EXTENSIONS OF THE SUBSTITUTED AMIDE REACTION: THE USE OF ALCOHOLS AND THE SYNTHESIS OF OXAZOLINES

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'X l-tlV V l s L usskin, R o b ert M ille r , 19211950 E x t e n s i o n s o f t h e s u b s t i t u t e d am ide 0 L9 , r e a c t i o n : t h e u se o f a lc o h o ls and the sy n th esis o f cxazolineso New Y o r k ,

LD3907

19^ 9 ° SO t y p e w r i t t e n l e a v e s o 2 9 cme T h e s i s ( F h o D „ ) - New Y o r k U n i v e r ­ s i t y , G ra d u a te S c h o o l. 1950° " R e f e r e n c e s " : p79-S0o C50662

c Xerox University Microfilms,

Shflf Ust

Ann Arbor, Michigan 48106

T H IS D IS S E R TA TIO N HAS BEEN M IC R O F IL M E D E X A C T L Y AS R EC E IV E D .

XIBRARY op 1XV TORK OSIVERSin

OHITERSm HEIGHT?

EXTENSIONS OF THE SUBSTITUTED AMIDE REACTION: THE USE OF ALCOHOLS AND THE SYNTHESIS OF OXAZOLINES.

Robert

A d isserta tio n

•\ \ € L usskin

in the departm ent o f chem istry

su b m itted to the f a c u l t y

o f th e G raduate School o f A rts

a n d S c i e n c e o f New Y o r k U n i v e r s i t y i n p a r t i a l f u l f i l l m e n t of th e r e q u ir e m e n ts f o r th e d e g re e o f D octor o f P h ilo s o p h y . Jlry • ■T dLO jm

so

I e x p r e s s my d e e p e s t a p p r e c i a t i o n t o P r o f e s s o r John J .

R itter,

n o t o n ly f o r s u g g e s t i n g th e problem , b u t

f o r th o u g h t f u l a d v ic e and f r i e n d l y d i r e c t i o n d u rin g i t s so lu tio n .

201040

To my p a r e n t s a n d my w i f e ,

whose c o n s t a n t

e n c o u r a g e m e n t was s u c h a n i m p o r t a n t c o n t r i b u t i o n t o w a r d its

s u c c e s s fu l com pletion,

I dedicate

th is

th esis.

CONTENTS

S ection

Page

I.

USE OF ALCOHOLS IN THE SUBSTITUTED AMIDE R E A C T IO N ................................................................... 1

II.

BETA HALO ETKYLAlvilDES AND OXAZOLINES 1. P r e p a r a t i o n and U ses o f O x a z o l i n e s - L iteratu re

S u r v e y .............................................................

11

2 . P r e p a r a t i o n o f Hal o Amides by t h e S u b s t i t u t e d Amide R e a c t i o n .......................................

17

3.

O x a z o l i n e s f r o m B e t a Hal o E t h y l a m i d e s

22

4.

O xazolines - -

Proof of S tru c tu re .

.

. .

26

5 . O x a z o l i n e s f r o m B e t a H alo E t h y l a m i d e s — T h e o re tic a l C onsiderations

.......................................

33

6 . Alpha A cetam ino A cid s - - A c e ty l Alpha

Phenyl G lycine III.

.....................................................................

41

THE REACTION OF NITRILES WITH NITRO ALCOHOLS OR NITRO O L E F I N S ................................................................... 44

IV.

E X P E R I M E N T A L .....................................................................48

V.

SUMMARY.................................................................................... 74

VI.

REFERENCES.............................................................................78

-

I.

1-

USE OF ALCOHOLS IN THE SUBSTITUTED AMIDE REACTION

The s u b s t i t u t e d am ide r e a c t i o n , by J . J . R i t t e r , n itriles

is

discovered

th e r e a c t i o n betw een o l e f i n s and

i n the p resen ce o f s tr o n g a c i d s .

The p r o d u c t s

are N -su b stitu tea am id es,(I). HA RgC :CH2 ■+'

R ' CN

---------- > R2C-CH3 ---------* R2C-CH3

NsG-R1 A

NHC0CH3(I)

O l e f i n s w h i c h may b e h y d r a t e d t o t e r t i a r y a l c o h o l s r e a c t e d r e a d i l y a t room t e m p e r a t u r e w i t h a w i d e v a r i e t y of n itr ile s

in s o lu tio n s of s u l f u r i c and a c e t i c a c id .

O l e f i n s w h i c h h y d r a tec! t o s e c o n d a r y a l c o h o l s r e a c t e d somewhat l e s s r e a d i l y ,

w ith co n cen trated s u lf u r ic acid

a l o n e , and o f t e n a t s l i g h t l y e l e v a t e d te m p e r a tu re s . M in ieri

( 1 ) in v e s tig a te d the r e a c t i o n o f trim e th y l-

e t h y l e n e w i t h a r o m a t i c an d a l i p h a t i c n i t r i l e s .

By

c o n d e n sin g a l l y l b e n z e n e and a c e t o n i t r i l e

in B ulfuric

a c i d a t 80° and h y d ro ly z in g the a c e t a t e ,

K a l i s h (2)

was a b l e t o p r e p a r e am phetam ine.

P laut

( 3) stu d ied

th e p ro p e rtie s of N -su b stitu ted acrylam ides prepared from a c r y l o n i t r l l e and o l e f i n s , and H a r t z e l ( 4 ) p r e p a re d b e n z o a t e s o f arnino a c i d s by t h e i n t e r a c t i o n o f u n ­ s a t u r a t e d e s t e r s and a c i d s w i t h b e n z o n i t r i l e .

Benson

-2

(5)» u s i n g cyanam ide, p r e p a r e d N - s u b s t i t u t e d u r e a s , ( H i H2 SO4. R2 C:CH2 +

H2 NCN

R2 C-GH3 1

K2 0

(II)

nhconh 2

A ll th e r e a c t i o n s were c a r r i e d o u t in a s tr o n g l y a c i d s o lv e n t and i t

had been e s t a b l i s h e d

(6)

t h a t h y d r a t i o n o f a n o l e f i n a n d d e h y d r a t i o n o f an a l c o h o l were r e v e r s i b l e r e a c t i o n s w h ic h p ro c e e d e d t h r o u g h a common i n t e r m e d i a t e ,

H2 0 ------- >

-CH:CH- -v H — » -CH-CH+ H (III)

I t was t h o u g h t p o s s i b l e

th e carbonium i o n , ( I I I ) .

th at,

-CH-CHHOH H *

-CH-CH- -*• H+ OH H

i n t h e s u b s t i t u t e d amide

reactio n ,

t h e o l e f i n m i g h t b e r e p l a c e d by t h e c o r r e s p o n d i n g

alcohol.

In a s e r i e s of e x p e rim e n ts perform ed j o i n t l y

w i t h F . R . B e n s o n (5)

t h r e e a m i d e s w e r e p r e p a r e d by t h e

i n t e r a c t i o n of the a lc o h o l and th e n i t r i l e :

N, N' d i i s o -

p r o p y l m a l o n a m i d e , N,N* d i t e r . b u t y l s u c c i n a m i d e , cyelohexylacetam ide.

a n d N-

The p r e p a r a t i o n a n d p r o p e r t i e s o f

t h e f i r s t two h a v e b e e n d e s c r i b e d ( 5 ) *

N -cyclohexyl-

a c e t a m i d e was p r e p a r e d by a d d i n g c y c l o h e x a n o l i n t w e n t y m inutes to a s o lu t i o n of a c e t o n i t r i l e

in s u lfu ric acid.

The s o l u t i o n was a l l o w e d t o

s t a n d two h o u r s ,

w ater,

s o l i d w as f i l t e r e d .

and th e p r e c i p i t a t e d

poured i n t o The

-

3-

r e c r y s t a l l i z e d p r o d u c t m e lte d a t 104° — in agreem ent w ith th e value r e p o rte d In the l i t e r a t u r e

( 7 )*

The r e a c t i o n o f p a r a m e t h y l c y c l o h e x a n o l a n d a c e t o n i t r i l e w as a t t e m p t e d u n d e r i d e n t i c a l c o n d i t i o n s . Upon d i l u t i o n o f t h e r e a c t i o n m i x t u r e w i t h w a t e r , a heavy o i l s e p a r a t e d .

A f t e r s t a n d i n g s e v e r a l weeks a

sm all y i e l d o f c o l o r l e s s c r y s t a l s , m e ltin g p o in t 78°7 8 . 5 ° , was i s o l a t e d f r o m t h e w a s h e d o i l .

C onsid eratio n

of th e s t r u c t u r e o f N (para m e th y lc y c lo h e x y l)a c e ta m id e showed t h e p o s s i b i l i t y

o f c i s and t r a n s fo rm s.

Because

th e bonds h o ld in g groups to th e r i n g a re n o t in th e p la n e of the r in g ,

a d isu b stitu ted

cyclohexane w ith s u b s t i t u e n t s

on d i f f e r e n t c a r b o n s e x h i b i t s g e o m e t r i c a l i s o m e r i s m .

(IV )

(V)

The r i n g h a s b e e n w r i t t e n i n t h e

" b o a t " form

b u t c o r r e s p o n d i n g i s o m e r s may b e w r i t t e n f o r t h e " c h a i r " form .

I t is

q u e s t i o n a b l e w h e th e r any " c h a i r " o r " b o a t"

iso m e rs o f any c y c lo h e x a n e have e v e r been i s o l a t e d , a l t h o u g h many a t t e m p t s h a v e b e e n made ( 4 7 ) . above r e p r e s e n t a t i o n , A i s h y d ro g en , C is

-NHCOCH^, f o r m u l a ( IV )

is

If,

in the

B i s m e th y l, and

t r a n s - a n d f o r m u l a (V)

-

is

4-

c i s N (para m e th y lc y c lo h e x y l)a c e ta m id e . The two I s o m e r s h a d b e e n p r e p a r e d by S k i t a ( 8 a)

who h a d d i s c o v e r e d t h a t r e d u c t i o n o f a c e t y l p a r a t o l u i d i d e i n e th a n o l w ith hydrogen o v er p la tin u m y ie ld e d N (para m e th y lc y c lo h e x y l)a c e ta m id e ,

trans

m e ltin g a t 7 0 °, and

red u ctio n in a c e tic -h y d ro c h lo ric acid so lu tio n y ielded th e c i s form , m e l t i n g a t 79°•

He sh o w ed t h e c o n f i g u r a t i o n

by h y d r o l y s i s a n d c o n v e r s i o n t o b e n z o a t e s a n d p h e n y l ureid es.

The l o w e r m e l t i n g a c e t a t e

gave b o t h a h i g h e r

m e l t i n g b e n z o a t e a n d p h e n y l u r e i d e , a n d c o n s e q u e n t l y was assum ed t o be t r a n s . The c r y s t a l s ,

(m .p. 7 8 ° - 7 8 .5 ° )

i s o l a t e d fro m

t h e s u b s t i t u t e d a m i d e r e a c t i o n w e r e f i r s t t h o u g h t t o be cis

N (para m e th y lc y c lo h e x y l)a c e ta m id e , b u t q u a n t i t a t i v e

an aly sis

showed 5 » 8 0 ^ n i t r o g e n .

c om pound, h o w e v e r , i s 9 . 0 2 ^ . not in v estig ated

The v a l u e f o r t h e e x p e c t e d

A l t h o u g h t h e s t r u c t u r e was

( l e s s t h a n o n e - t e n t h gr am w as i s o l a t e d )

t h e compound m i g h t b e N - b l s ( p a r a m e t h y l c y c l o h e x y l ) a c e t a m i d e , c o n t a i n i n g 5*57$ n i t r o g e n . r e p o r te d in the l i t e r a t u r e .

T h i s compound h a s n o t b e e n S kita

( 8b ) h a d d e m o n s t r a t e d

t h a t p a r a m e t h y l c y e l o h e x y l amine r e a d i l y u n d e r g o e s a l k y l a t i o n a n d i n t h e p r e p a r a t i o n from p a r a t o l u i d i n e he i s o l a t e d a 5 0 -5 0 m i x t u r e o f m e t h y l c y e l o h e x y l am ine and b i s ( m e t h y l -

cyclohexyl)am ine.

A s im i la r a l k y l a t i o n d u rin g the s u b s t i ­

t u t e d amide r e a c t i o n w ould a c c o u n t f o r t h e p r e s e n c e o f

-

5-

the d ia lk y l acetam ide.

RNHCOCH-. 3

H+ — >

R+- +■ NHo C 0 C H , c 3

The b u l k o f t h e p r o d u c t ,

RNHCOCH-, ------------- *

an o i l ,

Ro NHC0Ch' ^ 3

contained

a m i x t u r e o f t h e two g e o m e t r i c i s o m e r s o f N ( p a r a m e t h y l cyclohexyl)acetam ide. No c o m p l i c a t i o n s w e r e m e t when d l m e t h y l - n butyl carb in o l,

ter.

amyl a l c o h o l ,

and 2 - p e n ta n o l u n d e r ­

went r e a c t i o n e i t h e r w i t h a c e t o n i t r i l e o r b e n z o n i t r i l e . N ( d im e th y l- n - b u ty lc a r b in y l) a c e ta m id e ap p eared a s an o i l w h i c h s o l i d i f i e d on d i s t i l l a t i o n , found s a t i s f a c t o r y

b u t no s o l v e n t s w e r e

for re c ry stallizatio n .

The m e l t i n g

p o i n t o f N ( t e r . a m y l ) a c e t a m i d e when p r e p a r e d f r o m t r i m e th y le th y le n e and a c e t o n i t r i l e

has been r e p o r te d as

8 1 . 5 ° ( 1 )» b u t when p r e p a r e d f r o m t h e a l c o h o l a s a b o v e t h e m e l t i n g p o i n t was 9 b ° . Benzyl a l c o h o l ,

tre a te d w ith a c e to n itr ile

a c e tic -s u lfu ric acid so lu tio n ,

in

gave only b e n z y l a c e t a t e .

When, h o w e v e r , a c e t i c a c i d was o m i t t e d , was I s o l a t e d w i t h a y i e l d o f 10%.

N -benzylacetainide

This r e a c t i o n ,

th at

o f an a l c o h o l w h ich c a n n o t be d e h y d r a t e d to an o l e f i n , e s t a b l i s h e d th e f o r m a tio n o f carbonium io n a s th e i n i t i a l s t e p i n th e s u b s t i t u t e d amide r e a c t i o n .

-6-

By s t u d y i n g f r e e z i n g p o i n t d e p r e s s i o n s o f n itriles

and am ides i n s u l f u r i c a c i d ,

H a n tz s c h (9)

d is c o v e r e d t h a t b o th th e n i t r i l e s and am ides d i s s o l v e d as s a l t s .

When t h e n i t r i l e s was d i s s o l v e d i n s u l f u r i c

a c i d and th e n poured im m ediately i n t o w a te r, m a t e r i a l w as r e c o v e r e d .

From t h i s ,

the s t a r t i n g

and from t h e f a c t

t h a t t h e h e a t o f s o l u t i o n o f a n i t r i l e was l e s s

than

t h a t o f w a t e r h e c o n c l u d e d t h a t w a t e r was a s t r o n g e r base than n i t r i l e w ith i t

and,

f o r p ro to n .

therefore,

competed s u c c e s s f u l l y

H antzsch no ted t h a t i n s u l f u r i c

a c i d t h e s p e c t r a o f a m i d e s w er e v e r y n e a r l y t h e same a s t h o s e o f im id o e t h e r s w h ic h have t h e s t r u c t u r e , C onsequently, would be

R - C : N H2

' OR th e s t r u c t u r e o f am ides i n s u l f u r i c a c i d

R-C:|JH2

rather than

R-C-NH^

OH

0

This f o r m u la tio n fo llo w e d P a u l i n g 's o b s e r v a t i o n ( 1 0 ) t h a t th e re s o n a n c e energy — which, f o r a c e ta m id e , was c a l c u l a t e d

t o b e 21 K c a l / m o l ~

would be i n h i b i t e d

c o m p le te ly by th e a d d i t i o n o f a p r o to n to th e n i t r o g e n atom .

He n o t e d t h a t t h e c o r r e s p o n d i n g v a l u e f o r t h e

b asic d iss o c ia tio n c o n sta n t,

1 x 10

-2 0

, would be s m a l l

enough to d e m o n s tr a te t h a t p ro to n had n o t added t o th e am ine g ro u p o f th e am id e. H an tzsch (9) d eterm in e d t h a t th e spectrum o f amide i n s u l f u r i c a c i d d i d n o t change w i t h t i m e , w h e r e a s

-

the

spectrum o f n i t r i l e

c o r r e s p o n d i n g am ide.

7-

g r a d u a l l y a p p ro a c h e d t h a t o f the

T h u s , w hen p a r a t o l u o n i t r i l e was

d isso lv ed in concentrated s u lfu ric ac id ,

th e n i t r i l e

was r e g e n e r a t e d by i m m e d i a t e p r e c i p i t a t i o n w i t h w a t e r , and,

a f t e r tw elve h o u rs,

o n l y p a r a t o l u a m i d e was r e c o v e r e d .

These o b s e r v a t i o n s w ere i n t e r p r e t e d by H a n tz s c h a s f o lb w s :

RC5 N ♦ H — > R C : N H



H2°

+

R0:NHo—

i

RC :NH-t-H,0 i j

^

OH

OH

Benson ( 5 ) > i n h i s d i s c u s s i o n o f t h e s u b s t i t u t e d am ide r e a c t i o n ,

p o s t u l a t e d a d i f f e r e n t m echanism.

