lo r id e , and 540 s c . o f liq u id ammonia were jla o e d in a g la s s co n ta in er (adapted fo r nee la a bomb) and th e Mixture plaeed in a bomb®

The r e s e t ion was allow ed t o prooeed

fo r £4 hours w ith co n tin u a l m echanical shaking a t room t e ape rat are. The ex©ess liq u id ammonia was perm itted t o evaporate in th e hood and th e w hite s o lid resid u e was r e e r y s t a llis e d from hot e th y l a le o h o l. 6?*3 grans o f th e d lan id e (93 peroent o f th e t h e o r e t ic a l) was obtained (m. p* 19y~194°). P reparation o f,o jg o lo p r o p ip a -l,5 -sM r o -T ,4 ,^ ^ ^ (5~dlaethyl©n© h a r h itu rlo aold ) dnhydrous o x a llo aold was prepared from th e hydrate aooording t® th® aathod gi*®n l a Or©*®!® Sy&th®*®c.5°

O xalyl ohlorld®

jsr*-

parad aoeordlng to th® method o f S t a a d lB g * ^ by tr e a t in g o x a lle aold (anhydrous) w ith phosphorus pentachlorid® . The method o f £ inborn

17

was employed*

S ix and n in e -te n th s

grans (0*054 n o le s ) o f th e d lan id e o f © yoiop rop aae-1,1-d iearb oxylie aold was plaeed in a 100 ml* b o ilin g f la s k provided w ith an e f f i c i e n t r e f lu x eolusta and p roteeted a g a in st atn osp h eric a o lstu re* added r a p id ly 9«p grans (*07? n o le s ) o f o x a ly l ohloride®

To t h i s was The r ea o tio n

m ixture began to fr o th and fu n es o f hydrogen o h lo rid e were liberated® The Mixture was then heated fo r l~ * l/f hours on th e steam bath®

Twenty

oc® o f water was added t o th e fr o th y mass to d e str o y th e ex o ess o x a ly l ohloride®

The e n t ir e mass went in to so lu tio n and on sh ort sta n d in g .

20.

a volum inous, s l i g h t l y y e llo w ish p r e c ip ita te formed*

On f i l t r a t i o n

and r © crystal 11* at ion o f th e

s o lid fr©» hot water* as lo g l o r i t e fo r

d e c o lo r !* a tIo n , 3*5 grams o f

w h ite s a tin y , lu str o u s p la t e s were

obtained which did n ot m elt helow 300°.

The m a teria l charred a t

h igh er tem peratures* 19*30 mg* sample produced 33*04 mg. €0$ 19*30 mg. • • 7*290 mg. HgC 20*50 mg* sample produced 35*16 mg* C0ffl 7 0 .5 0 h . • * 7 .3 7 7 *0 13*11 mg* sample produced 2.056 e e . I 9 Frees* 771 mm. 1 Temp. 25

c*

17*713 mg. Sample produced 2*022 00 . Xt F rees. 770 am .. Temp. 75° c * Cftlc* f o r 0*11*0*1**

C*

Found*

C-

46»76^Ss1 * 3*92£i t * l i . l i * 46*51 46*09

K * 3 .9 0 1 I * 10.71 4*00 10*20

M olecular weight determ inations were mftde by th e h e llin g p o in t d e r a t i o n method u sin g e th y l a le o h o l as solven t*

R e la tiv e ly

la rg e q u a n titie s o f so lv e n t were required t o e f f e c t th e s o lu tio n o f th e so lid * h t h f l alaob ol “ U *5 T r l.l I

gt._ o f «»«EXa ■ C.JJ851 f -

T r i a l II

0.?*80 g r .

f t * o f so lv e n t * 30*70 g r.

79*13 g r.

B o llin g p o in t a le vat ion « ©.070®

0*065°

Colo, fo r C*Ba0*f?a* M. W. « 154* 1 Foundt

T r ia l I ,

154*7

T r ia l n * 15®* 6 Frej&aratlom o f oyolopropa^

add

r iv © -ten th s o f a gram o f th e dl amide o f eyoloprepam e~i,l*» d ie a rh o x y ilo so ld was hydrolysed by h e a tin g under r e flu x w ith a s o lu tio n

o f 0*5 grams potassium hydroxide in 20 ee* o f water u n t i l no anneal* gas was lib e r a te d (? hoars)* w ith d ilu t e s u lfu r lo sold*

Th® m ixture was cooled and n e u tr a lis e d A s l i g h t ex cess o f so ld was added*

The

s o t d lf le d s o lu tio n was f i l t e r e d to remove a very s l i g h t tu r b id it y end ex tra cted w ith th r e e 1 0 -co . p o rtio n s o f eth er ( a fou rth p o rtio n o f e th er on evaporation did n ot lea v e & s o lid resid u e)* e x tr a c t was d r ied ever o a ld u st ch lorid e*

The eth er

The eth er s o lu tio n , on

evaporation a t room tem peratore, y ield e d c o lo r le s s n e e d le s a sso c ia te d w ith a sm all amount o f o il*

The c r y s t a ls were pressed on a c la y p la te

t o remove th e o i l and r e d isso lv e d In e th e r .

