Preparation of alkyl ketimines

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THE UNIVERSITY OF OKLAHOMA GRADUATE COLLEGE

i

i !'

PREPARATION OF ALKYL KET3MINES

A THESIS SUBMITTED TO THE GRADUATE FACULTY in p a r t i a l f u lf illm e n t o f th e requirem ents f o r th e degree of DOCTOR OF. PHILOSOPHY

BY EARL FRANKLIN ENGLES, JR. Norman, Oklahoma 1951

UNIVERSITY OF OKLAHOMA l ib r a r y Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

UMI Number: DP10049

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PREPARATION OF ALKYL KETIMINES

APPROVED BY

GENERAL

THESIS COMITTEE

344624

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I I! ! I \

ACKNOWLEDGMENT The au th o r w ishes t o express h is sin cere a p p re c ia tio n to Dr. P. L. P ick ard , under whose d ire c tio n t h i s in v e s tig a tio n was c a rrie d out as a p a r t o f th e graduate program o f th e U niversity of Oklahoma.

He i s e s p e c ia lly a p p re c ia tiv e of th e

many h e lp fu l su g g estio n s, o f th e words of encourage­ ment, and of th e degree of freedom granted in t h i s work. He a ls o wishes to thank th e O ffice of Naval Research f o r t h e i r i n t e r e s t in t h i s work as expressed by th e g ran t which made t h i s work p o s s ib le . He owes much to th e f a c u lty and s ta f f of the Chemistry Department f o r t h e i r h e lp fu l su g g estio n s, f o r t h e i r confidence, and f o r t h e i r frie n d s h ip s .

iii

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TABLE OF CONTENTS Page LIST OF TABLES........................................................................................................

v

Chapter I.

INTRODUCTION............................................................................................

1

II.

EXPERIMENTAL............................................................................................

14

DISCUSSION OF RESULTS

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

34

SUMMARY........................................ * ............................................................

43

III. IV.

BIBLIOGRAPHY...............................................................................................................

|

iv

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45

LIST OF TABLES Table I. II, III, IV, V. V I.

Page P rev io u sly re p o rte d ketim ines . . Fenchyl k etim in es

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

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

Fenchyl amines

20

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

1 ,1 -D ip h en y leth y l k etim in es .

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

1 ,1 -D ip h en y leth y l amines

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

Fenchyl k eto n es . . . . . . .

. . . . . . . .

11

25 27 28

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

30

V II,

1 ,1 -D ip h en y leth y l k eto n es ..................................................................

31

V III,

R e la tiv e red u c tio n r a te s o f 1 ,1 -d ip h en y leth y l ketim ines • .

41

v

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CHAPTER I

INTRODUCTION Since 1891, when Hantzch and Kraft'*' rep o rted th e p re p a ra tio n of a ketim ine h y d ro ch lo rid e and v a rio u s N -su b s titu te d k etim in e s, th e re has been co n sid e rab le work d ire c te d toward th e p re p a ra tio n and study of t h i s type o f compound.

In t h e i r o r ig in a l work th e hydrochloride

was obtained by h e a tin g urethan w ith 1 ,1 -d ic h lo ro compounds, obtained by t r e a t in g k eto n es w ith phosphorous p e n ta c h lo rid e .

No r e p o r t was

made of e f f o r t s to i s o l a t e th e f r e e inline. During th e p e rio d o f 1913 to 1920, Moureu and K ignonac^»3,4,5,6,7 re p o rte d a number of k etim in es prepared by th e a c tio n o f a G rignard reag en t on a n i t r i l e .

In n e a rly a l l in sta n c e s t h e i r compounds were of

th e a r y l a lk y l o r a r y l a r y l ty p e , and were prepared by adding an alkylmagnesium or an arylmagnesium h a lid e to an arom atic n i t r i l e . D ieth y l e th e r was used as a s o lv e n t, and th e r e a c tio n s were s u f f ic ie n t ly exothermic to r e f lu x th e so lv e n t. When an a r y l h a lid e was u sed , th e a d d itio n product was decomposed by pouring th e re a c tio n m ixture onto crushed ic e and s o lid ammonium c h lo rid e .

The e th e r la y e r co n ta in in g th e im ine was ra p id ly

sep arated and d rie d w ith calcium c h lo rid e in th e c o ld .

Anhydrous

hydrogen c h lo rid e was then passed in to th e e th e r s o lu tio n , and th e ketim ine h y d ro ch lo rid e was recovered by f i l t r a t i o n .

Any ketone which

1

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2 was formed remained in th e e th e r s o lu tio n .

The hydrochloride was then

placed in dry e th e r and decomposed by passing anhydrous ammonia through th e suspension.

The inline was recovered by evaporation o f th e e th e r

f i l t r a t e a fte r f iltr a tio n , When th e Grignard reag en t used was prepared from an a lk y l h a lid e , th e procedure was m odified to prevent h y d ro ly sis of th e im ine. S u ffic ie n t e th e r was evaporated to b rin g about p r e c ip ita tio n of th e ketiminemagnesium h a lid e .