RC O N H g - > RC :NH +

2 H 2 S04 ^

OH + HgSO^ _ > R C r N H

RCN

RC :NH + H j O * +■ 2 H S 0 ^ “ _

HSO^

(VI)

He c l a i m e d , n itrile

is

(V II)

"th e tim e change w hich o c c u r s w i t h the the s h i f t o f the p o s i t i v e

n itro g e n to

RC :NH

the c a rb o n atom .

s p e c tr a f o r the n i t r i l e

c h a r g e from t h e

This r e s u l t s

in id en tical

and am ide s o l u t i o n s . "

The l a t t e r e x p l a n a t i o n d s

in disagreem ent w ith

p r e s e n t concepts of t h e o r e t i c a l o rg a n ic chem istry f o r the s h i f t of a p o s itiv e charge,

( 11),

i n v o l v i n g t h e m ove­

ment o f a p a i r o f e l e c t r o n s n e c e s s i t a t e s o n ly a sm a ll

-8-

a m o u n t o f e n e r g y c o m p a r e d t o t h e m ov em en t o f a h eav y nucleus. points

The p o s s i b i l i t y

of s h i f t i n g charges to d i f f e r e n t

i n a m o lecu le w ith o u t a f f e c t i n g the p o s itio n s o f

the atom ic n u c le i i s

e x p l a i n a b l e by th e c o n c e p t o f

r e s o n a n c e , a c c o r d i n g t o w h i c h t h e r e i s no in the

sh ift of a charge

time l a g

so t h a t th e a c t u a l s t a t e of

t h e m o l e c u l e may b e r e p r e s e n t e d b e s t a s a h y b r i d t o w hich e a c h r e s o n a n c e fo rm has c o n t r i b u t e d . (VI) a n d

S tructures

( V II ) a r e e x a m p l e s o f s u c h r e s o n a n c e f o r m s . A s l i g h t m o d i f i c a t i o n o f H a n t z s c h f s scheme

s u g g e s t e d i t s e l f f o r t h e m echanis m o f t h e r e a c t i o n o f am ides and n i t r i l e s

w ith co n cen trated s u lf u r ic acid.

S ince amides r e s o n a t e b e t w e e n s t r u c t u r e s (IX) a d d i t i o n o f p r o t o n

to

w hich would be s t a b i l i z e d

(V III)

t h e o x y g e n w o u ld g i v e

and (X)

by t h e a d d i t i o n a l r e s o n a n c e

form ( X I ) .

RC-NH2 RC:NH2

H _

+ RC: NH,

0

0-

OK

(V III)

(IX)

(X)

On t h e o t h e r h a n d ,

th e n i t r i l e

s a l t , (X II), in e q u i l i b r i u m (X III).

I t would b e t h e

RC-NH0 ii ^ + 0H (XI)

would form t h e n i t r i l i u m

w ith the u n - io n iz e d h y d r a te ,

slow i r r e v e r s i b l e

p r o to n from th e o x y g e n t o

s h i f t o f the

t h e n i t r o g e n w h i c h w ou ld r e s i l t

in th e f o rm a tio n o f th e s a l t o f th e am ide,(X IV ). H RCSN ----- >■ RC: NH ------* +

RC :NH ------> • HOH •‘• ( X I I I )

(X II)

RC:NH 2 ? OH (XIV)

The d i f f e r e n c e b e t w e e n t h i s m e c h a n i s m a n d H a n t z s c h 1s i s

t h a t h is p o s tu la te d the i r r e v e r s i b i l i t y

of th e a d d i t i o n of w ater to th e carbon c o n ta in in g the open s e x t e t o f e l e c t r o n s . rev ersib le

This a d d i t i o n ,

however,

is

— n o te th e d e h y d r a tio n of am ides to n i t r i l e s

--

c o n s e q u e n tly th e above s e r i e s o f r e a c t i o n s ap p e a re d lo g ical. Hammet ( 1 2 )

claim ed

1) t h a t t o l u o n i t r i l e

w as p r e s e n t e n t i r e l y a s t h e n i t r i l i u m acid ,

and

2) th at acetic

acid,

s a lt in s u lfu ric

a weaker base th an n i t r i l e ,

io n iz e d s u l f u r i c a c id com pletely.

ThiB l e f t a w e a k n e s s

i n th e t h e o r y o f t h e s u b s t i t u t e d amide r e a c t i o n , if

the n i t r i l e ,

form ,

n o t the n i t r i l i u m

i o n , were th e r e a c t i v e

i t would be n e c e s s a r y to p o s t u l a t e ,

th a t an eq u ilib riu m of free n i t r i l e

f o r i t w ould be d i f f i c u l t p o sitiv e n itriliu m carbonium io n .

a s d id Benson(5)»

e x i s t e d and t h a t a c e r t a i n

was p r e s e n t .

for,

co n cen tratio n

T h i s was a n e c e s s a r y a s s u m p t i o n

to im agine t h a t th e s tr o n g l y

i o n would a p p r o a c h th e p o s i t i v e l y

charged

In a m ix tu re o f ex cess a c e t i c a c i d and

-10-

m olar q u a n t i t i e s of n i t r i l e , t e r t i a r y

o lefin ,

acid ,

b u t in the r e a c tio n

f r e e n i t r i l e m ig h t be p r e s e n t ,

and s u l f u r i c

w i t h s e c o n d a r y o l e f i n s o r a l c o h o l s t h e n i t r i l e was a d ­ mixed w i t h a g r e a t e x c e s s o f c o n c e n t r a t e d s u l f u r i c a c i d . I f K a m m e t's t h e o r y w e r e c o r r e e t , free n itr ile

the c o n c e n tra tio n of

i n such a s o l u t i o n would have been n e g l i g i b l e .

In r e a c t i o n s i n v o l v i n g carbonium i o n s , s u b s t i t u t i n g group a t t a c k s

the p o s it i v e

carbon e i t h e r

by b i m o l e c u l a r d i s p l a c e m e n t o r by s o l v o l y s i s c a r b o n i u m i o n s r e a c t by d i s p l a c e m e n t , and

the

( 1 3 ) .Prim ary

te rtia ry

by s o l v o l y s i s ,

s e c o n d a r y by e i t h e r m e c h a n i s m , d e p e n d i n g on t h e

s o l v e n t and n a t u r e o f th e r e a g e n t .

R2 CH+ i-OSO^H r3 c

(B), w ith

+

+ hococh 3

-11-

II. 1.

BETA HALO ETHYLAMIDES AND OXAZOLINES P r e p a r a t i o n and Uses o f O x a z o lin e s - - L i t e r a t u r e

Survey.

A f t e r th e mechanism had b e e n s t u d i e d ,

the

s u b s t i t u t e d a m i d e r e a c t i o n was c a r r i e d o u t w i t h a l c o h o i and o l e f i n s c o n t a i n i n g an a d d i t i o n a l f u n c t i o n a l group, h a l o g e n , on t h e a l p h a p o s i t i o n . were b e t a h a l o e t h y l a m i d e s ,

FUCH-GHoX -i^ OH

RON

The p r o d u c t s o b t a i n e d

(XV)

lUSO^ — f— £

R0 CH-CHoX ^ NHCOR

(XV)

T h e se a m i d e s w e r e f o u n d t o u n d e r g o a n u m b e r o f r e a c t i o n s , o n e o f w h i c h was r i n g c l o s u r e t o f o r m f i v e - m e m b e r e d h e t e r o ­ cycles,

2 , 4 - d i a l k y l - A 2 - o x a z o l i n e s , (XVI). r 2 ch —

ch2

R2 CH-CH2X NHCOR

/ N ===== C R

(XVI)

T hese compounds a r e d e s c r i b e d i n t h e l i t e r a t u r e a n d th e s i x f o llo w in g m ethods o f p r e p a r a t i o n have been

reported.

1.

Of these, the first two are the most important.

The c . y c l o d e h y d r a t i o n o f s u b s t i t u t e d a m i d e e t h a n o l s .

RCONHCHp CHpOH * Vvenker ( 1 4 )

----- >

CH2 - 0 | ,C-R ch 2 - nx

i s o l a t e d 2 - s u b s t i t u t e d o x a z o l i n e s i n 35 %

y i e l d by h e a t i n g a m i d e s t o 2 6 0 ° . acid ic

cataly sts i t

In the p resen ce o f

was f o u n d t h a t t h e r e a c t i o n c o u l d

be c a r r i e d o u t a t low er te m p e r a tu r e s . ( 1 5 ) » a s w e l l a s Adams a n d L e f f l e r

T h u s , Berg m an n

(16 ),

converted

e t h a n o l b e n z a m i d e s t o 2 - p h e n y l o x a z o l i n e s by u s i n g th io n y l c h lo rid e or s u lf u r ic acid. expected,

As m i g h t h a v e b e e n

r e a c tio n proceeded w ith l e a s t d i f f i c u l t y

when t e r t i a r y

a l c o h o l s w ere em ployed.

RC0NHCH2 CR2

ch 2 - cr 2 >

OH

' >0 N= C - R

K r a b b e ( 1 7 ) d i s c o v e r e d t h a t P2 0 ^ , P C 1 ^ , a n d c h l o r o o x a l i c e s t e r a l s o were e f f e c t i v e c a t a l y s t s f o r th e 2.

A lkaline rin g

d eh y dration.

c lo su re of F .b e ta halo e th y la m id e s.

T h i s r e a c t i o n was f i r s t u s e d b y G a b r i e l ( 1 8 ) a n d soon a f t e r w a r d by E l f e l d t

(19).

-

13-

rconhch2ch2-x R By r e d u c i n g t h e r e a c t i o n t i m e t o l e s s

t h a n one m i n u t e ,

a n d t h u s m i n i m i z i n g h y d r o l y s i s , Adains a n d L e f f l e r were a b le

(16)

to r e p o r t y i e l d s o f 90$. V/enker ( 1 4 ) a t t e m p t e d t h e p r e p a r a t i o n o f t h e

p a r e n t co m p o u n d , o x a z o l i n e ,

from N -fo rm y l e t h a n o l a m i n e .

D i r e c t d e h y d r a t i o n w i t h h e a t o r P 2 0^ l e d o n l y t o e t h a n o l ­ am ine and c a r b o n m onoxide.

However, a f t e r f i r s t

converting

th e a lc o h o l to the c h lo r id e and then c y c l i z i n g w ith sodium h y d r o x i d e ,

he o b t a i n e d o x a z o l i n e

( 2 0 ).

HOCHoCHoNHo + CO HOCHoCHoNHCHO S0C1

3.

ClCH0 CHo NHCH0

The c . y c l i z a t i o n o f a m i d e e s t e r s

RgC-CHgOCOCH^ NHCOCH, 3

o r o f amino e s t e r s .

+ CH,C00H 3

-

14-

These r e a c t i o n s h av e a p p e a r e d o n ly i n p a t e n t l i t e r a t u r e ( 21 ) , ( 22 ) .

4.

The c o n d e n s a t i o n o f e t h a n o l a m i n e a n d a n i t r i l e . Ethoxymethoxy a c e t o n i t r i l e

in the presence o f eth an o l

a m i n e a n d s odiu m m e t h o x i d e y i e l d e d 2 - e t h o x y m e t h o x y m e t h y l oxazoline

(23).

Presum ably th e r e a c t i o n p ro ceed ed v ia

th e ainidine, which th e n ,

w ith the lo s s

o f am m onia, u n d e r ­

went r in g c lo s u re .

Et0CH 2 0CH2 CN h-

HGCH2 CH2 NH2 ---- >. EtOCHgOCHgC sNH NKCH2 GH2 0H

CH2 CCH2 0 E t

5.

Ring c l o s u r e o f a l l y l b e n z a m ld e d ilu te C^H^CONHCH CH: CH0 6 5 2 2

(48). CH_CH -CH 3-

6 . H eatin g a b e ta c h lo ro eth.yllm ino e t h e r .

On w a r m in g t o 1 0 0 ° b e n z i m i d y l c h l o r o e t h y l e t h e r r e a r r a n g e d to th e h y d r o c h l o r i d e o f 2 -p h e n y l o x a z o l i n e (49)•

-

C/-H[-C0CHo CHo C l O P || d d

15-

CH0 -CH 0 , d ^*^0

^

NH

HC1 N = C ^ C6 H5

The u s e s o f o x a z o l i n e s h a v e n o t b e e n widelyin v estig ated .

R obinette

( 2 4 ) a n d 7«ampner (46)

t h a t s u b s t i t u t e d o x a z o l i n e s w ere c a t i o n - a c t i v e agents.

reported surface

Compounds h a v i n g s u r f a c e a c t i v i t y a l s o r e s u l t e d

from th e r e a c t i o n o f o x a z o l i n e s w i t h a n h y d r i d e s

R„C ^27 —-CH^ 2^ :o N= C CH_ 3

a—c e t i c

(25).

R^C------CH^OCOCH

anhydride

NHCOCH ^

O x azo lin e-lactate s a lts

have b e e n u s e d i n

d e o d o r a n t p r e p a r a t i o n s b e c a u s e th e y were non t o x i c and h arm le ss t o

tex tiles

(26).

Hamer a n d R a t h b o r n e

(27) r e p o r t e d t h a t t h e p r o d u c t o f th e c o n d e n s a tio n o f 2 -m e th y l o x a z o l i n e m e th io d id e and p a ra dim ethylam ino

benzaldehyde form ed a p h o to g ra p h ic la y e r . dem onstrated t h a t ,

l i k e alpha p ic o lin e ,

The r e a c t i o n

th e m ethyl

group a t p o s i t i o n #2 o f th e o x a z o li n e had been a c t i v a t e d by t h e n e i g h b o r i n g c a r b o n - n i t r o g a n d o u b l e b o n d . CH2 -CH2^

CH2 - C ^ CH3 N— - c ^

H? H h

hch

H

CH2-QH2^ CH^w— t c ^ c i f !»-) H(g

-

16 -

RCHO CH

CH_N = C 3+i HC: CHR

HCW H

O x a z o lin e s have aro u sed i n t e r e s t as l o c a l an esth etic s,

and,

i n an a t t e m p t to improve th e a c t i o n

of procaine,

Adams a n d L e f f l e r ( 1 6 )

sy n th esized a s e r ie s

o f 2-am inophenyl d e r i v a t i v e s . They sh ow ed t h a t 2 ( m e t a O a m i n o p h e n y l ) ^ - o x a z o l i n e was e q u a l i n e f f i c i e n c y t o p r o c a i n e and had one t h i r d

the t o x i c i t y .

H ow ever,they

a l s o p o in te d o u t d isa d v a n ta g e s i n the use o f o x a z o lin e s . They h a d low s o l u b i l i t y w ere to o a c i d i c

in w ater.

— pH o f 4 t o 5 ~

a c i d s w ere n o t form ed r e a d i l y .

The h y d r o c h l o r i d e s and s a l t s o f o r g a n ic

Aqueous s o l u t i o n s o f t h e

f r e e b a s e u n d e r w e n t h y d r o l y s i s — s l o w l y a t room t e m p e r a t u r e and r a p i d l y

on b o i l i n g .

-

2.

17 -

P r e p a r a t i o n o f H a l o A m id e s by t h e S u b s t i t u t e d

Amide R e a c t i o n .

E ig h t halo am ides,

th e in te r m e d ia te s in the

p r e p a r a t i o n o f o x a z o l i n e s , w e r e p r e p a r e d by t h e s u b s t i t u t e d amide r e a c t i o n .

alcohol or o le fin

n itrile

alpha m ethylstyrene chlorohydrin

a c e to n itrile

b e t a h a l o amide

m.p.

N (phenylm ethyl 97-5 chlorom ethyl carbinyl)acetam ide

sty re n e chlorohydrin

N (phenylchloro m ethylcarblnyl) acetam ide

s t y r e n e brom ohydrin

N( p h e n y l b r o m o m ethylcarblnyl) acetam ide

m e th a lly l ch lo rid e

N (ter.b u ty lch lo ro )2 0 0 acetam ide

a l l y l ch lo rid e

100

84

b en zo n itrile

N ( t e r . b u t y l c h l o r o ) 130 benzam ide

ethylcyanoacetate

a lp h a carbethoxy 124 N (ter.b u ty lch lo ro ) acetam ide

benzyl cyanide

N (ter.b u ty lch lo ro ) phenylacetam ide

S8.5

N( 2 - p r o p y l - l chloro)phenylacetam ide

99

-18-

The r e a c t i o n s w e r e c a r r i e d o u t u n d e r t h e stan d ard co n d itio n s.

In the case of o le f in s g iv in g

seco n d ary carbonium io n s

t h e s o l v e n t was c o n c e n t r a t e d

s u l f u r i c a c i d a n d t h e r e a c t i o n t e m p e r a t u r e was e i t h e r 1 0 °-1 5 ° or 2 5 ° -3 0 ° .

W ith t e r t i a r y

s o l v e n t was a 1 : 1 m i x t u r e

(b y v o l u m e )

s u l f u r i c and g l a c i a l a c e t i c a c i d s , tem perature 10°-15°.

of concentrated

and th e r e a c t i o n

By r a i s i n g t h e t e m p e r a t u r e t o

30° th e y i e l d o f s u b s t i t u t e d

a c e t a t e and t e r t i a r y

carbonium io n s th e

amide from e t h y l cy an o -

o l e f i n s was I n c r e a s e d .

When

t h i s was a t t e m p t e d w i t h b e n z y l c y a n i d e a n d t h e same o lefin

(m eth ally l c h lo rid e )

co n tro lled .

In s p i t e

o f c o o lin g i n an ic e b a t h th e

tem perature rose r a p id ly decomposed.

t h e r e a c t i o n c o u l d n o t be

t o 90° and th e r e a c t a n t s were

The l o w e r e d a c t i v i t y

o f e th y l cyanoacetate

c o m p a r e d w i t h b e n z y l c y a n i d e m i g h t b e e x p l a i n e d on t h e follow ing b a s is .

In a g iv e n r e a c tio n ,

u s i n g t h e same

c o n d i t i o n s a n d t h e same o l e f i n a n d c h a n g i n g o n l y t h e n itrile, is

i t was t o b e e x p e c t e d t h a t t h e n i t r i l e

th e s t r o n g e s t b a s e w ould r e a c t m ost q u ic k ly .

r e a c t i o n was e s s e n t i a l l y a " n e u t r a l i z a t i o n " , the r e a c tio n o f an a c id o lefin )

th at The

th at is,

( t h e ca rb o n iu m i o n from t h e

w ith a b ase ( th e u n sh ared e l e c t r o n p a i r o f the

n itrile ).