The e th e r was evaporated

and the p rocess repeated u n t i l a l l o i l had been removed*

* h lt e c r y s t a ls

(0*3 g r * ) were obtain ed (m* p* 140-141°) as reported by P e r k in ^ fo r o y e lo p rep & n e-l,1 -d lea rb o x y lle acid*

The a cid was lik e w is e prepared

by th e h y d r o ly sis o f e th y l c y o lo p ro p a n e-1 ,1 -d io a rb o x y la te. P reparation o f t h , b U -(p -trq a o E h en « o rl)* « ter e f o g e lo p r o p » a « -l.ld ie arboxy H e a c id . Two-tenths o f a gram o f oyolop rop an e-1,1-d lcarb oxyl le acid was d is so lv e d in 5 ee* o f water and c a r e fu lly n e u tr a lis e d w ith a 10 percent sodium hydroxide s o lu tio n ,

k drop o f d ilu t e h yd rochloric

a eid was added t o make th e s o lu tio n s l i g h t l y a c id .

Tea ee* o f a lc o h o l

and 0*4 gr* o f p-bremepbeftaeyl bromide were added*

The m ixture was

heated under r e f lu x fo r 2 hours. o f th e h e a tin g .

A s o lid separated during th e ©curse

Three so* o f a lco h o l was added t o d is s o lv e th e s o lid

and th e s o lu tio n was allow ed t o cool*

The s o lid which separated was

re c r y s ta l U sed from 35 percent e th y l a lco h o l Cm. p. 15?°) • Boyer53 rep ort th e m eltin g p oin t as 146°• 1 0 .2k mg* sample produced 10*10 asg. €0* 10*24 mg* * * 2*316 mg* 8*0

A llen and

22

15*61 n&* sample produced 27*63 mg. COg 15*61 u g. » • 4 . 33a mg* % 0 gala* f o r ^21^l6^6®r2*

a * % a .i2 f. II • 3*08%

found.

0 * 48*25

H » 3.13

4 3 .2 9

3 .1 1

tj« jg a i& E a ja L ttL ^ d io a r b o j^ llo s o ld . fiie e s t e r wee prepared a s above.

B e o j y s t a lliz a t lo n from 95

p ercen t a lo o h e l gave c r y s t a ls which melted a t 178°•

5*941 «d* sample produced 16*6? mg,* 3Cg 5*941 mg. • • 2.853 mg. a 2o M i * fo r S j ^ g ^ i

c a 76*43. S • 5*05

to a s t*

3 * 76*54. H * 5*27

H yd rolysis o f 5»dim ethylene b a r b lta r lc s o ld . Two grata* o f th e b a r b itu r ic as id was hydrolysed by b eat i mg under r e flu x w ith a s o lu tio n o f o f water*

1 . 5

gr*

of

potassium hydroxide in

2 5

as*

The «1xture was heated u n t il ammonia gas was me lon ger lib e r a te d *

The s o lu tio n was se e le d and a o id lf l ed w ith d ilu t e s u lfu r le as id*

The

a s ld lf ie d s o lu tio n was e x tr e ste d w ith th r e e lo ~ c c » p o r tio n s o f ether* The e th e r e a l e x tr a c t was d ried ever s e d imm s u lf a t e and evaporated a t room temperature*

The s n a il amount o f o i l which was a sso c ia te d w ith th e

n e e d le s formed was removed. as b e fo r e , on a c la y p la te *

C o lo r le ss n e e d les

( a . p* i40*1419 ) were obtained whioh when mixed w ith th e c y o lo p r o p a a e -l.i~ die& rboxylla acid p r e v io u sly prepared, gave no m eltin g p o in t depression* The bis«(p'-bromophenaeyl) e s t e r was prepared (®* p* 152°) as b e fo r e . The h y d r o ly sis product I s . th e r e fo r e , o y c lo p r o p a n e -l.l-d io a r b o x y lio a c id .

sy n th e s is o f 5»dl methylene b a r b itu r ic a cid fry th e condensation o f th e .di amide o f cyolcp rop an »»l*l«d lcarb o*yllc acid and e th y l o&rboaafcc* Two grams o f th e diaodde o f cyclop rop an e-l /l-d lo a r b c x y lic acid* 5 gram s o f e t h y l c a r b o n a t e and 2 * 5 &r*

s o l i d so d iu m e t h o x l d e w ere

p l a c e d i n a s m a ll t e s t t a b s p r o v id e d w ith a m e c h a n ic a l s t i r r e r and p r o t o o t o d a g a i n s t a tm o s p h e r ic m o is tu r e *

The t o s t tu b e was p la n e d i a an

o i l b a t h a t 120° f o r 5 h o a r s * w ith c c m tin u e a s s t i r r i n g * m a t e r i e l was form ed*

iom e s o l i d

The p r o d u c t was rem oved t o a b e a k e r and d i s s o l v e d

i n a minimum am ount o f w a te r*

The s o l i d c o m p le te ly d is s o l v e d *

o f u n r e a c t e d e t h y l c a r b o n a t e fo rm ed o n ta p *

4 la y e r

On s o l d i f i x a t i o n w ith d i l a t e

h y d r o c h l o r i c a c id * a n am orphous g e l a t i n o u s p r e o l p i t a t e form ed* t i o n s y i e l d e d a m ass o f w h ite g e l a t i n o u s s o l i d *

F lltra *

The am o rp h o u s m a t e r i a l

when h e a t e d w ith w a t e r fo rm ed a s m a ll am ount o f a n o r a n g e o i l y t a r w hioh re m a in e d u n d is s o lv e d *