T his a d d itio n product was f i l t e r e d , washed

w ith e th e r , suspended in th e same s o lv e n t, and decomposed by re flu x in g w ith g la c ia l a c e tic ac id o r by p assin g anhydrous hydrogen ch lo rid e through th e suspension.

The ketim ine a c e ta te or hydrochloride was

then tre a te d w ith anhydrous ammonia as b efo re to y ie ld th e fre e k e tim in e , Mignonac 8 has a ls o rep o rted the p re p a ra tio n o f some a ry l k etim in es by o th e r methods.

In 1919, phenyl m ethyl k etim in e, phenyl

e th y l ketim in e, diphenyl k e tim in e, and a compound re fe rre d to as cy clo hexyl ketim ine were prepared by passing a m ixture of th e corresponding keto n es and ammonia over a fix ed bed c a ta ly s t of t h o r i a .

The ketones

were v ap o rized , mixed w ith ammonia, and passed slowly over th e c a ta ly s t bed a t 400°,

The e x it gases were cooled ra p id ly , and th e products

sep arated as soon as p o s s ib le .

T his procedure was followed in o rd er to

prevent a re v e rs a l of th e eq u ilib riu m , Rr G° " R2

+ NH3f c = : » FyC(lNH)R2

*

H20.

A y ie ld o f 15-20$ was re p o rte d f o r th e phenyl methyl k etim in e. y ie ld s were n o t given.

O ther

Only condensation products were obtained when

d ia lk y l ketones were tr e a te d in t h i s manner.

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Low p re ssu re red u ctio n o f ketoxim es, over n ic k e l as a c a ta ly s t, o •was used in 1920 by Mignonac7 to prepare some d ia r y l and some a ry l a lk y l k etim in es.

E x celle n t y ie ld s were obtained when d ia r y l ketoximes

were used, b u t u n s a tis fa c to ry r e s u lt s were rep o rted in th e case of d ia lk y l ketoxim es. In th e course o f th e work o f Moureu and Mignonac, they is o la te d d uring p u r if ic a tio n o f th e ketim ines by d i s t i l l a t i o n , some high b o ilin g compounds which they c a lle d k e tiso k e tira in e s.

They were obtained in

y ie ld s up to k%} and th e s tr u c tu r e in d ic a te s th a t th ey were formed by th e elim in a tio n o f a m olecule of ammonia between th e ketim ine and i t s tautom er, th e ene-amine form.

0-C-CHo-R

0 - C - CH9 - R ii * N + 0 - C = CH - R --------- »

ii

t

NH

+ NHC

i

NH2

’

3

0 - C = CH - R

Some support f o r t h i s co n ten tio n may be found in th e f a c t t h a t , in th o se cases where t h i s a c tio n took p la c e , th e ketim ine had a t l e a s t one hydrogen in th e alpha p o s itio n w ith re sp e c t to th e imino group. A d d itional evidence to support t h i s p o s tu la te may be found in th e work o f Vieissburger and G la s s ^ .

In t h i s case th e cyanohydrin of 2 , 4 , 6 - t r i -

raethylbenzaldehyde was tr e a te d w ith phenylmagnesium bromide to form an amino k eto n e, presumably by th e follow ing s e rie s of re a c tio n s involving such an ene-amine s h i f t .

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O ther w orkers have sin ce become a c tiv e in t h i s f i e l d .

In 1922,

B a ry ^ prepared diphenyl ketim ine and phenyl cyclopropyl ketim ine in good y ie ld s in an e th e r s o lu tio n .

A ddition of phenylmagnesium bromide

to p h e n y la c e to n itr ile , a c e t o n i t r il e , p r o p io n itr ile , and b u ty r o n itr ile produced only ketones and condensation p ro d u cts.

Decomposition of th e

ad d itio n compound was by th e u su al h y d ro ly tic tre a tm e n t. I t was re p o rte d by De Boosere

12 in 1923> th a t ganima-chloro-

b u ty r o n i t r i l e re a c te d w ith ethylmagnesium bromide to y ie ld e th y l cyclo­ pro p y l k etim in e.

This imine was rep o rted to be extrem ely r e s i s ta n t to

acid h y d ro ly s is.

However, i t d id hydrolyze slow ly upon re flu x in g w ith

a lc o h o lic potassium hydroxide. by Cloke

13

F u rth e r in v e s tig a tio n of t h i s re a c tio n

has sin ce shown th a t th e compound obtained was n o t th e

ketim ine as th o u g h t, but a s u b s titu te d p y rro lin e .

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5 Rajmart-Lueas^*', i n 1927, was i n te r e s te d in p rep arin g ketones by th e a d d itio n of phenylmagne sium bromide to t r i s u b s t i t u t e d a c e t o n i t r il e . In th e c o u rse of t h i s work, he observed t h a t th e ketim ine obtained from th e re a c tio n of phenylmagne sium bromide and tr im e th y la c e to n itr ile was s u f f i c i e n t ly s ta b le toward h y d ro ly sis to p erm it decom position o f th e ketiii'iinemagnesium h a lid e by ammonium c h lo rid e and i c e .