Therefore,

th e h ig h er the co n cen tratio n of

e l e c t r o n s on t h e n i t r o g e n o f t h e n i t r i l e ,

the s tr o n g e r

w o u l d be i t s a c t i o n a s a b a s e . sid eratio n ,

In the case under con­

e t h y l c y a n o a c e t a t e was a w e a k e r b a s e t h a n

b e n z y l c y a n i d e b e c a u s e t h e e s t e r g r o u p i s m or e e l e c t r o ­ n e g a tiv e th an p -en y l and thus reduced the e l e c t r o n d e n s ity at

t h e n i t r o g e n a to m t o a g r e a t e r e x t e n t . +■

R-0-C*-CH„-*-C:N I 0-

2

The p r o o f t h a t s u c h a s h i f t o f e l e c t r o n s o c c u r r e d i s found i n th e i o n i z a t i o n c o n s ta n ts o f tn e c o rre s p o n d in g acids,

e th y l m alonic,

s t r o n g e r (K 3 x 10

and p h e n y l a c e t i c .

The f o r m e r i s

than p h e n y la c e tic

(K 5 . 1 x 1 0 " 5 ) .

The e s t e r g r o u p a t t r a c t e d e l e c t r o n s

to i t ,

th u s w eakening

th e 0--H bond and e n c o u ra g in g th e tendency to i o n i z a t i o n . I t m i g h t b e n o t e d t h a t t h e p h e n y l g r o u p was n e i t h e r stro n g ly e le c tro n e g a tiv e nor stron gly e le c tr o p o s itiv e , b e c a u s e t h e i o n i z a t i o n c o n s t a n t o f p h e n y l a c e t i c a c i d was s i m i l a r to t h a t of a c e t i c a c i d i t s e l f

(K 1 . 8 6 x 1 0 " 5 ) .

In th e p r e p a r a tio n o f N (brom om ethylphenylcarbinyl) a c e ta m id e from s t y r e n e broraohydrin and a c e t o n i t r i l e a d e f i n i t e ad v an tag e in the use of the a lc o h o l in p la c e of t h e o l e f i n was n o t e d .

The a b o v e r e a c t i o n p r o c e e d e d u n d e r

normal c o n d i t i o n s to g iv e an e x c e l l e n t y i e l d during the a ttem p ted p r e p a r a tio n C5 H5 CH:CH-Br, a n d a c e t o n i t r i l e ,

( 9 2 %), b u t

from b e t a b r o m s t y r e n e , only poly m eric m a t e r i a l

c o n t a i n i n g n o n i t r o g e n w as i s o l a t e d . m ig h t be s u g g e s t e d .

An e x p l a t n a t i o n

I t was n e c e s s a r y t o p o s t u l a t e a

d e f i n i t e tim e o f r e a c t i o n betw een th e carbonium io n and the n i t r i l e .

C o n s id e rin g th e r e a c t i o n w ith brom o-

s t y r e n e , when t h e o ' l e f i n s t r u c k t h e a c i d i t a p r o t o n t o form th e carb o n iu m i o n . o f o th e r o l e f i n m olecules

th is

t o o k up

In the p resen ce

r e a c t e d t o form a p o ly m e r

a c c o r d i n g t o t h e u s u a l scheme f o r a c i d p o l y m e r i z a t i o n ( 2 8 )

C.H CH-.CHBr + H* ___ > 6 5

C,H r CH-CH B r 6 5+ 2 /

Br Br -CH-CH-CH-CH-

C ^ C H - C H - C H - C H Br 6 S'*- i i 2 B r c6 hjt

C,H CH:CHBr ...6. 5 ^ w

V

° 6 H5

C6H5

1 n

At the tem p eratu re o f the r e a c t i o n the p o l y m e r i z a t i o n was n o t r e v e r s i b l e . th a t sty ren e polym erizes r a p id ly

I t i s w e l l known

in the presen ce of a c id s

a n d i t was t h i s r a p i d p o l y m e r i z a t i o n — t h e r a p i d r e a c i o n b e tw e e n carbonium i o n and u n ch an g ed o l e f i n — t h a t d ifferen tiated amide r e a c t i o n .

i t from o t h e r o l e f i n s i n t h e s u b s t i t u t e d It

is

t r u e t h a t d i i s o b u t y l e n e , w hich

f o r m e d t h e d i m e r a n d t r i m e r r a p i d l y when t r e a t e d w i t h c o l d c o n c e n t r a t e d s u l f u r i c a c i d a l o n e g a v e no p o l y m e r i z a t i o n when t h e r e a c t i o n was c a r r i e d o u t i n t h e p r e s e n c e o f added n i t r i l e .

The r a t e o f p o l y m e r i z a t i o n m u e t , . t h e r e f o r e ,

21

be c o n s i d e r a b l y

slow er th a n t h a t o f s ty re n e .

When s t y r e n e b r o m o h y d r l n was t h e r e a c t a n t , the carbonium i o n m ight r e a c t e i t h e r w ith n i t r i l e w ith unchanged a lc o h o l .

In the f i r s t

or

case t h e amide

would be fo rm ed a n d i n t h e s e c o n d a s e c o n d a r y e t h e r , w h ich i t s e l f was i n e q u i l i b r i u m w i t h a l c o h o l and c a r b o n iu m ion:

C^Hr-CHCH 2B r ° 5, OH

C6 H5 GHOH2 Br ^

I

RON h2 so4

fC^CH- ^ \ \

BrCH0 d r

Ch:HirCHCH0 Br 6 5i 2 NHCOR

S i n c e c a r b o n i u m i o n was b e i n g c o n t l n u o u s l y removed t h e a t t a i n m e n t o f e q u i l i b r i u m b e tw e e n carbonium i o n a n d o l e f i n w a s n o t r e a l i z e d a n d no o l e f i n was b u i l t up f o r s u b s e q u e n t p o l y m e r i z a t i o n . S e v e ra l a tte m p te d r e a c t i o n s betw een c h lo r o a l c o h o l s o r o l e f i n s and n i t r i l e s were u n s u c c e s s f u l . l-c h lo ro -2-o ctanol

( p r e p a r e d by t h e a d d i t i o n o f h y p o -

chlorous a c id to 1 -o c te n e ) w ith a c e t o n i t r i l e acid y ie ld e d only a t a r .

in su lfu ric

W ith b e n z y l c y a n id e a

gummy m a s s r e s u l t e d f ro m w h i c h o n l y p h e n y l a c e t a m i d e

-22

c o u l d be I s o l a t e d .

A lly l c h lo r id e and b e n z o n l t r i l e

d i d n o t r e a c t — b e n z a m l d e was i s o l a t e d

— a n d t h e same

o l e f i n w i t h a c e t o n i t r i l e gave a s m a ll q u a n t i t y o f b la c k l i q u i d w h i c h sho wed no s i g n s o f s o l i d i f y i n g a f t e r two m onths.

3 . O x a z o l l n e s fro m B e t a Halo E t h y l a m i d e s .

The r i n g c l o s u r e o f t h e b e t a h a l o e t h y l a m i d e s t o o x a z o l i n e s was a c c o m p l i s h e d i n a n u m b e r o f w a y s . th e

If

crude am ide, a f t e r s e p a r a t i o n from th e r e a c t i o n m ix tu re ,

was n o t c r y s t a l l i z e d i m m e d i a t e l y ,

it

s lo w ly l i q u i f i e d and

a f t e r s t a n d i n g s e v e r a l m o n th s d e p o s i t e d c r y s t a l s o x azo lin e hydrochloride. by E l f e l d t

This phenomenon had b e e n r e p o r t e d

( I S ) who h a d n o t i c e d t h a t c r y s t a l l i n e

2-brotno)benzam ide,

of the

insoluble in w ater,

afte r

b e c o m e a_ s y r u p , m a i n l y s o l u b l e i n w a t e r .

N (l-propyl-

two wee ks h a d

From t h e s o l u b l e

p o r t i o n he i s o l a t e d 2 - p h e n y 1 -3 - m e th y l o x a z o l i n e .

Even

p u r i f i e d h a l o amides undergo s p o n ta n e o u s r i n g c l o s u r e , f o r when N ( t e r . b u t y l c h l o r o ) p h e n y l a c e t a m l d e — p r e p a r e d by t h e s u b s t i t u t e d am id e r e a c t i o n o f m e t h a l l y l c h l o r i d e a n d b e n z y l cy an id e — m e ltin g p o i n t 98° , v i a l a t 50° , 142°,

w as k e p t i n a s e a l e d

i n two .,.onths t h e m e l t i n g p o i n t h a d r i s e n t o

the m e ltin g p o in t of 2 -b e n z y l-4 ,4 -d lm e th y l oxazoline

-23-

hydrochloride. Three p r o c e d u r e s f o r th e r i n g c l o s u r e were fo llo w e d and f o u r o x a z o l i n e s p re p a re d .

Name 2 -b en zy l-4 ,4 d im e th y l- ^ 2 oxazoline

2-phenyl-4,4= dim ethyl-*^ oxazoline

S tru ctu re

M.P. I

M e th o d o f P r e p . Ila IIb

(CH-i LC .— Cfb • .0 N :C ^ CH2 C6 H5

75° +

erratic

( c h 3 ) 2 c-

8 7 . 5C

tar

■CHo “^ 0

III

no reactio n

NC6 h 5 2 -m ethy1-4phenyl- & oxazoline

c 6 H5 ? H — CH2 -

116°

'C CH-:

N

e th y l alpha (ch3 ) 2c — ch2 101v ( 4 * ,4 '-d im e th y l - 2-o xazolinyl) acetate CH2 C00CoH, 2 5

M e th o d I ; refluxed e ig h t hours,

no reac tio n

■0

tar

tar

A p y r i d i n e s o l u t i o n o f t h e a m i d e was th e p y rid in e d i s t i l l e d a t reduced

p r e s s u r e , and th e o x a z o l i n e h y d r o c h lo r id e w hich rem ain ed was d i s s o l v e d i n w a t e r .

The a q u e o u s s o l u t i o n was f i l t e r e d

t h r o u g h a f i l t e r a i d a n d made a l k a l i n e w i t h s o d iu m

■h

-24-

carbonate.

The f i l t r a t e

was e x t r a c t e d w i t h b e n z e n e a n d

a f t e r r e m o v i n g t h e s o l v e n t by d i s t i l l a t i o n

the p roduct

was r e c r y s t a l l i z e d o r d i s t i l l e d . M e th o d I l a : h o u rs i n an open f l a s k .

The a m id e was h e a t e d t w e n t y - f o u r The s o l i d was d i s s o l v e d i n w a t e r

and p u r i f i e d a s above. M ethod l i b :

The p r o c e d u r e was t h e same a s I l a

e x c e p t t h e a m i d e was h e a t e d i n a va cu um ( 1 mm.) f o r 2 - 6 hours. Method I I I ;

The a m i d e w as h e a t e d o n e m i n u t e

a t 6 0 ° w i t h one e q u i v a l e n t o f s o d i u m h y d r o x i d e i n a l c o h o l . The p r e c i p i t a t e d s a l t was f i l t e r e d ,

the s o lu tio n a c i d i f ie d

w i t h a c e t i c a c i d a n d t h e s o l v e n t r e m o v e d by d i s t i l l a t i o n . The r e s i d u a l o i l was d i s t i l l e d a t r e d u c e d p r e s s u r e . R e f l u x i n g th e amide i n c h l o r o b e n z e n e , a l o n e , o r i n b e n z e n e w i t h powdered p o t a s s i u m

c a r b o n a t e g a v e no

reaction .

In s e v e ra l attem pted c y c liz a tio n s a dark, ta r r y , R R w a t e r i n s o l u b l e p o l y m e r , - ( C- CH pO -C :N -) n - , was t h e m a in R product. P r e p a r a t i o n o f b e n z y l d i m e t h y l o x a z o l i n e by M e th o d I g a v e o n e e x c e l l e n t r e s u l t b u t t h r e e r e p e t i t i o n s o f the experim ent under a p p a re n tly i d e n t i c a l c o n d itio n s y i e l d e d o nly polym er.

R efluxing a lp h a carbethoxy N (te r.

b u ty lc h lo r o ) a c e ta m id e in p y r id in e gave a w a t e r - s o l u b l e compound w h i c h a f t e r n e u t r a l i z a t i o n h a d t o o h i g h a b o i l i n g

p o i n t to be d i s t i l l e d polym er, b e c a u se i t

a t one m i l l i m e t e r p r e s s u r e .

form ed a w a te r s o l u b l e h y d r o c h l o r i d e

was p r o b a b l y a d i f f e r e n t c l a s s f r o m t h e o t h e r . expected p ro d u c t,

This

The

e th y l a lp h a ( 4 ',4 *-dim ethyl-2-o x azo lin y l)

a c e t a t e h y d r o c h l o r i d e h a s a m e th y le n e gro u p w hich would enolize re a d ily

( p a g e 15)*

T h i s e n o l fo rm w o u l d b e f u r t h e r

s t a b i l i z e d by r e s o n a n c e w i t h t h e e s t e r g r o u p . presence of a base lik e be s u s c e p t i b l e

In the

p y r i d i n e s u c h a s t r u c t u r e w o u ld

t o p o l y m e r i z a t i o n by a s u c c e s s i o n o f

C laisen co n d e n sa tio n s.

HN = C ^ +•

i

HCC00Co HrH 2 5

HN = C

+

HN=C ■+•

^

i

HCC00Co Hc

do

o x a z o l i n e - C H 0 (CO-CH-) C00Co H, d i. n n d ,

i

HC: C - 0 -

oxazoline

-26-

4.

O xazolines — P ro o f o f S t r u c t u r e .

A lth o u g h th e r i n g c l o s u r e o f h a lo am ides to o x a z o l i n e s was a known r e a c t i o n ,

i t was f e l t

e q u iv o c a l p ro o f of the o x a z o lin e s t r u c t u r e p resented.

Therefore,

t h a t un­

s h o u l d be

a s s e e n i n t h e f l o w s h e e t , one

o x a z o l i n e was p r e p a r e d by t h r e e i n d e p e n d e n t m e t h o d s a n d th e s t r u c t u r e s of the in te rm e d ia te

com poun ds p r o v e d by

c o n v e r s i o n t o known com po un ds a n d c o m p a r i s o n o f p h y s i c a l p ro p erties. C^HcCH-CHo-Cl 6 5» 2

140°

Cz-HcCH

>

CH„ z >o

NHCOCH-, a ( XVII ) m .p. 1 00°

(x v iii) 116 °

r e flu x w ith

CgH5 CH-CH2 - 3 r NHC0CH-.

C6 H5 CH-CH2 OH

carbonate

(xfx)

NKCOC”

m . p . 84 NaOH a t 2 5 ° y f o r 24 h r s . c 6h

5c h -c h 2-o h nh

2 +

aq.H C1

(XXI) b.p . 1 03°-08 o a t 4 mm

KMnOj, v a t 30 c 6h

5 c h - c h 2o h nh

2 -k c i

(X XII ) m .p. 137°

(XXIV) b .p . l 8 0 ° - 2 0 3 ° a t 3 mm

c 6h

5c h -g c o h

NHCOCH, (XXIII) m.p. 1 5 2 °

-2 7 H e a t i n g N ( p h e n y l c h l o r o m e t h y l c a r b i n y l ) a c e t a m i d e ( X VII) o r N ( p h e n y lb ro m o m e th y lc a r b in y l)a c e ta m id e , (XIX), i n vacuo a t 140° f o r f o u r h o u r s y i e l d e d t h e h y d r o h a l i d e s a l t o f 2 -m e th y l 4 - p ’n e n y l o x a z o l i n e . tre a tm e n t of the

The f r e e b a s e , ( X V I I I ) , r e s u l t e d

s a l t w ith carbonate.

on

The h a l o a m i d e s

h a d b e e n p r e p a r e d by t h e s u b s t i t u t e d a m i d e r e a c t i o n o f aceto n itrile

in

s u lf u r ic a c id s o lu tio n w ith sty re n e

( o r bromo) h y d r i n .

chloro

The s t r u c t u r e o f t h e bromo a m i d e , ( X I X ) ,

was p r o v e d b y h y d r o l y s i s w i t h one e q u i v a l e n t o f s o d i u m h y d r o x i d e a t room t e m p e r a t u r e . ethanol,

An o i l ,

2-arr.ino-phenyl

(XXI), w h ic h fo rm e d a h y d r o h a l i d e , ( X X I I ) . m e l t i n g

a t 137° ( r e p o r t e d m e l t i n g p o i n t 1 3 6 ° - 3 7 ° ( 2 9 ) ) , was o b t a i n ­ ed.

In t h i s h y d ro ly s is

t h e r e a l s o was o b t a i n e d a h i g h -

b o i l i n g b y - p r o d u c t , an am in e,

f o r w hich,

ten tativ ely ,

the

stru ctu re,(X X IV ), is suggested. .Vhen N( p h e n y lb ro m o m e t h y l c a r b i n y l ) a c e t a m i d e was r e f l u x e d w i t h a q u e o u s sodium c a r b o n a t e

there r e s u lte d

p h e n y l - 2 - a c e t y l a m i n o e t h a n o l , ( XX), i n y i e l d o f Q9%.

2-

This

compound h a d n o t b e e n r e p o r t e d p r e v i o u s l y b u t on o x i d a t i o n w ith a lk a lin e

perm anganate a t 30° i t

gave a

6 5-/0

y ield

of

a c e t y l a l p h a p h e n y l g l y c i n e , ( X X I I I ) , a known co m pound, m eltin g a t 192°,

r e p o r t e d m .p.

191°

This r e a c t i o n e s t a b l i s h e d ph enyl-2-acety lam in o e th a n o l,

(30). the s tr u c tu r e

of 2-

w hich, by r e f l u x i n g i n

-2 8 benzene w i t h zin c brom ide,

was c o n v e r t e d t o 2 - m e t h y l -

4—p h e n y l o x a z o l i n e , ( X V I I I ) .