F i l t r a t i o n and c o o l i n g o f t h e f i l t r a t e p ro d u s e d a

s m a ll q u a n t i t y o f a w h ite s o l i d w hioh d r i e d t o a m ass o f h a rd * b r i t t l e * s h in y m a t e r i a l and whi eh d i d n o t m e lt below J0 0

o

3*

The p r o d u c t re s e m b le s

i n a l l r e s p e c t s t h e am orphous p o ly m e rs p r e v i o u s l y o b t a i n e d fro m t h e so d iu m e t h o x id e c o n d e n s a tio n o f u r e a and e t h y l c y c lo p repane-1 *l«*dloarbejiyl*

a te * ^ P reparation o f sty ren e dlbrosdde * according to th e method o f Swans and Morgas54 To a s o l u t i o n o f 4^*5 g ram s o f f r e s h l y d i s t i l l e d

s ty re n e In

400 eo* p u r e e t h e r w e re a d d ed 126*8 g ram s o f b ro m in e d i s s o l v e d i n 600 oo* e th e r *

The s o l u t i o n o f s t y r e n e was p l a c e d i n a n o p e n b e a k e r s u rro u n d *

ed by i o e - w a t e r and k e p t I n c o n s t a n t n o t i o n by a m e c h a n ic a l s t i r e e r * r a t e o f f le w o f t h e brom ine s o l u t i o n was r e g u l a t e d a c c o r d i n g t o t h e d i s c h a r g e o f c o lo r *

The c r u d e p r o d u c t o b t a in e d bp d i s t i l l i n g o f f t h e

The

24

e t h e r and s u b s e q u e n tly c i y s t & i l i s l m g th e re s id u e fr o m d i l u t e a l c o h o l y i e l d e d 120 g r* o f s t y r e n e dlbromide* t h e o r e t i c a l am ount*

Some s t y r e n e

The y i e l d was f d p e r c e n t o f t h e

dibrosdde

mas o b ta in e d fro m Dr* H a l l e r

o f t h e U n ite d S t a t e s D e p a rtm e n t o f A g r i c u l t u r e , S e l t s v l l l e , M aryland* A tte m p te d .s y n th e s is o f e t h y l 2-ph& m yL T c.yclopropage- 1» 1 -d 1 c a rb o x y 1 a t e * One h u n d re d g ra m s o f s t y r e n e d lb ro m id e and 5®*5 gram a o f e t h y l m&lcn&t* s e r e p la c e d i n a j - i l i o r , J-m ao x ed fiu s* c p r o v id e d w it h a r e f l u x c o n d e n s e r and a m e c h a n ic a l s t i r r e r *

A s o l u t i o n o f 16*7 g ram s o f so d iu m

i n 2 ? 5 tc * o f a b s o l u t e a l c o h o l m i s lo w ly ad d ed th r o u g h a d r o p p in g f u n n e l d u r i n g a p e r i o d o f 2 *1 /2 h o u rs *

t h e m ix tu r e was h e a t e d and s t l r r e d on

a n o 11-bath a t S0° f o r 5 h o u rs *

M ost o f t h e a l c o h o l was d i s t i l l e d o f f

and s u f f i c i e n t w a te r was ad d ed t o d i s s o l v e th e s o l i d so d iu m b ro m id e*

A d e e p -re d l i q u i d s e p a ra te d *

The l a t t e r was e x t r a c t e d w ith e t h e r *

The

e t h e r s o l u t i o n w as d r i e d o v e r so d iu m s u l f a t e a f t e r w hich t h e e t h e r was d is tille d *

At a p r e s s u r e o f 6*7 mm* * t h e g r e a t e r m ass o f t h e r e s i d u a l

liq u id d i s t i l l e d s o lid d is tille d

a t 7 2 -7 7 ° •

Above t h i s t e m p e r a t u r e , a s l i g h t l y y e lle w ls n

w hich was i d e n t i f i e d a s s t y r e n e d lb ro m id e by a m ixed

m e ltin g p o i n t d e te r m in a tio n *

R e fr a e t l o n a t l o a o f t h e i n i t i a l l i q u i d

f r a c t i o n was n o t v e ry e f f i c i e n t and a l l f r a c t i o n s c o l l e c t e d c o n t a i n e d b ro m in e a s I n d i c a t e d by s o d iu m * fu s io n e le m e n ta r y a n a ly s e s * p o s s e s s e d a n i r r i t a t i n g o d o r*

The f r a c t i o n s

M alo n io e s t e r was fo u n d i n e a c h o f t h e

f r a c t i o n s by t r e a t i n g e a c h f r a c t i o n w ith a q u e o u s ammonia* s h a k in g an d p e r m i t t i n g t h e m ix tu r e t o s t a n d o v e r n ig h t*

On p o u r i n g o f f t h e a q u e o u s

l a y e r and e v a p o r a t i n g t h e s o l u t i o n , a s o l i d w as o b t a i n e d w h ich was c r y s t a l l i s e d fro m e t h y l a l c o h o l an d by m ixed m e l t i n g - p o i n t d e te r m in a tio n * was shown t o be m alonam ide*

I n t h i s way* a l l t h e m a lo n ic e s t e r was

rem oved fro m t h e d i s t i l l a t e *

and r e f r a c ti© n a tio n o f th e d r ie d d i s t i l l a t e

g a v e a l i q u i d ®&iah d i s t i l l e d

a t ? 1 ° a t a p r e s s u r e o f 6- S am*

T he d i e -

t i l l a t a | a ? e a p o s i t i v e t e s t f o r h a lo g e n and f o r u m s u tu r a tio n *