They a lso ob­

served t h a t th e hydrobromide o f phenyl 2 -m eth y l-l,1 -d ip h en y lp ro p y l ketim ine hydrolyzed w ith d i f f i c u l t y . Phenyl cyclo p ro p y l ketim ine was prepared in 1929 by C lo k e ^ by two d i f f e r e n t m ethods.

The f i r s t involved th e re a c tio n of phenyl-

magnesium bromide and cyclopropyl cyanide in e th e r s o lu tio n .

The

second was by th e a d d itio n o f phenylmagnesium bromide to gamma-chlorob u ty ro n itrile .

The k etim in e formed a normal hydrochloride which r e a d ily

hydrolyzed i n h o t or co ld w ater to th e corresponding k etone.

When th e

h y d ro ch lo rid e was h eated under anhydrous c o n d itio n s, however, i t r e 4

arranged t o a compound which was q u ite s ta b le to h y d ro ly tic a c tio n . T his compound proved to be th e hydrochloride of 2 -p h en y lp y rro lin e.

The

tra n sfo rm a tio n i s d e p ic te d as fo llo w s:

CH-—CH-G=KH»HC1 --------------- >

mOH,

0:

CHw—0Ho

> >! OH, C-0

^V«HC1 //

In view of t h i s rearrangem ent to th e s ta b le p y rro lin e , i t seemed l i k e l y t h a t th e e th y l cyclopropyl ketim ine re p o rte d p rev io u sly by De Boo s e re as being s ta b le to h y d ro ly s is in acid s o lu tio n might

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a c tu a lly be 2 - e th y lp y rro lin e .

Cloke prepared e th y l cyclopropyl ketim ine

by th e re a c tio n o f e th y Imagne sium bromide on both cyclopropyl cyanide and on g am raa-ch lo ro b u ty ro n itrile.

The ketim ine formed a hydrochloride

which, c o n tra ry to th e re p o rt of De B oosere, hydrolyzed r e a d ily to th e corresponding k e to n e .

Upon h e a tin g under anhydrous c o n d itio n s, th e

hydrochloride rearranged in to a compound which v?as s ta b le to h y d ro ly sis and which was shown t o be 2 -e th y lp y rro lin e h y d ro ch lo rid e.

In a d d itio n ,

Cloke re p o rte d t h a t re flu x in g e th y l cyclopropyl ketim ine -with a lc o h o lic potassium hydroxide brought about i t s rearrangem ent to 2 -e th y lp y rro lin e , F ie se r and S elig rn an ^ , in 1939* rep o rted t h a t the ketim ine h ydrochloride o b tain ed by t r e a t i n g o -c h lo ro b e n z o n itrile w ith 1-m ethyl8-naphthylmagnesiuin bromide was d i f f i c u l t to h y d ro ly ze.

H ydrolysis was

f i n a l l y e ffe c te d by u sin g a m ixture o f forrd.c and s u lf u r ic a c id s . S ta b ility of t h i s compound to h y d ro ly sis was a ttr i b u te d to th e h in d erin g e f f e c t o f th e p e ri-m eth y l group and th e o rth o -c h lo ro s u b s titu e n t. A. year l a t e r , F ie se r and Bowen^ rep o rte d t h a t th e ketim ine h y d rochloride prepared by trie re a c tio n of 8-m ethyl-l-cyanonaphthalene and 4-m ethyl-7-hydrindylm agnesium bromide r e s is te d a l l attem p ts a t h y d ro ly s is .

Inasmuch as th e analagous o-chlorophenyl 8 -m e th y l-l-

n ap h th y l ketim ine hy d ro ch lo ride hydrolyzed to th e ketone, i t appears t h a t th e o rth o m ethylene group c o n trib u te s more to th e t o t a l h in d erin g e f f e c t than a c h lo rin e atom in th e same p o s itio n . In 1947j Easton‘S and S c h u ltz ^ independently rep o rted th e re a c tio n between ethylmagnesiuat bromide and 2 ,2 -d ip h en y l-3 -m eth y l-4 d im e th y la m in o b u ta n en itrile .

Among th e products obtained was e th y l

l,l-d ip hen y l-2 -m eth y l-3 -d it» eth y Iam in o p ro p y l k etim in e.

Wo ap p reciab le

h y d ro ly sis was e ffe c te d a f t e r re flu x in g f o r th re e hours in 6 N

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hydro ch lo ric a c id , and only p a r t i a l h y d ro ly sis was achieved a f t e r re flu x in g w ith con cen trated h ydrochloric a c id . Easton

20

has a ls o re p o rted h is p rep aratio n of th e isom eric

1 ,1-dipheny1-3-dim ethylam inobutyl k etim in e.

I t was s u f f ic ie n tly s ta b le

to perm it i s o la tio n by decom position o f th e in term ed iate k etim in e magnesium h a lid e w ith chipped ic e and a c e tic a c id , follow ed by tr e a tin g th e a c e ta te w ith 10% sodium hydroxide s o lu tio n . Lochte and co-w orkers2^-, in 1948, prepared s ta b le ketim ines by th e a c tio n o f m ethyl magnesium io d id e and phenylmagne sium bromide on 2 ,2 ,6 -trim e th y lc y c lo h e x a n e c a rb o n itrile .