When m i x e d ,

o x a z o l i n e p r e p a r e d by t h e t h r e e

sam ples of th e

d i f f e r e n t r o u t e s showed

no d e p r e s s i o n i n m e l t i n g p o i n t . A lth o u g h the above r e a c t i o n s

showed t h a t

o x a z o l i n e w as t h e p r o d u c t o f t h e c y c l i z a t i o n o f a n N - s u b s t i t u t e d halo acetam id e, ex isted

the p o s s i b i l i t y

still

t h a t on a c t i v a t i o n o f t h e m e t h y l g r o u p o f t h e

acetaraide,

f o r e x a m p l e , by t h e n e i g h b o r i n g p h e n y l g r o u p

in N (ter.b u ty lch lo ro )p h en y lacetam ld e,

r in g c lo su re in

a n o t h e r d i r e c t i o n m ig h t have t a k e n p l a c e .

C yclization

on t h i s a c t i v a t e d m e t h y l e n e g r o u p w o u l d y i e l d 5 , 5 - d i m e t h y l - 3 - p h e n y l - 2 - p y r r o l i d o n e f (XXV), a n d t h i s p o s s i b i l i t y , as w ell as

t h a t o f 2 - b e n z y l - 4 , 4 ~ d i m e t h y l o x a z o l i n e , (X X V I) ,

could n o t be n e g le c te d .

(CH3 )2 c

(CH 3 ) 2 C — CHg o

-QEr

CHCgH(

NH— C f o (XXV)

N = g' c h ? c 6h 5 (XXVI? 3

The f a c t t h a t 2 - p y r r o l i d o n e s w h i c h a r e u n ­ s u b s t i t u t e d o r only m o n o s u b s t i t u t e d a t p o s i t i o n #5 a re n o t b a s i c e n o u g h t o fo rm s a l t s w as n o t a r g u m e n t a g a i n s t form ula

(XXV), 5 » 5 - d i r a e t h y l - 3 - p h e n y l - 2 - p y r r o l i d o n e .

It

has been o b serv ed ( 1 ) , ( 5 ) t h a t i n am ides of the type,

-29-

R^C-NHCOR, t h e e l e c t r o n d e n s i t y on t h e a m i d e n i t r o g e n , due t o t h e i n d u c t i v e e f f e c t o f t h e t h r e e a l k y l g r o u p s , was i n c r e a s e d ,

so t h a t th e y formed s a l t s i n c o n c e n t r a t e d

hydrochloric a cid .

Even i n the b e t a c h lo r o e t h y l a m i d e s ,

w here t h e p r e s e n c e o f h a l o g e n would be e x p e c t e d t o r e d u c e th is in d u ctiv e e f f e c t,

th e am ides d i s s o l v e d i n c o n c e n t r a t e d

HC1 a n d w e r e p r e c i p i t a t e d u n c h a n g e d on t h e a d d i t i o n o f w ater. Benson (31) a tt e m p te d tc p r e p a r e 5 , 5 - d im e t h y l 3 - p h e n y l - 2 - p y r r o l i d o n e by means o f t h e s u b s t i t u t e d a m i d e

r e a c tio n and r in g c lo s u r e ,

b u t on s u b m i t t i n g t h e n i t r i l e

t o t h e c o n d i t i o n s o f t h e r e a c t i o n he o b t a i n e d o n l y t h e u n s u b s t i t u t e d a m id e , (X X VII).

CgHejCHpCN + CH2 :C C H 2 C1

N aN H g -------->

CH-j

HoSCK --------> C6 H5 CHCONH2

CgH gCH CN

CH2 C:CH 2

GH2 C;CH 2

2

CH-z

CH-z

D

(XXVII)

T h i s r e s u l t w o u l d b e e x p e c t e d on c o n s i d e r a t i o n o f a model o f th e n i t r i l e lies

in a s tr a ig h t lin e

( X XVIII). it

Because th e g ro u p ,

-CH-GN,

i s not p o ssib le f o r the n itro g e n

to a p p ro a c h b o n d in g d i s t a n c e of th e carbonium i o n .

T herefore,

f o r m a t i o n o f a f i v e m e m b e r e d r i n g by a n i n t r a m o l e c u l a r s u b s t i t u t e d am ide r e a c t i o n would be u n l i k e l y .

-30-

c 6 H5

(XXVIII)

Cl

(XXIX)

(XXX)

-3 1On t h e o t h e r h a n d , a m o d e l o f N( t e r . b u t y l c h l o r o ) phenylacetam ide d em o n strated t h a t , of the m o lecu le, strik e

by a s i m p l e r o t a t i o n

th e carbon h o ld in g the c h lo rin e could

e i t h e r t h e c a r b o n a l p h a t o t h e p h e n y l g r o u p (X X IX ) ,

o r th e oxygen o f th e amide l i n k a g e then o c c u r re d ,

i n the f i r s t

(XXX).

If reactio n

ca se th e p y r r o l i d o n e would

be fo rm ed , an d i n t h e s e c o n d , 2 - b e n z y l - 4 , 4 - d i m e t h y l oxazoline.

I n o r d e r t o d i f f e r e n t i a t e b e t w e e n t h e two

compounds t h e f o l l o w i n g i n f o r m a t i o n was e m p l o y e d . G a b r i e l (32)

h a d n o t e d t h a t on e v a p o r a t i o n o f

a h y d ro c h lo ric a c id s o lu t i o n of the o x azo lin e th e b e ta c h l o r o e t h y l a m i d e was r e g e n e r a t e d .

? Hr

-CH.2\

N =

■C‘

.

HCl^

CHg—

CH2 C1

0 NHCOR

R

I t was a l s o known t h a t a m i d e s , R-jC-NHCOR, w e r e c l e a v e d rap id ly

to th e c a rb o x y llc a c id ,

o lefin ,

a n d ammonium

c h l o r i d e by warm c o n c e n t r a t e d h y d r o c h l o r i c a c i d .

Thus,

on h e a t i n g N - d i i s o b u t y l a c e t a m i d e w i t h h y d r o c h l o r i c a c i d , d iiso b u ty len e,

a c e t i c a f c i d , a n d ammonium c h l o r i d e w e r e

formed ( 1 ).

( CH3 )3 C C H 2 9 (C H ) 2 5 ^ nhcoch3

HC1 -----h20

(C H 3 )3 CCH2 C :CHg +CH3 CO O H ^ ^ CH 3

+ NH4 .C1

-32-

I t was t h o u g h t ,

th erefo re,

t h a t by h e a t i n g t h e

unkno wn compound w i t h c o n c e n t r a t e d HC1 one o f t h e , t w o f o l l o w i n g s e r i e s o f r e a c t i o n s would o c c u r .

(A)

( CH-z) g C

J

1 0—

(B)

( CH-z) p C CHo 3 2| !>ohc6h5 NH— c f o

ch3 CHP :C— CHo 2 > c h c 6h5 HO— C : 0

CHo

^CHCgHc cfo

( XXXI)

(CH5 ) 2 C----- C H ^

(CH 5 ) 2 CCH2 C1

N= C ^ ch2 c 6 h5 CHptCCH^Cl * CH^

NH^Cl

+

NHCOCHpC/-H|^ 6 5

C6 H5 CK2 COOH

I d e n t i f i c a t i o n of the p ro d u c ts,

( XXXII)

e i t h e r the lactone,(X X X I),

o r p h e n y l a c e t i c a c i d , ( X X X I I ) , would c o n s t i t u t e s t r u c t u r e o f t h e o r i g i n a l com po und . cyclic

p ro o f o f the

When o n e grarn o f t h e

com po und , m e l t i n g a t 1 4 2 ° , was r e f l u x e d two a n d one

h a l f hours w ith f iv e cubic c e n tim e te r s o f c o n c e n tr a te d h y drochloric a cid , cooling.

a n o i l a p p e a r e d w h i c h s o l i d i f i e d on

The s o l i d was i d e n t i f i e d a s p h e n y l a c e t i c a c i d ,

m e l t i n g p o i n t (one r e c r y s t a l l i z a t i o n from w a t e r ) The m i x e d m e l t i n g p o i n t w i t h a n a u t h e n t i c was 7 5 ° .

74°.

sam ple (m .p. 76°)

One h a l f g r a m , o r 85% o f t h e t h e o r e t i c a l y i e l d

-3 3 was i s o l a t e d . On t h e b a s i s o f t h i s e x p e r i m e n t i t was c o n c l u d e d the h ig h e r m e ltin g isom er of N ( te r .b u ty lc h lo r o ) p h e n y la c e t a m i d e was 2 - b e n z y l - 4 , 4 - d i m e t h y l o x a z o l i n e h y d r o c h l o r i d e . O r,

to g e n e r a l i z e ,

u n d e r th e c o n d i t i o n s em ployed, ev en

when t h e m e t h y l o f a c e t a r n i d e h a s b e e n a c t i v a t e d ,

p y rrolidone

r in g c lo su re does n o t o ccu r.

5* O x a z o l i n e s f r o m B e t a H a lo E t h y l a m i d e s - T h e o retical C o n sid eratio n s.

The c h l o r i n e a t o m i n t h e N ( c h l o r o e t h y l ) a m i d e s was f o u n d t o b e r e p l a c e d e a s i l y .

When t h e r e a c t i o n m i x t u r e

in the p r e p a r a tio n o f a lp h a carbethoxy N ( te r .b u ty lc h lo r o ) a c e t a r n i d e was a l l o w e d t o s t a n d 2 -§- h o u r s I n s t e a d o f 45 m inutes b e fo re d i l u t i n g w ith w a te r, 65;% t o 4 3 ^0.

th e y i e l d f e l l from

E t h y l an d n o rm a l amyl e t h e r s were p r e p a r e d

by r e f l u x i n g N ( c h l o r o e t h y l ) a m i d e s w i t h t h e c a l c u l a t e d am o u n t o f s o d iu m i n a l c o h o l .

( CH,) 0 CCH0 C1 j5 d 1 d NHCOCH2 COOC2 H5

R0- ^

( C H3, ) d\ o CCHod 0R NHC0CH2 C00C2 H5

Cl

-3 4 A l l t h e p u r i f i e d am ides gave an im m ediate p r e c i p i t a t e of s i l v e r ch lo rid e w ith alco h o lic s ilv e r n i t r a t e .

On

s t a n d i n g a t room t e m p e r a t u r e w i t h a s o l u t i o n o f . 0 3 M KOH i n a q u e o u s a c e t o n e ,

t i t r a t i o n w i t h s t a n d a r d HC1

s h o w e d c o m p l e t e h y d r o l y s i s i n 4t h o u r s .

N (ter.b u ty l

c h l o r o ) b e n z a m i d e was h y d r o ly z e d to N ( t e r . b u t y l h y d r o x y ) b e n z a m l d e b y s t a n d i n g a t room t e m p e r a t u r e 4 8 h o u r s w i t h KOK i n a q u e o u s a c e t o n e .

OH

( CHjJgCCHgCl

(c h 3 )2 c c h 2 o h

NHCOCgH^

n h c o c 6h

In o r d e r to p re v e n t d eh y d ratio n , d i s t i l l a t i o n

5

o f the

h y d r o x y compound ha.d t o b e p e r f o r m e d r a p i d l y . The m a r k e d r e a c t i v i t y was p a r t i c u l a r l y

of t h e s e h a l o am ides

s t r i k i n g when i t was c o n s i d e r e d t h a t

t h e s t r u c t u r e o f t h e compounds p r e p a r e d f r o m t e r t i a r y c h l o r o a l c o h o l s o r o l e f i n s was s i m i l a r t o t h a t o f n e o p e n t y l c h l o r i d e , ( X X X I I I ) , i n w h i c h one o f t h e a l k y l g ro u p s o f th e n e o p e n t y l s t r u c t u r e had been r e p l a c e d by the group,

- N H C O R ( XXXIV).

CH,

» 3

C H ,- C - 0 H o Cl 3 i 2

CH_.-C-CH0 C1 3

i

2

NHCOR ( X X X II I)

(XXXIV)

-3 5 T'he l a c k o f r e a c t i v i t y

o f n e o p e n t y l compounds

was s t u d i e d by B a r t l e t t ( 3 3 ) a n d c o w o r k e r s . t o t h e t h e o r y o f t h e S ^-2 m e c h a n i s m

A ccording

(34), n u cleo p h ilic

d i s p l a c e m e n t on c a r b o n w o u l d o c c u r t h r o u g h a r e a r w a r d a t t a c k on th e carbon f a c e o p p o s i t e prim ary h a lid e s alm ost e n ti r e ly .

t h e h a l i d e ato m . W i t h

th e b l m o l e c u l a r r e a c t i o n would take p l a c e B a r t l e t t c o n s t r u c t e d m o le c u le s in w hich

t h e c a r b o n c o n t a i n i n g t h e n u c l e o p h i l i c g r o u p was s h i e l d e d f r o m d i s p l a c e m e n t , a n d f o u n d th e m u n r e a c t l v e . also

t h a t the la c k of r e a c t i v i t y

"chem ical" e x p la n a tio n .

He showed

h a d a s t e r l c an d n o t a

That i s ,

th e p resen ce of a neo­

p e n ty l group d id not e f f e c t th e p o l a r i z a b i l i t y c a r b o n - h a l o g e n bond.

Since i t

of the

i s known t h a t e l e c t r o n i c

e f f e c t s are tra n s m itte d th ro u g h double o r t r i p l e c a r b o n b o n d s , he m easured t h e r e a c t i v i t y

carbon-

o f compounds i n

w h i c h t h e h a l o m e t h y l g r o u p w as s e p a r a t e d f r o m t h e n e o ­ p e n ty l by a c e ty le n ic o r e t h y l e n i c l i n k a g e s . g e o m e t r i c a l f a c t o r s had b e e n n u l l i f i e d ,

Once t h e

he f o u n d t h a t

n e o p e n t y l compounds u n d e r w e n t b l m o l e c u l a r d i s p l a c e m e n t e v e n m o re r a p i d l y t h a n t h e i r n o r m a l c h a i n a n a l o g u e s . From c o n s i d e r a t i o n it

m ig h t have b een e x p e c te d

a m id es,

sin ce

of that

th ey w ere p rim ary

B a r tlett's the and

n e o p e n t y l g r o u p in g , w ou ld n o t r e a c t

exp erim en ts

N (te r .b u ty lc h lo r o ) co n ta in ed

a type

of

under in term o lecu la r

-36-

S^2 c o n d i t i o n s ,

and o n ly s l u g g i s h l y under S^l c o n d i t i o n s .

Since,

o x a z o l i n e s w e r e f o r m e d when t h e r e a c t i o n

however,

time w i t h b a s i c

r e a g e n t s was s h o r t ,

t h e r e was l i t t l e

doubt

t h a t a n i n t r a m o l e c u l a r d i s p l a c e m e n t o f h a lo g e n by oxygen had o c c u r r e d .

R 0 C— CH0 -C1 » ^ +• NH-C-OR

R0 C CH0 -C1 ^» vh + NH-C R

RpC GH^ ' + * 0 NH— C ^ R

Cl

— >

RpC----- CH? ' NH=C' + R

Cl

(XXXV)

The r e s u l t i n g

c o m p o u n d , ( XXXV), was t h e h y d r o c h l o r i d e o f

the o x a z o l i n e .

S t e r e o c h e m i c a l l y , a t t a c k by o x y g e n o n

t h e c a r b o n c o n t a i n i n g t h e h a l o g e n was f a v o r e d , a s w a s shown o n p a g e 3 0 .

T h i s c a r b o n was i n p o s i t i o n f o r r e a c t i o n

w ith t h e a l p h a c a r b o n o f t h e am ide,

o r , by r o t a t i o n a b o u t

a c a rb o n -c a rb o n bond, w i t h th e oxygen. r e a c t i o n u n d e r m ore d r a s t i c re a c tio n p erio d — led ,

N ucleo ph ilic

c o n d itio n s — h e a t and lo n g e r

a s was n o t e d ,

to l n t e r m o l e c u l a r

r a th e r than in tra m o le c u la r s u b s titu tio n . I t w as d e m o n s t r a t e d by B a r t l e t t

(3 5)

th a t b eta

ch lo ro e th y la m in e s r e a c t e d i n n e u t r a l or b a s ic s o l u t i o n via a c y c lic

e th y le n e im ine in te r m e d ia te .

-3 7 x R2 N-CH2 CH2 -C1

*

(R 2 N-CH2 y H2 > Cl

In the p re s e n c e of n u c le o p h ilic r e a g e n t s u n d e r w e n t r a p i d Sw2 r e a c t i o n t o p r o d u c e product.

* r 2 n - c h 2 ch2 - x

th e e t h y l e n e im ine the s u b s t i t u t e d

S in c e th e amides h a v i n g t h e g r o u p ,

R.:,C-NHCOR,

w e r e m or e b a s i c t h a n t h o s e w i t h a c a r b o n h o l d i n g o n e o r two g r o u p s ,

a c o r r e s p o n d in g m echanism c o n c e i v a b l y m ig h t

be p o s t u l a t e d t o e x p l a i n t h e e a s e o f r e p l a c e m e n t o f h a l o g e n by h y d r o x y l i n th e b e t a c h l o r o e t h y l a m i d e s .

— pCH2 - C l NHCOR

NHCOR

NH-COR

T h i s i n t e r m e d i a t e was n o t t h o u g h t p r o b a b l e , to acco u n t f o r o x azoline fo rm a tio n ,

it

for,

in order

was n e c e s s a r y t o

p o s t u l a t e i n t r a m o l e c u l a r a t t a c k by o x y g e n on t h e c h l o r i n e carbon.

The a c t i v a t e d i n t e r m e d i a t e f o r s u c h a r e a c t i o n

w o u l d i n c l u d e b o t h a f o u r a n d a t h r e e m em b er ed r i n g . system l i k e

t h a t w o u ld b e u n d e r s t r a i n a n d i t s

would i n v o l v e c o n s i d e r a b l e i n p u t o f e n e r g y .

Cl CR

A

form ation

-38A fter

stu d y in g

the

e th y la m id e s and r e l a t e d

the

series

of

the b eta h a lo

b elo w ,

an oth er

G a b r i e l a n d Heymann ( 3 2 )

ca rried

tra n sfo rm a tio n s: OH — >

RC0NHCHo C H „ B r C.

of

com pounds g iv e n

m ech an ism w as p o s t u l a t e d . out

rea ctio n s

C.

CH 0

CHr

c.