The

m a t e r i a l l a p r o b a b ly & m ix tu r e o f * - o romos t y r en e ( b* p* 71° a t 3 mm*) an d d d - b r e m o s ty r e n * (b * p . 71 a t a p r e s s u r e o f 6 ma*

a t 6 mm*) *

y & io a lc © s ta r b o l l s a t 73

If© a o a d e a s a t i o a b e tw e e n s t y m o d ib ro m id e and

a a lo f ilo © s ta r w a s , t h e r e f o r © , o b s e rv e d *

The a l c o h o l i c a l k a l i n e t r e a t­

m ent a e r e l y s o r t e d t o rw aove t h e e l ©stents o f h y d ro g e n b ro m id e fro m th e r e a c t i o n and p ro d u c e d t h e c o r r e s p o n d i n g u n s a t u r a t o d d e r i v a t i v e s * P r e p a r a t i o n o f 2 * 3 -& ib ro « a se a ta tt» F cn tem e- 2 was p r e p a r e d fro m pembaaoi-2 a c c o r d i n g to t h e method g iv e n I n O rg a n !a S y n t h e s e s * ^ F e n te a e - 2 (7 3 * 7 £ rasas) was d i s s o l v e d i n 600 o s . o f e t h e r and t h e e o l a t i o n was c o o le d I n an l e e - s a l t m ix tu re *

B rom ine (1 6 8 * 5 g ra m s)

mas a d d ed s l o w l y , t h e r a t e o f a d d i t i o n b e i n g r e g u l a t e d a c c o r d in g t o t h e d is c h a rg e o f c o lo r .

M e c h a n ic a l s t i r r i n g was m a in ta in e d th ro u g h o u t*

The e x c e ss o f b ro m in e mas removed by s h a k in g the e t h e r s o l u t i o n with a n aqueous sodium b i s u l f i t e s o l u t i o n *

The eth er s o l u t i o n w as th e n m ashed

su c c e s s iv e ly w ith a q u e o u s so d iu m h y d ro x id e and w a te r an d f i n a l l y d r i e d o v e r a n h y d ro u s c a lc iu m c h l o r i d e # 2 , J - d 1 broffiopentaae d i s t i l l e d * b o i l e d a t 1 7 3 -1 3 1 ° .

The e t h e r w as e v a p o r a t e d and t h e

At a p r e s s u r e o f 7 6 0 * 7 m%* • t h e p r o d u c t

The y i e l d was 13d gram s*

A second d i s t i l l a t i o n

p ro d u c e d 116 &r* o f m a t e r i a l b o i l i n g a t 1 7 3 -1 7 9 ° * s r e p o r t e d by i a g a e r and S a l sew *&

Attempt

a t t h e p r e p a r a t i o n o f e t h y l 2 -m a th v 1 - 1 - e t h y l c y c lo p r o p a n e - 1 , 1 -

d lo a rb o x y ia te On© hand ro d and s i x t e e n gram s ( 0 * 5 0 4 s o l e s ) o f 2 ,3 - d i b romp o n ta n e and 30 gr* ( 0*500 m o le s ) o f m & lenlo e s t e r w e re p la c e d i n a 3 -n e e k e d f l a s k

p r o r i d ©4 wl t a a r e f l u x a&M© u ser and a i& eohaals& l s t i r r e r *

4 s o lu tio n

©f 23 gram s o f sod iu m i n JJ® e o . o f a b s o l u t e a l c o h o l was s lo w ly added th r o u g h a d r o p p in g f u n n e l d u r i n g a p e r i o d o f 2 h o a rs *

t h e m ix t u r e was

h e a t e d and s t i r r e d

t h e m ix tu r e

on an o i l h a th a t S 0° f o r 5 h o a rs *

tu r n e d m ilk y a f t e r t h e f i r s t a d d i t i o n o f t h e so d iu m e t h o x ld e s o l u t i o n * M ost o f t h e a l c o h o l w as t h e n d i s t i l l e d

o f f and o n t h e a d d i t i o n o f w a t e r .

t h e so d iu m b ro m id e d i s s o l v e d and am o i l s e p a r a te d *

The m ix tu r e was

e x t r a c t e d w ith e t h e r and t h e e t h e r s o l u t i o n was d r i e d o v e r a n h y d ro u s so d iu m s u l f a t e *

On e v a p o r a t i o n o f t h e e t h e r and d i s t i l l a t i o n *

f r a c t i o n * w ere o b ta in e d *

The f i r s t *

tw o

b o i l i n g a t 10& -1100 * i s p r o b a b ly

210° I n a n i c e - s a l t m ix tu re * T he c l e a r s o l u t i o n was a llo w e d t o flo w s lo w ly i n t o a c o o le d m ix tu r e o f 600 g r* o f I c e and 110 g r* o f c o n c e n t r a t e d s u l f u r i c a c id w ith e f f i c i e n t s tirrin g *

The n i t r e s © d e r i v a t i v e was c o l l e c t e d o n a s u c t i o n f i l t e r *

w ashed w ith w a t e r an d d r i e d I n a d e s s i c a t o r s e t i n t h e r e f r i g ® r a t e r * One h u n d re d a n d tw e n ty -tw o gram s o f p r o d u c t w as o b ta in e d *

aa X ttasom ethaa# was pr@ pn.rsd % th@ m ethod g i r c n i n O rgan! g

6l

3 y a th e a e s "

•

J f itr o s o m e th y lttr e * was ad d ed t o a o o o i« d mi x t u r e o f e t h e r

@nd a 30 p e r c e n t a q u e o u s s o l u t i o n ©f p o ta s s iu m h y d ro x id e *

On w a rn in g

t h e m ixtur® t o $ ) ° » th© d ia e o m e th a n e d ls f c lH o d w i t h th@ e t h # r .