These im ines were s ta b le to

d r a s tic h y d ro ly tic treatm en t in a c id ic o r b a sic s o lu tio n .

T his

s t a b i l i t y was a ttr ib u te d to th e s te r ic e f f e c ts o f the 2 ,2 ,6 - tr im e th y lcyclohexyl group.

However, th e s t a b i l i t y of th e se ketim ines could

conceivable be due to a tau to m eric s h i f t .

( oh3 )2

( ch3 )2

/ » 2 - \ H C HC-CrWH \

/ T Sfa—CR

,

/ » H ,C

' R

ch3

\

V~

\ C=C-NHo

/ CHs— CH

' R

ch3

I f th e compounds d id e x is t in such an o le f in ic s tr u c tu r e , th e y would n o t be expected to hydrolyze. In an attem pt to show th a t s te r ic hindrance alone i s s u f f ic ie n t to s ta b i l i z e a ketim ine toward h y d ro ly s is, W illiams2^ prepared 1 ,2 ,2 ,3 te tra m e th y lc y c lo p e n ty l phenyl k etim in e.

T his compound hydrolyzed

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slowly in d ilu te acid or a lk a li to the corresponding ketone, and i t s in a b ility to undergo ene-aminization indicates that i t s s ta b ility i s due only to ste ric factors.

Similar resu lts were observed in the

reaction of phenylmagnesium bromide and trim eth ylaceton itrile. In an in v e s tig a tio n o f compounds re la te d to th e p o ten t a n a lg e sic dru g , Amidone, Cheney and

c o -w o r k e r s^ ,

in 1949, prepared s e v e ra l

k etim in es and acy lated ketim ines r e la te d to Amidone.

Pharm acological

d a ta in d ic a te d tha.t th ey were an alg esic and le s s to x ic than th e corresponding k eto n e. Also in 1949» S ta llin g s 2^ re p o rte d th e p rep aratio n o f se v e ra l im in es.

They were of th e d ia lk y l, a lk y l c y c lo a lk y l, d ic y c lo a lk y l, a lk y l

a r y l , and c y clo alk y l a ry l ty p e s .

They were prepared by th e decomposition

o f th e re sp e c tiv e ketiminemagnesium h a lid e w ith ammonium c h lo rid e and ic e .

In a study o f r e la tiv e r a te s of h y d ro ly sis o f th e compounds p re ­

p a red , he found t h a t th e ketim ines which were unable to undergo eneamine tautom erism were more slow ly hydrolyzed than those which were able to undergo t h i s change.

I t was a ls o noted th a t p ro g ressiv e s u b s titu tio n

o f m ethyl groups on th e carbon alpha to th e ketim ine fu n c tio n a l group in c re a se d th e s t a b i l i t y o f th e imine toward h y d ro ly s is.

Only recen tly, Vaughan2-’*2^ has prepared and studied a series of t o ly l alkyl and t o ly l to ly l ketim ines.

The addition product of the

n it r il e and the Grignard reagent was decomposed in an anhydrous medium by means of gaseous ammonia.

Good y ie ld s were obtained in th is manner.

A ll ketimines were reduced to the corresponding amines by low pressure c a ta ly tic reduction; and, with the exception of the o -to ly l tert-b u tyl ketimine, a l l were hydrolyzed to the corresponding ketones.

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27

Young

a ls o re c e n tly , has re p o rte d th e p re p a ra tio n of fo u r

d ia lk y l ketim in es by th e m odified method used by Vaughan.

Y ields were

from 43-60$. When t h i s in v e s tig a tio n was s ta r te d , very few a lk y l a lk y l k etim in es had been re p o rte d .

However, d u rin g th e course of t h i s work,

s e v e ra l were re p o rte d by o th er w orkers. The o b je c tiv e s of t h i s work were tw ofold.

I t was hoped t h a t a

method could be developed by which compounds o f t h i s c la s s could be prepared in f a i r y ie ld w ith some degree o f assu ran ce.

In a d d itio n , i t

was hoped t h a t some inform ation could be obtained concerning th e r e ­ la tio n s h ip between t h e i r s tru c tu re and t h e i r s t a b i l i t y toward h y d ro ly sis, ■While a good many re a c tio n s between a lk y l cyanides and a lk y lmagnesium h a lid e s have been c a r rie d o u t, th e o b je c tiv e has u s u a lly been th e p re p a ra tio n o f th e corresponding k eto n e.

The decom position of

th e a d d itio n compound was c a rrie d out in such a way th a t h y d ro ly sis was p ro b ab le, and th e is o la tio n of a ketim ine was f o r tu ito u s .

E xtraordinary

s t a b i l i t y toward h y d ro ly sis was a p r e re q u is ite to i t s recovery.