I

HC1 ------- =*

yd

R 0 C 0 C H o CHo NHo H C l

N = = C / R

I t w as known a l s o

that

the

eq u ilib riu m

m igh t o ccu r:

OH ROCOCHpCHpNHpHCl d

d

< * HC1

d

P h illies

and B a lt z le y

rea ctio n

proceeded

(37)

RONHCHpCHpCH ^ ^

p o stu la ted

th a t the

la tte r

the

in term ed ia te,

CHp—

In no c a s e w ere from

th eir

through

they

rea ctio n

th a t o x a zo lin es were reverse

rea ctio n

cla im ed ,

co n d itio n s" ,

that

o x a zo lin es,

to

secondary

a lso

were they

as

that b a sis sid e

to

am ine e s t e r s , to

in

the

under n e u tr a l

They c i t e d

in

fu rth er

w h ic h c a n n o t form

N -su b stitu ted

C-t5H R

B ecause

not occur at a ll

e t h a n o l am id e.

rearranged

p rod u cts

sta b le

CH2 ^

assum ed

am in e e s t e r .

" fa irly co u ld

1 NH

an o x a z o lin e

and on

e t h a n o l am id e

or a lk a lin e

ev id en ce

iso la te

form ed o n ly

they

forw ard r e a c t io n

to

m ix tu re,

o x a zo lin es,

the

/

of

a b le

cy clic

ethanol

-39am ides.

T h e i r c o n c l u s i o n s a r e "best s u m m a r i z e d i n a

s e rie s of equations. OH CH2

m

N = (XXXVII)

c 6h

NH-C-OH CH,

CH, (XXXVIII)

The l a t t e r r e a c t i o n ,

lik e

5ch

c h 2oh

NHCOCH-z

the c o rre s p o n d in g s te p i n th e

a l k a l i n e h y d ro ly s is of e s t e r s , ( 3 8 ) r e q u ire d c o n sid e ra b le energy.

C onsequently,

i t d id n o t take p la c e under the

m i l d c o n d i t i o n s e m p l o y e d by P h i l l i p s a n d 3 a l t z l e y . the in te r m e d ia te ,

-C

Once

(XXXVIII), h a d b e e n fo rm e d , h o w e v e r,

i t was i m m e d i a t e l y s t a b i l i z e d b y r u p t h r e o f t h e c a r b o n -

-4 1 oxygen bond w i t h t h e f o r m a t i o n of t h e e t h a n o l am ide. When t h e c o n d i t i o n s w e r e m o r e d r a s t i c , s o d iu m h y d r o x i d e i n

f o r example w ith

p l a c e o f s o d iu m c a r b o n a t e ,

r e a c tio n did n o t s to p a t

th e am ide,

the

b u t p r o c e e d e d by

h y d r o l y s i s to t h e amino a l c o h o l .

6 . Alpha A cetam ino A c id s — A c e t y l A lpha P henyl

G lycine.

I t s h o u l d be n o t e d t h a t h y d r o l y s i s o f t h e h a l o amide w i t h a l k a l i

c o n s t i t u t e d a p r e p a r a t i v e method

f o r 2 - a m i n o - l - a l c o h o l s , o t h e r w i s e p r e p a r e d e i t h e r from n i t r o a l c o h o l s o r from am ino e s t e r s .

:,.ore i m p o r t a n t ,

h y d r o l y s i s o f t h e h a l o a m i d e w i t h s o d iu m c a r b o n a t e a f f o r d e d an e x c e l l e n t r o u t e f o r th e s y n t h e s i s o f a lp h a a m ino a c i d s .

In t h e exam ple c i t e d ,

a c e ty l alpha phenyl

g l y c i n e was p r e p a r e d w i t h a 4 5 $ y i e l d fro m s t y r e n e by the a c t i o n o f a c e t o n i t r i l e

on th e b r o m o h y d r in , f o l l o w e d

by h y d r o l y s i s .

C6 H5 CH:CH2

HOBr ------ >

CH,CN CgH^CH-CHgBr — ^ CgHgCH-CHgBr OH

V

3

c 6h

5c h -c h 2o h

NHCOCH3

KMnO.'4

NHCOCH. 3

C5 H3 CH-COOH NHCOCH3

-42-

The d i r e c t p r e p a r a t i o n o f a m i n o a c i d s b y t h e s u b s t i t u t e d a m i d e r e a c t i o n h a d b e e n c a r r i e d o u t by condensing b e n z o n i t r i l e w ith u n s a tu r a te d e s t e r s

(4).

HpSOr RgCrCHCOOR

+

CgH^CN

-± -> HpO

Ro CCHo C 00 R 2 '

*

NHCOCgHg

H a r tz e l found th r e e d isa d v a n ta g e s in

t h i s method.

F irst,

a lp h a - b e t a u n s a tu r a t e d a c id s o r t h e i r e s t e r s r e a c t e d only when t h e b e t a c a r b o n was t e r t i a r y . amino a c i d s c o u l d be p r e p a r e d , o f t h e amino a c i d s ,

_ e c o n d , no a l p h a

and t h i r d ,

once form ed,

the b en zo ates

required d ra stic

co nditions fo r h y d ro ly sis. Of t h e many known m e t h o d s f o r t h e p r e p a r a t i o n o f amino a c i d s

(39),

t h e one m o s t r e l a t e d t o t h e p r e p a r a t i o n

o f a l p h a a m i n o a c i d s f r o m b e t a h a l o e t h y l a m i d e s was t h a t of B illm an (4 0 ). the a c e t a t e

o r benzoate o f a 2 -a m in o -l-a lc o h o l,

w ith a lk a lin e acid ,

This c o n s i s t e d i n s y n t h e s i z i n g e i t h e r oxidatio n

p e rm a n g a n a te to th e a c e t y l o r b e n z o y l amino

a n d h y d r o l y s i s t o t h e amin o a c i d b y r e f l u x i n g e i g h t

h o u r s i n 18$ h y d r o c h l o r i c a c i d . when c a r r i e d o u t on a m i d e s l i k e

The a c i d h y d r o l y s i s , e v e n ( C H , ) 2 CC00H NHCOR , was

accom plished in q u a n t i t a t i v e y i e l d s .

T h i s was a s t r i k i n g

e x a m p l e o f t h e e f f e c t o f s u b s t i t u e n t s on t h e c o u r s e o f

-4 3th e r e a c tio n .

U nlike the am ides a t t a c h e d to a te r tia r y -

c a rb o n which b re a k a t th e N - a l k y l b o n d ,

the carboxyl

g r o u p h a d so r e d u c e d t h e e l e c t r o n d e n s i t y a t t h e t e r t i a r y carbon th a t r e a c tio n did n o t occur th e r e ,

but rath er a t

th e N -carbon yl bond. In g e n e r a l t h e u s e o f t h e s u b s t i t u t e d amide r e a c t i o n f o r a l p h a am ino a c i d s o f f e r e d a n a d v a n t a g e o v e r B illm a n 's because o f s im p le r p ro c e d u re and w id e r a v a i l ­ ab ility

of s ta r t i n g m a te r ia ls .

-44-

III.

THE R E A C T I O N OF N I T R I T E S W I T H NITRO A L C O H O L S O R N I T R O OLEFINS

I t was a t t e m p t e d t o b r o a d e n t h e s c o p e o f t h e s u b s t i t u t e d amide r e a c t i o n t o i n c l u d e a l c o h o l s c o n t a i n i n g a d i f f e r e n t added f u n c t i o n a l group.

The b e t a n i t r o a l c o h o l s

(XXXIX) a n d t h e i r d e h y d r a t i o n p r o d u c t s , n i t r o o l e f i n s , w e r e s e l e c t e d because th e y r e a d i l y added n u c l e o p h i l i c r e a g e n ts a n d a l s o b e c a u s e t h e y may b e s y n t h e s i z e d f r o m n i t r o p a r a f f i n s and a ld e h y d e s

(41).

RCHCHoNO,

HgSO^ >

RC N

h

, Hr R C H C H 2N 0 2

2o NH C O R

OH

(XXXIX) RCHCH2NH2

(XL)

CaO

RCH-

-C ^ N

NH-

NHCOR

(X LII)

( XLI)

The p l a n was t o r e d u c e

the n i t r o

am ide,(X L ), w ith

h y d r o g e n o v e r Raney n i c k e l u n d e r t h e same c o n d i t i o n s w h i c h h a d b e e n f o u n d t o g i v e g o o d y i e l d s o f am in o a l c o h o l from n i t r o a l c o h o l ( 4 2 ) .

The a m in o a m i d e , ( X L I ) ,

could

-4 5 t h e n s u b j e c t e d t o r i n g c l o s u r e by d i s t i l l a t i o n calcium o x id e .

over

The l a t t e r was a s t a n d a r d r e a c t i o n f o r

t h e p r e p a r a t i o n o f 4 , 5 - d i h y d r o i m i d a z o l e s from t h e mono a c y l a t e d d i a m i n e s

(43).

The s e r i e s o f r e a c t i o n s

w o u l d h a v e p r o v i d e d a new a n d c o n v e n i e n t s y n t h e s i s f o r the 2 , 4 - d i a l k y l im id a z o lin e s ,( X L I I ) .

The i m i d a z o l i n e s

h a d b e e n shown t o h a v e c o n s i d e r a b l e b i o l o g i c a l i n t e r e s t ( 4 4 ) . When 2 - n i t r o - 3 - h e x a n o l , and n i t r o

p r e p a r e d from b u t y r a l d e h y d e

e t h a n e , was s u b j e c t e d t o t h e c o n d i t i o n s o f t h e

s u b s t i t u t e d amide r e a c t i o n w i t h b e n z o n i t r i l e , a r e d t a r was o b t a i n e d a f t e r d i l u t i n g t h e m i x t u r e w i t h w a t e r .

By

e x t r a c t i n g th e t a r w ith b o i l i n g hexane a sm all crop o f co lo rless

cry stals,

m e l t i n g a t 2 0 2 ° , was I s o l a t e d .

compound g a v e a n e g a t i v e n itro u s acid ,

and a f t e r

The

t e s t f o r th e n i t r o group w ith se v e ra l attem p ts a t re d u c tio n w ith

z in c and h y d r o c h l o r i c a c i d ,

no a m i n e r e s u l t e d .

The r e a c t i o n was r e p e a t e d w i t h l - n i t r o - 2 - p e n t a n o l a n d b e n z o n i t r i l e w i t h t h e same r e s u l t s : re d t a r o f n e e d le s m e ltin g a t 202°.

i s o l a t i o n fro m a

T h i s compound g a v e no

m ixed m e l t i n g p o i n t d e p r e s s i o n w i t h t h a t i s o l a t e d from t h e r e a c t i o n o f 2 - n i t r o - 3 - h e x a n o l and b e n z o n i t r i l e . agreed w ith the s tr u c tu r e

C^ gH^ON .

The a n a l y s i s

From t h e f a c t t h a t t h e

two co m pounds w e r e i d e n t i c a l i t was c o n c l u d e d t h a t i n b o t h cases a " d e a ld o liz a tio n " of the n i t r o a lc o h o l in to b u ty r -

-46-

a ld e h y d e and n i t r o p a r a f f i n had o c c u r r e d . th e b u ty raldehyde w ith b e n z o n i t r il e

R eaction of

le d to b u t y r a l d i -

b e n z a m id e ,(X L II), in agreem ent w ith a n a l y s i s .

CH ,( CH_) 0 CH-CHR + C.H-CN 3 2 21 i op

.sT

ch ( c h 2 ) 2 c h ( n h c o c 6h 5 ) 2 (XLII)

OH N02

Omega n i t r o s t y r e n e was p r e p a r e d a n a s u b j e c t e d t o t h e s u b s t i t u t e d amide r e a c t i o n b o t h i n th e p r e s e n c e and a b s e n c e o f a c e t i c a c i d as s o l v e n t . no r e a c t i o n o c c u r r e d , unchanged.

and th e n i t r o

With a c e t i c a c i d

o l e f i n was r e c o v e r e d

With a c e t o n i t r i l e an d c o n c e n t r a t e d s u l f u r i c

a c i d a n e x o t h e r m i c r e a c t i o n was n o t e d .

The s o l u t i o n

b ecam e b l a c k a n d , a f t e r p o u r i n g o v e r i c e a n d n e u t r a l i z i n g , y ie ld e d c r y s t a l s m eltin g a t 233°. d id n o t give a p o s itiv e n itro

group,

A lthough t h i s

compound

t e s t w ith n i t r o u s a c id f o r the

i t was f e l t t h a t a n i t r o

group s t i l l m ight

b e p r e s e n t wh os e r e a c t i o n s w e r e m a s k e d by t h e a m i d e g r o u p . Because the a n a l y s is f o r n i t r o g e n a g re e d w ith t h a t c a l c u l a t e d f o r the expected s tr u c t u r e , n itro eth an e,

a c e ty l-l-a m in o -l-p 'n e n y l-2-

a t t e m p t s w e r e made t o h y d r o g e n a t e t h e p r o d u c t

a t 2 5 ° u n d e r 1000 p . p . s . i .

fo r se v e ra l hours.

In a l l

c a s e s t h e s t a r t i n g m a t e r i a l was r e c o v e r e d u n c h a n g e d . was c o n c l u d e d ,

th erefo re,

It

t h a t a r e a c t i o n analogous to

-4 7t h a t w ith the n i t r o a lc o h o ls had o c c u rre d .

In th is

case

t h e p r o d u c t was b e n z a l d i a c e t a m i d e , ( X L I I I ) .

An a u t h e n t i c

s a m p l e was p r e p a r e d by h e a t i n g b e n z a l d e h y a e i n e x c e s s acetam ide.

The r e c r y s t a l l i z e d

A mixed m e l t i n g p o i n t w i t h th e amide s y n t h e s i s

(m .p. 233°)

p ro d u c t m elted a t 239°. p r o d u c t from t h e s u b s t i t u t e d

gave a v a lu e o f 234°.

c o n c l u d e d t h e compound was b e n z a l d i a c e t a m i d e .

I t was

I t m ight

be n o te d t h a t th e c a l c u l a t e d p e r c e n t o f n i t r o g e n

( 1 3 » 5 9 f»)

was a l m o s t i d e n t i c a l w i t h t h a t o f t h e e x p e c t e d n i t r o compound ( 1 3 . 4670) . CgH5 CH:CHN02 + CH3 CN CH(NHCOCH3 ) 2

(X LIII)

CgHgCHO + CH3 CONH2

A s s u m i n g t h a t w a t e r h a s b e e n r e p l a c e d by n i t r i l e , t h e s e t r a n s f o r m a t i o n s w e r e a n a l o g o u s t o t h e known a c i d h y d ro ly sis of n itro o le fin s

to a ld e h y d e s and n i t r o p a r a f f i n s ( 4 5 ) .

-48-

IV.

EXPERIMENTAL

N (ter.am yl)acetam lde To a s o l u t i o n o f 1 0 . 2 g . s u l f u r i c a c i d a n d 50 c . c . 7*0 g .

(0 .1

E) c o n c e n t r a t e d

g la c ia l a c e tic acid,

( 1 . 7 M) a c e t o n i t r i l e .

p o rtio n w ith s w irlin g 8 .8 g.

w er e a d d e d

Then w e r e a d d e d i n one ( 0 . 1 I.') t e r .

am yl a l c o h o l .

F o r 30 m i n u t e s t h e r e a c t i o n was e x o t h e r m i c a n d t h e t e m p e r a t u r e o f t h e s o l u t i o n was k e p t b e l o w 5 0 ° w i t h c o o l i n g .

I t was

t h e n a l l o w e d t o s t a n d o v e r n i g h t a t room t e m p e r a t u r e , p o u r e d i n t o 200 c . c .

w ater,

a n d n e u t r a l i z e d w i t h s o d iu m c a r b o n a t e .

The c r y s t a l s o f N ( t e r , a m y l ) a c e t a r n i d e w e r e c o l l e c t e d a n d r e c r y s t a l l i z e d from h e x a n e . of theory)

The y i e l d was 9 . 5 g .

of c o lo rle ss need les,

m elting a t 78°.

A n aly sis C a lcu la ted

as

{71%

% N itro g en

N (te r ,a m y l)a c e ta m id e ,

10.83 Found

1 0 .7 6

-49-

N (ter,am yl)benzam lde. To a s o l u t i o n o f 1 0 . 2 g . s u l f u r i c a c i d i n 50 c . c . 1 0 .3 g.

( 0 . 1 M) c o n c e n t r a t e d

g l a c i a l a c e t i c a c i d were added

( 0 . 1 M) b e n z o n i t r i l e .

E ig h t and e i g h t t e n t h s

grams t e r , a m y l a l c o h o l were added an d , a f t e r to e f f e c t s o lu tio n ,

were a llo w e d to s t a n d .

sw irling In itia lly ,

t h e t e m p e r a t u r e r o s e t o 38° i n one h a l f h o u r . A f t e r s t a n d i n g o v e r n i g h t a t room t e m p e r a t u r e t h e s t r a w - c o l o r e d s o l u t i o n was p o u r e d i n t o 200 c . c .

w ater.

The s o l i d

N ( t e r . a m y l ) b e n z a m i d e was c o l l e c t e d a n d r e c r y s t a l l i z e d from h e x a n e .

The y i e l d was 1 4 . 0 g .

(74^ o f th e o r y )

m e ltin g p o in t 54°.

% N itrogen

A n aly sis C a lc u la te d as N (ter.am yl)benzam lde,

C12H170N

7 *34

Found

7.38

N( 2 - p e n t y l > a c e t a m l a e . I n a 500 c . c . stirre r,

three-necked f la s k

th erm o m eter, and d ro p p in g f u n n e l,

b y a n i c e b a t h , w e r e m i x e d 20 g . a n d 110 g .

equipped w ith and surrounded

( 0 . 4 9 M) a c e t o n i t r i l e

( 1 . 1 M) c o n c e n t r a t e d s u l f u r i c a c i d .

was r e m o v e d a n d o v e r t h r e e h o u r s a t 2 9 ° - 3 2 ° ,

The b a t h 2 6 .4 g.