H i#

# t h « r s o l u t i o n o f th o 4 ia so m etb a m e urns a o i l e o t e d I n aool@d r>-so@lr@rs. ■ addition o f dia&oiae th a n e t o bem & aim alem lg e s t e r * T h i r t y - o n e a n d t h r e e - t e n t h s g ram s o f b e n s& lm a lo n io © s ta r was d i s s o l v e d I n 100 0 0 . o f a n h y d ro u s e t h e r and t h e s o l u t i o n o o o le d I n a n l a s - * s a l t m ix tu r e *

D la so m e th a n e i n o t h e r s o l u t i o n (fro m 20*6 g r* o f

m ltr c s o m e tliy lttF e a ) was a d d ed t o t h e abowe m ix tu r e an d th # a M ib la s d s o l u t i o n s ©©©led f o r 12 h o u r s I n a n l o e - a a l t m ix tu re *

The r e a o t l o n

m ix tu r e was t h e n p o o le d t o ~JQ0 l a a n @ ©eteo@ -dty ie© m i x t u r e .

t\ © o lo r*

l e s s m ass o f l u s t r o u s c r y s t a l s fo rm ed w h ich w e re f i l t e r e d and w h ich m e lte d a t 3*3-51°*

One r e 3r y s t a l l ! t a t i o n g a e e o o l o r l e s s , l u s t r o u s p l a t e s

o w h ich m e lte d a t 5^ *5*51 •

B ^w aporatloa o f t he e t h e r f i l t r a t e

and r e c r y s t a l ­

l i s a t i o n o f t h e s o l i d fro m e t h y l a l c o h o l l i k e w l a e ga@@ p l a t e s w hloh m e lte d a t 3 0 *5 *31°*

t h i r t y - s i x gram a o f m a t e r i a l w ere o b ta in e d r e p r e s e n t ­

i n g a y i e l d o f fS«7 p e r c e n t *

J3*74 »S* s e n p l e p ro d u c e d 76*54 53*74 mg* * * l§*7d

mg* H20

37*64 mg* s a a ^ l e p ro d u c e d 05*59 37*64 mg* * « i f *04

®S* 3Q2 mg* H20

®S* 30$

3 a lo * fo r C jjjBxgO ^f

3 * 62*04$j S * 6 * 2 ^

fo u n d s

0 » 61*75 62*02

3 * 6 .2 3 6 *1?

The p r o d u c t I s e t h y l 44»?h@ nyl- A* - p y r u s o l i n e - 3 , 3 - d io e r b o a y l u t e *

1 .flOGOjflEj &6JU * a ------< | I QOOO^Ec

23 * The above s t r u c t u r e i s a s s ig n e d by a n a lo g y a c c o r d in g t o t h e r e s e a r c h e s o f to o & i » r a ^

i n w h ich a A '- p y r a i d in© was p r e p a r e d by t h e a d d i t i o n

o f d la se m e th a m e t o t h e a n a lo g o u s m alem ta e s t e r c o n t a i n i n g a m e th y l i n s t e a d o f th® p h e n y l g ro u p ^ 1 *0 * t GHjCH * O C X O ^ H j^ ^ j • P y r o l y s i s o f e t h y l k~vh&m I - A **»py rm s o l 1 a e - j , 3-d t e a r b e i y 1 a t o Tw enty gram s o f t h e A * - p y r a i o l ! no was p la c e d i a i l a r g e t o a t tu b a p r o v i d e w ith a s i d e - a r m , an d a th e rm o m e te r s e t l a a s i l t c o r k .

The tube mm placed l a an ©11-bath m aintained a t 125° •

The p y r o ly s is

was conducted under a continuous streaai of n itr o g en gas* began a t f8°*

The teaperatur© o f th e m olten p yraiollm e was ao t perm itted

t o r is e above 120°•

A fter

a l l gas e v o lu tio n had o e a sed , the h ea tin g

continued fo r aa a d d itio n a l o n e -h a lf hoar* 3 hoars*

Gas © volution

was

The e n tir e p y r o ly s is reqpilred

A y e llo w , w w eet-srnelling o i l was produced*

i t a p ressu re o f

5 ®»* t th e m aterial d i s t i l l e d a t 141-142° and was a c o lo r le s s o il*

The

product gave a p o s i t i v e t e s t fo r u n satu ration w ith to tra n itro a eth a n e* 21*35 »g* sample produced 53*^2 sg;* GOo 2 1 .J 5 »g* * • 13*34 *4*%0 2 4 *0 $ »g* sam p le p ro d u c e d 60 * 5 5 *£* GOg

24*06 m^*

*

*

H *35 m * h2o

Gala» f o r

0 * 68*68$ H * 4*32

Founds

Q • 43*73$ s • 4*33 43*42 4*35

The m a t e r i a l w as p ro d u c e d i n 3 3 p e r c e n t y i e l d *

i, t a r r y d a r k -

brow n r e s i d u e re m a ia s d fro m t h e d i s t i l l a t i o n fro m w h ich n o t h i n g c o u ld is o la te d * To d e te r m in e w h eth er t h e p y r o ly s p s p r o d u c t o f e t h y l l$~ p h e n y lA ' ^ P ^ ^ ^ l l ^ ^ i ^ J - d i c a r h o a y l a t e p ro d u c e d t h e d e s i r e d c y c lo p r o p a n e d e r i v a t i v e , t h e m o le c u la r r e f l e c t i v i t y o f t h e p r o d u c t was o b ta in e d *

30.

gSM l& t

M o lecu lar are.