The

p h y sic a l and chem ical p ro p e rtie s o f such a c la s s o f compounds were of i n t e r e s t , and i t was hoped th a t a procedure could be found by which they could be p rep ared . S te ric f a c to r s are fre q u e n tly considered when th e question of s ta b ility a ris e s .

Such was th e case in t h i s approach to th e problem.

A s t e r i c a l l y hindered n i t r i l e was s e le c te d , and v a rio u s Grignard reag en ts were added to i t .

I t was a n tic ip a te d t h a t th e question of whether one

h in d e rin g group was s u f f ic ie n t fo r s t a b i l i t y o r n o t could be s e ttle d .

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i

Variation of the Grignard reagent was such that the carbon atom

if

-alpha to the imino group would be mono, d i, and trisu b stitu ted .

This

•i

>:

provided for ascertaining the e ffe c t o f increasing hindrance and pre-

'i!

| I j

sented an opportunity to observe the e ffe c t of a possible ene-amine

|

to explain the s ta b ility o f certain ketimines and the formation of

s h ift .

As has been pointed out e a r lie r , such a sh ift has been postulated

ketisoketim ines. The ketimines reported in th is introduction are given in Table I .

I

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I

TABLE I

j

|

KETIMINES

R -C(=NH)R 1 2

a

B o ilin g Point/mm

D* 4

t D

M elting P o in t of S a lts Source

to

TO

1

R 2

n

0

210(d)a

14

0-CH2-C (E t)(0 )

0

227(d)a

14

( ch3 )2ch- c(0 )2

0

250(d)a

14

ch2 c i - ch2- ch2

0

Cyclopropyl

Et

E thyl

0

Propyl

0

Iso b u ty l

88b 103(d)b

15 15

1.547622

98/8

0.990222 Tft 0.9751

1.535318

7

0

114/12

0.948920

1.527020

7

Cyclohexyl

0

138/5

Phenyl

0

127/3.5

1.084719

o-T olyl

0

137/4

1.061418*5 1.606518*5

7

p -T olyl

0

147/5

1.061720

7

Naphthyl

0

182/4.5

Cyclopropyl

0

136/25

Methyl

0

Iso p ro p y l

0

100/8

p-T olyl

Et

96/2

Ethyl

Af

120/26

0.895520

1.475520

12 5C

24

Isopropyl

Af

132/26

0.873720

1.467920

162°

24

103/13.5

145b

7

7 1.619119

7

1.609720

7 1.066320

1.562020

7 6 6 6

0.980516,5

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

]

1 j \ I Table I-—Continued t-B u ty l

Af

104/25

O ^ S T 2®

1.468420

Phenyl

Af

143/12

0.985120

1.532520

Cyclohexyl

Af

187/30

0.937820

1.495520

1 8 0 (d )c

24

E th y l

B11

90/8

0.947920

1.526020

189(d)®

24

Isopropyl

b”

94/4

0.934820

1.529820

193®

24

t-B u ty l

Bh

106/4

0.956320

1.517020

256(d)®

24

t-B u ty l

t-B u ty l

156/746

0 . 760120

1.4172

212(d)®

24

Iso p ro p y l

t-B u ty l

145/746

0 . 790820

1.427020

171®

24

E th y l

t-B u ty l

118/750

0.848720

1.471420

Iso p ro p y l

o -T olyl

224/740

0.953520

1.530020

249®

25

Iso p ro p y l

m-Tolyl

227/740

0.949920

1.534920

270(d)®

25

Iso p ro py l

p -T olyl

228/740

1.537420

223®

25

t-B u ty l

o -T olyl

235/740

1.514020

187®

25

t-B u ty l

m-Tolyl

238/740

0.951120 20 0.9337 20 O.9240

1 . 511820

236®

25

t-B u ty l

p -T o ly l

235/740

0.933820

1.512220

232(d)®

25

o-T o ly l

o-T olyl

313/740

1 . 051220

1.597520

175®

26

o-T o ly l

m-Tolyl

315/740

1.043420

1.596220

148®

26

o -T olyl

p -T o ly l

318/740

1.035520

1.596120

153°

26

m-Tolyl

m-Tolyl

321/740

1.044220

1.600520

160°

26

m-Tolyl

p-T o ly l

335/740

1.038520

1.593720

249(d)®

26

p -T o ly l

p -T o ly l

162/2

1.038720

1.596920

197®

26

e3-(c h 2 )2

sec-B utyl 101/2

0.868020

1.468920

27

y

sec-B u ty l 107/1

0. 861120

1.469920

27

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Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

II round bottomed f la s k was added 262 g. (1.35 moles) o f d iphenylaceton i t r i l e d isso lv e d in 375 m l. o f d ry benzene and 100 ml. of d ie th y l e th e r . A ddition was dropwise over a p eriod o f th re e hours. s t i r r e d and reflu x ed f o r t h i r t y h o u rs.

The m ixture was

To th e cooled re a c tio n m ixture

was added 192 g. (1.35 m oles) of m ethyl io d id e in 100 ml. o f benzene over a p eriod o f s ix h o u rs.

Sodium io d id e was p r e c ip ita te d im m ediately.