-50-

( 0 . 3 M) r e d i s t i l l e d 2 - p e n t a n o l w e r e a d d e d d r o p w i s e .

The

t e m p e r a t u r e was m a i n t a i n e d hy o c c a s i o n a l c o o l i n g i n a n ice h a th .

The c l e a r ,

ta n s o l u t i o n was a l l o w e d to rem ain

3 d a y s a t room t e m p e r a t u r e ,

then poured in to

600 c . c .

w a te r, and n e u t r a l iz e d w ith s o li d so d iu $ carb o n ate.A y e l l o w o i l s e p a r a t e d a n d was c o l l e c t e d i n a s e p a r a t o r y fu n n e l and th e w a te rs e x tr a c te d w ith e t h e r .

The o i l

and e t h e r e x t r a c t w ere combined, w ashed w i t h w a t e r , and d r i e d o v e r s o d iu m s u l f i e . r e s i d u e was d i s t i l l e d .

Upon r e m o v i n g t h e e t h e r ,

A head f r a c t i o n

the

o f s e v e r a l drops

was d i s c a r d e d a n d t h e ;„ain f r a c t i o n o f N ( 2 - p e n t y l ) a c e t a m i d e , d i s t i l l i n g a t 1 2 2 ° - 1 2 3 ° a t 14 mm. c r y s t a l l i z e d r e c e iv e r in c o lo rle s s needles.

(Ql% o f t h e o r y ) . eth y l a c e ta te ,

in the

The w e i g h t w as 1 0 . 5 g .

A p o r t i o n was t w i c e r e c r y s t a l l i z e d fro m

i n w h i c h i t was q u i t e

A nalysis

so lu b le,

and m elted

% N itrogen

Gli a l c u l a t e d a s N ( 2 - p e n t y l ) a c e t a m i d e ,

10.83 Found

1 0 .7 6

-51-

N (d im eth y 1 -n -b u ty lc arb in y l)acetam ld e. To a s o l u t i o n o f 1 0 . 2 g . s u l f u r i c a c i d i n 50 c . c . 7*0 g .

g l a c i a l a c e t i c a c i d were ad d ed

( 1 . 7 r.T) a c e t o n i t r l l e .

w i t h s w i r l i n g 1 0 . 6 g . ( 0 . 0 7 M)

d im eth y l-n -b u ty lcarb in o l (b .p . added q u ic k ly .

( 0 . 1 Vi) c o n c e n t r a t e d

5 ^ ° - 5 5 ° a t 17 mm.) w e r e

A f t e r s t a n d i n g t h r e e d a y s a t room t e m p e r a t u r e

t h e s o l u t i o n was p o u r e d i n t o

200 c . c .

w ater.

A fter n e u tra l­

i z i n g w i t h s odium c a r b o n a t e t h e o i l l a y e r was s e p a r a t e d , the w aters e x tr a c te d w ith e t h e r , e x t r a c t combined.

and the o i l and e th e r

A f te r w ashing w ith w a te r and d ry in g

o v e r s o d iu m s u l f a t e ,

t h e e t h e r was d i s t i l l e d ,

leav in g a

c r y s ta llin e re sid u e of N (d im eth y l-n -b u ty lcarb in y l)acetam id e. The y i e l d was 1 0 . 0 g . o r recry stallize

of theory.

A ttem p ts to

th e c ru d e amide from m e th a n o l,

iso propanol, w ater, hexane,

benzene,

ethanol,

eth y l a c e ta te ,

carbon t e t r a c h l o r i d e o r com binations o f these s o lv e n ts were u n s u c c e s s f u l .

The a m i d e e i t h e r was t o o s o l u b l e o r

p r e c i p i t a t e d a s an o i l from t h e c o o l e d s o l u t i o n . o f t h e r e s i d u e gave a p r o d u c t , pressure,

w hich s o l i d i f i e d

b .p .

225°-238° a t atm ospheric

i n th e r e c e i v e r and m e lte d a t

A n aly sis

% N itrogen

C alcu lated as N (d im e th y 1 -n -b u ty lcarb in y l) a c e t a m i d e , CfJH, n 0N Found

D istillatio n

8.93 8.89

-52-

N( c y c l o h e x . y l ) a c e t a m i d e . To a s o l u t i o n o f 4 . 1 g . i n 20 c . c .

( 0 . 1 IvI) a c e t o n i t r i l e

c o n c e n t r a t e d s u l f u r i c a c i d , were add ed i n

tw enty m in u te s 1 0 .0 g.

( 0 . 1 L;) c y c l o h e x a n o l .

The r e a c t i o n

m i x t u r e was s w i r l e d a f t e r e a c h a d d i t i o n o f t h e a l c o h o l a n d t h e t e m p e r a t u r e was k e p t b e t w e e n 3 0 ° a n d 4 0 ° by e x te rn a l cooling.

The l i g h t t a n s o l u t i o n s t o o d a t room

t e m p e r a t u r e a n a d d i t i o n a l two h o u r s a n d t h e n , w i t h s t i r r i n g , was p o u r e d i n t o 200 c . c .

w ater.

D uring n e u t r a l i z a t i o n

w i t h s o d iu m c a r b o n a t e a c o l o r l e s s p r e c i p i t a t e

of N (cyclo-

h e x y l ) a c e t a m i d e s e p a r a t e d from th e s o l u t i o n .

Upon f i l t r a t i o n

a n d r e c r y s t a l l i z a t i o n f r o m h e x a n e 9 . 7 6* ( 6 9 % o f t h e o r y ) needles,

m e l t i n g a t 104° were o b t a i n e d . A n aly sis

% N itrogen

C alculated as N (cy clo h ex y l)acetam id e, 9.79 Found

9.90

N( p h e n y l b r o m o m e t h y l c a r b i n y D a c e t a m i d e . To a s o l u t i o n o f 15 c . c . c .c.

aceto n itrile

i n 40

c o n c e n t r a t e d s u l f u r i c a c i d w e r e a d d e d i n 25 m i n u t e s

a t 35°-40°,

20 .0 g.

s ty r e n e brom ohydrin.

The c l o u d y ,

-53-

v i s c o u s s o l u t i o n was a l l o w e d t o s t a n d a t 2 5 ° - 3 0 ° f o r on e h o u r t h e n a d d e d t o a m i x t u r e o f 500 g . I n 10 m i n u t e s ,

after

s o d iu m c a r b o n a t e , filtratio n ,

ic e and w a te r.

p a r tly n e u tr a liz in g w ith s o lid

t h e o i l had s e t to a ta n s o l i d . A f t e r

w a s h i n g w i t h 1 0 % s o d iu m c a r b o n a t e s o l u t i o n

and w i t h w a te r ,

a n d d r y i n g on a B u c h n e r f u n n e l ,

the

c r u d e N ( p h e n y l b r o m o m e t h y l c a r b i n y l ) a c e t a m i d e was 2 2 . 3 6* (92^ o f t h e o r y ) .

E l e v e n g r a m s w er e r e c r y s t a l l i z e d

tw ice

by d i s s o l v i n g i n b o i l i n g a c e t o n e a n d a d d i n g w a t e r t o tu rb id ity .

On c o o l i n g i n i c e ,

4 .0 g.

c o lo rle ss n eedles,

m e l t i n g a t 8 3 ° - 8 4 ° were o b t a i n e d .

% N itrogen

A n aly sis C a lc u la te d a s N(phenylbrom om ethylc a r b i n y l ) a c e t a m i d e , C-j^H^gONBr

5.79

Fou nd

5*74

A ttem pted r e a c t i o n o f a c e t o n i t r i l e To a s o l u t i o n o f 4 6 . 0 g . s u l f u r i c a c i d and 12 .0 g.

a n d bromo s t y r e n e . ( 0 . 4 6 Ei) c o n c e n t r a t e d

( 0 .2 9 x) a c e t o n i t r i l e ,

a d d e d a t 4 0 ° - 4 5 ° i n 40 m i n u t e s 1 8 . 0 g . ( 0 . 1

11 )

A f t e r s t a n d i n g on e h o u r a t room t e m p e r a t u r e , c l o u d y s o l u t i o n was p o u r e d i n t o 300 c . c . opaque polym er s e p a r a t e d .

were

br om o s t y r e n e . the v isc o u s ,

w ater. A s tic k y ,

The compound g a v e a n e g a t i v e t e s t

f o r n i t r o g e n a f t e r s o d iu m f u s i o n .

- 54 -

N( t e r , b u t y l c h l o r o ) a c e t a m l d e . To a s o l u t i o n o f 4 1 . 0 g . ( 1 . 0

!.■:) a c e t o n i t r i l e

i n 9 2 g . ( 0 . 9 2 >.:) c o n c e n t r a t e d s u l f u r i c a c i d , w e r e a d d e d 4 7 . 0 g . ( 0 . 5 2 M) m e t h a l l y l c h l o r i d e i n 30 m i n u t e s .

The

t e m p e r a t u r e was m a i n t a i n e d a t 2 5 ° “ 3 3 ° w i t h a n i c e - w a t e r hath.

The l i g h t - c o l o r e d

s o l u t i o n w as a l l o w e d t o s t a n d

a n a d d i t i o n a l 50 m i n u t e s i n a n i c e b a t h , o v e r 200 g .

cracked ic e .

th en poured

The s o l u t i o n was k e p t c o l d

w h i l e s o l i d s o d iu m c a r b o n a t e was a d d e d a n d t h e o i l sep arated . 150 g .

The o i l was c o l l e c t e d a n d w a s h e d t w i c e w i t h

o f a s a t u r a t e d s o d iu m s u l f a t e

so lu tio n .

The

w e ig h t o f th e washed cru d e N ( t e r . b u t y l c h l o r o ) a c e t a m i d e was 4 3 g .

(55$ o f t h e o r y ) . A p o r t i o n

of

t h e o i l was

d isso lv ed

i n h o t w a t e r a n d c r y s t a l s s e p a r a t e d on

cooling.

A f t e r r e c r y s t a l l i z a t i o n f r o m w a t e r t h e m e l t i n g p o i n t was 198°-200°.

The p r o d u c t was s o l u b l e

in s o lu b le in benzene,

eth y l a c e ta te ,

in alco h o l, but a c e t o n e , and d i i s o ­

butylene. A nalysis

% N itrogen

C alculated as N (te r.b u ty lc h lo ro ) a c e t a m i d e , CgH^gONCl Found

9 .37

9 .57

-55-

N (ter.b u ty lch lo ro )b en zam ld e. To a s o l u t i o n o f 30 g .

( 0 . 5 i'-O a c e t i c ,

( 0 . 5 5 '!) c o n c e n t r a t e d s u l f u r i c a c i d , b en zo n itrile

a n d 31 S* ( 0 . 3 -0

i n 3 5 m i n u t e s w e r e a d d e d 32 g .

m e th ally l ch lo rid e.

55 g .

( 0 . 3 5 M)

The r e a c t i o n m i x t u r e was m a i n t a i n e d

a t 8 ° - 1 0 ° by m e a n s o f a n i c e b a t h . o f the o l e f i n had been co m p leted ,

A fte r the a d d itio n the b la c k ,v is c o u s

s o l u t i o n was a l l o w e d t o s t a n d o n e h o u r i n a n i c e b a t h a n d one h o u r a t room t e m p e r a t u r e . in to

300 g.

I t was t h e n p o u r e d

of an ic e -w a te r m ix tu re, and in

ten m inutes,

a f t e r s t i r r i n g and p a r t i a l n e u t r a l i z a t i o n w ith s o l i d carbonate,

N ( t e r . b u t y l c h l o r o ) b e n z a m i d e , w hich had s e p a r a t e d

a s an o i l ,

s e t to a brown p a s t e .

The p a s t e was c o l l e c t e d

o n a B u c h n e r f u n n e l a n d t w i c e r e c r y s t a l l i z e d f r o m 200 c . c . d iiso b u ty len e

to y i e l d 25 g.

c o l o r l e s s powder.

130°.

eth er,

of an alm ost

R e c r y s t a l l i z a t i o n o f 5 g* f r o m 300 c . c .

p etro leu m e th e r (b .p . m .p.

( 39$ o f th e o ry )

30° - 75°)

gave c o l o r l e s s n e e d l e s ,

The p r o d u c t was s o l u b l e i n b e n z e n e ,

eth y l a c e ta te ,

acetone,

m ethanol,

b u t a lm o st com pletely in s o lu b le A n aly sis

and e th a n o l,

in w ater.

% N itrogen

C alculated as N (te r.b u ty lc h lo ro ) b e n z a m i d e , C „ H n 0NC1 * 11 14 Fo und

d ib u ty l

6. 63 6.64

-56-

N( t e r . b u t y l c h l o r o ) p h e n y l a c e t a m i d e . To a s o l u t i o n o f 30 g .

( 0 . 5 M) a c e t i c a c i d ,

55 6 * ( 0 . 5 5 M) c o n c e n t r a t e d s u l f u r i c a c i d ,

a n d 30 g .

( 0 . 2 5 i'£) b e n z y l c y a n i d e w e r e a d d e d i n 50 m i n u t e s a t 8 ° 15°

( t h e m i x t u r e was c o o l e d i n a n i c e b a t h )

m eth ally l ch lo rid e.

2 3 g* ( 0 . 2 5 *0

The s o l u t i o n was a l l o w e d t o s t a n d

o v e r n i g h t an d t h e n p o u r e d i n t o 200 g .

i c e and w a te r .

The

a l m o s t c o l o r l e s s N ( t e r . b u t y l c h l o r o ) p h e n y l a c e t a m i d e was c o l l e c t e d , washed w it:, a sm all q u a n t i t y of c o ld w a te r, a n d d r i e d on a B u c h n e r f u n n e l . 74$ o f th e o r y . 25 c . c .

u n til

The w e i g h t was 4 2 . 5 6* o r

E i g h t e e n g r am s w e r e r e c r y s t a l l i z e d fro m

a c e t o n e by a d d i n g w a t e r a t t h e b o i l i n g p o i n t

th e s o l u t i o n became clo udy, and th e n c o o li n g .

The

c o l o r l e s s n e e d l e s w e i g h e d 14 g . a n d m e l t e d a t 9 8 . 5 ° A nalysis

% N itrogen

C a l c u l a t e d as N ( t e r . b u t y l c h l o r o ) phenylacetam ide,

C^H-^gONCl

6.20

Found

6.02

N (2-propyl-l-chloro)phenylacetam ide. To a s o l u t i o n o f 29 g . a n d 29 g .

( 0 . 4 M) a l l y l c h l o r i d e

( 0 . 2 5 M) b e n z y l c y a n i d e w e r e a d d e d 65 g.

concentr^ed s u lf u r ic a c id

i n 40 m i n u t e s a t 2 5 ° - 3 0 ° .

(O . 6 5 M) The

-5 7 red, viscous

s o l u t i o n was a l l o w e d t o s t a n d 1 \ h o u r s a n d

p o u r e d o v e r 200 g .

cracked ice.

yellow ,w axy s o l i d ,

two r e c r y s t a l l i z a t i o n s f ro m w a t e r

gave a n a l m o s t c o l o r l e s s ,

A fter f i l t e r i n g

m ic ro c ry sta llin e N (2-propyl-

1 - c h l o r o ) p h e n y l a c e t a m i d e , m e l t i n g p o i n t 99°* was 2 1 g .

the

The y i e l d

(40$ of th eo ry ) A n aly sis

$ N itrogen

C alculated as N (2-propyl-l-chloro) phenylacetam ide, C^H^ONCl

6.6 3

Found

6.64

Alpha c a r b e th o x y -N ( t e r . b u t y l c h l o r o ) a c e t a m l d e . To a s o l u t i o n o f 37 g . e s t e r and 92 g.

(0 .9 2

1

( 0 . 5 M) c y a n o c e t i c

) co ncentrated s u lf u r ic a c id

w e r e a d d e d d r o p w i s e i n 45 m i n u t e s 47 g . a lly l ch lo rid e.

( 0 . 5 2 M) m e t h -

The t e m p e r a t u r e was m a i n t a i n e d a t

2 5 ° - 3 2 ° by m ea ns o f a n i c e b a t h .

The l i g h t - c o l o r e d

s o l u t i o n was a l l o w e d

to s ta n d an

a d d i t i o n a l 45 m i n u t e s

i n an I c e b a t h ,

poured in to

300 g . i c e a n d w a t e r .

then

The o i l w a s e x t r a c t e d w i t h 150 c . c . b e n z e n e , s e p a r a t e d , a n d t h e b e n z e n e l a y e r w a s h e d w i t h 50 c . c . s e p a r a t i n g and d is c a r d in g the w ater la y e r ,

w ater. A f te r the benzene

was r e m o v e d by d i s t i l l a t i o n a t 50 mm. The o i l y a m i d e

-5 8 ( w e i g h t 7 2 . 5 g« o r

65

% o f theory)

so lid ified

l e s s p o w d e r on s t a n d i n g f i v e d a y s .

to a c o l o r ­

R ec ry stalliza tio n

1o f r o m e t h y l a c e t a t e g a v e a p r o d u c t m e l t i n g a t 124 .

% N itrogen

A nalysis

% C hlorine

C a l c u l a t e d a s Alpha c a r b e t h o x y - N ( t e r . b u ty lc h lo ro ) a c e ta m id e m onohydrate,

C9 H1 8 ° 4 NC1 Found

5 ,8 4

1 ^ .8 2

5*71

14.67

N (ter.butylhydroxy)benzam lde. A s o lu tio n of 4.5 g.

( 0 . 0 8 I.') KOH, 5 g .

N ( t e r . b u t y l c h l o r o ) b e n z a m i d e i n 50 c . c .

( 0 . 0 2 5 M)

w a t e r a n d 50 c . c .

a c e t o n e was a l l o w e d t o s t a n d a t room t e m p e r a t u r e 4 8 h o u r s t h e n r e f l u x e d two h o u r s . d istillatio n HC1.

The a c e t o n e was r e m o v e d by

a n d t h e s o l u t i o n made j u s t a c i d w i t h c o n c e n t r a t e d

The b r o w n p r e c i p i t a t e was c o l l e c t e d a n d r e c r y s t a l l i z e d

from w a t e r , m e l t i n g p o i n t 119°.