««««.

w \ /

n c c o s2H5

ca2 / 20c«2a5 ^ sooa^ oh3 * 7 0 .7 1 0 . Th® e t h y l o n i o compound* h o w e v e r, p ossess® ® t c o n ju g a t e d s y s te m a s s h o r n b e lo w .

38,

o*

~ °S a«s

0

Th® e x a l t a t i o n v a lu e f o r a c o n ju g a t e d s y s te m s u c h a s i s shown a b o /e * h a s n o t been re p o rte d in th e l i t e r a t u r e *

T he c y c lo p r o p a n e d e r i v a t i v e (A ) e cu id

n o t p o s s e s s a n e x a l t a t i o n v a lu e d u e t o t h e a b s e n c e o f a c o n ju g a t e d sy ste m * I t may be assum ed* t h e r e f o r e * t h a t t h e d e v i a t i o n o f t h e e x p e r im e n t a l m o le c u la r r e f r a c t i v l t y fro m t h e c a l c u l a t e d v a lu e i s d u e t o a c o n ju g a t e d s y s te m and t h a t t h e compound u n d e r c o n s i d e r a t i o n p o s s e s s e s t h e e t k y i e a l c s t r u c t u r e (B) a s o p p o se d t o t h e c y c lo p r o p a n e s t r u c t u r e (A )* A m a e a o lv s ls o f E t h y l 2 -a h e a y l«»l~p ro p e n e * 1 *l« d io a r b o x v l a t e * One gram o f t h e a b c

s p l a c e d i n a l a r g e t e s t tu b e and

35 he* o f c o n c e n t r a t e d a q u e o u s ammonia was added*

The m ix tu r e was s to p p e r e d

and a llo w e d t o s t a n d f o r 2 d a y s w it h f r e q u e n t s h a k in g ? T he o i l p a r t i a l l y d is s o lv e d *

The w a t e r i n s o l u b l e l a y e r was shown t o b e a o e to p h e a o n e by

31 . t h e p r e p a r a t i o n o f t h e 2 * t - d l & l tr o p h e n y lh y d r a r o n e d e r i v a t i v e (a * p . 237° ) an d

bp a

m ix ed m e ltin g p o i n t d e t e r a d n a t i on w ith

known

a c e to p n e n o a e - ^ *b-

d I n i i ro p h e s y Ih y d r a s o n e t h e am adous l e p e r was e v a p o r a te d on t h e s te a m b a th and t h e s o l i d r e s i d u e r e o i y s t a l l i z e d fro m e t h y l a lc o h o l*

The p r o d u c t (a * p*

1 7 0 -1 7 1 °) w as shown t o b e s u tiw n a s ld e by a m ixed m e l t i n g p o i n t d e te r m in a ­ tio n * The a m m o ao ly sis* t h e r e f o r e * c le a v e d t h e e t h y i e n l o l i n k a g e o f t h e p ro p e n e e s t e r * The a m m e a o ly sis was a l s o a tte m p te d u s i n g l i q u i d aam onla*

The

sam e r e s u l t s a s b e f o r e w e re o b t a in e d ( i *e* a c e to p h e a c s te and m alonam ide w e re I s o l a t e d } *

H ydrolysis o f E th y l 2 -p h e n y l-l-c r o o a n e - l.l-d lo a r b s x y la te . T h re e g ram s o f t h e a b o v e e s t e r was h e a te d u n d e r r e f l u x w ith a s o l u t i o n o f 2 g ram s o f p o ta s s iu m h y d r o x id e i n 20 ce* o f w a t e r f o r a p e r i o d o f J h o u rs *

The m ix tu r e was c o o le d an d f i l t e r e d t o

remove a

s l i g h t t u r b i d i t y a n d was t h e n n e u t r a l i s e d w ith d i l a t e s u l f u r i c a c id * The s o l u t i o n becam e c lo u d y *

I t w as t h e n e x t r a c t e d w ith two 1 0 - c c ♦

p o r t i o n s o f e t h e r and on e v a p o r a t i o n o f t h e e t h e r s o l u t i o n * a s l i g h t l y y e l l o w i s h o i l w as o b ta in e d * lis e d *

On s ta n d i n g * a p o r t i o n o f t h e o i l c r y s t a l ­

To p u r i f y t h e s o l i d a c i d p r e s e n t an d t o s e p a r a t e I t fro m any

o i l t h e s i l v e r s a l t was p r e p a r e d *

The p a r t i a l l y

s o l i d i f i e d o i l was

d i s s o l v e d i n a q u e o u s ammonia and s l i g h t l y m ore t h a n t h e c a l c u l a t e d q u a n t i t y o f a q u e o u s s i l v e r n i t r a t e was added*

The p r e c i p i t a t e d s i l v e r

s a l t was w ash ed w ith w a te r an d d i s s o l v e d I n a s m a ll am ount o f c o n c e n t r a t e d ammonia w a te r*