A fte r co o lin g , th e m ixture was washed w ith cold 10$ a c e tic acid to de­ s tro y any unreacted sodium h y dride.

The product was e x tra c te d w ith ben­

zene and e th e r and d rie d over calcium c h lo rid e .

D is tilla tio n y ie ld e d a

h ig h ly colored f r a c tio n b o ilin g c o n s ta n tly a t 135° a t 1 mm. p re ssu re . T his f r a c tio n was d isso lv e d in 500 m l. of e th e r and tr e a te d w ith 80 g. o f ad so rp tio n alum ina, f i l t e r e d , and r e d i s t i l l e d . c o n s ta n tly a t 142° a t 2 mm.; njj° 1.5744;

dJ °

The product b o ile d

1.0671; 227 g. (80.7$)

y ie ld ; MR^ ( c a lc d .) 64.03; MRp (e x p .) 64.13; Calcd. fo r N, 6.76; Found:

N, 6 .9 4 .

P rep aratio n of Methyl 1 .1-D iphenylethvl K etim ine. —The methyl Grignard re a g e n t was p repared by adding 123.5 g. (0.87 m oles) o f methyl io d id e to 21.16 g . (0 .8 7 moles) o f magnesium tu rn in g s in 250 ml. of an­ hydrous e th y l e th e r , to lu e n e was added.

Mien

th e a d d itio n was com pleted, an eq u al volume of

Then 60 g.

(0 .2 9 moles) o f th e d ip h e n y lp ro p io n itrile

in a to lu en e so lu tio n was added over a two hour p erio d . th en re flu x e d f o r tw enty hours.

The m ixture was

A fte r co o lin g , th e a d d itio n product was

decomposed w ith anhydrous ammonia.

The ketim ine was recovered from th e

to lu e n e -e th e r s o lu tio n a f t e r f i l t r a t i o n of th e magnesium amido h a lid e . I t d i s t i l l e d a t 138-9° a t 0 .5 mm.; n§° 1.5866; D^° 1.0550; 28 g. (43.4$) y ie ld ; MRg ( c a lc d .) 70.89;

MRp (e x p .) 71.10.

D eriv ativ es and an aly ses

a re l i s t e d in Table I I I .

Reproduced with permission o f the copyright owner. Further reproduction prohibited without permission.

22

P rep aratio n of E th y l 1,1-D lphenylethyI K etim ine. —The e th y lmagnesiura bromide was prepared by adding 94.81 g. (0.87 moles) o f e th y l bromide to 21.16 g. (0,87 moles) of magnesium tu rn in g s in 250 ml. of an;

hydrous e th y l e th e r ,

t ’hen th e p re p a ra tio n of the Grignard reag en t was

r

com plete, an equal volume of to lu en e was added.

Then 60 g. (0 .2 9 moles)

o f d ip h e n y lp ro p io n itrile i n to lu en e was added over a p eriod of two hour3. The re a c tio n m ixture was s t i r r e d and re flu x e d f o r t h i r t y - f i v e hours. The m ixture was cooled, and the a d d itio n product was decomposed w ith anhydrous ammonia.

The product was worked up as b e fo re , and th e ketim ine

is o la te d and p u rifie d by d i s t i l l a t i o n a t reduced p re ss u re .

I t d is tille d

a t 144-145° a t 0.5 mm.; n ?° 1.5808; D?° 1.0447; 35 g. (51$) y ie ld ; D 4 ( c a lc d .) 75*515 (e x p .) 75.69. D eriv ativ es and analyses are l i s t e d in Table I I I . P rep aratio n of Propyl 1.1-D iphenylethyl K etim ine. —The propyl G rignard reag en t was prepared by adding 71.2 g. (0 .5 8 moles) of n -p ro p y l \

bromide to 14.08 g. (0 .5 8 moles) of magnesium tu rn in g s in 200 ml. of an-

j

hydrous e th y l e th e r . o f to lu en e was added.

(i |

Upon com pletion o f t h i s r e a c tio n , an equal volume Then 40 g . (0 .1 9 moles) of d ip h e n y lp ro p io n itrile

in to lu en e was added over a two hour p e rio d . and re flu x e d f o r tw en ty -fo u r h o u rs.

The m ixture was s ti r r e d

At t h i s p o in t, decomposition of th e

a d d itio n product was e ffe c te d by passing anhydrous ammonia through th e m ixture u n t i l th e ev o lu tio n of h e a t ceased.

The product was worked up

in th e p re v io u sly d escrib ed manner, and th e ketim ine is o la te d and p u r if ie d by d i s t i l l a t i o n a t reduced p re ssu re . >

n^° 1.5731J

d£ °

I

Iffijj (e x p .) 80.20.

I t d i s t i l l e d a t 142-144° a t 1 mm.;

1.0328; 14.43 g. (29.83) y ie ld ; MRjj ( c a lc d .) 80.13; D eriv ativ es and an aly ses are l i s t e d in Table I I I ,

*J j J i Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

;

P re p aratio n of B utyl 1 ,1-D iphenylethyl Ketimine , —The Grignard

'

re a g e n t was p repared try adding 119.22 g. (0,87 moles) of n -b u ty l bromide to 21.16 g. (0 .8 7 moles) o f magnesium tu rn in g s in 250 ml. of anhydrous

r-

I

e th y l e th e r .