The . n ix e d m e l t i n g p o i n t

w i t h an a u t h e n t i c sample o f b e n z o i c a c i d

(m .p.

1 2 2 ° ) was

121° . 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 t h r e e w i t h 25 c . c . b e n zen e

a n d ihe

l e a v i n g an o i l which

was f r a c t i o n a t e d :

tim es

b e n z e n e r e m o v e d by d i s t i l l a t i o n ,

-59-

1)

1 .0 g.

b .p .

97 ° “230°

( n o t e : w a t e r was f o r m e d

d u rin g the d i s t i l l a t i o n ) 2)

1.4

g.

b .p .

231°-243°

3)

0 .2

g.

r e s i d ue

2.6

g.

to tal

F r a c t i o n #2 was r e d i s t i l l e d

t o g i v e a few d r o p s o f a

h e a d f r a c t i o n a n d a m a in f r a c t i o n o f N ( t e r . b u t y l h y d r o x y ) ben zam id e,b .p .

234°-239°.

% N itrogen

A nalysis C alculated as N (te r.b u ty lh y d ro x y )

7.26

b e n z a m i d e , C-,, oN n Hi pc 0 d Found

7.25

2 -phen.yl-2-acetylam lno e t h a n o l . F iv e grams o f c r u d e N (p h en y lb ro m o m eth y l c a r b i n y l ) a c e t a m i d e w ere r e f l u x e d one h o u r and a llo w e d t o s t a n d 12 h o u r s a t room t e m p e r a t u r e w i t h a s o l u t i o n o f 3*5 S'

s o d iu m c a r b o n a t e i n 75 c . c .

w ater.

Two-

t h i r d s o f t h e w a t e r w e r e r e m o v e d by d i s t i l l a t i o n , l e a v i n g some i n s o l u b l e cooling,

t a r w h i c h was s e p a r a t e d .

On

2-phenyl-2-acetylam ino e th an o l sep arated ,

was c o l l e c t e d by f i l t r a t i o n ,

and washed w ith co ld

-60-

b e n z e n e to remove t h e s e m i - s o l i d i m p u r i t i e s .

The c o l o r ­

l e s s n e e d l e s o f 2 - p h e n y l - 2 - a c e t y l a m i n o e t h a n o l w eighed 3*3 5* ( 8 9 % o f t h e o r y )

and gave a n e g a t i v e B e i l s t e i n

test.

A f t e r r e c r y s t a l l i z a t i o n from b e n z e n e - a l c o h o l s o l u t i o n th e m e l t i n g p o i n t was 1 1 4 ° - 1 1 6 ° .

The compound was s o l u b l e

concentrated, b u t in so lu b le in d ilu te

in

hydrochloric acid .

A cetyl alpha o h e n y lg ly c in e . F i v e t e n t h s o f a gram o f 2 - p h e n y l - 2 - a c e t y l a m i n o e t h a n o l w e r e d i s s o l v e d i n 13 c . c . s o d iu m h y d r o x i d e .

w a t e r c o n t a i n i n g 0 . 1 g.

Over a f i f t e e n m in u te p e r io d 1 .0 g.

s o l i d p o t a s s i u m p e r m a n g a n a t e was a d d e d a t 3 0 ° - 3 2 ° . r e a c t i o n was s l i g h t l y

exotherm ic.

t h e s o l u t i o n was f i l t e r e d c o l o r i z e d w ith 0 . 2 g.

A f t e r s t a n d i n g 30 m l n .

f r o m mangan&se d i o x i d e a n d d e ­

s o d iu m b i s u l f i t e .

On a c i d i f i c a t i o n

w ith h y d r o c h lo r ic a c i d and c o o lin g i n i c e , 0 . 3 g. of theory) slow ly.

The

(55^

of a c e ty l alp h a phenylglycine c r y s ta lliz e d

A f t e r r b c r y s t a l l i z a t i o n from w a t e r th e m e l t i n g

p o i n t was 1 9 1 . 5 ° - 1 9 2 . 0 ° .

2-am ino-2-ohenyl e t h a n o l . Ten g r a m s ( 0 . 0 6 M) o f c r u d e N ( p h e n y l b r o r n o m e t h y l c a r b i n y l ) a c e t a m l d e i n a s o l u t i o n o f 6 .0 g. h y d r o x i d e , 25 p . c .

a c e t o n e , a n d 100 c . c .

( 0 . 1 3 M) s o d iu m

w a t e r were a ll o w e d

-61-

t o s t a n d a t room t e m p e r a t u r e 2 4 h o u r s a n d t h e n w e r e r e f l u x e d lg- h o u r s . c.c.

The s o l u t i o n was e v a p o r a t e d t o 50

F iv e and s i x t e n t h s grams o f o i l s e p a r a t e d and

were d i s t i l l e d . 1)

2.3

g.

b .p .

1 0 3 ° “ 1 0 8 ° a t 4 mm.

2)

1.0

g.

b .p .

l 8 0 ° - 2 0 3 ° (some d e c o m p o s i t i o n )

3)

1.9

g.

resid u e

5 .2 g.

to tal

F r a c t i o n #1 ( 2 . 3 g . o r 4 1 $ o f t h e o r y ) was i d e n t i f i e d a s 2 - a m in o - 2 - p h e n y l e t h a n o l by c o n v e r s i o n to th e h y d r o ­ ch lo rid e .

A fte r evap o ratio n of a hydrochloric acid

s o l u t i o n o f th e am ine,

t h e d r i e d s a l t m e l t e d a t 1 3 7 °*

N (benzyl)acetam lde. C o n c e n t r a t e d s u l f u r i c a c i d (30 g . )

was a d d e d

i n 45 m i n u t e s a t 2 0 ° - 2 5 d t o a s o l u t i o n o f 1 1 . 0 g . ( 0 . 1 M) b e n z y l a l c o h o l a n d 1 2 . 3 S* standing o v ern ig h t, i n t o 200 g .

ice.

was d e c a n t e d .

( 0 . 3 m) a c e t o n i t r i l e .

the cloudy,

A fter

v i s c o u s m i x t u r e was p o u r e d

A h e a v y , gummy p o l y m e r p r e c i p i t a t e d a n d

The a q u e o u s s o l u t i o n was t h e n n e u t r a l i z e d

w i t h s o d iu m c a r b o n a t e a n d e x t r a c t e d w i t h 200 c . c .

eth er.

E v a p o r a t i o n o f t h e e t h e r l e f t 1 . 5 S» ( 1 0 $ o f t h e o r y )

of

N (b e n z y l)a c e ta m id e a s an o i l w hich s o l i d i f i e d o v e r n i g h t.

The m e l t i n g p o i n t ,

on one r e c r y s t a l l i z a t i o n

from w a te r ,

was 6 2 ° . A n aly sis

% N itrogen

'C a lc u la te d a s N ( b e n z y l)a c e ta m id e , 9.40 F ou nd

W( t e r . b u t y l e t h o x . y ) e t h y l m a l o n a t e mono a m i d e . A s o l u t i o n o f 1 . 9 g . ( 0 . 0 8 m) s o d i u m i n 150 c . c . e th a n o l and 1 9 .0 g.

( 0 . 0 9 M) e t h y l c a r b e t h o x y N ( t e r . b u t y l

c h l o r o ) a c e t a m i d e was r e f l u x e d 7 i h o u r s . A f t e r t h e s o l u t i o n had b een f i l t e r e d d istillatio n , 1 1 . 3 6* 6 .4 g. 17»7 g .

from s a l t ,

t h e a l c o h o l was r e m o v e d by

and the r e s i d u a l o i l ra p id ly d i s t i l l e d . d istillate,

b .p .

t o 2 1 0 ° a t 2 5 mm.

residue to tal

The d i s t i l l a t e

v>as t h e n r e f r a c t i o n a t e d .

1)

2 .8

g.

b . p . 55°

2)

2 .8

g.

b .p . 56°-80° a t

3)

4 .0 g.

1.2 g. 10.8 g.

7 mm.

N ( t e r . b u t y l e t h o x y ) e t h y l m a l o n a t e mono a m id e b .p .

4)

a t 10 mm.

r e s i d ue total

1 2 2 ° - 1 2 5 ° a t 7 mm.

-63-

A n aly sis

% N itrogen

Sap.

Eg.

C alculated as N (ter.d u ty leth o x y ) e t h y l m a l o n a t e mono a m i d e ,

Found

6.07

231

6.64

236.5

N( t e r . d u t y l a m o x . y ) e t h y l m a l o n a t e mono a m i d e . A s o l u t i o n o f 1 . 0 g . ( 0 . 0 4 5 M) s o d iu m i n 115 c . c .

n o r m a l am yl a l c o h o l a n d 9 . 6 g . ( 0 . 0 4 M) a l p h a

c a r b e t h o x y N ( t e r . b u t y l c h l o r o ) a c e t a m i d e was r e f l u x e d 7 hours. salt,

A f t e r t h e s o l u t i o n h ad b e e n f i l t e r e d

f ro m

t h e a l c o h o l was r e m o v e d o n a s t e a m b a t h a t 80 mm.,

and the r e s id u e r a p id ly d i s t i l l e d . 5.8 g.

d istillate,

2 .8 g.

r e s idue

8 .6

to tal

g.

The d i s t i l l a t e

b .p .

t o 1 5 0 ° a t 5 mm.

was r e f r a c t i o n a t e d .

1)

0 .9

g.- b . p . t o 4 5 ° a t 2mm.

2)

1 .9

g. b .p . 46°-53° a t

3)

1 .5 g.

1 .0 g.

D=0.&365

N ( t e r . b u t y l a m o x y ) e t h y l m a l o n a t e mono a m i d e , b.p .

4)

2 mm. n 2Q 1 . 4 4 9 0 ;

residue

5.3 g* total

1 4 0 ° - 1 4 5 ° a t 2 m m . ; n 2Q 1 . 4 5 0 6 ; D = 0 . 9 9 6 6

jo N i t r o g e n

A n aly sis

M ol.R ef

C alculated as N (ter.butylam oxy)ethyl m a l o n a t e mono a m i d e , C ^ H ^ O ^ N F ound

5*12

73*76

4.87

73*67

2 - b e n z y l - 4 . 4 - d l m e t h . y l A 2o x a z o l i n e . (A).

One gram o f N ( t e r . b u t y l c h l o r o ) p h e n y l o a c e t a m i d e was h e a t e d i n a n o v e n a t 50 f o r two m o n t h s . p The p r o d u c t , 2 - b e n z y l - 4 , 4 - d i m e t h y l A o x a z o l i n e h y d r o ­ ch lo rid e,

was s t i l l

c o lo r le s s b u t the

h a d c h a n g e d from n e e d l e s t o a p o w d e r . was 1 4 2 ° .

cry stallin e

form

The m e l t i n g p o i n t

The compound d i s s o l v e d i n w a t e r b u t was i n s o l u b l e

i n e t h y l a c e t a t e and benzene.

The a q u e o u s s o l u t i o n was

a c id to litm u s . To one gram o f t h e h y d r o c h l o r i d e w e r e a d d e d 10 g .

o f a 10% s o d iu m c a r b o n a t e s o l u t i o n .

base s e t t l e d

to th e bottom and a f t e r s e p a r a t i n g ,

a q u e o u s s o l u t i o n was e x t r a c t e d eth er. 2 g.

The o i l y

free

the

t h r e e t i m e s w i t h 15 c . c .

The e t h e r was c o m b i n e d w i t h t h e o i l a n d d r i e d o v e r

s o d iu m s u l f a t e ,

filte re d ,

and th e e t h e r e v a p o r a te d . p F o u r t e n t h s o f a gram o f 2 - b e n z y l - 4 , 4 - d i m e t h y l A o x a z o l i n e (m .p. 7 1°) were c o l l e c t e d .

-65-

(B).

Five

t e n t h s o f a gram o f N ( t e r . b u t y l -

c h lo r o ) p henylace tam ide i n 5 c . c . 71 h o u r s .

'Hater (1 0 c . c . )

r e m o v e d by d i s t i l l a t i o n , on s t a n d i n g o v e r n i g h t . w a te r and f i l t e r e d

p y r i d i n e were r e f l u x e d

was a d d e d a n d t h e s o l v e n t s l e a v i n g a sy ru p w hich c r y s t a l l i z e d

The s o l i d was d i s s o l v e d i n 10 c . c .

th ro u g h f i l t e r a i d . A f te r adding

s o d iu m c a r b o n a t e t o t h e c l e a r s o l u t i o n a n d e x t r a c t i n g w ith benzene,

t h e b e n z e n e was e v a p o r a t e d l e a v i n g 2 P

Q

b e n z y l 4 - 4 , d i m e t h y l ^ o x a z o l i n e , m e l t i n g p o i n t 75 • ( C). at

Five

1 2 0 ° f o r 24 h o u r s .

cry stallin e w ater,

t e n t h s o f th e amide were h e a t e d A t t h e en d o f t h i s p e r i o d t h e

o x a z o l i n e h y d r o c h l o r i d e was d i s s o l v e d i n

tre a te d w ith carb o n ate,

and e x t r a c t e d w ith benzene

a s u n d e r ( A ) . Upon e v a p o r a t i o n o f t h e s o l v e n t , resu lted of th is

the f r e e b a s e , m .p.

70°-71°*

there

Two r e p e t i t i o n s

e x p e r im e n t were a t t e m p t e d b u t i n b o t h c a s e s o n ly

balck ta r ,

in so lu b le in w ater,

24 h o u r h e a t i n g p e r i o d .

was i s o l a t e d a f t e r t h e

H e a t i n g t h e amide a t 130° a t

1 mm. f o r 6 h o u r s y i e l d e d o n l y s t a r t i n g m a t e r i a l . ( D).

R e f l u x i n g th e amide

9

$ hours in c h lo r-

b e n z e n e f o l l o w e d by e x t r a c t i o n w i t h w a t e r was u n s u c c e s s f u l - no o r o d u c t was i s o l a t e d f r o m t h e a q u e o u s s o l u t i o n .

-66-

% N itrogen

A nalysls C alculated as 2 -b e n z y l-4 ,4 -d im e th y l p A o x a z o l i n e , C^gH^^ON

7*41

Found

7*35

C alculated as 2 -b e n z y l-4 ,4 -d im e th y l A ^ o x a z o l i n e h y d r o c h l o r i d e , C^gH^gONCl

6.20

Found

6.25

2 2-phenyl-4,4-dlm eth.yl A o x azo lin e h y d ro c h lo rid e . -

A f t e r c r u d e N ( t e r . b u t y l c h l o r o ) b e n z a m i d e had been c o l l e c t e d ,

in stead of r e c ry s ta lliz in g

im m ediately,

i t was a l l o w e d t o s t a n d o v e r n i g h t i n a d e s i c c a t o r . L i q u i f a c t i o n o c c u r re d and an upp er o i l l a y e r s e p a r a te d fr o m a n a q u e o u s l a y e r .

The w a t e r was d i s c a r d e d a n d t h e

o i l d r i e d by d i s s o l v i n g i n b e n z e n e a n d r e m o v i n g t h e b e n z e n e - w a t e r a z e o t r o p e by d i s t i l l a t i o n .

In s_x weeks

th e r e s i d u a l o i l had c o m p le te ly c r y s t a l l i z e d .

The s o l i d

was r e c r y s t a l l i z e d f r o m b e n z e n e - m e t h a n o l s o l u t i o n t o give c o lo r le s s n e e d le s o f 2 -p h e n y l-4 ,4 -d im e th y l A oxazoline h y d ro ch lo rid e.

The m e l t i n g p o i n t was 2 2 0 ° .

The compound was s o l u b l e

i n w a te r and m ethanol, b u t in s o lu b le

in benzene,

eth y l a c e ta te ,

and a c e to n e .

-6 7A n aly sis

h N itrogen

C alculated as 2 -p h e n y l-4 ,4 -a im e th y l ^

o x azoline

hydrochloride

mono h y d r a t e , C-^H^gONCl

6.10

Found

6.08

2-pheny l-4 ,4 -d tm eth y l A o x a z o lin e . One gram o f c r u d e N( t e r , b u t y l c h l o r o ) b e n z a r n i d e was h e a t e d 45 m i n u t e s a t 1 3 5 ° a t 1 mm. t o f o r m 2 - p h e n y l 2 4 , 4 - d im e th y l A o x a z o l i n e h y d r o c h l o r i d e (m .o. 2 2 0 ° ). The c r u d e s a l t was d i s s o l v e d i n w a t e r , n e u t r a l i z e d w i t h carbonate,

a n d e x tra c te d w ith benzene.

The s o l v e n t was

r e m o v e d by d i s t i l l a t i o n l e a v i n g 0 . 5 £• o f 2 - p h e n y l - 4 , 4 a i m e t h y l 0>2 o x a z o l i n e w h i c h , a f t e r r e c r y s t a l l i z a x i o n f r o m b enzene, m e lte d a t 87*0°-87*5°*

In stead of r e c r y s t a l ll z i n g

t h e c r u d e o x a z o l i n e was d l f c t i l l e d b u t d u rin g the d i s t i l l a t i o n

(b .p .

1 0 5 ° - 1 1 0 ° a t 1 mm.)

p o l y m e r i z a t i o n o c c u r r e d and

t h e r e s i d u e was 50% by w e i g h t o f t h e s t a r t i n g m e ltin g p o in t o f the d i s t i l l a t e

to tal.

The

was 8 6 . 5 ° - 8 7 . 5 ° .

H e a t i n g t h e a m i d e 24 h o u r s a t 1 3 0 ° i n a n o p e n b eak er y ie ld e d only in s o lu b le

tar.

A nalysis

% N itrogen

C alculated as 2 -p h en y l-4 ,4 -d i:n eth y lA 2 o x a z o l i n e , C1 1 H1 ^0N Found

8.00

-68-

2 -m eth y l-4 -p h en y l-A

2

o x azoline. -

(A) f r o m t h e h y d r o x y a m i d e : T h r e e t e n t h s o f a gram o f 2 ~ p h e n y l - 2 - a c e t y l a m i n o e t h a n o l w e r e r e f l u x e d 2§- h o u r s w i t h a n e q u a l w e i g h t o f z i n c brom ide in 5 c . c .

benzene.