D i l u t e h y d r o c h l o r i c a c i d was ad d ed and t h e p r e c i p i t a t e d

s i l v e r c h l o r i d e was f i l t e r e d *

The a q u e o u s f i l t r a t e was e x t r a c t e d w ith

tw o lO K cc. p o r t i o n s o f e t h e r *

The e t h e r s o l u t i o n was d r i e d o v e r a n h y d ro u s

so d iu m s u l f a t e and t h e e t h e r e v a p o r a te d *

An o i l

re m a in e d w h ich so o n

c r y s t a l l i s e d t o y i e l d c o l o r l e s s p r is m s (a u p* 1 3 5 * 1 3 6 °)*

The m a t e r i a l

was shown t o h e i d e n t i c a l w it h m n lo a to a c i d by a m ix ed m e l t i n g p o i n t d e te r m in a tio n * h y d r o l y s i s o f t h e p ro p enem as t e r a p p a r e n t l y served t o c l e a v e t h e e t h y l e n i c l i n k a g e a s i n t h e p r e v i o u s am m o n o ly sis*

The l i t e r a t u r e

62

r e p o r t s t h e clea v a g e o f t h e e t h y l e n i c li n k a g e o f e t h y l 2~ p h e n y l~ lp ro p e n e * 1-o y o n © -1~ o a rhox y 1 a t e by t r e a t m e n t o f t h i s o y a n o e s t e r w ith b a riu m h y d ro x id e * A tte m p ts t o p r e p a r e

- t n v l 2 * > g h e n y l* l^ p ro p e a e -l » l - d l c a r b o x y l a t e *

Equdmolar q u a n t i t i e s o f m a lo n lc e s t e r a n d a c e to p h e n o n e w ere m ixed and p i p e r i d i n e a c e t a t e « p r e p a r e d by m ix in g e q u l m e la r am o u n ts o f p i p e r i d i n e and g l a c i a l a c e t i c a c i d , was ad d ed *

The m ix tu r e was p e m i t te d

t o s t a n d f o r 2 d a y s a t room temperature and t h e n h e a te d on t h e s te a m b a th f o r 12 h o u rs *

On working up the r e a c t i o n m ix tu r e * t h e s t a r t i n g

m a t e r i a l s w e re re c o v e re d *

I f t h e r e a c t i o n mixture i s h e a t e d u n d e r

r e f l u x f o r $ h o u rs * n o c o n d e n s a ti o n o c c u r s * r e f l u x f o r 34 h o u r s produced no r e a c t i o n *

lik e w is e * h e a t i n g u n d e r I n a l l c a s e s * th e m a lo n lo

e s t e r and a o e io p h e a o a e w ere re c o v e re d *

A f u r t h e r a t t e m p t u s i n g a c e t i c a n h y d r id e an d a n h y d ro u s t i n e c h l o r i d e a s c o n d e n s in g a g e n ts and h e a t i n g t h e m ix tu r e u n d e r r e f l u x f o r 100 h o u rs * was w ith o u t s u c c e s s * Am a t t e s t was made t o p r e p a r e t h e p ro p o n e d l e s t e r fro m t h e c o r r e s p o n d i n g c y a a o ^ e a te r *

&tfcyl c y a n o a c e t a t e was p r e p a r e d a c c o r d in g

t o t h e m ethod g iv e n i n O rg a n ic - S y n th e s e s ^ *

The c y a n o a c e t i c e s t e r so

p r e p a r e d was c o n d e n s e d w ith a c e to p h e n o n e a s d e s c r i b e d by S c h e i b e r and

if e l» e l« * 2 h o e te p h e n o ite ( l 3 a * l g ram s) was m ixed w ith 84*3 gram s o f e y a a e a c e tlc e s te r*

A n i l i n e - s i n e c h l o r i d e * p r e p a r e d by t r e a t i n g 14*0

gram s o f a n i l i n e w ith 2 0 * 5 p raise o f s i no c h l o r i d e * was added and t h e r e a c t i o n m ix tu r e was h e a te d f o r 12 h o u rs l a an a l e c t r ! o a l l y - h e a t e d o i l * h a t h m a in ta in e d a t 13$° •

On t h e a d d i t i o n o f e t h e r * s o l i d s i n e c h l o r i d e

was th ro w n o u t o f t h e s o l u t i o n *

t h e m ix tu r e was e x t r a c t e d w ith e t h e r

and t h e e t h e r s o l u t i o n d r i e d o v e r a n h y d ro u s so d iu m s u l f a t e *

The e t h e r

was e v a p o r a te d o n t h e s te a m h a t h an d t h e r e s i d u e f r a c t i o n a l l y d i s t i l l e d l a vacuo*

At 6 mm* * t h e m a t e r i a l d i s t i l l e d a t 1 5 7 ~ 1 5 ^ °-

and f o u r - t e n t h s gram s o f a c o l o r l e s s l i q u i d was o b ta in e d * JO p e r c e n t o f t h e t h e o r e t i c a l am ount*