An equal volume of to lu en e was added when th e Grignard

: | I.

p re p ara tio n was com plete.

Then 60 g. (0 .2 9 mo3.es) of d iphenylpropio-

n i t r i l e in to lu e n e was added during th e course o f two h o u rs. was s t i r r e d and reflu x ed f o r t h i r t y - s i x hours.

The m ixture

Then th e ketiminemag-

nesiura h a lid e was decomposed by means of anhydrous ammonia.

The magnesium

amido h a lid e was f i l t e r e d , and th e ketim ine was recovered from th e t o l u e n e -e th e r s o lu tio n and p u r if ie d by d i s t i l l a t i o n a t reduced p re ssu re . I t d i s t i l l e d a t 150-152° a t 0.5 mm.; n^° 1.5661$ D*° 1.0213; 35.5 g. (46.3$) y ie ld ; MR^ ( c a lc d .) 84.75j MR (e x p .) 84.77*

D e riv a tiv e s and

an aly ses a re l i s t e d in Table I I I . P rep a ra tio n of Amyl 1 ,1-D iphenylethyl K etim ine. —The amylmagnesium bromide was p repared by adding 131.41 g. (0.87 m oles) of n-amyl bromide to 21.16 g. (0.87 m oles) of magnesium tu rn in g s in 250 m l. of an'

hydrous e th y l e th e r.

An eq u al volume o f to lu e n e was added when t h i s

a d d itio n was com plete. j

Then 60 g. (0.29 m oles) of d ip h e n y lp ro p io n itrile

in to lu e n e was added over a two hour p erio d .

\

and re flu x e d f o r f o r ty h o u rs.

The m ixture was then s t i r r e d

The in te rm e d ia te a d d itio n product was

l ;

th en decomposed by means o f anhydrous ammonia in a manner p rev io u sly de-

1

s c rib e d .

1

and th e k etim ine was recovered from th e to lu e n e -e th e r so lu tio n and pu­

The in o rg an ic magiesium amido h a lid e was sep arated by f i l t r a t i o n ,

r i f i e d by d i s t i l l a t i o n a t reduced p re s s u re . j

165-166° a t 1 mm.; n^0 1.5591;

i

( c a lc d .) 89.37$

!\

d£°

(e x p .) 89.75*

The ketim ine d i s t i l l e d a t

1.0053; 35 g* (43*3$) y ie ld ; MRD D eriv ativ es and analyses a re in Table I I I .

■

1 j ■j

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

P re p a ra tio n o f iso-Amyl 1 .1-D iphenylethyl K etim ine. —The is o :j

;■

amyl G rignard re a g e n t was prepared by adding 131*41 g . (0 .3 7 moles) of iso -am y l bromide t o 21.16 g . (0 .8 7 moles) of magnesium tu rn in g s in 250 ml. o f anhydrous e th y l e th e r .

j;

f ]

Upon th e completion of t h i s a d d itio n , an equal

volume o f to lu e n e was added.

A to lu en e so lu tio n c o n tain in g 60 g.

( 0.29 m oles) o f d ip h e n y lp ro p io n itrile was added over a p eriod o f two h o u rs.

The m ix tu re was th en s t i r r e d and reflu x ed f o r f o r ty hours.

An­

hydrous ammonia was passed through th e m ixture u n t i l decom position of ) ;

th e ketiminemagnesiuifl h a lid e was com plete. when the e v o lu tio n o f h e at ceased.

This p o in t was in d ic a te d

The product was worked up in th e

u s u a l manner, and th e k etim in e p u rifie d by d i s t i l l a t i o n a t reduced p re s i

s u re .

I t d i s t i l l e d a t 152-154° a t 1 mm,3 r?° 1.5568s D?° 1.0069j 32.2 g, D 4

(43*6$) y ie ld j MR^ ( c a lc d .) 89.37J HRq (e x p .) 89.30.

D eriv ativ es and

an aly ses a re l i s t e d i n Table I I I , P re p a ra tio n o f o -T o ly l 1 .1-D iphenylethyl K etim ine. —The o - to ly l Grignard re a g e n t was prep ared by adding 148.8 g. (0.87 moles) of o-bromoj 1 to lu e n e t o 21,16 g . (0 .8 7 m oles) o f magnesium tu rn in g s in 250 ml, o f j

anhydrous e th y l e t h e r ,

■j

volume o f to lu e n e

hhen t h i s reag en t had been p rep ared , an equal

was then added. A to lu en e so lu tio n co n tain in g 60 g.