Twenty c u b i c c e n t i m e t e r s o f

b e n z e n e a n d 20 g .

o f 10% s o d iu m h y d r o x i d e s o l u t i o n w e r e

added and s t i r r e d

f i v e m in u te s. A f t e r s e p a r a t i o n and

e v a p o ra tio n o f the b e n z e n e ,th e A ^ o x a z o l i n e was r e c r y s t a l l i z e d

s o lid 2-m ethy1-4-phenyl from a l c o h o l - b e n z e n e

and m elted a t 115° - l l 6°. (B)

from t h e c h l o r o am id e:

F i v e t e n t h s o f a gra m o f N ( p h e n y l c h l o r o m e t h y l c a r b i n y l ) acetam ide in 5 c .c .

p y r i d i n e were r e f l u x e d 7 h o u r s .

The s o l v e n t was r e m o v e d by d i s t i l l a t i o n a t 40 mm. a b a th te m p e ra tu re o f 65°.

to

The b r o w n , o i l y r e s i d u e g a v e

a c l o u d y s o l u t i o n on d i l u t i o n w i t h w a t e r . A f t e r f i l t r a t i o n , n e u t r a l i z a t i o n o f the aqueous f i l t r a t e t h e b e n z e n e was e v a p o r a t e d , p h e n y l A 2o x a z o l i n e , m .p. (C)

w ith c a rb o n a te ,

l e a v in g 0 . 1 g. 2 - m e th y l- 4 -

114°-115°*

f r o m t h e bromo a m i d e :

E x p e r i m e n t (B) was r e p e a t e d u s i n g N ( p h e n y l b r o m o m e t h y l c a r b in y l) a c e ta m id e a s the s t a r t i n g m a t e r ia l.

A fter

rem oving th e p y r i d i n e , th e r e s i d u a l 2 - m e th y l - 4 - p h e n y l 2 A o x a z o l i n e h y d r o b r o m i d e m e l t e d a t 130 - 1 3 2 ° . By

-69-

A f t e r n e u t r a l i z a t i o n w i t h s o d iu m c a r b o n a t e , and r e c r y s t a l l i z a t i o n ,

th e f r e e b a s e , m .p.

ex tractio n , 1 1 5 °-ll6 °,

was

iso lated . N ( p h e n y l b r o m o m e t h y l c a r b i n y l ) a c e t a m i d e was h e a t e d two h o u r s a t 1 2 5 ° a n d 1 mm. The o i l was a i s s o l v e d in w a te r and th e o x a z o lin e p u r i f i e d as u s u a l . io „o p o i n t was 1 1 4 - 1 1 6 .

The m e l t i n g

M ix ed m e l t i n g p o i n t s o f 2 - m e t h y l - 4 - p h e n y l A o x a z o lin e p re p a re d in experim ents (A ),(B ),a n d

2

( C) s h o w e d

no d e p r e s s i o n . A n aly sis

% N itrogen

C a l c u l a t e d a s 2-me t h y l - 4 - p h e . . y l p o x a z o l i n e , C^H.^ON

8.70

Found

E t h y l alpha (4* , 4 ' - d i m e t h y l - 2 - A 2 oxazollnyl)acetate.Ten g r a m s ( 0 . 0 4 5 M) o f a l p h a c a r b e t h o x y •'N ( t e r . b u t y l c h l o r o ) a c e t a m i d e , was h e a t e d one m i n u t e a t 6 0 ° i n a s o l u t i o n o f 3 . 0 g . ( 0 . 0 5 M) KOH i n 120 c . c . A cetic acid

(2 .0 c . c .)

of ethanol.

was a d d e d t o n e u t r a l i z e

excess

a l k a l i a n d t h e s o l u t i o n was f i l t e r e d f r o m t h e p r e c i p i t a t e d potassium c h lo rid e . by d i s t i l l a t i o n

A f t e r th e s o lv e n t had been removed

a t 50 mm.,

t h e r e s i d u e was d i s t i l l e d .

-70-

The m a i n f r a c t i o n

(b .p .

100°-103° a t 5 m m .),w hich

s o l i d i f i e d i n th e receiver? and m e lte d a t 1 0 0 °-1 0 1 °, 2 was e t h y l a l p h a ( 4 ' , 4 ’ - d i m e t h y 1 - 2 A o x a z o l i n y l ) a c e t a t e . The w e i g h t was 3*1 S* o r 62% o f t h e o r y .

From t h e

d i s t i l l a t i o n a r e s i d u e o f 2 . 8 g . was o b t a i n e d .

% N itrogen

A n alysis C a l c u l a t e d a s e t h y l a l p h a (4-1, 4 ' - d i m e t h y 1 2 - A 2o x a z o lin y l)a c e ta te ,

7.57

Found

B utyraldibenzam ide. (A) fro m l - n i t r o - 2 - p e n t a n o l a n d b e n z o n i t r i l e : To a s o l u t i o n o f 7.4- g .

( 0 . 0 7 M) s u l f u r i c

( 0 . 0 2 :v!) b e n z o n i t r i l e w e r e a d d e d 2 . 5 g* 2 -p en tan o l (b .p . 20°.

a c i d an d 2 .1 g.

( 0 . 1 9 M) 1 - n i t r o -

7 3 ° “ 8 6 ° a t 2 mm.) i n 45 m i n u t e s a t 1 5 ° ”

A f t e r s t a n d i n g two h o u r s t h e r e a c t i o n m i x t u r e was

p o u r e d i n t o 40 c . c .

w ater.

The b l a c k , h e a v y gum was

s e p a r a t e d a n d w a s h e d w i t h 50 g . o f a

10

% s a lt so lu tio n .

E x t r a c t i o n o f t h e gum w i t h b o i l i n g h e x a n e l e f t a r e s i d u e of 1 .2 g. w hich, a f t e r th r e e r e c r y s t a l l i z a t i o n s alco h o l,

from

gave c o l o r l e s s n e e d le s o f b u t y r a ld i b e n z a m id e ,

m e ltin g p o i n t 202°.

-7 1(B) f r o m 2 - n i t r o - 3 - h e x a n o l a n d b e n z o n i t r i l e : To a s o l u t i o n o f 7 * 4 g . ( 0 . 0 7 -■•) s u l f u r i c a c i d a n d 2 . 1 g. ( 0 . 0 2 :■.•') b e n z o n i t r i l e w e r e a d d e d 2 . 5 g . 3-hexanol (b .p . 28°-31°«

(0 .1 7 .M )2 ~ n itro -

1 0 5 ° - 1 1 5 ° a t 12 mm.) i n 30 m i n u t e s a t

The d a r k r e d s o l u t i o n was a l l o w e d t o s t a n d

two h o u r s a n d t h e n a d d e d t o 40 g . was d i s s o l v e d i n 100 c . c .

eth er,

w ater.

d r i e d o v e r s o d iu m s u l f a t e ,

and th e e t h e r a llo w e d to e v a p o r a te . b o i l e d w ith hexane and f i l t e r e d buty rald ib en zam id e.

The h e a v y o i l

The r e s i d u e was

t o l e a v e 0 . 8 g.

of

A f t e r t h r e e r e c r y s t a l l i z a t i o n s from

a l c o h o l t h e m e l t i n g p o i n t was 2 0 2 ° a n d when m i x e d w i t h a s a m p l e fro m (A) no d e p r e s s i o n i n m e l t i n g p o i n t was noted. A n alysis

% N itrogen

C alculated as butyrald ib en zam id e,

CncfW,0oN 18 20 2 .2 Found ( A ) ;

9.46 9.41

(B)

9.52

B en zald lacetam ld e.(A) To a s o l u t i o n o f 5 4 . 8 g . 1 2 .5 g.

f r o m omega n i t r o s t y r e n e a n d a c e t o n i t r i l e : ( 0 . 5 3 M) s u l f u r i c a c i d a n d

( 0 . 3 M) a c e t o n i t r i l e w e r e a d d e d a t 2 5 ° - 3 1 ° i n

-72-

35 m i n u t e s 9 . 0 g . ( 0 . 0 6 M) omega n i t r o s t y r e n e .

The

m i x t u r e was a l l o w e d t o s t a n d two h o u r s a t room t e m p e r a t u r e , t h e n p o u r e d o v e r 200 g .

cracked ic e .

One h a l f a gram

o f u n r e a c t e d n i t r o s t y r e n e was c o l l e c t e d by f i l t r a t i o n . The f i l t r a t e

was c o o l e d t o 0 ° i n a n i c e a n d s a l t b a t h

a n d n e u t r a l i z e d w i t h 62 g . A lig h t,ta n p recip ita te

( 1 . 0 7 M) o f ammonia s o l u t i o n .

o f b e n z a l d i a c e t a m l d e upon t h e

l a s t a d d itio n o f the a l k a l i .

Upon f i l t r a t i o n a n d d r y i n g

t h e w e i g h t was 6 . 3 6* o r 5 0 % o f t h e o r y .

The a m id e was i n ­

s o lu b le in h exane, benzene, and d iis o b u ty le n e , s o lu b le in ch lo ro fo rm , and w ater.

and s o lu b le

slig h tly

i n warm e t h y l a c e t a t e

A f t e r two r e c r y ~ t a l l i z a t i o n s

fro m a l c o h o l ,

t h e m e l t i n g p o i n t was 2 3 3 ° • At f i r s t

t h e compound was t h o u g h t t o be

2-phenyl-2-acetylam ino n itro e th a n e , p r o d u c t gave a n e g a t i v e n i t r o u s a c i d g r o u o a n d no p r e c i p i t a t e potassium h y droxide.

b u t the p u r if i e d t e s t f o r the n i t r o

of potassium s a l t w ith a lc o h o lic

T reatm ent o f a m e th an o lic s o lu tio n

w i t h h y d r o g e n a n d Rane y n i c k e l ( t h e

c a t a l y s t was a c t i v e

a n d h a d b e e n u s e d s u c c e s s f u l l y by a n o t h e r o p e r a t o r i n another re a ctio n )

a t 2 8 ° - 2 9 ° a t 1000 p . p . s . i .

f o r 14-

h o u rs gave a q u a n t i t a t i v e r e c o v e r y o f s t a r t i n g m a t e r i a l .

-7 3 -

(B) f r o m b e n z a l d e h y d e a n d a c e t a m i d e : Ten a n d s i x t e n t h s g r a m s ( 0 . 1 ?/.) b e n z a l d e h y d e were b o i l e d 10 m i n u t e s w i t h 1 1 . 8 g . ( 0 . 2 ?;;) a c e t a m i d e .

The

c r y s t a l s w h i c h a p p e a r e d on c o o l i n g w e r e c o l l e c t e d by f i l t r a t i o n and r e c r y s t a l l i z e d from a l c o h o l . was 1 2 . 4 g . ( 6 0 % o f t h e o r y ) 239°• (A)

The y i e l d

a n d t h e m e l t i n g p o i n t was

The m i x e d m e l t i n g p o i n t w i t h t h e p r o d u c t from

( m. p . 2 3 3 ° ) was 2 3 4 ° A nalysis

/o N i t r o g e n

C alculated as b en zald iacetam id e 13*58 Found (A)

13*35

-7 4 -

V.

1.

SUMMARY

A l c o h o l s were employed s u c c e s s f u l l y i n p l a c e o f

o le fin s in -th e

s u b s t i t u t e d amide r e a c t i o n w i t h n i t r i l e s .

F o r t e r t i a r y a l c o h o l s t h e medium was a s u l f u r i c - a c e t i c a c i d s o l u t i o n a n d f o r s e c o n d a r y a l c o h o l s t h e medium was concentrated s u lf u r ic ac id . underw ent the r e a c tio n . pfcepared. 2.

Seven N - s u b s t i t u t e d am id es w ere

The ...echanism o f t h e r e a c t i o n was d i s c u s s e d .

E i g h t b e t a h a lo e t h y l a m i d e s w ere s y n t h e s i z e d from

n itriles ch lo rid e , h y d rin s, 3*

One p r i m a r y a l c o h o l , b e n z y l ,

a n d t h e f o l l o w i n g h a l o g e n compounds: m eth ally l ch lo rid e,

s t y r e n e c h l o r o - and bromo-

and a lp h a m e th y ls ty re n e c h lo r o h y d rin .

The h a l o g e n a t o m o f t h e b e t a h a l o e t h y l a m i d e s was

replaced e a s ily .

Two a l c o h o l s ,

2-phenyl-2-acetylam ino

e th a n o l and N (te r.b u ty lh y d ro x y )b e n z a m ia e ,

b.

ally l

were p r e p a r e d .

By t r e a t m e n t w i t h s o d iu m a l k o x i d e t h e e t h y l a n d

a m yl e t h e r s w e r e p r e p a r e d f r o m a l p h a c a r b e t h o x y - N ( t e r . b u ty lc h lo ro )acetam ide.

-7 5 5.

B e t a h a l o e t h y l a m i d e s w er e c y c l i z e d t o A ^ o x a z o l i n e s .

Four o x a z o l i n e s were p r e p a r e d , o n e , 2 - m e t h y l - 4 - p h e n y l A 2 oxazoline, 6.

by t h r e e i n d e p e n d e n t m e t h o d s .

I n c i d e n t a l to the p ro o f o f th e o x a z o li n e s t r u c t u r e

a c e t y l a l p h a p h e n y l g l y c i n e was p r e p a r e d w i t h a y i e l d

of

45% from s t y r e n e b ro rao h y d rin .

C6 H5 CHCH2 B r

CH^CN

OH

^

c6 h5 chch2 oh

NHCOCHj

c6 h5 chcoch

NHCOCH j

7.

CgH^CHCHgBr

*

NHCOCH^

Under t h e c o n d i t i o n s o f t h e s u b s t i t u t e d amide

reactio n n itro

a l c o h o l s o r n i t r o o l e f i n s were s p l i t t o

a ld e h y d e s w hich r e a c t e d w i t h the n i t r i l e am ides. RON RCH:CHN02

RCH(NHC0R)2

to form a l d -

-76-

Compounds P r e p a r e d by

the

S u b s t i t u t e d A m ide R e a c t i o n

U x. •

Compound

1 .

N (ter.am yl)acetam ide

-0 CD o

in: •

2.

N ( t e r . a m y l ) oenzamide

94°

3*

N (2-pentyl)acetam ide

55°

4.

N (benzyl)acetam ide

62°

5.

N (d im eth y 1 -n -b u ty lcarb in y l) o 00

6.

N (cyclo h ex y l)acetam id e

7.

N (para m ethy lcyclohexyl)

m

acetam ide

122°-23° ( 1 4 mm)

225°-38°

10.76

7 • 34-

7.38

10.85

10.76

8.93

8.89 9.90

9 .02 5 .66

5.67

100°

7.05

6.83

o

97.5°

10.85

5.79

129°-3^° (4 mm)

N (phenylraethylchlorom ethyl

% N itrogen Calc Found

9.40

104°

acetam ide 8.

B .P.

5.79

5.74

carbinyl)acetam ide dih ydrate

s.

N( p h e n y l c h l o r o m e t h y l carbinyl)acetam ide

10.

N (phenylbrom om ethylcarbinyl) CO

acetam ide 11.

N( t e r . b u t y l c h l o r o ) a c e t a m i d e

200°

9.37

9.57

12.

N (ter.butylchloro)benzam ide

130°

6 .63

6.67

13-

N( t e r . b u t y l c h l o r o ) p h e n y l 9 8.5°

6.20

6.02

99°

6 .6 3

6.64

acetam ide 14.

N ( 2 - p r o p y l - l - c h l o r o ) p h e n y 1acetam iae

-7 7 Comoound 15.

M. P .

% N itro g en C alc Found

B.P.

alpha carbethoxy-N ( t e r . b u t y l c h l o r o ) a c e t a m i d e mono­ hydrate

16.

- h y d ro c h lo r id e m onohydrate

-hydrochloride

-hydrobrom ide

87 .5 ° o 220

(1

8.00

mm)

6.10

6.08

75°

7.41

7.35

142°

6.20

6.25

116

6.70

132c

101

101°-03° (5 mm)

7-57 ' •

2 - p ’n eny 1 - 2 - a c e t y l a m i n o ethanol

21.

N( t e r . b u t y l h y d r o x y ) b e n z a m i d e

22.

N( t e r . b u t y l a m o x y ) e t h y l

7.82

116C

m a l o n a t e mono a m i d e 23-

105°-10°

e t h y l a l p h a ( 4 ' , 4 1- d i m e t h y l 2 -o x azo lin y l)acetate

20 .

14.67

2-m ethyl-4-phenyl A 2 oxazoline

19.

14.82

2-benzy l-4 ,4 -d im eth y l A 2 oxazoline

18.

C l:

5-71

2-phenyl-4,4-dirnethyl A 2 oxazoline

17.

124°

5.84

234°-39°

7.26

7.25

140°-5C° (2 mm)

5.12

4.87

140°-45° (7 mm)

6.64

6.07

N( t e r . b u t y l e t h o x y ) e t h y l m a l o n a t e mono a m i d e

24.

b u ty raldibenzam ide

202c

9.46

9.47

25.

benzaldiacetam ide

233C

13.58

13.35

-78-

VI.

1.

V in ieri,

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4.

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7.

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8.

(a) (b)

9. 10.

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1944,

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Chem ical Bond, C o r n e l l Univ.

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1946.

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T hesis,

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6.

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14i

w e n k e r , J. Am.

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15*

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16.

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17.

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18.

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2383

-79-

19.

E l f e l d t , B er.,

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20.

V/enker, J . A m . C h e m . S o c . , 6 0 ,

21.

Tryon,

U .S. 2 ,3 7 2 ,4 1 0 ,

Bar. 27,

1945.

22.

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U .S. 2 , 3 7 2 ,4 0 9 ,

:.ar. 27,

1945.

23.

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U .S. 2 ,4 1 6 ,5 5 2 ,

Feb. 25,

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24 .

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25.

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O ct. 29,

26.

Vfampner, U . S . 2 , 3 6 8 , 0 7 5 ,

27 .

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28.

P rice ,

Jan.

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1946.

2 3 , 1945.

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