F ifty -fiv e The y i e l d was

The p r o d u c t I s e t h y l 2 - p h e a y i - l -

p re p o n e - 1- c y a n o - 1- e a r b o x y 1a t e * H y d r o ly s is and s a t e r l f l e n t i o n o f e t h y l 2- p h e n y l - l - c y a n o - l - c r c p e n e - l o a rb o x y l a t e T w en ty -o n e and f i v e - t e n t h s g ram s o f t h e c y a n o - e a t e r was p la c e d i n a 2 JO ml* f l a s h f i t t e d

w ith a r e f l u x c o n d e n s e r*

1 1 t h th o r o u g h sn a k ­

in g t h e r e was f i r s t a d d ed 1J cc* o f a b s o l u t e a l c o h o l and t h e n g r a d u a l l y a c o o le d m ix tu r e o f 1J cc* a b s o l u t e a l c o h o l and 2 5 cc« c o n c e n t r a t e d s u l f u r i c a c id *

The m ix tu r e was h e a te d f o r 5 h o u r s on t h e s te a m b a th w ith

f r e q u e n t s h a k in g *

The f l a s k was c o o le d w e ll and s h a k e n w ith 100 so* o f

w a te r * and t h e n e x t r a c t e d w ith tw o J O - c c . p o r t i o n s o f e th e r *

The e t h e r e a l

e x t r a c t was w ashed * i t h a q u e o u s so d iu m c a r b o n a te s o l u t i o n u n t i l no l o n g e r a c i d an d t h e n d r i e d o v e r a n h y d ro u s so d iu m s u l f a t e * ed and t h e r e s i d u e f r a c t i o n a l l y d i s t i l l e d * ay axioms t e r was r e c o v e r e d u n ch an g ed *

The e t h e r was e v a p o r a t ­

The g r e a t e r p o r t i o n o f t h e

ic e to p h e n o n e and m e lo n ic e s t e r w ere

i s o l a t e d and i d e n t i f i e d r e s p e c t i v e l y a® t h e 2 *4 - d i a l t r o p h e a y l h y d r a x o » e

34 and a s til® dlamide*

H y d r o ly ti c t r e a t m e n t * t h e r e f o r e , s e r v e d t o c l e a v e

til® e th y le n lc li n k a g e a s b e fo re #

Isom® id e a tio n o f e th y l 4*bhesiyl«» A ^ o y r a c o ila e * ii*3«»dloarboaQrlate» P reparation o f e t h y l 4~p hepy 1 - & 2- p y r a s o l 1a e -5 ,5~ 3 i c a rb o x y l a t e * S e v e n gram s o f t h e A * - p y r a c e 1 i n e w as d i s s o l v e d i n 20 oc# o f

e th er and shaken w ith 30 -©• o f d ilu t e aqueous hyd rochloric acid (1 * I) fo r a period o f 15 minute®*

fh® aqueous la y e r was separated and the

o th e r la y er was dried over sodium s e l f at® and evaporated#

Mi o i l formed

which on sh o rt stan ding c r y s t a lliz e d to g ir o th lo k s o lid noodles#

fie-

c r y s t a l! ! sa tio n from 95 peraent e th y l a lco h o l gar® an almost q u a n tita tiv e y i e l d o f m aterial (at* p . 46- 47 0) *

4 mixed m eltin g p o in t o f t h is product

w ith th e A f~pyrat© lim e, produced a co n sid era b le m eltin g p o in t depression# The A 2-p y r a z o ila e so formed* evolved n itro g en only when heated to approxim ately 226° whereas th e A *-p y r e c o il ae evolved n itro g en a t 93°# j3*57 mg* sa m p le produced 37*94 «&* 302 33*57

*i*

*

*

21*99

mg* %©

31*23 mg* sa m p le p ro d u c e d 7 1 * 0 3 mg# 3 0 2 3 1 .2 3 mg. * • 17*69 mg* Hg© S a le , f o r

0 * 62*04^1 H * 6 .2 5 S

Found?

0 « 62*22 6 2 .1 7

a * 6 .3 d 6 .3 5

t h e i s o m e r i c a t i o n c o u ld n o t h a v e p ro c e e d e d so a s t o fo rm a d o u b le bond b e tw e e n atom s 1 a n d 5*

By a n a l o g y ^ * t h e a l t e r n a t i v e below

a ^^00002^5 *4— 5 9 ^

k

»

4

" ° :2"s

2

P y r o ly s is o f e th y l 4 -p h e a y l- A -p y r a tQ ila s -5 * 3 * d ic & rb o ra la tc *

2

Tw enty 5 ram# ©f t h e A - p y r a s o l l a e was p y r o ly s e d u n d e r a a

©

a tm o s p h e re o f n i t r o g e n a t 230-25& •

A f t e r e l l g e e © v o lu tio n h a s © e a se d •

t h e m a t e r i e l i t s h e a te d f o r an a d d i t i o n a l h o a r*

The e n t i r e p y r o l y s i s

req a i r e d t h r e e h o a r s * a f t e r w hloh t h e r e a c t i o n m s s h ad a d a rk ~ b ro w a c o l o r and a n u n p l e a s a n t o d o r*

A v e ry s m a ll p o r t i o n o f a w h ite c r y s t a l -

l i n e s o l i d ( n e e d l e s ) s u b lim e d and c o n d e n s e d on t h e s i d e s o f t h e p y r o l y s i s tu h e « ( a * p . 2 2 3 - 2 2 9 ° ) •

The m a t e r i a l was shown t o h e a 4 - p h e a y l p y r a s o l e

and a a y b e sto c o u n te d f o r by a ssu m in g s o n s h y d r o l y s i s o f t h e

ra s o lla e

e s t e r d u r i n g t h e h y d r o c h l o r i c a c i d - 3 s o n e r i r a t i o n * and s u b s e q u e n t i e c a r b o s y l a t i o n on p y r o l y s i s *

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