(0 ,2 9 moles) of d ip h e n y lp ro p io n itrile was added over a two hour p e rio d , I i The m ixture was s t i r r e d and re flu x e d f o r fo rty h o u rs. Decomposition of i

|

th e ketiminemagnesium h a lid e was e ffe c te d by means of anhydrous ammonia.

i

r

The product was worked up in th e u s u a l manner, and th e ketim ine is o la te d I j by d i s t i l l a t i o n a t reduced p re s s u re . I t d i s t i l l e d a t 172-175° a t 0.5 mm.

j

|

I t s o li d i f i e d , onsta n d in g , a t room tem perature.

|

from m ethanol, i t

On r e c r y s t a lli z a tio n

m elted a t 100°. D erivatives and an aly ses are l i s t e d

I ■in Table I I I .

| Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

73 CD ■o -5 o Q. C o CD

Q.

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TABLE I I I

o' 3 O

f- H

KETIMBJES

CD

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^-CCsNH)!^ ®1

o CD —s T1 C 3. CD

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B oilin g Point/mm

**2

D

P icrate M

krd

mrd

(c a lc d .)

(ex p .)

m.p.°C

N,#

methyl

1 , 1-diphenylethyl

1 3 8 -9 /0 .5

I .0550

1.5866

6 .1 4 a

7 0.89

7 1 .1 0

143

12 . 32k

eth y l

1 , 1-diphenylethyl

1 4 4 -5 /0 .5

1.0447

1.5808

5.84b

7 5 .5 1

75.69

139

1 2 .o?111

1 ,1-diphenylethyl

1 4 2-4/1.0

1.0328

1.5731

5 .8 2 °

80.13

80.20

200d

5.12n

butyl

1 ,1-diphenylethyl

1 5 0 -2 /0 .5

1.0213

1.5661

5 .4 6 d

84.75

84.77

168

1 1 .38**

amyl

1 ,1 —diphenylethyl

1 6 5 -6 /1 .0

1.0053

1.5591

4 .7 4 f

89.37

89.75

142

1 0 .90r

iso-am yl

1 , 1-diphenylethyl

1 5 2 -4 /1 .0

1.0069

1.5568

4 .9 9 f

89.37

89.30

174

1 0 .8 1 1*

o - t o ly l

1 y1-diphenylethyl

1 7 2 -5 /0 .5

262(d)

10.44*

CO t£> propyl

o

o

■-5O o

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hydrochloride;

k

r = 11.02; t ss 10 . 60.

:=

n *-i

a = 6 .2 7 ; b = 5 .9 0 ; c = 5 .5 7 ; d = 5 .

CM

T h eoretical values:

«o

c/)' c/) o' 3

5.01; h = 4 .6 8 ;

12.38; m = 1 1 .9 6 ; n :- 4 .8 7 ; p = : 11 .3 3 ;

26

P rep aratio n of Amines. —Host o f th e k etim in es re p o rted in t h i s ;

t h e s i s were reduced to the corresponding amines by hydrogen over Adam's

1

c a ta ly s t a t room tom perature and atm ospheric p re ss u re .

i] ! ■|

propyl l-3H3thyl-3-3CC“propylcyclopentyl ketimine, iso-amyl 1 ,I-dipnenyl-

However, sec-

e th y l k e tim in e, and o - to ly l 1 , 1 -d ip h e n y le th y l ketim ine d id n o t reduce

ji $ |

under th e so c o n d itio n s,

I

b u r e tte w ith a le v e lin g bulb a tta c h e d , a 125 nil. Jlrlemueyer f la s k , and

| i

a magnetic s t i r r e r .

The apparatus used f o r th e se hydrogenations co n sisted of a gas

Methanol was used as a s o lv e n t.

The c a ta ly s t and

m ethanol were placed in th e f la s k which was atta c h e d to the gas b u r e tte |

by g la ss tu b in g equipped with a three-w ay stopcock.

Air was removed

i

j

from th e system, except f o r th e gas b u r e tte which was f i l l e d w ith hydro­

ll

gen, by means o f a w ater a s p ir a to r .

;

th e system.

I

th e system f i l l e d w ith hydrogen a t atm ospheric p ressu re and w ith th e

Hydrogen was then p erm itted to e n te r

T his flu s h in g of th e system was re p e a te d th re e tim e s .

With

!i

! I I

u n t i l th e c a ta ly s t would tak e up no more hydrogen.

.]

k etim ine was then placed in th e f la s k , and th e flu s h in g process re p e a te d .

j IJf 8

As hydrogen was absorbed, th e amount was noted a t re g u la r tim e i n t e r v a ls .

\

re ad in g of th e b u re tte n o ted , th e co n ten ts in th e fla s k vrere s t i r r e d A known amount of

T his was continued u n t i l hydrogen was no longer taken up by th e system . Temperature and p re ssu re were noted f o r use in c o rre c tin g th e volume of hydrogen used to standard c o n d itio n s.

The c a ta ly s t was recovered by

|

f i l t r a t i o n , and th e amine was recovered from th e m ethanclic s o lu tio n by

I

d is tilla tio n .

|

l i s t o f th e amines p rep ared , t h e i r p h y s ic a l p ro p e rtie s , d e r iv a tiv e s , and

I

an aly ses are l i s t e d in Tables IV and V.

I t was p u r if ie d by d i s t i l l a t i o n a t reduced p re s s u re .

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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